tbuckley/cabot-search huggingface dataset:
Response to Comment on Juraschek et al. Cardiorespiratory Fitness and Incident Diabetes: The FIT (Henry Ford ExercIse Testing) Project. Diabetes Care 2015;38:1075–1081
Authors: Stephen P. Juraschek, Michael J. Blaha, Mouaz H. Al-Mallah
Journal: Diabetes Care (2015)

We thank Krachler and Lindahl for their letter (1), which highlights the complex relationship between fitness, obesity, and the pathogenesis of diabetes.

Along with obesity, fitness is a strong risk factor for diabetes in multiple cohort studies (2–4). However, the extent to which obesity serves as a confounder of this relationship is unclear. Our study shows that fitness is associated with incident diabetes independent of an incomplete measure of obesity, ascertained via self-report and medical records (5). However, even after accounting for BMI, available in medical records of 11,750 patients, the relationship between fitness and incident diabetes remained strong. While obesity may to some extent confound the relationship between …
Pregnancy after breast cancer: population based study
Authors: Angela Ives, Christobel Saunders, Max Bulsara, James Semmens
Journal: BMJ (2006)

<b>Objectives</b> To identify women who survived breast cancer and subsequently conceived and to determine the rate of pregnancy (proportion), management, outcome of the cancer, and outcome of the first subsequent pregnancy. <b>Design</b> Population based descriptive study with cases identified from the Western Australian data linkage system and validated by review of medical charts. Supplementary data obtained from hospital and clinician records. <b>Setting</b> Western Australia, 1982-2003. <b>Participants</b> Women aged &lt;45 with a diagnosis of breast cancer who subsequently conceived. <b>Main outcome measures</b> Pregnancy outcome and rate, survival, time from diagnosis to pregnancy. <b>Results</b> Sixty two (54%) women with a diagnosis of breast cancer who subsequently conceived did so less than two years after their diagnosis: 29 of them had an abortion, 27 had a live birth, and six miscarried. Within a proportional hazards regression model subsequent pregnancy was associated with improved overall survival (hazard ratio 0.59, 95% confidence interval 0.37 to 0.95). When the model was stratified by time from diagnosis subsequent pregnancy was associated with improved overall survival in women who waited at least 24 months to conceive (0.48, 0.27 to 0.83) and a non-significant protective effect was seen for women who waited at least six months to become pregnant. <b>Conclusions</b> Our study does not support the current medical advice given to premenopausal women with a diagnosis of with breast cancer to wait two years before attempting to conceive. This recommendation may be valid for women who are receiving treatment or have systemic disease at diagnosis, but for women with localised disease early conception, six months after completing their treatment, is unlikely to reduce survival.
Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial
Authors: Roy S Herbst, Yan Sun, Wilfried EE Eberhardt, Paul Germonpré, Nagahiro Saijo, Caicun Zhou, Jie Wang, Longyun Li, Fairooz Kabbinavar, Yukito Ichinose, Shukui Qin, Li Zhang, Bonne Biesma, John V Heymach, Peter Langmuir, Sarah J Kennedy, Hiroomi Tada, Bruce E Johnson
Journal: The Lancet Oncology (2010)
<i>BRAF</i> Mutation and <i>CDKN2A</i> Deletion Define a Clinically Distinct Subgroup of Childhood Secondary High-Grade Glioma
Authors: Matthew Mistry, Nataliya Zhukova, Daniele Merico, Patricia Rakopoulos, Rahul Krishnatry, Mary Shago, James Stavropoulos, Noa Alon, Jason D. Pole, Peter N. Ray, Vilma Navickiene, Joshua Mangerel, Marc Remke, Pawel Buczkowicz, Vijay Ramaswamy, Ana Guerreiro Stucklin, Martin Li, Edwin J. Young, Cindy Zhang, Pedro Castelo-Branco, Doua Bakry, Suzanne Laughlin, Adam Shlien, Jennifer Chan, Keith L. Ligon, James T. Rutka, Peter B. Dirks, Michael D. Taylor, Mark Greenberg, David Malkin, Annie Huang, Eric Bouffet, Cynthia E. Hawkins, Uri Tabori
Journal: Journal of Clinical Oncology (2015)

