tbuckley/cabot-search huggingface dataset:
SHV-129: A Gateway to Global Suppressors in the SHV β-Lactamase Family?
Authors: Marisa L. Winkler, Robert A. Bonomo
Journal: Molecular Biology and Evolution (2015)

Enzymes are continually evolving in response to environmental pressures. In order to increase enzyme fitness, amino acid substitutions can occur leading to a changing function or an increased stability. These evolutionary drivers determine the activity of an enzyme and its success in future generations in response to changing conditions such as environmental stressors or to improve physiological function allowing continual persistence of the enzyme. With recent warning reports on antibiotic resistance and multidrug resistant bacterial infections, understanding the evolution of β-lactamase enzymes, which are a large contributor to antibiotic resistance, is increasingly important. Here, we investigated a variant of the SHV β-lactamase identified from a clinical isolate of Escherichia coli in 2011 (SHV-129, G238S-E240K-R275L-N276D) to identify the first instance of a global suppressor substitution in the SHV β-lactamase family. We have used this enzyme to show that several evolutionary principles are conserved in different class A β-lactamases, such as active site mutations reducing stability and requiring compensating suppressor substitutions in order to ensure evolutionary persistence of a given β-lactamase. However, the pathway taken by a given β-lactamase in order to reach its evolutionary peak under a given set of conditions is likely different. We also provide further evidence for a conserved stabilizing substitution among class A β-lactamases, the back to consensus M182T substitution. In addition to expanding the spectrum of β-lactamase activity to include the hydrolysis of cefepime, the amino acid substitutions found in SHV-129 provide the enzyme with an excess of stability, which expands the evolutionary landscape of this enzyme and may result in further evolution to potentially include resistance to carbapenems or β-lactamase inhibitors.
TCT-95 The Long-term Hemodynamic Performance of Transcatheter Aortic Valve Replacement: A Report from the PARTNER I Trial
Authors: Melissa Daubert, Neil Weissman, Rebecca Hahn, Philippe Pibarot, Rupa Parvataneni, Michael Mack, Samir Kapadia, Robert Siegel, Lars G. Svensson, Susheel Kodali, Wilson Y. Szeto, Raj Makkar, Martin Leon, Pamela S. Douglas
Journal: Journal of the American College of Cardiology (2015)
A Phase 1, Dose Escalation Study of Paclitaxel with Gsk1120212 (Trametinib) for the Treatment of Advanced Melanoma
Authors: N. Coupe, P. Corrie, M. Hategan, J. Larkin, M.E. Gore, A. Gupta, A. Wise, S. Suter, C. Ciria, S. Love, L. Collins, M.R. Middleton
Journal: Annals of Oncology (2014)
Lenvatinib in Advanced, Radioactive Iodine–Refractory, Differentiated Thyroid Carcinoma
Authors: Kay T. Yeung, Ezra E.W. Cohen
Journal: Clinical Cancer Research (2015)

Abstract Management options are limited for patients with radioactive iodine refractory, locally advanced, or metastatic differentiated thyroid carcinoma. Prior to 2015, sorafenib, a multitargeted tyrosine kinase inhibitor, was the only approved treatment and was associated with a median progression-free survival (PFS) of 11 months and overall response rate (ORR) of 12% in a phase III trial. Lenvatinib, a multikinase inhibitor with high potency against VEGFR and FGFR demonstrated encouraging results in phase II trials. Recently, the pivotal SELECT trial provided the basis for the FDA approval of lenvatinib as a second targeted therapy for these patients. Median PFS of 18.3 months in the lenvatinib group was significantly improved from 3.6 months in the placebo group, with an HR of 0.21 (95% confidence interval, 0.4–0.31; P &amp;lt; 0.0001). ORR was also significantly increased in the lenvatinib arm (64.7%) compared with placebo (1.5%). In this article, we will review the molecular mechanisms of lenvatinib, the data from preclinical studies to the recent phase III clinical trial, and the biomarkers being studied to further guide patient selection and predict treatment response. Clin Cancer Res; 21(24); 5420–6. ©2015 AACR.
Cerebrospinal Fluid Markers in African Burkitt's Lymphoma With Central Nervous System Involvement&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: W C Wallen, R J Biggar, P H Levine, J Neequaye, F K Nkrumah
Journal: JNCI Journal of the National Cancer Institute (1982)

