tbuckley/cabot-search huggingface dataset:
Non-invasive risk scores for prediction of type 2 diabetes (EPIC-InterAct): a validation of existing models
Authors: Andre Pascal Kengne, Joline WJ Beulens, Linda M Peelen, Karel GM Moons, Yvonne T van der Schouw, Matthias B Schulze, Annemieke MW Spijkerman, Simon J Griffin, Diederick E Grobbee, Luigi Palla, Maria-Jose Tormo, Larraitz Arriola, Noël C Barengo, Aurelio Barricarte, Heiner Boeing, Catalina Bonet, Françoise Clavel-Chapelon, Laureen Dartois, Guy Fagherazzi, Paul W Franks, José María Huerta, Rudolf Kaaks, Timothy J Key, Kay Tee Khaw, Kuanrong Li, Kristin Mühlenbruch, Peter M Nilsson, Kim Overvad, Thure F Overvad, Domenico Palli, Salvatore Panico, J Ramón Quirós, Olov Rolandsson, Nina Roswall, Carlotta Sacerdote, María-José Sánchez, Nadia Slimani, Giovanna Tagliabue, Anne Tjønneland, Rosario Tumino, Daphne L van der A, Nita G Forouhi, Stephen J Sharp, Claudia Langenberg, Elio Riboli, Nicholas J Wareham
Journal: The Lancet Diabetes & Endocrinology (2013)

BackgroundThe comparative performance of existing models for prediction of type 2 diabetes across populations has not been investigated. We validated existing non-laboratory-based models and assessed variability in predictive performance in European populations.MethodsWe selected non-invasive prediction models for incident diabetes developed in populations of European ancestry and validated them using data from the EPIC-InterAct case-cohort sample (27 779 individuals from eight European countries, of whom 12 403 had incident diabetes). We assessed model discrimination and calibration for the first 10 years of follow-up. The models were first adjusted to the country-specific diabetes incidence. We did the main analyses for each country and for subgroups defined by sex, age (<60 years vs ≥60 years), BMI (<25 kg/m2 vs ≥25 kg/m2), and waist circumference (men <102 cm vs ≥102 cm; women <88 cm vs ≥88 cm).FindingsWe validated 12 prediction models. Discrimination was acceptable to good: C statistics ranged from 0·76 (95% CI 0·72–0·80) to 0·81 (0·77–0·84) overall, from 0·73 (0·70–0·76) to 0·79 (0·74–0·83) in men, and from 0·78 (0·74–0·82) to 0·81 (0·80–0·82) in women. We noted significant heterogeneity in discrimination (pheterogeneity<0·0001) in all but one model. Calibration was good for most models, and consistent across countries (pheterogeneity>0·05) except for three models. However, two models overestimated risk, DPoRT by 34% (95% CI 29–39%) and Cambridge by 40% (28–52%). Discrimination was always better in individuals younger than 60 years or with a low waist circumference than in those aged at least 60 years or with a large waist circumference. Patterns were inconsistent for BMI. All models overestimated risks for individuals with a BMI of <25 kg/m2. Calibration patterns were inconsistent for age and waist-circumference subgroups.InterpretationExisting diabetes prediction models can be used to identify individuals at high risk of type 2 diabetes in the general population. However, the performance of each model varies with country, age, sex, and adiposity.FundingThe European Union.
IL-21–induced Bε cell apoptosis mediated by natural killer T cells suppresses IgE responses
Authors: Michishige Harada, Kumiko Magara-Koyanagi, Hiroshi Watarai, Yuko Nagata, Yasuyuki Ishii, Satoshi Kojo, Shigetoshi Horiguchi, Yoshitaka Okamoto, Toshinori Nakayama, Nobutaka Suzuki, Wen-Chen Yeh, Shizuo Akira, Hiroshi Kitamura, Osamu Ohara, Ken-ichiro Seino, Masaru Taniguchi
Journal: The Journal of Experimental Medicine (2006)

