tbuckley/cabot-search huggingface dataset:
A Method to Correct for the Effects of Purifying Selection on Genealogical Inference
Authors: B. D. O'Fallon
Journal: Molecular Biology and Evolution (2010)

Accurate reconstruction of the divergence times among individuals is an essential step toward inferring population parameters from genetic data. However, our ability to reconstruct accurate genealogies is often thwarted by the evolutionary forces we hope to detect, most prominently natural selection. Here, I demonstrate that purifying selection acting at many linked sites can systematically bias current methods of genealogical reconstruction, and I present a new method that corrects for this bias by allowing a class of sites to have a time-dependent rate. The parameters influencing the time dependency can be estimated from the data, allowing for a general method to detect the presence of selected sites and correcting for their distortion of the apparent mutation rate. The method works well under a variety of scenarios, including gamma-distributed selection coefficients as well as entirely neutral evolution. I also compare the performance of the new method to relaxed clock models, and I demonstrate the method on a data set from the mitochondrion of the North Atlantic whale-"louse" Cyamus ovalis.
Prospective Comparison of [<sup>18</sup>F]Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography in Patients With Melanoma With Palpable Lymph Node Metastases: Diagnostic Accuracy and Impact on Treatment
Authors: Esther Bastiaannet, Theo Wobbes, Otto S. Hoekstra, Eric J. van der Jagt, Adrienne H. Brouwers, Ron Koelemij, John M.H. de Klerk, Wim J.G. Oyen, Sybren Meijer, Harald J. Hoekstra
Journal: Journal of Clinical Oncology (2009)

Purpose Patients with melanoma with potentially resectable lymph node metastases require accurate staging to prevent unnecessary surgery. [ 18 F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) is attractive for this because melanoma typically is FDG avid. The aim of this prospective multicenter study was to perform a head-to-head comparison of FDG-PET and computed tomography (CT) in staging of patients with melanoma with palpable lymph node metastases in terms of diagnostic accuracy and impact on treatment. Patients and Methods All consecutive patients with palpable, proven lymph node metastases of melanoma between mid 2003 and 2007 were prospectively included. The number/site of distant metastases detected with FDG-PET and CT were recorded. Histology/cytology or 6 months follow-up were the reference standard. Intended and performed treatment was recorded. Results Distant metastases were suspected by FDG-PET in 32% of the 251 patients and by CT in 29% (P = .26). Upstaging was correct in 27% by FDG-PET and in 24% by CT (P = .18). FDG-PET detected more metastatic sites (133 v 112, P = .03), detecting significantly more bone and subcutaneous metastases. Treatment changed in 19% of patients; in 79% as a result of both scans, in 17% exclusively by FDG-PET, and in 4% exclusively by CT. In 34 patients (14%), FDG-PET had an additional value over spiral CT, and in 23 patients (9%), CT had additional value over FDG-PET. Conclusion As a result of FDG-PET and CT, 27% of patients were upstaged, and treatment changed in one of five patients. FDG-PET and CT are equivalent in upstaging; however, FDG-PET detected more metastatic sites, especially bone and subcutaneous. FDG-PET and/or CT are indicated in the staging of patients with melanoma with palpable lymph node metastases.
Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial
Authors: Noriaki Ohuchi, Akihiko Suzuki, Tomotaka Sobue, Masaaki Kawai, Seiichiro Yamamoto, Ying-Fang Zheng, Yoko Narikawa Shiono, Hiroshi Saito, Shinichi Kuriyama, Eriko Tohno, Tokiko Endo, Akira Fukao, Ichiro Tsuji, Takuhiro Yamaguchi, Yasuo Ohashi, Mamoru Fukuda, Takanori Ishida
Journal: The Lancet (2015)
Predicting the unpredictable: is it possible clinically to separate H1N1 from non-H1N1 community-acquired pneumonia?
Authors: N. Sehgal, M. Woodhead
Journal: Thorax (2011)

