tbuckley/cabot-search huggingface dataset:
Experimental Determination and Prediction of the Fitness Effects of Random Point Mutations in the Biosynthetic Enzyme HisA
Authors: Erik Lundin, Po-Cheng Tang, Lionel Guy, Joakim Näsvall, Dan I Andersson
Journal: Molecular Biology and Evolution (2017)

The distribution of fitness effects of mutations is a factor of fundamental importance in evolutionary biology. We determined the distribution of fitness effects of 510 mutants that each carried between 1 and 10 mutations (synonymous and nonsynonymous) in the hisA gene, encoding an essential enzyme in the l-histidine biosynthesis pathway of Salmonella enterica. For the full set of mutants, the distribution was bimodal with many apparently neutral mutations and many lethal mutations. For a subset of 81 single, nonsynonymous mutants most mutations appeared neutral at high expression levels, whereas at low expression levels only a few mutations were neutral. Furthermore, we examined how the magnitude of the observed fitness effects was correlated to several measures of biophysical properties and phylogenetic conservation.We conclude that for HisA: (i) The effect of mutations can be masked by high expression levels, such that mutations that are deleterious to the function of the protein can still be neutral with regard to organism fitness if the protein is expressed at a sufficiently high level; (ii) the shape of the fitness distribution is dependent on the extent to which the protein is rate-limiting for growth; (iii) negative epistatic interactions, on an average, amplified the combined effect of nonsynonymous mutations; and (iv) no single sequence-based predictor could confidently predict the fitness effects of mutations in HisA, but a combination of multiple predictors could predict the effect with a SD of 0.04 resulting in 80% of the mutations predicted within 12% of their observed selection coefficients.
Ibrutinib discontinuation in Waldenström macroglobulinemia: Etiologies, outcomes, and IgM rebound
Authors: Joshua N. Gustine, Kirsten Meid, Toni Dubeau, Patricia Severns, Zachary R. Hunter, Yang Guang, Lian Xu, Steven P. Treon, Jorge J. Castillo
Journal: American Journal of Hematology (2017)

Ibrutinib is the first approved therapy for symptomatic patients with Waldenström macroglobulinemia (WM). The reasons for discontinuing ibrutinib and subsequent outcomes have not been previously evaluated in WM patients. We therefore conducted a retrospective review of 189 WM patients seen at our institution who received treatment with ibrutinib, of whom 51 (27%) have discontinued therapy. Reasons for discontinuation include: disease progression (n = 27; 14%), toxicity (n = 15; 8%), nonresponse (n = 5; 3%), and other unrelated reasons (n = 4; 2%). The cumulative incidence of ibrutinib discontinuation at 12, 24, 36, and 48 months from treatment initiation was 22%, 26%, 35%, and 43%, respectively. A baseline platelet count ≤100 K/µL and presence of tumor CXCR4 mutations were independently associated with 4-fold increased odds of ibrutinib discontinuation. An IgM rebound (≥25% increase in serum IgM) was observed in 37 patients (73%) following ibrutinib discontinuation and occurred within 4 weeks for nearly half of patients. The response rate to salvage therapy was 71%; responses were higher in patients without an IgM rebound and when salvage therapy was initiated within 2 weeks of stopping ibrutinib. Patients who discontinued ibrutinib due to disease progression versus nonprogression events had significantly shorter overall survival (21 versus 32 months; P = .046). Response to salvage therapy was associated with an 82% reduction in the risk of death following ibrutinib discontinuation. WM patients who discontinue ibrutinib require close monitoring, and continuation of ibrutinib until the next therapy should be considered to maintain disease control.
American Thoracic Society Meeting 2016.: Mitochondrial Transfer Via Tunnelling Nanotubes (TNT) Is a Novel Mechanism by Which Mesenchymal Stromal Cells Enhance Macrophage Phagocytosis in In Vivo Models of Acute Lung Injury
Authors: Megan Jackson, Thomas Morrison, Danny McAuley, Michael A. Matthay, Cecilia O'Kane, Anna Krasnodembskaya
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
Guidelines for the Content of Statistical Analysis Plans in Clinical Trials
Authors: Carrol Gamble, Ashma Krishan, Deborah Stocken, Steff Lewis, Edmund Juszczak, Caroline Doré, Paula R. Williamson, Douglas G. Altman, Alan Montgomery, Pilar Lim, Jesse Berlin, Stephen Senn, Simon Day, Yolanda Barbachano, Elizabeth Loder
Journal: JAMA (2017)

