tbuckley/cabot-search huggingface dataset:
Co-occurring Genomic Alterations and Association With Progression-Free Survival in BRAFV600-Mutated Nonmelanoma Tumors
Authors: Shiraj Sen, Funda Meric-Bernstam, David S. Hong, Kenneth R. Hess, Vivek Subbiah
Journal: JNCI Journal of the National Cancer Institute (2017)

BRAFV600 mutations occur in multiple nonmelanoma tumors, but no US Food and Drug Administration–approved BRAF-targeted therapies exist for these cancers. BRAF inhibitor vemurafenib was recently found to demonstrate activity across various BRAF-mutated nonmelanoma cancer types. However, most tumors ultimately become resistant to BRAF-targeted monotherapy. To identify whether co-occurring genomic alterations drive resistance to BRAF-targeted therapies, we analyzed next-generation sequencing data from 30 advanced BRAF-mutated nonmelanoma cancers treated with BRAF inhibitor monotherapy. Kaplan-Meier survival analysis and Cox proportional hazard regression analysis were performed and hazard ratios (HR) with 95% confidence intervals (CI) were calculated. All statistical tests were two-sided. We identified a strong association between co-occurring PI3K-mTOR pathway aberrations and primary resistance to BRAF-targeted therapy. PI3K-mTOR pathway aberrations were associated with a statistically significant reduction in progression-free survival (HR = 15.0, 95% CI = 3.6 to 63.0, P < .001) and overall survival (HR = 19.2, 95% CI = 3.7 to 100.0, P < .001). This suggests that co-occurring genomic alterations may predict response and resistance to BRAF inhibitor therapy and identify subgroups of BRAF-mutated nonmelanomas cancers.
Evolution, brain size, and variations in intelligence
Authors: Louis D Matzel, Bruno Sauce
Journal: Behavioral and Brain Sciences (2017)

Abstract Across taxonomic subfamilies, variations in intelligence ( G ) are sometimes related to brain size. However, within species, brain size plays a smaller role in explaining variations in general intelligence ( g ), and the cause-and-effect relationship may be opposite to what appears intuitive. Instead, individual differences in intelligence may reflect variations in domain-general processes that are only superficially related to brain size.
Cost-Effectiveness of Intensive versus Standard Blood-Pressure Control
Authors: Adam P. Bress, Brandon K. Bellows, Jordan B. King, Rachel Hess, Srinivasan Beddhu, Zugui Zhang, Dan R. Berlowitz, Molly B. Conroy, Larry Fine, Suzanne Oparil, Donald E. Morisky, Lewis E. Kazis, Natalia Ruiz-Negrón, Jamie Powell, Leonardo Tamariz, Jeff Whittle, Jackson T. Wright, Mark A. Supiano, Alfred K. Cheung, William S. Weintraub, Andrew E. Moran
Journal: New England Journal of Medicine (2017)

In the Systolic Blood Pressure Intervention Trial (SPRINT), adults at high risk for cardiovascular disease who received intensive systolic blood-pressure control (target, <120 mm Hg) had significantly lower rates of death and cardiovascular disease events than did those who received standard control (target, <140 mm Hg). On the basis of these data, we wanted to determine the lifetime health benefits and health care costs associated with intensive control versus standard control.We used a microsimulation model to apply SPRINT treatment effects and health care costs from national sources to a hypothetical cohort of SPRINT-eligible adults. The model projected lifetime costs of treatment and monitoring in patients with hypertension, cardiovascular disease events and subsequent treatment costs, treatment-related risks of serious adverse events and subsequent costs, and quality-adjusted life-years (QALYs) for intensive control versus standard control of systolic blood pressure.We determined that the mean number of QALYs would be 0.27 higher among patients who received intensive control than among those who received standard control and would cost approximately $47,000 more per QALY gained if there were a reduction in adherence and treatment effects after 5 years; the cost would be approximately $28,000 more per QALY gained if the treatment effects persisted for the remaining lifetime of the patient. Most simulation results indicated that intensive treatment would be cost-effective (51 to 79% below the willingness-to-pay threshold of $50,000 per QALY and 76 to 93% below the threshold of $100,000 per QALY), regardless of whether treatment effects were reduced after 5 years or persisted for the remaining lifetime.In this simulation study, intensive systolic blood-pressure control prevented cardiovascular disease events and prolonged life and did so at levels below common willingness-to-pay thresholds per QALY, regardless of whether benefits were reduced after 5 years or persisted for the patient's remaining lifetime. (Funded by the National Heart, Lung, and Blood Institute and others; SPRINT ClinicalTrials.gov number, NCT01206062 .).
Biomarkers for patients with trauma associated acute respiratory distress syndrome
Authors: Wujian Xu, Yong Song
Journal: Military Medical Research (2017)

