tbuckley/cabot-search huggingface dataset:
Effects of Beneficial Mutations in pykF Gene Vary over Time and across Replicate Populations in a Long-Term Experiment with Bacteria
Authors: Fen Peng, Scott Widmann, Andrea Wünsche, Kristina Duan, Katherine A Donovan, Renwick C J Dobson, Richard E Lenski, Tim F Cooper
Journal: Molecular Biology and Evolution (2017)

The fitness effects of mutations can depend on the genetic backgrounds in which they occur and thereby influence future opportunities for evolving populations. In particular, mutations that fix in a population might change the selective benefit of subsequent mutations, giving rise to historical contingency. We examine these effects by focusing on mutations in a key metabolic gene, pykF, that arose independently early in the history of 12 Escherichia coli populations during a long-term evolution experiment. Eight different evolved nonsynonymous mutations conferred similar fitness benefits of ∼10% when transferred into the ancestor, and these benefits were greater than the one conferred by a deletion mutation. In contrast, the same mutations had highly variable fitness effects, ranging from ∼0% to 25%, in evolved clones isolated from the populations at 20,000 generations. Two mutations that were moved into these evolved clones conferred similar fitness effects in a given clone, but different effects between the clones, indicating epistatic interactions between the evolved pykF alleles and the other mutations that had accumulated in each evolved clone. We also measured the fitness effects of six evolved pykF alleles in the same populations in which they had fixed, but at seven time points between 0 and 50,000 generations. Variation in fitness effects was high at intermediate time points, and declined to a low level at 50,000 generations, when the mean fitness effect was lowest. Our results demonstrate the importance of genetic context in determining the fitness effects of different beneficial mutations even within the same gene.
TCT-414 Diastolic-systolic velocity ratio to detect coronary stenoses
Authors: Guus de Waard, Christopher Cook, Ricardo Petraco, Sukhjinder Nijjer, Tim van de Hoef, Mauro Echavarria Pinto, Sayan Sen, Martijn Meuwissen, Paul Knaapen, Javier Escaned, Jan Piek, Niels van Royen, Justin Davies
Journal: Journal of the American College of Cardiology (2017)
Cancer Informatics: New Tools for a Data-Driven Age in Cancer Research
Authors: Warren Kibbe, Juli Klemm, John Quackenbush
Journal: Cancer Research (2017)

Cancer is a remarkably adaptable and formidable foe. Cancer exploits many biological mechanisms to confuse and subvert normal physiologic and cellular processes, to adapt to therapies, and to evade the immune system. Decades of research and significant national and international investments in
TCT-290 Long-Term Integration of Bioresorbable Vascular Scaffold in the Porcine Coronary Model of Spontaneous Untreated Atherosclerosis: a 4-year QCA, IVUS, OCT and Histology Study
Authors: Yanping Cheng, Qing Wang, Laura Perkins, Richard Rapoza, Jenn McGregor, Gerard Conditt, Aloke Finn, Greg Kaluza, Juan Granada
Journal: Journal of the American College of Cardiology (2017)
TCT-271 Percutaneous suture-mediated patent foramen ovale (PFO) closure: early results with NobleStitchEL device
Authors: Achille Gaspardone, Antonella De Santis, Emanuela D'Ascoli, Gregory Sgueglia, Gaetano Gioffrè, Maria Iamele, Fabiana Piccioni, Fabrizio D'Errico, Francesco Summaria, Anthony Nobles
Journal: Journal of the American College of Cardiology (2017)
P3.01-008 Clinicopathological and Immunohistochemical Features in Lung Invasive Mucinous Adenocarcinoma According to Computed Tomography Findings
Authors: Yuji Nojima, Katsuhiko Shimizu, Ai Maeda, Shinsuke Saisho, Riki Okita, Masao Nakata
Journal: Journal of Thoracic Oncology (2017)
Vigilancia centinela de la gripe en Europa, 1997/1998
Authors: M Zambon
Journal: Eurosurveillance (1998)

