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1
Zeisberg, Michael. "Fibroblasts emerge via epithelial-mesenchymal transition in chronic kidney fibrosis." Frontiers in Bioscience Volume, no. 13 (2008): 6991. http://dx.doi.org/10.2741/3204.
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Heo, J., and T. Park. "Abstract # 3204 Neuroprotective effects of TNF-alpha inhibitor on rat hippocampal organotypic slice cultures treated with the 1-42 beta–amyloid." Brain, Behavior, and Immunity 81 (October 2019): 1. http://dx.doi.org/10.1016/j.bbi.2019.08.011.
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Cano Garcia, L., S. Manrique Arija, F. Godoy-Navarrete, A. M. Cabezas-Lucena, G. Diaz-Cordobes, and N. Mena-Vázquez. "AB0865-HPR FREQUENCY OF DEPRESSION IN SYSTEMIC LUPUS ERYTHEMATOSUS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1456.2–1456. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3204.
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Objectives:Cross-sectional observational study of a series of SLE patients selected from the Rheumatology consultations.Methods:age ≥18 years with SLE (ACR 1997 criteria) capable of understanding and willing to take the questionnaires. Protocol: All patients with SLE undergoing follow-up in the rheumatology clinic are recorded in a database. A telephone call was made to all the patients included in the database and those patients who responded to the call and gave their verbal consent for the collection of data from their clinical history and completed the Goldberg questionnaire were finally included. The nurse was in charge of explaining the questionnaire to the patients. Variables: the main outcome variable was depression assessed by Goldberg (≥2 depression) and other variables were: previous diagnosis of depression, Charlson index, polypharmacy, psychiatric medication, referral to mental health or primary care, SLEDAI and SLICC. Descriptive, bivariate statistical analysis and multivariate logistic regression analysis (VD: Goldberg depression).Results:89 patients with SLE were included (95.5% women, mean age 49.44 ± 13.2 years and 18.28 ± 9.19 years of disease). The mean (SD) of the Goldberg scale in all the patients was 3.2 ± 2.9 and a total of 45 patients (50.4%) met criteria of depression according to Goldberg’s screening, of which 19 (21.3%) patients had a previous diagnosis of depression. Only 9 patients (10.1%) had had a mental health follow-up and 22 patients (24.7%) were being followed by the family doctor. A total of 87 patients (97.8%) presented polypharmacy: severe polypharmacy 59 (66.3%) and 33 (37.1%) psychiatric medication. The most used psychiatric medication was: 7 (7.8%) bromazepam, 6 (6.7%) citalopram, 5 (5.6%) diazepam. Regarding comorbidities, the Charlson index was 1.82 ± 1.21, also highlighting that 34 (27%) of the sample had Sjögren syndrome. In the multivariate analysis, polypharmacy (OR, 1.8 [95% CI, 1.0-3.1]) and Sjogren’s syndrome (OR, 3.8 [95% CI, 1.0-10.7]) were independently associated with depression by Goldberg.Conclusion:Depression is underdiagnosed and undertreated in patients with SLE. Depression is associated with polypharmacy and the perception of patients with SLE of being ill. It is important to correctly treat depression in the context of SLE comorbidity due to its great impact on quality of life.Disclosure of Interests:None declared
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van den Hombergh, W., M. van der Burgt, F. van den Hoogen, J. Fransen, and M. Vonk. "FRI0508 Type and Timing of First Symptoms in Systemic Sclerosis: Prediction of Disease Course: Table 1." Annals of the Rheumatic Diseases 73, Suppl 2 (June 2014): 571.2–571. http://dx.doi.org/10.1136/annrheumdis-2014-eular.3204.
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Moltό, A., H. Bachelez, K. Dawidowicz, D. Wendling, G. Hayem, F. Lioté, F. Aubin, A. Nassif, M. Viguier, and P. Richette. "SAT0257 Is hidradenitis suppurativa an extra articular feature of spondyloarthritis? Results from a multicentre national prospective study." Annals of the Rheumatic Diseases 71, Suppl 3 (June 2013): 558.3–559. http://dx.doi.org/10.1136/annrheumdis-2012-eular.3204.
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Shin, K., S. H. Park, W. Park, H. J. Baek, Y. J. Lee, S. W. Kang, J. Y. Choe, et al. "SAT0286 Monthly Ibandronate Reduces Bone Loss in Osteopenic Women with Rheumatoid Arthritis Receiving Long-Term Glucocorticoids: A 48-Week Double-Blinded Randomized Placebo-Controlled Investigator-Initiated Trial." Annals of the Rheumatic Diseases 74, Suppl 2 (June 2015): 762.1–762. http://dx.doi.org/10.1136/annrheumdis-2015-eular.3204.
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Nozawa, Naoki, Yasushi Kawaguchi, Michiko Tanaka, Akihisa Kato, Ai Kato, Hiroshi Kimura, and Yukihiro Nishiyama. "Herpes Simplex Virus Type 1 UL51 Protein Is Involved in Maturation and Egress of Virus Particles." Journal of Virology 79, no. 11 (June 1, 2005): 6947–56. http://dx.doi.org/10.1128/jvi.79.11.6947-6956.2005.
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ABSTRACT The UL51 gene of herpes simplex virus type 1 (HSV-1) encodes a phosphoprotein whose homologs are conserved throughout the herpes virus family. Recently, we reported that UL51 protein colocalizes with Golgi marker proteins in transfected cells and that targeting of UL51 protein to the Golgi apparatus depends on palmitoylation of its N-terminal cysteine at position 9 (N. Nozawa, T. Daikoku, T. Koshizuka, Y. Yamauchi, T. Yoshikawa, and Y. Nishiyama, J. Virol. 77:3204-3216, 2003). However, its role in the HSV replication cycle was unknown. Here, we generated UL51-null mutants (FDL51) in HSV-1 to uncover the function of UL51 protein. We show that the mutant plaques were much smaller in size and that maximal titers were reduced nearly 100-fold compared to wild-type virus. Electron microscopy indicated that the formation of nucleocapsids was not affected by the deletion of UL51 but that viral egress from the perinuclear space was severely compromised. In FDL51-infected cells, a large number of enveloped nucleocapsids were observed in the perinuclear space, but enveloped mature virions in the cytoplasm, as well as extracellular mature virions, were rarely detected. These defects were fully rescued by reinsertion of the UL51 gene. These results indicate that UL51 protein is involved in the maturation and egress of HSV-1 virus particles downstream of the initial envelopment step.
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Peng, Xiao-Xiao, Ruoying Yu, Xue Wu, Shu-Yu Wu, Can Pi, Zhi-Hong Chen, Xu-Chao Zhang, et al. "Correlation of plasma exosomal microRNAs with the efficacy of immunotherapy inEGFR/ALKwild-type advanced non-small cell lung cancer." Journal for ImmunoTherapy of Cancer 8, no. 1 (January 2020): e000376. http://dx.doi.org/10.1136/jitc-2019-000376.
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BackgroundImmunotherapy has become an important treatment option for patients with advanced non-small cell lung cancer (NSCLC). At present, none of these existing biomarkers can effectively stratify true responders and there is an urgent need for identifying novel biomarkers. Exosomes derived from the serum of patients with cancer have been proven to be reliable markers for cancer diagnosis. Here, we explored the possibility of using plasma-derived exosomal microRNAs as potential biomarkers for optimal selection of patients with advancedEGFR/ALKnegative NSCLC to immunotherapy.MethodsFrom June 2017 to February 2019, 30 patients with advancedEGFR/ALKwild-type (WT) NSCLC who received PD-1/PD-L1 inhibitors were enrolled. The efficacy evaluation was conducted after every three cycles of treatment according to RECIST 1.1. Plasma samples of these patients were collected before the administration of PD-1/PD-L1 inhibitors as baseline, and after every three cycles if the patients achieved partial response (PR) or complete response. Plasma from seven healthy individuals was also collected as normal control. Exosomes were prepared by ultracentrifugation followed by total RNA extraction, and exosome-derived miRNAs were profiled using small RNA next-generation sequencing followed by differential expression analysis.ResultsIn order to identify biomarker for better response, all five patients who achieved PR and four patients with progressive disease (PD) at efficacy evaluation were included for differential expression analysis. Based on unsupervised hierarchical clustering, exosomal miRNA expression profile was significantly altered in patients with NSCLC compared with normal controls with a total of 155 differentially expressed exosomal miRNAs. Interestingly, hsa-miR-320d, hsa-miR-320c, and hsa-miR-320b were identified significantly upregulated in the PD groups compared with the PR group at baseline before the treatment. In addition, we identified that hsa-miR-125b-5p, a T-cell suppressor, showed a trend of increased expression in the PD group at baseline and was significantly downregulated in the post-treatment plasma exosomes compared with pre-treatment samples of the PR patients.ConclusionPatients with NSCLC represent unique plasma exosomal miRNA profiles. Hsa-miR-320d, hsa-miR-320c, and hsa-miR-320b were identified as potential biomarkers for predicting the efficacy of immunotherapy in advanced NSCLCs. When T-cell suppressor hsa-miR-125b-5p was downregulated during the treatment, the patients may obtain increased T-cell function and respond well to immunotherapy.
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Saadi, Soheyla, and Jeffrey L. Platt. "IMMUNOLOGY OF XENOTRANSPLANTATION." Life Sciences 62, no. 5 (December 1997): 365–87. http://dx.doi.org/10.1016/s0024-3205(97)00964-8.
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Konno, Yuki, Tsutomu Toki, Satoru Tandai, Gang Xu, Kiminori Terui, Shouichi Ohga, Seiji Kojima, et al. "Mutations in Ribosomal Protein Genes of Diamond-Blackfan Anemia Patients in Japan." Blood 114, no. 22 (November 20, 2009): 3204. http://dx.doi.org/10.1182/blood.v114.22.3204.3204.
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Abstract Abstract 3204 Poster Board III-141 Diamond-Blackfan anemia (DBA) is an inherited congenital bone marrow failure syndrome, characterized by red blood cell aplasia, macrocytic anemia, and increased risk of malignancy. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, which occur in about 40% of patients. Approximately 90% of patients present during the first year of life or in early childhood. Recent studies have shown that the disease is associated with heterozygous mutations in the ribosomal protein (RP) genes RPS19, RPS24, and RPS17, encoding small ribosomal subunit proteins, and in RPL5, RPL11 and RPL35a, encoding large ribosomal subunit proteins, in about 50% of patients with DBA in Western countries. There have been no studies to determine the incidence of these mutations in Asian patients with DBA. In this study, 44 probands (46 patients) with DBA in Japan were screened for mutations of the 6 known DBA genes RPS19, RPS24, RPS17, RPL5, RPL11, and RPL35a, in addition to RPS14, which is implicated in the 5q- syndrome, a subtype of myelodysplastic syndrome characterized by a defect in erythroid differentiation. Mutations in RPS19, which have been found in 25% of patients in Western countries, were detected in 6 probands (13.6%). Missense mutations were noted in 5 of these probands, and a frameshift mutation caused by a single-nucleotide insertion was found in 1 case. Three of 7 patients had multiple malformations. Novel mutations in RPL5 were identified in 3 probands (6.8%). Insertion of 2 nucleotides was found in 1 case, affecting the reading frame. Two cases had point mutations, which resulted in a loss of the first initiation codon. All 3 patients with RPL5 mutations had multiple physical anomalies. Remarkably, 2 of 3 patients with RPL5 mutations had cleft palate, whereas no other DBA patients presented with cleft palate. Mutations in RPL11 were identified in 2 patients (4.5%). Deletion of 1 or 2 nucleotides was found in each case, leading to a shift in the reading frame. In contrast to previous reports on patients with RPL11 mutations, thumb anomalies were not seen. Deletion of 1 nucleotide in RPS17 was identified in 1 patient (2.3%), resulting in introduction of a premature stop codon. RPS17 mutations are rare and have been only reported in 2 patients with DBA. Anomalies were not seen in our patient. In summary, RP gene mutations were identified in 27.3% of DBA index cases in Japan. No mutations were detected in RPS14, RPS24 and RPL35a. In Japan, the frequency of mutations in the RP genes appears to be lower than in Western countries. Mutations in RPL5 are associated with multiple physical abnormalities, including cleft palate. Disclosures No relevant conflicts of interest to declare.
