tbuckley/cabot-search huggingface dataset:
How to Interpret Phase II Data for Everolimus Plus Bevacizumab in Renal Cell Carcinoma
Authors: Bernard Escudier
Journal: Journal of Clinical Oncology (2010)

In this issue of Journal of Clinical Oncology, Hainsworth et al 1 report the first phase II combination of everolimus and bevacizumab in renal cell carcinoma (RCC), which was considered very promising when presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO), May 30 to June 3, 2008, Chicago, IL. 2 Based on these promising preliminary data, two large studies were designed to test this regimen, one a first-line, large, randomized phase II study comparing this everolimus and bevacizumab regimen to the combination of bevacizumab and interferon (RECORD [Renal Cell Cancer Treatment With Oral RAD 001 Given Daily] 2 study), and one second-line phase III postsunitinib study, comparing the same regimen to everolimus plus placebo (proposed by the Cancer and Leukemia GroupB).When reading the Hainsworth et al 1 article, several issues should be raised.The first one is linked to the difference between the preliminary data reported at ASCO and the current article.The progressionfree survival (PFS) reported at ASCO was, respectively, 12 and 11 months in the previously untreated and the tyrosine kinase inhibitor (TKI) -pretreated groups.These numbers will probably remain in the mind of many investigators and are used as the rationale for the two protocols described above.However, the final PFS reported herein are, respectively, 9.1 and 7.1 months in the untreated and TKI-pretreated groups, which are 3 and 4 months fewer than in the preliminary report.Knowing these final PFS data, the rationale for the two large, ongoing or planned studies described above is becoming much weaker, and the necessity to embark on these large studies becomes questionable.It should be emphasized, for example, that the control arm in the RECORD 2 study (bevacizumab plus interferon) results in PFS of 8.5 to 10.2 months, 3,4 which is very likely to be similar to the everolimus plus bevacizumab arm.In addition, the chance that this combined regimen will be superior to the 11-month PFS obtained with other current standards of care, such as sunitinib or pazopanib, appears rather low. 5,6 second issue raised by this study concerns the usefulness of small phase II studies to build a rationale for large randomized studies.Interestingly, the Hainsworth et al 1 study really reports two small phase II trials, a 50-patient study in untreated patients and a 30-patient study in TKI-pretreated patients.Mixing these two populations in the same study can obviously be justified by avoiding the administrative burden required by two separate studies, but does not help to interpret the data.It could be argued that, in terms of safety, these two phase II trials allow better estimate of the tolerability of the combined regimen.
Prediction of outcome after mitral valve replacement in patients with symptomatic chronic mitral regurgitation. The importance of left atrial size.
Authors: D Reed, R D Abbott, M L Smucker, S Kaul
Journal: Circulation (1991)

BACKGROUND The ability to predict outcome after mitral valve replacement remains limited in patients with symptomatic chronic mitral regurgitation. The aims of this study were to determine the preoperative predictors of postoperative cardiac-related mortality and to assess the additive prognostic value of tests performed in such patients. METHODS AND RESULTS Accordingly, 176 patients (mean age, 57 +/- 14 years) who underwent mitral valve replacement were followed up for 3.8 +/- 0.5 years. Four categories of variables were analyzed to predict postoperative cardiac-related mortality: clinical, laboratory, two-dimensional echocardiographic (2DE), and cardiac catheterization. There were 39 cardiac-related deaths (29 due to congestive heart failure and 10 sudden). When the four categories were analyzed separately, two clinical, one laboratory, two 2DE, and one catheterization variable best predicted postoperative death. When these six variables were examined simultaneously, only three (one clinical and two 2DE) remained significant predictors of cardiac-related mortality: presence of pulmonary rales, left atrial size, and the ratio of left ventricular wall thickness to left ventricular cavity dimension in end systole. A model based on these three variables may predict cardiac-related death with considerable accuracy. Laboratory data did not add to clinical information for predicting death. 2DE variables provided significant additional information in this regard (p less than 0.001). Further addition of catheterization variables was not useful. Prognostic value did not change significantly when 50 patients with prior mitral valve surgery or 49 patients undergoing concomitant aortic valve replacement or coronary artery bypass surgery were excluded from analysis. CONCLUSIONS We conclude that 1) measures of both left ventricular systolic function and left atrial size are equally important in predicting postoperative cardiac-related mortality in patients with symptomatic chronic mitral regurgitation undergoing mitral valve replacement; 2) left atrial size may be important because it reflects the "history" (severity and duration) of mitral regurgitation; 3) 2DE assessment of left atrial size and left ventricular function provides prognostic information that is significantly greater than that obtained from clinical and laboratory parameters alone; the addition of catheterization variables does not increase the prognostic value of the clinical and 2DE data.
Soluble TNF Receptors and Kidney Dysfunction in the Elderly
Authors: Axel C. Carlsson, Tobias E. Larsson, Johanna Helmersson-Karlqvist, Anders Larsson, Lars Lind, Johan Ärnlöv
Journal: Journal of the American Society of Nephrology (2014)

