tbuckley/cabot-search huggingface dataset:
Gene Expression Markers of Efficacy and Resistance to Cetuximab Treatment in Metastatic Colorectal Cancer: Results from CALGB 80203 (Alliance)
Authors: Stephanie M. Cushman, Chen Jiang, Ace J. Hatch, Ivo Shterev, Alexander B. Sibley, Donna Niedzwiecki, Alan P. Venook, Kouros Owzar, Herbert I. Hurwitz, Andrew B. Nixon
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Formalin-fixed, paraffin-embedded tumor samples from CALGB 80203 were analyzed for expression of EGFR axis–related genes to identify prognostic or predictive biomarkers for cetuximab treatment. Patients and Methods: Patients (238 total) with first-line metastatic colorectal cancer (mCRC) were randomized to FOLFOX or FOLFIRI chemotherapy ± cetuximab. qRT-PCR analyses were conducted on tissues from 103 patients at baseline to measure gene expression levels of HER-related genes, including amphiregulin (AREG), betacellulin (BTC), NT5E (CD73), DUSP4, EGF, EGFR, epigen (EPGN), epiregulin (EREG), HBEGF, ERBB2 (HER2), ERBB3 (HER3), ERBB4 (HER4), PHLDA1, and TGFA. The interactions between expression levels and treatment with respect to progression-free survival (PFS) and overall survival (OS) were modeled using multiplicative Cox proportional hazards models. Results: High tumor mRNA levels of HER2 [hazard ratio (HR), 0.64; P = 0.002] and EREG (HR, 0.89; P = 0.016) were prognostic markers associated with longer PFS across all patients. HER3 and CD73 expression levels were identified as potential predictive markers of benefit from cetuximab. In KRAS wild-type (WT) tumors, low HER3 expression was associated with longer OS from cetuximab treatment, whereas high HER3 expression was associated with shorter OS from cetuximab treatment (chemo + cetuximab: HR, 1.15; chemo-only: HR, 0.48; Pinteraction = 0.029). High CD73 expression was associated with longer PFS from cetuximab treatment in patients with KRAS-WT (chemo + cetuximab: HR, 0.91; chemo-only: HR, 1.57; Pinteraction = 0.026) and KRAS-mutant (Mut) tumors (chemo + cetuximab: HR, 0.80; chemo-only: HR, 1.29; P = 0.025). Conclusions: Gene expression of HER3 and CD73 was identified as a potential predictive marker for cetuximab. These data implicate HER axis signaling and immune modulation as potential mechanisms of cetuximab action and sensitivity. Clin Cancer Res; 21(5); 1078–86. ©2014 AACR.
Effectiveness of the PLAYgrounds programme on PA levels during recess in 6-year-old to 12-year-old children
Authors: Mirka Janssen, Jos W R Twisk, Huub M Toussaint, Willem van Mechelen, Evert A L M Verhagen
Journal: British Journal of Sports Medicine (2013)

Worldwide levels of daily physical activity (PA) in children are low. This has negative health consequences. Schools have been recognised as key settings to promote PA. This study evaluates the effectiveness of the playground programme PLAYgrounds on increasing PA.PLAYgrounds was evaluated by a controlled trial, with a follow-up during one school year (10 months). Accelerometer data were collected on 1500 children in total, divided over 19 sampling moments (every 2 weeks). SOPLAY data were collected at nine sampling moments (once a month). Four intervention and four control schools were matched for playground size, number of pupils and PA levels at baseline. The intervention consisted of restructuring the playground by playground markings and by encouragement of the active use of the playground, through the provision of play equipment and educational measures such as adult encouragement and supporting physical education classes. Multilevel regression analyses were performed to analyse the effects of the intervention.PA levels in the intervention group (moderate PA) were significantly different (p<0.001) from the control group (light PA). During the intervention on an average 77.3% of the children engaged in moderate-to-vigorous physical activity in the intervention group and 38.7% in the control group. The effect of the intervention was significantly stronger for girls than for boys (p<0.001).The PLAYgrounds programme was effective in increasing PA levels in children during recess over the course of one school year. Thus, the programme could be used to provide structured PA promotion.
Central airway stenosis in a patient with autoimmune pancreatitis
Authors: M. Ito, M. Yasuo, H. Yamamoto, K. Tsushima, T. Tanabe, T. Yokoyama, H. Hamano, S. Kawa, T. Uehara, T. Honda, S. Kawakami, K. Kubo
Journal: European Respiratory Journal (2009)

