tbuckley/cabot-search huggingface dataset:
Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma
Authors: Toni K. Choueiri, Mayer N. Fishman, Bernard Escudier, David F. McDermott, Charles G. Drake, Harriet Kluger, Walter M. Stadler, Jose Luis Perez-Gracia, Douglas G. McNeel, Brendan Curti, Michael R. Harrison, Elizabeth R. Plimack, Leonard Appleman, Lawrence Fong, Laurence Albiges, Lewis Cohen, Tina C. Young, Scott D. Chasalow, Petra Ross-Macdonald, Shivani Srivastava, Maria Jure-Kunkel, John F. Kurland, Jason S. Simon, Mario Sznol
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Nivolumab, an anti-PD-1 immune checkpoint inhibitor, improved overall survival versus everolimus in a phase 3 trial of previously treated patients with metastatic renal cell carcinoma (mRCC). We investigated immunomodulatory activity of nivolumab in a hypothesis-generating prospective mRCC trial. Experimental Design: Nivolumab was administered intravenously every 3 weeks at 0.3, 2, or 10 mg/kg to previously treated patients and 10 mg/kg to treatment-naïve patients with mRCC. Baseline and on-treatment biopsies and blood were obtained. Clinical activity, tumor-associated lymphocytes, PD-L1 expression (Dako immunohistochemistry; ≥5% vs. &amp;lt;5% tumor membrane staining), tumor gene expression (Affymetrix U219), serum chemokines, and safety were assessed. Results: In 91 treated patients, median overall survival [95% confidence interval (CI)] was 16.4 months [10.1 to not reached (NR)] for nivolumab 0.3 mg/kg, NR for 2 mg/kg, 25.2 months (12.0 to NR) for 10 mg/kg, and NR for treatment-naïve patients. Median percent change from baseline in tumor-associated lymphocytes was 69% (CD3+), 180% (CD4+), and 117% (CD8+). Of 56 baseline biopsies, 32% had ≥5% PD-L1 expression, and there was no consistent change from baseline to on-treatment biopsies. Transcriptional changes in tumors on treatment included upregulation of IFNγ-stimulated genes (e.g., CXCL9). Median increases in chemokine levels from baseline to C2D8 were 101% (CXCL9) and 37% (CXCL10) in peripheral blood. No new safety signals were identified. Conclusions: Immunomodulatory effects of PD-1 inhibition were demonstrated through multiple lines of evidence across nivolumab doses. Biomarker changes from baseline reflect nivolumab pharmacodynamics in the tumor microenvironment. These data may inform potential combinations. Clin Cancer Res; 22(22); 5461–71. ©2016 AACR.
Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus
Authors: Jianxun Wang, Masayuki Mizui, Li-Fan Zeng, Roderick Bronson, Michele Finnell, Cox Terhorst, Vasileios C. Kyttaris, George C. Tsokos, Zhong-Yin Zhang, Maria I. Kontaridis
Journal: Journal of Clinical Investigation (2016)

Systemic lupus erythematosus (SLE) is a devastating multisystemic autoimmune disorder. However, the molecular mechanisms underlying its pathogenesis remain elusive. Some patients with Noonan syndrome, a congenital disorder predominantly caused by gain-of-function mutations in the protein tyrosine phosphatase SH2 domain–containing PTP (SHP2), have been shown to develop SLE, suggesting a functional correlation between phosphatase activity and systemic autoimmunity. To test this directly, we measured SHP2 activity in spleen lysates isolated from lupus-prone MRL/lpr mice and found it was markedly increased compared with that in control mice. Similar increases in SHP2 activity were seen in peripheral blood mononuclear cells isolated from lupus patients relative to healthy patients. To determine whether SHP2 alters autoimmunity and related immunopathology, we treated MRL/lpr mice with an SHP2 inhibitor and found increased life span, suppressed crescentic glomerulonephritis, reduced spleen size, and diminished skin lesions. SHP2 inhibition also reduced numbers of double-negative T cells, normalized ERK/MAPK signaling, and decreased production of IFN-γ and IL-17A/F, 2 cytokines involved in SLE-associated organ damage. Moreover, in cultured human lupus T cells, SHP2 inhibition reduced proliferation and decreased production of IFN-γ and IL-17A/F, further implicating SHP2 in lupus-associated immunopathology. Taken together, these data identify SHP2 as a critical regulator of SLE pathogenesis and suggest targeting of its activity as a potent treatment for lupus patients.
The effect of warfarin on the risk of prostate cancer
Authors: V. Tagalakis, H. Tamim, J. Collet, S. R. Kahn, M. Blostein, J. A. Hanley
Journal: Journal of Clinical Oncology (2006)