La circulacion del virus de la gripe esta asociada con el aumento en las consultas a medicos generalistas (1), con aumentos de los ingresos hospitalarios (2), asi como con un exceso de defunciones (3) y es un factor a tener en cuenta a la hora de elaborar la planificacion de la atencion sanitaria. En la Europa occidental, los virus de la gripe suelen circular en los meses invernales, por lo general entre octubre y marzo. Durante esta temporada, se intensifica la vigilancia de los sindromes respiratorios en diversos paises europeos.
Mutational Landscape of cfDNA Identifies Distinct Molecular Features Associated With Therapeutic Response to First-Line Platinum-Based Doublet Chemotherapy in Patients with Advanced NSCLC
Authors: Tao Jiang, Xuefei Li, Jianfei Wang, Chunxia Su, Wenbo Han, Chao Zhao, Fengying Wu, Guanghui Gao, Wei Li, Xiaoxia Chen, Jiayu Li, Fei Zhou, Jing Zhao, Weijing Cai, Henghui Zhang, Bo Du, Jun Zhang, Shengxiang Ren, Caicun Zhou, Hui Yu, Fred R. Hirsch
Journal: Theranostics (2017)

RationaleTo investigate whether the mutational landscape of circulating cell-free DNA (cfDNA) could predict and dynamically monitor the response to first-line platinum-based chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC).Methods Eligible patients were included and blood samples were collected from a phase III trial.Both cfDNA fragments and fragmented genomic DNA were extracted for enrichment in a 1.15M size panel covering exon regions of 1,086 genes.Molecular mutational burden (MMB) was calculated to investigate the relationship between molecular features of cfDNA and response to chemotherapy.Results In total, 52 eligible cases were enrolled and their blood samples were prospectively collected at baseline, every cycle of chemotherapy and time of disease progression.At baseline, alterations of 17 genes were found.Patients with partial response (PR) had significantly lower baseline MMB of these genes than those patients with either stable disease (SD) (P = 0.0006) or progression disease (PD) (P = 0.0074).Further analysis revealed that the mutational landscape of cfDNA from pretreatment blood samples were distinctly different among patients with PR vs. SD/PD.For patients with baseline TP53 mutation, those with PR experienced a significant reduction in MMB whereas patients with SD or PD experienced an increase after two, three or four cycles of chemotherapy.Furthermore, patients with low MMB had superior response rate and significantly longer progression-free survival than those with high MMB.Conclusion This study indicated that the mutational landscape of cfDNA has potential clinical value to predict the therapeutic response to first-line platinum-based doublet chemotherapy in NSCLC patients.At the single gene level, dynamic change of molecular mutational burden of TP53 is valuable to monitor efficacy (and, therefore, might aid in early recognition of resistance and relapse) in patients harboring this mutation at baseline.
Association Between Lead Time and Prostate Cancer Grade: Evidence of Grade Progression from Long-term Follow-up of Large Population-based Cohorts Not Subject to Prostate-specific Antigen Screening
Authors: Melissa Assel, Anders Dahlin, David Ulmert, Anders Bergh, Pär Stattin, Hans Lilja, Andrew J. Vickers
Journal: European Urology (2017)