<h3>Importance</h3> While guidance on statistical principles for clinical trials exists, there is an absence of guidance covering the required content of statistical analysis plans (SAPs) to support transparency and reproducibility. <h3>Objective</h3> To develop recommendations for a minimum set of items that should be addressed in SAPs for clinical trials, developed with input from statisticians, previous guideline authors, journal editors, regulators, and funders. <h3>Design</h3> Funders and regulators (n = 39) of randomized trials were contacted and the literature was searched to identify existing guidance; a survey of current practice was conducted across the network of UK Clinical Research Collaboration–registered trial units (n = 46, 1 unit had 2 responders) and a Delphi survey (n = 73 invited participants) was conducted to establish consensus on SAPs. The Delphi survey was sent to statisticians in trial units who completed the survey of current practice (n = 46), CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guideline authors (n = 16), pharmaceutical industry statisticians (n = 3), journal editors (n = 9), and regulators (n = 2) (3 participants were included in 2 groups each), culminating in a consensus meeting attended by experts (N = 12) with representatives from each group. The guidance subsequently underwent critical review by statisticians from the surveyed trial units and members of the expert panel of the consensus meeting (N = 51), followed by piloting of the guidance document in the SAPs of 5 trials. <h3>Findings</h3> No existing guidance was identified. The registered trials unit survey (46 responses) highlighted diversity in current practice and confirmed support for developing guidance. The Delphi survey (54 of 73, 74% participants completing both rounds) reached consensus on 42% (n = 46) of 110 items. The expert panel (N = 12) agreed that 63 items should be included in the guidance, with an additional 17 items identified as important but may be referenced elsewhere. Following critical review and piloting, some overlapping items were combined, leaving 55 items. <h3>Conclusions and Relevance</h3> Recommendations are provided for a minimum set of items that should be addressed and included in SAPs for clinical trials. Trial registration, protocols, and statistical analysis plans are critically important in ensuring appropriate reporting of clinical trials.
Exenatide did not reduce major cardiovascular outcomes in type 2 diabetes
Authors: Lorraine L. Lipscombe
Journal: Annals of Internal Medicine (2017)

ACP Journal Club19 December 2017Exenatide did not reduce major cardiovascular outcomes in type 2 diabetesLorraine L. Lipscombe, MDLorraine L. Lipscombe, MDWomen's College Hospital, Toronto, Ontario, Canada (L.L.L.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2017-167-12-067 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationHolman RR, Bethel MA, Mentz RJ, et al; EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377:1228-39. https://pubmed.ncbi.nlm.nih.gov/28910237Clinical Impact RatingsGIM/FP/GP: Cardiology: Endocrinology: References1 Pfeffer MA, Claggett B, Diaz R, et al; ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247-57. [PMID: 26630143] Google Scholar2 Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-22. [PMID: 27295427] Google Scholar3 Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834-44. [PMID: 27633186] Google Scholar4 Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet. 2013;381:117-24. [PMID: 23141817] Google Scholar Author, Article, and Disclosure InformationAffiliations: Women's College Hospital, Toronto, Ontario, Canada (L.L.L.)This article was published at Annals.org on 5 December 2017. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 19 December 2017Volume 167, Issue 12Page: JC67KeywordsHazard ratioHbA1cHospitalizationsHypoglycemiaMortalityMyocardial infarctionRenal failureSafetySerious adverse eventsType 2 diabetes ePublished: 19 December 2017 Issue Published: 19 December 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
An International Laboratory for Systems and Computational Neuroscience
Authors: Larry F. Abbott, Dora E. Angelaki, Matteo Carandini, Anne K. Churchland, Yang Dan, Peter Dayan, Sophie Deneve, Ila Fiete, Surya Ganguli, Kenneth D. Harris, Michael Häusser, Sonja Hofer, Peter E. Latham, Zachary F. Mainen, Thomas Mrsic-Flogel, Liam Paninski, Jonathan W. Pillow, Alexandre Pouget, Karel Svoboda, Ilana B. Witten, Anthony M. Zador
Journal: Neuron (2017)

