tbuckley/cabot-search huggingface dataset:
An open-label, multicohort Phase Ib trial of pembrolizumab (MK-3475) for advanced hematologic malignancies: KEYNOTE-013
Authors: Vincent Ribrag, Phillippe Armand, John Kuruvilla, Jean-Marie Michot, Craig H Moskowitz, Patricia Marinello, Ellen Snyder, Arun Balakumaran, Margaret A Shipp, Pier Luigi Zinzani
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Tumors, including hematologic malignancies, can use the PD-1 pathway to evade immune surveillance. Pembrolizumab, a highly selective, humanized monoclonal antibody that blocks interaction of PD-1 with its ligands PD-L1 and PD-L2, has demonstrated robust antitumor activity and a
Adipocyte-Derived Hormone Leptin Is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis
Authors: Anne-Cécile Huby, Galina Antonova, Jake Groenendyk, Celso E. Gomez-Sanchez, Wendy B. Bollag, Jessica A. Filosa, Eric J. Belin de Chantemèle
Journal: Circulation (2015)

Background— In obesity, the excessive synthesis of aldosterone contributes to the development and progression of metabolic and cardiovascular dysfunctions. Obesity-induced hyperaldosteronism is independent of the known regulators of aldosterone secretion, but reliant on unidentified adipocyte-derived factors. We hypothesized that the adipokine leptin is a direct regulator of aldosterone synthase ( CYP11B2 ) expression and aldosterone release and promotes cardiovascular dysfunction via aldosterone-dependent mechanisms. Methods and Results— Immunostaining of human adrenal cross-sections and adrenocortical cells revealed that adrenocortical cells coexpress CYP11B2 and leptin receptors. Measurements of adrenal CYP11B2 expression and plasma aldosterone levels showed that increases in endogenous (obesity) or exogenous (infusion) leptin dose-dependently raised CYP11B2 expression and aldosterone without elevating plasma angiotensin II, potassium or corticosterone. Neither angiotensin II receptors blockade nor α and β adrenergic receptors inhibition blunted leptin-induced aldosterone secretion. Identical results were obtained in cultured adrenocortical cells. Enhanced leptin signaling elevated CYP11B2 expression and plasma aldosterone, whereas deficiency in leptin or leptin receptors blunted obesity-induced increases in CYP11B2 and aldosterone, ruling out a role for obesity per se. Leptin increased intracellular calcium, elevated calmodulin and calmodulin-kinase II expression, whereas calcium chelation blunted leptin-mediated increases in CYP11B2 , in adrenocortical cells. Mineralocorticoid receptor blockade blunted leptin-induced endothelial dysfunction and increases in cardiac fibrotic markers. Conclusions— Leptin is a newly described regulator of aldosterone synthesis that acts directly on adrenal glomerulosa cells to increase CYP11B2 expression and enhance aldosterone production via calcium-dependent mechanisms. Furthermore, leptin-mediated aldosterone secretion contributes to cardiovascular disease by promoting endothelial dysfunction and the expression of profibrotic markers in the heart.
Phakic anterior chamber lenses for the correction of myopia11The following two letters address an article that appeared in the March 1999 issue of the Journal:Alió JL, de la Hoz F, Perez-Santonja J, et al. Phakic anterior chamber lenses for the correction of myopia. A 7-year cumulative analysis of complications in 263 cases. (Ophthalmology 1999;106:458–66)
Authors: M Keith J Wroblewski
Journal: Ophthalmology (1999)
The accuracy of osteoporotic fracture risk prediction tools: a systematic review and meta-analysis
Authors: Andréa Marques, Ricardo J O Ferreira, Eduardo Santos, Estíbaliz Loza, Loreto Carmona, José António Pereira da Silva
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objectives</h3> To identify and synthesise the best available evidence on the accuracy of the currently available tools for predicting fracture risk. <h3>Methods</h3> We systematically searched PubMed MEDLINE, Embase and Cochrane databases to 2014. Two reviewers independently selected articles, collected data from studies, and carried out a hand search of the references of the included studies. The Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS) checklist was used, and the primary outcome was the area under the curve (AUC) and 95% CIs, obtained from receiver operating characteristic (ROC) analyses. We excluded tools if they had not been externally validated or were designed for specific disease populations. Random effects meta-analyses were performed with the selected tools. <h3>Results</h3> Forty-five studies met inclusion criteria, corresponding to 13 different tools. Only three tools had been tested more than once in a population-based setting: FRAX (26 studies in 9 countries), GARVAN (6 studies in 3 countries) and QFracture (3 studies in the UK, 1 also including Irish participants). Twenty studies with these three tools were included in a total of 17 meta-analyses (for hip or major osteoporotic fractures; men or women; with or without bone mineral density). <h3>Conclusions</h3> Most of the 13 tools are feasible in clinical practice. FRAX has the largest number of externally validated and independent studies. The overall accuracy of the different tools is satisfactory (&gt;0.70), with QFracture reaching 0.89 (95% CI 0.88 to 0.89). Significant methodological limitations were observed in many studies, suggesting caution when comparing tools based solely on the AUC.
Cox proportional hazard analysis of sunitinib (SU) efficacy across subgroups of patients (pts) with progressive pancreatic neuroendocrine tumors (NET).
Authors: E. Raymond, P. Niccoli, J. Raoul, Y. Bang, I. Borbath, C. Lombard-Bohas, J. W. Valle, S. Patyna, R. C. Chao, D. Lu
Journal: Journal of Clinical Oncology (2010)

