tbuckley/cabot-search huggingface dataset:
Lower IgG somatic hypermutation rates during acute dengue virus infection is compatible with a germinal center-independent B cell response
Authors: Elizabeth Ernestina Godoy-Lozano, Juan Téllez-Sosa, Gilberto Sánchez-González, Hugo Sámano-Sánchez, Andrés Aguilar-Salgado, Aarón Salinas-Rodríguez, Bernardo Cortina-Ceballos, Héctor Vivanco-Cid, Karina Hernández-Flores, Jennifer M. Pfaff, Kristen M. Kahle, Benjamin J. Doranz, Rosa Elena Gómez-Barreto, Humberto Valdovinos-Torres, Irma López-Martínez, Mario H. Rodriguez, Jesús Martínez-Barnetche
Journal: Genome Medicine (2016)

Background: The study of human B cell response to dengue virus (DENV) infection is critical to understand serotype-specific protection and the cross-reactive sub-neutralizing response.Whereas the first is beneficial and thus represents the ultimate goal of vaccination, the latter has been implicated in the development of severe disease, which occurs in a small, albeit significant, fraction of secondary DENV infections.Both primary and secondary infections are associated with the production of poly-reactive and cross-reactive IgG antibodies.Methods: To gain insight into the effect of DENV infection on the B cell repertoire, we used VH region high-throughput cDNA sequencing of the peripheral blood IgG B cell compartment of 19 individuals during the acute phase of infection.For 11 individuals, a second sample obtained 6 months later was analyzed for comparison.Probabilities of sequencing antibody secreting cells or memory B cells were estimated using second-order Monte Carlo simulation.Results: We found that in acute disease there is an increase in IgG B cell diversity and changes in the relative use of segments IGHV1-2, IGHV1-18, and IGHV1-69.Somewhat unexpectedly, an overall low proportion of somatic hypermutated antibody genes was observed during the acute phase plasmablasts, particularly in secondary infections and those cases with more severe disease.Conclusions: Our data are consistent with an innate-like antiviral recognition system mediated by B cells using defined germ-line coded B cell receptors, which could provide a rapid germinal center-independent antibody response during the early phase of infection.A model describing concurrent T-dependent and T-independent B cell responses in the context of DENV infection is proposed, which incorporates the selection of B cells using hypomutated IGHV segments and their potential role in poly/cross-reactivity.Its formal demonstration could lead to a definition of its potential implication in antibody-dependent enhancement, and may contribute to rational vaccine development efforts.
Abstract 13189: Mildly Attenuated Heart Rate Response during Exercise and Adverse Cardiovascular Outcome: Follow-Up Of 10,323 Healthy Men and Women After Treadmill Exercise
Authors: Elad Maor, Eran Kopel, Yechezkel Sidi, Ilan Goldenberg, Shlomo Segev, Shaye Kivity
Journal: Circulation (2012)

Background: Attenuated heart rate during exercise is associated with adverse cardiovascular outcome. However, heart rate response threshold is poorly defined. We investigated the correlation of hea...
A phase 2, open-label study of niraparib in women with advanced, relapsed, high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer after ≥3 previous chemotherapy regimens.
Authors: Kathleen N. Moore, Bj Rimel, Shefali Agarwal, John Balser, Robert E. Martell, Bradley J. Monk
Journal: Journal of Clinical Oncology (2015)

