Journal articles: 'Chas. T. Main, Inc'

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Willoughby, Jay. "Confessions of an Economic Hit Man." American Journal of Islam and Society 22, no. 2 (April 1, 2005): 124–26. http://dx.doi.org/10.35632/ajis.v22i2.1719.

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Confessions of an Economic Hit Man is the story of why the so-calleddeveloping never seems to develop, as seen through the eyes of JohnPerkins, who was involved in “developing” several oil-rich nations. Theopening chapters deal with his childhood, which was permeated with elitismand ideas of how only the “right people” really mattered, his subsequentrebellion by defying his parents’ plan for his life, his initial contacts(through his wife) with government employment, and a 2-year Peace Corpsstint with an indigenous Indian tribe in Ecuador. While there, he wasrecruited by the National Security Agency. After his time was up, he washired by Chas. T. Main, Inc. to devise a 25-year forecast of seriously inflatedelectricity needs for Indonesia so that it would agree to take out an enormousloan. He did so, albeit with some misgivings, and his career as an economichit man (EMH) was launched.Claudine, his handler, made his task perfectly clear:We’re a small, exclusive club,” she said. “We’re paid – well paid – to cheatcountries around the globe out of billions of dollars. Alarge part of your jobis to encourage world leaders to become part of a vast network that promotesU.S. commercial interests. In the end, those leaders become ensnaredin a web of debt that ensures their loyalty. We can draw on them wheneverwe desire – to satisfy our political, economic, or military needs. In turn,these leaders bolster their political positions by bringing industrial parks,power plants, and airports to their people. Meanwhile, the owners of U.S.engineering and construction companies become very wealthy. (p. 17)Praised for his success, he was given “the opportunity, something fewmen ever receive, even at twice your age” (p. 57): to bring on boardPanama’s popular president, Omar Torrijos, who wanted all Panamanians,instead of only the small elite, to benefit. Torrijos’ assertion that sovereign ...

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Du, Wei-Shih, Young-Ye Huang, and Chi-Lin Yen. "Fixed point theorems for nonexpansive mappings on nonconvex sets in UCED Banach spaces." International Journal of Mathematics and Mathematical Sciences 31, no. 4 (2002): 251–57. http://dx.doi.org/10.1155/s0161171202107113.

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It is shown that every asymptotically regular orλ-firmly nonexpansive mappingT:C→Chas a fixed point wheneverCis a finite union of nonempty weakly compact convex subsets of a Banach spaceXwhich is uniformly convex in every direction. Furthermore, if{T i}i∈Iis any compatible family of strongly nonexpansive self-mappings on such aCand the graphs ofT i,i∈I, have a nonempty intersection, thenT i,i∈I, have a common fixed point inC.

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Ullah, Sami, Faiz Ahmad, and Anildav Singh. "Development and Testing of Intumescent Fire Retardant Coating on Various Structural Geometries." Applied Mechanics and Materials 699 (November 2014): 360–65. http://dx.doi.org/10.4028/www.scientific.net/amm.699.360.

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Materials are prone to fire and in modern construction their protection from fire is required. In any structure, various joints such as T-joint, I-beam and elbows are used. The geometry of the component has significant role in protection of structure. A weak joint may lead to failure of main structure. In order to meet these challenges, Intumescent fire retardant coating (IFRC) were developed and tested on various structural geometries such as T-joints, elbows, I-beams and pipe. The control coating formulation (IFC-C) was developed from main ingredients; Ammonium Polyphosphate (APP), expandable Graphite (EG), Melamine (Mel), Boric Acid (BA) mixed with bisphenol A epoxy resin and polyamide hardener. Another set of formulations containing various percentage of aluminium Tri-Hydrate (ATH). Fire test results of ATH based formulation showed that I-beam geometry showed the high expansion of 19 mm. T-joint showed the average surface temperature of 55°C after one hour of Bunsen burner test. The X-ray Diffraction (XRD) showed the presence of boron oxide, boron phosphate, sassolite and aluminium oxide in IFC-ATH5 residual char. The 5wt% ATH filler in IFC-C enhanced the fire protection performance of intumescent fire retardant coating formulation.

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Umekita, K., Y. Hashiba, R. Kudou, S. Miyauchi, M. Kimura, M. Matsuda, C. Iwao, et al. "AB0268 HUMAN T-CELL LEUKAEMIA VIRUS TYPE 1 MAY INVALIDATE T-SPOT.TB RESULTS AMONG RHEUMATOID ARTHRITIS PATIENTS: A RETROSPECTIVE OBSERVATIONAL STUDY." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1432.1–1433. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1588.

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Background:In clinical rheumatology, interferon-γ release assays (IGRAs) have been reported as a useful diagnostic test for latent tuberculosis infection (LTBI) before beginning the administration of biologics such as anti-TNF therapies (1). CD4-positive T cells are the main target in Human T-cell leukaemia virus type 1 (HTLV-1) infection. Several reports suggest that the reaction of tuberculin skin test (TST) is attenuated in HTLV-1-positive individuals compared with that in HTLV-1-negative individuals (2). However, it remains unclear whether IGRAs are reliable for detecting TB infection among HTLV-1-positive RA patients.Objectives:The present study aimed to investigate the usefulness of the T-SPOT.TBassay in HTLV-1-positive RA patients. In addition, the association between the existence of IFN-γ producing T cells and HTLV-1 proviral loads (PVLs) in HTLV-1-positive RA patients was analysed on the basis of the T-SPOT.TBassay results.Methods:We reviewed the medical records of 75 HTLV-1-negative and 29 HTLV-1-positive RA patients were suspected cases of LTBI and evaluated using the T-SPOT.TBassay as a clinical practice from April 2012 to July 2019. The results of T-SPOT.TBwere collected from medical records, retrospectively. Peripheral blood samples were obtained from HTLV-1-positive RA patients for the analysis of HTLV-1 PVLs values. The study protocol was approved by the research ethics committees of our hospitals.Results:Approximately 55% of the HTLV-1-positive RA patients showed invalid results for the T-SPOT.TBassay (p < 0.0001); the cause of invalid results was a spot-forming count of >10 spots in the negative controls of the T-SPOT.TBassay among HTLV-1-positive RA patients. Among HTLV-1-positive RA patients, HTLV-1 PVL values were significantly higher in 16 patients who showed invalid results than in 13 patients who did not (p = 0.003). There were no between-group differences in female patient ratio, age, RA disease activity and therapeutic regimens. IFN-γ producing cells were detected in the peripheral blood of HTLV-1-positive RA patients without stimulation with TB-specific antigens.Conclusion:The incidence of invalid results for the T-SPOT.TBassay has been reported to be as low as 0.6% (3). The results of this assay for screening of LTBI in HTLV-1-positive RA patients should be interpreted with caution. Furthermore, our results show that an increase in IFN-γ producing T cell numbers due to HTLV-1 infection in RA patients may affect the pathogenesis of RA.References:[1]Iannone, F., et al.J. Rheumatol. Suppl.91, 41-46 (2014).[2]Tachibana, N., et al.Int. J. Cancer42, 829-831 (1988).[3]Rego, K., et al.Tuberculosis (Edinb.)108, 178-185 (2018).Acknowledgments:We would like to thank Dr Yuki Hashikura and Ms Yuki Kaseda of the University of Miyazaki for their technical support in this work. We would also like to acknowledge Ms Yumiko Kai at the Institute of Rheumatology, Zenjinkai Shimin-no-Mori Hospital, for her help in data management.A part this work was supported by a grant from the Practical Research Project for Rare/Intractable Diseases of the Japan Agency for Medical Research and Development (Grant No. JP19ek0109356), a Health and Labor Sciences Research Grant on Rare and Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan (Grant No. 19FC1007), and a Grant-in-Aid for Clinical Research from Miyazaki University Hospital.Disclosure of Interests:Kunihiko Umekita Paid instructor for: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Speakers bureau: Bristol-Myers Squibb, Yayoi Hashiba: None declared, Risa Kudou: None declared, Shunichi Miyauchi: None declared, Masatoshi Kimura: None declared, Motohiro Matsuda: None declared, Chihiro Iwao: None declared, Yumi Kariya: None declared, Takeshi Kawaguchi: None declared, Katoko Takajo: None declared, Koushou Iwao: None declared, Yuuki Rikitake: None declared, Ichiro Takajo: None declared, Toshihiko Hidaka Paid instructor for: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Speakers bureau: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Akihiko Okayama: None declared

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Barcellini, Wilma, Anna Ines Gregorini, Giulia Soverini, Anna Zaninoni, Juri A. Giannotta, Cristina Vercellati, Valeria Ferri, Paola Bianchi, Agostino Cortelezzi, and Maria Domenica Cappellini. "Iron Overload and Cytokine Serum Levels in Congenital Hemolytic Anemias." Blood 128, no. 22 (December 2, 2016): 2458. http://dx.doi.org/10.1182/blood.v128.22.2458.2458.

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Abstract Background: Congenital hemolytic anemias (CHAs) are a heterogeneous group of inherited RBC disorders including membrane and enzyme defects and dyserythropoietic anemias. Iron overload is a well recognized complication of hereditary hemoglobinopathies, both in transfusion-dependent and independent cases. However, little is known in congenital hemolytic anemias, with the exception of anecdotic reports in pyruvate kinase deficiency and dyserythropoietic anemias. Aim: to describe the clinical and hematological features at diagnosis and enrolment, to investigate iron overload by hepatic and cardiac T2* MRI, and to study inflammatory/regulatory cytokine profiles (IL-6, TNF-alpha, IFN-gamma, IL-10, IL-17) and hepcidin levels in patients with CHAs. Confounding factors such as hemocromatosis genotyping, metabolic syndrome, and hepatic viral profile were also considered. Methods: Between July 2015 and April 2016, 38 patients were enrolled (13 hereditary spherocytosis -HS, 3 hereditary stomatocytosis - HSt, 8 congenital dyserythropoietic anemia type II - CDAII, 13 pyruvate kinase deficiency - PKD, 1 glucose-phosphate isomerase deficiency). HS cases were enrolled on the basis of ferritin >300 ng/mL at diagnosis. Cytokine levels were detected in serum by ELISA. Comparisons were made by Students T test (continuous) and Fisher's exact test (categorical), and correlations by Pearson's linear coefficient. Results: The main clinical and hematological findings are shown in table. Median Hb values progressively decreased in the 4 groups considered, being close to normal in HS and moderately reduced in CDAII patients, whereas hemolytic parameters were comparable among groups. Consistently with clinical severity, ferritin values were particularly high in CDAII (together with transferrin saturation-TfS) and PKD patients, notwithstanding chelation in about half cases of both groups. Of note, only 2 PKD patients were transfusion-dependent, suggesting that other factors are involved in iron overload. Splenectomy had been performed in 17/38 (44.7%), mainly CDAII. Liver iron concentration (LIC) showed a great heterogeneity in all groups, with a trend towards higher values in CDAII; 16/36 (44%) patients had a LIC>4 mg/g DW (23%, 33%, 38% and 88% in HS, HSt, PKD and CDAII, respectively). Cardiac T2* value was normal in all subjects, with the exception of a HS and a CDAII case. Regarding possible cofactors, 12/16 displayed at least one of the following: 1 homozygous for HFE C282Y and 1 for H63D mutations, 3 HCV+, 4 BMI>25, 2 alcohol abuse, 3 heterozygous for HFE mutations. The following positive correlations were observed at enrolment: LIC and ferritin (r=0.68, p<0.05), LIC and TfS (r=0.34, p=0.05), and cardiac T2* and TfS (r=0.34, p<0.05). Moreover Hb values at diagnosis negatively correlated with LIC (r=0.37, p<0.05). Interestingly, among the 28 cases with ferritin <800 ng/mL, 10 (36%) displayed liver iron overload (LIC>4), of whom 5 with the above listed cofactors. As regards cytokine levels, IL-10 was significantly increased in HS, PKD and CDAII groups compared with normal cases; TNF-alpha was decreased in HS and PKD, and IFN-gamma increased in HS and CDAII. Ferritin values were positively correlated with IL-6 and IFN-gamma, and TfS negatively with IL-6 (r= -0.38, p<0.05). Hepcidin values were slightly increased in CHAs compared with normal controls, and correlated positively with ferritin (r=0.33; p<0.05), and negatively with TfS (r= -0.56; p<0.001). Finally, hepcidin levels were positively correlated with IL-6 (r=0.62; p<0.001), and negatively with IFN-gamma (r=0.3; p<0.05). Conclusion: Iron overload is highly prevalent in CHAs, particularly in PKD and CDAII, is independent from transfusion support, and is also observed in cases with ferritin <800 ng/mL. T2* MRI is the gold standard approach to evaluate iron overload in CHAs (as in other congenital anemias) and its use is advisable, particularly in the presence of cofactors, for early chelation. Cytokine studies suggest the existence of a positive loop among ferritin, hepcidin, and inflammatory cytokines such as IL-6 and IFN-gamma, and of a negative loop among TfS, hepcidin, and the same inflammatory cytokines. These findings disclose important hints to understand the multiple biological mechanisms of iron overload, and support the rationale for new emerging therapies. Table Table. Disclosures Barcellini: Agios: Consultancy.

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Tkachev, Victor, Frank Kuhnert, Scott N. Furlan, Hengqi Zheng, Daniel J. Hunt, Lucrezia Colonna, Judith M. Carlson, et al. "Pharmacologic Blockade of Notch/Delta-like Ligand 4 Signaling Protects from Gastrointestinal Acute Graft-Versus-Host Disease in Non-Human Primates." Blood 132, Supplement 1 (November 29, 2018): 2027. http://dx.doi.org/10.1182/blood-2018-99-110030.

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Abstract The Notch signaling pathway is an evolutionarily conserved, cell-cell communication system with critical functions in organogenesis and tissue homeostasis, including hemato- and immuno-poiesis. Recent data have revealed important roles for Notch in the regulation of mature T cell differentiation and function. Studies in mouse models have identified Notch as a critical regulator of pathogenic T-cell responses during acute GVHD (aGVHD) (Zhang Y, 2011, Blood). However, the exact biological effects and the therapeutic potential of Notch pathway manipulation in clinical settings remains unclear. To address this question, we tested the activity of Notch pathway blockade in a non-human primate (NHP) aGVHD model, previously shown to exhibit donor T cell-intrinsic activation of the Notch pathway during aGVHD (Furlan SN, 2015, Sci Transl Med). To inhibit the Notch pathway, we used a blocking mAb to the Notch ligand DLL4, identified as the dominant ligand in a mouse aGVHD model (Tran, 2013, JCI; Chung, 2017, JCI). Prophylactic treatment regimens with either a single administration of anti-DLL4 mAb on day 0 (3 mg/kg), or with 3 doses (3 mg/kg each) on days 0, 7 and 14 significantly improved GVHD-free survival of allo-HCT recipients (median survival time (MST) = 26.5 days for the single dose regimen, and MST = 26 days for the triple dose regimen) in comparison with unprophylaxed controls (MST = 8 days, p<0.005; Fig 1A). Importantly, donor cell engraftment and hematopoietic reconstitution were normal (Fig 1B). Of note, DLL4 blockade dramatically changed the clinical phenotype of break-through GVHD, providing complete protection from gastrointestinal (GI) aGVHD, and instead showing clinical manifestations predominantly restricted to liver (Fig 1C, D). We next sought to determine the mechanism of GI aGVHD protection caused by DLL4 inhibition. Notably, anti-DLL4 GVHD prophylaxis decreased the expression of the gut-homing α4β7 integrin on CD8 T cells from the peripheral blood, spleen, mesenteric lymph nodes and colon in treated recipients (Fig 2A). Intestinal CD8 T cells also displayed a skewing towards a mature, effector-memory phenotype (Fig 2B) and reduced Ki67+ proliferation (Fig 2C). In contrast, CD8 T cells isolated from liver, the main site of break-through GVHD in anti-DLL4 mAb-treated animals, demonstrated a similar proliferation rate in anti-DLL4-treated compared to unprophylaxed cohorts (Fig 2C). Moreover, anti-DLL4 mAb prophylaxis was associated with an improved regulatory T cell/conventional T cell ratio in the colon but not in liver (Fig 2D). Collectively, our results show that the function of individual Notch ligands is preserved from mice to primates in aGVHD. We provide the first demonstration of the important role of Notch signaling in alloimmune T cell activation in a large animal model of aGVHD, and the therapeutic potential of DLL4 blockade for aGVHD prevention. Disclosures Tkachev: Regeneron Pharmaceuticals, Inc.: Research Funding. Kuhnert:Regeneron Pharmaceuticals, Inc.: Employment. Blazar:Kadmon Corporation, LLC: Consultancy, Research Funding. Carpenter:Regeneron Pharmaceuticals, Inc.: Employment. Harari:Regeneron Pharmaceuticals, Inc.: Employment. Thurston:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Kean:Regeneron Pharmaceuticals, Inc.: Research Funding.

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Duvic, Madeleine, Timothy M. Kuzel, Nam H. Dang, Miles Prince, Tatyana Feldman, Francine M. Foss, Matthew Guo, Lone Harild Ottesen, Chean Eng Ooi, and Youn H. Kim. "A Dose Finding Lead-in Study of E7777 (Diphtheria toxin fragment-Interleukin-2 Fusion Protein) in Persistent or Recurrent Cutaneous T-Cell Lymphoma (CTCL)." Blood 124, no. 21 (December 6, 2014): 3097. http://dx.doi.org/10.1182/blood.v124.21.3097.3097.

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Abstract Introduction: E7777 is a recombinant cytotoxic fusion protein composed of diphtheria toxin fragments A and B and human interleukin-2. E7777 has the same amino acid sequence as denileukin diftitox (DD) (approved as ONTAK in the USA for treatment of persistent or recurrent CTCL) but with improved purity and an increased percentage of active protein monomer species. This study is a pivotal multicenter open-label single-arm study comprising a Lead-In part (approx. 20 pts) to select the E7777 dose for the Main Study (70 patients [pts]) in which primary efficacy and safety of E7777 is assessed. Dose finding is necessary since the specific bioactivity of E7777 is 1.5 – 2 times that of the prior less purified form (ONTAK). The Lead-In study is reported in this abstract. Methods: A Continual Reassessment Method (CRM) is used for dose-finding with E7777 doses ranging from 3 – 18 µg/kg to be tested. The CRM is designed to target a DLT rate of approx. 20%. Inclusion criteria were patients ≥ 18 yr old, with a diagnosis of Mycosis Fungoides (MF) or Sézary Syndrome (SS) with stage I-IV disease at study entry, measurable CD25+ tumor, and who have received at least one prior therapy for CTCL. Prior commercial DD therapy was not allowed. E7777 was administered as monotherapy by iv infusion over 60 min on 5 consecutive days every cycle of 21 days. Pts were be dosed up to 8 cycles; additional dosing is allowed if deemed beneficial by the treating physician. Required premedication included an antihistamine, anti-pyretic, and anti-emetic; in case of infusion-related reaction low-dose systemic steroid premedication was allowed. The aim of the Lead–in study was to establish the maximum tolerated dose (MTD) and the recommended Main Study dose (based on the MTD and clinical judgment), and to assess safety and tumor response. Tumor responses were assessed according to the new ISCL/EORTC criteria (Olsen 2011). Results: Seventeen pts have been treated in the Lead-In. There were 8 males and 9 females, with median age 64 (range 26-81). Thirteen pts had MF (3, 7, 1, and 2 pts with Stage I, II, III, and IV disease, respectively) and 4 had SS (Stage IV). Fourteen or more pts had at least 4 lines of prior therapy. Pts were treated for a median of 4 cycles (range 1-8 cycles) and 8 patients are ongoing. Of the 9 pts who have discontinued from the study, 5 were for disease progression, 2 for AEs, 1 completed treatment per protocol, and 1 was pt choice. Pts were treated at doses ranging from 6 to 15 µg/kg; dose levels were assigned by the CRM based on the cumulative DLT information. The dose levels for each pt are shown in chronological order in the Table below, with the corresponding DLT assessments.TableContinual Reassessment MethodPatient #Dose (µg/kg)DLT16No29No312No415Yes56No6-129No13-1512No1615Yes1712No In the 17 patients treated, there were two DLTs; both occurred at the 15 µg/kg dose level and were capillary leak syndrome (CLS) (one Gr 2 with hospitalization, and one Gr 4). Based on preliminary results from these 17 pts, the highest dose with a DLT rate of ≤ 20% is 12 µg/kg. The most frequent AEs occurring in ≥ 3 pts were nausea (6 pts), ALT increased and AST increased (4 pts each), and vomiting, chills, fatigue, pyrexia, myalgia, rash, staph skin infection (3 pts each). Serious AEs considered related to study drug were CLS (2 pts) and pruritus, rash, diarrhea, vomiting, hypoxemia, and tumor flare (all in 1 pt each). AEs leading to drug discontinuation were CLS (2 pts). There were no deaths on study. Five pts achieved an objective response (OR) as assessed by the investigator, including 1 pt with relapse after allogeneic stem cell transplantation who received 8 courses and achieved a complete remission with associated skin graft-vs-host disease. These responses occurred at dose levels of 6, 9, and 12 µg/kg, including in 3 pts with stage IV disease (2 MF, 1 SS). Conclusion: Dose finding of E7777 in CTCL is proceeding with the CRM method. The toxicity profile is acceptable and so far no new safety signals compared to ONTAK has been identified. Initial signs of activity have been observed. Final data from this Lead-in study will be presented. Disclosures Duvic: Eisai Inc.: Member of safety monitoring committee for trial Other, Research Funding. Kuzel:Eisai Inc.: Research Funding. Dang:Eisai Inc.: Protocol Steering Committee Other, Research Funding. Prince:Eisai Inc.: Research Funding. Foss:Eisai Inc.: Consultancy. Guo:Eisai Inc.: Employment. Ottesen:Eisai: Employment. Ooi:Eisai Inc.: Employment. Kim:Eisai inc.: Protocol Steering Committee Other.