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Zaki, Mohamed H., Zhao Zhou, Francis L. McCabe, Hillary J. Millar, Christine McCauley, Jill Giles-Komar, and Marian T. Nakada. "A Novel Interleukin-IL-6 (IL-6) Dependent Syngeneic Multiple Myeloma (MM) Model in SCID Mice." Blood 104, no. 11 (November 16, 2004): 4891. http://dx.doi.org/10.1182/blood.v104.11.4891.4891.
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Abstract IL-6 is a multifunctional cytokine that is implicated in the pathophysiology of several malignant diseases including MM, an incurable malignant plasma cell disorder. IL-6 is known to enhance proliferation, differentiation and survival of malignant plasma cells in MM through an autocrine and/or a paracrine mechanism that involves the inhibition of apoptosis of the malignant cells, induction of resistance to chemotherapy and contribution to angiogenesis. Moreover, elevated levels of IL-6 in serum of patients with MM correlate with disease activity, unfavorable prognosis and refractoriness to standard therapy. Blocking IL-6 has been postulated to be an effective therapy (Klein et al, 1995) and several studies have investigated the effect of blocking IL-6 on MM cells and cell lines both in vitro and in vivo. However, the lack of a reliable IL-6 dependent MM model has hindered these efforts. Recently, mouse plasmacytomas were described as appropriate models to study the biology of human MM (Iankov et al., Immunobiology2004; 208(5)). The current study describes a new in vivo IL-6 dependent mouse plasmacytoma model in SCID mice. Mice were inoculated subcutaneously with 1 x 106 7TD1 cells, an IL-6 dependent mouse hybridoma/plasmacytoma cell line. Three days after tumor inoculation, mice were treated 2x/week i.p. with either PBS or 25 mg/kg of anti-mouse IL-6 (R & D systems, Clone MP520F3) or control mAb. Thirteen days after tumor implantation the mean tumor volume in the control mAb group and PBS group was 3204 +/− 360 SEM mm3, n = 10; and 2430 +/− 189 SEM mm3, n = 10, respectively. The mean tumor volume in the anti-IL-6 treated group was 635 +/− 149 SEM mm3, n = 10. Serum was tested by ELISA for levels of IL-6 and IgM (a mAb that is produced by 7TD1 cell line). IL-6 serum level was undetectable in naïve non-tumor bearing SCID mice. The IL-6 levels in the PBS treated group and control mAb group were 121 +/− 32 pg/ml and 125 +/− 14 pg/ml, respectively. IL-6 levels in animals treated with rat-anti- mouse IL-6 were not detected due to interference of the mAb with the ELISA. Serum IgM levels in optical density (OD) were 0.02 +/− 0.005 in the naïve non-tumor bearing animals, 0.80 +/− 0.02 in the PBS group, 0.77 +/− 0.03, in the control mAb group, and 0.19 +/− 0.17 in the rat anti-mouse IL-6 group. In conclusion the current study showed that 7TD1cells could be grown in SCID mice. Serum levels of both IgM and IL-6 were significantly elevated in the PBS and control mAb treated tumor-bearing animals. There was a significant reduction in the IgM levels in the rat anti-mouse IL-6 treated group (P <0.0001), a positive correlation between final tumor weight and serum IgM level (P < 0.0001, r2 = 0.782) and a 74% inhibition of tumor growth relative to either control mAb or vehicle control (P <0.0001). Taken together the current study introduces a new IL-6 dependant mouse plasmacytoma model that can be used to study the biology of MM and to test the efficacy of IL-6 blocking agents in vivo.
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Shiyayo, J., L. Padnick-Silver, and B. Lamoreaux. "POS1162 PREVALENCE AND IMPACT OF DERMATOLOGIC CONDITIONS IN PATIENTS WITH GOUT." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 909.2–910. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2521.
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BackgroundGout is the most common inflammatory arthritis in adults and affects approximately 3-5% of the population in Europe and the United States.1 Chronic hyperuricemia leads to monosodium urate (MSU) crystal deposition in both joints and soft tissues, including the heart, eyes, kidney, skin, and liver.2 Systemic manifestations of gout have been well-characterized, with dermatologic involvement typically described as subcutaneous tophi, miliary gout, gouty panniculitis, and gout nodulosis.2 Other dermatologic conditions may occur more often in gout patients and provide better understanding of a patient’s overall condition.ObjectivesThis claims-based study examined the prevalence of dermatological conditions in a large US population of gout patients. Patients with and without dermatologic conditions (identified by diagnosis codes) were compared to assess comorbidity burden, review healthcare utilization, and better understand the underlying consequences of dermatological manifestations of gout.MethodsThe Symphony 2012-2017 claims database was searched to identify patients with ≥1 ICD-9 or -10 gout code (ICD-9: 274.xx, ICD-10: M1*) using Bellweather software (PearlDiver Technologies™). All patients were in the database ≥1 year before and ≥2 years after first gout code (index). Patients were said to have a dermatologic condition if they had ≥1 diagnosis code for atopic dermatitis (ICD-9: 6918, ICD-10: L2*), psoriasis (ICD-9: 6961, ICD-10:L4*), osteomyelitis (ICD-9:73008, ICD-10: M86*), melanoma (ICD-9:1729, ICD-10: C43*), peripheral ulcers (ICD-9: 70710), varied cutaneous abscesses (ICD-9: 9829, ICD-10: L022*), or cellulitis (ICD-9:6826, ICD-10: L03*). Diagnosis code prevalence and healthcare utilization were examined and compared between those with/without a dermatological diagnosis code.ResultsOf the nearly 1.7 million identified gout patients, 29% had ≥1 dermatology diagnosis code. Patients with and without ≥1 dermatology code were of similar age at index (62.72 vs. 61.84 years) but those with ≥1 code were less often male (62% vs. 65%). The most common dermatological codes identified included cellulitis (10.7%), dermatitis (4.8%), psoriasis (2.2%), and osteomyelitis (2.1%, Table 1). Overall, comorbidity diagnosis codes were more prevalent in patients with ≥1 dermatology code, including hypertension, chronic kidney disease, cardiovascular disease, and type 2 diabetes (Table 1). Additionally, healthcare utilization and pain medication use were higher in gout patients with dermatological conditions despite similar ULT use.Table 1.Incidence of select dermatologic conditions in gout vs general US populations and comorbidity prevalence among gout patients with/without ≥1 dermatological diagnosis code.Dermatologic conditionsGout populationGeneral US populationp-valueCellulitis, incidence, cases/100,000 person-yrs10941993<0.001Osteomyelitis, incidence, cases/100,000 person-yrs219224<0.001Gout pts with ≥1 dermatology code (N=488,356)Gout pts without a dermatology code (N=1,201,082)Age, years, mean ± SD62.72 ± 12.3561.84 ± 12.67----Male, n (%)305,012 (63%)779,103 (65%)<0.001Comorbidity, n (%) Hypertension446,577 (91%)1,040,381 (87%)<0.001 Chronic kidney disease215,670 (44%)408,826 (34%)<0.001 Cardiovascular disease358,930 (73%)749,577 (62%)<0.001 Type 2 diabetes254,914 (52%)435,911 (36%)<0.001ConclusionThese claims-based analyses suggest the prevalence of dermatologic conditions other than those historically associated with gout. Additionally, gout patients with dermatologic conditions had higher comorbidity burden than those without. Therefore, as with other conditions, the skin may provide clues of a larger, systemic disease burden.References[1]Kuo CF, et al. Nat Rev Rheumatol 2015;11:649-62.[2]Khanna P, et al. J Clin Med 2020;9:3204.[3]McNamara DR, et al. Mayo Clin Proc 2007;82:817-21.[4]Momodu II, Savaliya V. Osteomyelitis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; August 11, 2021.Disclosure of InterestsJulie Shiyayo: None declared, Lissa Padnick-Silver Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Brian LaMoreaux Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics
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Mikulski, Damian, Izabela Dróżdż, Ewelina Perdas, Konrad Stawiski, Mateusz Nowicki, Małgorzata Misiewicz, Piotr Strzałka, Agnieszka Wierzbowska, and Wojciech Fendler. "Changes in the Microrna Expression Profile in Patients Undergoing Autologous Steam Cell Transplantation." Blood 138, Supplement 1 (November 5, 2021): 4789. http://dx.doi.org/10.1182/blood-2021-152179.
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Abstract Introduction: Autologous hematopoietic stem cell transplantation (AHSCT) is an acknowledged and effective treatment method for hematopoietic system diseases. MicroRNAs were reported to impact the bone marrow niche microenvironment and regulate proliferation and survival of the hematopoietic stem cells in such a manner may also influence bone marrow convalescence after AHSCT. The project aimed to identify changes in the signature of miRNAs freely circulating in the serum during AHSCT related to chemotherapy-induced injury and further bone marrow recovery using next-generation sequencing. Patients and methods: Serum samples from 10 patients undergoing ASCT were collected. Blood samples were taken from each patient at four time points: (T1) before conditioning with high dose chemotherapy, (T2) on the day of AHSCT (day 0), on day +7 (T3), and on +14 day after AHSCT (T4). The myeloablative conditioning regimen for patients with MM was melphalan 200 mg/m 2, while in lymphoma patients, BEAM was used. Total RNA was extracted from 200 μl serum using miRNeasy Serum/Plasma Advanced Kit (QIAGEN) following manufacture instructions. Libraries were prepared from 5 μl of total RNA using QIAseq® miRNA Library Kit. The libraries were pooled in equimolar concentrations and sequenced on a NextSeq 550 System using a single-end read length of 75 nucleotides at an average of 10 million reads per sample (Illumina). In bioinformatics analysis, after adapter cut-off, filtration and mapping, miRNAs were counted based on mapping to reference miRbase 22 (tools: fastp, bowtie, samtools, picard). MicroRNAs were filtered to have at least 10 counts-per-million (CPM) of classified sequences in at least two samples. MiRNAs expression levels between time points were compared using paired t-test with Bonferroni correction. Results: The study group consisted patients with multiple myeloma (N=4), Hodgkin lymphoma (HL, N=3), and non-HL (N=3) aged 48±13 years. There was a significant decrease in the hematological parameters during ASCT with a nadir at T3, including hemoglobin (T1 vs. T3, p<0.0012), white blood cell count (p<0.0001), neutrophil count (p=0.0003), and platelet count (p<0.0001). Similarly, the decrease was observed in hsa-miR-223-3p (T1 vs. T3, p=0.048) and hsa-miR-18a-5p (T2 vs. T3, p=0.033) with a nadir at T3. On the other hand, an increase with a peak at T3 was observed in the expression of hsa-miR-320b (T1 vs. T3, p=0.007), hsa-miR-320c (T1 vs. T3, p=0.007), hsa-miR-320a-3p (T1 vs. T3, p=0.009), and hsa-miR-320d (T1 vs. T3, p=0.042). Interestingly, we have observed a gradual decrease across study timepoints in the expression of hsa-let-7f-5p, hsa-let-7i-5p, and hsa-miR-155-5p with a nadir at T4 (T1 vs. T4, p=0.004, p=0.01, and p=0.019, respectively). Similar changes were observed in the expression of hsa-miR-486-5p, but the statistically significant decline was only noted between T3 and T4 (p=0.024). Conversely, a gradual decrease was also seen in the expression of hsa-miR-96-5p, but there was a significant increment between T3 and T4 (p=0.036). Figure 1 presents the heatmaps for the miRNAs with significant expression changes and corresponding hematological parameters during AHSCT. Conclusion: Several significant changes in the miRNA expression profile were identified, both related to the chemotherapy-induced injury and subsequent bone marrow recovery. Figure 1 Figure 1. Disclosures Wierzbowska: Novartis: Consultancy; Abbvie: Consultancy; Jazz: Research Funding; Janssen: Consultancy; Astellas: Consultancy; Celgene/BMS: Consultancy.