TPS5609 Background: Niraparib is a potent, orally active PARP-1 and -2 inhibitor in development for the treatment of tumors that exhibit defects in the PARP-mediated homologous recombination DNA repair pathway. In preclinical experiments, niraparib has shown activity against germ line BRCA mutated (gBRCAmut) ovarian cancer cells (OvCa) and other High-Grade Serous OvCa (HGSC) cells. At the recommended dose of 300 mg, 50% of patients with BRCA-mutant ovarian cancer who had received more than 3 lines of prior chemotherapy achieved RECIST responses in the phase 1 study. Methods: This is a multicenter (approximately 35 sites), open-label, Phase 2 study of niraparib in up to 225 women with advanced, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer. Eligible pts must have received ≥ 3 previous chemotherapy regimens (prior exposure to PARP inhibitors and/or prior anti-angiogenesis inhibitors are not excluded). The primary objective is to evaluate the antitumor activity of niraparib. Secondary objectives are 1) durability of antitumor activity; 2) antitumor activity in Homologous Recombination Deficiency (HRD)-positive pts and in pts with gBRCAmut; 3) disease control rate; 4) progression-free survival; and 5) safety and tolerability. Exploratory objectives are 1) QTc interval in a subset of niraparib-treated OvCa pts; 2) population pharmacokinetics for niraparib and its major metabolite; and 3) potential biomarkers of PARP inhibitor sensitivity and tolerability. Niraparib 300 mg is administered orally once daily on a 28 day cycle until discontinuation.. The overall analysis will use a 1-proportion statistical test that the ORR is ≥ 30%. The ORR will be evaluated in the HRD-positive and gBRCAmut subsets. The sample size at 1-sided alpha of 0.025 and > 80% power for the pooled subsets would be N = 200 using a normal approximation with continuity correction. The HRD-positive or gBRCAmut subset represents 100 patients of the total sample population. Clinical trial information: NCT02354586.
Decitabine Priming Enhances The Antileukemic Effects Of The Selective Inhibitor Of Nuclear Export (SINE) CRM1/XPO1 Antagonist (Selinexor) In Acute Myeloid Leukemia (AML)
Authors: Parvathi Ranganathan, Xueyan Yu, Jessica Hofstetter, Ramasamy Santhanam, Sharon Schacham, Michael Kauffman, William Blum, Guido Marcucci, Ramiro Garzon
Journal: Blood (2013)
A phase I trial and pharmacokinetic study of IMC-A12 in pediatric patients with relapsed/refractory solid tumors: A Children's Oncology Group Phase I Consortium study
Authors: S. Malempati, B. Weigel, A. M. Ingle, C. H. Ahern, J. M. Carroll, C. T. Roberts, F. E. Fox, S. Voss, P. C. Adamson, S. M. Blaney
Journal: Journal of Clinical Oncology (2009)

10013 Background: IMC-A12, a fully human IgG1 monoclonal antibody to the Insulin-Like Growth Factor-I Receptor (IGF-IR), is active preclinically in a variety of pediatric solid tumors. We performed a phase I trial to determine the toxicities, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of IMC-A12 in children with refractory solid tumors. Methods: IMC-A12 was administered as a weekly 1 hr IV infusion, without interruption. Two dose levels, 6 and 9 mg/kg, were evaluated using a standard 3+3 cohort design. After defining initial safety, patients (pts) with refractory Ewing sarcoma (ES) were treated in an expanded cohort at each dose level. Results: 24 eligible patients (11 male), median 15.3 yrs (range, 7.0 to 21.5), were enrolled. Among the 12 pts enrolled on the dose-escalation component, DLT (grade 4 thrombocytopenia) occurred in 1/6 pts at 6 mg/kg. No DLTs occurred in 6 pts at 9 mg/kg or in the ES cohort. 1/10 evaluable pts with ES at the 6 mg/kg dose had a partial response; no CRs were observed. Grade 2 or higher non-DLTs possibly attributable to IMC-A12 observed in the first course include anemia (n=4), leukopenia (n=1), lymphopenia (n=2), neutropenia (n=2), opportunistic infection (n=1), ↑liver transaminases (n=2), and hyperglycemia (n=1). No ≥ grade 3 hyperglycemia occurred. Mean (± SD) trough IMC-A12 concentrations were 59.8 ± 31.1 and 117 ± 70.8 μg/ml at the 6 and 9 mg/kg dose levels, respectively. A majority of pts at both dose levels exhibited &gt; 50% reduction in PBMC IGF-IR protein levels. Conclusions: In order to exceed target trough concentrations associated with optimal anti-tumor activity in pre-clinical models, 9 mg/kg IV weekly is the recommended Phase II IMC-A12 dose in children. A phase II protocol for children with refractory solid tumors will be performed. [Table: see text]
Comparison of pegfilgrastim vs. lenograstim in the treatment of chemotherapy-induced neutropenia in adult patients with acute myelogenous leukemia (AML)
Authors: O. P. Ranze, M. Arland, H.-G. Hoeffkes
Journal: Journal of Clinical Oncology (2004)

