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1
Fernandes, Juliano José R., Lorena E. L. M. Bomfim, Daniel Augusto A. Teixeira, Victor R. M. Couto, and Ana Laura A. Lopes. "PSXII-38 Effect of crude protein sources on feedlot performance and carcass traits of Nellore young bulls." Journal of Animal Science 97, Supplement_3 (December 2019): 426. http://dx.doi.org/10.1093/jas/skz258.845.
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Abstract In this trial, 120 Nellore young bulls of ± 386kg kg initial weight were used to evaluate the effect of different sources of crude protein on the feedlot performance (finishing phase) and carcass characteristics. Animals were maintained in fifteen pens for 105 days. Animals were individually weighed and blocked by initial body weight. Pens within a block were randomly assigned to one of three treatments: (D14) Control diet including 14% of crude protein (CP) on dry matter; (D12) Inclusion of 12.5% CP/dry matter and (D11), inclusion of 11% of CP/dry matter. Feed offered was monitored daily as well as feed refusals were collected and weighed to determine the DMI and feed efficiency (F:G). Animals were weighed every 28 d after 16 h feed withdrawal for calculating ADG. The D14 and D12 treatments increased the final weight (P = 0.008) when compared to D11 (564.13; 550.96 and 529.73 kg, respectively). The D14 treatment increased the ADG (1.69 kg; P = 0.002) when compared to D12 (1.54 kg) and D11 animals (1.35 kg). The same was observed for DMI (P = 0.001) (10.40kg, 9.77kg e 8.68kg, respectively) and % BW (P = 0.001), when D14 had the greatest value (2.2%), and D11 the worst (1.90%). There were no effect of the treatments for F:G (P = 0.202). Hot carcass weight was increased by the D14 treatment (P = 0.006) (311.97kg; 300.55 and 289.30kg, respectively). However, the cooling losses were not affected (P = 0.0843), as well as were observed for dressing (P = 0.089). Nevertheless, the carcass daily gain was improved by the D14 (P = 0.02), with animals increasing 1.13 kg/d; D12 with 1.01kg/d and D11, 0.91 kg. In conclusion, the sources of crude protein can affect the feedlot cattle performance, in agreement with the Brazilian Nellore requirement program (Br-Corte). However, in this trial, diets with 14% of CP improved the animal’s performance.
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Banek, Christopher T., Ashley J. Bauer, Anne Gingery, and Jeffrey S. Gilbert. "Timing of ischemic insult alters fetal growth trajectory, maternal angiogenic balance, and markers of renal oxidative stress in the pregnant rat." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 303, no. 6 (September 15, 2012): R658—R664. http://dx.doi.org/10.1152/ajpregu.00250.2012.
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Increased uterine artery resistance and angiogenic imbalance characterized by increased soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased free vascular endothelial growth factor (VEGF) are often associated with placental insufficiency and preeclampsia but not synonymous with hypertension. We hypothesized chronic reductions in utero-placental perfusion (RUPP) for 5 days (d) during either mid- (d12–d17) or late (d14–d19) gestation would have disparate effects on plasma sFlt-1 and VEGF levels and blood pressure. Five days of chronic RUPP was achieved by placement of silver clips on the abdominal aorta and ovarian arteries on either gestational d12 or d14. Arterial pressure was increased ( P < 0.05) in RUPP vs. normal pregnant (NP) in both d17 (10%) and d19 (25%) groups, respectively. Circulating free VEGF was decreased ( P < 0.05) and sFlt-1:VEGF ratio increased ( P < 0.05) after 5 days of RUPP ending on d19 but not d17 compared with NP controls. Angiogenic imbalance, measured by an endothelial tube formation assay, was present in the d19 RUPP but not the d17 RUPP compared with age-matched NP rats. Five days of RUPP from days 14 to 19 decreased fetal and placental weights 10% ( P < 0.01) compared with d19 NP controls. After 5 days of RUPP, from days 12 to 17 of pregnancy, fetal weights were 21% lighter ( P < 0.01) compared with d17 NP controls, but placental weight was unchanged. These findings suggest that the timing during which placental insufficiency occurs may play an important role in determining the extent of alterations in angiogenic balance, fetal growth restriction, and the severity of placental ischemia-induced hypertension.
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Liu, Dongxia, Qingrui Yang, Ming Li, Kun Mu, and Yuanchao Zhang. "Association of an asporin repeat polymorphism with ankylosing spondylitis in Han Chinese Population: A case-control study." Clinical & Investigative Medicine 33, no. 1 (February 1, 2010): 63. http://dx.doi.org/10.25011/cim.v33i1.11839.
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Objective: To investigate the role of a functional polymorphism consisting of an aspartic acid (D) repeat located in the asporin gene (ASPN) gene in the susceptibility to and clinical outcome of ankylosing spondylitis (AS). Methods: A total of 374 Chinese patients with ankylosing spondylitis and 421 controls of the same ethnic origin matched for age and sex were included in the study. The asporin D repeat polymorphism was genotyped by polymerase chain reaction with a fluorescent primer. Results: Significant differences between AS patients and controls were detected in the distribution of the 7 alleles found in our population. D14 and D16 alleles were significantly over-represented in AS patients (D14, P=0.001, odds ratio (OR)=1.857, 95% confidence interval(CI) 1.27-2.715; and D16, P < 0.0001, OR=2.605, 95% CI 1.75-3.879). D16 over-representation was more common in early-onset patients than in late-onset patients, although the difference did not reach significance (P= 0.071). Conclusion: The results support a role for an asporin D repeat polymorphism in the susceptibility to AS and an influence of this gene on the outcome of the disease. D14 and D16 allele variants of ASPN might be the susceptibility alleles for AS in the Han Chinese population, whereas the D13 allele variant may have a protective effect on the onset of AS.
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Brito dos Santos, Susana, Mark C. Allenby, Athanasios Mantalaris, and Nicki Panoskaltsis. "Early Erythroid Development Is Enhanced with Hypoxia and Terminal Maturation with Normoxia in a 3D Ex Vivo Physiologic Eythropoiesis Model." Blood 128, no. 22 (December 2, 2016): 2453. http://dx.doi.org/10.1182/blood.v128.22.2453.2453.
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Abstract Reproduction of dynamic physiologic erythropoiesis in vitro requires a three-dimensional (3D) architecture, erythroblast-macrophage interactions and cytokines such as erythropoietin (EPO). The role of oxygen concentration gradients in this process is unclear. We have created a 3D bone marrow (BM) biomimicry using collagen-coated polyurethane scaffolds (5mm3) to expand cord blood mononuclear cells (CBMNCs) in a cytokine-free environment for 28 days (D). Addition of EPO to this system induces mature erythropoiesis. We hypothesised that physiologic concentrations of cytokines - stem cell factor (SCF) / EPO - and a hypoxia (H)/normoxia (N) schedule to mimic BM oxygen gradients would enhance erythropoiesis. CBMNCs were seeded (4x106 cells/scaffold) in 3D serum-free cultures supplemented with 10ng/mL SCF (D0-D28), and 100mU/mL EPO (D7-D28), with medium exchange every 3D. Three conditions were compared: N (20%), H (5%) and 2-step oxygenation HN (H D0-D7 and N thereafter). Erythroid maturation was monitored weekly by flow cytometry (CD45/CD71/CD235a) both in situ (i.e., in scaffolds) and in supernatant (S/N) cells. D0-7 H was more efficient in early induction of CD235a in the absence of exogenous EPO (H 13% vs N 8% CD45loCD71+CD235alo cells, p<0.05). This maturation profile was also observed in D10 S/N cells, in which CD45loCD71+CD235a+ cells were proportionately more in H (30%) and HN (27%) than in N (16%, p<0.05). By D14, N and HN stimulated the appearance of CD45-CD71+CD235a+ cells, whereas H maintained the CD45loCD71+CD235a-/lo phenotype. By D21, a CD45-CD71+CD235a+ mature population was clearly distinguished in all conditions, most notably in N (16%) and HN (21%) vs H (9%). At D28, more mature CD45-CD71loCD235a+ cells were observed in normoxia conditions, N 3% and HN 4%, vs H 0.3%. A renewed population of erythroid progenitors was also evident at this time (H 62%, N 51% and HN 46% CD45loCD71lo/+CD235a- cells). In order to assess the impact of H and N on erythroid gene transcription, we evaluated erythroid signatures by qRT-PCR. GATA-1 expression was detected from D7, highest for H at D14 (p<0.05), and decreased thereafter. GATA-2 expression was up-regulated only at D28, in particular in N (p<0.05), and correlated with emerging erythroid progenitors identified at this stage. At D14, EPOR expression was maximal, especially in HN (p<0.05), simultaneous with high pSTAT5 levels, suggesting activation of EPOR signalling. Also at D14, H upregulated γ-globin (p<0.05). By Western Blot, only H and HN still produced γ-globin whereas β-globin expression was clearly detected in all conditions by D28. In situ production of cytokines was evaluated by cytometric bead array in the exhausted media. IL-6, G-CSF, GM-CSF, IL-1, TNF-α and IL-17 were detected at higher concentrations during the first 7 days, declining to undetectable thereafter. IL-21 was not detected at any point. IL-3 was detected from D13, with highest expression in H (p<0.05, D22). VEGF was also expressed after D7, highest in H (p<0.05, D16 & D19), concurrent with HIF-1α up-regulation observed at D7 and D14. TNF-α was produced with variable intensity from D4. These data suggested that D7-D14 was a crucial period for culture dynamics, in particular for H and HN, with up-regulation of erythroid transcription factors, EPOR signalling, and endogenous cytokine production. BFU-E and CFU-E also dominated the first 14 days of culture. Scanning electron microscopy at D17 and D25 revealed niche-like structures in situ, which expressed STRO-1, osteopontin and vimentin at D19 by confocal immunofluorescent microscopy, indicative of an endogenous stromal cell microenvironment. CD68+ cells were also detected at D19 in proximity to CD71+ cells suggesting formation of erythroblastic islands. In this 3D ex vivo biomimicry using near-physiologic cytokine and oxygen conditions, H induced initial erythroid commitment and established an early erythroid progenitor population. N was required at later maturational stages and enhanced the γ-globin to β-globin switch. We identified D7-D14 as a crucial timeframe in this system wherein endogenous cytokine production as well as up-regulation of GATA-1, EPOR and HIF-1α was observed. We propose that a combined HN schedule in this 3D BM biomimicy may enable a more robust and physiologic culture platform to study normal and abnormal erythroid differentiation. Disclosures No relevant conflicts of interest to declare.
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Mason, Emily F., Olga Pozdnyakova, Mikhail Roshal, Amir T. Fathi, Eytan M. Stein, Aaron C. Shaver, Mark G. Frattini, et al. "Bone Marrow Morphologic Findings in Patients Receiving IDH Inhibitor Therapy in Combination with Intensive Induction Chemotherapy: Challenges with Interpretation of the Day 14 Bone Marrow Biopsy." Blood 134, Supplement_1 (November 13, 2019): 1442. http://dx.doi.org/10.1182/blood-2019-123845.