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Song, Hoyoung. "Park Un's ‘philosophy of self-cultivation’: Focusing on the System of Thought in 'Gyukmongpyeon'." Institute of Korean Cultural Studies Yeungnam University 84 (August 31, 2023): 305–36. http://dx.doi.org/10.15186/ikc.2023.8.31.10.

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This article examines the system of thought concerning Park Un's philosophy of self-cultivation, based on one of his two main works, Gyukmongpyeon. Park Un was a representative scholar of Neo-Confucianism from the Gyeongbuk Seonsan region during the middle period of the Joseon Dynasty. He gained widespread recognition for his filial devotion to his parents. He studied under Park Young along with the Kim brothers, Kim Chwiseong and Kim Chwimun, contributing to the nationwide prominence of the Songdang school of thought. However, following the last wishes of his father, Park Jongwon, who had witnessed the tyrannical rule of King Yeonsan and the political chaos during King Jungjong's reign, he did not pursue a career in government. Instead, he stayed in his hometown, dedicated himself to scholarly pursuits, and worked to pass down his academic achievements to future generations. He also gained fame as a great scholar of his time through interactions and academic discussions with contemporary scholars like Lee Eonjeok and Lee Hwang. At the age of 50 (in 1542), Park Un compiled Gyukmongpyeon by selecting various sayings from the Cheng-Zhu school of Confucianism centered around Cheng Yi and Zhu Xi, focusing on ‘Geo Gyeong Gung Ri’. ‘Geo Gyeong’ refers to a self-cultivation method that targets the heart-mind to foster virtue, while ‘Gung Ri’ refers to a study method targeting principles to explore all things and expand knowledge. These two elements collectively indicate the self-cultivation philosophy of the Cheng-Zhu school that needs to be integrated to prevent the human mind from falling into desire. Lee Yulgok wrote in the postscript of Gyukmongpyeon: “Only after reading Master Park Un's Gyukmongpyeon did I realize how deep his research into the self-cultivation theory of the Cheng-Zhu school was, and how diligently he had studied. Had that not been the case, the sentences he selected could not have been so precise and heartfelt. Although we can't meet t he v arious masters o f the C heng-Zhu s chool today, Park Un has gathered all their beneficial teachings left for future generations. The grace he has bestowed upon future scholars is indeed immense.” Through compiling Gyukmongpyeon, Park Un not only succinctly and clearly organized the self-cultivation philosophy of previous sages but also significantly contributed to the scholarly activities of future generations.

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Walker, Brian A., Shweta S. Chavan, Jie He, Ruslana Tytarenko, Shan Zhong, Shayu Deshpande, Purvi Patel, et al. "A Survey of Fusion Genes in Myeloma Identifies Kinase Domain Activation Which Could be Targeted with Available Treatments." Blood 128, no. 22 (December 2, 2016): 117. http://dx.doi.org/10.1182/blood.v128.22.117.117.

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Abstract Introduction Although fusion genes other than the immunoglobulin (Ig) translocation, t(4;14), which results in IGH-WHSC1fusions, are not frequently detected in multiple myeloma (MM), recent evidence suggests that kinase fusion gene fusions do occur relatively frequently and may inform on treatment algorithms. Here we use a hybrid-capture based, next-generation sequencing assay to survey fusion genes in patients with MM. Methods We report on 1421 samples from 958 individuals diagnosed with either monoclonal gammopathy of unknown significance (MGUS), smoldering multiple myeloma (SMM) or MM who underwent targeted sequencing with the FoundationOne Heme® (F1H) assay. Tumor samples were obtained from bone marrow aspirates, enriched by CD138+selection using magnetic beads (AutoMACs, Miltenyi Biotech, Cologne, Germany or RoboSep, StemCell Technologies, Vancouver, Canada). RNA and DNA were extracted using the AllPrep DNA/RNA mini kit (Qiagen, Hilden, Germany), RNeasy RNA extraction kit (Qiagen) or Puregene DNA extraction kit (Qiagen). ≥ 50 ng of extracted DNA or RNA was processed on the F1H assay. The current assay analyzes the complete coding DNA sequence of 405 genes, as well as selected introns of 31 genes involved in chromosomal rearrangements as well as the RNA sequence of 265 commonly rearranged genes resulting in gene fusions. Genes included in this assay encode known or likely targets of therapy, either approved or in clinical trials, or are otherwise known drivers of oncogenesis. Sequencing was to an average depth of 510x and was performed using the Illumina HiSeq 2500. Sequences were analyzed for selected gene rearrangements including fusion genes which were detected by a combination of DNA and RNA sequencing. Results Rearrangements into the Ig loci were detected and included the 5 main translocations: t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20), as well as translocations involving MYC at 8q24. From a combination of DNA capture and RNA-seq expression values we used 107 samples in a training set with matching gene expression profiling data to determine cut-offs for FGFR3, WHSC1, CCND3, MAF, MAFB, CCND2 and CCND1to stratify patients into the 5 main translocation groups. We used these values to classify a further 391 samples with corresponding gene expression profiling (GEP) data, resulting in sensitivities and specificities of t(4;14), 98% and 100%; t(6;14), 100% and 99%; t(11;14), 99% and 95%; t(14;16), 77% and 100%; t(14;20), 100% and 100%, respectively. 40 non-Ig rearrangements were detected in 38 patients (4.2%), of which 21 in-frame fusion genes were predicted. Recurrent fusion-genes, identified in more than one patient, included EIF4E3-FOXP1, TXNDC5-MYC and SUB1-WHSC1. As well as TXNDC5, MYC was also partnered with FOXO3, both of which are known partners of the MYC translocation. 12 of the 21 in-frame fusion genes involved kinase domains, including fusions with BRAF (n=4), NTRK3 (n=2), ALK (n=1), ROS1 (n=1), MAPK14 (n=1), MAP3K14 (n=1), FGFR1 (n=1), and DLG2 (n=1). Fusions involving each of these genes have been documented in other cancers. BRAF fusions are thought to partner with genes encoding homodimerization domains, resulting in downstream activation of Ras signaling. Other kinase fusions result in receptor signaling and downstream activation of the Ras signaling pathway. Of the patients with kinase fusions, 2 had an activating KRAS, NRAS or BRAF mutation but only one was clonal (84% cancer clonal fraction). One patient with samples taken at different timepoints had a GTF2I-BRAF fusion and concomitant KRAS G13C mutation (16% allele frequency), both of which were not detectable 8 months later but an AGK-BRAF fusion was detected at that time suggesting clonal selection. Conclusion Non-Ig fusion genes are present in myeloma patients, but at a low frequency. Most of the fusions detected contained a kinase domain indicating activation of the Ras signaling pathway, which is also activated through KRAS, NRAS and BRAF mutations in 50% of patients. Although rare (1%), these kinase fusions are potential clinical targets in myeloma where kinase inhibitors, such as crizotinib, can be used which has shown to be effective against ALK and ROS1 fusions. Disclosures He: Foundation Medicine, Inc: Employment, Equity Ownership. Zhong:foundation medicine: Employment. Bailey:Foundation Medicine, Inc: Employment, Equity Ownership. Vergillo:Foundation Medicine, Inc: Employment. Ross:Foundation Medicine, Inc: Employment. Miller:Foundation Medicine: Employment, Equity Ownership. Stephens:Foundation Medicine: Employment, Equity Ownership. Mughal:Foundation Medicine: Employment, Equity Ownership. Davies:Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Morgan:Janssen: Research Funding; Univ of AR for Medical Sciences: Employment; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria.

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Du, Xiaoru. "IDEO Product Development Case Analysis." BCP Business & Management 13 (November 16, 2021): 396–401. http://dx.doi.org/10.54691/bcpbm.v13i.116.

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IDEO is one of the successful product development companies, it established in 1991 and combined with 3 companies (David Kelley Design, ID Two and Matrix Product Design). As one of the world’s leading design firms, IDEO won a large number of awards than other product development firms. This company has a rapidly development in last several years, owned over 660 employees in the various disciplines. IDEO help organizations in the public and private sectors to find new design approach to innovate and grow, its major well-know clients are include Apple Inc., AT&T, Coca-Cola, Microsoft, Steelcase, PNC Financial Services and Palm. The company utilize design thinking as their main design process approach and focus on investigate and satisfied consumers’ needs.

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Shah, Nilay R., Dawn E. Jaroszewski, Awais Ashfaq, Lucas A. Schroedl, Linda L. Staley, Octavio E. Pajaro, Vigneshwar Kasirajan, and Francisco A. Arabia. "SynCardia Portable Freedom Driver: A Single-Center Experience with 11 Patients." Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery 10, no. 3 (May 2015): 188–94. http://dx.doi.org/10.1097/imi.0000000000000161.

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Objective The portable Freedom Drive (SynCardia Inc, Tucson, AZ USA) for total artificial heart (TAH-t) support was approved for an investigational device exemption study in March 2010. We review our center's experience with the portable driver. Methods A retrospective review was conducted of patients who underwent TAH-t implantation and transfer to portable driver from September 2008 to June 2012, with follow-up through December 2012. Results A total of 30 patients underwent TAH-t implantation during this time period, with 11 patients successfully transferred to the Freedom Driver. Transfer to Freedom Driver after TAH-t implant was a median of 46 days (range, 225–86 days). Ninety-one percent (10) of 11 patients transferred to Freedom Driver were bridged to transplantation. One patient died on support. Five (45.5%) of 11 patients were discharged home and 5 (45.5%) remained in-patient on the portable driver before transplantation. Four patients (80%) successfully discharged home required at least 1 hospital readmission (range, 1–5 admissions per patient). Six patients (55%) transferred to the portable driver required a return to a main driver console. Two patients were temporarily maintained on the main driver then returned to the Freedom Driver for bridge to transplantation. Conclusions Patients with TAH-t can be considered for transfer to the portable Freedom Driver while awaiting transplantation. Issues that complicated this patient population included inadequate social support, hemodynamic instability, and concurrent morbidities. The potential benefits of the portable driver are currently undergoing assessment. These may include increased mobility and improved quality of life, opportunity for discharge home, and decreased overall medical costs.

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Paludo, Jonas, Radhika Bansal, Adam T. Holland, Kelsey L. Haugen, Megan T. Spychalla, Alli L. McClanahan, Tuan A. Truong, et al. "Pilot Implementation of Remote Patient Monitoring Program for Outpatient Management of CAR-T Cell Therapy." Blood 138, Supplement 1 (November 5, 2021): 568. http://dx.doi.org/10.1182/blood-2021-149103.

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Abstract Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is an effective treatment that has transformed hematologic malignancy management. However, its significant short-term toxicities, mainly cytokine release syndrome (CRS) and neurotoxicity, require frequent monitoring almost universally achieved via prolonged inpatient admissions. We have reported our institution's specialized, multi-disciplinary hospital-based outpatient (HBO) CAR-T service and experience (Bansal et.al, ASCO 2021). To enhance the HBO practice, we implemented a remote patient monitoring (RPM) program, comprised of in-home, electronic health record-integrated technology to monitor vital signs and neurologic symptoms for 30 days post CAR-T infusion. The RPM program's triaging algorithm generates alerts based on predetermined parameters to guide escalation of care if needed. In this report, we describe the characteristics of RPM program patients (pts), focusing on the alerts received within 48 hours (h) of first hospitalization in the post-CAR-T setting. Methods: Pts undergoing commercial CAR-T cell therapy at Mayo Clinic Rochester were enrolled in the RPM program as part of our standard of care from 06/2020 to 05/2021. Pts with detailed RPM data available were included in this analysis. Patient characteristics, health care utilization, inpatient interventions, and RPM alert data were reviewed. Wilcoxon test was used for continuous variables, chi-squared test was used for categorical variables. Results: Baseline characteristics are summarized in Table 1. Of 20 pts in this analysis, 13 had RPM alerts in the 48h preceding the first hospitalization post CAR-T. For the remaining 7 pts without RPM alerts, 3 were hospitalized within 24h of CAR-T infusion without significant RPM data, 1 patient hospitalized with acute pancreatitis (day +8 post CAR-T infusion), 1 for doubling of CRP (day +10), 1 for acute pain crisis (day +5), and 1 with neutropenic fever (day +5) with not reporting RPM data. The median RPM program duration was 18 days (range 3-32) which accounts for interruptions in the RPM monitoring while pts are hospitalized. The median number of data points per patient was 231 (range 22-532), with a median of 20 alerts per patient (range 2-81). The median missing data points per patient were 20 (10%) (range 0-95). Of the 13 pts with RPM alerts within 48h of first hospitalization, alerts met our definition of urgent criteria in 6 pts [temperature (temp) > 100F (n=3), temp > 100F + tachycardia (n=1), temp > 100F + hypoxia (n=1), and hypoxia (n=1)]. In the remaining 7 pts, the RPM alerts met our routine criteria definition [temp 99-100 (n=2), tachycardia + hypertension + weight loss (n=2), hypertension (n=2), new incontinence (n=1)]. CRS was reported in 12 pts [grade 1-2 (n=11), grade 3-4 (n=1)] and neurotoxicity in 8 pts [grade 1-2 (n=7), grade 3-4 (n=1)]. The median post CAR-T first hospitalization day was day +4 (range day +2-10), Figure 1. The median time from the last RPM alert to hospitalization was 5.8h for pts meeting urgent criteria vs 10.8h for those meeting routine criteria (p=0.13). Tocilizumab was used in 5 pts during the first hospitalization [3 (50%) in the urgent criteria group and 2 (28%) in the routine criteria group], with a median time from admission to tocilizumab of 12h in the urgent criteria group vs 43h in the routine criteria group (p=0.05). Early hospitalization (≤ 3 days) post CAR-T infusion was associated with later need for tocilizumab [median 51h (range 30-57) vs. 11.5h (range 6-33) from admission, p=0.03] than late hospitalization (> 4 days post CAR-T). Upon admission, oxygen supplementation was started on both pts with hypoxia noted in the RPM alerts. Only 1 patient (routine criteria group) required use of vasopressors while hospitalized, initiated more than 48h after admission. Conclusion: A CAR-T RPM program can identify adverse symptoms and vital sign changes in CAR-T pts managed in the outpatient setting. In this pilot implementation, the CAR-T RPM triaging algorithm identified pts requiring expedited hospitalization and facilitated early initiation of tocilizumab. The intermittent monitoring and proportion of missing data are the main limitations of the RPM in the acute care setting post-CAR-T infusion. Incorporation of wearable devices for continuous remote monitoring is being explored as a mitigating strategy to these limitations. Figure 1 Figure 1. Disclosures Paludo: Karyopharm: Research Funding. Dingli: Apellis: Consultancy; Janssen: Consultancy; GSK: Consultancy; Novartis: Research Funding; Sanofi: Consultancy; Alexion: Consultancy. Kapoor: Glaxo SmithKline: Research Funding; Sanofi: Consultancy; Amgen: Research Funding; AbbVie: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; Ichnos Sciences: Research Funding; Pharmacyclics: Consultancy; Takeda: Research Funding; Regeneron Pharmaceuticals: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy. Gertz: Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria. Wang: InnoCare: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kenderian: Humanigen, Inc.: Consultancy, Honoraria, Research Funding. Kumar: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Oncopeptides: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Bluebird Bio: Consultancy; Beigene: Consultancy; Tenebio: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Bennani: Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Merck: Research Funding; Vineti: Consultancy; Gamida Cell: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Legend: Consultancy; Celgene: Consultancy, Research Funding; Sorrento: Consultancy; Takeda: Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding.

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Munoz, Javier, Samantha Jaglowski, Matthew S. McKinney, Iris Isufi, Patrick J. Stiff, Jessica Sachs, Ann Ranger, Patricia Harris, Francis Payumo, and Luke P. Akard. "A Phase 1 Study of ACTR087 in Combination with Rituximab, in Subjects with Relapsed or Refractory CD20-Positive B-Cell Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 244. http://dx.doi.org/10.1182/blood-2019-123810.

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Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR087 comprises the extracellular domain of CD16 linked to a CD3ζ-signaling domain and a 4-1BB co-stimulatory domain. Here we present the clinical experience from Study ATTCK-20-2 (NCT02776813), a multicenter, phase 1 study of ACTR087 in combination with rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The main objectives of this first-in-human study were to evaluate the safety and antitumor activity of ACTR087+rituximab. Other objectives included evaluating ACTR T-cell persistence and other correlative biomarkers. Subjects must have had CD20+ NHL that was R/R after prior treatments, which must have included anti-CD20 antibody-containing chemotherapy. Subjects received lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR087. Additional doses of rituximab were administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study included a dose escalation phase (increasing doses of ACTR087) and an expansion phase (ACTR087 at the preliminary recommended phase 2 dose [RP2D]); all subjects received rituximab at a fixed dose of 375 mg/m2 q3w. Results: Two dose levels (DL) of ACTR087 were evaluated during dose escalation (n=17). The MTD was exceeded at DL2, with severe cases of cytokine release syndrome (CRS) and neurotoxicity. Statistical analysis of the relationship between non-hematologic toxicity and ACTR+ T-cell doses was retrospectively performed (two-parameter Bayesian logistic regression model) to estimate an RP2D of 35×106 ACTR+ T cells. Nine subjects enrolled in an expansion cohort and received ACTR087 at this RP2D in combination with rituximab. Among all subjects treated (n=26), the majority (69%) were diagnosed with DLBCL. Subjects had received a median of 3 (range 1-9) prior lines of therapy, with 77% having received ≥3 prior lines. ACTR087 showed dose-dependent expansion with peak levels generally observed 7 to 14 days post administration. In subjects with ongoing clinical response (CR), ACTR remained detectable through the last timepoint evaluated. Across all cohorts, Grade ≥3 TEAEs reported in >3 subjects regardless of causality were limited to hematologic events. Potential T cell-mediated toxicities were observed, including 4 serious cases of CRS (Gr 4 in 2 subjects, both with fatal sepsis) and 2 serious cases of neurotoxicity (1 Gr 5, 1 Gr 4 in a subject with fatal septic shock). Elevated baseline inflammatory markers (eg, ferritin, CRP) were observed in patients who developed Gr ≥3 CRS and neurotoxicity post ACTR087. Of note, severe CRS presented without fever and events occurred >7 days post ACTR087. Clinical activity was reported with an ORR of 50% in all dose levels tested, including durable complete responses, with one subject in CR for 869+ days (Table 1). Conclusions: ACTR087+rituximab demonstrated antitumor activity, with observed safety events that are expected with other autologous T-cell products. The time to onset and clinical presentation of severe CRS and neurotoxicity events in this study informed the safety monitoring and adverse reaction management guidance across clinical studies of ACTR T-cell products. Data from this first-in-human study of ACTR087+rituximab confirm the proof of concept and will be used to guide further development for the ACTR platform. Updated clinical data, as well as expanded biomarker correlations to efficacy and safety, will be presented. Disclosures Munoz: Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Portola: Research Funding; Incyte: Research Funding; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Juno: Consultancy, Other: advisory board. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Stiff:Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Akard:Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau.

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Watkins, Benjamin, Yvonne Suessmuth, Kayla Betz, Alison Yu, Brandi Bratrude, Muna Qayed, Kathryn Pellegrini, et al. "Transcriptomic Analysis of CD4+ T Cell Dysfunction during Gvhd: Evidence for Profound Reprograming of T Cell Signaling during Acute Gvhd That Is Controlled during CD28:CD80/86 Costimulation Blockade with Abatacept." Blood 134, Supplement_1 (November 13, 2019): 596. http://dx.doi.org/10.1182/blood-2019-131955.