Trauma is a major factor that contributes to the risk for acute respiratory distress syndrome (ARDS). Biomarkers that predict the risk, diagnosis, treatment response and prognosis of ARDS after trauma have been widely investigated. In addition to their applications in clinical diagnosis and treatment, these biomarkers provide important insights into our understanding of the pathogenesis of ARDS. This review begins with a brief introduction regarding the incidence and pathogenesis of trauma-associated ARDS. Then, we focus on reviewing the clinical trials that have been designed to investigate the value of biomarkers in ARDS after trauma. Biomarkers with a confirmed value in ARDS have been organized on the basis of key pathogenic processes that are central to ARDS and are described in detail. Among these, angiopoietin 2 (Ang-2), L-selectin, Clara cell protein 16 (CC16), soluable receptor for advanced glycation end products (sRAGE), Surfactant protein D (SP-D), histones, mtDNAs and some biomarker panels had a certain association with the diagnosis and prognosis of trauma-related ARDS. Further investigations are needed regarding the design of trials, the best sampling approaches and the optimal combinations of the biomarker panels.
ERS statement on protracted bacterial bronchitis in children
Authors: Ahmad Kantar, Anne B. Chang, Mike D. Shields, Julie M. Marchant, Keith Grimwood, Jonathan Grigg, Kostas N. Priftis, Renato Cutrera, Fabio Midulla, Paul L.P. Brand, Mark L. Everard
Journal: European Respiratory Journal (2017)

This European Respiratory Society statement provides a comprehensive overview on protracted bacterial bronchitis (PBB) in children. A task force of experts, consisting of clinicians from Europe and Australia who manage children with PBB determined the overall scope of this statement through consensus. Systematic reviews addressing key questions were undertaken, diagrams in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement constructed and findings of relevant studies summarised. The final content of this statement was agreed upon by all members. The current knowledge regarding PBB is presented, including the definition, microbiology data, known pathobiology, bronchoalveolar lavage findings and treatment strategies to manage these children. Evidence for the definition of PBB was sought specifically and presented. In addition, the task force identified several major clinical areas in PBB requiring further research, including collecting more prospective data to better identify the disease burden within the community, determining its natural history, a better understanding of the underlying disease mechanisms and how to optimise its treatment, with a particular requirement for randomised controlled trials to be conducted in primary care.
Abstract #3822: PDK1-SGK3 signaling in the absence of AKT activation in PIK3CA- mutant cancers
Authors: Krishna Vasudevan, David Barbie, Michael Davies, Rosalia Rabinovsky, Bryan Hennessy, Hsiuyi Tseng, Panisa Pochanard, So Young Kim, Ian Dunn, Anna Schinzel, Chontelle McNear, Jessica Kim, Jesse Boehm, Serena Silver, Yiling Lu, Katherine Stemke-Hale, Bhaskar Dutta, Corwin Joy, Aysegul Sahin, Ana Maria Gonzalez-Angulo, Ana Lluch, Lucia Rameh, Tyler Jacks, David Root, Eric Lander, Gordon Mills, William Hahn, William Sellers, Levi Garraway
Journal: Cancer Research (2009)