To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG).We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained.sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P < .001 and P < .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% ± 15% and 29% ± 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024).BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG.
Primary meningococcal arthritis associated with adult respiratory distress syndrome.
Authors: A Samanta, A Turner, S Roy, A O'Leary
Journal: Annals of the Rheumatic Diseases (1990)

A previously fit and well 20 year old man with primary meningococcal arthritis of the left knee is described. Despite intensive search there was no evidence of extra-articular meningococcal infection. He subsequently developed adult respiratory distress syndrome as a rare and previously undescribed complication.
Phosphorylation and Degradation of MdmX Is Inhibited by Wip1 Phosphatase in the DNA Damage Response
Authors: Xinna Zhang, Lin Lin, Huarong Guo, Jianhua Yang, Stephen N. Jones, Aart Jochemsen, Xiongbin Lu
Journal: Cancer Research (2009)

Abstract MdmX and Mdm2 regulate p53 tumor suppressor functions by controlling p53 transcriptional activity and/or stability in cells exposed to DNA damage. Accumulating evidence indicates that ATM-mediated phosphorylation and degradation of Mdm2 and MdmX may be the initial driving force that induces p53 activity during the early phase of the DNA damage response. We have recently determined that a novel protein phosphatase, Wip1 (or PPM1D), contributes to p53 regulation by dephosphorylating Mdm2 to close the p53 activation loop initiated by the ATM/ATR kinases. In the present study, we determine that Wip1 directly dephosphorylates MdmX at the ATM-targeted Ser403 and indirectly suppresses phosphorylation of MdmX at Ser342 and Ser367. Wip1 inhibits the DNA damage–induced ubiquitination and degradation of MdmX, leading to the stabilization of MdmX and reduction of p53 activities. Our data suggest that Wip1 is an important component in the ATM-p53-MdmX regulatory loop. [Cancer Res 2009;69(20):7960–8]
Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma1
Authors: Michael D. Prados, Kathleen R. Lamborn, Susan Chang, Eric Burton, Nicholas Butowski, Mary Malec, Ami Kapadia, Jane Rabbitt, Margaretta S. Page, Ann Fedoroff, Dong Xie, Sean K. Kelley
Journal: Neuro-Oncology (2006)

The purpose of this study was to define the maximum tolerated dose of erlotinib and characterize its pharmaco-kinetics and safety profile, alone and with temozolomide, with and without enzyme-inducing antiepileptic drugs (EIAEDs), in patients with malignant gliomas. Patients with stable or progressive malignant primary glioma received erlotinib alone or combined with temozolomide in this dose-escalation study. In each treatment group, patients were stratified by coadministration of EIAEDs. Erlotinib was started at 100 mg orally once daily as a 28-day treatment cycle, with dose escalation by 50 mg/day up to 500 mg/day. Temozolomide was administered at 150 mg/m2 for five consecutive days every 28 days, with dose escalation up to 200 mg/m2 at the second cycle. Eightythree patients were evaluated. Rash, fatigue, and diarrhea were the most common adverse events and were generally mild to moderate. The recommended phase 2 dose of erlotinib is 200 mg/day for patients with glioblastoma multiforme who are not receiving an EIAED, 450 mg/day for those receiving temozolomide plus erlotinib with an EIAED, and at least 500 mg/day for those receiving erlotinib alone with an EIAED. Of the 57 patients evaluable for response, eight had a partial response (PR). Six of the 57 patients had a progression-free survival of longer than six months, including four patients with a PR. Coadministration of EIAEDs reduced exposure to erlotinib as compared with administration of erlotinib alone (33%-71% reduction). There was a modest pharmacokinetic interaction between erlotinib and temozolomide. The favorable tolerability profile and evidence of antitumor activity indicate that further investigation of erlotinib is warranted.
Inhibition of Tumor Growth and Metastasis by Depletion of Vesicular Sorting Protein Hrs: Its Regulatory Role on E-Cadherin and β-Catenin
Authors: Masafumi Toyoshima, Nobuyuki Tanaka, Jun Aoki, Yoshinori Tanaka, Kazuko Murata, Masanao Kyuuma, Hideyuki Kobayashi, Naoto Ishii, Nobuo Yaegashi, Kazuo Sugamura
Journal: Cancer Research (2007)

