tbuckley/cabot-search huggingface dataset:
SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease
Authors: G. Calaminus, R. Kortmann, J. Worch, J. C. Nicholson, C. Alapetite, M. L. Garre, C. Patte, U. Ricardi, F. Saran, D. Frappaz
Journal: Neuro-Oncology (2013)

We conducted a nonrandomized international study for intracranial germinoma that compared chemotherapy followed by local radiotherapy with reduced-dose craniospinal irradiation (CSI) alone, to determine whether the combined treatment regimen produced equivalent outcome and avoided irradiation beyond the primary tumor site(s). Patients with localized germinoma received either CSI or 2 courses of carboplatin and etoposide alternating with etoposide and ifosfamide, followed by local radiotherapy. Metastatic patients received CSI with focal boosts to primary tumor and metastatic sites, with the option to be preceded with chemotherapy. Patients with localized germinoma (n = 190) received either CSI alone (n = 125) or combined therapy (n = 65), demonstrating no differences in 5-year event-free or overall survival, but a difference in progression-free survival (0.97 ± 0.02 vs 0.88 ± 0.04; P = .04). Seven of 65 patients receiving combined treatment experienced relapse (6 with ventricular recurrence outside the primary radiotherapy field), and only 4 of 125 patients treated with CSI alone experienced relapse (all at the primary tumor site). Metastatic patients (n = 45) had 0.98 ± 0.023 event-free and overall survival. Localized germinoma can be treated with reduced dose CSI alone or with chemotherapy and reduced-field radiotherapy. The pattern of relapse suggests inclusion of ventricles in the radiation field. Reduced-dose craniospinal radiation alone is effective in metastatic disease.
Sports participation of individuals with major upper limb deficiency
Authors: Mihai Bragaru, Rienk Dekker, Pieter U Dijkstra, Jan H B Geertzen, Corry K van der Sluis
Journal: British Journal of Sports Medicine (2013)

The aim of this study was to analyse sports participation of individuals with upper limb deficiency (ULD) and associated factors.Individuals with ULD originating from the Netherlands were invited, via their attending physiatrist or prosthetist, to answer a digital or paper questionnaire. The questionnaire consisted of 34 items related to personal characteristics, type of deficiency and participation in sports.Of the 175 respondents, 57% participated in sports for at least 60 min/week (athletes). Results of logistic regression analyses indicated that the presence of an additional health problem hindering sports participation (β=-1.31, p<0.001) and a more proximal onset of the limb deficiency (β=0.76, p=0.022) had a negative influence on sports participation. For individuals with an acquired ULD, a medium education level (β=0 0.77, p=0.108) and participation in sports before their amputation (β=1.11, p=0.007) had a positive influence on sports participation. The desire to stay healthy and the pleasure derived from sports participation represented the main reasons for participation in sports according to athletes. The presence of an additional medical problem and a lack of motivation were reasons for non-athletes to not participate in sports.The majority of individuals with ULD participate in sports regularly. The presence of an additional medical problem, as well as the level of ULD, educational level and participation in sports before amputation, was related to participation in sports.
The high burden of hospitalizations for primary EBV infection: a 6-year prospective survey in a French hospital
Authors: L. Hocqueloux, X. Causse, A. Valery, J.-C. Jandali, O. Maitre, C. Soin, J. Buret, F. Ouane, M. Niang, C. Mille, T. Prazuck, J. Guinard, A. Guigon
Journal: Clinical Microbiology and Infection (2015)
Margins in Ductal Carcinoma In Situ: Is Bigger Really Better?
Authors: M. Morrow, S. J. Katz
Journal: JNCI Journal of the National Cancer Institute (2012)