PIK3CA , which encodes the catalytic (p110\#945;, ) subunit of PI3 Kinase, is frequently mutated in a diverse range of human cancers including breast, colon and endometrial cancers. The most common tumor-associated  PIK3CA  mutations involve either the helical domain (exon 9; e.g., E542K and E545K) or the kinase domain (exon 20; e.g., H1047R) of p110\#945;, . These gain function  PIK3CA  mutations are thought to promote PI3K-mediated tumorigenesis primarily through downstream activation of the AKT/PKB kinase. However, we have found that many  PIK3CA -mutant cancer cell lines and human tumors may transduce an AKT-independent tumor signaling mechanism. Systematic immunoblot studies showed that many  PIK3CA -mutant cell lines lack activation of both AKT and its downstream effectors, do not require AKT signaling for anchorage independent growth, and exhibit reduced AKT membrane localization and PI(3,4,5)P3 levels. In contrast,  PIK3CA -mutant cell lines and breast tumors exhibited robust activation of and reliance upon PDK1, another oncogenic kinase recruited to the membrane by activated PI3K. Possible mechanisms of PDK1-dependent, AKT -independent growth in PIK3CA-mutant cells were investigated by systematic RNAi screening using a lentiviral shRNA library targeting >1000 kinases, phosphatases and other known cancer genes, with a particular emphasis on 20 known PDK1 substrates. For this,  PIK3CA- mutant cell lines were stratified into two groups based on p-AKT levels (high vs low) and analyzed the top 10% of 120 hairpins targeting PDK1 substrates whose effects on viability distinguished these two classes. This analysis found that shRNAs targeting  SGK3  (serum/glucocorticoid regulated kinase 3) most strongly suppressed viability in \#8220;low p-AKT\#8221;  PIK3CA -mutant cells. Further biochemical and functional studies confirmed that PDK1 activated SGK3, which localized to endosomes in these cells. Thus,  PIK3CA -mutant cancer cells with low AKT signaling may exhibit a selective dependency on SGK3 for viability. Altogether, these results indicate that in the absence of AKT activation, PDK1 may transmit an alternative signal that engages the AGC kinase SGK3 in cancer cells that harbor oncogenic  PIK3CA  mutations. This study thereby nominates both PDK1 and SGK3 in addition to AKT as \#8220;druggable\#8221; oncogenic effectors downstream of activating  PIK3CA  mutations.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3822.
Abstract 19778: Reframing Clinical Neurorehabilitation in Individuals After Stroke Using a Big-Data Approach
Authors: Swathi Kiran, Mahendra Advani, Jason Godlove, Veera Anantha
Journal: Circulation (2016)

Background and Objective:  Advances in connected health delivery systems to provide communication rehabilitation have provided a unique opportunity to maximize intervention effectiveness while collecting large sets of data to facilitate clinical decision making. Such data can be vastly insightful to neurorehabilitation in general where the evidence for gains in chronic stroke patients is weak.   Methods:  Over a span of 18 months (2013-2014), data was anonymously aggregated and analyzed from over 2,500 patients with post-stroke aphasia. Data was collected using a mobile therapy platform, Constant Therapy. The program was used by patients in the clinic with clinicians, at home as homework, and independently if they were not currently receiving therapy. This program was administered in a uniform way across patients but also individualized for each patient and dynamically adapted to each patient’s progress. Patients who completed between 3 and 1000 treatment sessions of at least 15 items or more were analyzed in a case-mix adjusted way controlling for intensity of practice and initial severity to determine which tasks demonstrated statistically significant improvement.   Results:  Our analyses take into account the number of patients who completed a specific task and show a significant change (p-values at least    Conclusion:  These results show that all patients, including the most severe, can make progress in their rehabilitation. Analysis of large data sets can be used to inform neurorehabilitation by highlighting therapies that are effective by taking into account etiology and individual performance variability.
Prognosis and Its Predictors After Incident Stroke in Patients With Type 1 Diabetes
Authors: Stefanie Hägg-Holmberg, Lena M. Thorn, Carol M. Forsblom, Daniel Gordin, Nina Elonen, Valma Harjutsalo, Ron Liebkind, Jukka Putaala, Turgut Tatlisumak, Per-Henrik Groop
Journal: Diabetes Care (2017)