Several cerebrospinal fluid markers were found to be elevated in Burkitt's lymphoma patients with central nervous system (CNS) involvement. Antibody levels to the virus capsid antigen of the Epstein-Barr virus and to the brain cell antigens myelin and cerebroside were elevated during active CNS disease, Immune complexes were present in levels above 100 μg/ml in most patients with CNS involvement but tended to be low or negative in patients without CNS disease. Oligoclonal IgG bands were present in 12 of 13 patients with CNS disease and in only 3 of 26 patients with no clinical evidence of disease. None of these markers were present in 6 other tumor patients without CNS disease. The presence of these markers in 12 of 13 patients in whom CNS disease was involved suggests that these markers may be useful in determining the status of the tumor with regard to involvement of the CNS.
Time to Surgery and Breast Cancer Survival in the United States
Authors: Richard J. Bleicher, Karen Ruth, Elin R. Sigurdson, J. Robert Beck, Eric Ross, Yu-Ning Wong, Sameer A. Patel, Marcia Boraas, Eric I. Chang, Neal S. Topham, Brian L. Egleston
Journal: JAMA Oncology (2015)

Time to surgery (TTS) is of concern to patients and clinicians, but controversy surrounds its effect on breast cancer survival. There remains little national data evaluating the association.
Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial
Authors: Richard G Margolese, Reena S Cecchini, Thomas B Julian, Patricia A Ganz, Joseph P Costantino, Laura A Vallow, Kathy S Albain, Patrick W Whitworth, Mary E Cianfrocca, Adam M Brufsky, Howard M Gross, Gamini S Soori, Judith O Hopkins, Louis Fehrenbacher, Keren Sturtz, Timothy F Wozniak, Thomas E Seay, Eleftherios P Mamounas, Norman Wolmark
Journal: The Lancet (2015)
Measuring the Therapeutic Relationship in Internet-Based Interventions
Authors: Maaike Ferwerda, Sylvia van Beugen, Piet C.L.M. van Riel, Peter C.M. van de Kerkhof, Elke M.G.J. de Jong, Jurgen V. Smit, Manon E.J. Zeeuwen-Franssen, Elisabeth B.M. Kroft, Henk Visser, Harald E. Vonkeman, Marjonne C.W. Creemers, Henriet van Middendorp, Andrea W.M. Evers
Journal: Psychotherapy and Psychosomatics (2015)
Specialty Fellowships Within General Surgery
Authors: James C. Hebert
Journal: JAMA Surgery (2015)

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Association between systemic inflammatory response syndrome and mortality in alcoholic hepatitis: A meta‐analysis
Authors: Veeravich Jaruvongvanich, Sikarin Upala, Anawin Sanguankeo
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. To the Editor: We were interested in the article written by Michelena et al.1 The authors performed a study in patients with alcoholic hepatitis (AH) to assess the association between systemic inflammatory response syndrome (SIRS) and mortality. They found that SIRS with or without infection was significantly associated with 90‐day mortality, and no significant difference in mortality was found between the two groups. Many recent studies showed the importance of SIRS on mortality in AH. Thus, we performed a systematic review and meta‐analysis of observational studies to determine the strength of association of SIRS and sepsis with mortality in patients with AH. We performed a comprehensive search of the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE databases up to October 2015. Participants in the included studies were adults who had AH and developed SIRS or sepsis during hospitalization without other causes of liver disease. We estimated the pooled risk ratio (RR) of mortality at 90 days, comparing participants with and without SIRS or sepsis using a fixed‐effect model. If studies did not have outcome data at 90 days, we used the available data at a time closest to 90 days. The between‐study heterogeneity was quantified using the Q statistic and I2. A total of four studies involving 1,093 patients (420 had SIRS) and four studies involving 57,529 (1449 had sepsis) were extracted and included in the meta‐analysis. There were significant associations between SIRS and mortality, with a pooled RR of 3.0 (95% confidence interval 2.07‐4.34, P < 0.01, I2 = 0%, Pheterogeneity = 0.41), and sepsis and mortality, with a pooled RR of 2.8 (95% confidence interval 1.58‐4.93, P < 0.01, I2 = 0%, Pheterogeneity = 0.93). From the result, SIRS and sepsis should be considered important prognostic factors of mortality in hospitalized AH patients. Both groups provided comparable RRs supported by recent studies showing no significant difference of mortality between the two groups.1 It is consistent with the proposed mechanism that the increased serum endotoxin level due to alcohol use activates innate immunity, causing increased release of proinflammatory cytokines (e.g., tumor necrosis factor‐alpha, interleukin‐1, interleukin‐6), which leads not only to the progression of liver injury but also to the systemic involvement resulting in SIRS.3 In conclusion, not only sepsis but also SIRS is significantly associated with mortality in AH. Further studies should be done to determine the inflammatory mediators that play a key role in developing SIRS in AH for potential therapeutic benefit.
Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5
Authors: Lilian E. Hunt, Boris Noyvert, Leena Bhaw-Rosun, Abdul K. Sesay, Lavinia Paternoster, Ellen A. Nohr, George Davey Smith, Niels Tommerup, Thorkild I. A. Sørensen, Greg Elgar
Journal: Genome Medicine (2015)
Saliva and viral infections
Authors: Paul L. A. M. Corstjens, William R. Abrams, Daniel Malamud
Journal: Periodontology 2000 (2015)