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Background: Ivosidenib (Ivo) and enasidenib (Ena) are potent, mutant-specific oral inhibitors of the IDH1 and IDH2 proteins, respectively, and are approved as single agents for the treatment of newly diagnosed (Ivo) and/or relapsed/refractory (Ivo and Ena) AML. When used as single agents, these inhibitors induce differentiation of leukemic blasts, often without a period of bone marrow (BM) aplasia (PMID 28588020, 29860938). A phase 1 study (NCT02632708) examining the safety and efficacy of Ivo or Ena in combination with intensive induction chemotherapy (IDHi/7+3) in newly diagnosed AML with mutant IDH1 or IDH2 (mIDH) has yielded encouraging response rates in preliminary reports (Stein et al. ASH 2018; Abstract 560). The effect of IDHi/7+3 on BM morphology and whether features of differentiation are seen in this context is unknown. Here, we report the clinicopathologic findings in a cohort of patients treated with IDHi/7+3 and describe a distinct pattern of BM response with implications for post-therapy disease monitoring. Methods: Investigators from participating sites for NCT02632708 were invited to contribute cases. 36 patients from 4 sites were included with IRB approval at all sites. For each patient, the diagnostic BM biopsy and aspirate smear (BMBx) and all subsequent BMBx performed until end of induction (EOI) or removal from study were reviewed at individual sites based on consensus criteria. A subset of cases was re-reviewed by all pathologists via photomicrographs and digital whole slide images. Patients were categorized into 3 groups based on their Day 14 (D14) BMBx: 1) Aplasia (D14A = <10% cellular; and <5% blasts); 2) Differentiation (D14D = >10% cellular; and >5% blasts at D14; with morphologic or flow cytometric evidence of blast differentiation at D14 or D21); or 3) Persistent AML (D14P = >10% cellular; and >5% blasts; and no differentiation or clearance of blasts at D14 or later time points). Clinicopathologic data was collected from the electronic medical record and from the study database. IDH mutation clearance (MC) was defined as a reduction in the mIDH variant allele frequency in BM mononuclear cells to a level below the limit of detection of the assay (0.02-0.04%) for ≥1 on-treatment time point on or after D28 of induction. Results: The cohort included 17 mIDH1 patients who received Ivo and 19 mIDH2 patients who received Ena (Table 1, Fig 1); 1 patient in each treatment group had mIDH1 and mIDH2. In the 31 patients evaluable for response at EOI, 27 achieved CR or CRi/p; 2 MLFS; and 2 SD. Of 29 patients with a morphologic response (CR, CRi/p, MLFS), 19 (66%) were classified as D14A (median 5% cellularity; median <5% blasts). Conversely, 10/29 patients (34%) exhibited D14D, with elevated BM cellularity (median 20% [10%, 20%]) and increased BM blast percentage (median 45% [5%, 80%]). In these cases, granulocytic and/or monocytic differentiation (Fig. 2) was most commonly seen at D14 (8/10) but emerged at D21 for 2/10 patients. Strikingly, despite the elevated cellularity and blast percentages at D14, 7/10 D14D patients subsequently achieved CR/CRi/p by D42 post-induction in the absence of additional intensive therapy; the remaining 3 patients achieved CR/CRi/p after a second cycle of induction. Of the 5 patients not evaluable at EOI, 3 had D14A and 2 had D14P. The 4/36 patients with D14P had a median BM cellularity of 27.5% and a median blast percentage of 33.5% at D14 with no evidence of differentiation. Differentiation was more common in patients treated with Ena (7/19 [36.8%]) than patients receiving Ivo (3/17 [17.6%]) and was seen in 4 of 6 patients with an IDH2R172 mutation. Only 1 of 8 patients with a co-occurring NPM1 mutation showed blast differentiation. Similar rates of IDH MC were seen in patients with D14A (4/22) and D14D (2/10). Conclusions: We describe here a distinct pattern of BM response, with delayed blast clearance and evidence of leukemic cell differentiation, in mIDH AML patients treated with IDHi/7+3. Our data suggest that patients with relatively high BMBx cellularity and residual blasts at D14 post-induction, even in the absence of evidence of differentiation at D14, should not be considered as induction failures and should be reassessed at later timepoints before being considered for additional induction therapy. Misinterpretation of D14 BMBx may ultimately lead to unnecessary therapy given that a significant subset of patients has an atypical BM response. Figure Disclosures Mason: Sysmex: Honoraria. Pozdnyakova:Sysmex corporation of America: Research Funding. Roshal:Celgene: Other: Provision of Services; Auron Therapeutics: Equity Ownership, Other: Provision of services; Physicians' Education Resource: Other: Provision of services. Fathi:Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy; Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria. Stein:Novartis: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees. Frattini:Celgene Corporation: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Mu:Agios Pharmaceuticals, Inc.: Employment. Almon:Agios Pharmaceuticals: Employment, Equity Ownership. Cooper:Agios: Employment, Equity Ownership. Stone:AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy; Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding. Hasserjian:Jazz Pharmaceuticals: Consultancy; Promedior, Inc.: Consultancy. Savona:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Ivosidenib and enasidenib are mutant-specific oral inhibitors of the IDH1 and IDH2 proteins, respectively, approved as single agents for the treatment of AML. This study will discuss their use in combination with intensive induction chemotherapy for the treatment of AML.
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Kardinaal, Alwine, Min Young Park, Jong Eun Jeon, Hee Jung Choi, Ji Yeon Kim, Oran Kwon, Els van Hoffen, and Anita Hartog. "Oral Cholera Vaccination as a Model to Assess Dietary Modulation of Gut Inflammation and Immunity." Current Developments in Nutrition 5, Supplement_2 (June 2021): 1129. http://dx.doi.org/10.1093/cdn/nzab061_013.
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Abstract Objectives The aim was to develop a human challenge model in which modulation of immune and inflammatory response by food ingredients can be evaluated. We hypothesized that oral cholera vaccination, in addition to inducing a specific antibody response, induces a significant increase in gut inflammatory response. Methods Twenty healthy men (age 30.6 ± 1.8 y; BMI 24.9 ± 0.6) were enrolled in the study. Fecal and blood samples were collected at baseline. After a 2-week run-in period (D0-D14), subjects were vaccinated with oral cholera vaccine Dukoral (D15). After a period of 2 weeks, a second vaccination was administered (D29). Fecal samples were collected the day before (D14; D28) and the days (D16/D17; D30/D31) after each vaccination, as well as on D42. Blood samples were collected before vaccination (D15; D29), and on D16 and D17/D31, on D43. Primary outcome was fecal calprotectin concentration, secondary outcomes were serum levels of cholera toxin (CTB)-specific IgA and IgG. Other markers of local and systemic inflammatory response included beta-defensins, IP-10, IL-1 ra and hsCRP. Changes over time were tested by means of a linear mixed model. Outliers were identified with the 1.5xIQR rule and excluded from analysis. Results Fecal calprotectin did not increase after the first vaccination. After the second vaccination, a significant increase was observed: from 12.8 ± 2.5 μg/g feces (mean ± SEM) on day 29 to 18.0 ± 2.9 μg/g on day 31 (P = 0.017). Plasma CTB-specific IgA and IgG were strongly increased after the first vaccination, with a further increase after the second vaccination. Plasma CRP slightly decreased on D17, compared to D15 (P = 0.016). IL-1ra significantly decreased 2 days after the first vaccination (P = 0.011), whereas no change was observed after the second vaccination. Beta-defensin was significantly increased at D31 compared to D29 (from 42.7 ± 7.0 to 80.7 ± 16.1 (P = 0.014)). IP-10 did not show any response to vaccination. Conclusions In addition to the expected antibody response, oral cholera vaccination induces an increase in fecal calprotectin and beta defensin, pointing to vaccine induced intestinal inflammation. These readouts may be added to intervention studies with dietary compounds to evaluate the potential for modulating immune responsiveness. Funding Sources Bio&Medical Technol Developm Program of the Natl Res Foundation, Min Science & ICT of Rep Korea.
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Tarantelli, Chiara, Eugenio Gaudio, Petra Hillmann, Filippo Spriano, Ivo Kwee, Andrea Rinaldi, Anastasios Stathis, et al. "Targeting the PI3K/mTOR Pathway in Lymphoma with PQR309 and PQR620: Single Agent Activity and Synergism with the BCL2 Inhibitor Venetoclax." Blood 128, no. 22 (December 2, 2016): 3017. http://dx.doi.org/10.1182/blood.v128.22.3017.3017.
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Abstract Background. The PI3K/AKT/mTOR pathway is an important therapeutic target in lymphomas. PQR309 is a dual PI3K/mTOR inhibitor that has shown in vitroanti-lymphoma activity (Tarantelli et al, ASH2015) and is in phase 2 trial (NCT02249429, , NCT02723877, NCT02669511). PQR620 is a novel mTORC1/2 inhibitor that has shown preclinical activity in solid tumor models (Beaufils et al, AACR 2016). Here, we present the in vitro and in vivo anti-lymphoma activity of PQR620 as single agent and also the in vivo results of PQR620 or PQR309 containing combinations with the BCL2 inhibitor venetoclax. Materials and Methods. The drug concentration causing 50% inhibition of cell proliferation (IC50) was obtained in lymphoma cell lines [diffuse large B cell lymphoma (DLBCL), no.=26; mantle cell lymphoma (MCL), no.=8; anaplastic large T-cell lymphoma, no.=5; others, no=5] exposed to increasing doses of PQR620 for 72h using a Tecan D300e Digital Dispenser on 384well plates. For in vivo experiments, NOD-Scid (NOD.CB17-Prkdcscid/J) mice were subcutaneously inoculated with 10 x106 (RIVA) or with 5 x106(SU-DHL-6) cells. Results. PQR620 had a median IC50 of 250 nM (95%CI, 200-269 nM) when tested on 44 lymphoma cell lines. Activity was higher in B cell (no.=36) than in T cell tumors (no.=8) (median IC50s: 250 nM vs 450 nM; P=0.002). At 72h, anti-tumor activityof PQR620 was mostly cytostatic and apoptosis induction was seen only in 6/44 cell lines (13%), Sensitivity to PQR620 or apoptosis induction did not differ between DLBCL and MCL, and they were not affected by the DLBCL cell of origin, by TP53 status or by the presence of MYC or BCL2 translocations. The activity of PQR620 as single agent underwent in vivo evaluation in two DLBCL models, the germinal center B cell type DLBCL (GCB-DLBCL) SU-DHL-6 and the acivated B cell-like DLBCL (ABC-DLBCL) RIVA. Treatments with PQR620 (100mg/kg dose per day, Qdx7/w) started with 100-150 mm3 tumors and were carried for 14 (SU-DHL-6) or 21 days (RIVA). In both models, PQR620 determined a 2-fold decrease of the tumor volumes in comparison with control, with significant differences in both SU-DHL-6 (D7, D9, D11, D14; P < 0.005) and RIVA (D14, D16, D19, D21; P < 0.005). Based on the previously reported synergy between the dual PI3K/mTOR inhibitor PQR309 and venetoclax (Tarantelli et al, ASH 2015), we evaluated the combination of the PQR620 or PQR309 with the BCL2 inhibitor venetoclax (100 mg/kg, Qdx7/w) in the SU-DHL-6 model. Both the venetoclax combination with the dual PI3K/mTOR inhibitor and the venetoclax combination with mTORC1/2 inhibitor were superior to the compounds given as single agents, leading to the eradication of the xenografts. The combination of PQR620 with venetoclax showed highly significant differences either versus control or single agents during all days of the experiment (D4, D7, D9, D11, D14; P < 0.001). Similarly, the combination of PQR309 with venetoclax showed highly significant differences versus venetoclax (D7, D9, D11, D14; P < 0.001) and PQR309 (D7, D9, D11; P < 0.005) alone. Conclusions. The novel mTORC1/2 inhibitor PQR620 had in vitro and in vivo anti-lymphoma activity as single agent. In vivo experiments showed that both PQR620 and the dual PI3K/mTOR inhibitor PQR309 can strongly benefit from the combination with the BCL2 inhibitor venetoclax. Disclosures Hillmann: PIQUR Therapeutics AG: Employment. Fabbro:PIQUR Therapeutics AG: Employment. Cmiljanovic:PIQUR Therapeutics AG: Employment, Membership on an entity's Board of Directors or advisory committees.
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El-Hamshary, Ola IM, Sarah K. Abdullah, and NH Al-Twaty. "Molecular Characterization and Biofilm Formation Study of Contaminant Bacteria Isolated from Domiaty and Hungarian Cheeses in Jeddah City." Journal of Pure and Applied Microbiology 15, no. 2 (June 1, 2021): 983–97. http://dx.doi.org/10.22207/jpam.15.2.57.
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The aim was to study the microbiological quality of Domiaty and Hungarian cheeses, molecular identification and biofilm formation of some selected contaminant bacteria. Samples were collected from two M and P big markets in Jeddah City through the period from February to October 2018, nine visits for two types of natural cheese. Results showed that the total bacterial counts (CFU/ml) from Domiaty cheese from two markets (M and P) were 0.1 x 105, 8 x 105 and 1 x 10 5 CFU/ml respectively (3 visits of M market) and 4 x 106, 0.4 x 106, 6.5 x 103, 1 x 103, 0.1 x 103 and 0.1 x 103 CFU/ml respectively (six samples from 6 visits from P market). Results showed that the total bacterial counts (CFU/ml) from Hungarian cheese were 1.5 x 10 5, 1x 10 4, 11 x 10 4 and 4 x10 6 CFU/ml respectively from (4 visits of M market) and 0.18 x 104, 3 x 106, 22 x 106, 6 x 106 and 5 x 104 CFU/ml respectively (5 visits from P market).Different bacterial isolates from cheese were identified by morphology and biochemical test. Bacterial isolates from cheeses were identified by VITEK MS as follow: Serratia liquefaciens (D6-1, D6-2, D14-1, D13-1 and D13-2), and Pseudomonas fluorescens (D14-2) were isolated from Domiaty cheese while Enterococcus faecium (H11-2), Serratia liquefaciens (H15-1) and Streptococcus thermophilus (H14-1) were isolated from Hungarian cheese. Some selected bacterial isolates were identified by 16S rRNA. Isolates were belong to MK757978 (Raoultilla terrigena (D15-1)), MK757979 (Bacillus cereus (D16-1)), MK757980 (Enterococcus faecalis (H10-2)), MK757982 (Enterococcus fiscalism (H11-1)), MK757981 (Serratia liquefactions (H13-1)), MK757984 (Anoxybacillus flavithermus (H17-1). All bacterial isolates have been tested for the formation of biofilm using a Tissue Culture Plate (TCP). Results revealed 12.5% and 46.15% of high biofilm formation respectively for bacterial isolates of Domiaty and Hungarian cheeses.
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Pinjisakikool, Teerapong. "The Influence of Personality Traits on Households’ Financial Risk Tolerance and Financial Behaviour." Journal of Interdisciplinary Economics 30, no. 1 (November 9, 2017): 32–54. http://dx.doi.org/10.1177/0260107917731034.
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Using a large sample that can represent the Dutch population, this article mainly studies the determinants of financial risk tolerance. I propose that the big five personality traits are the potential factors that can explain differences in financial risk tolerance among individuals. Furthermore, this article examines the effect of personality traits on the actual financial behaviour of households through financial risk tolerance. I find that all the big five personality traits including extraversion, agreeableness, conscientiousness, emotional stability and intellect significantly predict financial risk tolerance. Additionally, these personality traits as instrumental variables can also indirectly predict the financial behaviour of households. JEL: D10, D14, D19
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Karutz, M., and G. Soldner. "Einleitung / Stannum metallicum (ext.) / Plumbum D14, 2 Teile / Stannum D14, 1 Teil und Plumbum D14, 1 Teil / Stannum D14, 2 Teile." Der Merkurstab 69, no. 1 (2016): 37–41. http://dx.doi.org/10.14271/dms-20589-de.