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Makis, Alexandros, Nikolaos Chaliasos, and Antigone Siamopoulou. "Iron Chelation Treatment with Oral Solution of Deferiprone in Young Children with Hemoglobinopathies,." Blood 118, no. 21 (November 18, 2011): 3204. http://dx.doi.org/10.1182/blood.v118.21.3204.3204.
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Abstract Abstract 3204 Background - Aim. Children with transfusion dependent hemoglobinopathies rapidly develop iron overload in vital organs and iron removal with chelating agents is required early in life and in some cases after the age of 2. The oral administration of iron chelation is most welcome by thalassemic children and their parents who have problems with the discomfort and side effects of deferoxamine injections. Deferiprone, previously only in tablet form, was not suitable for young children under the age of 5 years. Recently the solution form of deferiprone has been introduced. There are limited clinical data on the safety and efficacy of deferiprone at a very young age. The aim of our study was the presentation of data regarding the safety and efficacy of liquid oral solution of deferiprone in young children with hemoglobinopathies less than 10 years old. Patients and methods. Nine young children (5 boys, 4 girls) receiving oral solution of deferiprone (Ferriprox® 100 mg/mL) were studied. The mean age at the beginning of the treatment was 6.5 (range 2–10). Six children had beta-thalassemia major, 1 thalassemia intermedia and 2 sickle cell/beta thalassemia. The mean number of red blood cell transfusions during the previous year was 10.6 (range 8–15). All the children had chronic iron overload requiring chelation therapy, as defined by serum ferritin concentration [mean ± standard error (SE): 2440±1275 μg/L]. All children were naïve to iron chelation therapy before this study, except for 2 patients who were on deferoxamine (mean dose=35 mg/kg/day; mean duration of use=1.5 years). One child was splenectomized. All children had negative anti-hepatitis C antibody status at baseline. Treatment was initiated at a daily dose of 50 mg/kg, divided into 3 doses, for the first 2 weeks. The dose was increased to 75 mg/kg, for another 2 weeks. If serum ferritin concentration at baseline was greater than 2500 μg/L, the dose was further increased to a total daily dose of 100 mg/kg after 4 weeks therapy. After initiation of the treatment, full blood count was assessed weekly, serum ferritin monthly, and liver and renal function bimonthly. The mean duration of treatment was 9.5 months (range 2–15 months). To evaluate the efficacy and safety of oral deferiprone treatment, biochemical parameters such as serum ferritin and liver enzymes were analyzed using the Student t-test. All parameters are presented as mean± SE. P-values less than 0.05 were considered statistically significant. Results. All children received the oral deferiprone without any problems of compliance. The hematological and biochemical markers during treatment are shown in Table 1. Adverse reactions to deferiprone were mild and transient: abdominal discomfort and diarrhea at initiation of therapy (1 child) and mild neutropenia (1 child) resolved within 8 days with no need of discontinuation of treatment. Deferiprone oral solution was effective in reducing serum ferritin (mean±SD) (initial 2440±1275 μg/L vs final 2030±915 μg/L, p<0.005) (Figure 1). Five children of the study were <6 years old. The baseline serum ferritin of these children was significantly lower than older children (2250 μg/L±880 vs 2950 μg/L±1550, p<0.005). The differences in changes in serum ferritin did not reach statistical significance. Conclusions. This small study shows that oral solution of deferiprone was well tolerated by young children and its use was not associated with major safety concerns. Furthermore, it was effective in decreasing serum ferritin. Further studies with large number of patients and longer follow-up, are needed to confirm the safety and efficacy profile of deferiprone in childhood. Disclosures: No relevant conflicts of interest to declare.
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Munday, Adam D., Rebecca A. Penkala, Pavel D. Davizon, Clyde J. Pierce, William E. Hobbs, John D. Kulman, Wendy E. Thomas, and Jose A. Lopez. "Elevated Cytosolic Cyclic AMP Inhibits Platelet Adhesion to Von Willebrand Factor by Disengaging the Glycoprotein Ib-IX-V Complex From Lipid Rafts." Blood 116, no. 21 (November 19, 2010): 3204. http://dx.doi.org/10.1182/blood.v116.21.3204.3204.
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Abstract Abstract 3204 A high pressure circulatory system has two diametrically opposed requirements for its function: it must be able to rapidly gel to prevent blood loss when the integrity of the vasculature is compromised while simultaneously maintaining fluidity when the vasculature is intact. The endothelium is primarily responsible for maintaining blood fluidity, producing rapidly acting labile substances that inhibit both the clotting of blood and the adhesion and aggregation of platelets. Among these substances are the prostaglandins (PGE1, PGI2, PGD2), which bind platelet membrane receptors, raise concentrations of intracellular cyclic adenosine monophosphate (cAMP), and inhibit platelet functions. The major effector of increased cAMP is the serine/threonine kinase protein kinase A (PKA). Of the numerous targets for PKA, one of the most highly phosphorylated upon cAMP increase is glycoprotein (GP) Ibβ, a component of the GPIb-IX-V complex, the platelet receptor for VWF that mediates the initial adhesion of platelet to the vessel wall at sites of injury. The GPIb-IX-V complex consists of 4 type I transmembrane polypeptides, GPIbα, GPIbβ, GPV and GPIX. GPIbα and GPIbβ are disulfide linked in a 1:2 ratio, and the resulting GPIb is non-covalently associated with GPIX and GPV in a 2:2:1 ratio. The VWF-binding site resides within the N-terminal 300 amino acids of GPIbα 500 Å above the platelet surface. Although current data indicate that PKA phosphorylation of the GPIbβ cytoplasmic domain (at Ser166) inhibits the ability of GPIbα to bind VWF, the molecular mechanism(s) have yet to be elucidated. The cytoplasmic domain of GPIbβ associates with calmodulin (in the juxtamembrane 20 amino acids) in resting platelets; calmodulin dissociates upon platelet activation. With elevated cytosolic cAMP, GPIbβ Ser166 becomes phosphorylated and associates with 14-3-3ζ. An interesting feature of the cytoplasmic sequence N-terminal to Ser166 is its extreme cationic nature, containing 8 Arg residues in a stretch of 17 amino acids. Other cytosolic proteins with similar polybasic sequence (MARCKS, GAP43) function as organizers of the signaling phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), and promote the formation of lipid rafts; we reasoned that the polybasic region of GPIbβ might function similarly, organizing rafts when unbound by protein, but not when occupied by calmodulin or 14-3-3ζ. Platelet activation increases raft-associated GPIb-IX-V two fold, with concomitant dissociation of calmodulin from GPIbβ. Here we present evidence that the cytoplasmic domain of GPIbβ plays a role in the localization of the GPIb-IX-V complex to lipid rafts. Treatment of platelets with agents that increase cAMP (PGI2 or forskolin) inhibited GPIb-IX-V-dependent platelet functions, including ristocetin-induced aggregation, shear-induced aggregation and adhesion to VWF under flow. This effect was prevented by the cell-permeable PKA-specific inhibitor H-89. Consistent with the functional importance of GPIb-IX-V localization to lipid rafts, PGI2 and forskolin reduced the raft content of GPIb-IX-V by 35%, and this effect was reversed by H-89. We have thus uncovered a mechanism for long-observed inhibition of platelet adhesion by agents that elevate cytosolic cAMP concentrations, which depends on modulating the quantity of GPIb-IX-V complexes associated with lipid rafts. “Resting” platelets ex vivo are relatively quiescent because calmodulin occupies the GPIbβ polybasic region. The situation changes rapidly when platelets are activated, with more of the complex assuming a ligand-competent state as calmodulin dissociates and the complex organizes rafts. Elevations of cAMP promote phosphorylation of GPIbβ, enabling 14-3-3ζ association, which also displaces the GPIbβ tail from the membrane, disrupting raft association and adhesive function. Disclosures: No relevant conflicts of interest to declare.
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Zino, Elisabetta, Giovanni Maria Severini, Benedetta Mazzi, Claudio Bordignon, Elena Benazzi, and Katharina Fleischhauer. "Sequencing of a new HLA-A * 32 subtype (A * 3202)." Immunogenetics 45, no. 1 (November 15, 1996): 76–77. http://dx.doi.org/10.1007/s002510050171.
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Huang, Gang, Katsuya Shigesada, Hee-Jun Wee, P. Paul Liu, Motomi Osato, and Yoshiaki Ito. "Molecular basis for a dominant inactivation of RUNX1/AML1 by the leukemogenic inversion 16 chimera." Blood 103, no. 8 (April 15, 2004): 3200–3207. http://dx.doi.org/10.1182/blood-2003-07-2188.
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Abstract The Runt domain transcription factor, PEBP2/CBF, is a heterodimer composed of 2 subunits. The DNA-binding α subunit, or RUNX protein, interacts with a partner PEBP2β/CBFβ through the evolutionarily conserved Runt domain. Each of the genes encoding RUNX1 and PEBP2β/CBFβ is frequently involved in acute myeloid leukemia. The chimeric protein, CBFβ(PEBP2β)/SMMHC, is generated as a result of inversion of chromosome 16 in such a way to retain the heterodimerization domain of PEBP2β at the amino-terminal side fused to the C-terminal coiled-coil region of smooth muscle myosin heavy chain (SMMHC). Here we show that, in the chimeric protein, the second heterodimerization domain is created by the fusion junction, enabling the chimeric protein to interact with RUNX1 at far greater affinity than PEBP2β and inactivate the RUNX1/AML1 function. To explain why and how heterozygous CBFB/MYH11 can inactivate homozygous RUNX1 near to completion, we propose a new model for this chimeric protein that consists of a Y-shaped dimer with unpaired N-terminal halves followed by a coiled-coil for the C-terminal region. (Blood. 2004;103:3200-3207)
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Li, Jia, Jing Ke, Cheng-lin Qin, and Xun Zhu. "LINC00680 modulates docetaxel resistance in breast cancer via the miR-320b/CDKL5 axis." International Journal of Immunopathology and Pharmacology 36 (January 2022): 039463202211056. http://dx.doi.org/10.1177/03946320221105608.