Abstract Over the last 10 years there have been only a handful of publications dealing with the oral virome, which is in contrast to the oral microbiome, an area that has seen considerable interest. Here, we survey viral infections in general and then focus on those viruses that are found in and/or are transmitted via the oral cavity; norovirus, rabies, human papillomavirus, Epstein‐Barr virus, herpes simplex viruses, hepatitis C virus, and HIV. Increasingly, viral infections have been diagnosed using an oral sample (e.g. saliva mucosal transudate or an oral swab) instead of blood or urine. The results of two studies using a rapid and semi‐quantitative lateral flow assay format demonstrating the correlation of HIV anti‐IgG/sIgA detection with saliva and serum samples are presented. When immediate detection of infection is important, point‐of‐care devices that obtain a non‐invasive sample from the oral cavity can be used to provide a first line diagnosis to assist in determining appropriate counselling and therapeutic path for an increasing number of diseases.
Tracking genetically engineered lymphocytes long-term reveals the dynamics of T cell immunological memory
Authors: Giacomo Oliveira, Eliana Ruggiero, Maria Teresa Lupo Stanghellini, Nicoletta Cieri, Mattia D’Agostino, Raffaele Fronza, Christina Lulay, Francesca Dionisio, Sara Mastaglio, Raffaella Greco, Jacopo Peccatori, Alessandro Aiuti, Alessandro Ambrosi, Luca Biasco, Attilio Bondanza, Antonio Lambiase, Catia Traversari, Luca Vago, Christof von Kalle, Manfred Schmidt, Claudio Bordignon, Fabio Ciceri, Chiara Bonini
Journal: Science Translational Medicine (2015)

Antigen exposure and differentiation phenotype influence long-term persistence of memory T cells after hematopoietic stem cell transplant.
Hominid spongyform encephalophagy: cooking time 1-1<sup>1</sup>/<sub>2</sub>hours, difficulty ***
Authors: Lucinda Whitton
Journal: BMJ (2015)

Lucinda Whitton provides a fun recipe for a “brain cake” for you to make this Christmas With shows such as “The Great British Bake Off” captivating the nation, baking has taken Britain by storm. This article shows you how to make a “brain cake”—from the core sponge to the basal layer and gyri. Not only is it “radiculously” tasty, it will get your neurones firing as you fight with the intricacies of the anatomy. So find the mixing bowl and conjure up your culinary creativeness this Christmas. Food for thought indeed. A simple Victoria sponge recipe will do the trick. Spherical baking trays are available from specialist kitchen shops but ovenproof bowls lined with greaseproof paper can be used instead. Preheat the oven to 180ºC. Butter two spherical baking trays or ovenproof bowls and line with greaseproof paper. Mix all ingredients in a large bowl until smooth. Divide the mixture between the two spherical bowls and one small cupcake baking tray (to make the cerebellum). Cook for 20-25 minutes until the cake is golden and bounces back when pressed down. Allow to cool while preparing the icing. #### Ingredients ##### Victoria sponge
Benefit of paramedics in non-ventricular fibrillation arrests is transitory
Authors: C J Mann, J R C Heyworth
Journal: BMJ (1995)

