tbuckley/cabot-search huggingface dataset:
Genomic epidemiology of age-associated meningococcal lineages in national surveillance: an observational cohort study
Authors: Dorothea M C Hill, Jay Lucidarme, Stephen J Gray, Lynne S Newbold, Roisin Ure, Carina Brehony, Odile B Harrison, James E Bray, Keith A Jolley, Holly B Bratcher, Julian Parkhill, Christoph M Tang, Ray Borrow, Martin C J Maiden
Journal: The Lancet Infectious Diseases (2015)

Invasive meningococcal disease (IMD) is a worldwide health issue that is potentially preventable with vaccination. In view of its sporadic nature and the high diversity of Neisseria meningitidis, epidemiological surveillance incorporating detailed isolate characterisation is crucial for effective control and understanding the evolving epidemiology of IMD. The Meningitis Research Foundation Meningococcus Genome Library (MRF-MGL) exploits whole-genome sequencing (WGS) for this purpose and presents data on a comprehensive and coherent IMD isolate collection from England and Wales via the internet. We assessed the contribution of these data to investigating IMD epidemiology.WGS data were obtained for all 899 IMD isolates available for England and Wales in epidemiological years 2010-11 and 2011-12. The data had been annotated at 1720 loci, analysed, and disseminated online. Information was also available on meningococcal population structure and vaccine (Bexsero, GlaxoSmithKline, Brentford, Middlesex, UK) antigen variants, which enabled the investigation of IMD-associated genotypes over time and by patients' age groups. Population genomic analyses were done with a hierarchical gene-by-gene approach.The methods used by MRF-MGL efficiently characterised IMD isolates and information was provided in plain language. At least 20 meningococcal lineages were identified, three of which (hyperinvasive clonal complexes 41/44 [lineage 3], 269 [lineage 2], and 23 [lineage 23]) were responsible for 528 (59%) of IMD isolates. Lineages were highly diverse and showed evidence of extensive recombination. Specific lineages were associated with IMD in particular age groups, with notable diversity in the youngest and oldest individuals. The increased incidence of IMD from 1984 to 2010 in England and Wales was due to successive and concurrent epidemics of different lineages. Genetically, 74% of isolates were characterised as encoding group B capsules: 16% group Y, 6% group W, and 3% group C. Exact peptide matches for individual Bexsero vaccine antigens were present in up to 26% of isolates.The MRF-MGL represents an effective, broadly applicable model for the storage, analysis, and dissemination of WGS data that can facilitate real-time genomic pathogen surveillance. The data revealed information crucial to effective deployment and assessment of vaccines against N meningitidis.Meningitis Research Foundation, Wellcome Trust, Public Health England, European Union.
Flavopiridol, A Novel Cyclin-Dependent Kinase Inhibitor, in Metastatic Renal Cancer: A University of Chicago Phase II Consortium Study
Authors: Walter M. Stadler, Nicholas J. Vogelzang, Robert Amato, Jeffery Sosman, David Taber, David Liebowitz, Everett E. Vokes
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Flavopiridol is the first cyclin-dependent kinase (cdk) inhibitor to enter clinical trials. Serum levels of flavopiridol obtained during phase I studies were sufficient to inhibit in vitro cancer cell growth. Because responses were observed in kidney cancer patients in the phase I trials, we performed a phase II trial of flavopiridol in this patient population. PATIENTS AND METHODS: Thirty-five minimally pretreated patients were accrued using a standard two-step mechanism. Flavopiridol (50 mg/m 2 /d) was administered by continuous infusion for 72 hours every 2 weeks, and response was evaluated every 8 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, at completion of drug infusion, and on day 7 of the first therapy cycle, and cell cycle parameters after phytohemagglutinin and interleukin-2 stimulation were assessed. RESULTS: There were two objective responses (response rate = 6%, 95% confidence interval, 1% to 20%). The most common toxicities were asthenia, occurring in 83% of patients (grade 3 or 4 in 9%), and diarrhea, occurring in 77% of patients (grade 3 or 4 in 20%). Also, nine patients (26%) experienced grade 3 or 4 vascular thrombotic events, including one myocardial infarction, two transient neurologic ischemic attacks, four deep venous thrombosis, and two pulmonary emboli. Cell cycle studies did not reveal any effect of flavopiridol on stimulated PBMCs. CONCLUSION: Flavopiridol, at the dose and schedule administered in this trial, is ineffective in metastatic renal cancer. In addition to the diarrhea observed in phase I studies, we also observed a higher incidence of asthenia and serious vascular thrombotic events than expected.