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Veggi, Kelle F. T., Marco Machado, Alexander J. Koch, Sandro C. Santana, Sedison S. Oliveira, and Michael J. Stec. "Oral Creatine Supplementation Augments the Repeated Bout Effect." International Journal of Sport Nutrition and Exercise Metabolism 23, no. 4 (August 2013): 378–87. http://dx.doi.org/10.1123/ijsnem.23.4.378.
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Purpose:We examined the effects of creatine supplementation on the response to repeated bouts of resistance exercise.Methods:Young men (24.1 ± 5.2 yr) were divided into Creatine (CM, n = 9) and Placebo (PL, n = 9) groups. On day (D) 1 and D15, subjects performed four sets of bicep curls at 75% 1-RM to concentric failure. On D8-D13, subjects consumed either 20g/d creatine monohydrate or placebo. Muscle soreness and elbow joint range of motion (ROM) were assessed on D1-D5 and D15-D19. Serum creatine kinase activity (CK) was assessed on D1, D3, D5, D15, D17, and D19.Results:The first exercise bout produced increases in muscle soreness and CK, and decreases in ROM in both groups (p < .001). The second bout produced lesser rises in serum CK, muscle soreness, and a lesser decrease in ROM (bout effect, p < .01 for all), with greater attenuation of these damage markers in CM than PL. CK levels on D17 were lower (+110% over D15 for CM vs. +343% for PL), muscle soreness from D15–19 was lower (–75% for CM vs. –56% for PL compared with first bout), and elbow ROM was decreased in PL, but not CM on D16 (p < .05 for all).Conclusions:Creatine supplementation provides an additive effect on blunting the rise of muscle damage markers following a repeated bout of resistance exercise. The mechanism by which creatine augments the repeated bout effect is unknown but is likely due to a combination of creatine’s multifaceted functions.
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Khan, Mohammad Abu Wayed, Md Nazrul Islam, SM Harun-ur-Rashid, and Mir Rowshan Akter. "Winterfield 2512 G-61 Strain of IBDV Vaccine (CEVAC® IBD L) Showed Reduced Pathogenicity in Commercial Chickens." Microbes and Health 1, no. 2 (March 8, 2013): 58–61. http://dx.doi.org/10.3329/mh.v1i2.14091.
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A live, freeze-dried commercial vaccine prepared from the Winterfield 2512 G-61 strain of infectious bursal disease virus (IBDV) was tested for its pathogenicity in commercial chickens. A total of 200 unvaccinated Cobb-500 chicks obtained commercial sources, raised in relative isolation from day old chick (DOC) were used in the experiment. A total of 3 chicks were randomly collected from the experimental flock on day 11 (D11), D13, D15, D17, D20, D23 and D26. The vaccine was administered through drinking water at D11 and the booster was also given on D17 through drinking water. All the sampled birds were euthanized for necropsy. The visible gross morbid lesions, bursa-body weight ratios and histomorphology including bursal lesion scores were recorded following necropsy and histopatholog. An infected flock was included in this study for comparison. Data of bursa-bodyweight ratios in relation to bursal lesion scores was analyzed statistically. No detectable gross lesions were found during necropsy and bursa-body weight ratios were 2.75±0.60, 2.71±0.39, 2.44±0.42, 3.39±0.13, 2.58±0.55, 2.15±0.16, 2.41±0.28 and 2.45±0.09 on D11, D13, D15, D17, D20, D23 and D26, respectively. Histopathological lesions were characterized as varying degrees of lymphoid depletion, and the bursal lesion scores were 0.67±0.33, 0.67±0.33, 2.00±0.58, 0.67±0.33, 1.0±0.00, 0.67±0.33 and 0.33±0.33 on D11, D13, D15, D17, D20 D23 and D26, respectively. The vaccine virus showed reduced levels of pathogenicity in broiler chickens. No disease outbreaks were noted in the vaccinated group, but significant changes were found in the naturally infected flock. DOI: http://dx.doi.org/10.3329/mh.v1i2.14091 Microbes and Health, 2012 1(2): 58-61
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Huang, Yan, Sarah Shelby, Yongjie Wang, Jing Ge, and Sami Dridi. "PSX-37 Late-Breaking Abstracts: Effects of metformin on body temperature regulation and breast muscle growth in male broiler chickens." Journal of Animal Science 98, Supplement_4 (November 3, 2020): 351–52. http://dx.doi.org/10.1093/jas/skaa278.617.
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Abstract Chickens provide models for human physiology research, as their normal physiological status mimics mammalian obesity and human Type II diabetes. Metformin is a common medication used to treat Type II diabetes. Prior studies have demonstrated metformin’s ability to induce the “browning” phenomenon of white adipose tissue and promote non-shivering thermogenesis (NST). The objective of this study was to determine if dietary supplementation of metformin can promote NST to reduce body fat mass and increase metabolism in broiler chickens. Male broiler chicks (n = 72) were randomly assigned to 12 pens (6 chickens/pen). Pens were randomly assigned to control basal diet (CON), basal plus 0.5 g/kg metformin (MET05), or basal plus 1.0 g/kg metformin (MET1). Two chicks were harvested from each pen on d7, d14, and d21. Total breast weight (TBW) and liver weight (LW) were recorded. IButton temperature loggers were implanted in chickens on d19. ADFI was highest in MET05 at d7 and d21, lowest in MET1 at d7, and highest in MET1 at d14. ADFI was lowest in CON group at d14 and d21. MET1 showed a negative effect on G:F at d7 and d14. MET05 group had the highest BW, TBW, and LW at all intervals. CON group had the lowest TBW at d14, but significantly higher than MET1 at d21. MET1 group had the lowest TBW at d7 and d21, lowest LW at d7 and d14, while CON group had the lowest LW at d21. CON had the highest breast/BW ratio, while MET1 group had the lowest. MET05 and MET01 had higher liver:BW ratio than CON group at d21. Data distribution showed less variation for internal body temperature in the MET05 group compared with CON and MET1. These results suggest that low dosage metformin helps regulate body temperature and increase breast muscle growth in broilers in earlier life stage.
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Broad, Elizabeth M., Ronald J. Maughan, and Stuart D. R. Galloway. "Effects of Exercise Intensity and Altered Substrate Availability on Cardiovascular and Metabolic Responses to Exercise After Oral Carnitine Supplementation in Athletes." International Journal of Sport Nutrition and Exercise Metabolism 21, no. 5 (October 2011): 385–97. http://dx.doi.org/10.1123/ijsnem.21.5.385.
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The effects of 15 d of supplementation with L-carnitine L-tartrate (LC) on metabolic responses to gradedintensity exercise under conditions of altered substrate availability were examined. Fifteen endurance-trained male athletes undertook exercise trials after a 2-d high-carbohydrate diet (60% CHO, 25% fat) at baseline (D0), on Day 14 (D14), and after a single day of high fat intake (15% CHO, 70% fat) on Day 15 (D15) in a double-blind, placebo-controlled, pair-matched design. Treatment consisted of 3 g LC (2 g L-carnitine/d; n = 8) or placebo (P, n = 7) for 15 d. Exercise trials consisted of 80 min of continuous cycling comprising 20-min periods at each of 20%, 40%, 60%, and 80% VO2peak. There was no significant difference between whole-body rates of CHO and fat oxidation at any workload between D0 and D14 trials for either the P or LC group. Both groups displayed increased fat and reduced carbohydrate oxidation between the D14 and D15 trials (p < .05). During the D15 trial, heart rate (p < .05 for 20%, 40%, and 60% workloads) and blood glucose concentration (p < .05 for 40% and 60% workloads) were lower during exercise in the LC group than in P. These responses suggest that LC may induce subtle changes in substrate handling in metabolically active tissues when fattyacid availability is increased, but it does not affect whole-body substrate utilization during short-duration exercise at the intensities studied.
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Tanokura, Masaru, Takuya Miyakawa, You-Lin Xue, Hidemitsu Nakamura, Feng Hou, Hui-Min Qin, Kosuke Fukui, et al. "Molecular mechanism of strigolactone perception by DWARF14." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1062. http://dx.doi.org/10.1107/s2053273314089372.
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The terpenoid, small-compound strigolactones (SLs) are plant hormones that regulate plant shoot branching, which is an important agronomic trait that determines crop yields. An α/β-hydrolase protein, DWARF14 (D14), has been recognized to be an essential component of plant SL signaling. Recently, it has been demonstrated that D14 interacts with a gibberellin (GA)-signaling repressor SLR1 in an SL-dependent manner [1], which suggests that SLR1 mediates crosstalk between the SL and GA signalings in the regulation of plant shoot branching. Although D14 functions in SL perception to promote the interaction with SLR1, its molecular mechanism remains unclear. Here, we report the crystal structure of D14 in the complex with 5-hydroxy-3-methylbutenolide (D-OH), which is a reaction product of SLs. The structure was solved at a 2.10-Å resolution when an SL synthetic analogue, (–)-ent-2'-epi-GR7, was soaked into D14 crystals [1]. In the complex structure, D-OH was located at a site far from the catalytic residues including H297 and appeared to function as a plug for the catalytic cavity to induce an overall hydrophobic surface with a hydrophilic patch between the two α-helices in the cap structure of D14. In the binding site, the indole amine of Trp205 formed a hydrogen bond with the oxygen atom of the C2' hydroxy group, which arose from the catalytic reaction of D14, instead of a water molecule in the structure of apo D14. In addition, the side chain of Phe245 moved 1.3 Å toward D-OH. Mutational analyses of D14 showed that the interaction between D14 and SLR1 required an enzymatic activity of D14 and the residues Trp205 and Phe245 were essential for the SL-dependent SLR1-binding of D14. These results suggest that the D14–D-OH complex mediates the interaction with SLR1 in which the D-OH-induced surface and/or structural change is crucial.
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Machado, Grazieli Marinheiro, Ester Siqueira Caixeta, Carolina Madeira Lucci, Rodolfo Rumpf, Maurício Machaim Franco, and Margot Alves Nunes Dode. "Post-hatching development of bovine embryos in vitro: the effects of tunnel preparation and gender." Zygote 20, no. 2 (March 23, 2011): 123–34. http://dx.doi.org/10.1017/s0967199411000086.
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SummaryThe objective of this study was to compare morphological characteristics, kinetics of development, and gene expression of male and female IVP embryos that were cultured until day (D)15 (fertilization = D0), using either phosphate-buffered saline (PBS) or Milli-Q water (MQW) to dilute the agarose gel used for tunnel construction. On D11, embryos (n = 286) were placed in agarose gel tunnels diluted in PBS and MQW. Embryos were evaluated for morphology, and embryo size was recorded on D11, D12.5, D14 and D15. Then, embryos were sexed and used for gene expression analyses (G6PD, GLUT1, GLUT3, PGK1, PLAC8, KRT8, HSF1 and IFNT). The percentage of elongated embryos at D15 was higher (p < 0.05) in the PBS (54%) than in the MQW (42%) gel. However, embryos produced in MQW were bigger (p < 0.05) and had a lower expression of GLUT1 (p = 0.08) than those cultured in PBS. There was a higher proportion of male than female embryos at D15 in both treatments, MQW (65% vs. 35%; p < 0.05) and PBS (67% vs. 33%; p < 0.05); however, embryo size was not significantly different between genders. Moreover, D15 female embryos had greater expression of G6PD (p = 0.05) and KRT8 (p = 0.03) than male embryos. In conclusion, the diluent used for tunnel construction affected embryo development in the post-hatching development (PHD) system, and the use of MQW was the most indicative measure for the evaluation of embryo quality. Male and female embryos cultured from D11 to D15, either in an MQW or PBS agarose gel, demonstrated similar development but different gene expression.
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Xu, Qianqian, Huaiyu Li, Wenting Zhou, Xiaoting Zou, and Xinyang Dong. "Age-Related Changes in Serum Lipid Levels, Hepatic Morphology, Antioxidant Status, Lipid Metabolism Related Gene Expression and Enzyme Activities of Domestic Pigeon Squabs (Columba livia)." Animals 10, no. 7 (July 1, 2020): 1121. http://dx.doi.org/10.3390/ani10071121.
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The objective of this study was to evaluate the age-related changes in antioxidant status and the lipid metabolism of pigeon squabs (Columba livia), by determining the BW, antioxidant indices, serum lipid levels, lipid metabolism-related enzyme activities, lipid metabolism-related gene expression, and liver morphology in squabs. Ten squabs were randomly selected and sampled on the day of hatching (DOH), days 7 (D7), 14 (D14) and 21 (D21) post-hatch, respectively. The results showed that BW of squabs increased linearly from DOH to D21. The minimum fold of BW gain was observed in the phase from D14 to D21. Serum triglyceride and free fatty acid levels displayed linear and quadratic trends as age increased, with these maximum responses in D14. Serum low-density lipoprotein cholesterol level responded to age linearly and quadratically with the minimum in D14. Serum high-density lipoprotein cholesterol level and the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol increased linearly with age, whereas the very low-density lipoprotein cholesterol level decreased linearly. The activities of glutathione peroxidase, catalase, and superoxide dismutase in liver displayed linear and quadratic trends as age increased, with these minimum responses in D14. Hepatic malondialdehyde concentration responded to age linearly and quadratically, with the maximum in D14. Activities of lipoprotein lipase, hepatic lipase, and 3-hydroxy-3-methyl glutaryl coenzyme A reductase in liver responded to age linearly and quadratically, with these minimum responses in D14. Hepatic hormone-sensitive lipase activity displayed linear and quadratic trends as age increased with the maximum in D14. Hepatic acetyl CoA carboxylase activity on D14 was significantly lower than squabs on DOH and D7. Hepatic carnitine palmitoyltransferase 1 mRNA expression responded to age linearly and quadratically, with minimum response in D14. Hepatic mRNA expression of acetyl CoA carboxylase and fatty acid synthetase increased linearly with age. Hepatic Oil-Red-O staining area displayed a quadratic trend as age increased, with the maximum response in D14. In conclusion, the phase from DOH to D14 was a crucial development stage for growth, antioxidant status and lipid metabolism in pigeon squabs. The results suggest it is better to take nutritional manipulation in squabs before D14.