The importance of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in the development of kidney disease is being unraveled. Yet, community-based data regarding the role of sTNFRs are lacking. We assessed serum sTNFRs and aspects of kidney damage cross-sectionally in two independent community-based cohorts of elderly participants: Prospective Investigation of the Vasculature in Uppsala Seniors (n=815; mean age, 75 years; 51% women) and Uppsala Longitudinal Study of Adult Men (n=778; mean age, 78 years). Serum sTNFR1 correlated substantially with different aspects of kidney pathology in the Uppsala Longitudinal Study of Adult Men cohort (R=-0.52 for estimated GFR, R=0.22 for urinary albumin-to-creatinine ratio, and R=0.17 for urinary kidney injury molecule-1; P<0.001 for all), with similar correlations in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort. These associations remained significant after adjustment for age, sex, inflammatory markers, and cardiovascular risk factors and were also evident in participants without diabetes. Serum sTNFR2 was associated with all three markers in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort (P<0.001 for all). Our findings from two independent community-based cohorts confirm and extend results of previous studies supporting circulating sTNFRs as relevant biomarkers for kidney damage and dysfunction in elderly individuals, even in the absence of diabetes.
Biogeography of the Intestinal Mucosal and Lumenal Microbiome in the Rhesus Macaque
Authors: Koji Yasuda, Keunyoung Oh, Boyu Ren, Timothy L. Tickle, Eric A. Franzosa, Lynn M. Wachtman, Andrew D. Miller, Susan V. Westmoreland, Keith G. Mansfield, Eric J. Vallender, Gregory M. Miller, James K. Rowlett, Dirk Gevers, Curtis Huttenhower, Xochitl C. Morgan
Journal: Cell Host & Microbe (2015)
Elimination of human leukemia cells in NOD/SCID mice by WT1-TCR gene–transduced human T cells
Authors: Shao-An Xue, Liquan Gao, Daniel Hart, Roopinder Gillmore, Waseem Qasim, Adrian Thrasher, Jane Apperley, Boris Engels, Wolfgang Uckert, Emma Morris, Hans Stauss
Journal: Blood (2005)
Phase III Trial Comparing Docetaxel and Cisplatin Combination Chemotherapy With Mitomycin, Vindesine, and Cisplatin Combination Chemotherapy With Concurrent Thoracic Radiotherapy in Locally Advanced Non–Small-Cell Lung Cancer: OLCSG 0007
Authors: Yoshihiko Segawa, Katsuyuki Kiura, Nagio Takigawa, Haruhito Kamei, Shingo Harita, Shunkichi Hiraki, Yoichi Watanabe, Keisuke Sugimoto, Takuo Shibayama, Toshiro Yonei, Hiroshi Ueoka, Mitsuhiro Takemoto, Susumu Kanazawa, Ichiro Takata, Naoyuki Nogami, Katsuyuki Hotta, Akio Hiraki, Masahiro Tabata, Keitaro Matsuo, Mitsune Tanimoto
Journal: Journal of Clinical Oncology (2010)