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Although acute graft-versus-host-disease (AGVHD) is one of the major causes of non-relapse mortality after hematopoietic stem cell transplant (HCT), we are still unable to predict which patients will develop the most severe form of this disease, or which molecular pathways are dysregulated in the T cells that cause disease. Thus, understanding the molecular features of AGVHD is a critical unmet need. To address this, we have performed a companion mechanistic study as a part of our completed Phase 2 trial of abatacept, a CD28:CD80/86 costimulation blockade agent, for severe AGVHD prevention (Clinicaltrials.gov # NCT01743131, 'ABA2'). ABA2 has demonstrated significant improvement in AGVHD in patients prophylaxed with abatacept in addition to calcineurin inhibition (CNI) + Methotrexate (MTX) compared to controls receiving CNI/MTX alone. To begin to uncover mechanisms responsible for the control of AGVHD with abatacept, and given that CD4+ T cells have been consistently documented to be the main therapeutic target of this drug, we interrogated the transcriptome of CD4+ T cells reconstituting in patients prophylaxed with abatacept compared to CNI/MTX. To perform this analysis, we flow cytometrically sorted CD4+ T cells on Days 21-28 post-transplant from all patients on ABA2, as well as a cohort of 12 untransplanted healthy controls, and subsequently performed mRNA-sequencing on these cells. Weighted Gene Correlation Network Analysis (WGCNA) was performed on the top 6000 most variant transcripts from the resulting sequencing data. Hierarchical clustering of the WGCNA co-expression matrix enabled the identification of self-assembling modules (SAMs) that met a threshold of coexpression (Figure 1A). For the ABA2 dataset, we considered the following variables in the WGCNA model: patient cohort (7/8 patients, 8/8 patients, healthy controls), +/- prophylaxis with abatacept, CMV reactivation, EBV reactivation, Grade of GVHD (0-4), relapse, non-relapse mortality, and all-cause mortality. The WGCNA clustering analysis resulted in the identification of 4 discrete SAMs, which were highly correlated with clinical variable metamodules. This analysis revealed a strong positive correlation of a 476-gene SAM (the Turquoise module) in patients prophylaxed with CNI/MTX + placebo and anti-correlation of this module in patients prophylaxed with CNI/MTX + abatacept, as demonstrated in both the WGCNA heatmap and through Gene Set Enrichment Analysis (Figure 1 A-B). These opposing correlations suggested that interrogation of this module would reveal mechanistic correlates with standard prophylaxis that were decoupled by abatacept. Pathway analysis using the Reactome database (Figure 1C) revealed the turquoise SAM to be dominated by four types of pathways: (1) Those that define canonical cell-cycle pathways (2) Those involved in T cell metabolism (3) Those involved in apoptosis and (4) Those involved in T cell activation, consistent with upregulation of these transcripts in placebo versus abatacept patients. In addition to being highly correlated with patients receiving placebo, the expression of a subset of the transcripts in the Turquoise module were also directly correlated with the severity of AGVHD in these patients. Thus, linear regression analysis of the 476 transcripts in this module identified a subset of 93 genes for which transcript expression level was increased both in placebo compared to abatacept, and for which expression level also positively correlated with Grade of AGVHD. As with the Turquoise module as a whole, this subset of genes also formed a highly correlated network, linking transcripts involved in T cell proliferation, apoptosis, activation, metabolism as well as the T cell checkpoint (Figure 1D). This analysis represents the first comprehensive interrogation of the transcriptomic correlates of AGVHD. It identifies a novel set of transcripts which positively associate with the severity of AGVHD, and which costimulation blockade with abatacept down-regulates and de-couples from AGVHD severity. These results suggest a profound reprograming of T cell activation with abatacept that is correlated with the control of AGVHD. Disclosures Qayed: Bristol-Myers Squibb: Honoraria. Langston:Astellas Pharma: Other: Research Support; Incyte: Other: Research Support; Jazz Pharmaceuticals: Other: Research Support; Chimerix: Other: Research Support; Takeda: Other: Research Support; Kadmon Corporation: Other: Research Support; Novartis: Other: Research Support; Bristol Myers Squibb: Other: Research Support. Blazar:Fate Therapeutics, Inc.: Research Funding; RXi Pharmaceuticals: Research Funding; Alpine Immune Sciences, Inc.: Research Funding; Abbvie Inc: Research Funding; Leukemia and Lymphoma Society: Research Funding; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-Founder; BlueRock Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kamon Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Five Prime Therapeutics Inc: Co-Founder, Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics and BlueRock Therapeuetics: Membership on an entity's Board of Directors or advisory committees. Kean:HiFiBio: Consultancy; BlueBirdBio: Research Funding; Gilead: Research Funding; Regeneron: Research Funding; EMDSerono: Consultancy; FortySeven: Consultancy; Magenta: Research Funding; Kymab: Consultancy; Jazz: Research Funding; Bristol Meyers Squibb: Patents & Royalties, Research Funding. OffLabel Disclosure: Abatacept: Approved for Rheumatoid Arthritis; used in this trial for prevention of GVHD.

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Trabucco, Sally E., Ethan S. Sokol, Jay A. Moore, Sophia Maund, Garrett M. Frampton, Vincent A. Miller, Jeffrey Venstrom, et al. "Prediction and Characterization of Diffuse Large B-Cell Lymphoma (DLBCL) Cell of Origin (COO) Subtypes Using Genomic Features from Targeted Next-Generation Sequencing." Blood 132, Supplement 1 (November 29, 2018): 1561. http://dx.doi.org/10.1182/blood-2018-99-116677.

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Abstract Introduction: DLBCL has two COO subtypes: Activated B Cell (ABC) and Germinal Center B cell (GCB). Patients with the ABC subtype have a poor prognosis compared to those with GCB, and COO can be predictive for response to some new therapeutic agents. Traditionally, COO subtype has been determined by microarray (ABC, GCB, unclassified), IHC-based algorithms (GCB or non-GCB), or expression-based Nanostring Lymph2Cx (ABC, GCB, unclassified). Some reports have failed to show a prognostic difference between GCB and non-GCB when employing IHC-based algorithms. This has led some to adopt the Lymph2Cx assay as the preferred method to assess COO, but in some cases the tumor content or RNA quality is inadequate to perform this assay. COO subtypes have differing gene mutations, with GCB typically characterized by EZH2 alterations and IGH:BCL2 translocations, while ABC is dominated by NF-KB and BCR signaling alterations such as MYD88 and CD79B short variants. Here we utilized mutational differences in COO subtypes to develop a COO DNA classification (COODC) model to predict COO from DNA-based features on a clinically utilized platform. Methods: Comprehensive genomic profiling (CGP) of DLBCL samples was performed using the DNA component of the FoundationOne® Heme platform; sequencing 465 genes for the GOYA trial (R-CHOP vs G-CHOP; N=499; NCT01287741), MAIN trial (R-CHOP +/- bevacizumab; N=44; NCT00486759), and cases from routine clinical care (FM-clinical; N=597). Gold standard COO classifications were determined in GOYA using the Lymph2Cx assay, and in MAIN using a modified Wright algorithm applied to a custom Nanostring expression panel. COODC was developed using a penalized lasso regression with 25-fold internal cross validation and cutoffs that optimize specificity and sensitivity. Concordance was calculated as the percentage of COODC calls matching the gold standard, excluding samples called unclassified in the gold standard or COODC. Results: We developed a novel DNA-based method to determine COO, which is 89% concordant with Lymph2Cx (Table) COODC was trained on 296 GOYA samples with Lymph2Cx COO calls and validated on 139 held-out samples from the same cohort (GOYA). Additional validation was performed on an independent first-line cohort (MAIN) and confirmed a high concordance (92%). COODC also provides prognostic value, confirming the worse prognosis of ABC (progression-free survival [PFS] hazard ratio [HR] 1.6; 95% confidence interval [CI]: 1.1-2.4; p=0.011) and unclassified (PFS HR 1.9; 95% CI: 1.1-3.2; p=0.021) compared with GCB. This approach also allows investigation into the genomics and underlying features of COO subtypes. Alterations in BCL2, EZH2, and TNFRSF14 were important determinants of the GCB phenotype, consistent with the enrichment of GCB samples among the EZB cluster in Schmitz et al. (N Engl J Med 2018), or C3 in Chapuy et al. (Nat Med 2018). Alterations in MYD88 and CD79B were highly predictive of ABC subtype, as expected. Alterations in NOTCH1, NOTCH2, and BCL6 were all slightly predictive of ABC subtype, despite the mixed phenotype of the BN2, N1 (Schmitz et al. N Engl J Med 2018), and C1 (Chapuy et al. Nat Med 2018) groups. Novel features include decreased average copy number of chromosome 6p, which encodes the HLA locus, in ABC (p=0.0064), and increased frequency of T>A and T>G alterations in GCB (p<0.0001 for both). We identified 2 major mutational signatures associated with COO: COSMIC signature 23, corresponding to a canonical activation-induced cytidine deaminase signature, enriched in ABC (p=0.002), and COSMIC signature 3, which trends to increased frequency in GCB (p=0.13). Conclusions: We have developed a new and clinically relevant method for determining DLBCL COO in specimens with tumor purity as low as 20%, without the need for RNA or matched normal tissue. This method is 89% (GOYA) to 92% (MAIN) concordant with the Lymph2Cx assay and maintains prognostic value. Integrating COO with CGP enables insights into disease biology, including the identification of novel features associated with COO. We identified a difference in mutational signatures between ABC and GCB, suggesting that different origin cells may contribute to different mutational processes. Disclosures Trabucco: Foundation Medicine Inc: Employment. Sokol:Foundation Medicine: Employment. Moore:Foundation Medicine, Inc.: Employment. Maund:Genentech: Employment. Frampton:Foundation Medicine Inc: Employment, Other: Employee and stockholder. Miller:Foundation Medicine: Employment, Other: Ownership interests none PLC*; Revolution Medicines: Membership on an entity's Board of Directors or advisory committees. Venstrom:Genentech Inc: Employment. Albacker:Foundation Medicine Inc: Employment; Foundation Medicine Inc: Employment. Sehn:Morphosys: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Oestergaard:Roche: Employment, Other: Ownership interests PLC. Bolen:Roche: Other: Ownership interests PLC*.

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Foureau, David M., Manisha Bhutani, Myra Robinson, Fei Guo, Duy Pham, Shelley Force Aldred, Ben Buelow, et al. "Ex Vivo Assessment of Tnb-383B, a Bcma-Bispecific Antibody, Against Primary Tumor and Endogenous T Cells from Relapsing Multiple Myeloma Patients." Blood 132, Supplement 1 (November 29, 2018): 1940. http://dx.doi.org/10.1182/blood-2018-99-118881.

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Abstract INTRODUCTION: The human B-Cell maturation antigen (BCMA) is a surface marker that is highly expressed on plasma cells and has been recognized as a novel target in multiple myeloma (MM). TNB-383B is a fully human bispecific monoclonal IgG4 antibody. TNB-383B consists of 2 heavy and 1 light chain(s) paired through knob-in-hole technology. The first heavy chain and a kappa light chain form the paratope to recognize and bind human CD3. The second heavy chain is comprised of two identical VH domains in sequence and targets human BCMA with high affinity and avidity. Herein, we describe the ability of TNB-383B to mediate killing of patient-derived tumor cell lysis by endogenous T-cells was assessed ex vivo. METHODS: Bone marrow mononuclear cells (BMMCs) were isolated by density gradient centrifugation from 7 relapsed MM patients enrolled in an IRB-approved biospecimen collection protocol. Freshly isolated BMMC subsets were characterized by flow cytometry, specifically plasma cell (PC) / cytotoxic T cell (CTL) distribution, PC BCMA expression and PC viability were determined. BMMCs were then incubated for 24h (± 2h) with TNB-383B, or negative control, at concentrations ranging from 0.001-1μg. Following incubation, PC lysis, viability, BCMA expression, as well as CTL distribution and degranulation were assessed by flow cytometry. Tukey's sequential trend test was performed for each measured variable, utilizing ANOVA models and contrast statements, to detect linear dose response trends to TNB-383B or negative control treatments. Additionally, a parametric model (EMax) was used for each measured variable to estimate dose response curves, interpolating between tested doses. Two-way factorial ANOVA was utilized to compare the main effects of E:T ratio (or PC phenotype) and dose level and the interaction effect between E:T ratio and dose level on measured variables. RESULTS: Dose-dependent PC lysis was triggered by TNB-383B at concentrations as low as 0.001μg (p=0.0102) while no significant loss of PC was observed with negative control (Figure). This effect was coupled with significant CTL degranulation as expressed by increased CD107a mean fluorescence intensity (MFI) specific to TNB-383B treatment (p=0.0153 at 1μg). Although apoptotic rates (7-AAD+, Annexin V+) of the remaining PC tend to increase among TNB-383B treated compared with isotype control-treated cells, this trend was not significant. As opposed to CTL degranulation, CTL proliferation was not significantly triggered by TNB-383B but was significantly increased when BMMCs were exposed to negative control antibody (p=0.0057 at 0.001 μg). BMMC containing effector to target (E:T) ratio >10 contained lower viable (7-AAD-) PC and higher apoptotic PC counts compared with BMMC specimen with E:T ratio <10 (p<0.001). Using CD45 expression as a surrogate marker of PC maturation and BCMA expression, CD45+ PC displayed higher BCMA expression than CD45- PC (p=0.0189) and were more sensitive TNB-383B-induced killing (p<0.001). Noticeably, overall BCMA expression pre/post TNB-383B exposure remained unaltered. CONCLUSION: Taken together, our findings demonstrate TNB-383B triggers primary PC lysis and CTL degranulation in a dose-dependent fashion ex vivo. The ex vivo bispecific monoclonal antibody assay employed in this study allowed us to identify underlying biological drivers of PC killing efficacy by TNB-383B and may provide a valuable preclinical platform to screen bispecific antibodies and clinical platform to identify mechanism of primary or acquired resistance to the drug. Enrollment of patients with relapsed/refractory MM into a phase I clinical trial with TNB-383B is expected in early 2019. Figure. Figure. Disclosures Foureau: Teneobio Inc.: Research Funding. Pham:Teneobio Inc.: Employment. Force Aldred:Teneobio Inc.: Employment. Buelow:Teneobio Inc.: Employment. Voorhees:Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Other: served on an IRC; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; Amgen Inc.: Speakers Bureau; TeneoBio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding.

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Astone, Giuseppina, Luca Vincenzo Cappelli, William Chiu, Clarisse Kayembe, Rui Wang, Bin Yang, Kirti Sharma, et al. "Selective STAT3 Degraders Dissect Peripheral T-Cell Lymphomas Vulnerabilities Empowering Personalized Regimens." Blood 138, Supplement 1 (November 5, 2021): 865. http://dx.doi.org/10.1182/blood-2021-153995.

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Abstract Introduction: Peripheral T-cell lymphomas (PTCLs) include heterogeneous entities of rare and aggressive neoplasms. The improved understanding of the biological/molecular mechanisms driving T-cell transformation and tumor maintenance has powerfully propelled new therapeutic programs. However, despite this progress, PTCLs remain an unmet medical need. Recurrent aberrations and the deregulated activation of distinct signaling pathways have been mapped and linked to selective subtypes. The JAK/STAT signaling pathway's deregulated activation plays a pathogenetic role in PTCL, including ALCL subtypes. STATs regulate the differentiation/phenotype, survival and cell-growth, metabolism, and drug resistance of T-cell lymphomas as well as host immunosuppressive microenvironments. Although many drugs' discovery programs were launched, a plethora of compounds has failed. Methods: We have discovered heterobifunctional molecules by an iterative medicinal chemistry SAR campaign that potently and selectively degrade STAT3 in a proteasome-dependent manner. Conventional PTCL cell lines and Patient Derived Tumor Xenograft (PDTX) and/or derived cell lines (PDTX-CL), carrying either WT- or mutated-STAT3, were exposed to increasing amounts (50nM⇒5µM) of STAT3-degraders. Proteins and mRNA transcripts (2⇒144hrs) were assessed by deep-proteomics and paired-end RNA sequencing, combined with WB/flow cytometry and qRT-PCR. Cell-titer-glo, cell titer blue, Annexin-V and S-cell cycle analyses were used as readouts. Chromatin accessibility, STAT3 DNA binding, 3D chromosomal architecture reorganization and 5-hmC profiling were assessed by ATACseq, CHIPseq and Hi-C and H3K27ac Hi-CHIP and mass-spectrometry. Drug testing/discovery combinations (96-well-plate) were performed using a semi-automated flow-cytometry. A battery of PTCL PDTX models were tested in pre-clinical trials. Results: Treatment of ALK+ ALCL (SU-DHL1) led to the rapid (~6hrs.) and profound down-regulation of STAT3 followed by the loss of canonical STAT3-regulated proteins (SOCS3, MYC, Granzyme B, GAS1, and IL2RA), without appreciable changes for other STAT family members (STAT1, STAT5b). In vitro, cytoplasmic, nuclear, and mitochondrial STAT3 downregulation was maintained up to 144 hrs. Loss of STAT3 in ALK+/- ALCL and BIA-ALCL cells was associated with major transcriptional changes (7116-10615 and 15114 DEGs in ALK- and ALK+ ALCL, respectively), underscoring public/shared as well as private time-dependent signatures. Main down-regulated pathways included JAK-STAT, MAPK, NF-kB, PI3K, TGFb, and TNFa. Comparison of STAT3 shRNA (ALK+ ALCL) and STAT3 degrader (ALK-/ALK+ ALCL) signatures demonstrated a substantial and concordant gene modulation (24hrs) among all models with the highest overlaps between ALK+ ALCL (Figure 3). To identify direct STAT3 gene targets, we analyzed CHIPseq peaks and predicted bindings sites, demonstrating that canonical genes, i.e., SOCS3, Granzyme B, GAS1, IL2RA, STAT3, and CD30, were significantly downregulated. Conversely, CD58, CD274, and MCH-I/II were upregulated at late time points. By mapping the STAT3 binding sites in ALK+ and ALK- ALCL, we have identified 1077 and 2763 STAT3 peaks within promoter/5'-/3'- and distant intergenic regions, corresponding to both coding and non-coding genes. Therapeutically, in vitro treatments led to cell cycle arrest and profound growth inhibition, and over time increased cell death of PTCL cells, including ALCL. Accordingly, growth inhibition of ALCL xenograft and PDTX tumors was also achieved (Figure 2). To identify drugs that could synergize withSTAT3-degrader activity, we tested a compound library (40) targeting pro-tumorigenic PTCL pathways as well as FDA-approved compounds. Ongoing studies are in progress. Conclusion: We have discovered selective STAT3 degraders which control PTCL growth. STAT3 degraders are powerful tools to define the STAT3 pathogenetic mechanisms and dissect genes/pathways to be targeted for T-cell lymphoma eradication. These data provide additional rationale for testing STAT3 degraders in the clinic for the treatment of aggressive malignancies including PTCL/ALCL. Figure 1 Figure 1. Disclosures Yang: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sharma: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Dey: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Karnik: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Elemento: Owkin: Consultancy, Other: Current equity holder; Volastra Therapeutics: Consultancy, Other: Current equity holder, Research Funding; Johnson and Johnson: Research Funding; Eli Lilly: Research Funding; Janssen: Research Funding; Champions Oncology: Consultancy; Freenome: Consultancy, Other: Current equity holder in a privately-held company; One Three Biotech: Consultancy, Other: Current equity holder; AstraZeneca: Research Funding. Horwitz: Affimed: Research Funding; Aileron: Research Funding; ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding. DeSavi: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Liu: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company.

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Syaiputra Wahyuda Meisa Diningrat, Luluk Janah, and Sakinatul Mardiyah. "Modified Bottle Cap for Improving Children’s Arithmetic Ability." JPUD - Jurnal Pendidikan Usia Dini 13, no. 2 (December 1, 2019): 249–63. http://dx.doi.org/10.21009/jpud.132.04.

