tbuckley/cabot-search huggingface dataset:
The CAP-IASLC-AMP molecular testing guideline for the selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors.
Authors: Marc Ladanyi, Phil T. Cagle, Mary Beth Beasley, Dhananjay Chitale, Sanja Dacic, Giuseppe Giaccone, Robert B. Jenkins, David J. Kwiatkowski, Juan-Sebastian Saldivar, Jeremy Squire, Erik Thunnissen, Neal Ian Lindeman
Journal: Journal of Clinical Oncology (2013)

11085 Background: The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) jointly initiated an effort to establish evidence-based recommendations for the molecular analysis of lung cancers required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Methods: Three co-chairs without relevant conflicts of interest were selected, one from each of the sponsoring societies: CAP (P.T.C.), IASLC (M.L.), and AMP (N.I.L.). Writing and advisory panels were formed from additional experts from these societies. Unbiased literature searches were performed to capture articles up to February 2012, yielding 1,533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for relevance. Evidence was formally graded for each of the recommendations first formulated by the co-chairs and panel members at a public meeting. Each guideline section was assigned to at least two panelists. Successive drafts were circulated for comments to the writing panel, the advisory panel, the public (online posting), and the three professional societies. Results: We generated 37 guideline items addressing 14 areas of EGFR and ALK testing. The major, evidence-based recommendations are to test for EGFR mutations and ALK fusions in all patients with advanced stage adenocarcinoma, regardless of sex, race, or smoking history, and to prioritize EGFR and ALK testing over other molecular predictive tests. Recommendations and expert consensus opinions were generated for all other key aspects of EGFR and ALK testing in lung cancer related to oncology and pathology practice and technical issues in molecular testing. Conclusions: As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards and thereby improving patient outcomes.
The intensive care delirium research agenda: a multinational, interprofessional perspective
Authors: Pratik P. Pandharipande, E. Wesley Ely, Rakesh C. Arora, Michele C. Balas, Malaz A. Boustani, Gabriel Heras La Calle, Colm Cunningham, John W. Devlin, Julius Elefante, Jin H. Han, Alasdair M. MacLullich, José R. Maldonado, Alessandro Morandi, Dale M. Needham, Valerie J. Page, Louise Rose, Jorge I. F. Salluh, Tarek Sharshar, Yahya Shehabi, Yoanna Skrobik, Arjen J. C. Slooter, Heidi A. B. Smith
Journal: Intensive Care Medicine (2017)
<i>In Situ</i> Vaccination after Accelerated Hypofractionated Radiation and Surgery in a Mesothelioma Mouse Model
Authors: Luis De La Maza, Matthew Wu, Licun Wu, Hana Yun, Yidan Zhao, Mark Cattral, Andrea McCart, BC John Cho, Marc de Perrot
Journal: Clinical Cancer Research (2017)

Abstract Purpose: How best to sequence and integrate immunotherapy into standard of care is currently unknown. Clinical protocols with accelerated nonablative hypofractionated radiation followed by surgery could provide an opportunity to implement immune checkpoint blockade. Experimental Design: We therefore assessed the impact of nonablative hypofractionated radiation on the immune system in combination with surgery in a mouse mesothelioma model. Blunt surgery (R1 resection) was used to analyze the short-term effect, and radical surgery (R0 resection) was used to analyze the long-term effect of this radiation protocol before surgery. Results: Nonablative hypofractionated radiation led to a specific immune activation against the tumor associated with significant upregulation of CD8+ T cells, limiting the negative effect of an incomplete resection. The same radiation protocol performed 7 days before radical surgery led to a long-term antitumor immune protection that was primarily driven by CD4+ T cells. Radical surgery alone or with a short course of nonablative radiation completed 24 hours before radical surgery did not provide this vaccination effect. Combining this radiation protocol with CTLA-4 blockade provided better results than radiation alone. The effect of PD-1 or PD-L1 blockade with this radiation protocol was less effective than the combination with CTLA-4 blockade. Conclusions: A specific activation of the immune system against the tumor contributes to the benefit of accelerated, hypofractionated radiation before surgery. Nonablative hypofractionated radiation combined with surgery provides an opportunity to introduce immune checkpoint blockades in the clinical setting. Clin Cancer Res; 23(18); 5502–13. ©2017 AACR.
Comparison of sputum collection methods for tuberculosis diagnosis: a systematic review and pairwise and network meta-analysis
Authors: Sumona Datta, Lena Shah, Robert H Gilman, Carlton A Evans
Journal: The Lancet Global Health (2017)