Breast cancer is now recognized to be a group of genetically distinct diseases with different behaviors. Outcomes are maximized when therapy is tailored to patient and disease characteristics. Ductal carcinoma in situ (DCIS) can be eliminated with mastectomy, but this approach is considered unnecessarily radical in most cases for an entity that is non–life threatening, usually asymptomatic, and may not progress to invasive cancer. Breast-conserving surgery (BCS) consisting of removal of the DCIS to clear margins (tumor not touching the inked surface) is the minimal standard of care. The need for negative margins is already incorporated in guidelines for DCIS management based on strong evidence from randomized clinical trials (1–3), as well as a meta-analysis of the individual patient data from the randomized trials of BCS vs BCS and radiotherapy (RT) (4). The main topic of debate now is whether more widely clear margins of resection can eliminate the need for RT. In this issue of the Journal, Wang et al. (5) use a network metaanalysis of the impact of different margin widths on local recurrence (LR) in DCIS to reach the somewhat surprising conclusion that wider margins should be a “priority” for all DCIS patients, regardless of the receipt of RT. This recommendation is based upon an analysis of 24 cohorts from 21 studies (three randomized trials) involving 7564 patients treated over 25 years. A margin width of 10 mm or greater was observed to decrease the risk of LR compared with a margin of 2 mm or greater (odds ratio = 0.46; 95% confidence interval = 0.29 to 0.69), leading to a recommendation by the authors for wide excision. This would represent a major change in the current standard surgical approach to DCIS, as illustrated even by the selected dataset used in the meta-analysis, where margins greater than 1 cm were obtained in only 4% of patients treated with RT and in 9% of those treated with excision alone. Before embarking on such a change in practice, clinicians need to ask whether the observed association between larger margins and lower LR is valid, whether there is evidence of a causal relationship, and whether this change would improve the health of women with DCIS. In any observational study, there is concern that the results could be influenced by important confounding factors. This is a particularly challenging problem in this meta-analysis incorporating the results of many observational studies where patients were not randomly assigned to the different margin widths. In fact, the authors acknowledge the possibility that bias caused by unobserved selection effects across studies cannot be excluded, particularly when only five of 21 studies included in the meta-analysis reported margin widths of 1 cm or more. This subset of patients may have differed from the much larger cohort used to determine recurrence for patients with smaller margins in ways that could
Antigen presentation to human T lymphocytes. I. Different requirements for stimulation by hapten-modified cells vs. cell sonicates.
Authors: S L Abramson, J M Puck, R R Rich
Journal: The Journal of Experimental Medicine (1981)

We have investigated the cellular and antigenic requirements for incubation of secondary proliferative responses by human T lymphocytes. Two distinct properties of antigen-presenting peripheral blood mononuclear cells were studied: (a) the ability for appropriate cell surface constituents to construct an immunogenic moiety, and (b) the ability to present similar antigenic determinants when they are not covalently bound. Only Ia+ hapten-modified cells were effective stimulators. In contrast, both Ia+ and Ia- cell sonicates could stimulate secondary proliferative responses, but only in the presence of an accessory cell. This accessory cell was present in Ia+ macrophage, but not in Ia+ non-T lymphocyte, preparations. In contrast, macrophages or soluble factors produced by macrophages were not required for primed T cells to undergo hapten-specific proliferation in response to hapten-modified Ia+ stimulator cells. Thus, although all Ia+ cells tested can stimulate primed cells to proliferate, not all Ia+ cells can function as accessory cells for responses to sonicates. This may reflect the unique ability of a subpopulation(s) of Ia+ cells to bind or process sonicates or soluble antigens for appropriate recognition by primed T cells.
GP130 activation induces myeloma and collaborates with MYC
Authors: Tobias Dechow, Sabine Steidle, Katharina S. Götze, Martina Rudelius, Kerstin Behnke, Konstanze Pechloff, Susanne Kratzat, Lars Bullinger, Falko Fend, Valeria Soberon, Nadya Mitova, Zhoulei Li, Markus Thaler, Jan Bauer, Elke Pietschmann, Corinna Albers, Rebekka Grundler, Marc Schmidt-Supprian, Jürgen Ruland, Christian Peschel, Justus Duyster, Stefan Rose-John, Florian Bassermann, Ulrich Keller
Journal: Journal of Clinical Investigation (2014)

Multiple myeloma (MM) is a plasma cell neoplasm that results from clonal expansion of an Ig-secreting terminally differentiated B cell. Advanced MM is characterized by tissue damage that involves bone, kidney, and other organs and is typically associated with recurrent genetic abnormalities. IL-6 signaling via the IL-6 signal transducer GP130 has been implicated as an important driver of MM pathogenesis. Here, we demonstrated that ectopic expression of constitutively active GP130 (L-GP130) in a murine retroviral transduction-transplantation model induces rapid MM development of high penetrance. L-GP130–expressing mice recapitulated all of the characteristics of human disease, including monoclonal gammopathy, BM infiltration with lytic bone lesions, and protein deposition in the kidney. Moreover, the disease was easily transplantable and allowed different therapeutic options to be evaluated in vitro and in vivo. Using this model, we determined that GP130 signaling collaborated with MYC to induce MM and was responsible and sufficient for directing the plasma cell phenotype. Accordingly, we identified Myc aberrations in the L-GP130 MM model. Evaluation of human MM samples revealed recurrent activation of STAT3, a downstream target of GP130 signaling. Together, our results indicate that deregulated GP130 activity contributes to MM pathogenesis and that pathways downstream of GP130 activity have potential as therapeutic targets in MM.
Use of Insulin Pumps in Pregnancies Complicated by Type 2 Diabetes and Gestational Diabetes in a Multiethnic Community
Authors: David Simmons, Colin F. Thompson, Caroline Conroy, David J. Scott
Journal: Diabetes Care (2001)