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Introduction: Increasing evidence has indicated that LINC00680 represents an oncogenic factor in cancer; however, the mechanism by which LINC00680 contributes to breast cancer (BC) remains unknown. Methods: A dual-luciferase reporter assay was used to explore the relationship between LINC00680, miR-320b, and cyclin-dependent kinase 5 (CDKL5). A CCK-8 assay and transwell assay were utilized to evaluate the proliferation and invasion in docetaxel-resistant BC cells, respectively. Results: LINC00680 and CDKL5 protein levels were both upregulated when induced by different concentrations of docetaxel. LINC00680 knockdown decreased the expression level of drug resistance-related genes, proliferation, and invasion of BC cells. Bioinformatics prediction and dual-luciferase assays revealed that miR-320b targeted the 3′-unstranslated regions (UTR) of both LINC00680 and CDKL5, suggesting that the modulation of LINC00680 on CDKL5 occurred via sequestering miR-320b. Conclusion: Overall, this study highlights the important role of LINC00680 in docetaxel resistance through the miR-320b/CDKL5 pathway and provides a novel therapeutic strategy for BC drug resistance.
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Zenker, Nicolas, and Lawrence B. Afrin. "Utilities of Various Mast Cell Mediators in Diagnosing Mast Cell Activation Syndrome." Blood 126, no. 23 (December 3, 2015): 5174. http://dx.doi.org/10.1182/blood.v126.23.5174.5174.
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Abstract Distinct from mastocytosis and simple allergy and characterized by constitutive mast cell (MC) activation and aberrant MC reactivity with little to no excessive MC accumulation, MC activation syndrome (MCAS) presents as acute-on-chronic multisystem polymorbidity of generally inflammatory ± allergic theme; severity may be disabling. Given suspicion of epidemic prevalence of MCAS (Molderings GJ et al., PLoS One 2013;8(9):e76241), diagnostic testing efficiency is important. Diagnosis (Molderings GJ et al., J Hematol Oncol 2011;4:10) presently rests on identifying clinical presentation consistent with chronic/recurrent aberrant MC mediator release, identifying elevated MC mediator levels, and eliminating other relevant diagnostic considerations. MCs produce >200 mediators, but few can be tested in clinical laboratories; even fewer are relatively specific to the MC. Mediators often tested in MCAS work-ups include serum tryptase (sTryp) and chromogranin A (sCgA), plasma prostaglandin D2 (pPGD2) and histamine (pHist) and heparin (pHep), random (r) and 24-hour (24h) urinary PGD2 (uPGD2) and N-methylhistamine (uNMH) and leukotriene E4 (LTE4), and 24h urinary 11-β-PGF2α (u11βPGF2α). Testing the entire suite may be prohibitively expensive, but few data on frequency of elevation of MC mediators are available to guide cost-effective testing (pHep may be the most sensitive per Vysniauskaite M et al., PLoS ONE 2015;10(4):e0124912). Test accuracy for many MC mediators (especially heparin and the eicosanoids) is also challenged by thermolability and half-lives as short as ~1 minute. Loss of specimen chill during handling (e.g., unrefrigerated centrifugation (UCF)) or transport may yield false negatives. Methods: We reviewed the charts of 198 adult pts (97% Caucasian, 84% female) evaluated at our center and diagnosed with MC activation disease (MCAD: MCAS (184), CM (4), indolent SM (9), aggressive SM (1)) from July 2014 through July 2015. Results: Table 1 shows performance in MCAS pts of MC mediators in tests accessioned at our center (testing accessioned elsewhere censored to reduce bias from variability in specimen handling by pts and lab staff not known to have been educated regarding proper specimen handling). Our sTryp results agree closely with Vysniauskaite et al. but are lower than found in smaller cohorts in Zblewski D et al., Blood 2014;124(21):3204 (>33%) and Ravi A et al., J Allergy Clin Immunol Pract 2014;2(6):775. Table 1. MC mediator performance in diagnostic testing for MCAS. Mediator # Tests Performed # Tests Yielding Elevated Result % Elevated % Elevated Comparisons Vysniauskaite (n=238) Zblewski (n=15) Ravi (n=25) sTryp 147 13 8.8 10 >40 40 sCgA 133 42 31.5 12 pPGD2 113 15 13.2 pHist 133 39 29.3 pHep* 121 35 28.9 59 r-uPGD2 102 10 9.8 r-uNMH 108 8 7.4 r-uLTE4 68 3 4.4 24h-uPGD2 107 41 38.3 24h-uNMH 111 6 5.4 22 8 24h-uLTE4 72 6 8.3 24h-u11βPGF2α 68 25 36.8 *Results affected by use of UCF in some cases; see below. Upon our recognition of oddly persistently negative pHep levels, a review of procedures in late December 2014 discovered specimen centrifugation since July 2014 had not been refrigerated. Refrigerated centrifugation (RCF) was immediately instituted, but lab issues led to inadvertent return in February 2015 to UCF which was re-discovered and re-corrected in March 2015. The rate of finding elevations in pHep levels (upper normal 0.02 anti-Factor Xa units/ml per Seidel et al., Thromb Haemost 2011;106(5):987) appeared strongly correlated with use of RCF (p <0.00001; Figure 1). RCF improved the rate of finding elevated pHep from 1 of 50 patients tested (2.0%) to 34 of 70 patients tested (48.6%). Other mediators did not appear significantly affected by UCF. Conclusions: In our cohort (5:1 female:male vs. previously reported 2-3:1 ratios), pHep, 24uPGD2, and 24u11βPG2α appeared the most sensitive indicators of MC activation; sTryp and urinary NMH and LTE4 appeared least sensitive. Our data confirm others' findings that sTryp is seldom elevated in MCAS; thus, normal sTryp decreases likelihood of mastocytosis but not MCAS. A sensitive assay is needed when testing pHep for evidence of MC activation as most elevated pHep levels in the MCAS population are below more commonly used assays' lower limits of detection (typically 0.10-0.20 anti-Factor Xa units/ml, geared to detect therapeutic pHep levels). Continuous specimen chilling appears important in accurately measuring pHep. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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Auerbach, Michael, William Strauss, Sarah Auerbach, Stella Rineer, and Huzefa Bahrain. "Efficacy of Total Dose Administration (TDI) of 1012 Mg of Ferumoxytol Over 15 Minutes for the Treatment of Iron Deficient Anemia." Blood 120, no. 21 (November 16, 2012): 3204. http://dx.doi.org/10.1182/blood.v120.21.3204.3204.
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Abstract Abstract 3204 For the majority with iron deficient anemia (IDA) a standard full repletion course of IV iron is 1 g. Iron sucrose and ferric gluconate require 4–10 administrations of 100–300mg to deliver a full course. We have employed TDI of 1 g LMW iron dextran, initially over 4 hours and now over 1 hour, in over two thousand patients with good success. No serious adverse events (SAEs) were observed. We sought to explore the potential for further convenience for patients and physicians alike afforded by administering 1.02 g of ferumoxytol (FER) as a 15 min infusion in a single setting instead of the standard regimen of 2 × 510mg injections separated by approximately 1 week. Herein we report the efficacy and safety of such an approach. Methods: 60 consecutive patients with IDA (hemoglobin [Hgb] <11 g/dL, transferrin saturation [TSAT] ≤19%, ferritin <100 ng/mL) and a history of intolerance of, or inadequate response to oral iron, received 1020 mg (34 mL) of FER diluted in 100 mL normal saline via infusion pump over 15 minutes. Vital signs were measured for 1 hour post-dose and adverse events (AEs) were collected via phone call 1, 2, and 7 days post-dose, and at clinic visits at 4 and 8 weeks post-dose. Efficacy assessments (Hgb, TSAT, ferritin, red blood cell distribution width [RDW]) occurred at 4 and 8 weeks post-dose. The primary endpoint was safety and tolerability (rate of AEs), while secondary efficacy endpoints included mean change in Hgb level, TSAT and RDW from Baseline to Week 4 and 8. Results: The mean age was 53.4 (24 – 89) years. The most common underlying cause for IDA was menorrhagia, followed by gastric bypass. No serious AEs occurred, and all but 2 received the planned dose. One subject complained of cough and flushing after initiation of the infusion and requested discontinuation with symptoms abating within 2 minutes without treatment. A second subject developed cough and pruritus, was treated with diphenhydramine and steroids and the symptoms resolved in minutes. Tryptase, a mast cell degranulation marker, was normal in both subjects. Twenty-six of 60 patients reported AEs. Thirteen of the AEs were mild and transient reactions associated with the infusion, none of which received therapy with the exception of the one previously described. All symptoms resolved completely within minutes. Thirteen reported mild self limited arthralgias, myalgias and/or headache within 24–48 hours after treatment. At baseline, the mean Hgb was 9.4 g/dL, TSAT 7.7%, ferritin 57 ng/mL and RDW 16.5%. At 4 weeks, the mean Hgb increase was 2.1 g/dL, and by 8 weeks, the mean increase in Hgb was 2.6 g/dL. The peak increase in TSAT occurred at Week 4, increasing from 15.2 to 23.1%, compared to an increase of 13.2 to 20.9% at Week 8. Similarly, ferritin was maximal at week 4 (214 ng/mL) and had decreased by week 8 to 118 ng/mL. In approximately 90% of subjects, the RDW was increased at both four and 8 weeks post-ferumoxytol administration, consistent with reticulocytosis and ongoing hematopoietic response. Conclusion: Ferumoxytol, administered as a 1.02g TDI over 15 min was well tolerated with no SAEs in IDA patients with a history of intolerance of, or inadequate response to oral iron. Ferumoxytol also demonstrated excellent efficacy in this population with a diverse group of etiologies for IDA. By 4 weeks, Hgb had increased 2.1 g/dL with a continued further increase to 2.6 g/dL by Week 8. RDWs were elevated at 4 and 8 weeks in 90% of subjects, consistent with an ongoing hematologic response. This study of 60 iron deficient anemia patients demonstrates the safety and ease of administering a complete 1.02g replacement dose of IV iron in 15 minutes with ferumoxytol. If these results are corroborated in other studies, the infusion of 1.02 g of ferumoxytol as a 15 minutes infusion represents an improved method of treating iron deficient anemia. Disclosures: Off Label Use: 1020 mg of ferumoxytol is off label as the maximum approved dose is 510 mg. Further the drug was administered to patients with a host of conditions associated with iron deficiency and currently is only on label for iron deficiency associated with chronic kidney disease. The purpose is to provide a full replacement dose of iron in 15 minutes, representing a significant improvement in the management of iron deficient anemia. Strauss:AMAG Pharmaceuticals, Inc.: Employment.
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Schieven, Gary L., Rosemary Zhang, Sidney Pitt, Kelly McGlinchey, Krista Menard, Richard Smykla, Vojkan Susulic, et al. "Dasatinib Once-Daily Dose Regimen Provides Robust Anti-Leukemic Activity While Avoiding Suppression of T Cell Activation." Blood 114, no. 22 (November 20, 2009): 2198. http://dx.doi.org/10.1182/blood.v114.22.2198.2198.