Epidemiological studies have suggested that the recent increase in the incidence and severity of immunoglobulin (Ig)E-mediated allergic disorders is inversely correlated with Mycobacterium bovis bacillus Calmette Guerin (BCG) vaccination; however, the underlying mechanisms remain uncertain. Here, we demonstrate that natural killer T (NKT) cells in mice and humans play a crucial role in the BCG-induced suppression of IgE responses. BCG-activated murine Vα14 NKT cells, but not conventional CD4 T cells, selectively express high levels of interleukin (IL)-21, which preferentially induces apoptosis in Bε cells. Signaling from the IL-21 receptor increases the formation of a complex between Bcl-2 and the proapoptotic molecule Bcl-2–modifying factor, resulting in Bε cell apoptosis. Similarly, BCG vaccination induces IL-21 expression by human peripheral blood mononuclear cells (PBMCs) in a partially NKT cell–dependent fashion. BCG-activated PBMCs significantly reduce IgE production by human B cells. These findings provide new insight into the therapeutic effect of BCG in allergic diseases.
The Glu228Ala polymorphism in the ligand-binding domain of death receptor 4 is not associated with rheumatoid arthritis
Authors: B Yazdani-Biuki, K Brickmann, U Langsenlehner, W Renner, M Truschnig, P Krippl, F Furst, W B Graninger, H-P Brezinschek
Journal: Annals of the Rheumatic Diseases (2008)

Rheumatoid arthritis (RA) is a chronic inflammatory disease resulting in inflammation of the synovial lining and destruction of the adjacent bone and cartilage. Although the initiating event of RA is still unknown, recent research has demonstrated the importance of the increased production of tumour necrosis factor (TNF) α in the perpetuation of the inflammatory process of this disease. Targeting this molecule with soluble receptors—that is, etanercept, or antibodies, like infliximab or adalimumab, a new class of highly effective antirheumatic drugs has been developed. Unfortunately, not all patients respond sufficiently to TNF blockade or become unresponsive, and therefore …
Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus
Authors: A Doria
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objective:</b> To evaluate traditional and non-traditional risk factors for subclinical atherosclerosis in systemic lupus erythematosus (SLE). <b>Methods:</b> A prospective cohort of 78 patients with SLE without overt atherosclerotic disease was studied. SLE clinical and laboratory parameters, disease activity and damage, treatment and traditional risk factors for atherosclerosis were evaluated. At baseline (T1) and after five years' follow up (T2), the serum levels of anti-oxidised palmitoyl arachidonoyl phosphocholine (oxPAPC), anti-heat shock protein 65, and anti-β<sub>2</sub>-glycoprotein I antibodies and C reactive protein were tested. At T2, intima-media thickness (IMT) was measured using duplex carotid sonography. Thickened intima, plaque, mean IMT (m-IMT), and maximum IMT (M-IMT) were assessed. <b>Results:</b> A thickened intima was seen in 22/78 (28%) patients and plaque in 13/78 (17%). M-IMT and m-IMT were (mean (SD)) 0.77 (0.34) mm and 0.55 (0.15) mm, respectively. Patients with carotid abnormalities were significantly older, had higher blood pressure and total serum cholesterol levels, and had taken a higher prednisone cumulative dosage than those without any lesions. The carotid abnormalities were associated with renal disease and ECLAM &gt;2 at T1, and with azathioprine treatment. In multivariate analysis, age and cumulative prednisone dose were associated with carotid abnormalities; age, hypertension, and anti-oxPAPC at T2 were correlated with higher M-IMT and m-IMT. <b>Conclusions:</b> In patients with SLE some non-traditional risk factors for atherosclerosis were identified, the most important of which was the cumulative prednisone dose. The role of some traditional risk factors, such as age and hypertension, was also confirmed. The predictive value of the new immunological and inflammatory markers of atherosclerosis seems to be masked by some disease related features.
Normalization of two-channel microarrays accounting for experimental design and intensity-dependent relationships
Authors: Alan R Dabney, John D Storey
Journal: Genome biology (2007)

In normalizing two-channel expression arrays, the ANOVA approach explicitly incorporates the experimental design in its model, and the MA plot-based approach accounts for intensity-dependent biases. However, both approaches can lead to inaccurate normalization in fairly common scenarios. We propose a method called efficient Common Array Dye Swap (eCADS) for normalizing two-channel microarrays that accounts for both experimental design and intensity-dependent biases. Under reasonable experimental designs, eCADS preserves differential expression relationships and requires only a single array per sample pair.
Phase II Randomized Comparison of Topotecan Plus Cyclophosphamide Versus Topotecan Alone in Children With Recurrent or Refractory Neuroblastoma: A Children's Oncology Group Study
Authors: Wendy B. London, Christopher N. Frantz, Laura A. Campbell, Robert C. Seeger, Babette A. Brumback, Susan L. Cohn, Katherine K. Matthay, Robert P. Castleberry, Lisa Diller
Journal: Journal of Clinical Oncology (2010)