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Norkin, Maxim, Myron Chang, An Qi, Helen Leather, Lakshmikanth Katragadda, Ying Li, Jan S. Moreb, et al. "A New Model to Predict Remission Status in Acute Myeloid Leukemia (AML) Patients Based on Day 14 Bone Marrow (D14 BM) Biopsy." Blood 126, no. 23 (December 3, 2015): 3852. http://dx.doi.org/10.1182/blood.v126.23.3852.3852.
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Abstract Introduction: Although day D14 BM after initiation of induction chemotherapy is accepted standard of care in AML patients (pts), it has poor predictive value and low accuracy for refractory disease. Currently there are no established clinical and laboratory factors which accurately predict which AML pts with positive D14 BM require immediate reduction chemotherapy for persistent disease and which pts achieve complete remission (CR) Methods: We retrospectively analyzed pretreatment factors and post-induction response in AML pts to determine if clinical and laboratory characteristics can improve the predictive value of the D14 BM evaluation. Results: Among 297 pts with D14 BM biopsies, 183 pts (61%) had positive D14 BM (either ≥ 5% myeloblasts or cellularity ≥ 20%). Of those with a positive D14 BM biopsy, no reinduction chemotherapy was given to 89 pts of which 57 (64%) pts had persistent disease at count recovery and 32 (36%) pts achieved CR. Persistent disease at count recovery after positive D14 BM was more likely associated with higher percentage of D14 myeloblasts, history of relapsed disease, and poor-risk disease category than pts with positive D14 BM who achieved CR. Age, D14 BM cellularity, and WBC at first day of induction chemotherapy had no significant influence on remission status in pts with a positive D14 BM (Table 1). We developed, and tested in a validation cohort, new prediction model using both D14 BM status and clinical/laboratory factors such as the percentage of blasts, history of relapsed disease, and poorer disease risk category. Then we compared results of this prediction model to that of D14 BM alone without the usage of clinical/laboratory prognostic factors. Our prediction model significantly improved the positive predictive value (84% vs.64% P=0.001) and the accuracy of prediction of recovery marrow status (0.88% vs. 80%, P=0.002) in AML pts with positive D14 BM (Table 2). Conclusion: In this study we developed and validated a new prediction model for interpreting D14 BM biopsies in AML pts after induction chemotherapy. With the addition of readily available clinical and laboratory information, our multivariable model provides a more accurate prediction of recovery bone marrow status and identification of patients with positive D14 BM who may not benefit from early reduction chemotherapy. Table 1. Clinical and Laboratory Characteristics of AML Patients with Positive D14 BM Who Did Not Receive Immediate Reinduction Chemotherapy. Persistent AML at count recovery CR+CRi P value Number 57 32 Age, years Median (min, max) 59 (19, 75) 55.5 (20, 78) 0.064* WBC Count at Induction, x 109/L Median (min, max) 5.7 (0, 285) 3 (0, 95) 0.25* D14 Cellularity, % Median (min, max) 10 (5, 40) 10 (3, 60) 0.079* D14 Blasts, % 0-10 10%-30 >30 13 20 24 15 13 4 0.0023* Disease Status Before Induction Therapy De novo Relapsed 19 38 26 6 <0.0001** Antecedent Hematologic Disorder Yes No 25 32 6 26 0.021** Risk Favorable/Normal High 13 44 19 13 0.0013*** AML, acute myeloid leukemia; CR, complete remission; CRi, complete remission with incomplete count recovery; D, day; WBC, white blood cell. *Wilcoxon rank sum test. **Fisher's exact test. ***Chi-square test Table 2. Performance of Models in Prediction of Recovery Bone Marrow using the D14 BM with and without Clinical/laboratory Diagnostic Factors (N = 203) Sensitivity Specificity PPV NPV Accuracy P value* Without prognostic factors 0.88 0.77 0.64 0.93 0.80 0.002 With prognostic factors** 0.78 0.93 0.84 0.90 0.88 *Comparison of accuracies by two-sample binomial test. **The percentage of myeloblasts in the D14 BM, disease status, and risk category were used as prognostic factors.NPV, negative predictive value; PPV, positive predictive variable. Disclosures No relevant conflicts of interest to declare.
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Barta, Stefan K., Yiyu Zou, John Schindler, Tushar Bhagat, Victor Ghetie, Ellen S. Vitetta, and Amit Verma. "Synergy of Sequential and Concurrent Administration of a Deglycosylated Ricin A Chain-Containing Combined Anti-CD19 and Anti-CD22 Immunotoxin (Combotox) and Cytarabine in a Murine Model of Advanced Acute Lymphoblastic Leukemia." Blood 118, no. 21 (November 18, 2011): 1526. http://dx.doi.org/10.1182/blood.v118.21.1526.1526.
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Abstract Abstract 1526 BACKGROUND: The immunotoxin combotox (1: 1 mixture of deglycosylated ricin-A chain (dgRTA)-containing anti-human CD19 and anti-CD22 monoclonal antibodies (MAbs) (Combotox) has demonstrated single agent activity in children (Herrera et al, 2009) and adults (Schindler et al, 2011) with relapsed/refractory B-lineage acute lymphoblastic leukemia (ALL). Even though single agent Combotox is effective in reducing the number of blasts, relapses usually occur early on especially in advanced disease. We designed experiments to explore potential synergy of concurrent and sequential administration of Combotox and cytarabine (Ara-C) in a murine model of advanced human pre-B cell ALL. MATERIALS AND METHODS: A xenograft model of advanced ALL in NOD mice was established using the human pre-B lymphoblast cell line NAML/6 (Herrera et al 2009). 6–8 week old NOD mice (Cg-Prkdcscid Il2rgtm1Wjl/SzJ) were injected in the tail vein with 8–10×106 NALM/6 cells. The presence of leukemic blasts in the blood was confirmed microscopically 7, 14 and 18 days after inoculation. Drug administration was done after establishment of increased blast counts in order to mimic human advanced disease. In the first experiment (concurrent schedule) mice were treated daily on Days (d) 12–17 with either 1) Ara-C, 2) Combotox, 3) Ara-C concurrent with Combotox, or 4) normal saline (control), respectively. In a second experiment (sequential schedule), mice were treated with either 1) Ara-C on Days (d) 7–9 after inoculation, 2) Combotox on d14, d16 and d18, 3) Ara-C d7-9 followed by Combotox on d14, d16 and d18 or 4) normal saline (control) on d7-9, d14, d16 and d18. The doses were 200mg/kg daily x3 for Ara-C and 2.4mg/kg anti-CD19-dgRTA plus 1.5mg/kg anti-CD22-dgRTA per injection every other day x3 for Combotox The median survival time (MST) for each treatment group was calculated. Overall survival was plotted as Kaplan-Meier curve and a 2-sided log-rank test was performed. A p-value <0.05 indicated statistical significance. RESULTS: Both concurrent (Experiment #1) and sequential administration (Experiment #2) of Ara-C combined with Combotox resulted in statistically significantly improved overall survival (p-value <0.05 for both schedules). The median survival time (MST) was 27 and 28 days respectively for concurrent and sequential combined chemo-immunotherapy with Ara-C and Combotox as compared to control (MST 17 & 19 days) and/or each agent by itself (MST Ara-C 19 & 20 days; Combotox 20 and 18 days) as demonstrated in Figures 1 and 2. CONCLUSION: The combination of Ara-C and Combotox resulted in improved survival in mice xenografted with NALM/6 cells, which served as a model for advanced B-lineage ALL. Whether concurrent or sequential administration has superior efficacy is under current active investigation. These results influenced the design of a clinical trial that will explore the safety and efficacy of Ara-C combined with Combotox in adults with relapsed/refractory ALL (clinicaltrials.gov identifier NCT01408160). Disclosures: No relevant conflicts of interest to declare.
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Kalda, Ankit. "Peer Financial Distress and Individual Leverage." Review of Financial Studies 33, no. 7 (July 9, 2019): 3348–90. http://dx.doi.org/10.1093/rfs/hhz077.
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Abstract Using health shocks to identify financial distress situations, I document that peer distress leads to a decline in individual leverage and debt on average. Individual leverage declines by 5.7% and remains deflated for at least five years following peer distress. This decline occurs as individuals borrow less on the intensive margin, pay higher fractions of their debt and save more while their income remains unchanged. As a result, individuals are less likely to default during the period following peer distress. The heterogeneity in responses highlight the role of changes in beliefs and preferences as the underlying mechanism. (JEL D10, D12, D14, D84, H31, R20) Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
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Bao, Delong, Chung-Shien Lee, Christina E. Trotta, and Craig Devoe. "Evaluation of Prognostic Factors after Induction Chemotherapy for Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 5269. http://dx.doi.org/10.1182/blood-2018-99-119830.
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Abstract Purpose: Recent studies have shown that dose escalation of daunorubicin from 45mg/m2 to 90mg/m2 during acute myeloid leukemia (AML) induction showed response benefit and overall survival in patients <=65 years. Yet, the further management of patients with persistent disease based on the evaluation of D14 bone marrow has often been questioned due to lack of data. The primary purpose of this study is to evaluate the overall remission rates of patients with a positive D14 bone marrow compared with those who had a negative D14 results, and to determine if blast % on the D14 bone marrow aspirate is a prognostic indicator for remission and survival in acute leukemia patients who underwent induction chemotherapy. We aim to investigate the relevance of the D14 bone marrow result by dividing the result into blast percent categories and investigate if the there is a correlation between D14 blast % and CR. Patients/Methods: This was an IRB approved retrospective chart review conducted at North Shore University Hospital. Adult patients with AML who received standard induction 7 + 3 Daunorubicin and Cytarabine from 2010 to 2015 were included. 150 patients were reviewed and those that were eligible were evaluated for various factors (D14 blast %, initial marrow blast %, gender, age, cytogenetic risk profile, initial WBC, initial hemoglobin, initial platelets and initial LDH levels, along with those lab values at D14) for tests of association with CR. These patients' D14 blast % biopsies were divided into blast percent categories as followed: (Chemotherapeutic/<1%, 1-10%, 10-30%, 30-60% and > 60%). Complete remission (CR) was defined as patients having <5% blasts on their day 28 bone marrow or day 63 and corresponding neutrophil count >1,000 and platelet count >100 k. Fisher's exact test was used to compare the proportion of patients who reached CR among the D14 blast % categories, and on other categorical data. The Wilcoxon test was utilized to compare CR on continuous variables. Results were considered statistically significant if p < 0.05. Results: 115 patients were analyzed and we found no significant association between D14 blast % and CR status. However, initial blast % was found to be significantly associated with CR status (p=0.009), specifically, those with >60% initially had the greatest CR rate. D14 hemoglobin, D14 platelets or D14 LDH levels were not significantly associated with CR status (p=0.67, p=0.33, and p=0.13, respectively). Similarly, initial WBC, hemoglobin, platelets and LDH levels were each not significantly associated with CR (p=0.99, p=0.51, p=0.47 and p=0.36, respectively). Results did provide evidence to suggest that D14 WBC was significantly associated with CR (p=0.02), but when both D14 WBC and initial blasts % were included in a multiple logistic model, WBC was no longer a significant predictor of outcome. As such, only initial blast percent (at time of diagnosis or initial visit) was deemed predictive of CR response day at D63 (p=0.0142); patients with initial blast >60% had the greatest rate of CR compared with <20% blasts initially. Conclusion: The data suggests that there is no statistical difference between the blast % on the D14 bone marrow and the achievement of CR during induction chemotherapy for AML. Secondary outcomes showed that the initial blast % was associated with CR especially in patients with an initial blast % >60%. Also, D14 WBC might be associated with remission. Prospective studies are required to confirm these findings. Disclosures No relevant conflicts of interest to declare.
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Deutsch, Yehuda E., German Campuzano-Zuluaga, Matthew P. Salzberg, Alexandra Gomez Arteaga, Justin M. Watts, Jennifer R. Chapman, Offiong F. Ikpatt, Francisco Vega, and Ronan T. Swords. "Clinical Utility of Morphological Evaluation of Day 14 Bone Marrow Biopsies in Acute Myeloid Leukemia Patients Undergoing Standard Induction Chemotherapy: Time to Change Practice?" Blood 124, no. 21 (December 6, 2014): 1004. http://dx.doi.org/10.1182/blood.v124.21.1004.1004.