miR-124 and Androgen Receptor Signaling Inhibitors Repress Prostate Cancer Growth by Downregulating Androgen Receptor Splice Variants, EZH2, and Src
Authors: Xu-Bao Shi, Ai-Hong Ma, Lingru Xue, Meimei Li, Hao G. Nguyen, Joy C. Yang, Clifford G. Tepper, Regina Gandour-Edwards, Christopher P. Evans, Hsing-Jien Kung, Ralph W. deVere White
Journal: Cancer Research (2015)

Abstract miR-124 targets the androgen receptor (AR) transcript, acting as a tumor suppressor to broadly limit the growth of prostate cancer. In this study, we unraveled the mechanisms through which miR-124 acts in this setting. miR-124 inhibited proliferation of prostate cancer cells in vitro and sensitized them to inhibitors of androgen receptor signaling. Notably, miR-124 could restore the apoptotic response of cells resistant to enzalutamide, a drug approved for the treatment of castration-resistant prostate cancer. We used xenograft models to examine the effects of miR-124 in vivo when complexed with polyethylenimine-derived nanoparticles. Intravenous delivery of miR-124 was sufficient to inhibit tumor growth and to increase tumor cell apoptosis in combination with enzalutamide. Mechanistic investigations revealed that miR-124 directly downregulated AR splice variants AR-V4 and V7 along with EZH2 and Src, oncogenic targets that have been reported to contribute to prostate cancer progression and treatment resistance. Taken together, our results offer a preclinical rationale to evaluate miR-124 for cancer treatment. Cancer Res; 75(24); 5309–17. ©2015 AACR.
Peritoneal carcinomatosis with synchronous liver metastases from colorectal cancer: Who will benefit from complete cytoreductive surgery?
Authors: Jean-Baptiste Delhorme, Laure Dupont-Kazma, Pietro Addeo, François Lefebvre, Elhocine Triki, Benoit Romain, Nicolas Meyer, Philippe Bachellier, Serge Rohr, Cécile Brigand
Journal: International Journal of Surgery (2015)
Healthy Babies after Intrauterine Transfer of Mosaic Aneuploid Blastocysts
Authors: Ermanno Greco, Maria Giulia Minasi, Francesco Fiorentino
Journal: New England Journal of Medicine (2015)

2089 correspondence reflects improvements in patient care rather than case selection.In response to de Miguel-Yanes et al.: we did not evaluate the subgroup with diabetes in our initial analysis.However, in contrast with de Miguel-Yanes et al., after stratifying our sample according to the presence of diabetes we observed higher mortality for the subgroup of patients with diabetes, and this difference persisted over time.We agree with Hussain and Al-Omran that surgical volume is an important predictor of outcomes for abdominal aortic aneurysm repair. 1 In our previous work, we found that the relationship between hospital volume and outcomes was quite different for endovascular repair versus open repair and that experience with one type of repair did not carry over to improved outcomes in the other type of repair.We therefore did not conduct propensity-score matching for procedure volume in our analysis, since doing so would have been helpful only for comparisons of the same procedure, not for comparisons between different procedures.