Purpose Single-agent topotecan (TOPO) and combination topotecan and cyclophosphamide (TOPO/CTX) were compared in a phase II randomized trial in relapsed/refractory neuroblastoma. Because responders often underwent further therapies, novel statistical methods were required to compare the long-term outcome of the two treatments. Patients and Methods Children with refractory/recurrent neuroblastoma (only one prior aggressive chemotherapy regimen) were randomly assigned to daily 5-day topotecan (2 mg/m 2 ) or combination topotecan (0.75 mg/m 2 ) and cyclophosphamide (250 mg/m 2 ). A randomized two-stage group sequential design enrolled 119 eligible patients. Toxicity and response were estimated. Long-term outcome of protocol therapy was assessed using novel methods—causal inference—which allowed adjustment for the confounding effect of off-study therapies. Results Seven more responses were observed for TOPO/CTX (complete response [CR] plus partial response [PR], 18 [32%] of 57) than TOPO (CR+PR, 11 [19%] of 59;P = .081); toxicity was similar. At 3 years, progression-free survival (PFS) and overall survival (OS) were 4% ± 2% and 15% ± 4%, respectively. PFS was significantly better for TOPO/CTX (P = .029); there was no difference in OS. Older age at diagnosis and lack of MYCN amplification predicted increased OS (P &lt; .05). Adjusting for randomized treatment effect and subsequent autologous stem-cell transplantation, there was no difference between TOPO and TOPO/CTX in terms of the proportion alive at 2 years. Conclusion TOPO/CTX was superior to TOPO in terms of PFS, but there was no OS difference. After adjustment for subsequent therapies, no difference was detected in the proportion alive at 2 years. Causal inference methods for assessing long-term outcomes of phase II therapies after subsequent treatment can elucidate effects of initial therapies.
Prognostic Significance of the European LeukemiaNet Standardized System for Reporting Cytogenetic and Molecular Alterations in Adults With Acute Myeloid Leukemia
Authors: Krzysztof Mrózek, Guido Marcucci, Deedra Nicolet, Kati S. Maharry, Heiko Becker, Susan P. Whitman, Klaus H. Metzeler, Sebastian Schwind, Yue-Zhong Wu, Jessica Kohlschmidt, Mark J. Pettenati, Nyla A. Heerema, AnneMarie W. Block, Shivanand R. Patil, Maria R. Baer, Jonathan E. Kolitz, Joseph O. Moore, Andrew J. Carroll, Richard M. Stone, Richard A. Larson, Clara D. Bloomfield
Journal: Journal of Clinical Oncology (2012)

To evaluate the prognostic significance of the international European LeukemiaNet (ELN) guidelines for reporting genetic alterations in acute myeloid leukemia (AML).We analyzed 1,550 adults with primary AML, treated on Cancer and Leukemia Group B first-line trials, who had pretreatment cytogenetics and, for cytogenetically normal patients, mutational status of NPM1, CEBPA, and FLT3 available. We compared complete remission (CR) rates, disease-free survival (DFS), and overall survival (OS) among patients classified into the four ELN genetic groups (favorable, intermediate-I, intermediate-II, adverse) separately for 818 younger (age < 60 years) and 732 older (age ≥ 60 years) patients.The percentages of younger versus older patients in the favorable (41% v 20%; P < .001), intermediate-II (19% v 30%; P < .001), and adverse (22% v 31%; P < .001) genetic groups differed. The favorable group had the best and the adverse group the worst CR rates, DFS, and OS in both age groups. Both intermediate groups had significantly worse outcomes than the favorable but better than the adverse group. Intermediate-I and intermediate-II groups in older patients had similar outcomes, whereas the intermediate-II group in younger patients had better OS but not better CR rates or DFS than the intermediate-I group. The prognostic significance of ELN classification was confirmed by multivariable analyses. For each ELN group, older patients had worse outcomes than younger patients.The ELN classification clearly separates the genetic groups by outcome, supporting its use for risk stratification in clinical trials. Because they have different proportions of genetic alterations and outcomes, younger and older patients should be reported separately when using the ELN classification.
Prognosis and Gene Expression Profiling of 20q13-Amplified Breast Cancers
Authors: Christophe Ginestier, Nathalie Cervera, Pascal Finetti, Séverine Esteyries, Benjamin Esterni, José Adélaïde, Luc Xerri, Patrice Viens, Jocelyne Jacquemier, Emmanuelle Charafe-Jauffret, Max Chaffanet, Daniel Birnbaum, François Bertucci
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Amplification of chromosomal region 20q13 occurs in breast cancer but remains poorly characterized. Experimental Design: To establish the frequency of 20q13 amplification and select the amplified cases to be studied, we used fluorescence in situ hybridization of bacterial artificial chromosome probes for three 20q13 loci (MYBL2, STK6, ZNF217) on sections of tissue microarrays containing 466 primary carcinoma samples. We used Affymetryx whole-genome DNA microarrays to establish the gene expression profiles of 20q13-amplified tumors and quantitative reverse transcription-PCR to validate the results. Results: We found 36 (8%) 20q13-amplified samples. They were distributed in two types: type 1 tumors showed ZNF217 amplification only, whereas type 2 tumors showed amplification at two or three loci. Examination of the histoclinical features of the amplified tumors showed two strikingly opposite data. First, type 1 tumors were more frequently lymph node–negative tumors but were paradoxically associated with a poor prognosis. Second, type 2 tumors were more frequently lymph node–positive tumors but were paradoxically associated with a good prognosis. Type 1 and type 2 showed different gene expression profiles. No 20q13 gene could be associated with type 1 amplification, whereas several 20q13 genes were overexpressed in type 2 tumors. Conclusions: Our results suggest that amplified tumors of types 1 and 2 are two distinct entities resulting from two different mechanisms and associated to different prognosis.
Physical activity as medicine: time to translate evidence into clinical practice
Authors: Mai-Lis Hellénius, Carl Johan Sundberg
Journal: British Journal of Sports Medicine (2011)