14524 Background: The anticancer activity of oral anticoagulants has been a matter of debate for several years. Recent evidence suggests that prolonged treatment with warfarin may be associated with a reduced incidence of newly diagnosed urogenital cancer during long-term follow-up of patients with venous thromboembolism. The aim of this study was to assess whether exposure to warfarin was associated with reduced risk of prostate cancer in a large population-based cohort. Methods: We conducted a matched case-control study nested within the population of beneficiaries of the Saskatchewan Prescription Drug Plan aged 50 years and older from 1981–2002 with no history of cancer since 1967. New cases of prostate cancer diagnosed between 1981 and 2002 were identified using the linked Saskatchewan Cancer Agency registry. Six controls per case matched on age, gender, and sampling time were randomly selected. The cumulative exposure to warfarin in the five years preceding the cancer diagnosis was assessed. Prescription counts were used to define warfarin exposure. Exposure in the year immediately preceding the cancer diagnosis was excluded to control for detection bias. Conditional logistic regression analysis was used to assess confounding by other drugs such as nonsteroidal anti-inflammatory medications. Results: Among 11502 cases and 69012 controls, 7.4% of cases and 7.1% of controls had a history of any warfarin use. Compared to men who had never used warfarin, adjusted odds ratio (OR) for prostate cancer among ever-users in the 5 year period was 0.94 (95% confidence interval (CI), 0.86–1.03). In those who accumulated 1, 2, 3 and 4 years of warfarin use, the adjusted ORs were 1.01 (95% CI, 0.89–1.16), 1.00 (95% CI, 0.82–1.23), 0.81 (95% CI, 0.60–1.09), and 0.80 (95% CI, 0.65–0.99), respectively (p-trend=0.03). Conclusion: Our results suggest that cumulative use of warfarin of at least 4 years may be associated with a reduced risk of prostate cancer. However, confounding by other determinants of prostate cancer associated with warfarin use is possible. Nonetheless, confirmation of these findings by prospective studies may provide the evidence necessary to consider the use of warfarin in prostate cancer prevention. No significant financial relationships to disclose.
All-Cause Mortality of Low Birthweight Infants in Infancy, Childhood, and Adolescence: Population Study of England and Wales
Authors: W. John Watkins, Sarah J. Kotecha, Sailesh Kotecha
Journal: PLoS Medicine (2016)