6669 Background: Two phase III trials in breast cancer patients treated with myelosuppressive chemotherapy showed that a single dose of pegfilgrastim provides neutrophil support comparable with that provided by an average of 11 daily injections of filgrastim. In acute myelogenous leukemia (AML) data are sparse regarding the recovery of neutrophil counts (NC) after therapy with G-CSF in chemotherapy-induced neutropenia. We compared the effects of pegfilgrastim vs. lenograstim by these patients (pts). Methods: Retrospective analysis of unselected pts with AML, 18–75 yrs of age, ECOG ≤ 2, excluding pregnancy received at least one cycle of chemotherapy. On day 1 after chemotherapy treatment either pegfilgrastim 6 mg/once per cycle or lenograstim 5 micg/kg b.w. was administered. Primary objective was the time to recovery (TTR) of NC ≥ 1.0 G/L in each treatment group after injection of G-CSF if NC nadired < 1.0 G/L temporarily. Secondary objectives were the rate of transfusion of packed red blood (PRB) and pooled platelets (PLT). Results: 29 pts, 11 m + 18 f, aged median 61.4 yrs (range: 27–75) received 47 cycles. In 5 pts (3 pts in the pegfilgrastim and 2 pts in the lenograstim group) treatment failed to elevate NC ≥ 1.0 G/L. There was a difference in the TTR of NC between pegfilgrastim 11.1 ± 6.2 days (range: 6–28) and lenograstim 13.3 ± 3.6 days (range: 6–22). Detailed characteristics are summarized in table 1. Conclusions: Both G-CSF showed adequate recovery of NC with a faster increase in those patients where pegfilgrastim was administered. Less frequently blood products were transfused in the pegfilgrastim group. According to the whole-sale pharmacy prices in Germany, G-CSF treatment per cycle for a median of 13 vials of lenograstim was about € 2,321/US $ 2,785 (range: € 1,071–3,928/US $ 1,285–4,714) compared with 1 syringe of pegfilgrastim € 1,762/US $ 2,114. No significant financial relationships to disclose.
Gemcitabine enhances the sensitivity of renal cell cancer to cytolysis by IL2-activated lymphocytes
Authors: D. P. Braun, B. Kloesel, K. A. Crist
Journal: Journal of Clinical Oncology (2008)

14020 Background: Limited clinical efficacy of immunotherapy (IT) necessitates new treatment (Tx) strategies. A relatively novel approach that is clinically feasible exploits the capacity of chemotherapy to affect tumor functions that govern sensitivity to immune-mediated killing. The current study tested this with renal cell cancer (RCC) cells exposed to clinically achievable doses of drugs prior to assessing their sensitivity to cytolysis by IL2-activated human lymphocytes (IL2 Ly). Methods: Human RCC line 769-P was incubated with pharmacologic concentrations of vinblastine, cisplatinum, paclitaxel, or gemcitabine (Gz) prior to evaluating killing by IL2 Ly. Optimum results with Gz prompted feasibility and mechanistic studies. Results: In vitro exposure to 20 uM Gz for 4 hrs, which is ≤ levels achieved in patients receiving Gz Tx of 1 gm/M2; 30 min infusion (½ life=60 min) increased RCC lysis by IL2 Ly from multiple donors from 623 ± 370 to 780 ± 477 lytic units (media vs Gz-precultured cells respectively, p=0.008). Genomic analysis demonstrated increased lytic sensitivity was associated with increased mRNA expression for: (i) adhesion molecules, ICAM-1, Necl-2 and MCAM (6.5, 2 and 2 fold respectively); (ii) MHC Class I-related molecules, MR-1 (7 fold) and HLA-A, B, E and F (1.5–3 fold); and, (iii) death receptors, FAS and TRAIL-receptor 2 (2 fold respectively). Flow cytometry confirmed the 2 fold increase in FAS death receptors on GZ-treated RCC cells without changes in tumor expression of killer cell inhibitory ligands associated with HLA-A, B, and C molecules. Gz suppressed cytotoxic function generation in Ly cultured for 3 days with IL2 but was not suppressive in 6 day cultures. Improved survival was shown in RCC-bearing immunocompetent mice given Gz + IL2 compared to mice treated with either drug alone. Conclusions: The results demonstrate RCC cells that survive Tx with a pharmacological dose of Gz exhibit significantly increased sensitivity to killing by human IL2 Ly. These methods can be used to identify classes of drugs that might be exploited to enhance sensitivity of chemo-resistant human tumors to immunotherapy. No significant financial relationships to disclose.
Fungal Mimicry of a Mammalian Aminopeptidase Disables Innate Immunity and Promotes Pathogenicity
Authors: Alana K. Sterkel, Jenna L. Lorenzini, J. Scott Fites, Kavitha Subramanian Vignesh, Thomas D. Sullivan, Marcel Wuthrich, Tristan Brandhorst, Nydiaris Hernandez-Santos, George S. Deepe, Bruce S. Klein
Journal: Cell Host & Microbe (2016)
A multicenter phase II study of abiraterone acetate (AA) in docetaxel pretreated castration-resistant prostate cancer (CRPC) patients (pts)
Authors: A. H. Reid, G. Attard, D. Danila, C. J. Ryan, E. Thompson, T. Kheoh, A. Molina, E. Small, H. Scher, J. S. De-Bono
Journal: Journal of Clinical Oncology (2009)