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The preliminary study showed that the main problem, however, faced by kindergarten students are lack of mathematics skill, such arithmetic ability in kindergarten Galis. Therefore, the present study aims to investigate the effectiveness of a modified bottle cap as an educational game tool towards enhancement of arithmetic ability. Samples were prepared for the quasi-experiment research design involving 60 children, aged 4-5 years. A detailed comparison is made between the experimental condition, consisted of 30 students, received the educational game tool activities and the control condition which consisted of 30 students, received the instructional activities as usual. Before and after two weeks of the intervention with the game tool of a modified bottle cap, measures of arithmetic ability were administered to either experiment or control class. The results of the study indicated that in the experiment class, children’s arithmetic ability increased significantly compared to children in the control class. The differences may have been due to the intervention. To conclude, the modified bottle cap as an educational game tool effective to improve children’s mathematics skill, especially for arithmetic ability. However, the findings required the extended study on other research methods and the bigger size of the samples. Keywords: Early Childhood, Modified bottle cap, Early Arithmetic Ability. References: Aqib, Zainal. (2010). Belajar dan Pembelajaran di Taman Kanak-Kanak. Bandung: Yrama Widya. Arsyad, A. (2017). Media Pembelajaran. PT Raja Grafindo Pursada. Aunio, Pirjo; Tapola, Anna; Mononen; and Niemivirta, M. (2016). Early Mathematics Skill Development, Low Performance, and Parental Support in the Finnish Context. In Blevins-Knabe; A.M.B. Austin (Ed.), Early Childhood Mathematic Skill Development in the home environment. Cham, Switzerland: Springer. Ayuni, D., & Setiawati, F. A. (2019). Kebun Buah Learning Media for Early Childhood Counting Ability. Jurnal Obsesi : Jurnal Pendidikan Anak Usia Dini, 3(1), 1. https://doi.org/10.31004/obsesi.v3i1.128 Barblett, L., Knaus, M., & Barratt-Pugh, C. (2016). The Pushes and Pulls of Pedagogy in the Early Years: Competing Knowledges and the Erosion of Play-based Learning. Australasian Journal of Early Childhood, 41(4), 36–43. https://doi.org/10.1177/183693911604100405 Barth, H., La Mont, K., Lipton, J., & Spelke, E. S. (2005). Abstract number and arithmetic in preschool children. Proceedings of the National Academy of Sciences of the United States of America, 102(39), 14116–14121. https://doi.org/10.1073/pnas.0505512102 Blevins-Knabe, B. (2016). Early Mathematical Development : How the Home Environment Matters. In Belinda Blevins-Knabe; Ann M. Berghout Austin (Ed.), Early Childhood Mathematics Skill Development in the Home Environment (pp. 8–9). Cham, Swutzerland: Springer. Copley, J. V. (2016). The Young Child and Mathematics. In M. Hogarty (Ed.), Numbers and Stories: Using Children’s Literature to Teach Young Children Number Sense (Second, pp. 1–14). https://doi.org/10.4135/9781483330907.n1 Depdiknas. (2005). Pedoman Pembelajaran di Taman Kanak-Kanak. Jakarta: Direktorat Pembinaan Taman Kanak-Kanak Sekolah Dasar. Depdiknas. (2007). Modul Pembuatan dan Penggunaan APE anak Usia 2-6 Tahun. Jakarta: Dirjen Pendidikan Luar Sekolah Direktorat PAUD. Dunekacke, S., Jenßen, L., Eilerts, K., & Blömeke, S. (2016). Epistemological beliefs of prospective preschool teachers and their relation to knowledge, perception, and planning abilities in the field of mathematics: a process model. ZDM - Mathematics Education, 48(1–2), 125–137. https://doi.org/10.1007/s11858-015-0711-6 Elizabeth, W. (2011). Cross-curricular Teaching to Support Child-initiated Learning in EYFS and KEY Stage I. In Suzanne and Kristine (Ed.), Early Childhood Educaiton: Yesterday, Today, and Tomorrow. New York: Routledge. Fitri, F., & Syamsudin, A. (2019, May). The Effectiveness of Race Track Games on Counting Ability and Child Learning Motivation. https://doi.org/10.2991/icsie-18.2019.78 Grindheim, L. T. (2017). Children as playing citizens. European Early Childhood Education Research Journal, 25(4), 624–636. https://doi.org/10.1080/1350293X.2017.1331076 Guslinda; Kurnia, R. (2018). Media Pembelajaran Anak Usia Dini. Surabaya: Jakad Publiser. Harris, B., & Petersen, D. (2017). Developing Math Skills in Early Childhood. Issue Brief. Mathematica Policy Research, Inc., (February), 1–6. Retrieved from http://ezproxy.library.uvic.ca/login?url=http://search.ebscohost.com/login.aspx?direct=true&db=eric&AN=ED587415&site=ehost-live&scope=site Haskell, S. H. (2000). The determinants of arithmetic skills in young children: Some observations. European Child and Adolescent Psychiatry, 9(SUPPL. 2), 77–86. https://doi.org/10.1007/s007870070011 Hurlock, Elisabeth, B. (1978). Perkembangan Anak, Jilid 2. Jakarta: Erlangga. Ismail, A. (2006). Education Games “Menjadi Cerdas dan Ceria dengan Permainan Edukatif.” Jacobi-Vessels, J. L., Todd Brown, E., Molfese, V. J., & Do, A. (2016). Teaching Preschoolers to Count: Effective Strategies for Achieving Early Mathematics Milestones. Early Childhood Education Journal, 44(1), 1–9. https://doi.org/10.1007/s10643-014-0671-4 Johnson, J. E., & Wu, M.-H. (2019). Perspectives on Play in Early Childhood Care and Educaiton. In M. B. Brown, Christopher; McMullen (Ed.), The Wiley Handbook of Early Childhood Care and Education (1st ed., p. 86). New Jersey: John Wiley & Sons. Kamus Besar Bahasa Indonesia Online. (2019). Retrieved from https://www.kamusbesar.com/prefix/nd Khasanah, I. (2013). Pembelajaran Logika Matematika Anak Usia Dini (Usia 4-5 Tahun) di TK Ikal Bulog Jakarta Timur. In Jurnal Penelitian PAUDIA (Vol. 2). Lai, N. K., Ang, T. F., Por, L. Y., & Liew, C. S. (2018). The impact of play on child development - a literature review. European Early Childhood Education Research Journal, 26(5), 625–643. https://doi.org/10.1080/1350293X.2018.1522479 Malapata, E., & Wijayanigsih, L. (2019). Meningkatkan Kemampuan Berhitung Anak Usia 4-5 Tahun melalui Media Lumbung Hitung. Jurnal Obsesi : Jurnal Pendidikan Anak Usia Dini, 3(1), 283. https://doi.org/10.31004/obsesi.v3i1.183 Manjale, N. B., & Abel, C. (2017). Significance and adequacy of instructional media as perceived by primary school pupils and teachers in. 4(6), 151–157. Martin, R. B., Cirino, P. T., Sharp, C., & Barnes, M. (2014). Number and counting skills in kindergarten as predictors of grade 1 mathematical skills. Learning and Individual Differences, 34, 12–23. https://doi.org/10.1016/j.lindif.2014.05.006 Naz, A. A., & Akbar, R. A. (2010). Use of Media for Effective Instruction its Importance : Some Consideration. Journal of Elementary Education, 18(1–2), 35–40. OECD. (2019). Mathematics Performance (PISA) 2015. https://doi.org/10.1787/04711c74-en Papadakis, S., Kalogiannakis, M., & Zaranis, N. (2017). Improving Mathematics Teaching in Kindergarten with Realistic Mathematical Education. Early Childhood Education Journal, 45(3), 369–378. https://doi.org/10.1007/s10643-015-0768-4 Passolunghi, M. C., Cargnelutti, E., & Pellizzoni, S. (2019). The relation between cognitive and emotional factors and arithmetic problem-solving. Educational Studies in Mathematics, 100(3), 271–290. https://doi.org/10.1007/s10649-018-9863-y Preeti. (2014). Education and role of media in education system. International Journal of Scientific Engineering and Research, 2(3), 174–175. Rahman, S. (2010). Alat Permainan Edikatif untuk Program PAUD. Palu: Tadulako University Press. Rohmah, N., & Waluyo, E. (2014). Arithmetic Dice Media as Counting Concept Introduction for Early Childhood. Naili Rohmah & Edi Waluyo / Indonesian Journal of Early Childhood Education Studies, 3(2), 127–133. https://doi.org/10.15294/ijeces.v3i2.9486 Rushton, S. (2011, June). Neuroscience, Early Childhood Education and Play: We are Doing it Right! Early Childhood Education Journal, 39(2), 89–94. https://doi.org/10.1007/s10643-011-0447-z Schacter, J., & Jo, B. (2017). Improving preschoolers’ mathematics achievement with tablets: a randomized controlled trial. Mathematics Education Research Journal, 29(3), 313–327. https://doi.org/10.1007/s13394-017-0203-9 Schwartz, S. (2005). Teaching YoungChildren Mathematics. Westport, Connecticut: Praeger. Selvi, K. (2010). Teachers’ competencies. Cultura. International Journal of Philosophy of Culture and Axiology, 7(1), 167–175. https://doi.org/10.5840/cultura20107133 Smaldino, S. E., Russel, J. D., & Lowther, D. L. (2014). Instructional Technology & Media for Learning (9th ed.). Jakarta: Kencana Prenada Media Group. Suryadi. (2007). Cara Efektif Memahami Perilaku Anak Usia Dini. Jakarta: Edsa Mahkota. Vogt, F., Hauser, B., Stebler, R., & Rechsteiner, K. (2018). Learning through play – pedagogy and learning outcomes in early childhood mathematics. 1807. https://doi.org/10.1080/1350293X.2018.1487160 Vogt, F., Hauser, B., Stebler, R., Rechsteiner, K., & Urech, C. (2018). Learning through play–pedagogy and learning outcomes in early childhood mathematics. European Early Childhood Education Research Journal, 26(4), 589–603. https://doi.org/10.1080/1350293X.2018.1487160 Wati, E. R. (2016). Ragam Media Pembelajaran (A. Jarot, Ed.). Yogyakarta: Kata Pena. Zulkardi, N. (2011). Building counting by traditional game: A Mathematics Program for Young Children. IndoMs. J.M.E, 2(1), 41–54.

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Sportes, C., F. Hakim, M. Krumlauf, R. Babb, T. Fleisher, M. Brown, J. Engel, R. Buffet, C. Mackall, and R. Gress. "Effects of rhIL-7 administration in humans on in vivo expansion of naïve, memory and effector subsets of CD4+ & CD8+ T-cells." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 2504. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.2504.

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2504 Background: IL-7 has a critical and non-redundant role in T-cell lymphopoiesis and peripheral T-cell homeostasis. IL-7 administration may prove clinically valuable in conditions of disease induced (HIV) or iatrogenic T-cell depletion and for modulation of vaccine immune responses. In the first phase I study in humans, recombinant human interleukin-7 (“CYT 99–007”, Cytheris Inc., Rockville, MD) was administered subcutaneously every other day for two weeks in adults with refractory malignancies at 3, 10, 30 and 60 μg/kg/dose. Biologic activity, defined as a 50% increase over baseline of peripheral blood CD3+ T-cells, was seen at and above the 10μg/kg/dose in all patients. The kinetics of proliferation and expansion of peripheral blood T-cell subsets were analyzed. Methods: Multicolor flow cytometry was performed at baseline, 1, 2 and 3 weeks. Among CD4+ cells, the most naïve were defined as CD45RA+ /CD31+. Among CD4+ & CD8+ cells, the main naïve, memory and effector populations were defined respectively as CD45RA+/CD27+, CD45RA-/CD27+ and CD45RA-/CD27-. Within each subset, the number of cells in cycle was defined by Ki67 staining. Results: Following IL-7 therapy, there was marked proliferation of all T-cells subsets, peaking at week 1, most striking for the naive subsets with 30–70% of circulating cells induced to cycle. Proliferation rates were halved by week 2 despite continuation of treatment, coincident with the observed down-regulation of the IL-7 receptor. Cycling returned to baseline by week 3. Significant proliferation was also induced in effector and memory CD4+ and CD8+ T-cells but to a lesser magnitude, resulting in a greater net expansion of the naïve subsets, still ongoing one week after the end of treatment. Conclusions: IL-7 administration induces marked expansion of naïve, memory and effector CD4+ & CD8+ T-cells in humans. Consistent with the known down-regulation of the IL-7 receptor upon IL-7 exposure, proliferation rates decrease during the second week of treatment. rhIL-7 induced T-cell expansion may prove clinically valuable in adoptive immunotherapy as an adjunct to tumor vaccination and / or immunorestorative agent. [Table: see text]

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Vovchenko, L., and N. Zhachko. "Dental status of children with congenital defects of the heart and main vessels in Ukraine." SUCHASNA STOMATOLOHIYA 118, no. 1 (2024): 21. http://dx.doi.org/10.33295/1992-576x-2024-1-21.

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Introduction: Congenital heart disease (CHD) is one of the most common congenital defect worldwide. The increase in the number of patients with CHD creates a group of people with individual special care needs, including dental care. Purpose: to evaluate oral health conditions (oral hygiene, caries experience, periodontal health) in children with CHD and compare their caries experience with the one of the group of healthy children in Ukraine. Materials and methods: Fifty-eight children with congenital heart disease and eighty healthy children aged 3-15 years were enrolled in this study. According to their age and period of dentition, all the children were subdivided into 3 groups: with primary, mixed and permanent dentition. Caries experience, oral hygiene, periodontal health and dental developmental defects were assessed. A one-sample Kolmogorov-Smirnov test and an independent-measures t-Test were used. All statistical analyses were performed using the statistical software (SPSS version 26.0, SPSS Inc.). The statistical significance was set at 5%. Results and discussion: The caries experience of children with CHD and healthy children in primary dentition was 4.0 and 6.4 respectively. The highest DMFT was registered in children with CHD in mixed (4.7) and permanent (4.6) dentitions. 33,3% of children with primary dentition and up to 52,9% in mixed dentition had poor oral hygiene. Conclusions: According to limitation of this epidemiological study, there were no significant differences in caries experience of children with congenital heart disease and healthy children in primary and mixed dentitions. These findings indicate the importance of preventive dental care and appropriate treatment of children with CHD. Key words: congenital heart disease, oral health, children, caries, airway volume, dentoalveolar abnormalities.

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Parkinson, Gerneiva, Anees B. Chagpar, Kellie Alleyne-Mike, Marcella Nunez-Smith, Alicia Zhou, Lily Servais, and Erin Wysong Hofstatter. "Investigation of HBOC germline mutations in women diagnosed with breast cancer in Trinidad and Tobago." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 6574. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.6574.

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6574 Background: Trinidad and Tobago (T&T) is the southern-most Caribbean island, and according to the WHO/PAHO, it has the 2nd highest breast cancer mortality rate in the region. Notably, a large proportion of breast cancer cases in T&T occur at a young age; with nearly 36% of them being diagnosed under the age of 50. There is a known association between a younger age at diagnosis and Hereditary Breast and Ovarian Cancer syndrome (HBOC). Yet, the prevalence of HBOC mutations remains unknown in T&T, as genetic counseling and testing services are extremely limited in the region. Therefore, we sought to determine the prevalence and spectrum of HBOC mutations in T&T. Methods: At the National Radiotherapy Center, T&T’s main oncology unit, female breast cancer patients, who met NCCN criteria for further genetic counseling and testing were recruited through chart reviews. After pre-test counseling, enrolled subjects had a detailed interview about their personal breast cancer diagnosis and family history. A saliva sample was collected using an Oragene kit, and analyzed by Color Genomics Inc. for 30 genes associated with hereditary cancers. Finalized results were returned to patients by genetic counselors from Color Genomics. Results: A total of 118 female patients who met NCCN guidelines for HBOC testing received genetic testing. A majority were 50 years of age or younger (69/118, 59%). The cohort was ethnically diverse: 34% African, 15% Asian, 48% multiple ethnicity, and 3% other/unknown. A pathogenic or likely pathogenic variant (positive result) was identified in 21.2% of the cohort (25/118) - most commonly identified in the BRCA1 gene (13/25, 52%), followed by BRCA2 (5/25, 20%), PTEN (2/25, 8%), BRIP1 (1/25, 4%), CHEK2 (1/25, 4%), MSH6 (1/25, 4%), PALB2 (1/25, 4%), and RAD51C (1/25, 4%). Conclusions: We found a strikingly high HBOC germline mutation prevalence rate of 21.2% among a cohort of female breast cancer patients meeting NCCN criteria for HBOC testing in T&T. Given the growing implications of germline HBOC mutations for breast cancer treatment and prevention, our results demonstrate an urgent need for funding, as well as the development of robust genetic counseling and testing services in T&T.

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Yanofiyanti, Tri. "ASUHAN KEBIDANAN KOMPREHENSIF PADA NY. K DI KLINIK UTAMA LESTARI TEMBILAHAN." Jurnal Kesehatan Husada Gemilang 6, no. 1 (February 20, 2023): 22–32. http://dx.doi.org/10.61129/jkhg.v6i1.74.

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Comprehensive midwifery care is care that is carried out thoroughly from pregnancy to family planning to reduce Maternal Mortality Rate (MMR) and Infant Mortality Rate (IMR). At the Utama Lestari Clinic, from January to December 2021, there were 539 pregnant women, pregnant women, BBL, 297 postpartum women and 963 family planning acceptors. Objective: To provide comprehensive care for Mrs. “K” at Klinik Utama Lestari using Varney's line of thought and documented in SOAP form. Methods: Midwifery management plan with Varney's line of thought and documented in SOAP form, implemented at Klinik Utama Lestari on 23 April s/d 05 July 2022. This midwifery care was carried out on Mrs. "K" aged 33 years G3P2A0H2. Results: The ANC had met the 10 T standard, the INC was running smoothly, there was a gap in the delivery of metergin, KN 1 was not given SHK, in postpartum and family planning there are no problems. Suggestion: Main Lestari Clinic can provide health workers such as midwives who are trained to check SHK and facilitate complete equipment. Asuhan kebidanan komprehensif adalah asuhan yang dilakukan secara menyeluruh dari mulai hamil sampai keluarga berencana untuk menurunkan Angka Kematian Ibu (AKI) dan Angka Kematian Bayi (AKB). Di Klinik Utama Lestari dari Januari sampai Desember tahun 2021 tercatat ibu hamil 539 orang, ibu bersalin, BBL, ibu nifas sebanyak 297 orang dan akseptor KB sebanyak 963 orang. Tujuan dalam asuhan ini Memberikan asuhan secara komprehensif pada Ny “K” di Klinik Utama Lestari dengan menggunakan alur fikir varney dan didokumentasikan dalam bentuk SOAP. Metode asuhan ini adalah Rancangan manajemen kebidanan dengan alur fikir varney dan didokumentasikan dalam bentuk SOAP, dilaksanakan di Klinik Utama Lestari pada tanggal 23 April s/d 05 Juli 2022. Asuhan kebidanan ini dilakukan pada Ny.”K” umur 33 Tahun G3P2A0H2. Dari hasil asuhan didapatkan Pada ANC telah memenuhi standar 10 T, INC berjalan dengan lancar, terdapat kesenjangan pada persalinan pemberian metergin, KN 1 tidak dilakukan pemberian SHK, pada nifas dan KB tidak terdapat masalah. Saran Bagi Klinik Utama Lestari dapat menyediakan tenaga kesehatan seperti bidan yang terlatih untuk pemeriksaan SHK dan memfasilitasi peralatan yang lengkap.

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Querol, Felipe, Sofía Pérez-Alenda, Juan Eduardo Megias, Juan José Carrasco, Marta Aguilar, Saturnino Haya, Ana R. Cid, and Santiago Bonanad Boix. "Benefits of Ehl Factor VIII Replacement Therapy in Hemophilia: Observations on Coverage, Physical Activity and Phisiotherapy." Blood 134, Supplement_1 (November 13, 2019): 2455. http://dx.doi.org/10.1182/blood-2019-125651.

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Introduction: Prevention of haemophilic arthropathy and quality of life´s (QoL) improvement are still the main goals in the haemophilia community. Haemophilic arthropathy is the result of clinical and subclinical bleeding during everyday activities and/or traumatic situations. Prophylaxis with extended half-life (EHL) factor replacement therapy is understood as an improvement solution for factor VIII (FVIII) PK properties, as half-life (T1/2) and area under the curve (AUC), however few real world data are yet available. EHL improved pharmacokinetic (PK) properties might directly drive into a reduction of the bleeding risk during physical activity (both therapeutical or leisure) for a longer period of time, allowing an increase in QoL. World Health Organization (WHO) has set recommendations focused on the benefits of moderate and intense physical activity to improve joint health as well as to prevent common pathologies (obesity, diabetes, hypertension, cancer, depression, anxiety) and even the risk of death (since the absence of physical activity is the 4th factor risk worldwide). The aim of this study was to define a safe program of physical activity, sport and physiotherapy along the time according the PK profile of patients treated with the EHL rurioctocog alfa pegol. Materials and methods: PK parameters (infusion frequency, dosage, T½, peak level, trough level at 24, 48 and 72 hours (NV24/NV48 and NV72), and time to reach 5%, 2% and 1% FVIII levels (T5,T2 and T1) were analyzed in patients with hemophilia A after switching from an standard half-life (SHL) FVIII to the EHL (rurioctocg alfa pegol) FVIII replacement therapy. Tailored physical activity and physiotherapy programmes in place during SHL treatment were re-evaluated after switching to the EHL according the new individual PK profile. The Functional Independence Score in Hemophilia (FISH) form was used to measure ambulation. Results: Ten patients with hemophilia A (9 severe and 1 moderate) with a mean age of 34.49 (9.46) were analyzed. All the PK parameters evaluated showed a significant statistical improvement after the switch from an SHL to this FVIII EHL (Figure 1, A.). Specifically, higher T½, peak levels and trough levels were achieved using a lower dosage and infusion frequency (Figure 1, B). After switching to the EHL, FVIII trough levels were higher than 5% until 3.4 days (81.5 hours) (Figure 1, C) post-infusion. This allowed us to establish a physiotherapy program as well as an intense-moderate physical activity program in patients without clinical evidence of bleeding events (Figure 1, D). The potentiation physical program to develop muscle tone for elbows, knees and ankles was authorized until the third day of EHL FVIII post-infusion. However, during SHL treatment, vigorous physical activity was never performed after 24 hours of FVIII post-infusion. No joint bleeding events appeared during everyday physical activities nor during physiotherapy programs aimed to maintain joint trajectory and muscle power. Regarding ambulation (FISH), all patients had hemophilic arthropathy in one joint. The results in the item "Run" were: 3 points for 3 patients (activity non comparable to normal activity), 2 points for 3 patients (requires an orthesis) and 1 point for 4 patients (activity not feasible). Conclusions: EHL FVIII replacement with rurioctocog alfa pegol improved significantly all PK parameters compared to SHL factors. The administration of this EHL allows moderate and vigorous physical activity after more than 72 hours post-infusion, due to higher FVIII coverage along the time. Disclosures Querol: Baxalta US INC.: Research Funding. Pérez-Alenda:Baxalta US INC.: Research Funding. Megias:Baxalta US INC.: Research Funding; Grifols: Research Funding. Carrasco:Baxalta US INC.: Research Funding. Cid:Novo Nordisk: Honoraria; Shire, a Takeda company: Honoraria. Bonanad Boix:Baxalta US INC.: Research Funding.

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Strozenko, Lyudmila A., Viktor S. Ponomarev, Yuriy F. Lobanov, Nikolay A. Dorokhov, Irina A. Sukmanova, Karina I. Shevchenko, Evgeniy V. Skudarnov, and Olga O. Sanina. "Polymorphic substitutions in folate cycle genes as predictors of hyperhomocysteinemia in children." Russian Pediatric Journal 27, no. 1 (February 28, 2024): 34–39. http://dx.doi.org/10.46563/1560-9561-2024-27-1-34-39.

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Introduction. Mutant alleles of genes of folate cycle enzymes can lead to the significant deterioration of its function and varying severity of pathology. Several defects in these genes lead to severe hyperhomocysteinemia, the most common form of which is a deficiency of cystathionine beta-synthase B. Aim: to establish polymorphic substitutions in the genes of folate cycle enzymes that contribute to the formation of hyperhomocysteinemia in children. Materials and methods. Two hundred seventy one children aged of 13–18 years were examined. The analysis of genetic polymorphisms of the folate cycle was carried out using a molecular genetic method. Quantitative determination of the blood homocysteine and folic acid level was performed by chemiluminescent immunoassay on microparticles. Statistical data processing was carried out using Statistica 6.1 application programs (StatSoft Inc., USA). Results. The frequency of the T allele of the MTHFR 677 gene was revealed to be higher in adolescents of the main group compared with the control (p = 0.043). The frequency of the homozygous genotype 66 AA of the MTRR gene in children of the comparison group was significantly higher (p = 0.049), however, the heterozygous genotype 66 AG of the MTRR gene was significantly more often detected in adolescents of the main group (p = 0.008). The average concentrations of homocysteine in children of the main group were 11.6 mmol/L, in adolescents of the control group 9.3 mmol/L (p = 0.021). Hyperhomocysteinemia in children of the main group was detected in 217 (80.1%) adolescents, and in 57 (49.6%) children of the control group (p < 0.001). The baseline serum folate level was determined in the children of the main group. The average amount of vitamin B9 in the blood of children of the main group was 3.7 ng/ml, and in 145 (53.5%) children this indicator was significantly reduced. Conclusion. Low levels of folic acid contribute to an increase in homocysteine in blood plasma. Taking vitamin B9 and vitamin folate complexes significantly reduces the level of homocysteine in blood plasma (p < 0.001).