Background Low birthweight (LBW) is associated with increased mortality in infancy, but its association with mortality in later childhood and adolescence is less clear. We investigated the association between birthweight and all-cause mortality and identified major causes of mortality for different birthweight groups. Methods and Findings We conducted a population study of all live births occurring in England and Wales between 1 January 1993 and 31 December 2011. Following exclusions, the 12,355,251 live births were classified by birthweight: 500–1,499 g (very LBW [VLBW], n = 139,608), 1,500–2,499 g (LBW, n = 759,283), 2,500–3,499 g (n = 6,511,411), and ≥3,500 g (n = 4,944,949). The association of birthweight group with mortality in infancy (<1 y of age) and childhood/adolescence (1–18 y of age) was quantified, with and without covariates, through hazard ratios using Cox regression. International Classification of Diseases codes identified causes of death. In all, 74,890 (0.61%) individuals died between birth and 18 y of age, with 23% of deaths occurring after infancy. Adjusted hazard ratios for infant deaths were 145 (95% CI 141, 149) and 9.8 (95% CI 9.5, 10.1) for the VLBW and LBW groups, respectively, compared to the ≥3,500 g group. The respective hazard ratios for death occurring at age 1–18 y were 6.6 (95% CI 6.1, 7.1) and 2.9 (95% CI 2.8, 3.1). Male gender, the youngest and oldest maternal age bands, multiple births, and deprivation (Index of Multiple Deprivation score) also contributed to increased deaths in the VLBW and LBW groups in both age ranges. In infancy, perinatal factors, particularly respiratory issues and infections, explained 84% and 31% of deaths in the VLBW and LBW groups, respectively; congenital malformations explained 36% and 23% in the LBW group and ≥2,500 g groups (2,500–3,499 g and ≥3,500 g groups combined), respectively. Central nervous system conditions explained 20% of deaths in childhood/adolescence in the VLBW group, with deaths from neoplasms and external conditions increasingly prevalent in the 1,500–2,499 g and ≥2,500 g birthweight groups. The study would have benefited had we had access to information on gestational age and maternal smoking, but since the former is highly correlated with birthweight and the latter with deprivation, we believe that our findings remain robust despite these shortcomings. Conclusions LBW is associated with infant and later child and adolescent mortality, with perinatal factors and congenital malformations explaining many of the deaths. By understanding and ameliorating the influences of upstream exposures such as maternal smoking and deprivation, later mortality can be decreased by reducing the delivery of vulnerable infants with LBW.
HIV-1 Vpu Mediates HLA-C Downregulation
Authors: Richard Apps, Gregory Q. Del Prete, Pramita Chatterjee, Abigail Lara, Zabrina L. Brumme, Mark A. Brockman, Stuart Neil, Suzanne Pickering, Douglas K. Schneider, Alicja Piechocka-Trocha, Bruce D. Walker, Rasmi Thomas, George M. Shaw, Beatrice H. Hahn, Brandon F. Keele, Jeffrey D. Lifson, Mary Carrington
Journal: Cell Host & Microbe (2016)
Loss of <i>ARID1A</i> Activates <i>ANXA1</i>, which Serves as a Predictive Biomarker for Trastuzumab Resistance
Authors: Katrien Berns, Amir Sonnenblick, Annemiek Gennissen, Sylvain Brohée, E. Marielle Hijmans, Bastiaan Evers, Debora Fumagalli, Christine Desmedt, Sibylle Loibl, Carsten Denkert, Patrick Neven, Wei Guo, Fan Zhang, Theo A. Knijnenburg, Tjalling Bosse, Michiel S. van der Heijden, Sanne Hindriksen, Wouter Nijkamp, Lodewyk F.A. Wessels, Heikki Joensuu, Gordon B. Mills, Roderick L. Beijersbergen, Christos Sotiriou, René Bernards
Journal: Clinical Cancer Research (2016)

Despite the substantial progress in the development of targeted anticancer drugs, treatment failure due to primary or acquired resistance is still a major hurdle in the effective treatment of most advanced human cancers. Understanding these resistance mechanisms will be instrumental to improve personalized cancer treatment.Genome-wide loss-of-function genetic screens were performed to identify genes implicated in resistance to HER2/PI3K/mTOR targeting agents in HER2+ breast cancer cell lines. Expression and adjuvant trastuzumab response data from the HER2+ breast cancer trials FinHer and Responsify were used to validate our findings in patient series.We find that reduced ARID1A expression confers resistance to several drugs that inhibit the HER2/PI3K/mTOR signaling cascade at different levels. We demonstrate that ARID1A loss activates annexin A1 (ANXA1) expression, which is required for drug resistance through its activation of AKT. We find that the AKT inhibitor MK2206 restores sensitivity of ARID1A knockdown breast cancer cells to both the mTOR kinase inhibitor AZD8055 and trastuzumab. Consistent with these in vitro data, we find in two independent HER2+ breast cancer patient series that high ANXA1 expression is associated with resistance to adjuvant trastuzumab-based therapy.Our findings provide a rationale for why tumors accumulate ARID1A mutations and identify high ANXA1 expression as a predictive biomarker for trastuzumab-based treatment. Our findings also suggest strategies to treat breast cancers with elevated ANXA1 expression. Clin Cancer Res; 22(21); 5238-48. ©2016 AACR.
Case 60-1964
Authors: Francis M. Ingersoll, Robert E. Scully
Journal: New England Journal of Medicine (1964)