Lead time (LT) is of key importance in early detection of cancer, but cannot be directly measured. We have previously provided LT estimates for prostate cancer (PCa) using archived blood samples from cohorts followed for many years without screening. To determine the association between LT and PCa grade at diagnosis to provide an insight into whether grade progresses or is stable over time. The setting was three long-term epidemiologic studies in Sweden including men not subject to prostate-specific antigen (PSA) screening. The cohort included 1041 men with PSA of 3–10 ng/ml at blood draw and subsequently diagnosed with PCa with grade data available. Multivariable logistic regression was used to predict high-grade (Gleason grade group ≥2 or World Health Organization grade 3) versus low-grade PCa at diagnosis in terms of LT, defined as the time between the date of elevated PSA and the date of PCa diagnosis with adjustment for cohort and age. The probability that PCa would be high grade at diagnosis increased with LT. Among all men combined, the risk of high-grade disease increased with LT (odds ratio 1.13, 95% confidence interval [CI] 1.10–1.16; p < 0.0001), with no evidence of differences in effect by age group or cohort. Higher PSA predicted shorter LT by 0.46 yr (95% CI 0.28–0.64; p < 0.0001) per 1 ng/ml increase in PSA. However, there was no interaction between PSA and grade, suggesting that the longer LT for high-grade tumors is not simply related to age. Limitations include the assumption that men with elevated PSA and subsequently diagnosed with PCa would have had biopsy-detectable PCa at the time of PSA elevation. Our data support grade progression, whereby following a prostate over time would reveal transitions from benign to low-grade and then high-grade PCa. Men with a longer lead time between elevated prostate-specific antigen and subsequent prostate cancer diagnosis were more likely to have high-grade cancers at diagnosis.
Naming disease states for clinical utility in prostate cancer: a rose by any other name might not smell as sweet
Authors: A.J. Armstrong, E.S. Antonarakis, M.-E. Taplin, W.K. Kelly, H. Beltran, K. Fizazi, W.L. Dahut, N. Shore, S. Slovin, D. George, M.A. Carducci, P. Corn, D. Danila, R. Dreicer, E. Heath, D. Rathkopf, G. Liu, D. Nanus, M. Stein, M.R. Smith, C. Sternberg, G. Wilding, P.S. Nelson, S. Halabi, P. Kantoff, N.W. Clarke, C.P. Evans, A. Heidenreich, N. Mottet, M. Gleave, M.J. Morris, H.I. Scher
Journal: Annals of Oncology (2017)
Amoxicillin for acute lower respiratory tract infection in primary care: subgroup analysis by bacterial and viral aetiology
Authors: R. Bruyndonckx, B. Stuart, P. Little, N. Hens, M. Ieven, C.C. Butler, T. Verheij, H. Goossens, S. Coenen, J. Almirall, C. Brugman, S. Chlabicz, A. De Sutter, M. Davies, M. Godycki-Cwirko, P. Fernandez, I. Hering, K. Hood, G.I.T. Schaberg, A. Torres, A. Kowalczyk, C. Lammens, M. Lemiengre, F. Leus, K. Loens, A. Mierzecki, M. Moore, M. Muras, G. O'Reilly, N.S. Romano, M.S. Prat, J. Swain, R. Veen, T. Worby
Journal: Clinical Microbiology and Infection (2017)
Evaluation and Management of Lower-Extremity Ulcers
Authors: Adam J. Singer, Apostolos Tassiopoulos, Robert S. Kirsner
Journal: New England Journal of Medicine (2017)

Even with the best available care, at least 25% of leg ulcers and foot ulcers are not fully healed after 6 months of treatment. This review summarizes the pathophysiological features and explains current management of venous, arterial, neuropathic diabetic, and pressure ulcers.
Bioradiotherapy for head and neck cutaneous squamous cell carcinoma.
Authors: Joshua David Palmer, Jon Strasser, Alexandra Hanlon, Elizabeth A Mauer, Michael Dzeda, Neil Hockstein, Robert Witt, Charles Schneider, Adam Raben
Journal: Journal of Clinical Oncology (2015)