4031 Background: Sunitinib (SU) improved median progression-free survival (PFS) vs. placebo in pts with pancreatic NET (11.4 vs 5.5 months for SU [n = 86] vs placebo [n = 85], hazard ratio [HR] 0.418; 95% CI 0.263, 0.662; p = 0.0001) in a phase III, randomized, double-blind trial (NCT00428597). We report exploratory subgroup analyses evaluating the impact of baseline characteristics on the efficacy of SU treatment, which may aid future study design. Methods: Pts with advanced, well-differentiated pancreatic endocrine tumors and disease progression in the past 12 months were randomized (1:1) to SU 37.5 mg daily or placebo, each with best supportive care (primary endpoint: PFS). The influence of baseline characteristics on treatment effect was assessed using Cox proportional hazards analysis. Results: The treatment effect was statistically significant regardless of age (< 65 vs. ≥ 65 yrs), race (White vs. non-White), gender, ECOG status (0 vs. 1 or 2), number of metastatic sites (≤ 2 vs. ≥ 3) or time from diagnosis to study enrolment (< 3 vs. ≥ 3 yrs). SU showed benefit over placebo in nonfunctioning tumors, with a trend for benefit in functioning pancreatic NET. Somatostatin analogs (SSAs) were allowed before and/or during the study; HR favored SU both in pts with no SSA treatment and those who received SSAs before and/or during the study. Similarly, SU improved PFS in chemo-naïve pts as well as those previously treated with chemotherapy. Baseline characteristics were also evaluated as potential prognostic factors. Multivariate analysis (Cox model) found only time from diagnosis (≥ 3 vs. < 3 yrs; HR 0.603; 95% CI 0.382, 0.952; p = 0.0299) was a potential independent prognostic variable. The PFS advantage with SU was greater when adjusting for time from diagnosis (HR 0.374; 95% CI 0.234, 0.599; p < 0.0001). Exploratory analysis of the 72 pts with available Ki-67 data showed a statistically significant improvement in PFS for the subset of pts with tumor Ki-67 index ≤ 5% (n = 43; HR 0.378; p = 0.0259). Conclusions: Sunitinib resulted in a clinically meaningful improvement in PFS vs placebo across all subgroups studied, supporting its use in pancreatic NET pts independent of baseline characteristics. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer Pfizer
Diabetes genetic score, diabetes, and arterial stiffness: a Mendelian randomisation analysis in Chinese
Authors: Min Xu, Ya Huang, Lan Xie, Yu Xu, Tiange Wang, Jieli Lu, Yuhong Chen, Di Zhang, Meng Dai, Xiaolin Huang, Ying Chen, Lin Ding, Lin Lin, Yufang Bi, Weiqing Wang, Lu Qi, Yimin Sun, Guang Ning
Journal: The Lancet (2015)
Abstract 171: Evaluation of Team Performance During Actual Medical Emergency Team and Cardiac Arrest Calls
Authors: Matthew Suen, Nicole Garcia, Peter T Morley
Journal: Circulation (2014)