An opportunity to reduce the burdens and inequalities in cardiovascular disease and gastric cancer caused by dietary salt: IMPACT NCD microsimulation study
Authors: Chris Kypridemos, Maria Guzman-Castillo, Lirije Hyseni, Piotr Bandosz, Kirk Allen, Iain Buchan, Simon Capewell, Martin O’Flaherty
Journal: The Lancet (2015)
The Effects of Calcium and Phosphorus in Hemodialysis
Authors: R S Goldsmith
Journal: Annual Review of Medicine (1976)

Combined use of Ca supplements (orally or by dialysis) to circumvent decreased intestinal Ca absorption and aluminum compounds to reduce plasma [Pi] has been demonstrated to decrease plasma [iPTH], to normal or near normal in many patients, and to decrease the percentage of bone surface involved in bone resorption. A highly significant positive relationship between change in plasma [iPTH] and bone resorbing surface has been reported. It seems evident, therefore, that PTH must be a major factor in the bone resorption of chronic renal failure, despite the relative skeletal resistance to PTH. As a result, correction of factors that increase PTH secretion should be considered a prime goal of therapy in these patients. The osteomalacic element of renal osteodystrophy, on the other hand, is only partially controlled by these maneuvers and probably requires the additional use of vitamin D or one of its active metabolites for full correction.
High-throughput sequencing insights into T-cell receptor repertoire diversity in aging
Authors: Jörg J. Goronzy, Qian Qi, Richard A. Olshen, Cornelia M. Weyand
Journal: Genome Medicine (2015)

Decline in T-cell generation leading to T-cell receptor repertoire contraction is a cornerstone of immune system aging, and consequent disorders. High-throughput sequencing enables in-depth immune repertoire characterization, but blood samples are too small to capture its total diversity. New computational models could enable accurate estimation of this diversity.
Interleukin-2 and high-dose cisplatin in patients with metastatic melanoma: a pilot study.
Authors: P A Demchak, J W Mier, N J Robert, K O'Brien, J A Gould, M B Atkins
Journal: Journal of Clinical Oncology (1991)

In this pilot study of metastatic melanoma, interleukin-2 (IL-2) and cisplatin (CDDP) chemotherapy were combined using an alternating schedule designed to explore potential synergism between these modalities. Bolus IL-2 was given at a dose of 600,000 IU/kg intravenously (IV) every 8 hours, days 1 to 5 and 15 to 19, followed by high-dose CDDP administered by two different regimens: (A) 135 to 150 mg/m2 IV bolus over 30 minutes with the chemoprotectant WR-2721 910 mg/m2 or (B) 50 mg/m2 IV over 2 hours every day for 3 days. The trial design allowed an assessment of response to each phase of therapy. Among 27 assessable patients, there were 10 (37%) overall responses, including three (11%) complete responses (CRs) with durations of 9, 16, and 30+ months. Tumor regression was noted in seven patients (partial response [PR], four; minor response [MR], three; response rate [RR], four of 27 [15%]) after IL-2 administration and in 14 patients (PR, 12; MR, two; RR, 12 of 27 [44%]) after CDDP treatment, demonstrating noncrossresistance between the components of the regimen. Major PRs (greater than 90% reduction of tumor burden) or CRs were only seen in patients responding to IL-2. Toxicity during IL-2 therapy was typical for high-dose IL-2 protocols and was reversible. Among the first 20 patients treated with CDDP regimen A, there were eight episodes of grade IV nephrotoxicity (creatinine level greater than 5.0 mg/dL), including three of six patients treated with an initial CDDP dose of 135 mg/m2. This side effect was more frequent among patients with liver metastasis (P less than .05, Fisher's exact test). No significant nephrotoxicity was noted in seven patients treated on regimen B. Although ototoxicity was frequent, minimal bone marrow and neurologic toxicity was noted. There were no treatment-related deaths. This combination showed at least additive activity against melanoma, and the more protracted CDDP schedule was well tolerated. This regimen may serve as a model for future combined immunotherapy and chemotherapy trials in metastatic melanoma.