6038 Background: Locally advanced, high-risk head and neck cutaneous squamous cell carcinomas (CSCC) are typically aggressive. We sought to compare treatment tolerability, disease control and survival between radiotherapy alone and radiotherapy plus cetuximab in CSCC patients. Methods: Patients diagnosed with high-risk CSCC based on NCCN criteria between 2006-2013 were included. Patients were divided into two groups: radiotherapy alone versus radiotherapy plus cetuximab. Primary analysis examined disease-free and overall survival, freedom from local and distant recurrence in the propensity score matched cohort. Propensity score analysis was performed with weighted factors including: Charlson Comorbidity Index score (age-adjusted), age. KPS, primary location, T and N stage, recurrent status, margin status, LVSI, PNI and grade. Toxicity was assessed using the CTCAE v4.0. Results: Among 68 patients meeting study criteria, we identified 29 treated with cetuximab plus RT and 39 with RT alone. Median follow-up for living patients was 30 months. Patients in the cetuximab group were more likely to have advanced N stage, positive margins and recurrent disease. After propensity score matching the groups were well balanced. OS and DFS were not statistically significant between the two groups but there were 37% more survivors free of disease in the cetuximab group. Loco-regional control was 77% and 54% in the cetuximab and radiation alone groups, respectively. The rate of distant metastases was lower in the cetuximab group 6.8% versus 17%. The incidence of grade 2-3 toxicity was 41% in the cetuximab group. There was one grade 3 cetuximab acneiform rash, one grade 4 dysphagia and no grade 5 toxicity. Conclusions: Although limited by small numbers; this therapy was well tolerated and there were more long-term survivors as well as less distant metastasis in the cetuximab group. This is the largest known report of CSCC patients treated with radiotherapy and cetuximab. These promising findings warrant further studies to establish the benefit of combined cetuximab and radiation in head and neck CSCC. Disease-free survival by year in propensity score adjusted cohorts. Years: 1 2 3 4 5 Weighted Cetuximab 86% 72% 72% 66% 66% No Cetuximab 77% 53% 43% 39% 29%
Phase II study of nab-paclitaxel in refractory small bowel adenocarcinoma and CpG island methylator phenotype (CIMP)-high colorectal cancer
Authors: M.J. Overman, L. Adam, K. Raghav, J. Wang, B. Kee, D. Fogelman, C. Eng, E. Vilar, R. Shroff, A. Dasari, R. Wolff, J. Morris, E. Karunasena, R. Pisanic, N. Azad, S. Kopetz
Journal: Annals of Oncology (2017)
Air pollution exposure and IPF: prevention when there is no cure
Authors: Kerri A Johannson
Journal: Thorax (2017)

The clinical management of idiopathic pulmonary fibrosis (IPF) is challenging. For patients with a progressive disease with no known cure, realistic goals include slowing the rate of disease progression, optimising comorbidities and functional status, managing symptoms, and preventing what is preventable. The latter is short however, mainly including smoking cessation and infection prevention measures. Despite adherence to recommended management, most patients deteriorate over time, with some experiencing acute exacerbation (AE), and the majority dying due to their IPF.1 Identifying modifiable risk factors that limit disease progression or death could change clinical practice, offering preventative tools with which to achieve the goal of improving patient quality and quantity of life.

Air pollution exposure is ubiquitous and a well-established risk factor for a wide range of adverse health outcomes including cardiovascular disease and all-cause mortality.2–4 Arguably the most common target is the respiratory system, given its exposure to the inhaled environment. Indeed, air pollution exposures are associated with increased risk of developing and exacerbating airway diseases, bronchiolitis obliterans post lung transplant, as well as being diagnosed with and dying from lung cancer.5–11 IPF was a relative latecomer to the world of air pollution epidemiology, although a number of plausible mechanisms exist to suggest a relationship.12 While it is unlikely that air pollution is the sole driver of disease, it may represent one form of environmental insult that precipitates or accelerates fibrosis in an already vulnerable lung.

In Thorax , Sese and colleagues contribute novel data to a growing body of literature …
R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease
Authors: Eiko Hayase, Daigo Hashimoto, Kiminori Nakamura, Clara Noizat, Reiki Ogasawara, Shuichiro Takahashi, Hiroyuki Ohigashi, Yuki Yokoi, Rina Sugimoto, Satomi Matsuoka, Takahide Ara, Emi Yokoyama, Tomohiro Yamakawa, Ko Ebata, Takeshi Kondo, Rina Hiramine, Tomoyasu Aizawa, Yoshitoshi Ogura, Tetsuya Hayashi, Hiroshi Mori, Ken Kurokawa, Kazuma Tomizuka, Tokiyoshi Ayabe, Takanori Teshima
Journal: The Journal of Experimental Medicine (2017)