EDITOR,--We agree with U M Guly and colleagues' conclusion that intervention by paramedics does not improve the outcome of cardiopulmonary arrest occurring outside hospital when compared with intervention by ambulance technicians using basic life support with early defibrillation.1 A retrospective study …
A Prognostic Model to Predict Mortality among Non–Small-Cell Lung Cancer Patients in the U.S. Military Health System
Authors: Jie Lin, Corey A. Carter, Katherine A. McGlynn, Shelia H. Zahm, Joel A. Nations, William F. Anderson, Craig D. Shriver, Kangmin Zhu, Joel A. Nations, William F. Anderson, Craig D. Shriver, Kangmin Zhu
Journal: Journal of Thoracic Oncology (2015)
Salivary cytokines as biomarkers of periodontal diseases
Authors: Katrin M. Jaedicke, Philip M. Preshaw, John J. Taylor
Journal: Periodontology 2000 (2015)

Research into biomarkers of periodontitis is driven by mainly three targets: to identify 'at risk' patients before periodontal tissue destruction occurs; to determine disease activity and progression; and to build up our understanding of this complex disease with the purpose of finding new therapeutic targets. Whilst blood and gingival crevicular fluid were previously the biological samples of choice, saliva has recently gained more attention as a readily accessible oral fluid which has a mediator profile similar to that of serum and gingival crevicular fluid. The aim of this paper was to give a comprehensive overview of salivary cytokines in periodontitis, highlighting extensively studied cytokines such as interleukin-1beta and interleukin-6, but also cytokines that have been the subject of only a few studies and which warrant further investigation. Cross-sectional and longitudinal studies of salivary cytokines, and the potential of cytokines as periodontitis biomarkers, are evaluated. Finally, a discussion of potential confounding factors, such as concurrent systemic diseases and smoking, is presented.
We must join forces in the battle against COPD
Authors: Bartolome R. Celli
Journal: European Respiratory Journal (2015)

We applaud and totally agree with the concept expressed by A. Ostrem and colleagues that in order to win the battle against chronic obstructive pulmonary disease (COPD) we must all join forces. Indeed, the coincidence of important research questions related to COPD between the document generated by the International Primary Care Respiratory Group (IPCRG) in 2010 [1] and the recently published American Thoracic Society (ATS)/European Respiratory Society (ERS) statement on research questions in COPD [2] is evidence of the agreement that exists among everyone interested in this topic. ATS/ERS task force agrees coordinated action by all groups (including patients) aimed at combating COPD is beneficial <http://ow.ly/R2oNy>
Hunt promises to investigate claims of mental health trust’s failure over unexpected deaths
Authors: Gareth Iacobucci
Journal: BMJ (2015)

The health secretary, Jeremy Hunt, has pledged to investigate allegations that a mental health trust in England failed to properly investigate the unexpected deaths of more than 1000 people.

The intervention came after a leaked report1 examining unexpected deaths at Southern Health NHS Foundation Trust found that some cases in which patients with mental health illness and learning disabilities had died had not been fully examined owing to a “failure of leadership” at the trust.

The report was commissioned by NHS England after the death in 2013 of Connor Sparrowhawk, an 18 year old patient in a Southern Health hospital …
Prenatal exposure to antibiotics and wheezing in infancy: a birth cohort study
Authors: Maja Popovic, Franca Rusconi, Daniela Zugna, Claudia Galassi, Franco Merletti, Enrica Migliore, Morena Trevisan, Tiziana Nannelli, Luigi Gagliardi, Lorenzo Richiardi
Journal: European Respiratory Journal (2015)