The performance of laboratory tests to diagnose pulmonary tuberculosis is dependent on the quality of the sputum sample tested. The relative merits of sputum collection methods to improve tuberculosis diagnosis are poorly characterised. We therefore aimed to investigate the effects of sputum collection methods on tuberculosis diagnosis.We did a systematic review and meta-analysis to investigate whether non-invasive sputum collection methods in people aged at least 12 years improve the diagnostic performance of laboratory testing for pulmonary tuberculosis. We searched PubMed, Google Scholar, ProQuest, Web of Science, CINAHL, and Embase up to April 14, 2017, to identify relevant experimental, case-control, or cohort studies. We analysed data by pairwise meta-analyses with a random-effects model and by network meta-analysis. All diagnostic performance data were calculated at the sputum-sample level, except where authors only reported data at the individual patient-level. Heterogeneity was assessed, with potential causes identified by logistic meta-regression.We identified 23 eligible studies published between 1959 and 2017, involving 8967 participants who provided 19 252 sputum samples. Brief, on-demand spot sputum collection was the main reference standard. Pooled sputum collection increased tuberculosis diagnosis by microscopy (odds ratio [OR] 1·6, 95% CI 1·3-1·9, p<0·0001) or culture (1·7, 1·2-2·4, p=0·01). Providing instructions to the patient before sputum collection, during observed collection, or together with physiotherapy assistance increased diagnostic performance by microscopy (OR 1·6, 95% CI 1·3-2·0, p<0·0001). Collecting early morning sputum did not significantly increase diagnostic performance of microscopy (OR 1·5, 95% CI 0·9-2·6, p=0·2) or culture (1·4, 0·9-2·4, p=0·2). Network meta-analysis confirmed these findings, and revealed that both pooled and instructed spot sputum collections were similarly effective techniques for increasing the diagnostic performance of microscopy.Tuberculosis diagnoses were substantially increased by either pooled collection or by providing instruction on how to produce a sputum sample taken at any time of the day. Both interventions had a similar effect to that reported for the introduction of new, expensive laboratory tests, and therefore warrant further exploration in the drive to end the global tuberculosis epidemic.Wellcome Trust, Joint Global Health Trials consortium, Innovation For Health and Development, and Bill & Melinda Gates Foundation.
Secondary Prevention of Cardiovascular Disease in Patients With Type 2 Diabetes Mellitus
Authors: Neha J. Pagidipati, Ann Marie Navar, Karen S. Pieper, Jennifer B. Green, M. Angelyn Bethel, Paul W. Armstrong, Robert G. Josse, Darren K. McGuire, Yuliya Lokhnygina, Jan H. Cornel, Sigrun Halvorsen, Timo E. Strandberg, Tuncay Delibasi, Rury R. Holman, Eric D. Peterson
Journal: Circulation (2017)

Intensive risk factor modification significantly improves outcomes for patients with diabetes mellitus and cardiovascular disease. However, the degree to which secondary prevention treatment goals are achieved in international clinical practice is unknown.
Abstract 165: The 18 kDa FGF-2 Prevents the Doxorubicin-induced Cardiac Damage and Amp-activated Kinase Activation, in vitro and in vivo
Authors: Navid Koleini, Jon Jon Santiago, Barbara E Nickel, Robert Fandrich, Davinder S Jassal, Elissavet Kardami
Journal: Circulation Research (2015)