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Abstract Introduction Early bone marrow (BM) evaluation (during aplasia or at “day 14” (D14)) in patients with AML undergoing conventional induction therapy has been adopted from clinical practice in pediatric acute lymphoblastic leukemia (ALL). While it has been shown that early persistence of AML correlates with decreased complete remission (CR) rates and overall survival (OS), unlike in ALL, there are no data to indicate that early initiation of re-induction therapy based on these findings will positively influence outcome. In fact, early re-induction, especially in older patients, may increase morbidity and mortality from prolonged cytopenias, infectious complications, and longer hospital stays. Moreover, it can be challenging to determine the nature of scattered blasts identified in a hypocellular BM at D14, as they may represent normal recovering marrow elements or malignant blasts. Even if malignant, the chemosensitivityof these cells will only be fully determined by later assessment of the BM at the time of expected count recovery (“day 28”). For these reasons, early re-induction therapy may not be advisable. In this retrospective study, we sought to evaluate the validity of D14 BM assessments as post-therapy prognostication to guide treatment decisions in AML. Methods We conducted a retrospective institutional study (2006-2014) of AML patients undergoing routine induction chemotherapy where diagnostic, interim (around D14) and recovery (D21-42) BM evaluations were available for review. Clinical information and pathology data were retrieved from our institutional database. Responses at D14 were categorized morphologically into three categories: optimal response (OR, blasts ≤5%), indeterminate response (IR, blasts 6-19%), and residual leukemia (RL, blasts ≥20% or a relative decrease in blast count from baseline of <20%). Published response criteria were used to define responses at marrow recovery. Suboptimal response (SOR) at D14 was defined as either IR or RL during the assessment period. Mann-Whitney's U test was used to compare non-normally distributed variables. The Fisher's exact test was employed to assess for associations between response to treatment at D14 and likelihood of recovering in CR. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a D14 BM to predict CR were calculated for patients that were observed without re-induction. Results Evaluable patients (n=98) had a mean age of 51 years (20-73), and 45% were male. The median BM blast percentages at diagnosis, D14 and recovery were respectively 54.5%, 0% and 2.5% (Figure 1). There was a significantly greater absolute decrease in blast percentage from diagnosis to D14 in patients who recovered in CR compared to those who did not achieve CR (median: 53.5% vs 23.0%, P = 0.001). In patients that got early re-induction therapy for SOR at D14, the relative differential in baseline and D14 BM blasts was significantly lower compared to patients with D14 SOR who did not get re-induction therapy (median: 21.8% vs 77.8%, P=0.004) Ninety patients did not receive early re-induction therapy. Of these, 86 (95.6%) achieved CR and 4 patients (4.4%) recovered counts with residual leukemia. Fourteen (14.3%) patients were classified as SOR at D14. Of these, 6 (6.7%) did not receive re-induction therapy and 4 of these 6 patients (67%) achieved a CR. Eight patients received early re-induction therapy based on SOR at D14 (IR = 2, RL = 6); of these, 4 patients (50%) achieved CR at count recovery. Achieving an OR at D14 was predictive of achieving CR at recovery (sensitivity = 95.3%, PPV = 97.6%). However, not achieving an OR at D14 had low specificity (50%) and NPV (33.3%) for achieving CR (P = 0.021). Conclusions Our results indicate that a SOR at the D14 BM evaluation does not uniformly identify patients with primary induction failure (low NPV) and should not be used to dictate the timing of re-induction therapy. We confirmed the PPV of achieving an OR at D14 as previously reported, but we argue that no additional prognostic data is provided by an OR at D14, beyond what can already be predicted by pre-treatment variables (e.g., age and chromosomal abnormalities). We suggest that the D14 BM should be omitted from the routine evaluation of AML patients during induction therapy outside the context of a clinical trial. Figure 1 Figure 1. Progression and percentage of blasts at diagnosis, day 14 and recovery assessments (n = 98). Disclosures No relevant conflicts of interest to declare.
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Devoe, Craig E., Delong Bao, Christina Trotta, Chung-Shien Lee, and Joanna Stein Fishbein. "Evaluation of prognostic factors after induction therapy in AML." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e18528-e18528. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e18528.
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e18528 Background: Acute myeloid leukemia (AML) is a hematologic myeloid malignancy that carries a poor prognosis. Standard of care is induction chemotherapy with daunorubicin and cytarabine also known as 7 + 3. Bone marrow aspirates are assessed on day 14 (D14) and day 28 (D28). Achievement of CR (complete remission) is predicative of overall survival (OS ).Morphological review of BM (bone marrow) on D14 remains the standard evaluation for any indication for CR. Methods: Our primary objective was to determine if blast % on the D14 bone marrow aspirate is a prognostic indicator for remission in acute leukemia patients who underwent induction chemotherapy. Institutional review board was approved. A retrospective chart review was conducted at North Shore University Hospital. Adult patients with AML who received standard induction chemotherapy from 2010 to 2015 were included. 150 patients were reviewed and their D14 blast %, initial marrow blast %, gender, age, cytogenetics and initial WBC were assessed. The patients’ D14 blast % biopsies were divided into blast percentiles: < 1%, 1-10%, 10-30%, 30-60% and > 60%. CR was defined as patients having < 5% blasts on their D28 bone marrow or day 63 and corresponding neutrophil count > 1,000 and platelet count > 100,000. Results: Fisher’s exact test was used to compare the proportion of patients who reached CR among the D14 blast % categories. The Wilcoxon test was utilized to compare CR on continuous variables. Results were considered statistically significant if p < 0.05. D14 hemoglobin and D14 platelets were not significantly associated with CR status (p = 0.67, p = 0.33, and p = 0.13, respectively). D14 WBC was significantly associated with CR (p = 0.02), but when both D14 WBC and initial blasts % were included in a multiple logistic model, WBC was no longer a significant predictor of outcome. Only initial blast percent at time of diagnosis was deemed predictive of CR response at day D63 (p = 0.0142). Conclusions: Initial blast > 60% was found to be significantly associated with the greatest CR rate. This study provides evidence of initial blast % being a prognostic factor for CR.
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Gao, Yong, Ellen Paxinos, Justin Galovich, Ryan Troyer, Heather Baird, Measho Abreha, Cissy Kityo, Peter Mugyenyi, Christos Petropoulos, and Eric J. Arts. "Characterization of a Subtype D Human Immunodeficiency Virus Type 1 Isolate That Was Obtained from an Untreated Individual and That Is Highly Resistant to Nonnucleoside Reverse Transcriptase Inhibitors." Journal of Virology 78, no. 10 (May 15, 2004): 5390–401. http://dx.doi.org/10.1128/jvi.78.10.5390-5401.2004.
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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) isolates derived from HIV-infected, treatment-naive Ugandan infants were propagated and tested for sensitivity to antiretroviral (ARV) drugs. Although most subtype A and D isolates displayed inhibition profiles similar to those of subtype B strains, a subtype D isolate identified as D14-UG displayed high-level resistance to nevirapine in peripheral blood mononuclear cell cultures (>2,000-fold) and in MT4 cell cultures (∼800-fold) but weaker resistance to delavirdine (∼13-fold) and efavirenz (∼8-fold) in MT4 cell cultures. To investigate the possible mechanism for this resistance to nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs), the RT coding region in pol was sequenced and compared to the consensus RT sequence of NNRTI-resistant and NNRTI-sensitive subtype A, B, and D HIV-1 isolates. D14-UG did not contain the classic amino acid substitutions conferring NNRTI resistance (e.g., Y181C, K103N, and G190A) but did have some putative sites associated with drug resistance, I135L, T139V, and V245T. Wild-type and mutated protease-RT genes from D14-UG and an NNRTI-sensitive subtype D isolate from Uganda (D13-UG) were cloned into pNL4-3 to produce recombinant viruses and to determine the effects of the mutations on susceptibility to ARV drugs, specifically, NNRTIs. The results showed that I135L and/or V245T mutations can confer high-level resistance to nevirapine and delavirdine as well as low level cross-resistance to efavirenz. Finally, ex vivo fitness analyses suggested that NNRTI-resistant sites 135L and 245T in wild-type isolate D14-UG may reduce RT fitness but do not have an impact on the fitness of the primary HIV-1 isolate.
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Przyborowski, Mateusz, Sebastian Gasparis, Maciej Kała, Wacław Orczyk, and Anna Nadolska-Orczyk. "The Variability of Puroindoline-Encoding Alleles and Their Influence on Grain Hardness in Modern Wheat Cultivars Cultivated in Poland, Breeding Lines and Polish Old Landraces (Triticum aestivum L.)." Agronomy 10, no. 8 (July 25, 2020): 1075. http://dx.doi.org/10.3390/agronomy10081075.
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Wheat (Triticum aestivum L.) grain hardness is determined mainly by variations in puroindoline genes (Pina-D1 and Pinb-D1), which are located on the short arm of chromosome 5D. This trait has a direct effect on the technological properties of the flour and the final product quality. The objective of the study was to analyze the mutation frequency in both Pin genes and their influence on grain hardness in 118 modern bread wheat cultivars and breeding lines cultivated in Poland, and 80 landraces from Poland. The PCR products containing the Pin gene coding sequences were sequenced by the Sanger method. Based on detected the SNPs (single-nucleotide polymorphisms) we designed CAPS (cleaved amplified polymorphic sequence) markers for the fast screening of Pinb alleles in a large number of genotypes. All analyzed cultivars, breeding lines, and landraces possess the wild-type Pina-D1a allele. Allelic variation was observed within the Pinb gene. The most frequently occurring allele in modern wheat cultivars and breeding lines (over 50%) was Pinb-D1b. The contribution of the remaining alleles (Pinb-D1a, Pinb-D1c, and Pinb-D1d) was much less (approx. 15% each). In landraces, the most frequent allele was Pinb-D1a (over 70%), followed by Pinb-D1b (21% frequency). Pinb-D1c and Pinb-D1g were found in individual varieties. SKCS (single-kernel characterization system) analysis revealed that grain hardness was strictly connected with Pinb gene allelic variation in most tested cultivars. The mean grain hardness values were significantly greater in cultivars with mutant Pinb variants as compared to those with the wild-type Pinb-D1a allele. Based on grain hardness measured by SKCS, we classified the analyzed cultivars and lines into different classes according to a previously proposed classification system.
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Peters, Rowayda, Gregor Hutter, Adriano Aguzzi, Mathias Heikenwaelder, Christoph Renner, and Alexander Knuth. "Expansion of Umbilical Cord Blood Hematopoietic Stem Cells for Clinical Use." Blood 110, no. 11 (November 16, 2007): 4049. http://dx.doi.org/10.1182/blood.v110.11.4049.4049.
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Abstract Umbilical cord blood (UCB) is an alternative donor source for allogeneic hematopoietic stem cell transplantation. However, transplantation in adults is frequently limited by the small number of cells available in a unit. We have previously developed the technology to expand hematopoietic stem cells (HSC) and stromal/mesenchymal stem cells (SMSC) from all UCB frozen samples (13, 3). The incubation of thawed UCB mononuclear cells (MNC) in the presence of SCF (25ng/ml), FLt-3 (25ng/ml), MGDF (10ng/ml) & IL-6 (20ng/ml) and 10% human serum in stroma-free liquid culture not only generated long term expansion of transplantable UCB HSC (non-adherent). Also, long-term expansion of SMSC (adherent cells) was successful. In order to upscale the expansion to use for clinical applications, we analyzed 3 frozen UCB comparing the expansion from 24-well plates (previous) versus expansion in bags (VueLife™) after 10 and 14 days of culture. Results show substantial expansion in total cell count (TCC, 4.8, 10.9: 2.4, 3.8 fold) at d10 and d14 from wells & bags respectively. TCC increased further in the presence of SMSC (38% & 33% in CD34+ cell count cultured in wells). CD133+CD34+CD38- HSC multiplied (11, 25 fold, d10/d14 & colony forming cells (CFC) 19 fold at d14 bags respectively). Heterogeneous cell populations were detected after d 14 in bags: T and B -lymphoid (%CD3/%CD19; 65/4:50w/3), megakaryocytic (%CD61; 7:4) and myeloid (%CD33; 31:43) at d0/d14 respectively. Further, expanded cells (250,000) containing a small number of CD133+CD34+CD38- (15,000–30,000) were injected into the liver of sub-lethally irradiated newborn Balb/C Rag2-Cγ−/− mice. Our preliminary data show no engraftment from cells expanded in wells and bags after 6 weeks of transplantation from d10 cultures (human CD45 + <1%). However, positive engraftment in mouse PB was detected from cells expanded for 14 d (wells, 1.16–2.5% & bags, 1.21–3.9%) as compared to control mice (CD45; 30% PB & 70% BM) receiving selected CD34 + (300,000 CD34+ at d0). Primitive repopulating cells (PRC), and multilineage human CFC were detected after transplantation. On d14 of HSC expansion, UCB MNC derived adherent cells (SMSC) were enriched by trypsinization. SMSC were established in serum free and serum plus culture as well. The immunophenotype of harvested SMSC was CD29+, CD44+ and CD45−, CD34− and CD133− at percentages + >90%. Following repeated trypsinization, SMSC count increased 41–96 folds. CFU-Fibroblast colonies (92–173) were generated from 104 SMSC after 2 weeks in MesenCult medium. We have previously differentiated SMSC into hepatocytes. Now we also generated adipocytes in an induction medium containing, Insulin, dexamethasone & indomethacin. SMSC formed Oil-droplet vacuoles in the cytoplasm in 3 weeks. The culture conditions we defined to maintain UCB PRC should be developed clinically. SMSC described herein exhibit in vitro properties of multipotent stem cells.
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Zhou, Xiujuan, Ling Liu, Yufei Li, Kang Li, Xiaoli Liu, Junjie Zhou, Chenkun Yang, Xianqing Liu, Chuanying Fang, and Jie Luo. "Integrative Metabolomic and Transcriptomic Analyses Reveal Metabolic Changes and Its Molecular Basis in Rice Mutants of the Strigolactone Pathway." Metabolites 10, no. 11 (October 26, 2020): 425. http://dx.doi.org/10.3390/metabo10110425.