To demonstrate the efficacy of docetaxel and cisplatin (DP) chemotherapy with concurrent thoracic radiotherapy (TRT) for patients with locally advanced non-small-cell lung cancer (LA-NSCLC).Patients age 75 years or younger with LA-NSCLC, stratified by performance status, stage, and institution, were randomly assigned to two arms consisting of DP (docetaxel 40 mg/m(2) and cisplatin 40 mg/m(2) on days 1, 8, 29, and 36) or mitomycin, vindesine, and cisplatin (MVP) chemotherapy with concurrent TRT.Between July 2000 and July 2005, 200 patients were allocated into either the DP or MVP arm. The survival time at 2 years, a primary end point, was favorable to the DP arm (P = .059 by a stratified log-rank test as a planned analysis and P = .044 by an early-period, weighted log-rank as an unplanned analysis). There was a trend toward improved response rate, 2-year survival rate, median progression-free time, and median survival in the DP arm (78.8%, 60.3%,13.4 months, and 26.8 months, respectively) compared with the MVP arm (70.3%, 48.1%, 10.5 months, and 23.7 months, respectively), which was not statistically significant (P > .05). Grade 3 febrile neutropenia occurred more often in the MVP arm than in the DP arm (39% v 22%, respectively; P = .012), and grade 3 to 4 radiation esophagitis was likely to be more common in the DP arm than in the MVP arm (14% v 6%, P = .056).DP chemotherapy combined with concurrent TRT is an alternative to MVP chemotherapy for patients with LA-NSCLC.
S20 Medical Thoracoscopy is Safe and Effective in Patients with Small or No Pleural Effusions
Authors: AA Soosay, R Syyed, SH Baird Monklands
Journal: Thorax (2012)

<h3>Introduction</h3> Current BTS guidelines recommend the utilisation of medical thoracoscopy (MT) for cytology negative, exudative pleural effusions. A large pleural cavity is required between the lung and chest wall for safe MT. The presence of little or no pleural fluid, despite there being pleural disease present, makes the procedure technically challenging with a higher potential for complications, bleeding and failure of the procedure. <h3>Objective</h3> We compare the safety and efficiency of MT performed in patients with small or absent pleural effusions, with patients with moderate or large effusions. <h3>Methods</h3> A retrospective review of case notes, radiology and pathology reports of patients who underwent MT between January 2010 and March 2012 was conducted. All procedures were performed or assisted by a level II thoracoscopist with the aid of live ultrasound scanning (USS). Pleural effusion size was estimated using chest x-ray and bedside USS. A small effusion was defined as blunting of the costophrenic angle only on chest x-ray and less than 100ml fluid estimation on USS. Patients were divided into two groups based on effusion size (absent or small effusion and moderate or large effusion). Data was collected and analysed for minor and major complications and diagnostic yield. <h3>Results</h3> 43 MT were performed during the period. 88% of patients were male (n=38). The mean patient age was 70.1 years (SD 8.69). 41.9% patients had absent/small effusions (n=18). There were no major complications documented in either group. The minor complication rate was 8% in the moderate/large effusions group (n=2) and 11% in the absent/small effusions group (n=2). The minor complications noted were trapped lung, surgical emphysema, wound infection and haematoma. The diagnostic yield was 96% in the moderate/large effusions group (n=24) and 94% in the absent/small effusions group (n=17). <h3>Conclusions</h3> Despite its technical challenges, MT can be performed safely and effectively with minimal minor complications and high diagnostic yield in patients with small pleural effusions and even when no fluid is present when performed by thoracoscopists with appropriate experience level.
FTY720-induced human pulmonary endothelial barrier enhancement is mediated by c-Abl
Authors: L. Wang, E.T. Chiang, J.T. Simmons, J.G.N. Garcia, S.M. Dudek
Journal: European Respiratory Journal (2010)

Strategies to improve pulmonary endothelial barrier function are needed to reverse the devastating effects of vascular leak in acute respiratory distress syndrome. FTY720 is a pharmaceutical analogue of the potent barrier-enhancing phospholipid sphingosine 1-phosphate (S1P). FTY720 decreases vascular permeability by an incompletely characterised mechanism that differs from S1P. Here, we describe its barrier-promoting effects on intracellular signalling and junctional assembly formation in human pulmonary endothelium. Permeability of cultured human pulmonary endothelial cells was assessed using transendothelial electrical resistance and dextran transwell assays. Junctional complex formation was assessed using membrane fractionation and immunofluorescence. Pharmacological inhibitors and small interfering (si)RNA were utilised to determine the effects of individual components on permeability. Unlike S1P, FTY720 failed to induce membrane translocation of adherens junction or tight junction proteins. β-catenin, occludin, claudin-5 or zona occludens protein (ZO)-1/ZO-2 siRNAs did not alter FTY720-induced barrier enhancement. FTY720 induced focal adhesion kinase (FAK) phosphorylation and focal adhesion formation, with FAK siRNA partially attenuating the prolonged phase of barrier enhancement. Inhibition of Src, protein kinase (PK)A, PKG, PKC or protein phosphatase 2A failed to alter FTY720-induced barrier enhancement. FTY720 increased c-Abl tyrosine kinase activity and c-Abl siRNA attenuated peak barrier enhancement after FTY720. FTY720 enhances endothelial barrier function by a novel pathway involving c-Abl signalling.
N-Terminal Pro-Brain Natriuretic Peptide, C-Reactive Protein, and Urinary Albumin Levels as Predictors of Mortality and Cardiovascular Events in Older Adults
Authors: Caroline Kistorp
Journal: JAMA (2005)