Presentation of CaseA thirty-four-year-old gravida 2, para 2, divorcee was admitted to the hospital because of pain in the abdomen.Twenty-three days earlier, two days after the onset of a normal menstrual period, pain in both lower quadrants of the abdomen developed suddenly; the pain was crampy and was unrelated to the ingestion of food or to emptying of the bladder or bowel. A similar pain had occurred at the time of the previous menstrual period. The pain persisted, and four days later she entered the Emergency Ward, where pelvic examination revealed a tender mass, 4 by 4 cm., . . .
Contamination during production of heater-cooler units by Mycobacterium chimaera potential cause for invasive cardiovascular infections: results of an outbreak investigation in Germany, April 2015 to February 2016
Authors: Sebastian Haller, Christiane Höller, Anja Jacobshagen, Osamah Hamouda, Muna Abu Sin, Dominique L. Monnet, Diamantis Plachouras, Tim Eckmanns
Journal: Eurosurveillance (2016)

Invasive infections with Mycobacterium chimaera were reported in patients with previous open chest surgery and exposure to contaminated heater-cooler units (HCUs). We present results of the surveillance of clinical cases and of contaminated HCUs as well as environmental investigations in Germany up until February 2016. Clinical infections occurred in five male German cases over 50 years of age (range 53-80). Cases had been exposed to HCUs from one single manufacturer during open chest surgery up to five years prior to onset of symptoms. During environmental investigations, M. chimaera was detected in samples from used HCUs from three different countries and samples from new HCUs as well as in the environment at the manufacturing site of one manufacturer in Germany. Our investigation suggests that at least some of the M. chimaera infections may have been caused by contamination of HCUs at manufacturing site. We recommend that until sustainable measures for safe use of HCUs in operation theatres are implemented, users continue to adhere to instructions for use of HCUs and Field Safety Notices issued by the manufacturer, implement local monitoring for bacterial contamination and continuously check the websites of national and European authorities for current recommendations for the safe operation of HCUs.
Elevated Levels Of γ-Globin Gene Promoter 5-Hydroxymethylcytosine are Associated With Increased DNA Hypomethylation and HbF Expression
Authors: Maria Armila Ruiz, Angela Rivers, Kestis Vaitkus, Tatiana Kouznetsova, Nadim Mahmud, Joseph DeSimone, Donald Lavelle
Journal: Blood (2013)
Off-label use of inhaled tobramycin in Ontario, Canada
Authors: Mina Tadrous, Wayne Khuu, J Michael Paterson, Muhammad M Mamdani, David N Juurlink, Tara Gomes
Journal: Thorax (2016)

Inhaled tobramycin solution is indicated for use in the management of <i>Pseudomonas aeruginosa</i> in patients with cystic fibrosis (CF). Concerns have been raised regarding increasing off-label use of inhaled tobramycin, particularly for the management of COPD. We conducted an 8-year repeated cross-sectional study examining the indication for prescription claims for inhaled tobramycin in Ontario paid for by the Public Drug Benefit Program, which covers all Ontario residents with financial needs or aged 65 and older. Inhaled tobramycin prescription claims increased approximately 3 times greater from 86 prescriptions in the second quarter of 2007 to 261 prescriptions in the first quarter of 2015. Approximately half of all prescriptions (range: 46–65%) per quarter were dispensed to patients with CF. A large proportion of prescriptions (range: 31–36%) were dispensed to individuals who did not have a diagnosis of CF but had a diagnosis of COPD. In 2014, there were 324 unique users of inhaled tobramycin solution in the Ontario Public Drug Program (OPDP). Only half of users (54%; n=163) had a diagnosis of CF. Our study found increasing prescriptions of inhaled tobramycin from 2007 to 2015 in the OPDP with approximately half of these claims being for off-label use, mostly among patients with COPD.
Abstract 13656: Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: the CHARGE Consortium
Authors: Abbas Dehghan
Journal: Circulation (2013)