OBJECTIVE—To describe the use of insulin pump therapy in women with gestational diabetes mellitus (GDM) or type 2 diabetes in pregnancy and persistent hyperglycemia despite multiple injections of subcutaneous insulin. RESEARCH DESIGN AND METHODS—As part of a service audit, deliveries to women with diabetes at a single South Auckland hospital were reviewed from 1991 through 1994. Glycemic control was estimated by the mean of self-recorded and laboratory postprandial glucose concentrations. In a nested case-control study, pregnancies complicated by GDM/type 2 diabetes with use of an insulin pump were compared with those without insulin pump therapy and peak insulin requirements of 100–199 units/ day, matched for ethnicity and type of diabetes. RESULTS—A total of 30 of 251 Polynesian, European, and South Asian women with singleton pregnancies complicated by insulin-requiring GDM/type 2 diabetes used an insulin pump. An additional two women with high insulin requirements discontinued pump therapy. None of the women with GDM/type 2 diabetes experienced severe hypoglycemia, whereas 79% of the women had improved glycemic control within 1–4 weeks. Mothers using a pump had greater insulin requirements (median maximum 246 vs. 130 units per day) and greater weight gain (10.6 vs. 5.0 kg). Their babies were more likely to be admitted to the Special Care Baby Unit but were neither significantly heavier nor experienced greater hypoglycemia than control subjects. CONCLUSIONS—Insulin pump therapy seems to be safe and effective for maintaining glycemic control in pregnancies complicated by GDM/type 2 diabetes and requiring large doses of insulin.
Fatty acid kinetic responses to exercise. Effects of obesity, body fat distribution, and energy-restricted diet.
Authors: J A Kanaley, P E Cryer, M D Jensen
Journal: Journal of Clinical Investigation (1993)

Upper body obesity (UB Ob) is associated with a reduced net free fatty acid (FFA) response to epinephrine compared with nonobese (Non Ob) and lower-body obese (LB Ob) women. Because catecholamines regulate some of the metabolic responses to exercise, we hypothesized that UB Ob would have a reduced net FFA response to exercise. Plasma FFA rate of appearance (Ra) ([1-14C]palmitate) and fatty acid oxidation (indirect calorimetry) were therefore measured during 2.5 h of stationary bicycle exercise (45% VO2 peak) in 13 UB Ob, 11 LB Ob, and 8 Non Ob premenopausal women. 10 UB Ob and 8 LB Ob women were retested after an approximately 8-kg weight loss. Results: During exercise Non Ob and LB Ob women had greater increments in FFA availability (51 +/- 7 and 53 +/- 8 mmol, respectively) than UB Ob women (27 +/- 4 mmol, P < 0.05). Total exercise FFA availability and fatty acid oxidation were not different between Non Ob, LB Ob, and UB Ob women, however. Following weight loss (approximately 8 kg), the FFA response to exercise increased (P < 0.01) and remained greater (P < 0.05) in LB Ob than in UB Ob women. In conclusion, the FFA response to exercise was reduced in UB Ob women before and after weight loss, but no effects on fatty acid oxidation were apparent.
The MUC1 mucin protects against<i>Helicobacter pylori</i>pathogenesis in mice by regulation of the NLRP3 inflammasome
Authors: Garrett Z Ng, Trevelyan R Menheniott, Alison L Every, Andrew Stent, Louise M Judd, Yok Teng Chionh, Poshmaal Dhar, Jasper C Komen, Andrew S Giraud, Timothy C Wang, Michael A McGuckin, Philip Sutton
Journal: Gut (2015)