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Abstract Abstract 2198 Poster Board II-175 Dasatinib (SPRYCEL®), a small molecule tyrosine kinase inhibitor is 325-fold more potent against BCR-ABL than imatinib. Targeting BCR-ABL in chronic myeloid leukemia (CML), dasatinib offers the most favorable benefit-risk ratio with the dose regimen of 100-mg once daily (in comparison with 3 other treatment arms: 50 mg BID, 140 mg QD and 70 mg BID. Duration of cytogenetic response and progression-free survival were similar across all 4 arms, but there was significantly less frequent grade 3-4 neutropenia, thrombocytopenia, anemia and pleural effusion in the 100-mg QD arm compared to the other 3 arms combined (Shah et al, J Clin Oncol 26:3204, 2008). The undiminished efficacy of once daily dosing occurs despite the fact that orally administered dasatinib has a pronounced peak-to-trough plasma pharmacokinetics profile and a relatively short half-life (∼3-5 h), which allows for complete recovery of BCR-ABL kinase activity within 8-12 hrs after a daily dose. The clinical efficacy of once daily dasatinib supports the notion that continuous target (BCR-ABL) inhibition is not required for anti-leukemic activity although the truncated exposure may help to ameliorate other side-effects of “on” or “off” targets inhibition. In addition to BCR-ABL, dasatinib potently inhibits SRC-family kinases (SFKs) with an IC50 in the low single digit nM range; SFKs play key roles in T cell activation. Based on continuous exposure studies, it had been suggested that dasatinib may act as an immunomodulator in vivo. We investigated the effects of variation in exposure duration in vivo and in vitro on the anti-leukemic and T cell activation inhibition activities of dasatinib in preclinical models. Methods. Anti-leukemic activity was determined in vitro in K562 and KU812 CML cell lines, and in vivo as xenografts in K562. BCR-ABL kinase activity was monitored with a phospho-specific CRKL antibody. Human T cells were isolated from PBMC by rosetting with sheep red blood cells and stimulated with anti-CD3/CD28 antibodies for 48 h. Cytokines production were measured by ELISA. T cell proliferation was determined at 3 days by 3H-thymidine incorporation. Immunocompetency of dasatinib treated mice were determined using the mouse cardiac allograft model and the in vivo MLR T cell proliferation model. Results. Transient (1-6 h) dasatinib exposure of CML cells that caused >80% inhibition of phospho-CRKL is highly cytotoxic. Degree of cytotoxicity directly correlates with the magnitude of BCR-ABL kinase inhibition. In vivo single dose of 30 mg/kg dasatinib administered IV was highly cytotoxic to K562 xenografts as determined by in vivo-in vitro colony formation assay. Intermittent IV dosing regimens of dasatinib (Q4D or Q7D) were effective against K562 xenografts. Dosing regimen in mice (5 mg/kg, PO) that closely mimic the pharmacokinetics of 100 mg oral dose in human was equally efficacious as administering the same dose in 2 split doses (BID, 2.5 mg/kg, PO). In terms of effects on T cell activation, a linear relationship was observed between serum concentration and in vitro T cell proliferation IC50 values. Modeling the human PK profile, delayed dasatinib treatment of T cells after T cell stimulation in vitro led to a time dependent decrease in potency as measured by both IC50 and Emax values. Comparison of serum adjusted IC50 values from these studies to the human PK profile suggests that dasatinib at the approved 100-mg once-daily dose would permit T cell activation on a daily basis. A similar pattern was observed in preclinical in vivo models. Dasatinib was found to be completely protective in a mouse model of cardiac allograft rejection at a dose of 25 mg BID, whereas a dose of 15 mg BID was not protective. In the MLR model, dasatinib inhibits T cell proliferation at 50 mg/kg but at the clinically relevant dose of 5 mg/kg was completely devoid of T cell inhibitory effects. Taken together, these results suggest that dasatinib may be able to provide anti-leukemic activity while avoiding suppression of T cell activation at clinically relevant doses. Disclosures: Schieven: Bristol-Myers Squibb Co: Employment. Zhang:Bristol-Myers Squibb Co: Employment. Pitt:Bristol-Myers Squibb Co: Employment. McGlinchey:Bristol-Myers Squibb Co: Employment. Menard:Bristol-Myers Squibb Co: Employment. Smykla:Bristol-Myers Squibb Co: Employment. Susulic:Bristol-Myers Squibb Co: Employment. Wen:Bristol-Myers Squibb Co: Employment. Wiebesiek:Bristol-Myers Squibb Co: Employment. Townsend:Bristol-Myers Squibb Co: Employment. Lee:Bristol-Myers Squibb Co: Employment.
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Gaber, Taqiuddine, Marius Bill, Madlen Jentzsch, Karoline Schubert, Heike Weidner, Laura Kloss, Laura Schmalbrock, et al. "Prognostic Implications of Pri-Mir-320a Expression in Acute Myeloid Leukemia Patients." Blood 124, no. 21 (December 6, 2014): 1037. http://dx.doi.org/10.1182/blood.v124.21.1037.1037.
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Abstract Background: Most acute myeloid leukemia (AML) patients (pts) stilldo not achieve long-term survival. Better risk stratification and novel therapeutic avenues are needed to improve pts outcomes. The expression of microRNAs has been demonstrated to be altered in AML & miR-based therapies are entering clinical trials. MiR-320a, maps to chromosome 8p21.3 & is known to play a role in several tumors; e.g. higher miR-320a expression suppresses the progression of colorectal cancer. In AML miR-320a has been shown to inhibit cell proliferation, likely by targeting the transferrin receptor 1. Objective: The objective of this study was to investigate whether a differential expression of pri-miR-320a associated with outcome in AML pts. Methods: We assessed the expression levels of pri-miR-320a, a precursor molecule of mature miR-320a. The pri-miR-320a expression levels in 129 AML pts were assessed by quantitative reverse transcription polymerase chain reaction & normalized to a housekeeping gene (18S). The 75th percentile was chosen as a cut-off discriminating between high & low pri-miR-320a expressers. We analyzed 129 AML pts (median age at HCT 64 years [y]; range 22–74 y) who received reduced intensity conditioning (RIC; Fludarabine 30mg/m^2 at day -4 to -2 & 2 Gy total body irradiation at day 0)-hematopoietic cell transplantation (HCT) at the University of Leipzig, with pretreatment bone marrow available. The median follow-up was 4.5 y for pts alive. European LeukemiaNet (ELN) genetic classification was: favorable (n=33; 25.6%), intermediate I (n=33; 25.6%), intermediate II (n=29; 22.5%) or adverse (n=30; 23.3%). The pts were also characterized for FLT3-ITD status, CEBPA, IDH1, IDH2 and NPM1 mutations. Results: At diagnosis high pri-miR-320a expression associated by trend with lower hemoglobin levels (P=.094), lower white blood cell counts (P=.079) & lower peripheral blast counts (P=.096). High pri-miR-320a expressers less frequently had NPM1 (P=.038) or CEBPA (P=.025) mutations. Interestingly, pri-miR-320a expression was significantly lower in pts with trisomy 8 (P=.018) compared to non-trisomy 8 pts & in the ELN intermediate II group none of the trisomy 8 pts was in the high pri-miR-320a expressing group. Analysis of our AML pts, showed a significant association between pri-miR-320a expression status & clinical outcome. In the entire group of pts high pri-miR-320a expressers had a longer overall survival (OS; P=.086; Figure 1) by trend & a significantly longer event-free survival (EFS; P=.032). The strongest impact of pri-miR-320a was found in the ELN intermediate II group, where high pri-miR-320a expression was associated by trend with longer OS (P=.059; Figure 1) & a significantly longer EFS (P=.034). In multivariate analysis, the prognostic impact of pri-miR-320a expression status was confirmed in the entire group of pts (OS: P<.01, hazard ratio (HR) 0.45, 95% confidence interval (CI) 0.27-0.75; EFS: P<.01, HR 0.45, 95% CI 0.28-0.71). Conclusion: High expression of pri-miR-320a associates with distinct clinical & molecular features. Interestingly, in AML pts with trisomy 8 pri-miR-320a that maps to chromosome 8 has a significantly lower expression, indicating a possible leukemogenic link to trisomy 8 associated AML. High pri-miR-320a expression significantly associates with better outcome especially in the ELN intermediate II group. These results suggest that pri-miR-320a could be used as a marker to refine current AML risk stratifications. Increasing miR-320a, by e.g. miR-replacement therapies, might improve outcomes of AML pts. Figure 1: Figure 1:. OS (A) and EFS (B) in AML pts according to pri-miRNA-320a expression status, OS (C) and EFS (D) in AML pts in the ELN intermediate II group according to pri-miRNA-320a expression status Disclosures No relevant conflicts of interest to declare.
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De Swart, Louise, Chloé Reiniers, Tim Bagguley, Corine van Marrewijk, David Bowen, Jaroslav Cermak, Eva Hellström-Lindberg, et al. "Hepcidin and GDF15 Levels during the First 2 Years Follow-up in Patients with Low and Int-1 Risk Myelodysplastic Syndromes (MDS) from the European Leukemianet MDS Registry." Blood 124, no. 21 (December 6, 2014): 3267. http://dx.doi.org/10.1182/blood.v124.21.3267.3267.