Background: Previous genome-wide association (GWA) studies identified multiple genetic loci for myocardial infarction (MI) and coronary heart disease (CHD), using mainly case-control studies. Data ...
Single-cell analysis of CD4+ T-cell differentiation reveals three major cell states and progressive acceleration of proliferation
Authors: Valentina Proserpio, Andrea Piccolo, Liora Haim-Vilmovsky, Gozde Kar, Tapio Lönnberg, Valentine Svensson, Jhuma Pramanik, Kedar Nath Natarajan, Weichao Zhai, Xiuwei Zhang, Giacomo Donati, Melis Kayikci, Jurij Kotar, Andrew N. J. McKenzie, Ruddy Montandon, Oliver Billker, Steven Woodhouse, Pietro Cicuta, Mario Nicodemi, Sarah A. Teichmann
Journal: Genome biology (2016)

Differentiation of lymphocytes is frequently accompanied by cell cycle changes, interplay that is of central importance for immunity but is still incompletely understood. Here, we interrogate and quantitatively model how proliferation is linked to differentiation in CD4+ T cells.
P0951 : MIR-21 inhibition and FXR activation synergistically ameliorate disease pathogenesis in a mouse model of NAFLD
Authors: P.M. Rodrigues, M.B. Afonso, A.L. Simão, M. Caridade, C.C. Carvalho, A. Trindade, A. Duarte, P.M. Borralho, M.V. Machado, H. Cortez-Pinto, C.M.P. Rodrigues, R.E. Castro
Journal: Journal of Hepatology (2015)
Computer error may have led to incorrect prescribing of statins to thousands of patients
Authors: Gareth Iacobucci
Journal: BMJ (2016)

Thousands of patients in England may have been incorrectly prescribed or taken off statins because of a major IT glitch.

The Medicines and Healthcare Products Regulatory Agency (MHRA) has launched an investigation after a fault was discovered with the digital QRISK2 calculator in SystmOne, run by TPP, which assesses cardiovascular risk.

The MHRA said that a third of GP surgeries in England may have been affected and has told the affected practices to contact patients who …
Mobilized Peripheral Blood Stem Cells (PBSC) Compared with Bone Marrow (BM) as the Stem Cell Source for Unrelated Donor Allogeneic Transplantation with Reduced Intensity Conditioning (RIC-alloSCT) in Patients with Acute Myeloid Leukemia (AML) in Complete Remission (CR): a Retrospective Analysis From the ALWP of EBMT.
Authors: Arnon Nagler, Myriam Labopin, Avichai Shimoni, Dietger Niederwieser, Nadezda Basara, Ghulam J Mufti, Axel R. Zander, Renate Arnold, Hildegard Greinix, Jan J. Cornelissen, Graham H Jackson, Charles Craddock, Donald W. Bunjes, Arnold Ganser, Nigel H. Russell, Slawomira Kyrcz-Krzemien, Mohamad Mohty, Vanderson Rocha
Journal: Blood (2009)
A Model to Identify Sarcopenia in Patients With Cirrhosis
Authors: Puneeta Tandon, Gavin Low, Marina Mourtzakis, Laura Zenith, Robert P. Myers, Juan G. Abraldes, Abdel Aziz M. Shaheen, Hina Qamar, Nadia Mansoor, Michelle Carbonneau, Kathleen Ismond, Sumeer Mann, Alshimaa Alaboudy, Mang Ma
Journal: Clinical Gastroenterology and Hepatology (2016)
Cre-inducible human CD59 mediates rapid cell ablation after intermedilysin administration
Authors: Dechun Feng, Shen Dai, Fengming Liu, Yosuke Ohtake, Zhou Zhou, Hua Wang, Yonggang Zhang, Alison Kearns, Xiao Peng, Faliang Zhu, Umar Hayat, Man Li, Yong He, Mingjiang Xu, Chunling Zhao, Min Cheng, Lining Zhang, Hong Wang, Xiaofeng Yang, Cynthia Ju, Elizabeth C. Bryda, Jennifer Gordon, Kamel Khalili, Wenhui Hu, Shuxin Li, Xuebin Qin, Bin Gao
Journal: Journal of Clinical Investigation (2016)