Autoimmune pancreatitis is a unique form of chronic pancreatitis characterised by a high-serum immunoglobulin (Ig)G4 concentration involving various extra pancreatic lesions. A 63-yr-old female with autoimmune pancreatitis complained of cough. Chest computed tomography revealed an irregular stenosis of the central airway, lung hilar and mediastinal lymph node swelling, and a marked thickness of the bronchovascular bundle. Bronchoscopic examination revealed an irregular tracheobronchial stenosis accompanied with an oedematous mucosa and engorged vessels. Lung hilar and mediastinal lymph node swelling, central airway stenosis and bronchoscopic findings remarkably resembled those of sarcoidosis. Bronchial biopsy specimens demonstrated diffuse infiltrations of plasma cells, lymphocytes and eosinophils with fibrosis. Immunostaining showed infiltration of several IgG4-positive plasma cells. The patient was treated with oral prednisolone at 1 mg·kg −1 ·day −1 for pancreatic lesions. A month later, the lung lesions, including central airway stenosis, lung hilar and mediastinal lymph node swelling, and bronchovascular bundle thickness, had dramatically improved along with improvement of pancreatitis, thus indicating a close association between the two conditions. This is the first report of a patient with autoimmune pancreatitis showing central airway stenosis similar to that of sarcoidosis.
The position of diagnostic laparoscopy in current fertility practice
Authors: Jan Bosteels, Bruno Van Herendael, Steven Weyers, Thomas D'Hooghe
Journal: Human Reproduction Update (2007)

In everyday clinical practice, it is not always clear if and when exactly in the fertility work-up a diagnostic laparoscopy should be offered. The aim of this review is to analyse the available evidence with respect to alternative diagnostic methods for detecting tuboperitoneal infertility and with respect to the position of diagnostic laparoscopy in women with infertility. A literature search of the National Library of Medicine and the National Institutes of Health (PubMed) was performed using the key words 'diagnostic laparoscopy and infertility'. The study methodology was carefully considered in an effort to present conclusions preferably based on randomized controlled trials (RCTs). The routine use of diagnostic laparoscopy for the evaluation of all cases of female infertility is currently under debate. According to data published in retrospective non-controlled studies, diagnostic laparoscopy after several failed cycles of ovulation induction enables the detection of a significant proportion of pelvic pathology amenable to treatment. A Cochrane review has shown that laparoscopic ovarian diathermy in clomiphene-resistant polycystic ovarian syndrome is at least as effective as gonadotrophin treatment, and results in a lower multiple pregnancy rate. The role of laparoscopy before the start of treatment with intrauterine insemination is controversial, according to one RCT. In women with bilateral ultrasonically visible hydrosalpinges, two RCTs have demonstrated increased implantation and pregnancy rates in IVF cycles after salpingectomy. Although RCTs which have studied the benefit of laparoscopic surgery in moderate or severe endometriosis are still lacking, its value has generally been accepted. In conclusion, some specific clinical settings, solid evidence is available to recommend the use of diagnostic laparoscopy in current fertility practice. There is however a need for more RCTs to answer remaining questions regarding its value in the diagnosis and treatment of some patients with infertility.
Stem cells: you can't tell a cell by its cover
Authors: I. Rogers
Journal: Human Reproduction Update (2003)

Embryonic stem (ES) cells are capable of unlimited self-renewal and have the ability to give rise to all tissue types in the body. The use of human ES cells for tissue and cell therapeutics has been suggested, but is limited by ethical concerns as these cells are derived from the inner cell mass of human embryos. In addition, the need for HLA matching of ES cell-derived tissues for allogeneic transplantation would require a bank of several thousand ES cell lines to make tissue therapeutics practical. Recently, adult stem cells-of which those in bone marrow are the best studied-have been shown to be capable of multilineage differentiation into cells of various non-blood tissues. Umbilical cord blood (UCB) haematopoietic stem cells have been shown to be equivalent to bone marrow stem cells for reconstitution of the haematopoietic system. Preliminary studies have also demonstrated that UCB haematopoietic stem cells are multipotent and capable of differentiating into non-blood cell types. This observation raises the exciting possibility of replacing human ES cells for tissue and cell therapeutics with UCB blood haematopoietic stem cells that are normally discarded with the placenta after delivery.
Helper T Cell Type 1 and 2 Cytokines Regulate C-C Chemokine Expression in Mouse Pleural Mesothelial Cells
Authors: KAMAL A. MOHAMMED, NAJMUNNISA NASREEN, MELISSA J. WARD, VEENA B. ANTONY
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