Although patients with type 1 diabetes have a poor prognosis after a stroke, predictors of survival after an incident stroke in these patients are poorly studied.In this observational study, a total of 144 patients of 4,083 with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study suffered an incident stroke in 1997-2010, and were followed for a mean 3.4 ± 3.1 years after the stroke. Information was recorded on hard cardiovascular events and death as a result of cardiovascular or diabetes-related cause, collectively referred to as vascular composite end point. Information was collected from medical records, death certificates, and the National Care Register of Health Care. Predictors at the time of the incident stroke were studied for the end points.During follow-up, 104 (72%) patients suffered a vascular composite end point. Of these, 33 (32%) had a recurrent stroke, 33 (32%) a hard cardiovascular event, and 76 (53%) died of cardiovascular or diabetes-related causes, with an overall 1-year survival of 76% and 5-year survival of 58%. The predictors of a vascular composite end point were hemorrhagic stroke subtype (hazard ratio 2.03 [95% CI 1.29-3.19]), as well as chronic kidney disease stage 2 (2.48 [1.17-5.24]), stage 3 (3.04 [1.54-6.04]), stage 4 (3.95 [1.72-9.04]), and stage 5 (6.71 [3.14-14.34]). All-cause mortality increased with deteriorating kidney function.Patients with type 1 diabetes with an incident stroke have a poor cardiovascular prognosis and a high risk of all-cause mortality. In particular, hemorrhagic stroke subtype and progression of diabetic kidney disease conveys worse outcome.
Screening for Colorectal Cancer
Authors: Donald M. Kirkpatrick
Journal: Annals of Internal Medicine (2003)

Letters18 February 2003Screening for Colorectal CancerDonald M. Kirkpatrick, MDDonald M. Kirkpatrick, MDSt. John Medical Center; Longview, WA 98632 (Kirkpatrick)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-138-4-200302180-00020 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I hope that Pignone and colleagues (1) have countered the groundswell fostered by Lieberman and associates (2, 3) for screening colonoscopy in asymptomatic, average-risk adults. The latter studies demonstrated that six cases of colon cancer may have been missed by one-time stool card analysis and sigmoidoscopy in 3196 patients. However, widespread media coverage ignored the 10 serious complications of screening, which included a cerebrovascular accident and a myocardial infarction. At least one of the three deaths within 30 days of colonoscopy was probably the eventual result of a procedure complication. Lieberman and associates' study sample excluded patients ...References1. Pignone M, Rich M, Teutsch SM, Berg AO, Lohr KN. Screening for colorectal cancer in adults at average risk: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;137:132-41. [PMID: 12118972] LinkGoogle Scholar2. Lieberman DA, Weiss DG, Bond JH, Ahnen DJ, Garewal H, Chejfec G. Use of colonoscopy to screen asymptomatic adults for colorectal cancer. Veterans Affairs Cooperative Study Group 380. N Engl J Med. 2000;343:162-8. [PMID: 10900274] CrossrefMedlineGoogle Scholar3. Lieberman DA, Weiss DG. One-time screening for colorectal cancer with combined fecal occult-blood testing and examination of the distal colon. N Engl J Med. 2001;345:555-60. [PMID: 11529208] CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: St. John Medical Center; Longview, WA 98632 (Kirkpatrick) PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoScreening for Colorectal Cancer in Adults at Average Risk: A Summary of the Evidence for the U.S. Preventive Services Task Force Michael Pignone , Melissa Rich , Steven M. Teutsch , Alfred O. Berg , and Kathleen N. Lohr Screening for Colorectal Cancer Michael Pignone Metrics 18 February 2003Volume 138, Issue 4Page: 356KeywordsColonoscopyColorectal cancerLongitudinal studiesLungsMedical risk factorsMedicareMorbidityMyocardial infarctionSafetyStroke ePublished: 18 February 2003 Issue Published: 18 February 2003 CopyrightCopyright © 2003 by American College of Physicians. All Rights Reserved.PDF DownloadLoading ...
The poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888 potentiates the antitumor activity of temozolomide in the B16F10 syngeneic melanoma model: Correlation with pharmacokinetic levels and a reduction in poly(ADP-ribose) polymer by ELISA.
Authors: Luis Rodriguez, Joann Palma, Kenneth Jarvis, Velitchka Bontcheva-Diaz, Jason Stavropoulos, Gail Bukofzer, Luciana Godzicki, Milagros Colon-Lopez, Mary Saltarelli, Xuesong Liu, Yan Shi, Ran Guan, Yan Luo, Amanda Olson, Jennifer Bouska, Guidong Zhu, Thomas Penning, Vincent Giranda, Rick Lesniewski, Saul Rosenberg, David Frost, Cherrie Donawho
Journal: Cancer Research (2007)