Introduction: Protection of the heart from chemotherapeutic (Doxorubicin, DOX) drug-induced toxicity is a desirable goal, to limit side effects of cancer treatments. DOX toxicity has been linked to the activation (phosphorylation) of the AMP-activated kinase, AMPK. The 18 kDa low molecular weight isoform of fibroblast growth factor 2 (Lo-FGF-2) is a known cardioprotective and cytoprotective agent. In this study we have tested the ability of Lo-FGF-2 to protect from DOX-induced damage in rat cardiomyocytes in vitro, and in transgenic mouse models in vivo, in relation to AMPK activation. Methods: Rat neonatal cardiomyocytes in culture were exposed to DOX (0.5 μM) in the presence or absence of pre-treatment Lo-FGF-2 (10 ng/ml). Compound C was used to block phosphorylation (activity) of AMPK. Levels of cell viability/death (using Calcein-AM/Propidium iodide assay), phospho -and total AMPK, and apoptotic markers such as active caspase 3 were analyzed. In addition, transgenic mice expressing only Lo-FGF2, and wild type mice, expressing both high molecular weight (Hi-FGF2) as well as Lo-FGF2 were subjected to DOX injection (20 mg/kg, intraperitoneal); echocardiography was used to examine cardiac function at baseline and at 10 days post-DOX. Results: DOX-induced cell death of cardiomyocytes in culture was maximal at 24 hours post-DOX coinciding with significantly increased in activated (phosphorylated) AMPK. Compound C attenuated DOX-induced cardiomyocyte loss. Pre-incubation with Lo-FGF-2 decreased DOX induced cell death, and also attenuated the phosphorylation of AMPK post-DOX. Relative levels of phospho-AMPK were lower in the hearts of Lo-FGF2-expressing male mice compared to wild type. DOX-induced loss of contractile function (left ventricular ejection fraction and endocardial velocity) was negligible in Lo-FGF2-expressing mice but significant in wild type mice. Conclusion: Lo-FGF-2 protects the heart from DOX-induced damage in vitro and in vivo, by a mechanism likely involving an attenuation of AMPK activity.
Dynamin-Related Protein 1 Inhibition Attenuates Cardiovascular Calcification in the Presence of Oxidative Stress
Authors: Maximillian A. Rogers, Natalia Maldonado, Joshua D. Hutcheson, Claudia Goettsch, Shinji Goto, Iwao Yamada, Tyler Faits, Hiromi Sesaki, Masanori Aikawa, Elena Aikawa
Journal: Circulation Research (2017)

Rationale: Mitochondrial changes occur during cell differentiation and cardiovascular disease. DRP1 (dynamin-related protein 1) is a key regulator of mitochondrial fission. We hypothesized that DRP1 plays a role in cardiovascular calcification, a process involving cell differentiation and a major clinical problem with high unmet needs. Objective: To examine the effects of osteogenic promoting conditions on DRP1 and whether DRP1 inhibition alters the development of cardiovascular calcification. Methods and Results: DRP1 was enriched in calcified regions of human carotid arteries, examined by immunohistochemistry. Osteogenic differentiation of primary human vascular smooth muscle cells increased DRP1 expression. DRP1 inhibition in human smooth muscle cells undergoing osteogenic differentiation attenuated matrix mineralization, cytoskeletal rearrangement, mitochondrial dysfunction, and reduced type 1 collagen secretion and alkaline phosphatase activity. DRP1 protein was observed in calcified human aortic valves, and DRP1 RNA interference reduced primary human valve interstitial cell calcification. Mice heterozygous for Drp1 deletion did not exhibit altered vascular pathology in a proprotein convertase subtilisin/kexin type 9 gain-of-function atherosclerosis model. However, when mineralization was induced via oxidative stress, DRP1 inhibition attenuated mouse and human smooth muscle cell calcification. Femur bone density was unchanged in mice heterozygous for Drp1 deletion, and DRP1 inhibition attenuated oxidative stress–mediated dysfunction in human bone osteoblasts. Conclusions: We demonstrate a new function of DRP1 in regulating collagen secretion and cardiovascular calcification, a novel area of exploration for the potential development of new therapies to modify cellular fibrocalcific response in cardiovascular diseases. Our data also support a role of mitochondrial dynamics in regulating oxidative stress–mediated arterial calcium accrual and bone loss.
Effects of Canagliflozin on Cardiovascular Biomarkers in Older Adults With Type 2 Diabetes
Authors: James L. Januzzi, Javed Butler, Petr Jarolim, Naveed Sattar, Ujjwala Vijapurkar, Mehul Desai, Michael J. Davies
Journal: Journal of the American College of Cardiology (2017)