The recruitment of leukocytes to an area of injury or inflammation site is one of the most fundamental host defenses. Pulmonary tuberculosis is characterized by granulomatous inflammation with an extensive infiltration of mononuclear cells. In tuberculous pleurisy pleural mesothelial cells are exposed to mycobacteria in the pleural space. In this study we demonstrate that mouse pleural mesothelial cells (PMCs), when stimulated with BCG or IFN- γ , produced MIP-1 α and MCP-1 in vitro. IFN- γ enhanced the BCG-mediated MIP-1 α and MCP-1 expression in a concentration-dependent manner. The RT-PCR studies also confirmed that both BCG and IFN- γ induce chemokine expression. IL-4 inhibited the BCG-mediated MIP-1 α and MCP-1 expression in a concentration-dependent manner. The lower concentrations of IL-4 were ineffective; however, at higher concentrations, the inhibitory effect of IL-4 persisted for 24 h and decreased thereafter. BCG stimulation resulted in an increase of IFN- γ and IL-4 receptors on PMCs. Our results demonstrate that Th1 and Th2 cytokines may regulate the C-C chemokine expression in PMCs and thus play a biologically important role in mononuclear cell recruitment to the pleural space.
Early patterns of wheezing in asthmatic and nonasthmatic children
Authors: Alfredo Cano Garcinuño, Isabel Mora Gandarillas
Journal: European Respiratory Journal (2013)

The aim of this study was to describe the time patterns of wheezing in both asthmatic and nonasthmatic children during the first 36 months of life, and to determine whether there are asthma-related breakpoints in the incidence of wheezing. Data from a historical cohort of children followed from birth to 6 years (SLAM cohort) were used. Wheezing episodes until 36 months and asthma at 6 years were both recorded by a doctor. Monthly mean incidence rate of wheezing and rate ratio were calculated. Joinpoint regression models were built to identify breakpoints in the risk of wheeze. Complete information was available for 3739 children. Wheezing in the first 36 months was more frequent in asthmatic than in nonasthmatic children (rate ratio 2.62, 95% CI 1.81–3.78). Differences were appreciable within the first months and increased steadily thereafter because of a persistently high rate in asthmatic children. No breakpoint in the rate ratio could be identified. Asthmatic children exhibited a one-phase curve of incidence and nonasthmatic children exhibited a two-phase curve. However, children with allergic asthma also displayed a two-phase curve. There is no identifiable breakpoint during the first 36 months of life at which the incidence of wheezing in asthmatic children begins to stand out.
Quantitative angiographic morphology of the coronary artery lesions at risk of thrombotic occlusion.
Authors: Y Taeymans, P Théroux, J Lespérance, D Waters
Journal: Circulation (1992)

Coronary angiography in acute myocardial infarction has revealed complicated atherosclerotic plaque and a high rate of thrombotic occlusion. However, the characteristics of lesions at high risk of subsequent occlusion are not well known.In the present study, the qualitative and quantitative angiographic features of 38 coronary artery lesions that occluded within 3 years to cause an acute myocardial infarction were compared with 64 control segments from the same patients that did not occlude. Compared with control lesions, the lesions that occluded were more likely to have a division branch originating within the stenosis (76% versus 52%, p less than 0.05). The percent lumen diameter reduction was more severe (47.5 +/- 17.8% versus 41 +/- 12.5%, p less than 0.05) and the inflow (21 +/- 10 degrees versus 16 +/- 7 degrees, p less than 0.05) and outflow (20 +/- 10 degrees versus 16 +/- 8 degrees, p less than 0.05) angles of the stenosis were steeper. Time to myocardial infarction after the angiogram interacted with the importance of these features (p less than 0.02). Thus, paired analysis of the lesions that occluded within 3 months and of the most severe control lesion from each patient showed percent lumen diameter reduction of 62.1 +/- 11.5% and 46.4 +/- 11.4%, respectively (p less than 0.001). The length of the stenosis, its asymmetry, and the irregularity of the contours did not help differentiate occlusive from control segments.Coronary artery lesions at high risk of thrombotic occlusion share common characteristics that favor higher shear stress and flow separation.
Identification and characterization of IgA antibodies against β2-glycoprotein I in childhood Henoch-Schönlein purpura
Authors: Y.H. Yang, C.J. Chang, Y.H. Chuang, H.Y. Hsu, H.H. Yu, J.H. Lee, L.C. Wang, Y.T. Lin, B.L. Chiang
Journal: British Journal of Dermatology (2012)