The neural basis of decision-making has been elusive and involves the coordinated activity of multiple brain structures. This NeuroView, by the International Brain Laboratory (IBL), discusses their efforts to develop a standardized mouse decision-making behavior, to make coordinated measurements of neural activity across the mouse brain, and to use theory and analyses to uncover the neural computations that support decision-making.
The Banff Working Group Classification of Definitive Polyomavirus Nephropathy: Morphologic Definitions and Clinical Correlations
Authors: Volker Nickeleit, Harsharan K. Singh, Parmjeet Randhawa, Cinthia B. Drachenberg, Ramneesh Bhatnagar, Erika Bracamonte, Anthony Chang, W. James Chon, Darshana Dadhania, Vicki G. Davis, Helmut Hopfer, Michael J. Mihatsch, John C. Papadimitriou, Stefan Schaub, Michael B. Stokes, Mohammad F. Tungekar, Surya V. Seshan
Journal: Journal of the American Society of Nephrology (2017)

Polyomavirus nephropathy (PVN) is a common viral infection of renal allografts, with biopsy-proven incidence of approximately 5%. A generally accepted morphologic classification of definitive PVN that groups histologic changes, reflects clinical presentation, and facilitates comparative outcome analyses is lacking. Here, we report a morphologic classification scheme for definitive PVN from the Banff Working Group on Polyomavirus Nephropathy, comprising nine transplant centers in the United States and Europe. This study represents the largest systematic analysis of definitive PVN undertaken thus far. In a retrospective fashion, clinical data were collected from 192 patients and correlated with morphologic findings from index biopsies at the time of initial PVN diagnosis. Histologic features were centrally scored according to Banff guidelines, including additional semiquantitative histologic assessment of intrarenal polyomavirus replication/load levels. In-depth statistical analyses, including mixed effects repeated measures models and logistic regression, revealed two independent histologic variables to be most significantly associated with clinical presentation: intrarenal polyomavirus load levels and Banff interstitial fibrosis ci scores. These two statistically determined histologic variables formed the basis for the definition of three PVN classes that correlated strongest with three clinical parameters: presentation at time of index biopsy, serum creatinine levels/renal function over 24 months of follow-up, and graft failure. The PVN classes 1–3 as described here can easily be recognized in routine renal biopsy specimens. We recommend using this morphologic PVN classification scheme for diagnostic communication, especially at the time of index diagnosis, and in scientific studies to improve comparative data analysis.
Correlation of the Eosinophilic Histopathological Scoring System with Esophageal Gene Expression in Patients with Eosinophilic Esophagitis
Authors: Tetsuo Shoda, Ting Wen, Julie M. Caldwell, Jonathan Kuhl, Seema S. Aceves, Peter Bonis, Kelley E. Capocelli, Margaret H. Collins, Evan S. Dellon, Gary W. Falk, Glenn Furuta, Nirmala Gonsalves, Sandeep Gupta, Ikuo Hirano, John Leung, Paul Menard-Katcher, Jonathan M. Spergel, Barry K. Wershil, Guang-Yu Yang, Marc E. Rothenberg
Journal: Journal of Allergy and Clinical Immunology (2018)
A phase I trial of the oral hedgehog inhibitor taladegib (LY2940680) in combination with weekly paclitaxel in patients with advanced, solid tumours.
Authors: Rosalind Margaret Glasspool, Sarah Patricia Blagden, Michelle Lockley, James Paul, Carol Hopkins, Fiona Thomson, Jennifer Brown, Ricardo Fernandes, Nivea Douglas, Chantevy Pou, Aishah Hanif, Craig Campbell, Pratik S. Multani, Trevor Tucker, Iain A. McNeish, T.R. Jeffry Evans
Journal: Journal of Clinical Oncology (2017)