Objectives:  To evaluate the performance of non-technical skills during actual medical emergencies using the Team Emergency Assessment Measure.   Method:  A validated scoring tool specific for medical emergency teams, the Team Emergency Assessment Measure (TEAM), was used to evaluate team performance. The tool includes 11 parameters divided into categories of leadership, teamwork and task management. Each parameter is scored from 0 to 4. A twelfth score, from 1 to 10, represents an overall rating of the team’s performance. The scoring was completed at the conclusion of each medical emergency call where a member of the medical emergency team contributed to the care of the patient.   Results:  Between February and June 2014 team performance was assessed in a total of 179 code calls (164 MET calls and 15 cardiac arrest calls). The median total score for the eleven parameters was 35.0 (Inter-Quartile Range 32.0-38.0) out of a possible maximal score of 44. The median score for global rating was 8.0 (IQR 7.0-8.0) out of 10. The overall score was higher when the team leader was a member of the emergency team (36.0 [IQR 33-39]) compared to a leader who was not a member of the emergency team (30.5 [IQR 26.5-33.5]). All eleven parameters were scored significantly higher if the team leader was a member of the emergency team. Leadership scores and overall performance both decreased significantly when a MET call was upgraded to a cardiac arrest call, probably as a result of the attendance of additional personnel.   Conclusion:  The assessment of non-technical skills can be performed on actual medical emergencies. Team leaders who were designated members of the Medical Emergency Team performed better than others in the team leader role. Specific areas identified for improvement (eg. upgraded calls) can now be targeted in educational programs.
Etoposide phosphate with carboplatin in the treatment of elderly patients with small-cell lung cancer: A phase II study
Authors: E. Quoix, J.L. Breton, C. Daniel, P. Jacoulet, D. Debieuvre, N. Paillot, R. Kessler, L. Moreau, D. Coëtmeur, E. Lemarié, B. Milleron
Journal: Annals of Oncology (2001)
Human Herpesvirus 8 Infection in Patients With POEMS Syndrome–Associated Multicentric Castleman’s Disease
Authors: Laurent Bélec, Ali Si Mohamed, François-Jerôme Authier, Marie-Charlotte Hallouin, Aye Myat Soe, Sylvie Cotigny, Philippe Gaulard, Romain K. Gherardi
Journal: Blood (1999)
A Molecular Evolutionary Reference for the Human Variome
Authors: Li Liu, Koichiro Tamura, Maxwell Sanderford, Vanessa E. Gray, Sudhir Kumar
Journal: Molecular Biology and Evolution (2015)

Widespread sequencing efforts are revealing unprecedented amount of genomic variation in populations. Such information is routinely used to derive consensus reference sequences and to infer positions subject to natural selection. Here, we present a new molecular evolutionary method for estimating neutral evolutionary probabilities ( EP s) of each amino acid, or nucleotide state at a genomic position without using intraspecific polymorphism data. Because EP s are derived independently of population-level information, they serve as null expectations that can be used to evaluate selective forces on alleles at both polymorphic and monomorphic positions in populations. We applied this method to coding sequences in the human genome and produced a comprehensive evolutionary variome reference for all human proteins. We found that EP s accurately predict neutral and disease-associated alleles. Through an analysis of discordance between allelic EP s and their observed population frequencies, we discovered thousands of novel candidate sites for nonneutral evolution in human proteins. Many of these were validated in a joint analysis of disease-associated variants and population data. The EP method is also directly applicable to the analysis of noncoding sequences and genomic analyses of nonmodel species.
Abstract 552: Biological Properties and Regenerative Potential, in vitro and in vivo, of Human Cardiac Stem Cells Isolated from Each of the Four Chambers of the Adult Human Heart
Authors: Daniele Torella, Georgina M Ellison, Ioannis Karakikes, Valentina Galuppo, Daniela De Serio, Francesco Onorati, Pasquale Mastroroberto, Attilio Renzulli, Ciro Indolfi, Bernardo Nadal-Ginard
Journal: Circulation (2006)

The fact that the mammalian adult heart harbors resident stem cells has opened a new exciting field for cardiac biology and pathophysiology. Yet, many questions remain to be answered before exploit...
Abstract 20389: Transendocardial Stem Cell Injection Site Tissue Viability Predicts Scar Size Reduction in Myocardial Segmental Analysis in a Swine Model of Ischemic Cardiomyopathy
Authors: Molly Roy, Viky Y Suncion, Jose E Rodriguez, Vasileios Karantalis, Luiza Bagno, Bo Wang, Samuel Golpanian, Wayne Balkan, Muzammil Mushtaq, Joshua M Hare, Alan Heldman
Journal: Circulation (2014)