In the spring of 2009 a novel influenza A virus (H1N1) of swine origin was identified in the USA and Mexico and rapid spread led to the declaration of a global influenza pandemic by the World Health Organization in June 2009.1 2 The virus, which derives six genes from triple-reassortant North American swine virus lineages and two genes from Eurasian swine virus lineages, predominantly affected children and young adults with a low incidence of acute illness in those over 60 years of age.3 By June 2010, cases had been identified in over 200 countries and territories worldwide and over 18 000 associated deaths were reported.4

Infection with the pandemic virus caused a broad spectrum of clinical disease ranging from acute self-limiting upper respiratory tract illness with fever to fulminant pneumonitis and respiratory failure. Gastrointestinal and CNS symptoms were also common. Rates of admission to ICUs (13–45.3% of patients being hospitalised) were much higher than previously seen with seasonal influenza.5–8 Rapid progression of severe hypoxaemia, typically starting on day 4–5 after the onset of symptoms, was observed with up to 80% of patients admitted to an ICU requiring mechanical ventilation.6 Frequent radiological findings were of diffuse alveolar and interstitial infiltrates, often worse in the lower zones.

A number of risk factors were identified for the development of severe disease including age  65 years, presumably relating to immunity conferred from prior exposure to antigenically-related H1N1 virus in previous outbreaks. Paradoxically, death …
Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: an analysis of 10 549 patients from the International Myeloma Working Group
Authors: Heinz Ludwig, Brian G. M. Durie, Vanessa Bolejack, Ingemar Turesson, Robert A. Kyle, Joan Blade, Rafael Fonseca, Meletios Dimopoulos, Kazuyuki Shimizu, Jesus San Miguel, Jan Westin, Jean-Luc Harousseau, Meral Beksac, Mario Boccadoro, Antonio Palumbo, Bart Barlogie, Chaim Shustik, Michele Cavo, Philip R. Greipp, Douglas Joshua, Michel Attal, Pieter Sonneveld, John Crowley
Journal: Blood (2008)
Tumor necrosis factor in myocardial hypertrophy and ischaemia — an anti-apoptotic perspective
Authors: M Sack
Journal: Cardiovascular Research (2000)

Time for primary review 21 days. 

Tumour necrosis factor-alpha (TNFα) is a multifunctional cytokine that has been implicated as mediator of diverse physiologic and pathophysiologic events. These processes include inflammation, cellular survival, growth, differentiation and apoptosis. The local homeostatic cellular effects of cytokines may be considered ‘autocoid’ in nature. This word is derived from the Greek words autos (‘self’) and akos (‘remedy’), and refers to locally acting, biologically active agents, both peptides and non-peptides, that are distinct from neurotransmitters and hormones [1].

Recent studies have highlighted the pathogenic role of TNFα in the development of myocardial disease, such as the direct correlation between serum TNFα levels and the severity and progression of heart failure [2–4] and the development of myocarditis in mice that overexpress TNFα specifically in the heart [5]. Taken together, these studies suggest that TNFα is a mediator of cardiac pathology, acting at least in part via inflammatory pathways and via the activation of programmed cell death i.e. apoptosis [6,7].

However, in addition to mediating inflammation and apoptosis, cytokines play a critical role in the control and maintenance of signalling pathways that regulate mammalian physiology in multiple organ systems. Specifically in the heart, biomechanical stress promotes endogenous TNFα production by myocytes and non-myocytes. Therefore, as in other organ systems, the question arising is whether TNFα plays an adaptive role in mediating cardiac cell growth and in remodelling the cardiac extracellular matrix in response to biomechanical stress. The hypothesis that TNFα could have a short term adaptive and long term maladaptive role was proposed and reviewed by Mann [8] in 1996. Recent studies support the view that TNFα can have beneficial effects in cardiac homeostasis.