2594 Background: Aberrant Hedgehog (Hh) signaling is implicated in carcinogenesis and is associated with poor prognosis in multiple tumours types. Hh inhibitors increase sensitivity to paclitaxel in taxane-resistant cell lines. Taladegib is an orally bioavailable, potent inhibitor of Smoothened, a key Hh pathway component, with activity in basal cell carcinoma. The single agent recommended dose is 400mg od. We present the dose escalation phase of a phase I study of weekly paclitaxel with oral taladegib. Methods: Primary objective: determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of taladegib on a continuous oral daily dosing regimen in combination with paclitaxel (80mg/m 2 , iv, day 1, 8 and 15 q 28) in patients with advanced solid cancers. Secondary objectives: assess the safety and tolerability, determine the recommended phase II dose (RP2D), and evaluate the pharmacokinetics of taladegib and paclitaxel. Exploratory objective: assess preliminary efficacy. A standard 3 + 3 dose escalation design was used. All patients received up to 6 cycles of paclitaxel. In addition, successive cohorts received continuous oral taladegib continued until progression or unacceptable toxicity as follows: dose level 1: 100mg od; 2: 200mg od; 3: 400mg od. Results: No DLTs were seen at dose level 1 or in the first 3 patients at dose level 2. 3 DLTs of grade 2 neuropathy were seen at dose level 3 (400mg taladegib); therefore, dose level 2 was expanded to 6 patients. No DLT was seen in the fourth patient and 2 additional patients have started treatment. After the DLT period 2 patients developed G2 and 4 developed G1 neuropathy. Other non DLT, drug-related G3 toxicities: uncomplicated neutropenia x2, muscle cramp x1 and fatigue x1. To date, 3 patients have had partial responses. Conclusions: The combination of daily oral taladegib and weekly paclitaxel is feasible. DLT of G2 neuropathy was seen at 400mg. Promising activity has been seen in solid tumours. A dose expansion cohort is due to commence in high grade ovarian carcinoma. ISRCTN No:ISRCTN15903698 Eudract Ref:2014-004695-37 Funded by Cancer Research UK C8361/A18775 and Ignyta. Sponsored by NHS Greater Glasgow and Clyde. Clinical trial information: ISRCTN15903698.
Cell Biology of T Cell Receptor Expression and Regulation
Authors: Andrés Alcover, Balbino Alarcón, Vincenzo Di Bartolo
Journal: Annual Review of Immunology (2017)

T cell receptors (TCRs) are protein complexes formed by six different polypeptides. In most T cells, TCRs are composed of αβ subunits displaying immunoglobulin-like variable domains that recognize peptide antigens associated with major histocompatibility complex molecules expressed on the surface of antigen-presenting cells. TCRαβ subunits are associated with the CD3 complex formed by the γ, δ, ε, and ζ subunits, which are invariable and ensure signal transduction. Here, we review how the expression and function of TCR complexes are orchestrated by several fine-tuned cellular processes that encompass (a) synthesis of the subunits and their correct assembly and expression at the plasma membrane as a single functional complex, (b) TCR membrane localization and dynamics at the plasma membrane and in endosomal compartments, (c) TCR signal transduction leading to T cell activation, and (d) TCR degradation. These processes balance each other to ensure efficient T cell responses to a variety of antigenic stimuli while preventing autoimmunity.
Ведение больных гастроэзофагеальной болезнью в свете последнего американского консенсуса
Authors: S.M. Tkach
Journal: GASTROENTEROLOGY (2013)

В статье дан обзор положения нового консенсуса по диагностике и ведению пациентов с гастроэзофагеальной рефлюксной болезнью (ГЭРБ), разработанного Американским колледжем гастроэнтерологии, обсуждается вопрос, насколько подходы, рекомендованные в консенсусе, отличаются от применяющихся в Украине. Сделан акцент на необходимости эмпирических подходов к контролю лечения и рецидивов при неосложненной ГЭРБ, в то время как в Украине достаточно часто в таких случаях проводится эзофагогастродуоденоскопия. Даны рекомендации по применению ИПП-теста.
Progression By Lymphocytosis Correlates with Favourable Long-Term Clinical Outcomes in Chronic Lymphocytic Leukemia (CLL)
Authors: Alexandra Bazeos, Craig Gower, Francine Swann, Peter C Trask, Mark Dixon, Noelle Crompton, Nelson Kinnersley, Othman Al-Sawaf, Valentin Goede, Günter Fingerle-Rowson, Kathryn Humphrey
Journal: Blood (2016)
An open-label, phase II study of tipifarnib for the treatment of HRAS mutant solid tumors, including squamous cell carcinomas of the head and neck.
Authors: Alan Loh Ho, Nicole Grace Chau, Deborah Jean Lee Wong, Maria E. Cabanillas, Jessica Ruth Bauman, Keith Christopher Bible, Marcia S. Brose, Emiliano Calvo, Valentina Boni, Francis Burrows, Carrie L. Melvin, Catherine Rose Scholz, Antonio Gualberto
Journal: Journal of Clinical Oncology (2017)