The mucin MUC1, best known for providing an epithelial barrier, is an important protective host factor in both humans and mice during Helicobacter pylori pathogenesis. This study aimed to identify the long-term consequences of MUC1 deficiency on H. pylori pathogenesis and the mechanism by which MUC1 protects against H. pylori gastritis.Wildtype and Muc1(-/-) mice were infected for up to 9 months, and the gastric pathology, immunological response and epigenetic changes assessed. The effects of MUC1 on the inflammasome, a potent inflammatory pathway, were examined in macrophages and H. pylori-infected mice deficient in both MUC1 and inflammasome components.Muc1(-/-) mice began to die 6 months after challenge, indicating Muc1 deficiency made H. pylori a lethal infection. Surprisingly, chimaeric mouse infections revealed MUC1 expression by haematopoietic-derived immune cells limits H. pylori-induced gastritis. Gastritis in infected Muc1(-/-) mice was associated with elevated interleukin (IL)-1β and epigenetic changes in their gastric mucosa similar to those in transgenic mice overexpressing gastric IL-1β, implicating MUC1 regulation of an inflammasome. In support of this, infected Muc1(-/-)Casp1(-/-) mice did not develop severe gastritis. Further, MUC1 regulated Nlrp3 expression via an nuclear factor (NF)-κB-dependent pathway and reduced NF-κB pathway activation via inhibition of IRAK4 phosphorylation. The importance of this regulation was proven using Muc1(-/-)Nlrp3(-/-) mice, which did not develop severe gastritis.MUC1 is an important, previously unidentified negative regulator of the NLRP3 inflammasome. H. pylori activation of the NLRP3 inflammasome is normally tightly regulated by MUC1, and loss of this critical regulation results in the development of severe pathology.
Heritability and molecular genetic studies of endometriosis
Authors: F. Z. Bischoff
Journal: Human Reproduction Update (2000)

Endometriosis is a common disease defined as the growth of endometrial tissue outside the uterine cavity that often results in a vast array of gynaecological problems including dyspareunia, dysmenorrhoea, pelvic pain and infertility. Despite the increasing evidence that supports a genetic component to this common gynaecological condition, the basic aetiology and pathogenesis of endometriosis remain unknown. It is likely that endometriosis is a common polygenic/multifactorial disease caused by an interaction between multiple genes as well as the environment. Such conditions do not have a clear Mendelian pattern of inheritance. Recent molecular cytogenetic studies on endometriotic tissue and an established endometriosis-derived cell line provide novel evidence that acquired chromosome-specific alterations may be involved in endometriosis, possibly reflecting clonal expansion of chromosomally abnormal cells. Molecular DNA studies examining the role of loss of heterozygosity in endometriotic lesions has identified candidate tumour suppressor gene loci, including 5q, 6q, 9p, 11q and 22q, that may play a role in the malignant transformation of endometriotic implants to endometrioid ovarian cancers. Evidence of mutations in the tumour suppressor PTEN gene in the endometrioid subtype of epithelial ovarian cancer further suggests that somatic genetic alterations represent early events in the transformation of benign endometriotic cells. Genetic factors are also likely to influence individual susceptibility to endometriosis. There is now evidence that heritable allelic differences in drug-metabolizing enzymes play an important role in the development of endometriosis. Further studies are warranted to identify major susceptibility gene(s) and the mechanism involved in endometriosis to assist in the development of better methods for early detection, diagnosis and prevention.
A Dose-Escalation Study of Recombinant Human Interleukin-18 Using Two Different Schedules of Administration in Patients with Cancer
Authors: Michael J. Robertson, John M. Kirkwood, Theodore F. Logan, Kevin M. Koch, Steven Kathman, Lyndon C. Kirby, William N. Bell, Linda M. Thurmond, Jill Weisenbach, Mohammed M. Dar
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. A phase I study of recombinant human IL-18 (rhIL-18) was done to determine the toxicity, pharmacokinetics, and biological activities of rhIL-18 administered at different doses in two different schedules to patients with advanced cancer. Experimental Design: Cohorts of three to four patients were given escalating doses of rhIL-18 as a 2-h i.v. infusion either on 5 consecutive days repeated every 28 days (group A) or once a week (group B) for up to 6 months. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic measurements. Results: Nineteen patients (10 melanoma and 9 renal cell cancer) were given rhIL-18 in doses of 100, 500, or 1,000 μg/kg (group A) or 100, 1,000, or 2,000 μg/kg (group B). Common side effects included chills, fever, headache, fatigue, and nausea. Common laboratory abnormalities included transient, asymptomatic grade 1 to 3 lymphopenia, grade 1 to 4 hyperglycemia, grade 1 to 2 anemia, neutropenia, hypoalbuminemia, liver enzyme elevations, and serum creatinine elevations. No dose-limiting toxicities were observed. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-γ, granulocyte macrophage colony-stimulating factor, and IL-18–binding protein were observed following dosing. Conclusions: rhIL-18 can be given in biologically active doses by either weekly infusions or daily infusions for 5 days repeated every 28 days to patients with advanced cancer. Toxicity was generally mild to moderate, and a maximum tolerated dose of rhIL-18 by either schedule was not determined.
STUDIES ON HYPERSENSITIVITY OF HUMAN TISSUES IN VITRO
Authors: Eugene J. Gangarosa, Joseph T. Inglefield, Cyril G. A. Thomas, Herbert R. Morgan
Journal: The Journal of Experimental Medicine (1955)