Background:  Transendocardial Stem Cell Injections (TESI) decrease scar size. We hypothesized that there is greater scar size reduction when TESI occurs in infarct-border zone (IZ/BZ) with more viability (>6mV Unipolar voltage) compared to segments with less viability (   Methods:  Gottingen mini-swine (n=28) underwent 150-minute occlusion of the LAD coronary artery followed by reperfusion. Cardiac magnetic resonance imaging (CMR) was obtained before and after therapy. At 90 days post-MI, transendocardial injection of either: Combination of CSCs and MSCs (1M/200M, Combo, n=7), MSCs (200M, n=6), or placebo (Plasmalyte, n=6) were administered to the IZ/BZ. Biplane left ventriculography and endocardial border tracings were recorded and compared. TESI was guided to 10 sites in IZ/BZ using ventriculographic wall motion correlated with CMR. Sites were mapped according to the 16-myocardial segment model. We analyzed 320 segments in 20 swine pre-and post-TESI. Injection sites were recorded with the electroanatomical mapping of the NOGA system. The unipolar voltage of each injection site and the occurrence of premature ventricular contractions (PVCs) were recorded.   Results:  Agreement between NOGA regional map and endocardial tracings regional map was 0.749 with 95% CI (0.670, 0.828). Allocation of TESI sites were assessed according to the endocardial tracing generated 16 segment maps. Scar size was only reduced in segments with TESI site voltages greater than 6mV (Combo: from 0.67g to 0.51g P=0.02, MSC: from 0.7g to 0.61g P=.002) compared to no change in scar size in segments with 6mV vs. 0.05). Additionally, there was a greater reduction of transmural scar (from 1.09g to 0.62g P=0.03 ) compared to an unchanged non-transmural scar after TESI (between group comparison P   Conclusions:  These findings suggest that the site of TESI is an important parameter, and responses to TESI are voltage dependent. A unipolar voltage of >6mV, but not the presence of PVC, predicts scar size reduction.
Alterations of oxidative phosphorylation in meningiomas and peripheral nerve sheath tumors
Authors: René G. Feichtinger, Serge Weis, Johannes A. Mayr, Franz A. Zimmermann, Barbara Bogner, Wolfgang Sperl, Barbara Kofler
Journal: Neuro-Oncology (2015)

Changes in the mode of aerobic energy production are observed in many solid tumors, though the kinds of changes differ among tumor types. We investigated mitochondrial energy metabolism in meningiomas and peripheral nerve sheath tumors, taking into consideration the histologic heterogeneity of these tumors.Oxidative phosphorylation (OXPHOS) complexes and porin (a marker for mitochondrial mass) were analyzed by immunohistochemical staining of meningiomas (n = 76) and peripheral nerve sheath tumors (schwannomas: n = 10; neurofibromas: n = 4). The enzymatic activities of OXPHOS complexes and citrate synthase were determined by spectrophotometric measurement. Western blot analysis of OXPHOS complexes, porin, and mitochondrial transcription factor A was performed. Furthermore, mitochondrial DNA copy number was determined.The tumors differed with regard to mitochondrial energy metabolism. Low levels of a subset of OXPHOS complexes were frequently observed in World Health Organization grade I meningiomas (percent of cases with a reduction; complex I: 63%; complex II: 67%; complex IV: 56%) and schwannomas (complex III: 40%, complex IV: 100%), whereas in neurofibromas a general reduction of all complexes was observed. In contrast, expression of complexes III and V was similar to that in normal brain tissue in the majority of tumors. Mitochondrial mass was comparable or higher in all tumors compared with normal brain tissue, whereas mitochondrial DNA copy number was reduced.The reduction of OXPHOS complexes in meningiomas and peripheral nerve sheath tumors has potential therapeutic implications, since respiratory chain-deficient tumor cells might be selectively starved by inhibitors of glycolysis or by ketogenic diet.
Evaluation of platelet count and indices in pulmonary tuberculosis and pneumonia
Authors: Füsun Sahin, Esra Yazar, Pinar Yildiz
Journal: European Respiratory Journal (2011)

Recent studies show that platelets (Plt.) have important roles in the immune system. It is known that MPV (mean platelet volume) and PDW (platelet distribution width) increase during platelet activation. Some research indicates their roles in coronary artery disease, thromboembolic disease and endotoxemia. The aim of our study, changes in platelet count and indices are investigated in pulmonary tuberculosis and pneumonia. Platelet count and indices were evaluated in 98 patients with active tuberculosis (mean age 38.78±15.42) and 35 patients with pneumonia (mean age 40.46±17.34) and 20 healthy control (mean age 36.20±11.62). Radiological extents of the diseases were assessed. In the active tuberculosis group values were significantly higher (Plt: 381683±125046; MPV: 8.57±1.39; PDW: 14.67±2.10; PCT (plateletcrit): 0.31±0.09) than pneumonia group (Plt: 283457±76101; MPV: 8.74±0.55; PDW: 13.74±1.34; PCT: 0.25±0.04) and healthy control group (Plt: 266150±55084; MPV: 8.57±0.42; PDW: 12.84±0.86; PCT: 0.24±0.03). In the pneumonia group values were significantly lower than active tuberculosis group; but only PDW values were significantly higher than healthy control group (p
A multi-center, open-label study to evaluate the safety and efficacy of pentostatin, cytoxan, and rituxan (PCR) in the treatment of previously untreated or treated, stage III or IV, low-grade CLL
Authors: R. R. Mena, R. Robles, M. Auerbach, M. Moezi, D. Headley
Journal: Journal of Clinical Oncology (2007)