Sodium glucose co-transporter 2 inhibitors may reduce cardiovascular and heart failure risk in patients with type 2 diabetes mellitus (T2DM).The goal of this study was to examine the effects of canagliflozin on cardiovascular biomarkers in older patients with T2DM.In 666 T2DM patients randomized to receive canagliflozin 100 or 300 mg or placebo, the study assessed the median percent change in serum N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hsTnI), soluble (s)ST2, and galectin-3 from baseline to 26, 52, and 104 weeks.Both serum NT-proBNP and serum hsTnI levels increased in placebo recipients, but they remained largely unchanged in those randomized to canagliflozin. Hodges-Lehmann estimates of the difference in median percent change between pooled canagliflozin and placebo were -15.0%, -16.1%, and -26.8% for NT-proBNP, and -8.3%, -11.9%, and -10.0% for hsTnI at weeks 26, 52, and 104, respectively (all p < 0.05). Serum sST2 was unchanged with canagliflozin and placebo over 104 weeks. Serum galectin-3 modestly increased from baseline with canagliflozin versus placebo, with significant differences observed at 26 and 52 weeks but not at 104 weeks. These results remained unchanged when only patients with complete samples were assessed.Compared with placebo, treatment with canagliflozin delayed the rise in serum NT-proBNP and hsTnI for over 2 years in older T2DM patients. These cardiac biomarker data provide support for the beneficial cardiovascular effect of sodium glucose co-transporter 2 inhibitors in T2DM. (A Safety and Efficacy Study of Canagliflozin in Older Patients [55 to 80 Years of Age] With Type 2 Diabetes Mellitus; NCT01106651).
Interet diagnostique et thérapeutique de la CPRE pour les complications biliaires du greffé hépatique
Authors: F Chermak, P Bauret, P Puche, F Navarro, JP Carabalona, D Larrey, GP Pageaux
Journal: Endoscopy (2006)

Les complications biliaires sont fréquentes après transplantation hépatique avec une prévalence de 8 à 30%; les sténoses de l'anastomose cholédococholédocienne représentent la majorité de ces complications; leur traitement n'est pas codifié et la place de la cholangiographie rétrograde endoscopique (CPRE) reste débattue. BUT: évaluer chez le greffé hépatique le rôle diagnostique et thérapeutique de la CPRE proposée en première intention dans les complications biliaires post opératoires.
Dendritic cells should not be overlooked when studying the effect of IL-38 administration in arthritis
Authors: Kuo Jiang, Yunshan Guo, Lin Xiao, Wenjie Pan, Jianbing Ma
Journal: Annals of the Rheumatic Diseases (2017)

We read with great interest the article by Boutet et al 1 aiming to determine the effect of interleukin (IL)-38 overexpression in the joints of arthritic mice and in human macrophages. This prospective study showed for the first time that IL-38 overexpression attenuates the severity of experimental arthritis. The authors reported that IL-38 may exert its anti-inflammatory effects by decreasing the production of proinflammatory cytokines by macrophages and synovial fibroblasts. We really appreciate the work conducted by the authors and their findings support the use of IL-38 administration as a novel treatment strategy in arthritis. However, there are still some unresolved issues and unexplored aspects which need to be addressed.