4946   Poly(ADP-ribose) polymerase (PARP) is essential in recognizing DNA-damage and facilitating DNA repair. This is consistent with the observation that PARP-1/-2 knockout mice have increased sensitivity to DNA damaging agents including radiation. Therefore, inhibition of PARP should enhance the efficacy of chemotherapeutic agents by increasing the extent of DNA damage. ABT-888 is a potent, orally bioavailable PARP-1/-2 inhibitor (K i  2-2.5 nM). ABT-888 has been shown to potentiate the activity of DNA damaging agents in a variety of preclinical models. The ability of ABT-888 to enhance the antitumor efficacy of temozolomide (TMZ) was evaluated in the current study. ABT-888 showed significant potentiation of TMZ  in vivo  in a dose-responsive manner with no observed toxicity. In the B16F10 model, TMZ as a single agent demonstrated significant efficacy (%TGI= 60-80), however, when TMZ and ABT-888 were administered in combination, significant improvement over TMZ alone was obtained (%TGI=75-93). As expected, ABT-888 did not show single agent activity in this model or other xenograft models evaluated. Various schedules of ABT-888 (administered prior to TMZ or overlaying several days prior to and/or after TMZ) showed no advantage in increasing potentiation compared to co-administration with TMZ. Pharmacokinetic levels (plasma and tumor) of ABT-888 correlated with antitumor efficacy. Moreover, in mice treated with ABT-888 at timepoints corresponding to the C max  of ABT-888, intratumor drug levels also correlated with the significant poly(ADP-ribose)/PAR polymer inhibition in a dose-proportional/time-dependent manner as determined by ELISA. Overall, our studies demonstrated that the potentiation of TMZ activity by ABT-888 correlated with the plasma and tumor drug levels, as well as inhibition of a pharmacodynamic marker, PAR polymer, in this preclinical model. ABT-888 is currently being evaluated in clinical trials (CTEP/NCI) utilizing a PAR ELISA to assess the reduction in PAR/PARP activity in patients.
Antibacterial and β‐Lactamase Inhibitory Activity of Monocyclic β‐Lactams
Authors: Lena Decuyper, Marko Jukič, Izidor Sosič, Aleš Žula, Matthias D'hooghe, Stanislav Gobec
Journal: Medicinal Research Reviews (2017)

Due to the widespread emergence of resistant bacterial strains, an urgent need for the development of new antibacterial agents with novel modes of action has emerged. The discovery of naturally occurring monocyclic β-lactams in the late 1970s, mainly active against aerobic Gram-negative bacteria, has introduced a new approach in the design and development of novel antibacterial β-lactam agents. The main goal was the derivatization of the azetidin-2-one core in order to improve their antibacterial potency, broaden their spectrum of activity, and enhance their β-lactamase stability. In that respect, our review covers the updates in the field of monocyclic β-lactam antibiotics during the last three decades, taking into account an extensive collection of references. An overview of the relationships between the structural features of these monocyclic β-lactams, classified according to their N-substituent, and the associated antibacterial or β-lactamase inhibitory activities is provided. The different paragraphs disclose a number of well-established classes of compounds, such as monobactams, monosulfactams, monocarbams, monophosphams, nocardicins, as well as other known representative classes. Moreover, this review draws attention to some less common but, nevertheless, possibly important types of monocyclic β-lactams and concludes by highlighting the recent developments on siderophore-conjugated classes of monocyclic β-lactams.
Comparative Oxidase Activity of Melanotic and Amelanotic Melanomas&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/xref&gt;
Authors: Jesse P. Greenstein, Glenn H. Algire
Journal: JNCI Journal of the National Cancer Institute (1944)

Comparative Oxidase Activity of Melanotic and Amelanotic Melanomas Get access Jesse P. Greenstein, Jesse P. Greenstein senior biochemist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Glenn H. Algire Glenn H. Algire assistant surgeon (R) National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 5, Issue 1, August 1944, Pages 35–38, https://doi.org/10.1093/jnci/5.1.35 Published: 01 August 1944
Leisure-time physical activity and incident metabolic syndrome: a systematic review and dose-response meta-analysis of cohort studies
Authors: Dongdong Zhang, Xuejiao Liu, Yu Liu, Xizhuo Sun, Bingyuan Wang, Yongcheng Ren, Yang Zhao, Junmei Zhou, Chengyi Han, Lei Yin, Jingzhi Zhao, Yuanyuan Shi, Ming Zhang, Dongsheng Hu
Journal: Metabolism (2017)