The role of prenatal antibiotic exposure in the development of childhood wheezing is debated. We evaluated whether this association could potentially be explained by confounding factors. Antibiotic use in the first and third trimester of pregnancy, wheezing in children aged ≤18 months and confounding factors were assessed in singletons participating in the NINFEA ( Nascita e Infanzia: gli Effetti dell'Ambiente ) birth cohort (n=3530 for first-trimester exposure and n=3985 for third-trimester exposure). There was no evidence of an association between antibiotic exposure in the first trimester of pregnancy and ever-wheezing (adjusted risk ratio (RR) 1.02, 95% CI 0.80–1.30) or recurrent wheezing (RR 0.99, 95% CI 0.54–1.82). For the third-trimester exposure, the crude RRs (95% CI) of ever-wheezing and recurrent wheezing were 1.34 (1.10–1.64) and 2.72 (1.80–4.11), respectively, which decreased to 1.12 (0.90–1.39) and 2.09 (1.32–3.29) after adjustment. The RRs of wheezing after genitourinary infections during pregnancy were increased independently of antibiotic treatment. In conclusion, the association between prenatal antibiotic exposure and infant wheezing could be largely explained by confounding factors, in particular respiratory infections during pregnancy. An excess risk of wheezing after antibiotic exposure during the third trimester of pregnancy remains after adjustment.
Risk of Retinal Neovascularization in Cases of Uveitis
Authors: Apurva K. Patel, Craig W. Newcomb, Teresa L. Liesegang, Siddharth S. Pujari, Eric B. Suhler, Jennifer E. Thorne, C. Stephen Foster, Douglas A. Jabs, Grace A. Levy-Clarke, Robert B. Nussenblatt, James T. Rosenbaum, H. Nida Sen, Pichaporn Artornsombudh, Srishti Kothari, John H. Kempen
Journal: Ophthalmology (2015)
LO1 : Safety of ombitasvir/paritaprevir/ritonavir plus dasabuvir for treating HCV GT1 infection in patients with severe renal impairment or end-stage renal disease: The RUBY-I study
Authors: P.J. Pockros, K.R. Reddy, P.S. Mantry, E. Cohen, M. Bennett, M.S. Sulkowski, D. Bernstein, T. Podsadecki, D. Cohen, N.S. Shulman, D. Wang, A. Khatri, M. Abunimeh, E. Lawitz
Journal: Journal of Hepatology (2015)
Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial
Authors: Johan A Maertens, Issam I Raad, Kieren A Marr, Thomas F Patterson, Dimitrios P Kontoyiannis, Oliver A Cornely, Eric J Bow, Galia Rahav, Dionysios Neofytos, Mickael Aoun, John W Baddley, Michael Giladi, Werner J Heinz, Raoul Herbrecht, William Hope, Meinolf Karthaus, Dong-Gun Lee, Olivier Lortholary, Vicki A Morrison, Ilana Oren, Dominik Selleslag, Shmuel Shoham, George R Thompson, Misun Lee, Rochelle M Maher, Anne-Hortense Schmitt-Hoffmann, Bernhardt Zeiher, Andrew J Ullmann
Journal: The Lancet (2015)
Pre-treatment patient selection for nivolumab benefit based on serum mass spectra
Authors: Jeffrey Weber, Alberto J Martinez, Heinrich Roder, Joanna Roder, Krista Meyer, Senait Asmellash, Julia Grigorieva, Maxim Tsypin, Carlos Oliveira, Arni Steingrimsson, Kevin Sayers, Antonella Bacchiocchi, Mario Sznol, Ruth Halaban, Harriet Kluger
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts The durability of anti-tumor responses observed in patients treated with antibodies blocking PD-1 has provided a central role for these drugs in melanoma therapeutics. Identifying predictive biomarkers to aid therapeutic decision making is critical for realizing the full potential
Pulse oximetry oxygen saturation during the 6-min walk test: a limit for stopping the test without resuming it
Authors: Giancarlo Piaggi, Simone Gambazza, Riccardo Guarise, Manuela Piran
Journal: European Respiratory Journal (2015)

We read with interest the systematic review on [1] and the new procedures for [2] field tests for chronic respiratory diseases. However, we would like to raise some concerns regarding the indications given when oxygen desaturation occurs during the 6-min walk test (6MWT). Caution should be taken when adopting new ERS/ATS recommendation on 6-min walk test procedure <http://ow.ly/PX9OB>
Bosutinib As Second-Line Therapy in Patients (Pts) with Chronic Phase Chronic Myeloid Leukemia (CP CML) Resistant or Intolerant to Prior Imatinib: 60-Month Update of a Phase 1/2 Study
Authors: Tim H. Brümmendorf, Jorge E. Cortes, H. Jean Khoury, Hagop M. Kantarjian, Dong-Wook Kim, Philippe Schafhausen, Mirjana Zeremski, Mark Shapiro, Eric Leip, Carlo Gambacorti-Passerini, Jeffrey H. Lipton
Journal: Blood (2014)