First, is ionised calcium-binding adapter molecule 1 (Iba1) an appropriate marker for …
Exercise and cardiovascular benefit in subjects with COPD: the need for randomised trials
Authors: Charlotte E. Bolton, Nichola S. Gale, John R. Cockcroft
Journal: European Respiratory Journal (2014)

From the authors: 

We thank C.E. Bolton and colleagues for their interest in our report about arterial stiffness in patients with chronic obstructive pulmonary disease (COPD) [1]. Our paper has two major findings: 1) aortic pulse wave velocity (PWV) in COPD is not related to systemic inflammation; and 2) aortic PWV does not respond to pulmonary rehabilitation [1]. According to C.E. Bolton and colleagues, these findings are unexpected as two previous papers did report small, but significant reductions in aortic PWV with exercise and/or pulmonary rehabilitation [[2, 3]. However, Vivodtzev et al. [2] used carotid-brachial pulse wave velocity as an outcome of arterial stiffness, which is known to be more susceptible to modification by exercise training than central (aortic) elastic …
Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma
Authors: Christian Grommes, Alessandro Pastore, Nicolaos Palaskas, Sarah S. Tang, Carl Campos, Derrek Schartz, Paolo Codega, Donna Nichol, Owen Clark, Wan-Ying Hsieh, Dan Rohle, Marc Rosenblum, Agnes Viale, Viviane S. Tabar, Cameron W. Brennan, Igor T. Gavrilovic, Thomas J. Kaley, Craig P. Nolan, Antonio Omuro, Elena Pentsova, Alissa A. Thomas, Elina Tsyvkin, Ariela Noy, M. Lia Palomba, Paul Hamlin, Craig S. Sauter, Craig H. Moskowitz, Julia Wolfe, Ahmet Dogan, Minhee Won, Jon Glass, Scott Peak, Enrico C. Lallana, Vaios Hatzoglou, Anne S. Reiner, Philip H. Gutin, Jason T. Huse, Katherine S. Panageas, Thomas G. Graeber, Nikolaus Schultz, Lisa M. DeAngelis, Ingo K. Mellinghoff
Journal: Cancer Discovery (2017)

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.Significance: Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B-mutant human PCNSLs. Cancer Discov; 7(9); 1018-29. ©2017 AACR.See related commentary by Lakshmanan and Byrd, p. 940This article is highlighted in the In This Issue feature, p. 920.
ANCA-associated vasculitis: mission incomplete
Authors: Sergey V Moiseev, Pavel I Novikov, Ilya Smitienko
Journal: Annals of the Rheumatic Diseases (2017)

Over the last decades, introduction of high-dose corticosteroids and immunosuppressive agents and later rituximab into the current algorithms for remission induction and maintenance treatment resulted in a tremendous improvement in the survival of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). However, in the recent meta-analysis of observational studies, Tan et al showed a 2.7-fold increased risk of death in patients with AAV when compared with the general population.1 Notably, there was a trend towards lower mortality in the most recent compared with the earlier cohorts. In our own study in 242 patients with granulomatosis with polyangiitis, we also found a significant decrease in mortality in the recent years (2004–2012 vs 1970–2003; p=0.04) and a shift towards a higher percentage of cardiovascular events and complications of immunosuppression as the causes of death.2 

The results of Tan et al ’s meta-analysis are not surprising and suggest that AAV, particularly if not promptly diagnosed and treated, remains a life-threatening disease and requires proper management. The pitfalls of the current treatment for AAV are well known and include relatively frequent relapses, especially in proteinase-3 (PR3) ANCA-positive patients (up to 50% within 5 years), delayed diagnosis and late initiation of treatment in a proportion of patients, high rate of end-stage renal disease (ESRD), which did not change significantly in the current era, unknown optimal duration of maintenance therapy, burden of immunosuppression (eg, infections and malignancy), and increased risk of cardiovascular and thromboembolic events, which may be related …