In this mini-review we will focus on the role of TNFα in mediating myocardial cell survival, growth and differentiation as adaptation … 

* Corresponding author. Tel.: +27-21-406-6358; fax: +27-21-447-8789 sack{at}samiot.uct.ac.za
Toward a<i>NOTCH1/FBXW7/RAS/PTEN</i>–Based Oncogenetic Risk Classification of Adult T-Cell Acute Lymphoblastic Leukemia: A Group for Research in Adult Acute Lymphoblastic Leukemia Study
Authors: Amélie Trinquand, Aline Tanguy-Schmidt, Raouf Ben Abdelali, Jérôme Lambert, Kheira Beldjord, Etienne Lengliné, Noémie De Gunzburg, Dominique Payet-Bornet, Ludovic Lhermitte, Hossein Mossafa, Véronique Lhéritier, Jonathan Bond, Françoise Huguet, Agnès Buzyn, Thibaud Leguay, Jean-Yves Cahn, Xavier Thomas, Yves Chalandon, André Delannoy, Caroline Bonmati, Sebastien Maury, Bertrand Nadel, Elizabeth Macintyre, Norbert Ifrah, Hervé Dombret, Vahid Asnafi
Journal: Journal of Clinical Oncology (2013)

Purpose The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. Patients and Methods In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). Results N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P &lt; .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P &lt; .001). Conclusion These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.
Meta-analysis of frusemide to prevent or treat acute renal failure
Authors: K. M Ho
Journal: BMJ (2006)

Use of a placebo control in surgical trials is a divisive issue. We argue that, in principle, placebo controls for surgery are necessary in the same way as for medicine. However, there are important differences between these types of trial, which both increase justification and limit application of surgical studies. We propose that surgical randomised placebo-controlled trials are ethical if certain conditions are fulfilled: (1) the presence of equipoise, defined as a lack of unbiased evidence for efficacy of an intervention; (2) clinically important research question; (3) the risk to patients is minimised and reasonable; (4) there is uncertainty about treatment allocation rather than deception; (5) there is preliminary evidence for efficacy, which justifies a placebo-controlled design; and (6) ideally, the placebo procedure should have some direct benefit to the patient, for example, as a diagnostic tool. Placebo-controlled trials in surgery will most often be justified when surgery is performed to improve function or relieve symptoms and when objective outcomes are not available, while the risk of mortality or significant morbidity is low. In line with medical placebo-controlled trials, the surgical trial (1) should be sufficiently powered and (2) standardised so that its results are valid, (3) consent should be valid, (4) the standard treatment or rescue medication should be provided if possible, and (5) after the trial, the patients should be told which treatment they received and there should be provision for post-trial care if the study may result in long-term negative effects. We comment and contrast our guidelines with those of the American Medical Association.
Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial
Authors: Jean-Charles Soria, Enriqueta Felip, Manuel Cobo, Shun Lu, Konstantinos Syrigos, Ki Hyeong Lee, Erdem Göker, Vassilis Georgoulias, Wei Li, Dolores Isla, Salih Z Guclu, Alessandro Morabito, Young J Min, Andrea Ardizzoni, Shirish M Gadgeel, Bushi Wang, Vikram K Chand, Glenwood D Goss
Journal: The Lancet Oncology (2015)
Molecular and Physiological Effects of α-Tropomyosin Ablation in the Mouse
Authors: Prabhakar Rethinasamy, Mariappan Muthuchamy, Tim Hewett, Greg Boivin, Beata M. Wolska, Christian Evans, R. John Solaro, David F. Wieczorek
Journal: Circulation Research (1998)

Abstract —Tropomyosin (TM) is an integral component of the thin filament in muscle fibers and is involved in regulating actin-myosin interactions. TM is encoded by a family of four alternatively spliced genes that display highly conserved nucleotide and amino acid sequences. To assess the functional and developmental significance of α-TM, the murine α-TM gene was disrupted by homologous recombination. Homozygous α-TM null mice are embryonic lethal, dying between 8 and 11.5 days post coitum. Mice that are heterozygous for α-TM are viable and reproduce normally. Heterozygous knockout mouse hearts show a 50% reduction in cardiac muscle α-TM mRNA, with no compensatory increase in transcript levels by striated muscle β-TM or TM-30 isoforms. Surprisingly, this reduction in α-TM mRNA levels in heterozygous mice is not reflected at the protein level, where normal amounts of striated muscle α-TM protein are produced and integrated in the myofibril. Quantification of α-TM mRNA bound in polysomal fractions reveals that both wild-type and heterozygous knockout animals have similar levels. These data suggest that a change in steady-state level of α-TM mRNA does not affect the relative amount of mRNA translated and amount of protein synthesized. Physiological analyses of myocardial and myofilament function show no differences between heterozygous α-TM mice and control mice. The present study suggests that translational regulation plays a major role in the control of TM expression.
Placebo Response in Randomized Controlled Trials of Antidepressants for Pediatric Major Depressive Disorder
Authors: Jeffrey A. Bridge, Boris Birmaher, Satish Iyengar, Rémy P. Barbe, David A. Brent
Journal: American Journal of Psychiatry (2008)