A new simple method of evaluating specific cytotoxicity to tuberculoprotein in the study of tuberculin hypersensitivity in vitro by comparing cell populations is presented. Utilizing this technic it was possible to reproduce Rich's results (1, 2) using human tissues of reticuloendothelial origin. The demonstration of the specific cytotoxic phenomenon in tuberculin-sensitive human tissues indicates that the principle elaborated by Rich (2) of specific changes in the individual fixed tissue cells in tuberculin hypersensitivity, possibly related to cellular antibodies, applies to human subjects as well as to the animals heretofore studied. Preliminary observations suggest that macrophages from donors with clinically active tuberculosis are more sensitive to tuberculoprotein than macrophages from tuberculin-positive donors without clinically active disease. Macrophages from tuberculin-positive donors appeared to be more sensitive to tuberculoprotein than fibroblasts derived from the same tissue. An inhibition of cell proliferation was seen when both cell types were exposed to PPD. In addition macrophages responded to tuberculoprotein with gross morphological changes and eventual cytolysis.
Coarse Particulate Matter Air Pollution and Hospital Admissions for Cardiovascular and Respiratory Diseases Among Medicare Patients
Authors: Roger D. Peng
Journal: JAMA (2008)

Health risks of fine particulate matter of 2.5 microm or less in aerodynamic diameter (PM2.5) have been studied extensively over the last decade. Evidence concerning the health risks of the coarse fraction of greater than 2.5 microm and 10 microm or less in aerodynamic diameter (PM10-2.5) is limited.
Adipocytes from Munc18c-null mice show increased sensitivity to insulin-stimulated GLUT4 externalization
Authors: Hajime Kanda, Yoshikazu Tamori, Hiroaki Shinoda, Mari Yoshikawa, Motoyoshi Sakaue, Jun Udagawa, Hiroki Otani, Fumi Tashiro, Jun-ichi Miyazaki, Masato Kasuga
Journal: Journal of Clinical Investigation (2005)

Insulin-stimulated glucose uptake in adipocytes is mediated by translocation of vesicles containing the glucose transporter GLUT4 from intracellular storage sites to the cell periphery and the subsequent fusion of these vesicles with the plasma membrane, resulting in the externalization of GLUT4. Fusion of the GLUT4-containing vesicles with the plasma membrane is mediated by a soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) complex consisting of vesicle-associated membrane protein 2 (VAMP2), 23-kDa synaptosomal-associated protein (SNAP23), and syntaxin4. We have now generated mouse embryos deficient in the syntaxin4 binding protein Munc18c and show that the insulin-induced appearance of GLUT4 at the cell surface is enhanced in adipocytes derived from these Munc18c−/− mice compared with that in Munc18c+/+ cells. Wortmannin, an inhibitor of PI3K, inhibited insulin-stimulated GLUT4 externalization, without affecting GLUT4 translocation to the cell periphery, in Munc18c+/+ adipocytes, but it did not affect GLUT4 externalization in Munc18c−/− cells. Phosphatidylinositol 3-phosphate, which induced GLUT4 translocation to the cell periphery without externalization in Munc18c+/+ cells, elicited GLUT4 externalization in Munc18c−/− cells. These findings demonstrate that Munc18c inhibits insulin-stimulated externalization of GLUT4 in a wortmannin-sensitive manner, and they suggest that disruption of the interaction between syntaxin4 and Munc18c in adipocytes might result in enhancement of insulin-stimulated GLUT4 externalization.