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Plants have evolved many metabolites to meet the demands of growth and adaptation. Although strigolactones (SLs) play vital roles in controlling plant architecture, their function in regulating plant metabolism remains elusive. Here we report the integrative metabolomic and transcriptomic analyses of two rice SL mutants, d10 (a biosynthesis mutant) and d14 (a perception mutant). Both mutants displayed a series of metabolic and transcriptional alterations, especially in the lipid, flavonoid, and terpenoid pathways. Levels of several diterpenoid phytoalexins were substantially increased in d10 and d14, together with the induction of terpenoid gene cluster and the corresponding upstream transcription factor WRKY45, an established determinant of plant immunity. The fact that WRKY45 is a target of IPA1, which acted as a downstream transcription factor of SL signaling, suggests that SLs contribute to plant defense through WRKY45 and phytoalexins. Moreover, our data indicated that SLs may modulate rice metabolism through a vast number of clustered or tandemly duplicated genes. Our work revealed a central role of SLs in rice metabolism. Meanwhile, integrative analysis of the metabolome and transcriptome also suggested that SLs may contribute to metabolite-associated growth and defense.
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Kagiyama, Megumi, Yoshinori Hirano, Tomoyuki Mori, Sun-Yong Kim, Junko Kyozuka, Yoshiya Seto, Shinjiro Yamaguchi, and Toshio Hakoshima. "Structures of D14 and D14L in the strigolactone and karrikin signaling pathways." Genes to Cells 18, no. 2 (January 10, 2013): 147–60. http://dx.doi.org/10.1111/gtc.12025.
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Yoshimura, Masahiko, Sojung F. Kim, Ryosuke Takise, Shuhei Kusano, Sakuya Nakamura, Masanori Izumi, Akiko Yagi, Kenichiro Itami, and Shinya Hagihara. "Development of potent inhibitors for strigolactone receptor DWARF 14." Chemical Communications 56, no. 94 (2020): 14917–19. http://dx.doi.org/10.1039/d0cc01989e.
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Strigolactones (SLs) are plant hormones that suppress shoot branching through perception by their receptor protein DWARF 14 (D14). Based on the binding model of DL1, a small-molecule D14 inhibitor, more potent compounds were developed.
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Rosenzwajg, Michelle, Marie-Catherine Giarratana, Jean-Claude Gluckman, Luc Douay, and Ladan Kobari. "Incidence of Ex Vivo Expansion on the Capacity of Cord Blood Graft To Generate Immune Cells: Rational for Co-Infusion of Expanded and Non Expanded Fractions?." Blood 104, no. 11 (November 16, 2004): 407. http://dx.doi.org/10.1182/blood.v104.11.407.407.
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Abstract The aim of our study was to determine whether ex vivo expansion of umbilical cord blood (UCB) progenitor cells induces changes in their capacity to generate immune cells. CD34+ CB cells were cultured for 14 days with SCF, FLT3-l, TPO and G-CSF, inducing a total cells, CD34+ and LTC-ICs increase of 1500, 120 and 8 fold respectively. Non expanded (d0) and 14-day expanded (d14) CD34+ cells were compared for their capacity to produce T lymphocytes (TLs) using the fetal thymus organ culture system and DCs generated from d0 and d14 CD34+ cells were compared for their differentiation, phenotype and function. Total percentages of CD4+, CD4+CD8− and CD4+CD8+ TLs obtained from d0 and d14 CD34+ cells were comparable. In both fractions, most of the CD4+ T cells co-expressed iCD3 but a lower proportion of d14 derived TLs expressed sCD3. However, there was no significant difference between d0 and d14 derived TLs in term of Vb chain representation, all TCR-Vb chains examined being represented in each case. These data indicate that d0 and d14 CD34+ cells have a similar capacity to generate TLs and that expansion does not induced any skewing of the TCR-Vb repertoire. D0 and d14 CD34+ cells were next cultured with SCF, FL, GM-CSF and TNF-a to compare their capacity to differentiate into DCs. Similar percentages of CD1a+ DCs expressing the same levels of HLA-DR and co stimulatory molecules were obtained. DCs derived from d14 CD34+ cells were less potent to stimulate allogeneic TLs, but the pattern of cytokines produced by stimulated TLs was similar and no shift towards a predominant Th1 or Th2 response was observed. Moreover, in spite of a quantitative increase (15 fold) related to the CD34 pool amplification, we observed a decreased capacity (13-fold) of d14 cells to generate DCs compared to d0 CD34+ cells. Overall, these results indicate that ex vivo expansion of CD34+ cells doesn’t induce any major modification in T Lymphopoiesis capacity while alters somehow the capacity of the graft to generate DCs. We discuss in the context of UCB transplantation, the putative interest of co-infusion of expanded and non expanded fractions in view of improving myelopoiesis in the graft without subverting the immune reconstitution.
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Rouze, Anahita, Guillaume Voiriot, Elise Guivarch, Françoise Roux, Jeanne Tran Van Nhieu, Daniel Isabey, Laurent Brochard, Bernard Maitre, Armand Mekontso-Dessap, and Jorge Boczkowski. "Inflammatory Cellular Response to Mechanical Ventilation in Elastase-Induced Experimental Emphysema: Role of Preexisting Alveolar Macrophages Infiltration." BioMed Research International 2018 (December 19, 2018): 1–10. http://dx.doi.org/10.1155/2018/5721293.
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An excessive pulmonary inflammatory response could explain the poor prognosis of chronic obstructive pulmonary disease (COPD) patients submitted to invasive mechanical ventilation. The aim of this study was to evaluate the response to normal tidal volume mechanical ventilation in an elastase-induced murine model of pulmonary emphysema. In this model, two time points, associated with different levels of lung inflammation but similar lung destruction, were analyzed. C57BL/6 mice received a tracheal instillation of 5 IU of porcine pancreatic elastase (Elastase mice) or the same volume of saline (Saline mice). Fourteen (D14) and 21 (D21) days after instillation, mice were anesthetized, intubated, and either mechanically ventilated (MV) or maintained on spontaneous ventilation (SV) during two hours. As compared with Saline mice, Elastase mice showed a similarly increased mean chord length and pulmonary compliance at D14 and D21, while bronchoalveolar lavage cellularity was comparable between groups. Lung mechanics was similarly altered during mechanical ventilation in Elastase and Saline mice. Activated alveolar macrophages CD11bmid were present in lung parenchyma in both Elastase SV mice and Elastase MV mice at D14 but were absent at D21 and in Saline mice, indicating an inflammatory state with elastase at D14 only. At D14, Elastase MV mice showed a significant increase in percentage of neutrophils in total lung, as compared with Elastase SV mice. Furthermore, alveolar macrophages of Elastase MV mice at D14 overexpressed Gr1, and monocytes showed a trend to overexpression of CD62L, compared with Elastase SV mice. In an elastase-induced model of pulmonary emphysema, normal tidal volume mechanical ventilation may produce an increase in the proportion of pulmonary neutrophils, and an activation of alveolar macrophages and pulmonary monocytes. This response seems to be observed only when the emphysema model shows an underlying inflammation (D14), reflected by the presence of activated alveolar macrophages CD11bmid.
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Norkin, Maxim, Jan Moreb, Helen Leather, Randy A. Brown, Jack W. Hsu, John W. Hiemenz, W. Stratford May, et al. "Clinical and Laboratory Factors Influencing The Probability Of Complete Remission In AML Patients With Positive Day 14 Bone Marrows." Blood 122, no. 21 (November 15, 2013): 1412. http://dx.doi.org/10.1182/blood.v122.21.1412.1412.
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Abstract Background Early response to induction therapy for AML assessed by bone marrow (BM) evaluation on day 14 (D14) post chemotherapy is considered an important predictor of achieving complete remission (CR). Our aim was to identify clinical and laboratory factors influencing the probability of CR in AML patients (pts) with positive D14 BM without receiving further chemotherapy. Methods Records of pts with AML treated between 1998 and 2011 were retrospectively reviewed to identify subjects with positive D14 BM who did not receive re-induction chemotherapy. The distribution of following variables such as age, white blood cell count (WBC) at the time of induction therapy, BM cellularity, percentage of blasts, disease status, and risk was compared by the univariate analysis. Recovery BM status (positive vs. negative for disease) as the response variable and age, WBC at the time of induction therapy, BM cellularity, percentage of blasts, disease status, and risk as explanatory variables were assessed by the logistic regression analysis. Poor risk AML was defined as the presence of adverse karyotype, treatment related disease or presence of antecedent hematologic disorder. Positive BM was defined as either cellularity ≥20% or ≥5% myeloblasts by IHC staining. CR was defined according to IWG 2003 criteria. Results 169/378 (44%) had a positive D14 BM after induction therapy and 92/169 (54%) did not receive re-induction chemotherapy. 68/92 (74%) underwent repeated BM evaluation at WBC recovery, which occurred 4-5 weeks after induction chemotherapy. Recovery BM showed refractory AML in 38/68 (56%) of cases. However, in 30/68 (44%) cases CR was achieved despite previously positive D14 BM. As demonstrated in Table 1, clinical and laboratory characteristics of the CR and refractory groups showed significant differences in the absolute percentage of D14 myeloblasts, abnormal vs. normal myeloblast phenotype, de novo vs. relapse disease status, and risk stratification. Higher blast percentage (P=.0016) was associated with significantly higher probability of having refractory AML and each 1% increase blasts on D14 BM increased the odds of refractory AML on recovery BM by 6% (OR=1.06 95% CI 1.022-1.099) (Figure 1) In contrast, no clear association between D14 BM cellularity and the recovery BM status was found. The results from the multivariate analysis were comparable with that from the univariate analysis. Blast percentage, disease status, and AML risk were strongly and jointly associated with the status of BM recovery. By using a logistic model including myeloblast percentage, myeloblast phenotype, disease status, and AML risk category we correctly predicted 31 refractory AML cases out of 38 (sensitivity = 82%) and we correctly predicted 23 CR cases out of 30 (specificity = 77%). For example, based on our formula, which incorporated blast percentage, disease status, and AML risk we estimated that in a patient with de novo, not a poor risk AML with 5% blasts on D14 BM the probability of positive recovery BM status was 6%, whereas in a patient with relapsed poor risk AML and 50% blasts on D14 BM the probability of positive recovery BM status was 98%. Conclusions Significant proportion of pts with positive D14 BM may achieve CR without subsequent chemotherapy administration. Low blast percentage, absence of phenotypically abnormal myeloblasts, de novo diagnosed AML, and absence of poor risk AML are associated with a significantly higher probability of CR. We developed a useful formula for predicting remission status in the setting of positive D14 BM that would be valuable in clinical trial protocols involving decision trees for re-induction chemotherapy. Disclosures: No relevant conflicts of interest to declare.
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Xiao, Yang, Guoqing Wang, Miranda E. Gerrard, Sarah Wieland, Mary Davis, Mark A. Cline, Paul B. Siegel, and Elizabeth R. Gilbert. "Changes in adipose tissue physiology during the first two weeks posthatch in chicks from lines selected for low or high body weight." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 316, no. 6 (June 1, 2019): R802—R818. http://dx.doi.org/10.1152/ajpregu.00017.2019.
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Chickens from lines selected for low (LWS) or high (HWS) body weight (BW) differ in appetite and adiposity. Mechanisms associated with the predisposition to becoming obese are unclear. The objective of the experiment was to evaluate developmental changes in depot-specific adipose tissue during the first 2 wk posthatch. Subcutaneous (SQ), clavicular (CL), and abdominal (AB) depots were collected at hatch (DOH) and days 4 (D4) and 14 (D14) posthatch for histological and mRNA measurements. LWS chicks had decreased SQ fat mass on a BW basis with reduced adipocyte size from DOH to D4 and increased BW and fat mass with unchanged adipocyte size from D4 to D14. HWS chicks increased in BW from DOH to D14 and increased in fat mass in all three depots with enlarged adipocytes in the AB depot from D4 to D14. Meanwhile, CCAAT/enhancer-binding protein-α, neuropeptide Y, peroxisome proliferator-activated receptor-γ, and acyl-CoA dehydrogenase mRNAs differed among depots between lines at different ages. Plasma nonesterified fatty acids were greater in LWS than HWS at D4 and D14. From DOH to D4, LWS chicks mobilized SQ fat and replenished the reservoir through hyperplasia, whereas HWS chicks were dependent on hyperplasia and hypertrophy to maintain adipocyte size and depot mass. From D4 to D14, adipose tissue catabolism and adipogenesis slowed. Whereas LWS fat depots and adipocyte sizes remained stable, HWS chicks rapidly accumulated fat in CL and AB depots. Chicks predisposed to be anorexic or obese have different fat development patterns during the first 2 wk posthatch.
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Lecru, Line-Alice, Daniel Combarros, Eloy Castilla-Castaño, Christelle Navarro, and Marie Christine Cadiergues. "Treatment of Harvest Mite Infestation in Dogs Using a Permethrin 54.5% and Fipronil 6.1% (Effitix®) Topical Spot-On Formulation." Veterinary Sciences 6, no. 4 (December 7, 2019): 100. http://dx.doi.org/10.3390/vetsci6040100.