The authors examined characteristics and predictors of response to placebo in all available reports of short-term randomized controlled trials of antidepressants for pediatric major depressive disorder.Response, defined as a score <or=2 on the improvement item of the Clinical Global Impression scale, and potential predictors were extracted from 12 published and unpublished randomized controlled trials of second-generation antidepressants in participants 6-18 years of age with major depression.The single best predictor of the proportion of patients taking placebo who responded to treatment was the number of study sites. Baseline severity of illness also emerged as a significant inverse predictor of placebo response, although the strength of this relationship was diminished when number of sites was controlled for. After one large fluoxetine trial was excluded, younger participants showed a higher placebo response rate than older adolescents. Higher placebo response rates in more recent studies were explained by an increasing trend toward large multisite trials and by publication delays and failures to publish some negative trials.The recent shift toward large multisite trials of antidepressant medications for pediatric major depression may be contributing to an increasing incidence of response to placebo. Pharmacotherapy studies of pediatric depression that carefully recruit patients with at least moderately severe depression may be more informative and efficient than many trials conducted to date. Such studies should have sufficient power to determine whether age moderates medication and placebo response.
Anti-TNF and skin inflammation in IBD: a new paradox in gastroenterology?
Authors: Jan Hendrik Niess, Silvio Danese
Journal: Gut (2013)

Tumour necrosis factor-α (TNF-α) is a proinflammatory cytokine with a key role in inducing the inflammatory response to injuries. While its role in triggering inflammation has been clearly established, some TNF-α-mediated pathways remain unknown.1 Pharmacological blockade of TNF-α with selective monoclonal antibodies has revolutionised the management of patients with immune-mediated inflammatory disorders (IMIDs).2 However, inflammatory bowel disease (IBD) patients treated with anti-TNF agents can paradoxically experience other IMIDs, including inflammatory skin lesions, joint lesions and sarcoidosis.3 ,4 In most patients, symptoms included morning stiffness and pain in the hands and wrists, without signs of arthritis with synovitis and an association with high titres of antinuclear antibodies (ANAs; >1:280) has been reported.5

The anti-TNF-α agents have been associated with the onset of eczematiform and psoriasiform skin eruptions.6 The association of xerosis and pruriginous ill-limited plaques with erythematous or squamous vesicles characterises the eczema-like lesions developing with such treatment, while the psoriasiform eruptions are characterised by scaly erythematous plaques and pustolosis with eventual nail involvement (figure 1). Psoriasiform lesions in patients receiving anti-TNF-α agents can be considered paradoxical, as these agents are used to treat psoriasis.7



Figure 1 
A 32-year-old Crohn's disease patient developed psoriasis after nine infusions of scheduled infliximab treatment at the dose of 5 mg/kg.