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Gazaleeva, Galina, Liudmila Nazarenko, and Elena Dmitrieva. "The research of the absorption potential effect of the minerals surface on the cassiterite flotation process." Izvestiya vysshikh uchebnykh zavedenii Gornyi zhurnal, no. 3 (May 14, 2020): 70–79. http://dx.doi.org/10.21440/0536-1028-2020-3-70-79.

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Introduction. The use of flotation for tin additional recovery and in order to increase integrated use of raw materials is one of the main trends in tin ores beneficiation technology development. Research aim is to identify the mechanism of reagents action on the pulp particles surface during the flotation of tin-containing products containing cassiterite. 78 "Izvestiya vysshikh uchebnykh zavedenii. Gornyi zhurnal". No. 3. 2020 ISSN 0536-1028 Methodology. Pulp absorption potential was measured on Dispersion DT-310 electro-acoustic spectrometer from Dispersion Technolodgy Inc., USA. The object of research was the cleaning products of the collective concentrate obtained from beneficiation sludge tailings of Solnechny enrichment plant (the Khabarovsk Territory). The surface of the initial product was sequentially treated with the following reagents: sodium hexametaphosphate, kerosene, liquid glass, aluminum sulfate and the Asparal-F collector reagent with measurements of the absorption potential. At the same time, open flotation experiments were carried out with fractionated removal of the foam product. Results. The research results have shown that the main influence on pulp absorption potential is exerted by a depressor - aluminum sulfate. With its consumption of 800 and 1600 g/t, the value of the absorption potential decreases to the level of minus 1.3–1.4 mV, having a negative extremum. With a further increase in depressor consumption to 2400 g/t, there is a abrupt jump in the absorption potential to positive values. The study of absorption potential value dependence on Asparal-F reagent-collector consumption has shown that an increase in the collector flow rate to 400 g/t causes a abrupt jump and alternation of the potential from + to – (– 0.05 mV) and the intersection of the curve with the zero point allows to determine its optimal flow rate 360 g/t. Flotation of the initial product with fractional removal of foam has shown that it was this jump that led to an increase in the quality of fractions from 0.40 to 1.04% in terms of tin content. Further processing of the obtained flotation tin product according to the gravitational scheme made it possible to obtain conditioned tin concentrate with a tin content of 24.8%. Conclusions. The study of thin intermediate products tin flotation process in the tailings processing flow chart of Solnechny enrichment plant with pulp ζ-potential evaluation revealed some regularities of this indicator influence on the flotation results and the optimal consumption of flotation reagents.

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Savastano, Maria Cristina, Clara Rizzo, Gloria Gambini, Alfonso Savastano, Benedetto Falsini, Daniela Bacherini, Carmela Grazia Caputo, et al. "Choriocapillaris Vascular Density Changes: Healthy vs. Advanced Exudative Age-Related Macular Degeneration Previously Treated with Multiple Anti-VEGF Intravitreal Injections." Diagnostics 11, no. 11 (October 22, 2021): 1958. http://dx.doi.org/10.3390/diagnostics11111958.

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Purpose: To assess choriocapillaris vascular density (VD) in healthy and advanced exudative age-related macular degeneration (ae-AMD) patients by new full-range optical coherence tomography angiography (OCT-A). Method: In this observational, cross-sectional study, 21 healthy and 21 ae-AMD eyes, already treated with anti-VEGF, were enrolled. Angio-View retina patterns centered on fovea (6.4 × 6.4 mm) were acquired for all participants using Solix full-range OCT (Optovue Inc., Freemont, CA, USA). The main outcome was to compare choriocapillaris VD between healthy and ae-AMD eyes. Automated measurements of whole image choriocapillaris VD (%) and fovea grid-based (%) were collected for the analysis. Angio-View patterns were used to assess the flow area (mm2) of macular neovascularization (MNV) by contour flow measure algorithm. Best-corrected visual acuity (BCVA) of both groups was also used for the statistical analysis. Results: The mean age was 60.9 (±8.3) in healthy and 73.33 (±15.05) in ae-AMD eyes. The mean BCVA (ETDRS letters) was 98.47 (±1.50) in healthy and 7.04 (±5.96) in ae-AMD eyes. The Mann–Whitney test comparing choriocapillaries VD for whole and fovea healthy and ae-AMD eyes showed statistical significance (p < 0.0001 (t = 4.91; df = 40) and p < 0.0001 (t = 6.84; df = 40), respectively). Regarding, the correlation between MNV and VD of choriocapillaries, neither whole nor fovea areas were statistically significant (F = 0.38 (R2 = 0.01) and 1.68 (R2 = 0.08), respectively). Conclusions: Choriocapillaris VD showed a statistically significant reduction in comparison to healthy eyes in ae-AMD eyes. Choriocapillaris impairment can be seen in the early phase of MNV pathogenesis.

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Konovalova, G. V., and E. I. Koveshnikova. "Effects of experimental Trichinella spiralis larvae infection in rats and mice on hematological and biochemical parameters of the host at different infection stages." Russian Journal of Parasitology 17, no. 2 (June 20, 2023): 250–56. http://dx.doi.org/10.31016/1998-8435-2023-17-2-250-256.

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The purpose of the research is the study of effects of experimental Trichinella spiralis infection in rats and mice on hematological and biochemical blood parameters of the host at different infection stages.Materials and methods. The experiment was performed on mature outbred male rats and male mice that were infected by T. spiralis larvae orally administered at the rate of 10 larvae/1 g of body weight. Blood samples were taken from the rats at 40 days and 3 months after infection; from the mice, on day 40 after infection. The main parameters of peripheral blood in the rats were determined by a MicroCC-20 Plus hematological analyzer (High Technology, Inc. (USA)) using reagents from Clinical Diagnostic Solutions, LLC (Russia). Biochemical blood parameters in the rats and mice were determined by a Clima MC-15 analyzer, RAL Technical el Laboratoria, S.A. (Spain) using reagents produced by Diakon-DS, CJSC (Russia).Results and discussion. At 40 days and 3 months after the rats were experimentally infected with T. spiralis, we observed a consistent increase in the hemoglobin concentration, erythrocytes and leukocytes, and hematocrit, and a decrease in the alkaline phosphatase activity and ALT, and an increase in total protein. On day 40 after infection in the mice, an increase in total protein was observed as in the rats, and a decrease in blood urea. The changes detected in hematological and biochemical parameters in the rats and mice were associated with the toxic effect of Trichinella infection and the response of the host organism. Such changes are dependent on the infection stage and animal species.

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Yundra Liana, Elva. "ASUHAN KEBIDANAN KOMPREHENSIF PADA NY “R” DI KLINIK UTAMA LESTARI TEMBILAHAN TAHUN 2021." Jurnal Kesehatan Husada Gemilang 5, no. 1 (February 28, 2022): 31–38. http://dx.doi.org/10.61129/jkhg.v5i1.66.

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Background: Comprehensive care in midwifery care is a series of continuous and comprehensive activities, starting from pregnancy, childbirth, postpartum, family planning services. Purpose: Able to carry out comprehensive midwifery care based on the Varney management approach and documented in the SOAP method at the Lestari main clinic in 2021. Result: This comprehensive midwifery care was carried out on Mrs. R. Age 35 years G3P2A0H2 In ANC care that met the 10 T standard, the INC went well, the stage I lasted 2 hours 10 minutes, the stage II lasted 9 minutes, the stage III lasted 10 minutes, and the IV stage lasted for 2 hours, there was no laceration of the birth canal. The baby was born spontaneously, weight 3600 g, body length was 49 cm and neonates visits were carried out 3 times. The postpartum period went normally without any complications, 4 visits were made and family planning care Mrs. R chose 1 month injection KB as her contraceptive method. From these results it can be concluded that the comprehensive care provided to Mrs. R has met the standards. Suggestion: It is hoped that all health workers will be able to update their knowledge by attending training and seminars related to midwifery. Asuhan komprehensif dalam asuhan kebidanan merupakan serangkaian kegiatan yang berkelanjutan dan menyeluruh, dimulai dari kehamilan, persalinan, nifas, pelayanan KB. Tujuan Penelitian Mampu melaksanaan Asuhan kebidanan komprehensif dasar pendekatan manajemen varney dan didokumentasikan dalam metode SOAP diklinik utama Lestari tahun 2021. Hasil Penelitian Asuhan kebidanan komprehensif ini dilakukan pada Ny.R Umur 35 Tahun G3P2A0H2 Pada asuhan ANC telah memenuhi standart 10 T, INC berjalan dengan baik, kala I berlangsung selama 2 jam 10 menit, kala II berlangsung selama 9 menit, kala III berlangsung selama 10 menit, dan kala IV berlangsung selama 2 jam, tidak terdapat laserasi jalan lahir. Bayi lahir spontan, berat badan 3600 gr, panjang badan 49 cm dan dilakukan kunjungan neonatus sebanyak 3 kali. Masa nifas berjalan normal tanpa ada penyulit, dilakukan kunjungan sebanyak 4 kali dan asuhan keluarga berencana Ny.R memilih KB suntik 1 bulan sebagai metode kontrasepsinya. Dari hasil tersebut dapat disimpulkan bahwa asuhan komprehensif yang diberikan pada Ny.R sudah memenuhi standart. Saran Diharapkan untuk semua tenaga kesehatan untuk dapat mengupdate ilmu dengan mengikuti pelatihan serta seminar yang berhubungan dengan kebidanan.

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Wee, Rachel K., Hiroyuki Takamatsu, Ryoichi Murata, Jianbiao Zheng, Martin Moorhead, Naoki Takezako, Shigeki Ito, et al. "A Comparison of Minimal Residual Disease Detection Among ASO-PCR, Dd-PCR and Deep-Sequencing in Patients with Multiple Myeloma Who Underwent Autologous Stem Cell Transplantation." Blood 126, no. 23 (December 3, 2015): 1782. http://dx.doi.org/10.1182/blood.v126.23.1782.1782.

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Abstract Background: Most patients with multiple myeloma (MM) are considered to be incurable, and relapse, due to minimal residual disease (MRD), is the main cause of death among these patients. Even though allele-specific oligonucleotide real-time quantitative PCR (ASO-qPCR) of immunoglobulin heavy chain gene rearrangement has been used to assess the MRD in MM due to its excellent sensitivity and specificity, ASO-qPCR has a major limitation in its relative quantification method because it needs a reference standard curve, which is usually made with dilutions of diagnostic myeloma DNA or from plasmids containing the target IgH rearrangement gene. Recently, droplet digital PCR (ddPCR) was developed to perform reliable absolute quantification of target genes. Based on the principle of single target gene detection, the sensitivity can be increased when the larger amount of DNA is analyzed. Here we assessed the prognostic value of MRD assessment in autografts from MM patients in the autologous stem cell transplantation (ASCT) setting using ASO-qPCR, ddPCR and next-generation sequencing (NGS) approaches. Methods: Twenty-three Japanese patients with newly diagnosed MM who received various induction regimens prior to ASCT without any post-ASCT therapy were retrospectively analyzed. Median age 57 (range 39-67); males 11, females 12; ISS 1 (n=7), 2 (n=12), 3 (n=3), not assessed (n=1). 11 patients were analyzed by G-banding and FISH (t(4;14), del17p, t(14;16)) and 4 patients showed high-risk chromosomal abnormalities (t(4;14) (n=2), t(14;16) (n=1), -13 by G-banding (n=1)). All patients had achieved a very good partial response (VGPR) or better after ASCT. Analyzed samples included: (1) BM slides from 20 MM patients at diagnosis, (2) fresh/frozen BM cells from 3 MM patients at diagnosis, and (3) obtained autografts. IGH-based ASO-qPCR was performed as described previously (Methods Mol Biol 2009). ddPCR was performed by the QX200 Droplet Digital PCR system (Bio-RAD Inc.) with a total 6000 ng of genomic DNA combined with the same ASO-primers and TaqMan-probes used in the ASO-qPCR. Droplets were generated by the QX200 droplet generator. End-point PCR (40 cycles) was performed on a C1000 Touch Thermal cycler (Bio-RAD Inc). The PCR product was loaded in the QX200 droplet reader and analyzed by QuantaSoft 1.7.4 (Bio-Rad Inc). NGS-based MRD assessment was performed using the immunosequencing platform (Adaptive Biotechnologies, South San Francisco, CA) (Martinez-Lopez et al Blood 2014). Results: Nineteen patients could be analyzed by ASO-qPCR and ddPCR, while all 23 patients could be analyzed by NGS. We compared MRD results in autografts between ddPCR and NGS. We observed a high correlation between ddPCR and NGS results of MRD (r=0.82, P<0.0001). Although 19 samples were MRD negative by ASO-qPCR (MRDASO (-)), 12 samples were MRD positive by NGS (0.6-46 x 10-6, median 3.5 x 10-6) (MRDNGS (+)) and 7 samples were MRD positive by ddPCR (1.2-102 x 10-6, median 7.5 x 10-6) (MRDddPCR (+)), demonstrating the higher sensitivity of NGS (10-6 or higher) and ddPCR compared to ASO-qPCR (10-4 -10-5). Two high-risk chromosomal abnormality cases (t(4;14) (n=1), -13 by G-banding (n=1)) could achieve MRDNGS (-) in autograft. We evaluated the association of clinical outcome with MRD in autografts using ddPCR and NGS. To investigate the value of sensitive MRD detection by ddPCR and NGS, we compared PFS in 7 MRDddPCR (+) cases (Group 1) with 12 MRDddPCR (-) cases (Group 2) and 12 MRDNGS (+) cases (Group 3) with 11 MRDNGS (-) (Group 4). Group 2 and Group 4 showed significantly better PFS than Group 1 (P = 0.028) and Group 3 (P=0.033), respectively (Figure 1A and 1B). We also compared 5 MRDddPCR (-) & MRDNGS (+) cases (Group 5) with 11 MRDNGS (-) cases (Group 4). Group 4 tended to show better PFS than Group 5 (P=0.063, Figure 1C). Conclusions: In this study, we showed the prognostic value of ddPCR and NGS-based MRD assessment in autografts of patients with MM. Although the ddPCR had improved sensitivity in detecting MRD in autografts and demonstrated higher prognostic value compared with ASO-qPCR, the NGS platform showed the highest sensitivity and prognostic value among these methods. Disclosures Zheng: Adaptive Biotechnologies Corp: Employment, Equity Ownership. Moorhead:Adaptive Biotechnologies Corp: Employment, Equity Ownership. Faham:Adaptive Biotechnologies Corp.: Employment, Other: Stockholder.

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Mazhara, G. A. "Modeling of the Optimal Investment Portfolio Focused on Risk Minimization." Modern Economics 38, no. 1 (April 20, 2023): 69–75. http://dx.doi.org/10.31521/modecon.v38(2023)-11.

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Abstract. Introduction. Portfolio optimization modelling is a study aimed at determining the best way to allocate an investor's funds between securities of different companies. The study uses a number of methods and approaches, such as: multicriteria optimization methods - optimization of criteria for minimum and maximum, modeling of the optimal stock portfolio with minimal risk, to determine the best way to allocate funds that will help investors achieve maximum return while minimizing risk. Purpose. There are a lot of publicly traded companies in the modern American stock market. Having chosen the companies that may grow in the future, the problem of allocating your funds among them remains relevant. Building an optimal portfolio of securities using various economic and mathematical methods solves the problem of allocating financial resources, focusing on the desired future profit and the level of risk exposure. Results. The model for this study was built using one of the methods of multi-criteria optimization - criteria convolution, taking into account portfolio diversification and the specified constraints. The optimization is based on the "Modern Portfolio Theory" of the prominent scientist Harry Markowitz. Conclusions. As a result, we built an optimal and diversified portfolio of shares, in which each company on the list represents at least 1%. All constraints have been met and the main conditions have been fulfilled - the portfolio minimizes risk and maximizes profit. With a minimum risk of 5.39%, we expect a return of 1.75%. Such results can be obtained if we use a convolution of the criteria where the preference is given to minimizing risk - 0.7. The largest contributors to the portfolio were the following companies: T-Mobile Us Inc., McKesson Corporation, The Kroger Co., Microsoft Corporation, and Apple Inc. These companies account for a significant portion of the portfolio - 65%. Given the focus on portfolio diversification and the ratio of risk to potential return, we can say that the portfolio is efficient and can be used in practice.

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Benevolenskaya, S., I. Kudryavtsev, M. Maria, K. Serebriakova, A. Budkova, I. Grigor’eva, E. Kuvardin, et al. "AB0033 T- AND B-CELL SUBSETS AS ADDITIONAL DIAGNOSTIC TOOL FOR PRIMARY SJOGREN’S SYNDROME AND SYSTEMIC LUPUS ERYTHEMATOSUS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1151–52. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4010.

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BackgroundSystemic lupus erythematosus (SLE) and primary Sjogren’s syndrome (pSS) are chronic autoimmune diseases with complex pathogenesis. T-lymphosytes are known to be prime effectors of autoimmune diseases, while B-lymphosytes play a key role as sources of antibodies and antigen presenting cells. Considering the implications of T- and B-cells in the pathophysiology of SLE ans pSS, the assessment of their distribution in the blood could be helpful in the complex process of determining a precise diagnosis.ObjectivesThe study aimed to compare composition of peripheral blood T- and B-cell subsets and investigate their diagnostic utility in patients with SLE and pSS.MethodsThe study was performed with 37 patients suffering from SLE, 57 patients with pSS, and 49 apparently healthy volunteers (HVs). The diagnosis of SLE was performed according to the 2019 EULAR – ACR classification criteria, the diagnosis of pSS- according to the 2016 EULAR – ACR criteria. 11 patients in pSS group met the criteria for both pSS and SLE. The relative distribution and percentage of T- and B-cell subsets were evaluated by flow cytometry. T helper (Th) and cytotoxic T-cell subsets (Tcyt) were identified by using CD3, CD4, and CD8 antibodies. Regulatory T cells (Tregs) were characterized by the expression of CD3, CD4, and high IL-2R alpha chain (CD25high) levels. All peripheral blood B-cells were identified by using CD19 antibody, detection of subpopulations of B cells based on expression of IgD, CD38, CD27. The absolute and relative values of B-lymphocyte subpopulations were evaluated using three main classifications: based on IgD / CD38 expression (classification Bm1-Bm5), co-expression of IgD / CD27 and CD38 / CD27. The statistical analysis of data was performed with STATISTICA Version 12.0 Inc. Method of discriminant analysis was performed to evaluate diagnostic utility of relative values of T- and B-cell subsets.ResultsIn the discriminant model the top significance was documented while assessing the percentage of naive B-cells (Bm1, IgDdimCD38low), germinal center B-cells (Bm 3+Bm4, IgDlowCD38hi), naive B-cells (IgDdimCD27low), unswitched memory B-cells (IgDdimCD27dim), naive mature B-cells (CD27dimCD38low), transient B-cells (CD27lowCD38hi), all T-cells (CD3hi), Tregs (CD3hiCD4hiCD25hi), Tcyt (CD3hiCD8hi) and Th (CD3hiCD4hi), model percent correct was 78%, p <0,05. The discriminant function was either f1 for distinguishing HVs versus ill patients SLE and pSS (all participants are accounted) or f2 for SLE versus pSS (only participants with disease are accounted). During ROC analysis, performed for the differential diagnosis of healthy and sick patients, this discriminant model had a sensitivity of 86,5% and a specificity of 72,8%, the area under the curve (AUC) 0.94, p <0.001. Among the group of ill patients, the differential diagnosis between SLE and pSS had a sensitivity of 69,6% and specificity of 64,8%, AUC 0.87, p <0.001. Graphic representation of the discriminant analysis is performed on Figure 1. The group of patients, meeting the criteria for both pSS and SLE, is between the main groups.Figure 1.Graphic distribution of SLE, pSS and pSS+SLE patients, as well as HVs analyzed by discriminant analysis.ConclusionT- and B-cell peripheral blood subsets might provide an additional diagnostic tool for distinction SLE, pSS and HVs. Differential diagnosis between pSS and SLE is difficult, because this diseases may coexist.References[1]Guillermo Carvajal Alegria, Pierre Gazeau1, Sophie Hillion et al. Could Lymphocyte Profiling be Useful to Diagnose Systemic Autoimmune Diseases? Clinic Rev Allerg Immunol (2017) 53:219–236[2]Sandra Gofinet Pasoto, Victor Adriano de Oliveira Martins, Eloisa Bonfa. Sjögren’s syndrome and systemic lupus erythematosus: links and risks. Open Access Rheumatol. 2019; 11: 33–45.Disclosure of InterestsNone declared

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Modarres, Maryam, Maryam Abunasri, Fatemeh Alhani, and Elham Ebrahimi. "The Effectiveness of Implementing Family-Centered Empowerment Model on Irrational Thoughts of Iranian Infertile Women: A Randomized Clinical Trial." Journal of Caring Sciences 11, no. 4 (August 27, 2022): 224–31. http://dx.doi.org/10.34172/jcs.2022.22.

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Introduction: Infertility is one of the main problems of the family and is one of the factors that determine the identity and personality of Iranian infertile women. Family-centered empowerment model is a step toward increasing the self-efficacy of patients and enabling them to take responsibility of their illness. This study aimed to determine the effectiveness of applying family-centered empowerment model on irrational thoughts of Iranian infertile women. Methods: This study was a randomized clinical trial conducted on 80 infertile women and their husbands that were randomly divided into two intervention and control groups. Irrational Parenthood Cognitions questionnaire was given to the intervention and control groups to complete before and 3 months after the intervention. Data were analyzed using SPSS Statistics for Windows, version 13.0 (SPSS Inc., Chicago, IL, USA). Results: The mean (SD) of irrational thoughts’ scores in the control group before and after the study were 33.92 (5.98) and 33.20 (6.83) respectively, and in the intervention group were 34.55 (5.61) and 19.97 (3.52), respectively. The result of independent t-test showed a significant reduction in irrational thoughts of women in the intervention group after the family-centered empowerment model intervention. Conclusion: The family-centered empowerment model after three months of continuous implementation was able to effectively reduce the irrational thoughts about having children in infertile women.