Cell ablation is a powerful tool for studying cell lineage and/or function; however, current cell-ablation models have limitations. Intermedilysin (ILY), a cytolytic pore-forming toxin that is secreted by Streptococcus intermedius, lyses human cells exclusively by binding to the human complement regulator CD59 (hCD59), but does not react with CD59 from nonprimates. Here, we took advantage of this feature of ILY and developed a model of conditional and targeted cell ablation by generating floxed STOP-CD59 knockin mice (ihCD59), in which expression of human CD59 only occurs after Cre-mediated recombination. The administration of ILY to ihCD59+ mice crossed with various Cre-driver lines resulted in the rapid and specific ablation of immune, epithelial, or neural cells without off-target effects. ILY had a large pharmacological window, which allowed us to perform dose-dependent studies. Finally, the ILY/ihCD59-mediated cell-ablation method was tested in several disease models to study immune cell functionalities, hepatocyte and/or biliary epithelial damage and regeneration, and neural cell damage. Together, the results of this study demonstrate the utility of the ihCD59 mouse model for studying the effects of cell ablation in specific organ systems in a variety of developmental and disease states.
Empirical and targeted therapy of candidemia with fluconazole versus echinocandins: a propensity score–derived analysis of a population-based, multicentre prospective cohort
Authors: L.E. López-Cortés, B. Almirante, M. Cuenca-Estrella, J. Garnacho-Montero, B. Padilla, M. Puig-Asensio, I. Ruiz-Camps, J. Rodríguez-Baño, B. Padilla, P. Muñoz, J. Guinea, J.R. Paño Pardo, J. García-Rodríguez, C. García Cerrada, J. Fortún, P. Martín, E. Gómez, P. Ryan, C. Campelo, I. de los Santos Gil, V. Buendía, B. Pérez Gorricho, M. Alonso, F. Sanz Sanz, J. María Aguado, P. Merino, F. González Romo, M. Gorgolas, I. Gadea, J.E. Losa, A. Delgado-Iribarren, A. Ramos, Y. Romero, I. Sánchez Romero, O. Zaragoza, M. Cuenca-Estrella, J. Rodríguez-Baño, A.I. Suarez, A. Loza, A.I. Aller García, E. Martín-Mazuelos, M.R. Pérez de Pipaón, J. Garnacho, C. Ortiz, M. Chávez, F.L. Maroto, M. Salavert, J. Pemán, J. Blanquer, D. Navarro, J.J. Camarena, R. Zaragoza, V. Abril, C. Gimeno, S. Hernáez, G. Ezpeleta, E. Bereciartua, J.L. Hernández Almaraz, M. Montejo, R.A. Rivas, R. Ayarza, A.M. Planes, I. Ruiz Camps, B. Almirante, J. Mensa, M. Almela, M. Gurgui, F. Sánchez-Reus, J. Martinez-Montauti, M. Sierra, J.P. Horcajada, L. Sorli, J. Gómez, A. Gené, M. Urrea, M. Valerio, A. Díaz-Martín, F. Puchades, A. Mularoni
Journal: Clinical Microbiology and Infection (2016)
Influence of patient's age on GPs' definition of hypertension
Authors: T. Coleman
Journal: BMJ (1995)

thrombolysis.The company has been active in helping to encourage the adoption of fast track systems to ensure that patients are treated as early as possible.Taking thrombolysis out of the hospital and into the community without adequate cardiological support may not, however, be the best way of ensuring that patients receive the earliest and most appropriate treatment.