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Abstract Background: The EUMDS registry is a prospective observational registry to collect data on lower risk MDS. 17 Countries and 133 centers are participating. We analyzed serum from 101 patients for ferritin, hepcidin, growth differentiation factor 15 (GDF15) and C-reactive protein (CRP) at six-month intervals in order to evaluate temporal changes in iron metabolism. Objective: To explore hepcidin and GDF15 levels over time in lower risk MDS patients and their relation with WHO2001 subtype, transfusion history and conventional iron parameters. Results: The median age of the study population was 73 years (range 44-95 years). The majority was male: 64%. Distribution according to WHO2001 MDS subtype was RCMD (41%), RARS (25%), RA (14%), RAEB (11%), 5q-syndrome (6%) and RCMD-RS (3%). Table 1 shows iron parameters at registration, 1 year and 2 years follow-up both in transfusion-dependent (TD) and transfusion-independent (TI) patients and stratified according to MDS subtypes: RS (RARS/RCMD-RS) or MDS Other (RA/RCMD/RAEB/5q-syndrome). Serum ferritin was increased in TD patients with a median concentration at registration of 550µg/L and at 2 years 818µg/L, compared to TI patients (median <250µg/L, all time points). During follow-up ferritin was most elevated in patients who received >10 red blood cell (RBC) units: median at registration 1482µg/L - 2 years 1970µg/L. Ferritin correlated significantly with hepcidin (r=0.57; p<0.001) as well as CRP: r=0.27, p<0.001. Median CRP was within reference range (<10mg/L) for both TD and TI patients at registration and during follow-up, but mainly TD patients had elevated CRP levels >50mg/L. Median serum hepcidin levels were elevated in TD patients at registration and remained elevated during follow-up, especially in patients with >10 RBC units transfused (median 27.4nmol/l at registration, 12.8nmol/l at 2 years). Remarkable fluctuation in hepcidin levels occurred in patients with elevated hepcidin during follow-up. Even in the longitudinal cohorts hepcidin fluctuated considerably, maybe due to the interval between the previous transfusion and the measurement of hepcidin or due to diurnal fluctuation. Hepcidin was lowest in MDS RS TI patients and showed a tendency to decrease over time from a median level of 4.4nmol/l at registration to 2.4nmol/l after 2 years, associated with ineffective erythropoiesis. This is supported by the high median GDF15 in these patients. Lowest GDF15 was found in TD patients with ‘MDS Other’ associated with transfusional load. The number of transfused RBC units did not affect the median GDF15 levels. Conclusions: Hepcidin levels were influenced by RBC transfusion history, but hepcidin levels appear to decrease over time in the RS subtype only. Interestingly, increase in hepcidin after transfusions was already visible early in follow-up, depending on the transfusional load and erythropoietic activity of the bone marrow. GDF15 concentration appeared to be most related to MDS subtype, functioning as a marker of ineffective erythropoiesis. Table1: ferritin, hepcidin and GDF15 during-follow-up Registration 1 yr follow-up 2 yrs follow-up N Median (p25-p75) N Median (p25-p75) N Median (p25-p75) Ferritin (µg/L) 101 286 (138 - 558) 83 287 (149 - 845) 66 347 (191 - 818) MDS Other: TI 53 205 (87 - 389) 31 148 (78 - 288) 25 202 (71 - 319) MDS Other: TD 20 479 (279 - 877) 29 845 (481 - 1538) 22 841 (323 - 2387) RARS/RCMD-RS: TI 25 268 (195 - 558) 19 233 (170 - 323) 10 319 (222 - 379) RARS/RCMD-RS: TD 3 610 (108 - 1382) 4 1909 (1206 - 2935) 9 712 (590 - 1222) Hepcidin (nmol/L) 100 5.2 (3.0 - 9.9) 83 5.8 (2.7 - 14.0) 66 5.2 (2.5 - 9.9) MDS Other: TI 53 4.6 (2.8 - 8.4) 31 4.4 (2.3 - 8.1) 25 4.2 (2.5 - 6.8) MDS Other: TD 20 11.1 (4.9 - 21.0) 29 17.2 (9.2 - 22.3) 22 9.6 (4.5 - 17.1) RARS/RCMD-RS: TI 24 4.2 (2.1 - 6.1) 19 3.5 (1.6 - 5.1) 10 2.4 (1.6 - 3.9) RARS/RCMD-RS: TD 3 9.8 (6.0 - 11.1) 4 9.3 (7.3 - 12.1) 9 5.2 (2.9 - 9.3) TI: 0 RBC units 81 4.5 (2.8 - 8.4) 51 4.0 (2.0 - 7.5) 37 3.1 (2.1 - 6.7) TD: ≤10 RBC units 17 10.6 (4.7 - 14.9) 14 9.2 (5.3 - 17.2) 14 4.3 (2.4 - 8.7) TD: >10 RBC units 2 27.4 (15.7 - 39.1) 18 18.1 (12.7 - 24.5) 15 12.8 (9.3 - 21.3) GDF15 (ng/L) 101 1945 (1207 - 3611) 82 2467 (1659 - 4318) 66 2582 (1519- 5332) MDS Other: TI 53 1831 (1100 - 3176) 31 1902 (1076 - 2698) 25 1702 (1136 - 3564) MDS Other: TD 20 1452 (1169 - 2789) 28 2583 (1937 - 4493) 22 2556 (1661 - 4050) RARS/RCMD-RS: TI 25 3532 (2124 - 4211) 19 3148 (2195 - 4560) 10 3661 (1986 - 5524) RARS/RCMD-RS: TD 3 2196 (1869 - 2893) 4 2996 (1806 - 5141) 9 5555 (3204 - 7488) Disclosures Hellström-Lindberg: Celgene: Research Funding. Symeonidis:Celgene: Research Funding; Novartis Oncology: Research Funding; Amgen: Research Funding; Novartis Oncology: Consultancy; Amgen: Consultancy. de Witte:Novartis: Research Funding; Novartis: Honoraria; Celgene: Consultancy; Novartis: Consultancy.
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Carter, Joseph J., and Richard L. Whelan. "The Immunologic Consequences of Laparoscopy in Oncology." Surgical Oncology Clinics of North America 10, no. 3 (July 2001): 655–78. http://dx.doi.org/10.1016/s1055-3207(18)30056-5.
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Wang, Yan, Xiaojing Yu, Lihua Wang, Weiyuan Ma, and Qing Sun. "miR-320b Is Down-Regulated in Psoriasis and Modulates Keratinocyte Proliferation by Targeting AKT3." Inflammation 41, no. 6 (August 22, 2018): 2160–70. http://dx.doi.org/10.1007/s10753-018-0859-7.
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Dür, M., G. Steiner, V. Fialka-Moser, A. Kautzky-Willer, M. Stoffer, B. Prodinger, C. Dejaco, J. Smolen, and T. Stamm. "AB1179-HPR Associations between Occupational Balance and Immunology: Differences in Health Conditions, Employment Status Und Gender." Annals of the Rheumatic Diseases 73, Suppl 2 (June 2014): 1227.1–1227. http://dx.doi.org/10.1136/annrheumdis-2014-eular.3207.
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Strazzulla, Alessio, Maria Concetta Postorino, Nabil Belfeki, Laura Iordache, Astrid de Pontfarcy, Aurelia Pitsch, Pierre Leroy, Sebastien Jochmans, Mehran Monchi, and Sylvain Diamantis. "Risk of Multidrug Resistant Bacteria Acquisition in Patients with Declared β-Lactam Allergy during Hospitalization in Intensive Care Unit: A Retrospective Cohort Study (2007-2018)." Journal of Immunology Research 2022 (January 12, 2022): 1–6. http://dx.doi.org/10.1155/2022/8906316.
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Introduction. The risk of extended spectrum β-lactamase (ESBL) bacterial acquisition in patients with β-lactam allergy has been poorly investigated. In a previous study conducted over a 6-year long period (2007-2012), we found that patients with declared β-lactam allergy had a higher risk of ESBL bacterial carriage at admission in intensive care unit (ICU), but they had not a higher risk of ESBL bacterial acquisition. We present the final results of the study which was eventually conducted over a 12-year long period (2007-2018). Materials and Methods. The study included all patients admitted in ICU and receiving antibiotic treatment from January 2007 to December 2018. ESBL bacterial acquisition was the main clinical outcome. Mortality in ICU, multidrug resistant bacterial carriage at admission and discharge were the secondary outcomes. Results. Overall, 3332 patients were included, 132/3332 (3.9%) were labelled β-lactam allergic, while 3200/3332 (96.1%) did not presented β-lactam allergy. No significant difference in rates of ESBL acquisition was detected (4/132, 3% vs. 78/3200, 2.4%; p = 0.17 ). Patients with β-lactam allergy had higher rates of ESBL bacterial carriage at admission (19/132, 14.4% vs. 248/3200, 7.8%, p = 0.01 ) and at discharge (22/132, 16.7% vs. 351/3200, 11%, p = 0.04 ) than nonallergic patients. No differences in mortality, duration of hospitalization, and carriage of methicillin resistant Staphylococcus aureus were reported. Female gender was the only factor associated with β-lactam allergy at the multivariate analysis. Conclusions. This study confirms that patients with declared β-lactam allergy had not a higher risk of ESBL bacterial acquisition during hospitalization in ICU. However, they had a higher ESBL bacterial carriage at admission.
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Illmer, Christoph, Sibylle Madlener, Zsuzsanna Horvath, Philipp Saiko, Annemarie Losert, Irene Herbacek, Michael Grusch, Georg Krupitza, Monika Fritzer-Szekeres, and Thomas Szekeres. "Immunologic and Biochemical Effects of the Fermented Wheat Germ Extract Avemar." Experimental Biology and Medicine 230, no. 2 (February 2005): 144–49. http://dx.doi.org/10.1177/153537020523000209.
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Avemar (MSC) is a nontoxic fermented wheat germ extract demonstrated to have antitumor effects. Avemar has the potential to significantly improve the survival rate in patients suffering from malignant colon tumors. We studied its effects in the HT-29 human colon carcinoma cell line. Avemar had an inhibiting effect on colonies of HT-29 cells with an IC50 value of 118 μg/ml (7 days of incubation); this value could be decreased to 100 and 75 μg/ml in the presence of vitamin C. In the cell line examined, Avemar induced both necrosis and apoptosis, as demonstrated by Hoechst/propldium iodide staining. The incubation of cells with 3200 μg/ml Avemar for 24 hrs caused necrosis in 28% and the induction of apoptosis in 22% of the cells. Avemar inhibited the cell-cycle progression of HT-29 cells in the G1 phase of the cell cycle. In addition, Avemar inhibited the activity of the key enzyme of de novo DNA synthesis, ribonucleotide reductase. In addition, we determined the effects of Avemar on the activity of cyclooxygenase-1 and -2. Both enzymes were significantly inhibited by Avemar with IC50 values of 100 and 300 μg/ml, respectively. We outline new explanations for its antitumor activity, which might serve as the basis for further studies using Avemar.
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Jeong, Kyunguk, Mincheol Kim, Se Ah Jeon, Young‐Hoo Kim, and Sooyoung Lee. "A randomized trial of Lactobacillus rhamnosus IDCC 3201 tyndallizate (RHT3201) for treating atopic dermatitis." Pediatric Allergy and Immunology 31, no. 7 (May 31, 2020): 783–92. http://dx.doi.org/10.1111/pai.13269.
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Diakos, Christofer, Sheng Zhong, Yuanyuan Xiao, Mi Zhou, Gisele M. Vasconcelos, Gerd Krapf, Ru-Fang Yeh, et al. "TEL-AML1 regulation of survivin and apoptosis via miRNA-494 and miRNA-320a." Blood 116, no. 23 (December 2, 2010): 4885–93. http://dx.doi.org/10.1182/blood-2009-02-206706.
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Abstract There is increasing evidence that miRNA and transcription factors interact in an instructive fashion in normal and malignant hematopoiesis. We explored the impact of TEL-AML1 (ETV6-RUNX1), the most common fusion protein in childhood leukemia, on miRNA expression and the leukemic phenotype. Using RNA interference, miRNA expression arrays, and quantitative polymerase chain reaction, we identified miRNA-494 and miRNA-320a to be up-regulated upon TEL-AML1 silencing independently of TEL expression. Chromatin immunoprecipitation analysis identified miRNA-494 as a direct miRNA target of the fusion protein TEL-AML1. Using bioinformatic analysis as well as functional luciferase experiments, we demonstrate that survivin is a target of the 2 miRNAs. miRNA-494 and miRNA-320a were introduced to the cells by transfection and survivin expression determined by Western blot analysis. These miRNAs blocked survivin expression and resulted in apoptosis in a similar manner as TEL-AML1 silencing by itself; this silencing was also shown to be Dicer-dependent. miRNAs-494 and -320a are expressed at lower levels in TEL-AML1+ leukemias compared with immunophenotype-matched nonTEL-AML1 acute lymphoblastic leukemia subtypes, and within TEL-AML1+ leukemias their expression is correlated to survivin levels. In summary our data suggest that TEL-AML1 might exert its antiapoptotic action at least in part by suppressing miRNA-494 and miRNA-320a, lowering their expression causing enhanced survivin expression.
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Rosenberg, Yvonne, Chunyuan Luo, Yacov Ashani, Bhupendra P. Doctor, Randy Fischer, Gary Wolfe, and Ashima Saxena. "Pharmacokinetics and immunologic consequences of exposing macaques to purified homologous butyrylcholinesterase." Life Sciences 72, no. 2 (November 2002): 125–34. http://dx.doi.org/10.1016/s0024-3205(02)02203-8.