Abstract Abnormally high signals from receptor tyrosine kinases (RTK) are associated with carcinogenesis, and impaired deactivation of RTKs may also be a mechanism in cancer. Hepatocyte growth factor–regulated tyrosine kinase substrate (Hrs) is one of the master regulators that sort activated receptors toward lysosomes and shut down their signals. Hrs contains a ubiquitin-interacting motif and is involved in the endosomal sorting of monoubiquitinated membrane proteins, such as growth factor receptor and E-cadherin. Here, we investigated the role of Hrs in determining the malignancy of cancer cells and discovered that the targeted disruption of Hrs by small interfering RNA effectively attenuated the proliferation, anchorage-independent growth, tumorigenesis, and metastatic potential of HeLa cells in vitro and in vivo. The restoration of Hrs expression increased cell proliferation and anchorage-independent growth in a mouse embryonic fibroblast line established from a Hrs knockout mouse. Further analysis revealed that Hrs depletion was associated with the up-regulation of E-cadherin and reduced β-catenin signaling. The aberrant accumulation of E-cadherin most likely resulted from impaired E-cadherin degradation in lysosomes. These results suggest that Hrs may play a critical role in determining the malignancy of cancer cells by regulating the degradation of E-cadherin. [Cancer Res 2007;67(11):5162–71]
Rates of Protein Evolution Are Positively Correlated with Developmental Timing of Expression During Mouse Spermatogenesis
Authors: Jeffrey M. Good, Michael W. Nachman
Journal: Molecular Biology and Evolution (2005)

Male reproductive genes often evolve very rapidly, and sexual selection is thought to be a primary force driving this divergence. We investigated the molecular evolution of 987 genes expressed at different times during mouse spermatogenesis to determine if the rate of evolution and the intensity of positive selection vary across stages of male gamete development. Using mouse-rat orthologs, we found that rates of protein evolution were positively correlated with the developmental timing of expression. Genes expressed early in spermatogenesis had rates of divergence similar to the genome median, while genes expressed after the onset of meiosis were found to evolve much more quickly. Rates of protein evolution were fastest for genes expressed during the dramatic morphogenesis of round spermatids into spermatozoa. Late-expressed genes were also more likely to be specific to the male germline. To test for evidence of positive selection, we analyzed the ratio of nonsynonymous to synonymous changes using a maximum likelihood framework in comparisons among mouse, rat, and human. Many genes showed evidence of positive selection, and most of these genes were expressed late in spermatogenesis and were testis specific. Overall, these data suggest that the intensity of positive selection associated with the evolution of male gametes varies considerably across development and acts primarily on phenotypes that develop late in spermatogenesis.
Network Analysis in Public Health: History, Methods, and Applications
Authors: Douglas A. Luke, Jenine K. Harris
Journal: Annual Review of Public Health (2007)

Network analysis is an approach to research that is uniquely suited to describing, exploring, and understanding structural and relational aspects of health. It is both a methodological tool and a theoretical paradigm that allows us to pose and answer important ecological questions in public health. In this review we trace the history of network analysis, provide a methodological overview of network techniques, and discuss where and how network analysis has been used in public health. We show how network analysis has its roots in mathematics, statistics, sociology, anthropology, psychology, biology, physics, and computer science. In public health, network analysis has been used to study primarily disease transmission, especially for HIV/AIDS and other sexually transmitted diseases; information transmission, particularly for diffusion of innovations; the role of social support and social capital; the influence of personal and social networks on health behavior; and the interorganizational structure of health systems. We conclude with future directions for network analysis in public health.
A unique requirement for the leukotriene B4 receptor BLT1 for neutrophil recruitment in inflammatory arthritis
Authors: Nancy D. Kim, Richard C. Chou, Edward Seung, Andrew M. Tager, Andrew D. Luster
Journal: The Journal of Experimental Medicine (2006)