Follow-up investigations of large cohorts of men and women in USA demonstrate that a low cardiorespiratory fitness constitutes the largest attributable fraction for all cause death.1 These findings are highly relevant for a majority of populations all over the world. Sedentary lifestyle is a dangerous modern health threat. Physical inactivity is linked to almost all common health problems including cardiovascular diseases, type II diabetes, obesity/overweight, cancer, dementia and depression. Furthermore, the great value of physical activity in the prevention and treatment of disease has been proven over recent years. Physical activity is essential for improved health as well as for longevity. The last decade has also provided strong data that counselling on physical activity in healthcare is effective. A systematic literature review concluded that …
The genomic landscape shaped by selection on transposable elements across 18 mouse strains
Authors: Christoffer Nellåker, Thomas M Keane, Binnaz Yalcin, Kim Wong, Avigail Agam, T Grant Belgard, Jonathan Flint, David J Adams, Wayne N Frankel, Chris P Ponting
Journal: Genome biology (2012)

Abstract Background Transposable element (TE)-derived sequence dominates the landscape of mammalian genomes and can modulate gene function by dysregulating transcription and translation. Our current knowledge of TEs in laboratory mouse strains is limited primarily to those present in the C57BL/6J reference genome, with most mouse TEs being drawn from three distinct classes, namely short interspersed nuclear elements (SINEs), long interspersed nuclear elements (LINEs) and the endogenous retrovirus (ERV) superfamily. Despite their high prevalence, the different genomic and gene properties controlling whether TEs are preferentially purged from, or are retained by, genetic drift or positive selection in mammalian genomes remain poorly defined. Results Using whole genome sequencing data from 13 classical laboratory and 4 wild-derived mouse inbred strains, we developed a comprehensive catalogue of 103,798 polymorphic TE variants. We employ this extensive data set to characterize TE variants across the Mus lineage, and to infer neutral and selective processes that have acted over 2 million years. Our results indicate that the majority of TE variants are introduced though the male germline and that only a minority of TE variants exert detectable changes in gene expression. However, among genes with differential expression across the strains there are twice as many TE variants identified as being putative causal variants as expected. Conclusions Most TE variants that cause gene expression changes appear to be purged rapidly by purifying selection. Our findings demonstrate that past TE insertions have often been highly deleterious, and help to prioritize TE variants according to their likely contribution to gene expression or phenotype variation.
Release and re-hook: a novel method with combined use of clips and nylon snare to close a colonic defect after endoscopic mucosal resection
Authors: Hrvoje Ivekovic, Dejan Vrzic, Branko Bilic, Nadan Rustemovic, Rajko Ostojic
Journal: Endoscopy (2015)