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Background—The study aims to assess the efficacy of a permethrin 54.5%-fipronil 6.1%-based spot-on solution in dogs naturally infested with Neotrombicula in an open-label controlled study. Methods—Ten naturally infested dogs received one drop per affected site on day (D) 0, and on D14, the rest of the pipette was applied on the skin between the shoulders. Five dogs served as sentinels. Parasite score (0–3), skin lesions (0–4), and investigator pruritus scale (0–4) were assessed on D0, D1, D14, and D28. Results—No treated dogs developed adverse reactions. Parasite score of sentinel dogs was maintained between 1.8 (D0, D1, and D28) and 2.2 (D14). In treated dogs, D0 parasite score was 2.4. It was significantly reduced from D1 (0.5; p < 0.002) to D28 (0.1; p < 0.002). The lesion score was 2.9 on D0 and D1; it was significantly reduced on D14 (0.6; p < 0.002) and D28 (0.1; p < 0.002). Similarly, investigator pruritus scale (D0, 2.2) scores significantly decreased on D14 (0.4; p < 0.004) and D28 (0.2; p < 0.002). Conclusions—The combination permethrin-fipronil appears to be well-tolerated, rapidly and durably effective in the control of localized canine harvest mite infestation.
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Schmiedlin-Ren, Phyllissa, Laura J. Reingold, Christopher S. Broxson, Ahren C. Rittershaus, Josh S. Brudi, Jeremy Adler, Scott R. Owens, and Ellen M. Zimmermann. "Anti-TNFα alters the natural history of experimental Crohn's disease in rats when begun early, but not late, in disease." American Journal of Physiology-Gastrointestinal and Liver Physiology 311, no. 4 (October 1, 2016): G688—G698. http://dx.doi.org/10.1152/ajpgi.00216.2015.
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Anti-TNFα therapy decreases inflammation in Crohn's disease (CD). However, its ability to decrease fibrosis and alter the natural history of CD is not established. Anti-TNF-α prevents inflammation and fibrosis in the peptidoglycan-polysaccharide (PG-PS) model of CD. Here we studied anti-TNF-α in a treatment paradigm. PG-PS or human serum albumin (HSA; control) was injected into bowel wall of anesthetized Lewis rats at laparotomy. Mouse anti-mouse TNF-α or vehicle treatment was begun day (d)1, d7, or d14 postlaparotomy. Rats were euthanized d21-23. Gross abdominal and histologic findings were scored. Cecal levels of relevant mRNAs were measured by quantitative real-time PCR. There was a stepwise loss of responsiveness when anti-TNFα was begun on d7 and d14 compared with d1 that was seen in the percent decrease in the median gross abdominal score and histologic inflammation score in PG-PS-injected rats [as %decrease; gross abdominal score: d1 = 75% ( P = 0.003), d7 = 57% ( P = 0.18), d14 = no change ( P = 0.99); histologic inflammation: d1 = 57% ( P = 0.006), d7 = 50% ( P = 0.019), d14 = no change ( P = 0.99)]. This was also reflected in changes in IL-1β, IL-6, TNF-α, IGF-I, TGF-β1, procollagen I, and procollagen III mRNAs that were decreased or trended downward in PG-PS-injected animals given anti-TNF-α beginning d1 or d7 compared with vehicle-treated rats; there was no effect if anti-TNF-α was begun d14. This change in responsiveness to anti-TNFα therapy was coincident with a major shift in the cytokine milieu observed on d14 in the PG-PS injected rats (vehicle treated). Our data are consistent with the clinical observation that improved outcomes occur when anti-TNF-α therapy is initiated early in the course of CD.
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Cadiergues, Marie C., Christelle Navarro, Eloy Castilla-Castaño, Line A. Lecru, and Charline Pressanti. "Treatment of Neotrombicula species infestation in cats using a 10% (w/v) fipronil topical spot-on formulation: a pilot study." Journal of Feline Medicine and Surgery 20, no. 6 (June 19, 2017): 587–90. http://dx.doi.org/10.1177/1098612x17715153.
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Objectives Few data are available concerning therapeutic aspects of feline trombiculiasis. This study evaluated the efficacy of a 10% w/v fipronil-based spot-on solution in 15 cats with natural Neotrombicula species infestation. Methods Ten cats received 1 drop per affected site on day (D)0 and D14, with the rest of the 0.5 ml pipette applied on the skin between the shoulders. Five cats served as non-treated controls. Parasite score (0 = absent; 3 = severe, >10 parasites/zone) was assessed on D0, D14 and D28 on all animals. Skin lesions (SCORing Feline Allergic Dermatitis lesion severity scale [SCORFAD]) and investigator pruritus scale (IPS; 0 = cat comfortable, grooming like any normal cat; 4 = cat uncomfortable, pruritic all the time) were assessed on treated cats on the same days. Global assessment of efficacy, tolerance and ease of use (GAS; 1 = very poor; 5 = excellent) was assessed on D28. Results All the cats completed the study. Parasite scores of the control cats were maintained throughout the trial (mean ± SD: D0 4 ± 0.7, D14 3.2 ± 1.1 and D28 3.2 ± 0.4). In treated cats, SCORFAD (D0 3.2 ± 5.4, D14 1.1 ± 2.1 [ P <0.002] and D28 0.5 ± 1.3 [ P <0.002]), parasite (D0 3.9 ± 1.3, D14 1.2 ± 0.8 [ P <0.005] and D28 0.4 ± 0.5 [ P <0.005]) and IPS (D0 1 ± 1.2, D14 0.5 ± 1.1 [ P <0.05] and D28 0.3 ± 0.7 [ P <0.05]) scores significantly decreased throughout the trial. On D28, the GAS was 4.2 ± 0.9. There were no adverse effects from treatment. Conclusions and relevance The 10% w/v fipronil preparation appeared to be effective, safe and practical in the treatment of localised Neotrombicula species infestation in these cats.
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Meier, Stephan, and Charles Sprenger. "Present-Biased Preferences and Credit Card Borrowing." American Economic Journal: Applied Economics 2, no. 1 (January 1, 2010): 193–210. http://dx.doi.org/10.1257/app.2.1.193.
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Some individuals borrow extensively on their credit cards. This paper tests whether present-biased time preferences correlate with credit card borrowing. In a field study, we elicit individual time preferences with incentivized choice experiments, and match resulting time preference measures to individual credit reports and annual tax returns. The results indicate that present-biased individuals are more likely to have credit card debt, and to have significantly higher amounts of credit card debt, controlling for disposable income, other socio-demographics, and credit constraints. (JEL D12, D14, D91)
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Aaronson, Daniel, Sumit Agarwal, and Eric French. "The Spending and Debt Response to Minimum Wage Hikes." American Economic Review 102, no. 7 (December 1, 2012): 3111–39. http://dx.doi.org/10.1257/aer.102.7.3111.
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Immediately following a minimum wage hike, household income rises on average by about $250 per quarter and spending by roughly $700 per quarter for households with minimum wage workers. Most of the spending response is caused by a small number of households who purchase vehicles. Furthermore, we find that the high spending levels are financed through increases in collateralized debt. Our results are consistent with a model where households can borrow against durables and face costs of adjusting their durables stock. (JEL D12, D14, D91, J38)
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Inderst, Roman, and Marco Ottaviani. "Financial Advice." Journal of Economic Literature 50, no. 2 (June 1, 2012): 494–512. http://dx.doi.org/10.1257/jel.50.2.494.
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Financial advice could play an essential role in well-functioning markets for retail financial products, given that many consumers find it difficult to evaluate the complex products on offer. However, conflicts of interest, which are pervasive in some parts of the industry, can turn advice into a curse rather than a blessing for consumers, especially when consumers are not sufficiently wary. Through a simple model of financial advice, we overview the pros and cons of various policy interventions, such as imposing mandatory disclosure, banning commissions, and regulating contract cancellation terms. (JEL D14, D18, G21, G28)
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Laitner, John, Dan Silverman, and Dmitriy Stolyarov. "The Role of Annuitized Wealth in Post-retirement Behavior." American Economic Journal: Macroeconomics 10, no. 3 (July 1, 2018): 71–117. http://dx.doi.org/10.1257/mac.20160343.
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This paper develops a tractable model of post-retirement behavior with health status uncertainty and state-verification difficulties. The model distinguishes between annuitized and non-annuitized wealth and features means-tested Medicaid assistance with nursing home care. We show how to solve the potentially complex dynamic problem analytically, making it possible to characterize optimal behavior with phase diagrams. The analysis provides an integrated treatment of portfolio composition and consumption/wealth accumulation choices. We show the model can explain both the “retirement-saving puzzle” and the “annuity puzzle.” (JEL D14, D15, G11, I18, I38, J14, J26)
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Lührmann, Melanie, Marta Serra-Garcia, and Joachim Winter. "The Impact of Financial Education on Adolescents’ Intertemporal Choices." American Economic Journal: Economic Policy 10, no. 3 (August 1, 2018): 309–32. http://dx.doi.org/10.1257/pol.20170012.
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We study the impact of financial education on intertemporal choice in adolescence. The educational program was randomly assigned among high school students, and choices were measured using an incentivized experiment. Students who participated in the program make more time-consistent choices; are more likely to allocate payments to a single payment date, as opposed to spreading payment across two dates; and display increased consistency of choice with the law of demand. These findings suggest that financial education increases the quality of intertemporal decision-making and decreases narrow bracketing. (JEL C93, D14, D15, I21, J13)
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Seba, Viviane, Gabriel Goetten de Lima, Bruno L. Pereira, Gabriel Silva, Luiza Steffens Reinhardt, Pablo Ricardo Arantes, Bor Shin Chee, et al. "Development, Characterization and Cell Viability Inhibition of PVA Spheres Loaded with Doxorubicin and 4′-Amino-1-Naphthyl-Chalcone (D14) for Osteosarcoma." Polymers 13, no. 16 (August 6, 2021): 2611. http://dx.doi.org/10.3390/polym13162611.
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Chalcones (1,3-diaryl-2-propen-1-ones) are naturally occurring polyphenols with known anticancer activity against a variety of tumor cell lines, including osteosarcoma (OS). In this paper, we present the preparation and characterization of spheres (~2 mm) from polyvinyl alcohol (PVA) containing a combination of 4′-Amino-1-Naphthyl-Chalcone (D14) and doxorubicin, to act as a new polymeric dual-drug anticancer delivery. D14 is a potent inhibitor of osteosarcoma progression and, when combined with doxorubicin, presents a synergetic effect; hence, physically crosslinked PVA spheres loaded with D14 and doxorubicin were prepared using liquid nitrogen and six freeze–thawing cycles. Physical-chemical characterization using a scanning electron microscope (SEM), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) presented that the drugs were incorporated into the spheres via weak interactions between the drugs and the polymeric chains, resulting in overall good drug stability. The cytotoxicity activity of the PVA spheres co-encapsulating both drugs was tested against the U2OS human osteosarcoma cell line by 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) assay, and compared to the spheres carrying either D14 or doxorubicin alone. The co-delivery showed a cytotoxic effect 2.6-fold greater than doxorubicin alone, revealing a significant synergistic effect with a coefficient of drug interaction (CDI) of 0.49. The obtained results suggest this developed PVA sphere as a potential dual-drug delivery system that could be used for the prominent synergistic anticancer activity of co-delivering D14 and doxorubicin, providing a new potential strategy for improved osteosarcoma treatment.
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Donnellan, William Bruce, Monalisa Ghosh Ghosh, Sunil Rangarajan, Bradley Jackson, Uma Borate, Harry P. Erba, and James M. Foran. "Use of flow cytometry during induction chemotherapy to determine outcomes in acute myeloid leukemia." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 7104. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.7104.
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7104 Background: The use of MRD to predict outcome in AML is controversial. We sought to determine concordance between FC and BM biopsy morphology on day 14 (D14BM) and CR bone marrow (CRBM) specimens and whether MRD detected by FC predicted for inferior outcomes. Methods: We performed a retrospective analysis of adult AML patients treated between 2005 and 2010 with standard induction chemotherapy. Based upon BM morphology and FC, patients were designated as BM+FC+, BM+FC-, BM-FC+, or BM-FC-. Outcomes assessed included induction failure, RFS and OS. Results were adjusted for age at diagnosis, NCCN risk classification, and secondary AML status. Results: Of 287 evaluable patients, 74 had D14 BM and FC results and 98 had CR BM and FC results. Using BM morphology as the gold standard, discordance rates for the presence and absence of disease for the D14 BM by FC were 29% and 23% respectively. Multivariate analysis revealed that patients categorized as BM-FC+ at D14 were more likely to experience induction failure (HR 8.62, CI 0.36-208) and had lower RFS and OS (HR 1.47, 1.95 CI 0.40-5.41, 0.52-7.36 respectively). Analysis of the CR BM samples showed similar results. Conclusions: In this retrospective study there was a high discordance rate between FC and BM morphology on D14 BM and CR BM. While there was a trend toward inferior patient outcomes when disease was detected by FC but not morphology, this was not statistically significant. Limitations of our study include the retrospective nature of the analysis, paucity of patient samples that had a FC evaluation, lack of data to see if positive FC at D14 or CR changed clinician therapy choices and interpretation bias by pathologists as a result of access to FC results during BM morphology interpretation. Larger prospective studies are needed to evaluate whether MRD detected by FC as early as D14 during AML therapy affects clinical outcomes.
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Miller, D. R., P. F. Coccia, W. A. Bleyer, J. N. Lukens, S. E. Siegel, H. N. Sather, and G. D. Hammond. "Early response to induction therapy as a predictor of disease-free survival and late recurrence of childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group." Journal of Clinical Oncology 7, no. 12 (December 1989): 1807–15. http://dx.doi.org/10.1200/jco.1989.7.12.1807.