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Cichocki, Frank, Bahram Valamehr, Dhifaf Sarhan, Bin Zhang, Sarah Cooley, Michael R. Verneris, Bruce R. Blazar, et al. "Development and Scale-up of a Novel GMP Method for Enrichment and Expansion of Terminally Differentiated Adaptive Natural Killer Cells (FATE-NK100) with Enhanced Anti-Tumor Function." Blood 128, no. 22 (December 2, 2016): 1225. http://dx.doi.org/10.1182/blood.v128.22.1225.1225.

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Abstract Natural killer (NK) cells are innate lymphoid cells that mediate immune responses against pathogens and cancer. Human NK cells are distinguished by the surface phenotype CD3-CD56+ and differential expression of the CD56 surface antigen defines subsets. CD56bright NK cells are presumed to be precursors of CD56dim NK cells, and terminal maturation of CD56dim NK cells is associated with acquisition of CD57. Rather than being an immunosenescence marker CD57 acquisition represents a shift toward greater effector function, including increased CD16 signaling (Fc receptor responsible for triggering antibody-dependent cellular cytotoxicity), enhanced cytotoxicity and decreased responsiveness to interleukin (IL)-12 and IL-18 stimulation. Cytomegalovirus (CMV) infection is uniquely associated with expansion of CD57+ NK cells expressing the activating receptor NKG2C.We have reported that in vivo expanded of CD57+NKG2C+ NK cells (referred to as adaptive NK cells) persist for over one year and are directly associated with reduced leukemia relapse after reduced intensity hematopoietic cell transplantation. Ex vivo expansion to enrich the subset of cells with the adaptive NK cell phenotype represents a new strategy to obtain high numbers of NK cells with enhanced effector function for use in adoptive transfer to treat cancer patients. The main challenge in enriching for CD57+ NK cells using current ex vivo expansion protocols is that IL-15, the cytokine that drives NK cell proliferation and is critical for NK cell survival preferentially expands less mature NK subsets that fail to terminally differentiate in culture. Our group has developed a novel NK cell expansion method that overcomes this barrier. Peripheral blood mononuclear cells from CMV seropositive donors are depleted of CD3+ T cells and CD19+ B cells and cultured for 7-9 days with IL-15 and a small molecule inhibitor of glycogen synthase kinase 3-beta (GSK3β), a multifunctional kinase downstream of the PI(3)K pathway. Compared to vehicle control, addition of the GSK3β inhibitor led to a substantial increase (2.2-fold ± 0.19, n=23, p<0.0001) in the CD57+ NK cell population. NK cells were highly enriched (90.9% ± 2.2) relative to the pre-cultured population post CD3/CD19 depletion (23.3% ± 2.5) (p<0.0001) Sorting experiments where purified NK cell subsets were cultured with monocytes obtained from the same donor and either vehicle or GSK3β inhibitor clearly demonstrated that the GSK3β inhibitor enhanced NK cell maturation. Importantly, NK cells expanded in the presence of the GSK3β inhibitor exhibited enhanced interferon (IFN)-γ production relative to the vehicle control in response to leukemia cells in vitro (2.15-fold ± 0.60, n=7, p=0.0002)and were superior in their ability to control tumor growth out to at least one month in a xenogeneic adoptive transfer model. To determine whether inhibition of GSK3β acted directly or indirectly on NK cells to drive terminal differentiation, purified CD56+ NK cells were cultured with or without monocytes in the presence or absence of the GSK3β inhibitor.The presence of differentiated monocytes was required for effective terminal NK cell differentiation, suggesting a monocyte-dependent, indirect effect of GSK3β (Figure 1A). Monocytes cultured with the GSK3β inhibitor exhibited markedly higher surface expression of an array of markers associated with monocyte maturation including HLA-DR, IL-15Rα, CD80, CD83 and CCR7 (Figure 1B). Thus, our data demonstrate that efficient NK cell differentiation is dependent upon the maturation state of the co-cultured monocytes.We have scaled our process to manufacture a GMP product (referred to as FATE-NK100) for clinical use. Using a representative apheresis product from a CMV seropositive donor containing 19.8 x 108 CD57+ NK cells and 1.7 x 108 CD57+NKG2C+ adaptive NK cells, we achieved 6.4-fold NK cell expansion resulting in a final GMP-grade product containing 142.2 x 108 CD57+ NK cells and 15.8 x 108 CD57+NKG2C+ adaptive NK cells.The cytotoxicity of activity of these ex vivo expanded adaptive NK cells in response to tumor targets is superior that of CD3/CD19-depleted haploidentical NK cells activated overnight with either IL-2 or IL-15 in the NK products in current clinical trials.These data have been presented to the FDA in preparation for a clinical trial of FATE-NK100 in lymphodepleted patients with advanced AML anticipated for Q1 2017. Disclosures Cichocki: Fate Therapeutics, Inc: Research Funding. Valamehr:Fate Therapeutics, Inc: Employment. Cooley:Fate Therapeutics: Research Funding. Bjordahl:Fate Therapeutics, Inc: Employment. Rezner:Fate Therapeutics, Inc: Employment, Equity Ownership. Rogers:Fate Therapeutics, Inc: Employment. Green:Fate Therapeutics, Inc: Employment. McKenna:Fate Therapeutics, Inc: Research Funding. Shoemaker:Fate Therapeutics: Employment, Equity Ownership. Wolchko:Fate Therapeutics: Employment. Miller:Fate Therapeutics: Consultancy, Research Funding; Oxis Biotech: Consultancy, Other: SAB.

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Stoddart, Angela, Anthony Fernald, Rachel Joy Bergerson, Jianghong Wang, Megan E. McNerney, Theodore Karrison, John Anastasi, et al. "Retroviral Insertional Mutagenesis In Egr1+/- mice, Haploinsufficient For a Human Del(5q) Myeloid Leukemia Gene, Develop Myeloid Neoplasms With Proviral Insertions In Genes Syntenic To Human 5q." Blood 122, no. 21 (November 15, 2013): 1275. http://dx.doi.org/10.1182/blood.v122.21.1275.1275.

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Abstract Therapy-related myeloid neoplasm (t-MN) is a distinctive clinical syndrome occurring after treatment with chemotherapy and/or radiotherapy, typically for a primary malignant disease. Loss of the long arm of chromosome 5, del(5q), is the most common recurring cytogenetic abnormality and is observed in 40% of t-MN patients, as well as 10-15% of patients with primary MDS or AML de novo. These deletions typically encompass over 70Mb [spanning 5q14-q33] and numerous genes, making the identification of relevant del(5q) genes very challenging. In previous studies, we identified a commonly deleted region within 5q and identified Egr1 as a del(5q) haploinsufficient myeloid leukemia gene. Using Egr1+/- mice, we previously showed that Egr1 cooperates with mutations, induced by the alkylating agent, ENU, to induce a myeloproliferative disorder with ineffective erythropoiesis (MPD). However, loss of Egr1 on its own was not sufficient for the development of MPD. To identify cooperating mutations in MPDs in Egr1 haploinsufficient mice, we conducted a retroviral insertional mutagenesis (RIM) screen. Egr1 WT (n=61) and Egr1+/- (n=77) neonates were injected with the MOL4070LTR retrovirus. Although the overall survival of MOL4070LTR-treated Egr1+/- and WT controls was similar, Egr1+/- mice developed MPD or AML with a shorter latency and at a higher overall frequency than WT littermate controls. Forty-six percent of WT mice developed myeloid disease versus 61% for Egr1+/- mice, with a median survival of 474 d for Egr1 WT and 389 d for Egr1+/- mice (p=0.03). We mapped the retroviral integration sites in myeloid neoplasms from 29 WT and 46 Egr1+/- mice using barcoded splinkerette PCR and Illumina high-throughput sequencing. To identify and analyze the statistically significant common insertion sites (CISs) we used the TAPDANCE software developed by A. Sarver. In total, 159 CISs were identified in WT mice and 365 CISs were identified in Egr1+/- mice. Several of these CIS-associated genes, such as Sox4, Pim1 and Myb have been previously identified in other genetic screens according to the Retroviral Tagged Cancer Gene Database (RTCGD). As the main goal of this study is to identify mutations that cooperate with Egr1 haploinsufficiency, we were particularly interested in CISs that were identified exclusively or more frequently in Egr1+/- mice with myeloid neoplasms. The TAPDANCE software automatically identifies associations between phenotypes and CISs using Fisher’s exact test with multiple testing correction. Using this analysis, we identified six CISs that were statistically associated with myeloid neoplasms in Egr1+/- mice, but not WT mice. The candidate cancer genes proximal to these proviral insertions included Evi1, Gfi1, Evi5, and Cd47. Analysis of transcript levels revealed elevated expression of Evi1, but not Gfi1, Evi5, or Cd47 in myeloid leukemias with proviral insertions proximal to these genes. Of interest was a CIS associated with Egr1+/- mice that mapped to a region of mouse chromosome 18 that is syntenic to human 5q31.2, proximal to the Dnajc18, Ecscr, Tmem173, Cxxc5 and Psd2 genes and adjacent to the commonly deleted region. Moreover, an analysis of co-occurring CISs revealed that this CIS co-occurred with a CIS that mapped to a region of mouse chromosome 13 that is syntenic to human 5q31.1, also deleted in t-MN patients and proximal to the Tifab, and H2afy genes. Of the genes in these two CISs, CXXC5, TMEM173, TIFAB, and H2AFY each show significantly decreased expression in bone marrow cells from t-MN del(5q) patients, consistent with haploinsufficiency. Identification of the relevant del(5q) genes in t-MN continues to be a challenge for developing therapeutic targets. Loss of expression of the tumor suppressor gene, EGR1, which is expressed at haploinsufficient levels in t-MN patients with a del(5q), on its own is not sufficient for the development of myeloid leukemia. Here we performed a forward genetic screen with Egr1+/- mice and have identified several candidate del(5q) genes, including CXXC5, TMEM173, TIFAB, and H2AFY, that should now be evaluated as candidate genes that cooperate with EGR1 haploinsufficiency in the pathogenesis of t-MN. The identification of aberrant pathways resulting from haploinsufficiency of EGR1 in cooperation with these del(5q) genes may potentially lead to the new therapeutic targets for t-MNs with chromosome 5 abnormalities. Disclosures: Largaespada: Discovery Genomics, Inc: Consultancy, Share Holder Other; NeoClone Biotechnology, Inc: Consultancy, Share Holder, Share Holder Other.

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Luangwilai, Thiansiri, Harvinder Sidhu, and Mark Nelson. "Understanding the factors affecting the self-heating process of compost piles: Two-dimensional analysis." ANZIAM Journal 63 (June 6, 2022): C15—C29. http://dx.doi.org/10.21914/anziamj.v63.17119.

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Industrial compost piles contain large volumes of bulk organic materials. Normally, there are two main heat generation processes—oxidation of cellulosic materials and biological activity within the compost pile. Biological heating occurs at a lower temperature range, but it may `kick-start' the oxidation reaction. Nevertheless, biological heating is desirable and is a key component in composting operations. However, there are cases when the temperature within the compost piles increases beyond the ignition temperature of cellulosic materials which can result in spontaneous ignition. This investigation considers the self-heating process that occurs in a compost pile using a two-dimensional spatially-dependent model incorporating terms that account for self-heating due to both biological and oxidative mechanisms. The variation of temperature distribution within different pile geometries is examined. References P. C. Bowes. Self heating: evaluating and controlling the hazard. Amsterdam: Elsevier Press, 1984 W. F. Brinton, Jr. E. Evans, M. L. Droffner, and R. B. Brinton. Standardized test for evaluation of compost self-heating. BioCycle 36 (1995), pp. 60–65 M. Escudey, A. Arias, J. Forster, N. Moraga, C. Zambra, and A. C. Chang. Sewage sludge self-heating and spontaneous combustion. Field, laboratory and numerical studies. High Temp. Mater. Proc. 27.5 (2008), pp. 337–346. doi: 10.1515/HTMP.2008.27.5.337 R. T. Haug. The Practical Handbook of Compost Engineering. USA: Lewis Publishers, 1993. doi: 10.1201/9780203736234 W. Hogland, T. Bramryd, and I. Persson. Physical, biological and chemical effects of unsorted fractions of industrial solid waste in waste fuel storage. Waste Manage. Res. 14.2 (1996), pp. 197–210. doi: 10.1006/wmre.1996.0019 P. F. Hudak. Spontaneous combustion of shale spoils at sanitary landfill. Waste Manage. Res. 22.6 (2002), pp. 687–688. doi: 10.1016/s0956-053x(01)00077-0 F. Kuwahara, Y. Sano, A. Nakayama, K. Nakasaki, and T. Fukazawa. Numerical modelling of a composting process with aeration. J. Porous Media 12.10 (2009), pp. 927–938. doi: 10.1615/JPorMedia.v12.i10.10 T. Luangwilai and H. S. Sidhu. Determining critical conditions for two dimensional compost piles with air flow via numerical simulations. Proceedings of the 15th Biennial Computational Techniques and Applications Conference, CTAC-2010. Ed. by W. McLean and A. J. Roberts. Vol. 52. ANZIAM J. 2011, pp. C463–C481. doi: 10.21914/anziamj.v52i0.3753 T. Luangwilai, H. S. Sidhu, and M. I. Nelson. A two dimensional, reaction-diffusion model of compost piles. Proceedings of the 10th Biennial Engineering Mathematics and Applications Conference, EMAC-2011. Ed. by M. Nelson, M. Coupland, H. Sidhu, T. Hamilton, and A. J. Roberts. Vol. 53. ANZIAM J. 2012, pp. C34–C52. doi: 10.21914/anziamj.v53i0.5083 T. Luangwilai, H. S. Sidhu, and M. I. Nelson. One-dimensional spatial model for self-heating in compost piles: Investigating effects of moisture and air flow. Food Bioprod. Process. 108 (2018), pp. 18–26. doi: 10.1016/j.fbp.2017.12.001 T. Luangwilai, H. S. Sidhu, and M. I. Nelson. Understanding effects of ambient humidity on self-heating of compost piles. CHEMECA 2018. Institution of Chemical Engineers. 2018, p. 68. url: https://search.informit.org/doi/10.3316/informit.049196748938234 T. Luangwilai, H. S. Sidhu, and M. I. Nelson. Understanding the role of moisture in the self-heating process of compost piles. CHEMECA 2012. Engineers Australia. 2012, pp. 1834–1846. url: https://search.informit.org/doi/10.3316/INFORMIT.867764346204981 T. Luangwilai, H. S. Sidhu, M. I. Nelson, and X. D. Chen. Biological self-heating of compost piles with airflow. CHEMECA 2009. Engineers Australia. 2009, pp. 2683–2692. url: https://search.informit.org/doi/10.3316/informit.799299549211365 T. Luangwilai, H. S. Sidhu, M. I. Nelson, and X. D. Chen. Modelling air flow and ambient temperature effects on the biological self-heating of compost piles. Asia-Pacific J. Chem. Eng. 5.4 (2010), pp. 609–618. doi: 10.1002/apj.438 T. Luangwilai, H. S. Sidhu, M. I. Nelson, and X. D. Chen. Modelling the effects of air flow, ambient temperature and radiative boundary conditions in compost piles. CHEMECA 2010. Engineers Australia. 2010, pp. 3585–3596. url: https://search.informit.org/doi/10.3316/informit.484992904303574 T. Luangwilai, H. S. Sidhu, M. I. Nelson, and X. D. Chen. Modelling the effects of moisture content in compost piles. CHEMECA 2011. Engineers Australia. 2011, pp. 1473–1484. url: https://search.informit.org/doi/10.3316/informit.174710980721893 T. Luangwilai, S. D. Watt, S. Fu, H. S. Sidhu, and M. I. Nelson. Modelling the effects of ambient temperature variation on self-heating process of compost piles. Engineers Australia (2019), pp. 84–96. url: https://search.informit.org/doi/10.3316/informit.689351109484953 N. O. Moraga, F. Corvalan, M. Escudey, A. Arias, and C. E. Zambra. Unsteady 2D coupled heat and mass transfer in porous media with biological and chemical heat generations. Int. J. Heat Mass Trans. 52 (2009), pp. 5841–5848. doi: 10.1016/j.ijheatmasstransfer.2009.07.027 PDE Solutions Inc. FlexPDE v 6.05. PDE Solutions Inc. Cambridge MA, 2009. url: http://www.pdesolutions.com R. Rynk. Fires at composting facilities: causes and conditions Part I. BioCycle 41.1 (2000), pp. 54–58 H. S. Sidhu, M. I. Nelson, and X. D. Chen. A simple spatial model for self-heating compost piles. Proceedings of the 13th Biennial Computational Techniques and Applications Conference, CTAC-2006. Ed. by W. Read and A. J. Roberts. Vol. 48. ANZIAM J. 2007, pp. C135–C150. doi: 10.21914/anziamj.v48i0.86

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Wang, Meng, Iulian Pruteanu, Adam D. Cohen, Alfred L. Garfall, Michael C. Milone, Lifeng Tian, Vanessa E. Gonzalez, et al. "Identification and Validation of Predictive Biomarkers to CD19- and BCMA-Specific CAR T-Cell Responses in CAR T-Cell Precursors." Blood 134, Supplement_1 (November 13, 2019): 622. http://dx.doi.org/10.1182/blood-2019-122513.

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CD19-specific chimeric antigen receptor (CAR) T cell therapies have been highly effective against B cell malignancies. We previously demonstrated that differential responses to anti-CD19 CAR T cell therapy in chronic lymphocytic leukemia (CLL) are associated with early memory T cell signature in apheresed, pre-manufacturing T-cells (CAR T-cell precursors). We tested the hypothesis that the composition of CAR-T precursor cells determines clinical efficacy in adult and pediatric Acute Lymphoblastic Leukemia (ALL), Non-Hodgkin's Lymphoma (NHL), Multiple Myeloma (MM), and CLL. Apheresed T cells were engineered to express 4-1BB plus CD3-zeta-signaling CARs targeting CD19, or B cell maturation antigen (BCMA). The same 9-day manufacturing process was used for all trials. CAR T cell kinetics were monitored using a CAR gene-specific quantitative PCR assay and standard clinical response assessments were performed. Apheresed T cells from 36 CLL, 30 adult ALL, 58 pediatric ALL, 33 NHL, and 25 MM patients were immunophenotyped by flow cytometry. The CLL cohort was used to discover phenotypically distinct subpopulations associated with the two main response groups; these associations were validated in the remaining patient cohorts. Eight CD8+ T cell populations or clusters were identified using the shared-nearest-neighbor clustering method (PMID: 31178118) in the CLL cohort. T cell subsets exhibiting naive (cluster 6) or early memory (cluster 4) features were significantly enriched in responding patients, whereas an effector memory CD8 subpopulation (cluster 2) marked the non-responding patients. Mapping these clusters onto apheresed CD8+ T cells from the other four diseases showed that cluster 4 predicted response to CAR T cell therapy in NHL and myeloma but not in adult and pediatric ALL. We also examined the expression of activation-regulated molecules including HLA-DR, Ki67, and exhaustion-related molecules PD1, CTLA4, TIM3, and LAG3. A CD27+ CD8+ population expressing low level CTLA4 but none of the activation or negative regulatory molecules was significantly enriched in responding CLL patients; this cluster validated in NHL and myeloma. A similar analysis on apheresed CD4+ T cells identified an early memory population (cluster 6) enriched in CLL responders, which expresses CCR7 and CD27 but not CD45RO, CD127, CD28, or other late memory/effector molecules. However, this population did not validate in any of the other diseases. Though not statistically significant, the CD4+ clusters with the largest effect size for enrichment in responders from NHL and myeloma trials exhibited early memory T cell features and lack of HLA-DR expression, suggesting that quiescent early memory state in CD4 may also be associated with clinical responses. A separate analysis of checkpoint inhibitory receptors and activation markers in memory CD4 T cell subsets confirmed the early memory, non-activated state of this population in CLL and was validated in myeloma but none of the other diseases. In vivo activation was a shared theme in CD4+ T cells for non-responding patients as well, though these CLL-defined CD4+ apheresed T cells clusters did not significantly validate in other diseases. In summary, our data confirm and extend our predictive biomarker profile in CLL to mature B cell and plasma cell malignancies by showing that a non-cycling, non-activated early memory CD8+ T cell population in pre-manufacturing cells was validated as a biomarker in myeloma, and NHL. We also showed that responder-associated apheresed CD4+ T cells with early memory features identified in CLL after CD19 CAR T infusions are validated in myeloma after BCMA CAR T. Thus, differentiation state and in vivo activation, and potentially exhaustion, separate response groups. Our findings inform next-generation CAR T-cell manufacturing using the populations identified herein as a starting population. Disclosures Pruteanu: Novartis: Employment. Cohen:Poseida Therapeutics, Inc.: Research Funding. Garfall:Surface Oncology: Consultancy; Novartis: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Tmunity: Research Funding. Milone:Novartis: Patents & Royalties: patents related to tisagenlecleucel (CTL019) and CART-BCMA; Novartis: Research Funding. Gill:Novartis: Research Funding; Tmunity: Research Funding; Carisma: Equity Ownership, Research Funding; Sensei: Consultancy; Aro: Consultancy; Fate: Consultancy. Frey:Novartis: Research Funding. Ruella:Nanostring: Consultancy, Speakers Bureau; Novartis: Patents & Royalties: CART for cancer; AbClon: Membership on an entity's Board of Directors or advisory committees. Lacey:Novartis: Patents & Royalties: Patents related to CAR T cell biomarkers; Tmunity: Research Funding; Novartis: Research Funding. Svoboda:Merck: Research Funding; BMS: Consultancy, Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Celgene: Research Funding; Kite: Consultancy; Seattle Genetics: Consultancy, Research Funding; Kyowa: Consultancy; AstraZeneca: Consultancy. Chong:Tessa: Consultancy; Novartis: Consultancy; Merck: Research Funding. Fraietta:LEK Consulting: Consultancy; Cabaletta: Research Funding; Tmunity: Research Funding. Davis:Cabaletta: Research Funding; Tmunity: Research Funding. Nasta:Rafael: Research Funding; Aileron: Research Funding; Takeda/Millennium: Research Funding; Incyte: Research Funding; Roche/Genentech: Research Funding; Merck: Consultancy; Atara: Research Funding; Debiopharm: Research Funding. Levine:CRC Oncology: Consultancy; Vycellix: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership; Novartis: Consultancy, Patents & Royalties, Research Funding; Cure Genetics: Consultancy; Avectas: Membership on an entity's Board of Directors or advisory committees; Brammer Bio: Membership on an entity's Board of Directors or advisory committees; Incysus: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Maude:Kite: Consultancy; Novartis: Consultancy. Schuster:Nordic Nanovector: Honoraria; Pfizer: Honoraria; AstraZeneca: Honoraria; Pharmacyclics: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Loxo Oncology: Honoraria; Merck: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors with royalties paid to Novartis, Research Funding; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Stadtmauer:Celgene: Consultancy; Tmunity: Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Abbvie: Research Funding. Grupp:Novartis: Consultancy, Research Funding; Roche: Consultancy; GSK: Consultancy; Cure Genetics: Consultancy; Humanigen: Consultancy; CBMG: Consultancy; Novartis: Research Funding; Kite: Research Funding; Servier: Research Funding; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards. Porter:Incyte: Membership on an entity's Board of Directors or advisory committees; American Board of Internal Medicine: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Glenmark Pharm: Membership on an entity's Board of Directors or advisory committees; Immunovative: Membership on an entity's Board of Directors or advisory committees; Genentech: Employment; Wiley and Sons: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. June:Novartis: Research Funding; Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties. Melenhorst:Novartis: Research Funding, Speakers Bureau; Parker Institute for Cancer Immunotherapy: Research Funding; Stand Up to Cancer: Research Funding; Incyte: Research Funding; IASO Biotherapeutics, Co: Consultancy; Simcere of America, Inc: Consultancy; Shanghai Unicar Therapy, Co: Consultancy; Colorado Clinical and Translational Sciences Institute: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau; National Institutes of Health: Research Funding.