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Han, Hu, and Lijuan Liu. "Long noncoding RNA TUG1 regulates degradation of chondrocyte extracellular matrix via miR-320c/MMP-13 axis in osteoarthritis." Open Life Sciences 16, no. 1 (January 1, 2021): 384–94. http://dx.doi.org/10.1515/biol-2021-0037.
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Abstract Osteoarthritis (OA) is a common chronic joint disease. This study aimed to explore the function of long noncoding RNA taurine-upregulated gene 1 (TUG1) in the progression and initiation of OA. Levels of TUG1, microRNA-320c (miR-320c) and fucosyltransferase 4 (FUT4) were examined via quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide and flow cytometry assays were used to detect cell viability and apoptosis, respectively. The expression of relative proteins was measured using Western blot. The interaction between miR-320c and TUG1 or FUT4 was confirmed utilizing dual-luciferase reporter and RNA immunoprecipitation assays. In this study, levels of TUG1 and FUT4 were distinctly upregulated, but miR-320c level significantly decreased in OA tissues and chondrocytes derived from OA tissues as well as in IL-1β-stimulated C28/I2 cells. Mechanically, TUG1 sponged miR-320c and miR-320c targeted FUT4. In addition, TUG1 knockdown accelerated cell proliferation and repressed apoptosis and extracellular matrix (ECM) degradation in IL-1β-induced C28/I2 cells, whereas these effects of TUG1 deletion were rescued by either miR-320c inhibitor or FUT4 upregulation. Meanwhile, TUG1 sponged miR-320c to regulate FUT4 expression in IL-1β-induced C28/I2 cells. Collectively, TUG1 modulated cell proliferation, apoptosis and ECM degradation in IL-1β-induced C28/I2 cells via the miR-320c/FUT4 axis, providing a new insight into the OA treatment.
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LEE, SANG-WON, YONG-BEOM PARK, JUNG-SOO SONG, and SOO-KON LEE. "The Mid-Range of the Adjusted Level of Ferritin Can Predict the Chronic Course in Patients with Adult Onset Still’s Disease." Journal of Rheumatology 36, no. 1 (January 2009): 156–62. http://dx.doi.org/10.3899/jrheum.080537.
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Objective.To find a measure that can predict the disease course in patients with adult onset Still’s disease (AOSD).Methods.We retrospectively investigated the medical records of 71 hospitalized patients with AOSD. Patients were divided according to chronic and nonchronic disease course. The initial laboratory results were defined as those at the time of admission, the extremely deviated laboratory results as the highest or the lowest results, and the adjusted laboratory results as area under the curve divided by the days of hospitalization. All measures were compared and the odds ratio (OR) for the chronic disease pattern was assessed.Results.The mean age was 39.7 ± 13.5 years and women accounted for 63 of the total 71 (88.7%). Thirty patients (42.3%) had self-limited disease, 9 (12.7%) intermittent disease, and 23 (32.4%) the chronic disease pattern (32.4%). Nine patients (12.7%) died. The initial levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and ferritin, the highest levels of lactate dehydrogenase (LDH) and ferritin, and the adjusted level of ferritin in patients with chronic disease were significantly higher than those with nonchronic disease. Among them, only the middle range of the adjusted ferritin level (784.1~4120.0 ng/ml) was found to have a significant predictive value for the chronic disease pattern (OR 81.7, p = 0.007).Conclusion.A novel measure, the adjusted level of ferritin during the first hospitalization, might be useful to predict progression to chronic disease in patients with AOSD.
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Wieber, K., X. Baraliakos, J. Braun, and S. Capellino. "Abstract # 3209 The dopaminergic pathway – A potential new route to modulate inflammation in rheumatoid arthritis." Brain, Behavior, and Immunity 81 (October 2019): 2. http://dx.doi.org/10.1016/j.bbi.2019.08.013.
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Schalbetter, S. M., T. Notter, F. Müller, J. Scarborough, D. Mattei, U. Weber, J. Richetto, and U. Meyer. "Abstract # 3224 Role of microglia deficiency in brain maturation and behaviors relevant to neurodevelopmental disorders." Brain, Behavior, and Immunity 81 (October 2019): 5. http://dx.doi.org/10.1016/j.bbi.2019.08.024.
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Bruchard, Mélanie, Cédric Rebé, Valentin Derangère, Dieudonnée Togbé, Bernhard Ryffel, Romain Boidot, Etienne Humblin, et al. "The receptor NLRP3 is a transcriptional regulator of TH2 differentiation." Nature Immunology 16, no. 8 (June 22, 2015): 859–70. http://dx.doi.org/10.1038/ni.3202.
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Silke, John, James A. Rickard, and Motti Gerlic. "The diverse role of RIP kinases in necroptosis and inflammation." Nature Immunology 16, no. 7 (June 18, 2015): 689–97. http://dx.doi.org/10.1038/ni.3206.
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Winter, Deborah R., and Ido Amit. "DCs are ready to commit." Nature Immunology 16, no. 7 (June 18, 2015): 683–85. http://dx.doi.org/10.1038/ni.3208.
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Suriyaphan, Nattanit, Pimpin Incharoen, Songporn Oranratnachai, Pimtip Sanvarinda, Narumol Trachu, Dittapol Muntham, Phichai Chansriwong, and Thanyanan Reungwetwattana. "Correlation of clinical characteristics and immunologic profile of stage III NSCLC patients." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e20552-e20552. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e20552.
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e20552 Background: Recently, immunotherapy has significantly increased mPFS and mOS in unresectable stage III NSCLC whom completed concurrent chemoradiation (CCRT). Predictive biomarker for immunotherapy in this setting has not been established yet. Methods: This is a retrospective study in stage III NSCLC patients in Ramathibodi hospital between year of 2013 and 2019. Clinical data of 176 patients were retrieved from electronic medical record. Only 64 patients had adequate tissue for tissue array for immunohistochemistry (IHC) staining of protein expression in CD3, CD4, CD8, FOXP3, PDL-1, CD163, CD 138, CD20 in stroma and tumor cells. We also performed IHC staining for Microsatellite Instability (MSI). Optimum cut point for each protein expression was performed by C-statistic. Survival analysis was performed. All statistical analysis was performed by Stata version 15. Results: Of 176 patients, majority of patient were male (63.6%), age ≥65 years (63.6%), never-smoker (40.9%), stage IIIB (44.9%) and adenocarcinoma (67.6%). EGFR-positive patients were 47.7%. Most of the patients underwent CCRT (32.4%), only 11.9% underwent trimodality treatment. Doublet-carboplatin based chemotherapy was the most common regimen (61.5%). The mOS was 2.9 years and mPFS was 1.6 years. Multivariable analysis showed stage IIIB patients, patients whom received only systemic treatment or best palliative care had significantly shorter OS. Trimodality treatment showed significantly longer OS compared to bimodality (CCRT) (HR = 0.18, P= 0.02), as well as cisplatin-based chemotherapy had significantly longer OS compared to carboplatin-based regimen (HR = 0.47, P= 0.005). Of 64 patients whom had tissue testing in our study, majority of patients had of MSI-low (81.25%), PD-L1 negative (78.13%). Regarding tumor microenvironment, patients with high protein expression of CD3, CD4, CD8 and CD20 in stromal cells showed significantly longer OS, whereas MSI and PD-L1 were not significantly associated with survival outcomes. Conclusions: OS in stage III NSCLC in our population (2.9 years) is comparable with other studies (2.4 years). Trimodalities treatment significantly increased OS compared to CCRT. High protein expression of CD3, CD4, CD8 and CD20 in stroma probably potential prognostic and predictive biomarkers for immunotherapy in stage III NSCLC. Larger cohort is needed to explore.
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Kong, Li, Yang Sun, Maosheng Chen, Yan Dai, and Zhen Liu. "Downregulation of microRNA‑320a inhibits proliferation and induces apoptosis of retinoblastoma cells via targeting TUSC3." Experimental and Therapeutic Medicine 20, no. 5 (August 25, 2020): 1. http://dx.doi.org/10.3892/etm.2020.9137.
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Angela Tosca, Maria, Gian Luigi Marseglia, Giorgio Ciprandi, and ControL’Asma” Study Group. "The real-world “ControL’Asma” study: a nationwide taskforce on asthma control in children and adolescents." Allergologia et Immunopathologia 49, no. 1 (January 2, 2021): 32–39. http://dx.doi.org/10.15586/aei.v49i1.14.
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Background: Asthma control is the goal of asthma management. A nationwide study on this aspect was launched by the Italian Society of Paediatric Allergy and Immunology (ControL’Asma study). Objective: To define variables associated with different asthma control grades in a nationwide population of asthmatic children and adolescents. Methods: This cross-sectional real-world study included 480 asthmatic children and adolescents (333 males, median age 11.2 years) consecutively enrolled in 10 third level pediatric allergy clinics. According to the Global Initiative for Asthma (GINA) document, history, medication use, perception of asthma symptoms assessed by visual analog scale (VAS), clinical examination, lung function, childhood asthma control test (cACT)/asthma control test (ACT), and asthma control level were evaluated. Results: Considering GINA criteria, asthma was well controlled in 55% of patients, partly controlled in 32.4%, and uncontrolled in 12.6%. Regarding cACT/ACT, asthma was uncontrolled in 23.2%. Patients with uncontrolled asthma had the lowest lung function parameters and VAS scores, more frequent bronchial obstruction and reversibility, and used more oral and inhaled corticosteroids (CS). Conclusions: The ControL’Asma study, performed in a real-world setting, showed that asthma in Italian children and adolescents was usually more frequent in males. Asthmatic patients had an early onset and allergic phenotype with very frequent rhinitis comorbidity. Uncontrolled and partly controlled asthma affected about half of the subjects, and the assessment of asthma symptom perception by VAS could be a reliable tool in asthma management.
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Sawicki, Caroline M., January K. Kim, Michael D. Weber, Timothy D. Faw, Kathryn M. Madalena, Jessica K. Lerch, D. Michele Basso, Jonathan P. Godbout, and John F. Sheridan. "Abstract # 3205 The Role of Microglia in the Development and Exacerbation of Stress-Induced Pain Behavior." Brain, Behavior, and Immunity 76 (February 2019): e43. http://dx.doi.org/10.1016/j.bbi.2018.11.310.
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Knight, J., J. D. Rizzo, T. Wang, N. He, B. R. Logan, S. R. Spellman, S. J. Lee, M. R. Verneris, J. M. Arevalo, and S. W. Cole. "Abstract # 3208 Molecular correlates of socioeconomic status predict acute myelogenous leukemia relapse following hematopoietic cell transplantation." Brain, Behavior, and Immunity 81 (October 2019): 1–2. http://dx.doi.org/10.1016/j.bbi.2019.08.012.
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Hanna Jr, Michael. "Portrait of Dr Michael G. Hanna, Jr." Human Vaccines & Immunotherapeutics 10, no. 7 (July 7, 2014): 1778–80. http://dx.doi.org/10.4161/hv.32094.