17508 Background: The decision to treat indolent CLL is often based on progressive bulky disease, worsening symptoms, and increasing hematological variations. When treatment is indicated, these lymphoproliferative disorders are sensitive to combination immunochemotherapies utilizing pentostatin (P), a purine analog, cyclophosphamide (C), a DNA alkylator, and rituximab (R), an anti-CD20 monoclonal antibody. PCR represents a promising new approach in the treatment of patients with low grade CLL. Methods: Eligibility criteria allow previously treated and treatment-naïve patients diagnosed with low-grade stage II/III/IV CLL (modified Rai classification). Treatment consisted of intravenous infusions of P (4 mg/m 2 ), C (600 mg/m 2 ), and R (375 mg/m 2 ) on day 1 of a 21-day cycle for a total of up to 10 cycles. Clinical evaluations (including CT scan) were performed after cycles 2, 4, 6, 8, and 10 (if necessary). Results: The intent-to-treat (ITT) population consisted of 80 CLL patients (median age 64, range 35–83) who received a total of 368 cycles (median 5 per patient). ECOG status at enrollment was 0 (68.4%), 1 (27.6%) and 2 (3.9%). The overall response rate of the 59 evaluable patients was 61% (CR 6.8%, Cru 16.9%, PR 37.3%). 7 cases of grade 4 neutropenia, 2 cases of grade 4 respiratory distress, and 1 case of grade 4 anemia were reported. 5 deaths, all in elderly patients (&gt;70 years old), have been recorded, due to acute respiratory failure, myocardial infarction, pulmonary edema, sepsis, and one unknown cause of death. Conclusions: This immunochemotherapeutic regimen is active in Grade II/III/IV CLL and the incidence of significant toxicities was low with deaths occurring only in elderly (&gt;80 YO) patients. The presented results are preliminary and this study is currently on-going. No significant financial relationships to disclose.
THE MAMMALIAN CELL-VIRUS RELATIONSHIP
Authors: Richard L. Crowell, Jerome T. Syverton
Journal: The Journal of Experimental Medicine (1961)

Sustained infection of HeLa cells by Coxsackie B3 virus, dependent on presence of viral inhibitor in culture medium, was achieved. Persistent treatment of carrier cultures with anti-Coxsackie B3 hyperimmune monkey serum eventually eliminated virus from carrier cultures indicating that a lysogenic virus-cell relationship was not operative. Free virus was produced continuously by carrier cultures despite washing and neutralization with antiserum to eliminate free virus temporarily. In carrier cultures, about 1.5 to 1.9 plaque-forming units of virus per cell were cell-associated; approximately 6 per cent of this cell-associated virus was not neutralizable by antiserum. In growth medium containing anti-B3 antibody, cells from carrier cultures formed colonies as efficiently as cells from B3-cured cultures. Assays of carrier cultures for infectious centers indicated that less than 1 per cent of cells produced free infectious virus. The Coxsackie B3 virus-carrier state appeared to represent surface residence of B3 virus on the majority of carrier cells with restriction of productive infection to a small proportion of the population. Coxsackie B3 carrier HeLa cultures, unlike control cultures, were not destroyed by challenge with Coxsackie B1, B3, or B5 viruses. The B3 carrier state did not interfere with superinfection by herpes, vaccinia, and types 1 to 3 polioviruses. In contrast to parental or B3-cured lines, B3-carrier HeLa cultures superinfected with Coxsackie B1 virus produced no significant virus, and cultures superinfected with B5 viruses produced new virus to a limited extent only. Specific interference with Coxsackie virus superinfection by the B3-carrier state of HeLa cells was shown to be attributable to failure of attachment in the instance of Coxsackie B1 virus, and failure of penetration and/or eclipse in the instance of B5 virus. The interfering effect was circumvented successfully by superinfection of carrier cells with ribonucleic acid extracted from Coxsackie B1 and B5 viruses.