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Afrianti, Lidia. "ASUHAN KEBIDANAN KOMPREHENSIF “NY. V” DI KLINIK UTAMA LESTARI." Jurnal Kesehatan Husada Gemilang 5, no. 2 (August 30, 2022): 35–44. http://dx.doi.org/10.61129/jkhg.v5i2.70.

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Comprehensive care is a series of ongoing and comprehensive activities so as to be able to suppress or reduce MMR and IMR. Objectives Able to provide comprehensive midwifery care services with a midwifery management approach with a varney mindset documented in the form of SOAP. The method used is the midwifery management approach with the Varney step mindset as outlined in the form of SOAP. Comprehensive midwifery care is carried out from February to April at the Main Lestari Tembilahan Clinic in 2021. Comprehensive midwifery care is carried out on Mrs. V Age 29 years G3P2A0. The results of ANC care did not meet the 10 T standard because they did not get TT immunization during pregnancy, INC care was quite good, stage 1 ± 7 hours, stage II ± 45 minutes, stage III ± 7 minutes, and stage IV 2 hours, the baby was born crying strongly, body weight 3,800 gr, body length 49 cm, neonatal visits were made 3 times. Postpartum period was normal without difficulty, postpartum visits were made 4 times and family planning care for Mrs. V chose the 3-Month Injectable KB as his contraception method. It was concluded that comprehensive care was given to Mrs. V, there is a gap, namely not getting TT immunization during pregnancy, In stage III care, namely giving metgin to the mother to prevent bleeding. It is hoped that health workers can be input for students in order to improve the quality of midwifery care services. Asuhan komprehensif merupakan serangkaian kegiatan yang berkelanjutan dan menyeluruh sehingga mampu menekan atau mengurangi AKI dan AKB.Tujuan Mampu memberikan pelayanan asuhan kebidanan komprehensif dengan pendekatan manajemen kebidanan dengan pola fikir varney didokumentasikan dalam bentuk SOAP. Metode yang digunakan yaitu pendekatan manajemen kebidanan dengan pola fikir langkah varney yang dituangkan dalam bentuk SOAP. Asuhan kebidanan komprehensif dilaksanakan bulan Februari sampai April di Klinik Utama Lestari Tembilahan Tahun 2021. Asuhan kebidanan komprehensif dilakukan pada Ny. V Umur 29 Tahun G3P2A0. Hasil asuhan ANC tidak memenuhi standart 10 T karena tidak mendapatkan imunisasi TT saat hamil, Asuhan INC cukup baik, kala 1 ± 7 jam, kala II ± 45 menit, kala III ± 7 menit, dan kala IV 2 jam, bayi lahir menangis kuat, berat badan 3.800 gr, panjang badan 49 cm, dilakukan kunjungan neonatus 3 kali. Masa nifas normal tanpa kesulitan, dilakukan kunjungan nifas 4 kali dan asuhan keluarga berencana Ny. V memilih KB Suntik 3 Bulan sebagai metode kontrasepsinya. Disimpulkan asuhan komprehensif diberikan pada Ny. V terdapat kesenjangan yaitu tidak mendapatkan imunisasi TT saat hamil, Pada asuhan kala III yaitu pemberian metergin pada ibu untuk mencegah perdarahan.Diharapan tenaga kesehatan dapat menjadi masukan bagi mahasiswa dalam rangka peningkatan mutu pelayanan asuhan kebidanan.

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Coppe, Alessandro, Emma I. Andersson, Andrea Binatti, Vanessa R. Gasparini, Sabrina Bortoluzzi, Michael J. Clemente, Marco Herling, Jaroslaw P. Maciejewski, Satu Mustjoki, and Stefania Bortoluzzi. "Subset-Specific Recurrence of Mutations and Identification of Functional Modules Provides New Clues about the Pathogenesis of Large Granular Lymphocyte Leukemia." Blood 128, no. 22 (December 2, 2016): 4117. http://dx.doi.org/10.1182/blood.v128.22.4117.4117.

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Abstract Background: Large granular lymphocyte (LGL) leukemia is a rare disease characterized by a clonal persistence of cytotoxic T cells or natural killer (NK) cells. Patients usually suffer from cytopenias and other organ-related autoimmune phenomena. These are putatively mediated by the cytotoxic LGL cells constitutively activated following an antigen-driven immune response. In addition to gain-of-function mutations in the STAT3 gene, which occur in 40-50% of patients, recurrent alterations only in the STAT5b and TNFAIP3 tumor suppressor genes have been described thus far. However, based on gene expression analyses, JAK/STAT pathway activation and deregulation of several pro-apoptotic (sphingolipid and FAS/FAS ligand) and pro-survival signaling pathways (PI3K/AKT and RAS) are common features of LGL leukemia. In this project, we aimed to characterize the genomic landscape of LGL leukemia using exome sequencing and systems genetics approaches in a patient cohort including both T- and NK-LGL cases and patients without known STAT mutations. Methods: The study cohort included 19 patients diagnosed with LGL leukemia that underwent exome sequencing analysis with matched germline controls. 13 patients had CD8+ T LGL and 3 patients CD4+ T LGL phenotype and 3 patients were NK LGL cases. From the T LGL leukemia cases CD8+ or CD4+ T cells were sorted (according to the dominant phenotype) and used as the tumor sample. In NK LGL leukemias, sorted CD3neg,CD16/56+ NK cells constituted the tumor fraction that underwent exome sequencing. Polyclonal blood lymphocytes depleted from LGL cells were used as germline controls. The exome was captured with the Nimblegen SeqCap EZ Exome Library v2.0 and the sequencing was performed with the Illumina HiSeq2000 sequencing platform. All bioinformatics steps were carried out using a custom bioinformatics pipeline. Putative somatic variants were identified by subtracting, for each patient, the ones called in the normal samples from those found in the tumor sample. After filtering by call quality and allele frequency in ExAC database, somatic variants were prioritized according to the predicted impact from the SnpEff software. Genes hit by variants putatively altering their function were finally mapped to Kegg and Reactome to generate pathway-derived meta gene networks for the identification of affected functional components. Results: 4 patients had STAT3 mutations and 4 additional cases had STAT5B mutations. In addition to STAT mutations, a number of novel somatic variants, which were recurrently mutated were discovered. These included the tumor suppressor gene FAT4, the epigenetic regulator KMT2D, as well as genes involved in the control of cell proliferation (CDC27 and ARL13B). With the systems genetics approach based on integration of pathway-derived mutated gene network topologies for identification of connected components we were able to discover affected functional modules. The main network component included key genes, which either directly interact (such as the FLT3 tyrosine kinase) or are functionally connected (such as ADCY3, ANGPT2, CD40LG, PRKCD, PTK2, KRAS, and RAB12 genes) with STAT proteins. Additional modules with putative pathogenetic relevance in LGL leukemia and mutated in the absence of STAT mutations were cell cycle control (CDC27, PLK1, CDC25B, RAD21), Notch signaling (NOTCH2, NOTCH3 and MAML3) and epigenetic regulation through histone-lysine methyltransferase activity (KMT2D and ASH1L). The comparison of various LGL leukemia subtypes revealed that the mutation burden was especially high among the CD4+ T LGL leukemia cases. Part of the genes and modules affected were shared between the different subtypes of LGL leukemia, but for example KIR2DL1 mutations were only found in CD8+ and NK LGL leukemia cases. Conclusions: With the exome sequencing and systems genetic approach we were able to discover specific gene networks, which are recurrently mutated in LGL leukemia and particularly in patients without STAT mutations. As several mutated genes are directly or indirectly connected with the STAT pathway, the data strengthen the key role of JAK/STAT signaling in LGL leukemia. The novel identified pathway modules beyond STAT networks provide intriguing insights into the pathobiology of LGL leukemia. Disclosures Maciejewski: Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Mustjoki:Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Honoraria, Research Funding.

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Kakkad, Nimisha, Naveen S. Yadav, Puja Hazari, Shweta Narwani, Kirti Somkuwar, Sakeenabi Basha, Varsha Verma, et al. "Comparative Evaluation of Tensile Bond Strength of Poly Ether Ether Ketone (PEEK) and Zirconia Copings Using Resin Cement with or without Adhesive: An In Vitro Study." Materials 15, no. 12 (June 12, 2022): 4167. http://dx.doi.org/10.3390/ma15124167.

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This in vitro research aimed to evaluate the Tensile Bond Strength of Poly Ether Ether Ketone and Zirconia copings using resin cement with or without Visio.link adhesive. From commercially available Zirconia and PEEK, blocks were machined milled using (CAD)/(CAM) to obtain 20 Zirconia and 20 PEEK copings. These specimens were sandblasted using 110 μm of alumina. The two main groups (20 Zirconia and 20 PEEK copings) were divided further into 4 subgroups, GROUP 1 (n = 10) PEEK substructure with self-adhesive resin cement without pretreatment, and GROUP 2 (n = 10) PEEK substructure with self-adhesive resin cement pre-treated with Visio.link adhesive. GROUP 3 (n = 10) Zirconia copings with self-adhesive resin cement without pretreatment. GROUP 4 (n = 10) Zirconia copings with self-adhesive resin cement pre-treated with Visio.link adhesive. Universal testing machine was used to evaluate the tensile bond strength of these copings. The results were analyzed using SPSS software Version 25.0 (SPSS Inc., Chicago, IL, USA). One-way ANOVA and independent t-test were used to compare the mean scores. Statistically significant increase was observed in Tensile Bond Strength of samples when Visio.link adhesive was used. Tensile Bond Strength of PEEK copings and Zirconia copings with Visio.link adhesive is considerably greater than PEEK copings and Zirconia copings without adhesive. The mean Tensile Bond Strength of Zirconia (with or without adhesive) is less as compared to Tensile Bond Strength of PEEK (with or without adhesive), but the difference is not statistically significant.

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Al-keilani, Maha S., and Dua H. Alsmadi. "THE HDAC INHIBITOR SODIUM PHENYLBUTYRATE ENHANCES THE CYTOTOXICITY INDUCED BY 5-FLUOROURACIL, OXALIPLATIN, AND IRINOTECAN IN COLORECTAL CANCER CELL LINES." International Journal of Pharmacy and Pharmaceutical Sciences 10, no. 1 (January 1, 2018): 155. http://dx.doi.org/10.22159/ijpps.2018v10i1.22947.

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Objective: The main objective of this study was to evaluate the ability of sodium phenylbutyrate (NaPB) to enhance the cytotoxicity of 5-fluorouracil, oxaliplatin, and irinotecan against colorectal cancer cell lines expressing wild-type and mutant p53.Methods: The antiproliferative effect of NaPB alone or in combination with 5-fluorouracil, oxaliplatin, or irinotecan in HCT-116 and HT-29 colorectal cancer cell lines was investigated using the MTT cell proliferation assay. IC50 values were calculated using Compusyn Software 1.0 (Combosyn Inc.). Synergy values (R) were calculated using the ratio of IC50 of each primary drug alone divided by combination IC50s. For each two pairs of experiments, student’s t-test was used for analysis. In combination studies, one-way ANOVA test; Tukey post-hoc testing was performed using R 3.3.2 software. P-value<0.05 was considered significant.Results: NaPB inhibited the growth of HCT-116 and HT-29 cell lines in a dose-dependent manner (IC50s 4.7 mmol, and 10.1 mmol, respectively). HT-29 cell lines (mutant p53) were more sensitive to NaPB at low concentrations (<4 mmol). Moreover, the addition of NaPB to HCT-116 and HT-29 with 5-fluorouracil, oxaliplatin, or irinotecan synergistically induced the antiproliferative effect (R>1.6, p-value<0.05).Conclusion: NaPB enhanced the cytotoxicity of conventional chemotherapy against colorectal cancer cell lines harboring wild-type or mutant p53. Thus NaPB is a promising potential adjuvant chemotherapy in colorectal cancer.

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Byčenkienė, Steigvilė, Touqeer Gill, Abdullah Khan, Audrė Kalinauskaitė, Vidmantas Ulevicius, and Kristina Plauškaitė. "Estimation of Carbonaceous Aerosol Sources under Extremely Cold Weather Conditions in an Urban Environment." Atmosphere 14, no. 2 (February 4, 2023): 310. http://dx.doi.org/10.3390/atmos14020310.

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The present study investigated the characteristics of carbonaceous species in an urban background site. Real-time measurements of inorganic (sulfate, nitrate, ammonium, chloride, and black carbon [BC]) and organic submicron aerosols (OA) were carried out at the urban background site of Vilnius, Lithuania, during January–February 2014. An aerosol chemical speciation monitor (ACSM, Aerodyne Research Inc., Billerica, MA, USA) and co-located 7-λ aethalometer (AE-31, Magee Scientific, Berkeley, CA, USA) were used to analyze the chemical compositions, sources, and extinction characteristics of the PM1. Extremely contrasting meteorological conditions were observed during the studied period due to the transition from moderately cold (~2 °C) conditions to extremely cold conditions with a lowest temperature of −25 °C; therefore, three investigation episodes were considered. The identified periods corresponded to the transition time from the moderately cold to the extremely cold winter period, which was traced by the change in the average temperature for the study days of 1–13 January, with T = −5 °C and RH = 92%, in contrast to the period of 14–31 January, with T = −14 °C and RH = 74%, and the very short third period of 1–3 February, with T = −8 °C and RH = 35%. On average, organics accounted for the major part (53%) of the non-refractory submicron aerosols (NR-PM1), followed by nitrate (18%) and sulfate (9%). The source apportionment results showed the five most common OA components, such as traffic and heating, to be related to hydrocarbon-like organic aerosols (HOAtraffic and HOAheating, respectively), biomass-burning organic aerosols (BBOA), local organic aerosol (LOA), and secondary organic aerosol (SOA). Traffic emissions contributed 53% and biomass burning 47% to the BC concentration level. The highest BC and OA concentrations were, on average, associated with air masses originating from the southwest and east–southeast. Furthermore, the results of the PSCF and CWT methods indicated the main source regions that contributed the most to the BC concentration in Vilnius to be the following: central–southwestern and northeastern Poland, northwestern–southwestern and eastern Belarus, northwestern Ukraine, and western Russia. However, the potential sources of OA were widely distributed.

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Ferrer, Gerardo, Byeongho Jung, Aslam Rukhsana, Pui Yan Chiu, Andrea Nicola Mazzarello, Florenca Palacios, Shih-Shih Chen, et al. "Ibrutinib Treatment Reduces Myeloid Derived Suppressor Cell Numbers and Function in Chronic Lymphocytic Leukemia." Blood 132, Supplement 1 (November 29, 2018): 239. http://dx.doi.org/10.1182/blood-2018-99-114799.

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Abstract In chronic lymphocytic leukemia (CLL), bidirectional interactions of leukemic B cells with components of a complex, yet incompletely defined tumor microenvironment (TME) are critical for leukemic cell survival and proliferation. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, blocks signals that are crucial for survival of CLL cells which are delivered by the B cell receptor (BCR) and certain other receptors. However since BTK and its family members are expressed by other cell types, ibrutinib can also affect non-leukemic cells, thereby altering their function. Here, we focused on understanding how myeloid-derived suppressor cells (MDSCs), a non-leukemic cell type within the TME, and their main target, T cells, are affected by ibrutinib therapy. Using blood cells from a set of 20 previously untreated patients receiving ibrutinib, we analyzed circulating MDSCs and their subsets 15 days before and 1, 2 and 3 months after treatment initiation. As anticipated, at the first month time point the absolute CLL B-cell count increased significantly (P=0.024), followed by a progressive reduction at consecutive time points (P<0.001). In contrast, absolute MDSC numbers slowly and continuously decreased over time, achieving a significant reduction by the third month (P=0.009). When dividing MDSCs into their cellular subsets, the same pattern was observed for granulocyte-like MDSCs (gMDSCs) (P=0.005) but not for monocyte-like MDSCs (mMDSCs); for the latter an insignificant change was found. Of note, when comparing the changes of MDSC and gMDSC numbers to that of CLL B-cell counts, MDSC and gMDSC neared statistical significance at month one (P<0.1) and achieved significance at the second month (MDSCs: P<0.001; gMDSCs: P=0.033). We also observed differences in T-cell subpopulations shortly after ibrutinib treatment began. T cell counts increased significantly at the second month compared to pre-treatment (P=0.024); this was the case for both CD4+ and CD8+ cells (P = 0.022 and 0.010, respectively). In addition, CD8+ T cells maintained significance through the third month (P = 0.033). When exploring T cell subsets defined by cytokine production, we observed a spike at the second month of CD4+IL17F+ and of CD8+IL17F+, CD8+IL17A+ and CD8+FoxP3+ T cells. However, by the 3rd month, only the IFNγ-producing subset of CD4+ and CD8+ T cells were significantly higher (P = 0.049 and 0.042, respectively). Next we analyzed the function of gMDSCs and mMDSCs in the presence of ibrutinib in vitro, addressing the two main effects of these cells on T lymphocytes: suppression of T-cell proliferation and modulation of T-cell differentiation. Specifically, ibrutinib did not directly reduce T-cell expansion in the absence of MDSCs and did not alter the effect of CLL gMDSCs nor mMDSCs on T-cell proliferation, since the significant reduction induced by gMDSCs (P=0.047) and the insignificant, variable effect of mMDSCs were unchanged by the drug. However when we analyzed the influence of gMDSCs, mMDSCs and monocytes on naïve CD4+ T-cell differentiation in the presence or absence of ibrutinib, to our surprise the only T cell subpopulation directly compromised by ibrutinib was the Th1/IFNγ-producing subset. This was opposite that observed in co-cultures with gMDSCs, mMDSCs or normal monocytes in the presence of ibrutinib where Th1 cells expanded significantly (P= 0.021, 0.010, and 0.005, respectively). In the latter co-cultures not containing ibrutinib, more IL-4-producing (Th2) cells were found. Additionally, ibrutinib had a positive effect on IL-22+ (Th22) and FoxP3+ (Treg) cell numbers in the presence of MDSCs and monocytes. In summary, opposite to what we observed for CLL B and T cells, MDSC counts fell progressively after initiating ibrutinib therapy, possibly due to a direct effect of ibrutinib on BTK in MDSCs or an indirect effect mediated by diminishing signals from CLL B cells that would normally be delivered after BCR engagement. Ibrutinib did not directly alter the T cell suppressive ability of MDSCs, but it did skew T-cell differentiation to Th1 cells when MDSCs were present, in line with our finding higher Th1 cells in the blood after 3 months of treatment. Thus over time, ibrutinib shifts the CLL TME from an immunosuppressive to a more immune effective one. Disclosures Chen: Beigene: Research Funding; Verastem: Research Funding; Pharmacyclics: Research Funding. Barrientos:Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy. Kolitz:Magellan Health: Consultancy, Honoraria. Rai:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees. Chiorazzi:Janssen, Inc: Consultancy; AR Pharma: Equity Ownership.

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Lopez, Joaquin Martinez, Margarita Sanchez Beato, Martinez Nerea, Ignacio Varela, Sophia Derdak, Inmaculada Rapado, Sergi Beltran, et al. "Characterization of Subclonal Changes Along Progression in Multiple Myeloma." Blood 120, no. 21 (November 16, 2012): 2924. http://dx.doi.org/10.1182/blood.v120.21.2924.2924.