Henoch-Schönlein purpura (HSP) is a common IgA-mediated vasculitis in children. The antigenic target for IgA is to be determined.To test whether β2-glycoprotein I (β2GPI) is an antigenic target for IgA in childhood HSP, and to evaluate the clinical implications and pathogenic role of such IgA autoantibodies.The reactivity of patients' plasma samples and purified polyclonal IgA with β2GPI, β2GPI-derived peptides and endothelial cells was tested by enzyme-linked immunosorbent assay. The association between clinical manifestations and IgA anti-β2GPI antibodies was also analysed. Finally, IgA-mediated cytotoxicity on endothelial cells was further evaluated.At the acute stage, patients with HSP had significantly higher plasma levels of IgA antibodies against β2GPI than healthy controls [reference units (RU) 1.14 ± 0.8 vs. 0.42 ± 0.24, P < 0.001]. IgA anti-β2GPI antibodies were associated with the presence of joint manifestations (with vs. without joint involvement, 1.15 ± 0.64 vs. 0.85 ± 0.47, P = 0.0341) and heavy proteinuria (with vs. without heavy proteinuria, 2.09 ± 2.02 vs. 1.04 ± 0.62, P = 0.0028). Polyclonal IgA from plasma samples positive for IgA anti-β2GPI antibodies bound well not only to β2GPI with Kd values < 10(-5) mol L(-1), but also to some β2GPI-dereived linear peptides (P3, P5, P7, P11 and P12). Moreover, β2GPI-reactive polyclonal IgA also bound well to endothelial cells and induced complement-dependent cell lysis.These findings reveal the clinical and pathogenic relevance of IgA anti-β2GPI antibodies in childhood HSP and suggest that β2GPI may be an important autoantigen for HSP.
The need for proximal mechanisms to understand individual differences in altruism
Authors: Gustavo Carlo, Rick A. Bevins
Journal: Behavioral and Brain Sciences (2002)

There are three concerns regarding Rachlin's altruism model. First, proximal causal mechanisms such as those identified by cognitive neuroscientists and behavioral neuropharmacologists are not emphasized. Second, there is a lack of clear testable hypotheses. And third, extreme forms of altruism are emphasized rather than common forms. We focus on an overarching theme – proximal mechanisms of individual differences in altruism.
RESPONSES TO IMMUNIZATION IN THE THYMUS OF THE ADULT MOUSE
Authors: Edward P. Cohen, Jaroslav Majer, Karen Friedman
Journal: The Journal of Experimental Medicine (1969)

The rate of synthesis of RNA in the thymus glands of adult mice increased after immunization with sheep red blood cells (SRBC). The specific activity of some fractions of RNA, separated first by density gradient centrifugation and then by polyacrylamide gel electrophoresis, was 16-fold higher on day 3 after immunization than control mice not injected. RNA synthesis in the thymus was inhibited by rabbit anti-mouse thymus serum, injected along with antigen. A material was found in RNA extracts from the thymus glands of mice immunized with SRBC which converted a small proportion of either spleen cells or peritoneal cells from nonimmunized mice to form sheep cell hemolysins. Neither extracts from the glands of nonimmunized mice nor the livers of immunized mice were active. Extracts from the thymus glands of mice immunized with rabbit red blood cells (RRBC) were inactive and activity was destroyed by ribonudease. The residual antigen content was not determined. Biologically active extracts from the thymus had a different electrophoretic mobility from active extracts from the spleen.
Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice
Authors: Denis Bedoret, Hugues Wallemacq, Thomas Marichal, Christophe Desmet, Florence Quesada Calvo, Emmanuelle Henry, Rodrigue Closset, Benjamin Dewals, Caroline Thielen, Pascal Gustin, Laurence de Leval, Nico Van Rooijen, Alain Le Moine, Alain Vanderplasschen, Didier Cataldo, Pierre-Vincent Drion, Muriel Moser, Pierre Lekeux, Fabrice Bureau
Journal: Journal of Clinical Investigation (2009)