TPS2618 Background: Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FT). FT catalyzes the post-translational attachment of farnesyl groups to signaling proteins that are requisite for localization to the inner cell membrane. While all RAS isoforms (KRAS/NRAS/HRAS) are FT substrates, only HRAS is exclusively dependent upon farnesylation for membrane localization and signaling activation, making HRAS mutant tumors uniquely susceptible to tipifarnib mediated inhibition of FT. Tipifarnib has demonstrated robust activity in HRAS mutant head and neck squamous cell carcinoma (HNSCC) and HRAS mutant squamous non-small cell lung cancer (NSCLC) patient derived xenograft (PDX) models resistant to standard therapies. Methods: This is a multi-institutional, open-label Phase II trial evaluating the efficacy and safety of tipifarnib for pts with HRAS mutant solid tumors. Pts must have either unresectable, locally advanced or metastatic non-hematological malignancies that harbor a missense HRAS mutation. The primary endpoint of the study is overall response rate. Secondary endpoints include safety and tolerability, PFS, duration of response. Two cohorts (N = 18 each) are enrolling, each being evaluated with a Simon two-stage design. Cohort 1 is for patients with malignant thyroid tumors of any histology. Cohort 2 was originally designated for pts with any other solid tumor. The prespecified activity goal for the first stage of accrual in Cohort 2 was met. Based on data observed in the first stage of this group, enrollment to the second stage of Cohort 2 has been limited to HRAS mutant HNSCC since August 2016. Enrolled patients are treated with tipifarnib 900 mg administered orally twice daily on days 1-7 and 15-21 of 28-day treatment cycles until progression of disease or unacceptable toxicity. Clinical trial information: NCT02383927.
Selective Cell Penetrating Peptide‐Functionalized Polymersomes Mediate Efficient and Targeted Delivery of Methotrexate Disodium to Human Lung Cancer In Vivo
Authors: Weijing Yang, Yifeng Xia, Yuan Fang, Fenghua Meng, Jian Zhang, Ru Cheng, Chao Deng, Zhiyuan Zhong
Journal: Advanced Healthcare Materials (2017)

Abstract It is a long challenge to develop nanomedicines that simultaneously possess tumor cell selectivity and penetration functions. Here, it is reported that selective cell penetrating peptide (RLWMRWYSPRTRAYGC)‐functionalized polymersomes (SCPP‐PS) mediate efficient and targeted delivery of methotrexate disodium (MTX) to human lung cancer in vivo. SCPP‐PS with an SCPP density of 18.7% is self‐crosslinked, has a small size (63–65 nm), and high MTX loading (up to 19.4 wt%), shows selective uptake and fast penetration into A549 lung cancer cells, and efficiently releases MTX intracellularly. Interestingly, MTX‐loaded SCPP‐PS (MTX‐SCPP‐PS) displays much lower IC 50 than those of MTX‐PS and free MTX. Installing SCPP to polymersomes has no detrimental effect to their long blood circulation time but significantly increases drug accumulation in A549 tumor (5.3% injected dose per gram at 8 h post injection). Remarkably, SCPP‐PS exhibits deep penetration in to A549 tumors. MTX‐SCPP‐PS completely inhibits tumor progression and significantly improves survival rates in mice bearing A549 lung tumor xenografts as compared to MTX‐PS and free MTX groups (median survival time: 75 vs 45 and 38 d, respectively), without causing noticeable adverse effects. These results highlight that functionalization of nanomedicines with SCPP is a feasible strategy to achieve efficient and targeted tumor therapy.
Human-Machine Collaboration—A New Form of Paternalism?
Authors: Isabelle Scholl, Raymond U. Osarogiagbon, Glyn Elwyn
Journal: JAMA Oncology (2017)

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Drug-induced inhibition of phosphorylation of STAT5 overrides drug resistance in neoplastic mast cells
Authors: B Peter, S Bibi, G Eisenwort, B Wingelhofer, D Berger, G Stefanzl, K Blatt, H Herrmann, E Hadzijusufovic, G Hoermann, T Hoffmann, J Schwaab, M Jawhar, M Willmann, W R Sperr, J Zuber, K Sotlar, H-P Horny, R Moriggl, A Reiter, M Arock, P Valent
Journal: Leukemia (2017)