The intestinal microbial ecosystem is actively regulated by Paneth cell-derived antimicrobial peptides such as α-defensins. Various disorders, including graft-versus-host disease (GVHD), disrupt Paneth cell functions, resulting in unfavorably altered intestinal microbiota (dysbiosis), which further accelerates the underlying diseases. Current strategies to restore the gut ecosystem are bacteriotherapy such as fecal microbiota transplantation and probiotics, and no physiological approach has been developed so far. In this study, we demonstrate a novel approach to restore gut microbial ecology by Wnt agonist R-Spondin1 (R-Spo1) or recombinant α-defensin in mice. R-Spo1 stimulates intestinal stem cells to differentiate to Paneth cells and enhances luminal secretion of α-defensins. Administration of R-Spo1 or recombinant α-defensin prevents GVHD-mediated dysbiosis, thus representing a novel and physiological approach at modifying the gut ecosystem to restore intestinal homeostasis and host-microbiota cross talk toward therapeutic benefits.
Updated Guidelines for Metastatic Hormone-sensitive Prostate Cancer: Abiraterone Acetate Combined with Castration Is Another Standard
Authors: Nicolas Mottet, Maria De Santis, Erik Briers, Liam Bourke, Silke Gillessen, Jeremy P. Grummet, Thomas B. Lam, Henk G. van der Poel, Olivier Rouvière, Roderick C.N. van den Bergh, Philip Cornford
Journal: European Urology (2017)
TAS 102 in refractory metastatic colorectal cancer: UK Expanded Access Programme experience.
Authors: Ciara O'Brien, Sophia Callaghan, George Papaxoinis, James Bennett, Chern Siang Lee, Rhiannon Mai Evans, Tim Iveson, Richard Adams, Saifee Mullamitha
Journal: Journal of Clinical Oncology (2017)

e15043 Background: Trifluridine/tipiracil (TAS-102), an oral combination of a nucleoside analogue and thymidine phosphorylase inhibitor, showed significant survival benefit in the RECOURSE study. We assessed TAS-102 clinical activity in an unselected patient population with refractory metastatic colorectal cancer in the UK Expanded Access Programme (EAP). Methods: Pharmacy databases were used to identify patients treated with TAS-102 on the UK EAP at three tertiary referral Cancer Centres (Manchester, Cardiff and Southampton) between December 2015 and December 2016. Case notes, laboratory tests and histopathology were reviewed to ascertain survival data and prognostic variables. Results: Of the 78 patients treated with TAS-102, median ECOG PS was 1, 56% of patients were male and median age was 64 years (range 27- 80 years). 31 patients had 3 or more metastatic sites of disease. 26 patients were RAS mutant and 1 patient was B-RAFmutant. Median number of cycles of TAS-102 was 2 cycles (range 1-11 cycles) with one third of patients requiring a dose reduction due to toxicity. 39% of patients developed grade 3 or 4 neutropenia and 12% febrile neutropenia. Response assessment was not performed in 12 patients due to death prior to assessment (6 patients) or withdrawal of patient consent for TAS-102 treatment (6 patients). Where best disease response was assessed by RECIST 1.1 criteria, 26.6% patient showed clinical benefit (stable disease or partial response) whereas 73.3% of patients had confirmed progressive disease. Median follow-up period was 5.2 months with 45 deaths in the study period. Median overall survival (OS) was 6.6 months. OS was significantly worse for patients with hypoalbuminemia (Albumin &lt; 30g/dl) at cycle 1 day 1 TAS-102 (p = 0.028). Anaemia, renal or liver impairment and number of metastatic sites of disease had no impact on patient survival. RAS mutant colorectal cancer patients showed a trend to improved outcome on TAS-102 which did not reach statistical significance within the study follow-up period. Conclusions: TAS-102 shows modest clinical benefit in treatment refractory metastatic colorectal cancer patients on the UK expanded access programme.
Zebrafish abcb11b mutant reveals strategies to restore bile excretion impaired by bile salt export pump deficiency
Authors: Jillian L. Ellis, Kevin E. Bove, Erin G. Schuetz, Daniel Leino, C. Alexander Valencia, John D. Schuetz, Alexander Miethke, Chunyue Yin
Journal: Hepatology (2017)