5047 Background: Despite castration, androgens remain critical to prostate cancer. Abiraterone acetate (AA) specifically and irreversibly inhibits CYP17, a key enzyme in androgen biosynthesis. Methods: 47 CRPC pts who had failed androgen deprivation therapy and had prior docetaxel chemotherapy received AA orally (1000mg QD) in 28 day cycles. Low dose glucocorticoids were allowed. Results: Patient demographics in table . Total maximal PSA declines with AA at any point on study of ≥30%, ≥50%, and ≥ 90% were observed in 32 (69%), 24 (51%) and 7 (15%) pts respectively. A similar trend in PSA response was seen at wk 12. 35 pts were evaluable by RECIST; 6 (17%) pts had a partial response and 23 (66%) pts had stable disease. 23% of pts showed ECOG improvement (PS 1 to 0 in 10 pts, PS 2 to 1 in 1 pt); 53% of pts maintained PS. Median duration on treatment was 167 days (95% CI 130–201). 17 pts received &gt;6 cycles of AA; 8 pts received ≥ 12 cycles. Toxicities related to mineralocorticoid excess were mainly grade 1–2 (hypokalemia 51%; HTN 17%; edema 13%) and were treated with eplerenone or corticosteroids. Conclusions: AA has anti-tumor activity in these heavily pretreated pts, as evidenced by sustained PSA declines, improvement in PS and RECIST responses. A phase III trial assessing the efficacy and safety of AA and prednisone in CRPC pts who have failed docetaxel chemotherapy is underway. [Table: see text] [Table: see text]
Erlotinib, gemcitabine, paclitaxel and radiation for locally advanced pancreatic cancer: a phase I study
Authors: D. Iannitti, T. Dipetrillo, D. Cruff, S. Sambandam, C. Maia, M. Hughes, N. Oldenburg, K. Thornton, T. Kennedy, H. Safran
Journal: Journal of Clinical Oncology (2004)

4093 Background: The Brown University Oncology Group and the Radiation Therapy Oncology Group have investigated concurrent gemcitabine, paclitaxel, and concurrent radiation for patients with locally advanced pancreatic cancer. The EGFR tyrosine kinase inhibitor erlotinib is a radiation sensitizer that may enhance local control and delay systemic recurrence. We performed a phase I study of erlotinib with gemcitabine, paclitaxel and radiation. Methods: Patients with locally advanced pancreatic adenocarcinoma and patients with locally residual disease or involved margins after resection were eligible. All patients received gemcitabine, 75mg/m2, and paclitaxel, 40mg/m2, weekly for 6 weeks with radiation, 50.4 Gy. Radiation included the primary tumor and draining lymph nodes with a 2 to 3 cm margin. Erlotinib was initiated with the first day of chemoradiation (chemo/RT) at three planned dose levels: 50 mg/day, 100 mg/day, and 150 mg/day. Three weeks post chemo/RT, all patients received erlotinib, 150 mg/day, until progression. Results: 12 patients are assessable for toxicity, 6 on dose level one, and 6 on dose level two. Nine patients had locally advanced disease, and 3 had undergone resection but had positive margins. Dose limiting toxicities of grade 3 diarrhea and dehydration occurred in 2 of 6 patients at dose level two. An acneiform rash, most prominent in the face, occurred in 9 of 12 patients. Diarrhea and rash generally occurred together beginning in the 2nd and 3rd weeks of treatment. Four of 9 patients with locally advanced disease had a partial response. Three additional patients had a greater than 75% reduction in CA19–9 with extensive necrosis in the mass on post-treatment CT. Conclusions: Diarrhea and rash are the dose limiting toxicities with the addition of erlotinib to gemcitabine, paclitaxel and radiation. The protocol is being amended to add a 75 mg erlotinib dose level with chemo/RT. No significant financial relationships to disclose.
Pro-BNP for detection of sunitinib-induced cardiac toxicity in patients with renal cell carcinoma.
Authors: M. Schmidinger, M. Bojic, U. Vogl, W. Lamm, C. Zielinski
Journal: Journal of Clinical Oncology (2010)