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Abstract Abstract 2924 Background: Clonal composition and clone dynamic changes of neoplasms are a controversial issue, whose investigation is now facilitated by the development of massive parallel sequencing. Here we have analyzed the changes in the mutational spectrum associated with progression, treatment response and relapse in a multiple myeloma patient. We sequenced exomes for the primary quiescent-tumor, the progression and the relapsed samples. M&M: Patient and samples description Samples from asymptomatic, progression and relapse phases were compared by FISH and Whole exome massive parallel sequencing in a multiple myeloma patient carrying the t(4;14)(p16.3;q32) alteration. At relapse the cytogenetic study identified the presence of two major clones, 13q14 deletion and t(4;14)(p16.3;q32) in the 60% of the cells, and 17p13 deletion in the 12% of the cells. Whole exome sequencing was performed at CNAG (Barcelona, Spain) following standard protocols for high-throughput paired-end 76pb sequencing on the Illumina HiSeq2000 instruments (Illumina Inc., San Diego, CA). The variant calling was performed using an in house written software calling potential mutations showing a minimum independent multi-aligner evidence. Results: We performed whole exome sequencing on 3 tumor samples from the same patient: the first one at the time of diagnosis correspond to bone marrow infiltrated by 7% of plasma cells. The two additional samples, at progression and relapse, were done in CD138+ bone marrow cells, at this moment the percentage of infiltration was of 84% and 64% respectively. The germinal DNA from the same patient was used as reference. The mean coverage obtained for the four samples were 93x, with around 85% of bases with at least 20X coverage. After filtering, a total of 104 single nucleotide variations (SNV) were identified, some of them in more than one sample. The variations were classified into silent (25), missense (71), nonsense (6), and essential splice (2), according to their potential functional effect. In addition to t(4;14) and del13q14, progression and relapse samples shared 36 common SNVs. There were also some variants gained and/or loss in the different time points, suggesting the presence of at least five different clones, independent but related in their evolution. The two main clones were present in progression and relapse samples, but the ratio of the mutant alleles decreased in parallel to the decrement in the percentage of cells carrying on the described cytogenetic alterations Conclusions: There is a coupling between the cytogenetic and tumor sequence changes indicating that tumor at progression was composed by a dominant clone, together with multiple minor clones. Relapse after treatment was associated with multiple changes in the clone dynamics, progressive reduction of the main clone, emerging of new subclones and lost of minor clones. Dynamic changes along progression could be facilitated/induced by the therapy received. Disclosures: No relevant conflicts of interest to declare.

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Wolohan, John T. "The Sport Lawyer’s Guide to Legal PeriodicalsWritten by Glenn Wilde M. Wong and T. Jesse Published 1994 by William S. Hein & Co., Inc., 1285 Main Street, Buffalo, New York, 14209-1987 (678 pages, $75.00)." Journal of Legal Aspects of Sport 4, no. 2 (August 1994): 72–73. http://dx.doi.org/10.1123/jlas.4.2.72.

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Ashgi, Findy, and Adi Pancoro. "Analisis Single Nucleotide Polymorphism Gen Faktor Transkripsi MYB dalam Biosintesis Antosianin Kulit Buah Mangga (Analysis of Single Nucleotide Polymorphism Gene Transcription Factor MYB in Mango Skin Anthocyanin Biosynthesis)." Jurnal Hortikultura 31, no. 1 (December 27, 2021): 1. http://dx.doi.org/10.21082/jhort.v31n1.2021.p1-10.

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Perkembangan pasar bebas berdampak terhadap selera produk-produk pertanian, seperti warna buah mangga. Antosianin merupakan senyawa yang bertanggung jawab dalam menginduksi warna pada buah. Senyawa ini diregulasi oleh gen faktor transkripsi MYB. Mutasi Single Nucleotide Polymorphism (SNP) daerah ekson gen MYB dapat mengubah asam amino yang memengaruhi aktivitas enzim yang mengakibatkan munculnya variasi fenotipe warna buah di antara individu-individu dalam spesies yang sama. Penelitian ini bertujuan menemukan SNP pada gen MYB dari kulit buah mangga varietas Arum Manis, Gedong Gincu, Manalagi, Golek, dan Cengkir. Penelitian dilakukan dengan tiga tahap utama, yaitu isolasi DNA kulit buah mangga, Polymerase Chain Reaction (PCR), dan proses sekuensing oleh Macrogen Inc. (Singapore). Hasil multiple sequence alignment asam amino gen faktor transkripsi MYB menunjukkan adanya perbedaan basa yang mengakibatkan munculnya stop codon dari SNP 337 A→T dan SNP 338 A→G yang memengaruhi fenotipe warna kulit buah. SNP yang memunculkan stop codon dapat direkomendasikan untuk membedakan fenotipe pigmentasi antosianin pada kulit buah mangga Gedong Gincu yang bewarna merah dengan warna kulit buah mangga yang lainnya. Adanya SNP menyebabkan prematur stop codon yang terjadi pada gen faktor transkripsi MYB dan diduga berpengaruh terhadap pigmentasi antosianin.KeywordsMangga; SNP; Faktor transkripsi; Antosianin; MYBAbstract The development of free markets gives an impact on appetite for agricultural products, such as the color of mangoes fruit skin. Anthocyanins are compounds that are responsible for giving color to the fruit skin, these compounds are regulated by the MYB transcription factor genes. Single Nucleotide Polymorphism (SNP) mutations in the exon region of the MYB gene can change amino acids that affect enzyme activity, resulting in phenotypic variations in fruit color among individuals in the same species. This study aims to find SNP in MYB genes from mango peel varieties Arum Manis, Gedong Gincu, Manalagi, Golek, and Cengkir. The research was conducted in three main stages, namely isolation of mango peel DNA, Polymerase Chain Reaction (PCR), and sequencing process by Macrogen Inc (Singapore). The results of multiple sequence alignment of the amino acid MYB transcription factor genes showed a base difference which resulted in the appearance of a stop codon from SNP 337 A→T and SNP 338 A→G which affected the phenotype of fruit skin color. The SNP that raises the stop codon can be recommended to differentiate the anthocyanin pigmentation phenotype on the red skin of the mango Gedong Gincu from the skin color of other mangoes. The presence of SNP causes premature stop codon that occurs in the MYB transcription factor gene and is thought to have an effect on anthocyanin pigmentation.

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Patay, Bradley A., Andrew Carson, Timothy J. Martins, Sylvia Chien, Mary-Elizabeth M. Percival, Taylor Sekizaki, Cody Hammer, and Pamela S. Becker. "Precision Medicine Assays Detect Novel Targetable FLT3 Fusions Amenable to Therapeutic Intervention in a Patient with Refractory Acute Myeloid Leukemia." Blood 128, no. 22 (December 2, 2016): 5170. http://dx.doi.org/10.1182/blood.v128.22.5170.5170.

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Abstract Context: The 5-year survival rate for acute myeloid leukemia (AML) is 26.6%. The prognosis of patients with adverse events such as older age or unfavorable risk cytogenetics remains poor, even for those who undergo allogeneic hematopoietic cell transplant. AML is a heterogeneous disease and novel N-of-1 clinical trial designs may offer benefit to individuals compared to conventional clinical trials by offering improved utilization of investigational chemotherapy regimens. Precision medicine based assays that reveal a deeper understanding of the cancer biology and potential for novel therapeutics may improve survival in the future. Objective: The goal of the clinical trial on which this patient was enrolled, Individualized Treatment for Relapsed/Refractory Acute Leukemia Based on Chemosensitivity and Genomics/Gene Expression Data (ClinicalTrials.gov Identifier:NCT01872819) was to determine feasibility of a study that utilized results of comprehensive mutation analysis and an in vitrohigh throughput functional assay to choose treatment for individual patients with refractory AML. Feasibility was defined as initiating chosen treatment within 21 days. A secondary objective was to achieve a response (cytoreduction or at least partial response) greater than that expected for comparable refractory patient populations with other salvage regimens. Design, Setting, and Patient: A single center enrolled individuals who had failed at least 2 inductions at initial diagnosis or >1 salvage regimen for relapsed AML. Patients could receive any FDA approved drug or combination regimen based on molecular analysis and high throughput drug sensitivity assay. A 58 year old female was enrolled into this protocol with MECOM (EVI1) rearranged, Monosomy 7 refractory AML. Methods and Main Outcome Measures: The patient had various assays performed on her samples, including next generation sequencing and a high throughput in vitro assay that analyzed enriched blast samples for sensitivity to 150 drugs or drug combinations. MyAML™, a next generation sequencing panel, analyzed 194 genes including breakpoint hotspot loci with long paired end sequencing and high depth that optimized detection of large insertion and deletions and other structural variants found in AML at low variant allele frequency. Results: The MyAML assay detected multiple variants including: NRAS:c.38G>A; p.Gly13Asp VAF = 100%, RUNX1:c.494_495ins; p.165_R166ins VAF = 42%, WT1:c.1149_1150ins; p.E384Pfs*5 VAF=38%. Fusions were also detected: t(13;17)(q12.2;q11.2), t(8;13)(q21.13;q12.2), and t(9;12)(q32;p13.2) which involved FLT3 novel fusions. FLT3 internal tandem duplications (ITD) or tyrosine kinase domain (TKD) variants were not detected. The assay also detected the Monosomy 7 and confirmed the t(2;3) as a THADA-MECOM (EVI1) fusion to the nucleotide breakpoint. These variants involved activated signaling, myeloid transcription factor and DNA demethylation pathways. The high throughput drug sensitivity assay identified sensitivity to kinase inhibitors such as the MEK inhibitor selumetinib (IC50 8.1 X 10e-9 M), Flt3 inhibitor staurosporine (IC50 1.4 X 10e-8 M) and Abl kinase inhibitor ponatinib (IC50 2.7 X 10e-8 M). Insurance coverage for these agents was not able to be obtained as this indication would be considered off label. However, based on the FLT3 fusion we identified using MyAML, we decided to treat the patient with the tyrosine kinase inhibitor sorafenib that we were able to obtain through a patient assistance program. This novel case is the first demonstration of a FLT3 fusion detection with a drug sensitivity assay suggesting that kinase inhibitors with multiple targets might be suitable for this type of variant. Conclusion: Specialized assays designed to identify clonal and subclonal architecture of genes associated with specific diseases can reveal variants that present therapeutic options not currently utilized for high risk patients, suggesting broader use of this approach could improve current clinical outcomes. Disclosures Patay: Invivoscribe, Inc: Consultancy. Carson:Invivoscribe, Inc: Employment. Becker:GlycoMimetics: Research Funding.

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Cornillon, Jérôme, Lena Absi, Aurélie Bourmaud, Micha Srour, Fabien Tinquaut, Emmanuelle Tavernier, and Denis Guyotat. "Early Mixed T-Cell Chimerism After Allogeneic Hematopoietic Stem Cells Transplantation Is Highly Predictive For Progression Free Survival." Blood 122, no. 21 (November 15, 2013): 2079. http://dx.doi.org/10.1182/blood.v122.21.2079.2079.

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Abstract Introduction Chimerism analysis after allogeneic hematopoietic stem cells transplantation (HSCT) allows documentation and understanding of important clinical events such as engraftment, graft failure, and/or relapse. Few data are available on whether T-cell chimerism might be more informative than global chimerism. In this study, we focused on selective CD3+ T-cell chimerism and its interest to predict events after allogeneic HSCT. Methods This is a single center retrospective study. Only patients with a survival more than 3 months were included. Information concerning donors, recipients, conditioning regimen, graft harvesting and follow-up were collected in our center using prospective forms from Promise database. Evaluation of T-cell chimerism was performed on CD3+ blood cells after immunomagnetic sorting, by PCR-STR (short-tandem repeats) multiplex technique using 15 different markers. Analysis of the tandem repeat polymorphism was performed by sequencer and Genscan software (Applied Biosystem Inc.). Chimerism was evaluated in 2 ways: positive or negative, and % of recipient. An analysis with repeated measures was also performed to determine the utility of a positive measure of chimerism, independently of the date of sample after allograft, to predict a relapse. Results Between January 2006 and December 2011, 148 patients (pts) were admitted in our unit for allogeneic HSCT (32% with myeloablative conditioning and 68% with reduced conditioning). Median age was 54.3 years, 59 male, 89 female. Diagnosis included AML/MDS (n=77), ALL (n=23), Aplastic anemia (n=4), lymphoma and CLL (n=23), myeloma (n= 8) and myeloproliferative disorders (n=13). The donor was matched sibling (n=51), matched unrelated (10/10) (n=74) or mismatched unrelated (9/10)(n=23). Graft source was PBSC (n=97), BM (n=33) or CB (n=18). At transplant, 108 pts (73%) were in complete remission, 19 (13%) presented partial response and 21 (14%) have progressive disease. At time of analysis, median follow-up was 1.75 years. Median overall Survival (OS) was estimated at 2 years. Forty-seven pts (32%) presented relapse. Seventy pts (47%) are still alive. Main causes of death were HSCT related (n=38), relapse or progression (n=33) and other (n=7). Acute GVHD grade II-IV incidence was 32% (13.5% grade III-IV) and 58% for chronic GVHD. At day +30, 56% of pts presented a mixed T-cell chimerism with 36 (24.3%) pts with a chimerism higher than 25% recipient. At day +90, 41% have remained positive. For NRM, aGVHD and age were the only prognostic parameters statistically identified. For PFS, only T-cell chimerism with a positive 25% cut-off at D+30 was identified as a prognostic factor (p=.0017, HR(IC 95%) 2.52(1.39; 4.58). PFS was not reached if T-cell chimerism was inferior to 25% at D+30 versus 1.35 years (figure 1). The results were concordant in a subgroup analysis performed according to the myeloid or lymphoid neoplasia status. Otherwise, cGVHD incidence was higher if T-cell chimerism was less than 25% at D+30 (70% vs. 18%). Finally, the analysis with repeated measures confirmed that positive T-cell chimerism is strongly correlated with relapse (p=.001; HR (CI95%) 90.18(30.11; 270.13)). Conclusion After allogeneic HSCT, mixed T-cell chimerism higher than 25% at day +30 is strongly correlated with poor PFS, independently of source of cells, donors, intensity of conditioning, diagnosis or disease status at transplant. Considering this high-risk population, early intervention should probably be considered. Disclosures: No relevant conflicts of interest to declare.

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Chontos, Ashley, Joseph M. Akana Murphy, Mason G. MacDougall, Tara Fetherolf, Judah Van Zandt, Ryan A. Rubenzahl, Corey Beard, et al. "The TESS-Keck Survey: ^* Science Goals and Target Selection." Astronomical Journal 163, no. 6 (May 30, 2022): 297. http://dx.doi.org/10.3847/1538-3881/ac6266.

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Abstract The Kepler and TESS missions have demonstrated that planets are ubiquitous. However, the success of these missions heavily depends on ground-based radial velocity (RV) surveys, which combined with transit photometry can yield bulk densities and orbital properties. While most Kepler host stars are too faint for detailed follow-up observations, TESS is detecting planets orbiting nearby bright stars that are more amenable to RV characterization. Here, we introduce the TESS-Keck Survey (TKS), an RV program using ∼100 nights on Keck/HIRES to study exoplanets identified by TESS. The primary survey aims are investigating the link between stellar properties and the compositions of small planets; studying how the diversity of system architectures depends on dynamical configurations or planet multiplicity; identifying prime candidates for atmospheric studies with JWST; and understanding the role of stellar evolution in shaping planetary systems. We present a fully automated target selection algorithm, which yielded 103 planets in 86 systems for the final TKS sample. Most TKS hosts are inactive, solar-like, main-sequence stars (4500 K ≤ T eff <6000 K) at a wide range of metallicities. The selected TKS sample contains 71 small planets (R p ≤ 4 R ⊕), 11 systems with multiple transiting candidates, six sub-day-period planets and three planets that are in or near the habitable zone (S inc ≤ 10 S ⊕) of their host star. The target selection described here will facilitate the comparison of measured planet masses, densities, and eccentricities to predictions from planet population models. Our target selection software is publicly available and can be adapted for any survey that requires a balance of multiple science interests within a given telescope allocation.

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Radysh, I. I., L. S. Kruglova, V. V. Boyarintsev, and N. V. Vasilchenko. "Efficacy of Physical Rehabilitation after Anterior Cruciate Ligament Reconstruction: Non-Randomized Trial." Kuban Scientific Medical Bulletin 30, no. 2 (February 27, 2023): 35–43. http://dx.doi.org/10.25207/1608-6228-2023-30-2-35-43.

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Background. Anterior cruciate ligament rupture is the most common knee joint injury, especially in young people with a healthy and active lifestyle. The concept of quality of life has been dynamically developing. The scope of its application is expanding in various fields of medicine to provide a comprehensive assessment of treatment and rehabilitation efficacy.Objective — to assess the feasibility of complex individual physical rehabilitation of patients after early and delayed arthroscopic reconstruction of the anterior cruciate ligament (ACL).Methods. Open simple non-randomized trial enrolled 834 patients with the anterior cruciate ligament rupture of the knee joint. In the first group (431 patients), ACL plastic surgery was performed in the early stages — between weeks 2 and 6. In the second group (403 patients), ACL reconstruction was performed in the later stages — from week 7 to 1 year, inclusive. Each group was divided into two subgroups — the main one, in which restorative treatment and comprehensive individual rehabilitation were carried out, and the control group, with rehabilitation treatment in accordance with the standards of postoperative treatment. The study was conducted in Traumatology, Orthopedics and Medical Rehabilitation Unit of Clinical Hospital No. 1. Patients were included in the trial from 2016 to 2021. The follow-up period for each patient was one year. Statistical data processing was performed by means of Statistica 12.0 (StatSoft, Inc., USA). Independent samples were compared using non-parametric criteria: Mann — Whitney U-test and Wilcoxon T-test.Results. No statistical differences were found in the distribution according to gender, age and body mass index. A comparative analysis of scale medians of Medical Outcomes Study 36Item Short-Form Health Survey (MOSSF-36), conducted in patients before surgery, revealed no statistically significant differences ( p>0.05) between the main and control subgroups in both groups. Analyzing medians before ACL reconstruction showed a significant decrease in comparison with population studies ( p < 0.0001, Mann — Whitney U-test). The analysis of physical and mental component summaries via MOSSF-36 revealed statistically significant differences in the effectiveness of treatment of patients in 1 year after ACL plastic surgery and complex individual rehabilitation. Thus, in the main subgroups, the values of treatment efficacy medians were significantly higher than in the control ones, regardless of the timing of ACL plastic surgery ( p < 0.001, Mann — Whitney U-test). The results testify to higher median efficacy values in patients of the main subgroup of group 1 than in other subgroups ( p < 0.001, Mann — Whitney U-test). The study of correlative relationships demonstrated a stronger relationship between the medians of physical and mental component summaries in the main subgroup of the first group (correlation coefficient = 0.76), if compared to the main subgroup of the second group (coefficient = 0.67).Conclusion. The study testified to the treatment efficacy proved using the scales of physical and mental component summaries. They demonstrated more significant treatment efficacy one year after arthroscopic ACL reconstruction and individual rehabilitation in the main subgroup of group 1 than in the other subgroups.

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Inomata, Takenori, Masahiro Nakamura, Masao Iwagami, Akie Midorikawa-Inomata, Jaemyoung Sung, Keiichi Fujimoto, Yuichi Okumura, et al. "Stratification of Individual Symptoms of Contact Lens–Associated Dry Eye Using the iPhone App DryEyeRhythm: Crowdsourced Cross-Sectional Study." Journal of Medical Internet Research 22, no. 6 (June 26, 2020): e18996. http://dx.doi.org/10.2196/18996.

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Background Discontinuation of contact lens use is mainly caused by contact lens–associated dry eye. It is crucial to delineate contact lens–associated dry eye's multifaceted nature to tailor treatment to each patient’s individual needs for future personalized medicine. Objective This paper aims to quantify and stratify individual subjective symptoms of contact lens–associated dry eye and clarify its risk factors for future personalized medicine using the smartphone app DryEyeRhythm (Juntendo University). Methods This cross-sectional study included iPhone (Apple Inc) users in Japan who downloaded DryEyeRhythm. DryEyeRhythm was used to collect medical big data related to contact lens–associated dry eye between November 2016 and January 2018. The main outcome measure was the incidence of contact lens–associated dry eye. Univariate and multivariate adjusted odds ratios of risk factors for contact lens–associated dry eye were determined by logistic regression analyses. The t-distributed Stochastic Neighbor Embedding algorithm was used to depict the stratification of subjective symptoms of contact lens–associated dry eye. Results The records of 4454 individuals (median age 27.9 years, SD 12.6), including 2972 female participants (66.73%), who completed all surveys were included in this study. Among the included participants, 1844 (41.40%) were using contact lenses, and among those who used contact lenses, 1447 (78.47%) had contact lens–associated dry eye. Multivariate adjusted odds ratios of risk factors for contact lens–associated dry eye were as follows: younger age, 0.98 (95% CI 0.96-0.99); female sex, 1.53 (95% CI 1.05-2.24); hay fever, 1.38 (95% CI 1.10-1.74); mental illness other than depression or schizophrenia, 2.51 (95% CI 1.13-5.57); past diagnosis of dry eye, 2.21 (95% CI 1.63-2.99); extended screen exposure time >8 hours, 1.61 (95% CI 1.13-2.28); and smoking, 2.07 (95% CI 1.49-2.88). The t-distributed Stochastic Neighbor Embedding analysis visualized and stratified 14 groups based on the subjective symptoms of contact lens–associated dry eye. Conclusions This study identified and stratified individuals with contact lens–associated dry eye and its risk factors. Data on subjective symptoms of contact lens–associated dry eye could be used for prospective prevention of contact lens–associated dry eye progression.

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