A 2008 systematic review identified all cases of TNF-α-antagonist-induced psoriasis within the literature, revealing more than 110 reports of patients developing new-onset psoriasis while receiving …
A Prospective Study of Aspirin Use and the Risk of Pancreatic Cancer in Women
Authors: E. S. Schernhammer, J.-H. Kang, A. T. Chan, D. S. Michaud, H. G. Skinner, E. Giovannucci, G. A. Colditz, C. S. Fuchs
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: In vitro experiments and limited animal studies suggest that aspirin and nonsteroidal anti-inflammatory drugs may inhibit pancreatic carcinogenesis. Because few studies have examined the association between aspirin use and pancreatic cancer in humans and the results have been inconsistent, we examined the relationship between aspirin use and the development of pancreatic cancer in the Nurses' Health Study. Methods: Among 88 378 women without cancer at baseline, we documented 161 cases of pancreatic cancer during 18 years of follow-up. Aspirin use was first assessed at baseline in 1980 and updated biennially thereafter. All statistical tests were two-sided. Results: Participants were classified according to history of aspirin use. In a multivariable analysis, the risk of pancreatic cancer was not associated with current regular aspirin use (defined as two or more standard tablets per week; relative risk [RR] = 1.20, 95% confidence interval [CI] = 0.87 to 1.65), compared with use of fewer than two tablets per week. Increasing duration of regular aspirin use, compared with non-use, was associated with a statistically significant increase in risk: Women who reported more than 20 years of regular aspirin use had an increased risk of pancreatic cancer (RR = 1.58, 95% CI = 1.03 to 2.43; Ptrend = .01). Among women who reported aspirin use on at least two of three consecutive biennial questionnaires compared with consistent non-users of aspirin, the risk increased with dose (one to three tablets per week: RR = 1.11, 95% CI = 0.70 to 1.76; four to six tablets per week: RR = 1.29, 95% CI = 0.70 to 2.40; seven to 13 tablets per week: RR = 1.41, 95% CI = 0.76 to 2.61; and ≥14 tablets per week: RR = 1.86, 95% CI = 1.03 to 3.35) (Ptrend = .02). Conclusion: Extended periods of regular aspirin use appear to be associated with a statistically significantly increased risk of pancreatic cancer among women.
Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial
Authors: Jan B Vermorken, Anke ME Claessen, Harm van Tinteren, Helen E Gall, Renate Ezinga, Sybren Meijer, Rik J Scheper, Chris JLM Meijer, Elizabeth Bloemena, Janet H Ransom, Michael G Hanna, Herbert M Pinedo
Journal: The Lancet (1999)
ChromEvol: Assessing the Pattern of Chromosome Number Evolution and the Inference of Polyploidy along a Phylogeny
Authors: Lior Glick, Itay Mayrose
Journal: Molecular Biology and Evolution (2014)

We announce the release of chromEvol version 2.0, a software tool for inferring the pattern of chromosome number change along a phylogeny. The software facilitates the inference of the expected number of polyploidy and dysploidy transitions along each branch of a phylogeny and estimates ancestral chromosome numbers at internal nodes. The new version features a novel extension of the model accounting for general multiplication events, other than doubling of the number of chromosomes. This allows the monoploid number (commonly referred to as x, or the base-number) of a group of interest to be inferred in a statistical framework. In addition, we devise an inference scheme, which allows explicit categorization of each terminal taxon as either diploid or polyploid. The new version also supports intraspecific variation in chromosome number and allows hypothesis testing regarding the root chromosome number. The software, alongside a detailed usage manual, is available at http://www.tau.ac.il/∼itaymay/cp/chromEvol/.
Different management for Helicobacter pylori positive and negative patients with gastro-oesophageal reflux disease?
Authors: J M Lee, C A O'Morain
Journal: Gut (1998)

Available evidence would suggest that Helicobacter pylori infection does not contribute to the pathogenesis of gastro-oesophageal reflux disease.The prevalence of H pylori infection in patients with reflux disease is no greater than that in control populations.There are some data suggesting that the organism has a protective role: patients with duodenal ulcers develop reflux disease after H pylori eradication, whereas in patients with oesophageal reflux those with H pylori infection have less severe reflux changes.There is also evidence indicating that the presence of H pylori augments the anti-secretory properties of both the H 2 receptor antagonists and proton pump inhibitors (PPIs), suggesting that eradication therapy may not be beneficial.However, the considerable recent interest in the association between H pylori and reflux disease has largely been generated by studies outlining the interactions between H pylori infection and acid suppression in the long term.In H pylori positive patients, therapy with PPIs is associated with a proximal extension of the infection and its associated gastritis.In addition long term PPI therapy is reported to be associated with an accelerated development of atrophic gastritis, suggesting that H pylori should be diagnosed and treated.Although these latter findings in particular need confirmation, H pylori eradication therapy should be considered in this patient group, at least until there is evidence to the contrary.