SAT0102 Stem Cell Augmentation for Cardiovascular Risk in Rheumatoid Arthritis with Olmesartan: Star-O Study
Authors: A. Syngle, N. Garg, P. Krishan
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Cardiovascular disease remains the leading cause of mortality in rheumatoid arthritis (RA). Endothelial progenitor cells (EPCs) are depleted and contribute to increased cardiovascular (CV) risk in RA.<sup>1</sup> Olmesartan exerts a protective cardiovascular effect in diabetes by augmenting EPCs.<sup>2</sup> However, this vasculoprotective effect of olmesartan has not yet been investigated in RA. <h3>Objectives</h3> To investigate the impact of olmesartan on circulating endothelial progenitor cell population in RA. <h3>Methods</h3> Forty RA patients fulfilling the 2010 Rheumatoid Arthritis classification criteria were randomized to receive 24 weeks of treatment with olmesartan (10mg/day, n=20) or placebo (n=20) as an adjunct to existing stable antirheumatic drugs. EPCs (CD34<sup>+</sup>/CD133<sup>+</sup>) were quantified by Flow cytometry. Flow mediated dilatation (FMD) was assessed by AngioDefender™ (Everest Genomic Ann Arbor, United States). Inflammatory measures included DAS28, CRP, ESR, pro-inflammatory cytokines (TNF-α, IL-6 and IL-1), serum nitrite and adhesion molecules (ICAM-1 and VCAM-1) at baseline and after 24 weeks treatment. <h3>Results</h3> At baseline, inflammatory measures, pro-inflammatory cytokines, adhesion molecules and nitrite levels were elevated and EPCs and endothelial function were impaired among both groups. EPCs significantly 0.018±0.001 to 0.031±0.001 increased p&lt;0.01 after treatment with olmesartan but did not show significant change with placebo 0.019±0.001 to 0.022±0.001, p=0.14. After 24 weeks of treatment, FMD improved significantly from (5.2±1.4 to 9.0±1.10, p=0.01) as compared to placebo (p=0.47) group. Olmesartan significantly decreased systolic/diastolic blood pressure (mean difference, -7.5/-1.6, p=0.01) as compared with placebo (mean difference, -4.1/-1.2, p&gt;0.05). After 24 weeks: inflammatory measures DAS28, ESR, CRP (All p=0.01) and nitrite (p=0.03) were significantly reduced after treatment with olmesartan. Proinflammatory cytokines TNF-α, IL-6 and VCAM-1 significantly (p=0.38, p=0.02 and 0.01 respectively) reduced in olmesartan group. Significant negative correlation was observed between EPCs and CRP (Fig. 1A), TNF- α (Fig. 1B), IL-6, VCAM-1 (Fig. 1D) and FMD (Fig. 1C) after treatment with olmesartan. <h3>Conclusions</h3> First study to show that olmesartan improves inflammation, EPC biology and endothelial dysfunction in RA possibly through its anti-inflammatory effect via inhibition of proinflammatory cytokines. This anti-inflammatory effect may be of therapeutic relevance in RA. <h3>References</h3> Grisar J et al. Circulation. 2005;111:204-211. Bahlmann FH et al. Hypertension. 2005;45:526-29 <h3>Acknowledgements</h3> This study was supported by Research Grant from Universal Grant Commission, New Delhi [F. No.41-725/2012 (SR)]. <h3>Disclosure of Interest</h3> None declared
Alice Bennett, M.D., Ph.D.: A Woman of Firsts
Authors: Kenneth J. Weiss
Journal: American Journal of Psychiatry (2015)

The 19th century witnessed the proliferation of asylums and awareness that female patients might best be treated by female doctors.The Woman's (originally Female) Medical College of Pennsylvania had been graduating female physicians since before the Civil War.Dr. Hiram Corson, a leading Montgomery County physician, was eager to see them employed in mental asylums.Alice Bennett, a schoolteacher from Wrentham, Mass., obtained her degree from the Woman's Medical College of Pennsylvania in 1876.She enrolled in the auxiliary school at the University of Pennsylvania to study anatomy.Meanwhile, she offered care to poor women in Philadelphia and