Neutrophil recruitment into tissue plays an important role in host defense and disease pathogenesis, including the inflammatory arthritides. A multitude of diverse chemoattractants have been implicated in neutrophil recruitment, suggesting that they have overlapping functions in mediating this critical biological response. However, here we demonstrate a unique, non-redundant role for the leukotriene B4 receptor BLT1 in mediating neutrophil recruitment into the joint in the K/BxN mouse model of inflammatory arthritis. We demonstrate that neutrophil expression of BLT1 was absolutely required for arthritis generation and chemokine production in this model, and that specific BLT1 inhibition reversed established disease. Adoptive transfer of wild-type (WT) neutrophils restored arthritis and chemokine production in BLT1−/− mice. Surprisingly, the primary effect of the transferred WT neutrophils into BLT1−/− mice was to promote the entry of endogenous BLT1−/− neutrophils into the joints of these mice. However, continued joint inflammation was dependent on the presence of WT neutrophils, indicating an ongoing specific requirement for BLT1-activated neutrophils in mediating BLT1−/− neutrophil recruitment by other chemoattractants. These experiments demonstrate that neutrophil BLT1 functions in a novel and essential non–cell-autonomous manner to enable the recruitment of additional neutrophils not expressing this receptor, thereby amplifying the inflammatory response in autoantibody-induced arthritis.
Transfer of Communication Skills to the Workplace: Impact of a 38-Hour Communication Skills Training Program Designed for Radiotherapy Teams
Authors: Isabelle Merckaert, France Delevallez, Anne-Sophie Gibon, Aurore Liénard, Yves Libert, Nicole Delvaux, Serge Marchal, Anne-Marie Etienne, Isabelle Bragard, Christine Reynaert, Jean-Louis Slachmuylder, Pierre Scalliet, Paul Van Houtte, Philippe Coucke, Darius Razavi
Journal: Journal of Clinical Oncology (2015)

This study assessed the efficacy of a 38-hour communication skills training program designed to train a multidisciplinary radiotherapy team.Four radiotherapy teams were randomly assigned to a training program or a waiting list. Assessments were scheduled at baseline and after training for the training group and at baseline and 4 months later for the waiting list group. Assessments included an audio recording of a radiotherapy planning session to assess team members' communication skills and expression of concerns of patients with breast cancer (analyzed with content analysis software) and an adapted European Organisation for Research and Treatment of Cancer satisfaction with care questionnaire completed by patients at the end of radiotherapy.Two hundred thirty-seven radiotherapy planning sessions were recorded. Compared with members of the untrained teams, members of the trained teams acquired, over time, more assessment skills (P = .003) and more supportive skills (P = .050) and provided more setting information (P = .010). Over time, patients interacting with members of the trained teams asked more open questions (P = .022), expressed more emotional words (P = .025), and exhibited a higher satisfaction level regarding nurses' interventions (P = .028).The 38-hour training program facilitated transfer of team member learned communication skills to the clinical practice and improved patients' satisfaction with care.
Gastrointestinal events in at-risk patients starting non-steroidal anti-inflammatory drugs (NSAIDs) for rheumatic diseases: the EVIDENCE study of European routine practice
Authors: Angel Lanas, Maarten Boers, Javier Nuevo
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Data concerning rates of gastrointestinal (GI) events in non-steroidal anti-inflammatory drug (NSAID) users derive mainly from clinical trials. The EVIDENCE study quantified the incidence of symptomatic uncomplicated and/or complicated GI events in at-risk European patients treated with NSAIDs in real-life practice. <h3>Methods</h3> This non-interventional study assessed 4144 adults with at least one GI risk factor who recently initiated NSAID therapy for osteoarthritis (85%), rheumatoid arthritis (11%), ankylosing spondylitis (3%) or a combination (1%). Patient characteristics and medical history were collected from medical records. GI events (upper and lower) were recorded at in-clinic visits during 6 months' follow-up. <h3>Results</h3> Mean time on index NSAID at enrolment was 33 days. The incidence (per 100 person-years) was 18.5 per 100 person-years for uncomplicated GI events and 0.7 per 100 person-years for complicated GI events. Upper GI events were far more common (12%) than lower GI events (1%) during study follow-up (median 182 days (range 61–320)). Other reported rates for cardiovascular, anaemia or non-GI events were much less frequent. A minority (28%) of patients had ongoing proton pump inhibitor use at enrolment, with strong variation by practice and country. <h3>Conclusions</h3> EVIDENCE is the largest prospective study of the real-life management of European patients treated with NSAIDs for rheumatic diseases and at increased GI risk. It shows that GI events from the upper GI tract are far more common than those from the lower GI tract. It also shows adherence to guidelines for gastroprotection is generally low. <h3>ClinicalTrials.gov identifier</h3> NCT01176682.
Biology of Gastroesophageal Reflux Disease: Pathophysiology Relating to Medical and Surgical Treatment
Authors: Tom R. DeMeester, MD, Jeffrey H. Peters, MD, Cedric G. Bremner, MD, Parakh Chandrasoma, MD
Journal: Annual Review of Medicine (1999)