A 67-year-old man presented to our department for a screening colonoscopy, during which a 2-cm type IIa nonpolypoid lesion was found in the ascending colon ([Fig. 1 a]). After submucosal injection (saline with methylene blue) and adequate lifting of the lesion, a single-piece endoscopic mucosal resection (EMR) was performed. The post-EMR defect consisted only of serosal lining ([Fig. 1 b]).
Oligoclonal CD4<b><sup>+</sup></b>T Cell Expansions in Lung Transplant Recipients with Obliterative Bronchiolitis
Authors: Steven R. Duncan, Colm Leonard, James Theodore, Mark Lega, Reda E. Girgis, Glenn D. Rosen, Argyrios N. Theofilopoulos
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Obliterative bronchiolitis (OB) is a dreaded and frequent complication of lung transplantation with a poorly understood immunopathogenesis. To further evaluate disease mechanisms, we used T cell antigen receptor (TCR) β-chain variable region RNase protection assays, after polymerase chain reaction amplification of TCR cDNA, to quantitate circulating CD4+ and CD8+ repertoires of transplant recipients with OB or no evidence of rejection (NER). All six recipients with OB had markedly abnormal CD4 expansions (2.5 ± 0.5 expansions/recipient) attributable to oligoclonal proliferations. Only two of six recipients with NER had a single, much lesser, CD4+ abnormality each (p < 0.01). Moreover, one of these patients developed OB shortly thereafter, and the other NER abnormality may have predated transplantation. In contrast, CD8+ expansions were common in both recipient populations. Findings of CD4+ expansions had 100% sensitivity and 80% specificity for the presence or imminent development of OB. These data suggest proliferations of CD4+ T cells are important in OB pathogenesis, and these are most likely part of a major histocompatibility complex Class II–dependent process of indirect alloantigen presentation. These CD4+ clones are likely to have facultative helper functions for the multiple and diverse immune processes that have been implicated in OB. Furthermore, the close association of CD4+ expansions with OB raises possibilities of development of novel diagnostic and therapeutic approaches.
Parachuting injuries: a study of 110,000 sports jumps.
Authors: N Ellitsgaard
Journal: British Journal of Sports Medicine (1987)

A study was undertaken to examine the type, location, incidence and mechanism of injury sustained by amateur parachutists in Denmark during a five-year-period. A total of 110,000 parachute jumps resulted in six (0.005%) fatalities and 155 (0.14%) cases, requiring medical treatment. The latter group sustained 176 injuries of which 36.9% were significant soft tissue lesions and 63.1% fractures. Landing is the most dangerous part of the parachuting procedure, causing 83.8% of the accidents, while 9.3% were caused by faults during opening of the parachute. Based on the injury pattern, some modifications to the procedures and equipment are mentioned. A simplification of the parachute landing fall and the development of safer parachutes may reduce the incidence of casualties. An enforcement of the present regulations is necessary as many injuries are the result of noncompliance with regulations due to ignorance, inexperience or carelessness.
Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice
Authors: Norman Woller, Sarah Knocke, Bettina Mundt, Engin Gürlevik, Nina Strüver, Arnold Kloos, Bita Boozari, Peter Schache, Michael P. Manns, Nisar P. Malek, Tim Sparwasser, Lars Zender, Thomas C. Wirth, Stefan Kubicka, Florian Kühnel
Journal: Journal of Clinical Investigation (2011)

Vaccination using DCs pulsed with tumor lysates or specific tumor-associated peptides has so far yielded limited clinical success for cancer treatment, due mainly to the low immunogenicity of tumor-associated antigens. In this study, we have identified intratumoral virus-induced inflammation as a precondition for effective antitumor DC vaccination in mice. Administration of a tumor-targeted DC vaccine during ongoing virus-induced tumor inflammation, a regimen referred to as oncolysis-assisted DC vaccination (ODC), elicited potent antitumoral CD8+ T cell responses. This potent effect was not replicated by TLR activation outside the context of viral infection. ODC-elicited immune responses mediated marked tumor regression and successful eradication of preestablished lung colonies, an essential prerequisite for potentially treating metastatic cancers. Unexpectedly, depletion of Tregs during ODC did not enhance therapeutic efficacy; rather, it abrogated antitumor cytotoxicity. This phenomenon could be attributed to a compensatory induction of myeloid-derived suppressor cells in Treg-depleted and thus vigorously inflamed tumors, which prevented ODC-mediated immune responses. Consequently, Tregs are not only general suppressors of immune responses, but are essential for the therapeutic success of multimodal and temporally fine-adjusted vaccination strategies. Our results highlight tumor-targeting, replication-competent viruses as attractive tools for eliciting effective antitumor responses upon DC vaccination.