ContextB-type natriuretic peptides have been shown to predict cardiovascular disease in apparently healthy individuals but their predictive ability for mortality and future cardiovascular events compared with C-reactive protein (CRP) and urinary albumin/creatinine ratio is unknown.ObjectiveTo assess the prognostic value of the N-amino terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP) vs CRP and urinary albumin/creatinine ratio in an older adult population.Design, Setting, and ParticipantsA population-based prospective study of 764 participants aged 50 to 89 years from a community in Copenhagen, Denmark, in which 658 participants provided blood and urinary samples and were examined between September 1, 1998, and January 24, 2000. Of these participants, 626 without heart or renal failure were enrolled. A subgroup of 537 had no history of cardiovascular disease at baseline. During 5 years of follow-up (to December 31, 2003), 94 participants died and 65 developed a first major cardiovascular event.Main Outcome MeasuresRisk of mortality and first major cardiovascular event by baseline levels of NT-proBNP, CRP, and urinary albumin/creatinine ratio levels.ResultsAfter adjustment for the cardiovascular risk factors of age, sex, smoking, diabetes mellitus, hypertension or ischemic heart disease, total cholesterol, and serum creatinine, the hazard ratio (HR) of mortality for values above the 80th percentile of NT-proBNP was 1.96 (95% confidence interval [CI], 1.21-3.19); for CRP, 1.46 (95% CI, 0.89-2.24); and for urinary albumin/creatinine ratio, 1.88 (95% CI, 1.18-2.98). Additional adjustment for left ventricular systolic dysfunction did not markedly attenuate the predictive value of NT-proBNP (HR, 1.82; 95% CI, 1.11-2.98). The absolute unadjusted increase in mortality risk for participants with values above the 80th percentile vs equal to or below the 80th percentile was 24.5% for NT-proBNP, 7.8% for CRP, and 19.5% for urinary albumin/creatinine ratio. The NT-proBNP levels were associated with first major cardiovascular events (nonfatal myocardial infarction, fatal coronary heart disease, unstable angina, heart failure, stroke, and transient ischemic attack) with an adjusted HR of 3.24 (95% CI, 1.80-5.79) vs 1.02 (95% CI, 0.56-1.85) for CRP and 2.32 (95% CI, 1.33-4.05) for urinary albumin/creatinine ratio when comparing participants with values above the 80th percentile with those with values equal to or below the 80th percentile.ConclusionsMeasurements of NT-proBNP provide prognostic information of mortality and first major cardiovascular events beyond traditional risk factors. NT-proBNP was a stronger risk biomarker for cardiovascular disease and death than CRP was in nonhospitalized individuals aged 50 to 89 years.
Transferred WT1-Reactive CD8 <sup>+</sup> T Cells Can Mediate Antileukemic Activity and Persist in Post-Transplant Patients
Authors: Aude G. Chapuis, Gunnar B. Ragnarsson, Hieu N. Nguyen, Colette N. Chaney, Jeffrey S. Pufnock, Thomas M. Schmitt, Natalie Duerkopp, Ilana M. Roberts, Galina L. Pogosov, William Y. Ho, Sebastian Ochsenreither, Matthias Wölfl, Merav Bar, Jerald P. Radich, Cassian Yee, Philip D. Greenberg
Journal: Science Translational Medicine (2013)

Donor-derived WT1-specific CD8 + T cells transferred after hematopoietic cell transplantation mediate antileukemic activity and can establish persistent responses without toxicity to normal tissues in high-risk leukemia patients.
Response to Letter Regarding Article, “Diagnosis of Acute Aortic Dissection by D-Dimer: The International Registry of Acute Aortic Dissection Substudy on Biomarkers (IRAD-Bio) Experience”
Authors: Toru Suzuki, Alessandro Distante, Antonella Zizza, Santi Trimarchi, Massimo Villani, Jorge Antonio Salerno Uriarte, Luigi De Luca Tupputi Schinosa, Attilio Renzulli, Federico Sabino, Richard Nowak, Robert Birkhahn, Judd E. Hollander, Francis Counselman, Ravi Vijayendran, Eduardo Bossone, Kim Eagle
Journal: Circulation (2010)
High levels of indium exposure relate to progressive emphysematous changes: a 9-year longitudinal surveillance of indium workers
Authors: Atsuko Amata, Tatsuya Chonan, Kazuyuki Omae, Hiroshi Nodera, Jiro Terada, Koichiro Tatsumi
Journal: Thorax (2015)