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Ladwig, Karl-Heinz, Birgitt Marten-Mittag, Hannelore Löwel, Angela Döring, and Wolfgang Koenig. "Influence of depressive mood on the association of CRP and obesity in 3205 middle aged healthy men." Brain, Behavior, and Immunity 17, no. 4 (August 2003): 268–75. http://dx.doi.org/10.1016/s0889-1591(03)00056-4.
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Niraula, A., J. F. Sheridan, and J. P. Godbout. "Abstract # 3200 IL-6 production during repeated social defeat stress primes monocytes to induce anxiety-like behavior." Brain, Behavior, and Immunity 76 (February 2019): e42-e43. http://dx.doi.org/10.1016/j.bbi.2018.11.309.
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Wangrangsimakul, Tri, Rachel C. Greer, Chulapong Chanta, Supalert Nedsuwan, Stuart D. Blacksell, Nicholas P. J. Day, and Daniel H. Paris. "Clinical Characteristics and Outcome of Children Hospitalized With Scrub Typhus in an Area of Endemicity." Journal of the Pediatric Infectious Diseases Society 9, no. 2 (March 13, 2019): 202–9. http://dx.doi.org/10.1093/jpids/piz014.
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Abstract Background Scrub typhus, caused by Orientia tsutsugamushi, is a major cause of acute febrile illness in children in the rural tropics. Methods We recruited 60 febrile pediatric patients with a positive scrub typhus rapid diagnostic test result and 40 healthy controls from Chiang Rai Province in northern Thailand. Diagnosis was confirmed by the detection of (1) O. tsutsugamushi–specific DNA in blood or eschar samples with a polymerase chain reaction assay, (2) a fourfold rise in immunoglobulin M (IgM) titer to ≥1:3200 in paired plasma samples with an indirect immunofluorescence assay (IFA), or (3) a single IgM titer of ≥1:3200 in an acute plasma sample with an IFA. Demographic, clinical, and laboratory data were collected, and patients were followed up for 1 year. Results Diagnosis was confirmed in 35 (58%) of 60 patients, and all controls tested negative for scrub typhus. Patients with confirmed scrub typhus had clinical symptoms, including fever (35 of 35 [100%]), eschar (21 of 35 [60%]), cough (21 of 35 [60%]), tachypnea (16 of 35 [46%]), lymphadenopathy (15 of 35 [43%]), and headache (14 of 35 [40%]). Only 4 (11%) of 35 patients received appropriate antibiotic treatment for scrub typhus before admission. The median fever-clearance time was 36 hours (interquartile range, 24–53 hours). Complications observed include hepatitis (9 of 35 [26%]), severe thrombocytopenia (7 of 35 [20%]), pneumonitis (5 of 35 [14%]), circulatory shock (4 of 35 [11%]), and acute respiratory distress syndrome (3 of 35 [9%]). Treatment failure, defined by failure to defervesce within 72 hours of antibiotic treatment initiation, was noted in 8 (23%) of 35 patients, and 1 (3%) of the 35 patients died. No evidence of relapse or reinfection was found. Conclusion Pediatric scrub typhus in northern Thailand is often severe and potentially fatal with delays in treatment a likely contributing factor. Additional studies to investigate the bacterial, pharmacologic, and immunologic factors related to treatment outcome along with measures to improve public awareness should be prioritized.
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Honma, Daisuke, Emi Nosaka, Machiko Shiroishi, Yoshimi Takata, Yasuhiro Hama, Yuka Yamamoto, Nobuaki Adachi, et al. "DS-3201, a Potent EZH1/2 Dual Inhibitor, Demonstrates Antitumor Activity Against Non-Hodgkin Lymphoma (NHL) Regardless of EZH2 Mutation." Blood 132, Supplement 1 (November 29, 2018): 2217. http://dx.doi.org/10.1182/blood-2018-99-113379.
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Abstract Enhancer of zests homologous (EZH)1 and its close homolog EZH2 are component of polycomb repressive complex (PRC) 2 protein complex, and play redundant and crucial role for the maintenance of transcriptional repression by tri-methylating histone H3 lysine 27 (H3K27). Hyper tri-methylation of H3K27 has been associated with lymphoma and myeloma progression, suggesting that PRC2 is a therapeutic target for hematological malignancies. Selective EZH2 inhibitors induce compensatory activation of EZH1 which in turn re-activates PRC2 function. We hypothesized that dual inhibition of EZH1 and EZH2 is more effective than selective EZH2 inhibition as anti-tumor therapy. We have developed a novel EZH1 and EZH2 dual inhibitor DS-3201, which simultaneously inhibited the enzymatic activity of EZH1 and EZH2 in nano-molar concentration. DS-3201 showed anti-proliferative effect against various NHL cells, such as diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and peripheral T-cell lymphoma, with GI50 values less than 100 nM regardless of EZH2 gain-of-function mutations. DS-3201 also induced differentiation of undifferentiated NHL cells with increment of cell lineage specific markers and which induced cell death in vitro. DS-3201 also showed synergistic effect with the standard of care agents for NHL in vitro and in vivo. An open-label phase 1 clinical study was initiated to examine the safety and pharmacokinetics of multiple-dose monotherapy of DS-3201b which is the salt form of DS-3201 in patients with NHL (ClinicalTrials.gov Identifier: NCT02732275). Eighteen patients with relapsed or refractory NHL were enrolled. The patients received oral administration of DS-3201b once daily in a 28-day cycle at dose of 150, 200 and 300 mg. Preliminary efficacy results (D. Maruyama, et al. ASH 2017), showed that the overall response rate was 58.8% (10/17) with 1 complete response and 9 partial responses (PR). Thirteen NHL patients including five follicular lymphoma (FL) and one DLBCL were analyzed for gene mutation status by targeted gene sequencing. EZH2 mutation was detected only in one FL patient, who achieved PR. It was suggested that DS-3201b has clinical activity against NHL, regardless of the mutation status of EZH2. Disclosures Honma: Daiichi Sankyo: Employment. Nosaka:Daiichi Sankyo: Employment. Shiroishi:Daiichi Sankyo: Employment. Takata:Daiichi Sankyo: Employment. Hama:Daiichi Sankyo: Employment. Yamamoto:Daiichi Sankyo RD Novare: Employment. Adachi:Daiichi Sankyo: Employment. Maruyama:Mundipharma International: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Dai-ichi-Sankyo: Honoraria; Bristol-Myers Squibb: Honoraria; Biomedis International: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Fujifilm: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Dai-Nippon-Sumitomo: Honoraria; Asahi Kasei Pharma: Honoraria; AstraZeneca: Research Funding; Solasia Pharma: Research Funding; Pfizer: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Novartis: Research Funding; Otsuka: Research Funding; Amgen Astellas BioPharma: Research Funding; Astellas Pharma: Research Funding; Abbvie: Research Funding; GlaxoSmithKline: Research Funding; Zenyaku Kogyo: Honoraria, Research Funding. Tobinai:Chugai Pharma: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Eisai: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SERVIER: Research Funding; Abbvie: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; HUYA Bioscience International: Consultancy, Honoraria. Ishida:Kyowa Hakko Kirin Co.Ltd: Honoraria, Research Funding; Celgene K.K: Honoraria, Research Funding; Bayer AG: Research Funding; Mundiparma K: Honoraria. Kusumoto:Bristol-Myers Squibb: Honoraria, Research Funding; Chugai Pharmaceutical Co. Ltd: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding. Tsukasaki:Daiich-Sankyo: Consultancy; Ono Pharma: Consultancy; HUYA: Consultancy, Research Funding; Chugai Pharma: Honoraria, Research Funding; Eisai: Research Funding; Celgene: Honoraria; Mundy Pharma: Honoraria; Kyowa-hakko/Kirin: Honoraria; Seattle Genetics: Research Funding. Fujioka:Daiichi Sankyo: Employment. Watanabe:Daiichi Sankyo: Employment. Kanno:Daiichi Sankyo: Employment. Kumazawa:Daiichi Sankyo RD Novare: Employment. Fujitani:Daiichi Sankyo: Employment. Araki:Daiichi Sankyo: Employment. Fujiwara:Daiichi Sankyo: Employment.
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ANDERSEN, TRINE, LEA MUNTHE-FOG, PETER GARRED, and SØREN JACOBSEN. "Serum Levels of Ficolin-3 (Hakata Antigen) in Patients with Systemic Lupus Erythematosus." Journal of Rheumatology 36, no. 4 (February 4, 2009): 757–59. http://dx.doi.org/10.3899/jrheum.080361.
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Objective.Ficolin-3 is a serum protein of putative importance in autoimmunity. Our objective was to investigate any differential expression of ficolin-3 in patients with systemic lupus erythematosus (SLE) or its clinical subsets.Methods.Serum levels of ficolin-3 (S-ficolin-3) were determined in 95 patients with SLE and 103 healthy controls using an ELISA.Results.Median S-ficolin-3 was 56.1 μg/ml (range 0 to ≥ 87.3) and 32.4 μg/ml (10 to ≥ 87.3) in patients and controls, respectively (p < 0.001). Increased S-ficolin-3 was associated with hemolysis, positive Coombs test, and lymphopenia, but not with SLE Disease Activity Index scores or C-reactive protein. In one patient without detectable S-ficolin-3, the FCN3 gene appeared normal.Conclusion.The elevation of S-ficolin-3 and its association with specific manifestations in SLE may indicate a pathogenetic role of ficolin-3 in SLE.
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Batra, Suruchi K., Christopher R. Heier, Lina Diaz-Calderon, Christopher B. Tully, Alyson A. Fiorillo, John van den Anker, and Laurie S. Conklin. "Serum miRNAs Are Pharmacodynamic Biomarkers Associated With Therapeutic Response in Pediatric Inflammatory Bowel Disease." Inflammatory Bowel Diseases 26, no. 10 (August 14, 2020): 1597–606. http://dx.doi.org/10.1093/ibd/izaa209.
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Abstract Background We sought to identify microRNAs (miRNAs) associated with response to anti-TNF-α or glucocorticoids in children with inflammatory bowel disease (IBD) to generate candidate pharmacodynamic and monitoring biomarkers. Methods Clinical response was assessed by Pediatric Crohn’s Disease Activity Index and Pediatric Ulcerative Colitis Activity Index. Quantitative real-time polymerase chain reaction via Taqman Low-Density Array cards were used to identify miRNAs in a discovery cohort of responders (n = 11) and nonresponders (n = 8). Seven serum miRNAs associated with clinical response to treatment, along with 4 previously identified (miR-146a, miR-146b, miR-320a, miR-486), were selected for further study. Candidates were assessed in a validation cohort of serum samples from IBD patients pre- and post-treatment and from healthy controls. Expression of miRNA was also analyzed in inflamed mucosal biopsies from IBD patients and non-IBD controls. Results Discovery cohort analysis identified 7 miRNAs associated with therapeutic response: 5 that decreased (miR-126, miR-454, miR-26b, miR-26a, let-7c) and 2 that increased (miR-636, miR-193b). In the validation cohort, 7 of 11 candidate miRNAs changed in the same direction with response to anti-TNF-α therapies, glucocorticoids, or both. In mucosal biopsies, 7 out of 11 miRNAs were significantly increased in IBD vs healthy controls. Conclusions Five candidate miRNAs associated with clinical response and mucosal inflammation in pediatric IBD patients were identified (miR-126, let-7c, miR-146a, miR-146b, and miR-320a). These miRNAs may be further developed as pharmacodynamic and response monitoring biomarkers for use in clinical care and trials.