This chapter reviews the biology of gastroesophageal reflux disease, relating pathophysiology to medical and surgical therapy. Various definitions of the disease are presented and workable criteria are developed to identify patients with the disease. The central importance of the lower esophageal high-pressure zone as a barrier to reflux is emphasized, along with an analysis of its biomechanical alteration in disease. The composition of the refluxed gastric juice is characterized in regard to its potential for mucosal injury. Evidence is provided that cardiac-type mucosa is an acquired sequel to acid-induced squamous mucosal injury in the terminal esophagus. A hypothesis regarding the process of intestinalization of cardiac-type mucosa to form Barrett's esophagus is presented. An integrated concept of the pathophysiology of gastroesophageal reflux disease is constructed. Practical concepts regarding the treatment of gastroesophageal reflux disease are developed, based on a review of studies on the natural history of the disease and the long-term outcome of therapy.
Evolution of a Complex T Cell Receptor Repertoire during Primary and Recall Bacterial Infection
Authors: Dirk H. Busch, Ingrid Pilip, Eric G. Pamer
Journal: The Journal of Experimental Medicine (1998)

The mechanisms underlying the genesis and maintenance of T cell memory remain unclear. In this study, we examined the evolution of a complex, antigen-specific T cell population during the transition from primary effector to memory T cells after Listeria monocytogenes infection. T cell populations specific for listeriolysin O (LLO)91–99, the immunodominant epitope recognized by H2-Kd–restricted T lymphocytes, were directly identified in immune spleens using tetrameric H2-Kd–epitope complexes. The T cell receptor (TCR) Vβ repertoire of specific T cells was determined by direct, ex vivo staining with a panel of mAbs. We demonstrate that LLO91–99-specific, primary effector T cell populations have a diverse TCR Vβ repertoire. Analyses of memory T cell populations demonstrated similar TCR diversity. Furthermore, experiments with individual mice demonstrated that primary effector and memory T cells have indistinguishable TCR repertoires. Remarkably, after reinfection with L. monocytogenes, LLO91–99-specific T cells have a narrower TCR repertoire than do primary effector or memory T cells. Thus, our studies show that the TCR repertoire of primary effector T lymphocytes is uniformly transmitted to memory T cells, whereas expansion of memory T cells is selective.
Vitamin B status in patients with chronic fatigue syndrome
Authors: L C Heap, T J Peters, S Wessely
Journal: Journal of the Royal Society of Medicine (1999)

Some patients with chronic fatigue syndrome say they benefit from taking vitamin supplements. We assessed functional status for the B vitamins pyridoxine, riboflavin and thiamine in 12 vitamin-untreated CFS patients and in 18 healthy controls matched for age and sex. Vitamin-dependent activities--aspartate aminotransferase (AST) for pyridoxine, glutathione reductase (GTR) for riboflavin, transketolase (TK) for thiamine--were measured in erythrocyte haemolysates before and after in-vitro addition of the relevant vitamin. For all three enzymes basal activity (U/g Hb) was lower in CFS patients than in controls: AST 2.84 (SD 0.62) vs 4.61 (1.43), P < 0.001; GTR 6.13 (1.89) vs 7.42 (1.25), P < 0.04; TK 0.50 (0.13) vs 0.60 (0.07), P < 0.04. This was also true of activated values: AST 4.91 (0.54) vs 7.89 (2.11), P < 0.001; GTR 8.29 (1.60) vs 10.0 (1.80), P < 0.001; TK 0.56 (0.19) vs 0.66 (0.08), P < 0.07. The activation ratios, however, did not differ between the groups. These data provide preliminary evidence of reduced functional B vitamin status, particularly of pyridoxine, in CFS patients.