<h3>Background</h3> During the last decade it has been clarified that the inhalation of indium compounds can evoke alveolar proteinosis, cholesterol granuloma, pulmonary fibrosis and emphysema. In this study, we aimed to elucidate the characteristics and time course of pulmonary disorders among indium workers using comprehensive pulmonary examinations at an indium-processing factory. <h3>Methods</h3> Data for 84 male workers who underwent the examinations for nine consecutive years from 2002 to 2010 were analysed regarding their symptoms, serum indium concentration (sIn), serum markers of interstitial pneumonia, pulmonary function test parameters and high-resolution CT (HRCT) findings of the lungs. <h3>Results</h3> In association with improvements in the work environment and work practice, the sIn levels decreased with significant reductions in the KL-6 and surfactant protein D (SP-D) levels. Regarding the HRCT findings, the interstitial lesions regressed partially, whereas emphysematous lesions increased progressively in the workers with high sIn values. FEV<sub>1</sub>/FVC decreased with the years and the rate of decrease was significantly greater in those with high sIn. The biological half-life of sIn was estimated to be 8.09 years. <h3>Conclusions</h3> The present findings suggest that the sIn, SP-D, KL-6 levels and radiological interstitial changes can be reduced in indium workers by alleviating exposure to indium, whereas emphysematous lesions can progress among those with a history of heavy exposure.
Knock-In Mouse Model of Dilated Cardiomyopathy Caused by Troponin Mutation
Authors: Cheng-Kun Du, Sachio Morimoto, Kiyomasa Nishii, Reiko Minakami, Mika Ohta, Naoto Tadano, Qun-Wei Lu, Yuan-Yuan Wang, Dong-Yun Zhan, Misato Mochizuki, Satomi Kita, Yoshikazu Miwa, Fumi Takahashi-Yanaga, Takahiro Iwamoto, Iwao Ohtsuki, Toshiyuki Sasaguri
Journal: Circulation Research (2007)

We created knock-in mice in which a deletion of 3 base pairs coding for K210 in cardiac troponin (cTn)T found in familial dilated cardiomyopathy patients was introduced into endogenous genes. Membrane-permeabilized cardiac muscle fibers from mutant mice showed significantly lower Ca(2+) sensitivity in force generation than those from wild-type mice. Peak amplitude of Ca(2+) transient in cardiomyocytes was increased in mutant mice, and maximum isometric force produced by intact cardiac muscle fibers of mutant mice was not significantly different from that of wild-type mice, suggesting that Ca(2+) transient was augmented to compensate for decreased myofilament Ca(2+) sensitivity. Nevertheless, mutant mice developed marked cardiac enlargement, heart failure, and frequent sudden death recapitulating the phenotypes of dilated cardiomyopathy patients, indicating that global functional defect of the heart attributable to decreased myofilament Ca(2+) sensitivity could not be fully compensated by only increasing the intracellular Ca(2+) transient. We found that a positive inotropic agent, pimobendan, which directly increases myofilament Ca(2+) sensitivity, had profound effects of preventing cardiac enlargement, heart failure, and sudden death. These results verify the hypothesis that Ca(2+) desensitization of cardiac myofilament is the absolute cause of the pathogenesis of dilated cardiomyopathy associated with this mutation and strongly suggest that Ca(2+) sensitizers are beneficial for the treatment of dilated cardiomyopathy patients affected by sarcomeric regulatory protein mutations.
Cdk5 Is a Key Factor in Tau Aggregation and Tangle Formation In Vivo
Authors: Wendy Noble, Vicki Olm, Kazuyuki Takata, Evelyn Casey, O Mary, Jordana Meyerson, Kate Gaynor, John LaFrancois, Lili Wang, Takayuki Kondo, Peter Davies, Mark Burns, None Veeranna, Ralph Nixon, Dennis Dickson, Yasuji Matsuoka, Michael Ahlijanian, Lit-Fui Lau, Karen Duff
Journal: Neuron (2003)
Let Them Eat Fish
Authors: Vera C. Mazurak, Philip C. Calder, Barbara S. van der Meij
Journal: JAMA Oncology (2015)

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