4627 Background: Sunitinib was shown to induce cardiac toxicity in patients with metastatic RCC. Thus, frequent and detailed assessment of cardiac function and close clinical observation have been considered essential when treating these patients. However, frequent echocardiograms might not be feasible in every single patient in the routine clinical practise. Similarly, electrocardiograms (ECGs) may show a variety of changes, often requiring a cardiologist to interpret the findings within the clinical context. A suitable marker for cardiac toxicity should be easily assessable and detect both pending cardiac damages and clinically relevant cardiac events. Pro-B-type natriuretic peptide (pro-BNP) is a widely studied neuro-hormonal mediator of cardiac damage. The aim of this prospective analysis was to investigate the role of pro-BNP as an early indicator for sunitinib-induced cardiac toxicity. Methods: All patients with mRCC assigned for first-line treatment with sunitinib were analyzed for history or evidence of cardiac diseases. Monitoring included assessment of clinical symptoms, ECGs, echocardiograms and biochemical markers of cardiac damage, i.e. pro-BNP and cardiac Troponin T (TNT). Echocardiograms and ECGs were obtained at baseline, every 3 months and at increase of biochemical markers. Pro-BNP and TNT were assessed at baseline and then every 4 weeks. A significant clinical finding indicating cardiac damage was defined as a pathological echocardiogram, development of clinical symptoms or increased TNT. Results: Twenty two out of 26 patients (84.6%) presented with increased pro-BNP serum levels after a median treatment period of 6 weeks (range 1-71 weeks). Among these patients, 12 (55%) had significant clinical findings, with a pro-BNP level mostly above 1000 pg/ml. Normal pro-BNP levels were always associated with the complete absence of clinical findings for cardiac toxicity. Conclusions: Our observations indicate that pro-BNP serum levels may serve as an easily assessable marker for cardiac toxicity. The cut off level of 1000 ng/ml may represent the threshold for clinically relevant cardiac damage and should lead to temporary treatment interruption and involvement of a cardiologist. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Pfizer, Roche, Wyeth
Prenatal Factors in Singletons with Cerebral Palsy Born at or near Term
Authors: Karin B. Nelson, Eve Blair
Journal: New England Journal of Medicine (2015)

The notion that cerebral palsy is related mainly to birth asphyxia is widespread, but birth asphyxia plays a relatively minor role, accounting for less than 10% of cases. Disordered developmental processes appear to be the predominant influences.
Interdependent MHC-DRB exon-plus-intron evolution in artiodactyls.
Authors: F W Schwaiger, E Weyers, J Buitkamp, A J Ede, A Crawford, J T Epplen
Journal: Molecular Biology and Evolution (1994)

Exon 2 sequences of an expressed MHC-DRB locus from sheep were examined for polymorphisms in both the antigen-binding regions and the adjacent intronic mixed simple tandem repeat. Twenty-one novel exon 2 Ovar-DRB alleles were identified. Short nucleotide motifs are extensively shared between certain exon 2 regions of Ovar-DRB alleles. The simple repeat variations, the number of different amino acids at usually polymorphic sites, and the number of silent substitutions were reduced in the intraspecies analyses of sheep DRB sequences, compared with those of cattle and goats. It was paradoxical that the abundance of different sheep alleles was similar to that of cattle and goats. This paradox may be explained by postulating a relatively small number of "ancient" alleles, with the present-day Ovar-DRB alleles being generated by reciprocal exchange of nucleotide motifs. At the antigen-binding sites, new combinations of amino acids were maintained in Ovar-DRB alleles by strong positive selection. In sheep--and less pronounced in goats and cattle--the DRB alleles can be divided into two groups. In one group, silent substitutions are increased when compared with the other. This suggests separate evolutionary pathways for certain groups of DRB alleles within a species. The simple repetitive sequences are also discussed with respect to the evolution of DRB alleles.
Increased postprandial apolipoprotein B-48 level after a test meal in diabetic patients: A multicenter, cross-sectional study
Authors: Cheol-Young Park, Joong-Yeol Park, Jongwon Choi, Dae Jung Kim, Kyong Soo Park, Kun-Ho Yoon, Moon-Kyu Lee, Sung-Woo Park
Journal: Metabolism (2016)