taught anatomy at the Woman's Medical College.In 1880, she became the first woman to receive a doctoral degree from the University of Pennsylvania.Dr. Bennett was surprised when Dr. Corson offered her a position as resident physician (essentially medical superintendent) at the women's department of the new asylum in Norristown in 1880.She accepted and became the first woman in America to assume psychiatric leadership; others soon followed.While learning on the job during her 16-year tenure, Dr. Bennett developed a reputation for the humane care of patients, for the nonuse of restraints, and for explaining women's abnormal behavior in legal cases.Her testimony in the 1888 trial of triple murderer Sarah Whiteling was an early, if not the first, appearance of a female physician applying psychiatry to the law.Already prominent in Pennsylvania medicine, in 1889 Dr. Bennett set out to attend the meeting of the state medical society in Pittsburgh when she heard the announcement of the Johnstown Flood.The probability of widespread psychological effects propelled her into action, as she made her way to the disaster scene, seeking women in distress.In effect, she was a psychiatric first responder to a disaster, and she was cited accordingly by Cambria County.Endorsed again by Dr. Corson, Dr. Bennett became the first female president of a medical society (Montgomery County) in 1890.Dr. Corson was so devoted to Dr. Bennett and to the promotion of women in medicine that he arranged for Thomas Hovenden to paint her portrait (shown here).Disenchanted with scrutiny of her participation in ovariectomy for some psychiatric conditions, she resigned from the asylum in 1896.The coda to her psychiatric career was her position as personal physician to the mentally ill daughter of industrialist Cyrus McCormick for 4 years.After disappearing from medical practice until 1910, Dr. Bennett reemerged in New York City, where she delivered over 2,000 babies at the Blackwells' New York Infirmary for Women and Children until her death in 1925.
SAT0227 The Effect of Deuteration of VX-509 (Decernotinib) on Drug-Drug Interactions (DDI) with Midazolam
Authors: J. Huang, F. Yang, J. Yogaratnam, J. Shen
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> VX-509 is an oral selective Janus Kinase 3 inhibitor that has been studied in patients with rheumatoid arthritis (RA). <i>In vitro</i> and <i>in vivo</i> studies suggest that a major metabolite of VX-509, VRT-1123001 (M3) is a potent inhibitor of Cytochrome P450 3A4 (CYP3A4). It was hypothesized that deuteration of VX-509 could decrease the formation of M3 <i>in vivo</i> and consequently reduce the inhibition of CYP3A4. Midazolam (MDZ), a sensitive CYP3A4 substrate, is commonly used as a probe to study the potential DDI of CYP3A4 inhibitors. <h3>Objectives</h3> To evaluate the effect of deuteration on the extent of DDI between VX-509 and MDZ in healthy subjects. <h3>Methods</h3> Fourteen healthy subjects (ages 23-52 years, 12 female and 2 male) were randomized into two cohorts and received 4 treatments in a partial crossover design - (A) single oral dose of MDZ 2 mg; (B) [<sup>2</sup>H]-VX-509 100 mg once daily (qd) on Days 1-8; (C) VX-509 100 mg qd on Days 1-8; (D) [<sup>2</sup>H]-VX-509 200 mg qd on Days 1-8. Treatments B, C and D all received an oral dose of MDZ 2 mg on Day 7. Full PK profiles of MDZ and its metabolite, [<sup>2</sup>H]-VX-509, VX-509 and M3 were obtained. Geometric least-squares mean (GLSM) ratios (and associated 90% confidence intervals) of AUC<sub>0–∞</sub>) and C<sub>max</sub> of MDZ with and without coadministration of [<sup>2</sup>H]-VX-509 or VX-509 were calculated to evaluate the extent of DDI. <h3>Results</h3> [<sup>2</sup>H]-VX-509 100 mg qd increased MDZ exposure by 4.2-fold, significantly less than that of VX-509 100 mg (6.9-fold, p&lt;0.05), indicating that [<sup>2</sup>H]-VX-509 is a moderate CYP3A4 inhibitor at 100 mg qd and that deuteration reduced the extent of DDI with CYP3A4 substrates [Table 1]. Deuteration of VX-509 reduced the systemic exposure to M3 without affecting the exposure to VX-509 following doses of 100 mg qd [Table 2]. The effect of [<sup>2</sup>H]-VX-509 on MDZ exposure was approximately 2-fold higher following 200 mg qd dose than that following 100 mg qd dose. The most common treatment emergent AE was nervous system disorders (N=2). Both VX-509 and [<sup>2</sup>H]-VX-509 were generally safe and well tolerated. <h3>Conclusions</h3> Deuteration of VX-509 significantly reduced the extent of DDI between VX-509 and MDZ without affecting the exposure to VX-509 in healthy subjects. These results suggest deuteration could be a useful method to improve the clinical DDI profile of a compound. <h3>Disclosure of Interest</h3> J. Huang Shareholder of: Vertex, Employee of: Vertex, F. Yang Shareholder of: Vertex, Employee of: Vertex, J. Yogaratnam Shareholder of: Vertex, Employee of: Vertex, J. Shen Shareholder of: Vertex, Employee of: Vertex
Identification of plasma microRNA profiles for primary resistance to EGFR-TKIs in advanced non-small cell lung cancer (NSCLC) patients with EGFR activating mutation
Authors: Shuhang Wang, Xiaomei Su, Hua Bai, Jun Zhao, Jianchun Duan, Tongtong An, Minglei Zhuo, Zhijie Wang, Meina Wu, Zhenxiang Li, Jian Zhu, Jie Wang
Journal: Journal of Hematology & Oncology (2015)

EGFR mutation is a strong predictor of efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) therapy in advanced non-small cell lung cancer (NSCLC). However, around 20–30 % of EGFR-mutated cases showed no response to EGFR-TKIs, suggesting that other determinants beyond EGFR mutation likely exist. This study analyzed the role of microRNAs (miRNAs) in primary resistance to EGFR-TKIs in advanced NSCLC patients with EGFR mutation. Training group: 20 advanced NSCLC patients with EGFR 19 deletion treated with first-line EGFR-TKIs were enrolled; half of them had dramatic responses while the other half had primary resistance. Matched plasma samples were collected for miRNA profiling using TaqMan low-density array (TLDA). Bioinformatics analyses were used to identify related miRNAs possibly accounted for resistance. Testing group: Quantitative reverse transcriptase PCR (qRT-PCR) was employed to detect the level of miRNA with significant differential expression in the training set. Validation group: Another cohort with EGFR 19 deletion mutations, who had dramatically different responses to EGFR-TKI, was used to validate the difference of miRNA expression between the sensitive and resistant groups using RT-PCR. Training group: 153 miRNAs were found to be differentially expressed between the sensitive and resistant groups. Potential target genes were predicted with a target scan database. Twelve differentially expressed miRNAs were selected for the analysis because of their known roles in tumorigenesis of lung cancer, resistance to drugs, and regulation of EGFR pathway. Training group: three out of the 12 miRNAs (miR-21, AmiR-27a, and miR-218) were verified to have significantly higher expression (P miR-21 = 0.004, P miR-27a = 0.009, P miR-218 = 0.041, respectively) in the resistant group compared to the sensitive group. Validation group: The expression levels of these three miRNAs were validated to be significantly different (P = 0.011, 0.011, 0.026, respectively) in the validation cohort (n = 34). Higher expression levels of miR-21, AmiR-27a, and miR-218 detected in this study suggest potential roles of these miRNAs in primary resistance to EGFR-TKI in advanced NSCLC patients with EGFR exon 19 deletion mutations. These findings need to be further confirmed in a study with a larger sample size.