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The Childrens Cancer Study Group (CCSG) CCG-160 protocol series was designed to evaluate prognostic factors in acute lymphoblastic leukemia (ALL). Patients were assigned to one of three prognostic groups based upon initial WBC count and age. To determine the optimal duration of therapy, CCG-160 patients completing 2 years of treatment in continuous remission were randomized ("late randomization") to discontinue therapy or receive another year of maintenance therapy. The prognostic significance of early response to induction therapy, as measured by the percentage of lymphoblasts in the day-14 bone marrow (d14 BM) aspirate, was evaluated in 2,516 children. For 1,490 patients with complete data, the status of the d 14 BM was a highly significant predictor of disease-free survival (DFS) by univariate and multivariate analysis (P less than .0001). The observed/expected (O/E) failure rate in patients with d14 M1 (less than 5% blasts), M2 (4% to 25% blasts), or M3 (greater than 25% blasts) BM rating who were subsequently M1 on day 28 or day 42, was .87, 1.59, and 2.30, respectively (P less than .0001). Patients with M2 or M3 d14 BM were more likely to have L2 ALL (modified French-American-British [FAB] morphologic classification), P less than .001. The significance of the d14 BM rating persisted after correction was made for WBC count and clinical prognostic groups using current CCSG criteria, except in infants less than 12 months of age. The d14 BM was also the most significant predictor of DFS in 975 patients after late randomization at 2 years following diagnosis. The O/E failure rate in patients with d14 M1, M2, or M3 BM was .88, 1.78, and 2.02, respectively (P = .0002, trend). Other significant predictors of late relapse were prognostic groups (P = .0003, trend) and initial WBC count (P = .004, trend). Predictive for both early and late relapse of ALL, early response should be monitored closely and alternative treatment regimens should be considered for slow responders.
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Charles, Pierre, Agnès Dechartres, Benjamin Terrier, Pascal Cohen, Stanislas Faguer, Antoine Huart, Mohamed Hamidou, et al. "Reducing the initial number of rituximab maintenance-therapy infusions for ANCA-associated vasculitides: randomized-trial post-hoc analysis." Rheumatology 59, no. 10 (March 9, 2020): 2970–75. http://dx.doi.org/10.1093/rheumatology/kez621.
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Abstract Objective The randomized, controlled MAINRITSAN2 trial was designed to compare the capacity of an individually tailored therapy [randomization day 0 (D0)], with reinfusion only when CD19+ lymphocytes or ANCA had reappeared, or if the latter’s titre rose markedly, with that of five fixed-schedule 500-mg rituximab infusions [D0 + D14, then months (M) 6, 12 and 18] to maintain ANCA-associated vasculitis (AAV) remissions. Relapse rates did not differ at M28. This ancillary study was undertaken to evaluate the effect of omitting the D14 rituximab infusion on AAV relapse rates at M12. Methods MAINRITSAN2 trial data were subjected to post-hoc analyses of M3, M6, M9 and M12 relapse-free survival rates in each arm as primary end points. Exploratory subgroup analyses were run according to CYC or rituximab induction and newly diagnosed or relapsing AAV. Results At M3, M6, M9 and M12, respectively, among the 161 patients included, 79/80 (98.8%), 76/80 (95%), 74/80 (92.5%) and 73/80 (91.3%) from D0, and 80/81 (98.8%), 78/81 (96.3%), 76/81 (93.8%) and 76/81 (93.8%) from D0+D14 groups were alive and relapse-free. No between-group differences were observed. Results were not affected by CYC or rituximab induction, or newly diagnosed or relapsing AAV. Conclusions We were not able to detect a difference between the relapse-free survival rates for up to M12 for the D0 and D0+D14 rituximab-infusion groups, which could suggest that omitting the D14 rituximab remission-maintenance dose did not modify the short-term relapse-free rate. Nevertheless, results at M12 may also have been influenced by the rituximab-infusion strategies for both groups.
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Griffiths, D., M. Uchiyama, P. Nurse, and T. S. Wang. "A novel mutant allele of the chromatin-bound fission yeast checkpoint protein Rad17 separates the DNA structure checkpoints." Journal of Cell Science 113, no. 6 (March 15, 2000): 1075–88. http://dx.doi.org/10.1242/jcs.113.6.1075.
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To further dissect the genetic differences between the checkpoint pathway following S-phase cdc arrest versus DNA damage, a genetic screen was performed for checkpoint mutants that were unable to arrest mitosis following cell-cycle arrest with a temperature-sensitive DNA polymerase delta mutant, cdc20-M10. One such checkpoint mutant, rad17-d14, was found to display the cut phenotype following S-phase arrest by cdc20-M10, but not by the DNA synthesis inhibitor hydroxyurea, reminiscent of the chk1 mutant. Unlike chk1, rad17-d14 was not sensitive to UV irradiation. Interestingly, the ionising radiation sensitivity of rad17-d14 was only at higher doses, and cells were found to be defective in properly arresting cell division following irradiation in S phase, but not G(2) phase. Biochemical analysis attributes the checkpoint defects of rad17-d14 to the failure to phosphorylate the checkpoint effector Chk1p. To investigate if Rad17p monitors the genome for abnormal DNA structures specifically during DNA synthesis, chromatin association of Rad17p was analysed. Rad17p was found to be chromatin associated throughout the cell cycle, not just during S phase. This interaction occurred irrespective of the arrest with cdc20-M10 and, surprisingly, was also independent of the other checkpoint Rad proteins, and the cell-cycle effectors Chk1p and Cds1p.
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Machado, Marco, Rafael Pereira, Felipe Sampaio-Jorge, Franz Knifis, and Anthony Hackney. "Creatine supplementation: effects on blood creatine kinase activity responses to resistance exercise and creatine kinase activity measurement." Brazilian Journal of Pharmaceutical Sciences 45, no. 4 (December 2009): 751–57. http://dx.doi.org/10.1590/s1984-82502009000400020.
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The purpose of this study was to determine the effects of creatine supplementation and exercise on the integrity of muscle fiber, as well as the effect of the supplementation on the creatine kinase (CK) assay measurement. Forty-nine sedentary individuals participated in a double-blind study and were divided into two groups: C (n=26) received 4x5-day packages of 0.6 g.kg-1 of body weight contained 50% of creatine + 50% of dextrose, and P (n=23) received packages containing only dextrose. On the first day the groups performed a 1RM test for bench press, seated row, leg extension, leg curl and leg press. On D7 they received the supplements. On the fourteenth day, they performed a training session of five exercises, each in three sets of ten repetitions at 75% of 1RM. Blood was collected before (D14) and after the exercise session (D15). Differing levels of blood creatine were tested to determine the influence on the assay measurements of CK. ANOVA and Tukey's post-hoc tests were used to compare groups and different times of study protocol (P<0.05). No changes were observed in CK activity of the groups from D0, D7 and D14. On D15 CK activity increases 140% (women) and 200% (men). There was no difference in CK activity between groups. Blood creatine levels up to 5mM produced no significant effect on CK assay results. CK activity increased after resistance exercise, while creatine supplementation produced no difference in the muscle cellular integrity nor compromised assay methodology.
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Messina, Carlo, Matteo G. Carrabba, Elisa Sala, Michela Tassara, Raffaella Milani, Paola Ronchi, Cristina Tresoldi, et al. "Early Blast Clearance Evaluation after Induction Chemotherapy for Acute Myeloid Leukemia By Multiparameter Flow Cytometry and WT1-RNA Quantification: A Single Center Experience." Blood 124, no. 21 (December 6, 2014): 5333. http://dx.doi.org/10.1182/blood.v124.21.5333.5333.
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Abstract Introduction: in acute myeloid leukemia (AML) the response to treatment is evaluated upon full recovery of peripheral blood counts by bone marrow (BM) assessment using morphology and cytogenetics, if appropriate number of metaphases is obtained. Real time quantitative PCR (RQ-PCR) and multiparametric flow citometry (MFC) are sensitive techniques to assess minimal residual disease (MRD) mostly used to refine risk stratification and to guide therapy. Evaluation of response to induction chemotherapy (CT) during aplasia (around day 14 from start of induction) has shown a significant prognostic impact, the presence of residual disease predicting a worse prognosis. All reported studies on early BM blast clearance evaluation rely on morphology as a single technique. Unfortunately, at day 14 BM is often not evaluable for cytology and morphologyc blast count. Unpredictability and intra-observer variability must also be considered when assessing blast count by morphology alone. No studies analysing early BM blast clearance by means of MFC and/or PCR have been published and the correlation between the two assays is unknown in this setting. Moreover, it is to be established if early intensification (around day 15 from start of induction) with a second cycle of CT could increase the CR rate in pts with disease persistence in the BM evaluated at day 14. Matherial and methods: we retrospectively evaluated data of 23 newly diagnosed AML pts who received induction CT at our center between 02/2009 and 05/2014, and for whom analysis of BM both at day 14 and after hematologic recovery (around day 28) was performed. The aim of our study was to define the prognostic value of early MRD quantification by MFC (d14-LAIP) and WT1 quantification by PCR (d14-WT1) in predicting the response to induction. Firstly we compared d14-LAIP and d14-WT1 to identify the more sensitive and specific assay in predicting the response to induction, in particular for cases not evaluable for morphologic blast count. Then we compared the outcome of pts who received or did not receive an early intensification for persistence of disease at d14 BM evaluation. Results: 20 pts received the 3+7 induction regimen, 3 pts the ICE induction regimen. After BM evaluation at day 14, 7 pts received early reinduction CT (FLAG-IDA regimen) starting at day 16 (median), 16 pts did not receive further therapy before BM evaluation at day 28. Overall CR rate was 70% (16 pts), PR/NR 30% (7 pts), TRM 4% (1 pt). At day 14, leukemic blast percentage was not evaluable by morphology in 8 (35%) cases due to marrow aplasia, in 1 (4%) case blasts were <5%, in 14 (61%) cases blasts were ≥5%; by MFC (23 cases), in 9 (39%) cases blasts were ≤2%, in 14 (61%) were >2%; by PCR (17 cases), in 4 (24%) cases WT1 was <250 cp/10e4 ABL, in 13 (76%) WT1 was ≥250 cp/10e4 ABL. At day 28 BM evaluation, of the 8 pts with aplastic marrow at day 14, 6 (75%) were in CR and 2 (25%) in PR/NR, of the 14 pts with blasts ≥5% at day 14, 9 (64%) were in CR and 5 (36%) in PR/NR. Analysis of the paired results from nadir to recovery revealed that d14-LAIP 2% had a positive predictive value (PPV) of CR at day 28 of 71% and negative predictive value (NPV) of 89%, with a sensitivity of 83% and a specificity of 80%, d14-WT1 250 had a PPV of 50% and NPV of 25%, with a sensitivity of 57% and a specificity of 20%. The d14-LAIP analysis was strongly associated with CR after induction (p 0.034). Considering the 14 pts with blasts ≥5% at day 14, 6/7 (86%) who received early reinduction CT and 3/7 (43%) who did not, obtained the CR at day 28 (p ns). Discussion: in our series d14-LAIP proved to be more predictive of response after induction CT than d14-WT1. Although one-third of pts had an early morphologic response not evaluable due to marrow aplasia MFC proved to be a useful assessment tool with a 100% applicability. Moreover, correlation between D14-LAIP and d14-WT1 was > 90%. Our data confirm the prognostic value of day 14 BM evaluation and suggest that MRD detection, also in aplasia, could drive early reinduction CT which probably could increase the CR rate, without significantly clinical complications. Anyway, this last point must be confirmed with a larger study. Disclosures Bordignon: MolMed S.p.A: Chairman and CEO Other.
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Yin, Bao Ying, Yong Zhang, Jian Hong Sun, Ji Xia Li, and Ye Fei Ma. "Connexin37 mRNA expression in in vivo and in vitro mouse oocyte." Zygote 17, no. 2 (May 2009): 163–68. http://dx.doi.org/10.1017/s0967199408005170.
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SummaryTo evaluate gene expression of Connexin37 (Cx37) in oocytes from in vitro follicles at different stages, mouse preantral follicles were isolated and cultured for 12 days in vitro. Compared with in vitro follicles, follicles grown in vivo were collected at day 14 (d14), d16, d18, d20, d22 and d24 with the same stages for gene expression of Cx37 in oocytes. Our results showed that Cx37 mRNA increased along with follicular development, reached the highest level at the onset of antrum cavity formation and decreased after antrum formation in both in vivo and in vitro mouse oocytes. However, Cx37 mRNA was significant higher (p < 0.01) in in vitro cultured oocytes than in vivo oocytes. Moreover, significantly higher levels of Cx37 mRNA were found in oocytes from in vitro disrupted follicles (p < 0.01) and non-grown follicles (p < 0.05) than those from normal follicles with a similar size. These data determine temporal gene expression of Cx37 in oocytes from follicules at different stages and indicate that the gene expression level of Cx37 in oocytes could be evaluated as a criterion to the regulatory mechanism of Cx37 in an in vitro model.
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Choi, Syngjoo, Raymond Fisman, Douglas Gale, and Shachar Kariv. "Consistency and Heterogeneity of Individual Behavior under Uncertainty." American Economic Review 97, no. 5 (November 1, 2007): 1921–38. http://dx.doi.org/10.1257/aer.97.5.1921.
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By using graphical representations of simple portfolio choice problems, we generate a very rich dataset to study behavior under uncertainty at the level of the individual subject. We test the data for consistency with the maximization hypothesis, and we estimate preferences using a two-parameter utility function based on Faruk Gul (1991). This specification provides a good interpretation of the data at the individual level and can account for the highly heterogeneous behaviors observed in the laboratory. The parameter estimates jointly describe attitudes toward risk and allow us to characterize the distribution of risk preferences in the population. (JEL D11, D14, D81, G11)