Bile salt export pump (BSEP) adenosine triphosphate–binding cassette B11 (ABCB11) is a liver‐specific ABC transporter that mediates canalicular bile salt excretion from hepatocytes. Human mutations in ABCB11 cause progressive familial intrahepatic cholestasis type 2. Although over 150 ABCB11 variants have been reported, our understanding of their biological consequences is limited by the lack of an experimental model that recapitulates the patient phenotypes. We applied CRISPR/Cas9‐based genome editing technology to knock out abcb11b, the ortholog of human ABCB11, in zebrafish and found that these mutants died prematurely. Histological and ultrastructural analyses showed that abcb11b mutant zebrafish exhibited hepatocyte injury similar to that seen in patients with progressive familial intrahepatic cholestasis type 2. Hepatocytes of mutant zebrafish failed to excrete the fluorescently tagged bile acid that is a substrate of human BSEP. Multidrug resistance protein 1, which is thought to play a compensatory role in Abcb11 knockout mice, was mislocalized to the hepatocyte cytoplasm in abcb11b mutant zebrafish and in a patient lacking BSEP protein due to nonsense mutations in ABCB11. We discovered that BSEP deficiency induced autophagy in both human and zebrafish hepatocytes. Treatment with rapamycin restored bile acid excretion, attenuated hepatocyte damage, and extended the life span of abcb11b mutant zebrafish, correlating with the recovery of canalicular multidrug resistance protein 1 localization. Conclusions: Collectively, these data suggest a model that rapamycin rescues BSEP‐deficient phenotypes by prompting alternative transporters to excrete bile salts; multidrug resistance protein 1 is a candidate for such an alternative transporter. (Hepatology 2018;67:1531‐1545).
O Regresso da Difteria à Europa
Authors: M Rey, O Patey, F Vincent-Ballereau
Journal: Eurosurveillance (1996)

Desde que a vacinacao contra a difteria passou a ser feita por rotina, esta doenca quase desapareceu na maioria dos paises da Europa. Assim, a ocorrencia de um grande surto epidemico de difteria em Estados da antiga URSS, que se tornaram recentemente independentes ­ New Independent States ­ (NIS), constitui um facto totalmente inesperado. Este ressurgimento de casos nos NIS levanta as seguintes questoes:
Cirrhosis of the Liver
Authors: W. H. J. Summerskill, Charles S. Davidson, J. Henry Dible, G. Kenneth Mallory, S. Sherlock, Michael D. Turner, Stanley J. Wolfe
Journal: New England Journal of Medicine (1960)

SINCE Laënnec1 (1869) defined cirrhosis of the liver, it has become apparent that the disease may occur in a variety of clinical and pathological forms. Accepted etiologic factors contribute to hepatic disease in hemochromatosis, Wilson's disease and biliary or cardiac cirrhosis, but the cause of cirrhosis in the majority of patients remains uncertain. A common association of cirrhosis in the Western world is with alcoholism, although the specific effect of alcohol, malnutrition or other factors in its genesis has not been established. Frequently, no accepted clinical relation can account for the presence of cirrhosis, which has therefore been termed "cryptogenic." . . .
Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab
Authors: Koichi Sato, Hiroaki Akamatsu, Eriko Murakami, Atsushi Hayata, Nahomi Tokudome, Keiichiro Akamatsu, Yasuhiro Koh, Hiroki Ueda, Masanori Nakanishi, Nobuyuki Yamamoto
Journal: Annals of Oncology (2017)
TCT-687 Alcohol Ablation and Surgical Myectomy Lead to Excellent Clinical Outcomes When Prescribed According to Consensus Guidelines: A Single Center Experience
Authors: David Zisa, Johny Kuttab, Saleh Alshalash, Carlos Davila, Ethan Rowin, Benjamin Wessler, Martin Maron, Navin Kapur, Andrew Weintraub, Carey Kimmelstiel
Journal: Journal of the American College of Cardiology (2017)