The respiratory tract is continuously exposed to both innocuous airborne antigens and immunostimulatory molecules of microbial origin, such as LPS. At low concentrations, airborne LPS can induce a lung DC-driven Th2 cell response to harmless inhaled antigens, thereby promoting allergic asthma. However, only a small fraction of people exposed to environmental LPS develop allergic asthma. What prevents most people from mounting a lung DC-driven Th2 response upon exposure to LPS is not understood. Here we have shown that lung interstitial macrophages (IMs), a cell population with no previously described in vivo function, prevent induction of a Th2 response in mice challenged with LPS and an experimental harmless airborne antigen. IMs, but not alveolar macrophages, were found to produce high levels of IL-10 and to inhibit LPS-induced maturation and migration of DCs loaded with the experimental harmless airborne antigen in an IL-10-dependent manner. We further demonstrated that specific in vivo elimination of IMs led to overt asthmatic reactions to innocuous airborne antigens inhaled with low doses of LPS. This study has revealed a crucial role for IMs in maintaining immune homeostasis in the respiratory tract and provides an explanation for the paradox that although airborne LPS has the ability to promote the induction of Th2 responses by lung DCs, it does not provoke airway allergy under normal conditions.
Home energy efficiency and radon related risk of lung cancer: modelling study
Authors: J. Milner, C. Shrubsole, P. Das, B. Jones, I. Ridley, Z. Chalabi, I. Hamilton, B. Armstrong, M. Davies, P. Wilkinson
Journal: BMJ (2014)

<b>Objective</b> To investigate the effect of reducing home ventilation as part of household energy efficiency measures on deaths from radon related lung cancer. <b>Design</b> Modelling study. <b>Setting</b> England. <b>Intervention</b> Home energy efficiency interventions, motivated in part by targets for reducing greenhouse gases, which entail reduction in uncontrolled ventilation in keeping with good practice guidance. <b>Main outcome measures</b> Modelled current and future distributions of indoor radon levels for the English housing stock and associated changes in life years due to lung cancer mortality, estimated using life tables. <b>Results</b> Increasing the air tightness of dwellings (without compensatory purpose-provided ventilation) increased mean indoor radon concentrations by an estimated 56.6%, from 21.2 becquerels per cubic metre (Bq/m<sup>3</sup>) to 33.2 Bq/m<sup>3</sup>. After the lag in lung cancer onset, this would result in an additional annual burden of 4700 life years lost and (at peak) 278 deaths. The increases in radon levels for the millions of homes that would contribute most of the additional burden are below the threshold at which radon remediation measures are cost effective. Fitting extraction fans and trickle ventilators to restore ventilation will help offset the additional burden but only if the ventilation related energy efficiency gains are lost. Mechanical ventilation systems with heat recovery may lower radon levels and the risk of cancer while maintaining the advantage of energy efficiency for the most airtight dwellings but there is potential for a major adverse impact on health if such systems fail. <b>Conclusion</b> Unless specific remediation is used, reducing the ventilation of dwellings will improve energy efficiency only at the expense of population wide adverse impact on indoor exposure to radon and risk of lung cancer. The implications of this and other consequences of changes to ventilation need to be carefully evaluated to ensure that the desirable health and environmental benefits of home energy efficiency are not compromised by avoidable negative impacts on indoor air quality.
Classification of common variable immunodeficiencies using flow cytometry and a memory B-cell functionality assay
Authors: Amelia L. Rösel, Carmen Scheibenbogen, Ulrike Schliesser, André Sollwedel, Bodo Hoffmeister, Leif Hanitsch, Horst von Bernuth, Renate Krüger, Klaus Warnatz, Hans-Dieter Volk, Sybill Thomas
Journal: Journal of Allergy and Clinical Immunology (2014)
A mutated B cell chronic lymphocytic leukemia subset that recognizes and responds to fungi
Authors: Robbert Hoogeboom, Kok P.M. van Kessel, Frans Hochstenbach, Thera A. Wormhoudt, Roy J.A. Reinten, Koen Wagner, Arnon P. Kater, Jeroen E.J. Guikema, Richard J. Bende, Carel J.M. van Noesel
Journal: The Journal of Experimental Medicine (2013)

B cell chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is a clonal expansion of CD5+CD19+ B lymphocytes. Two types of CLLs are being distinguished as carrying either unmutated or somatically mutated immunoglobulins (Igs), which are associated with unfavorable and favorable prognoses, respectively. More than 30% of CLLs can be grouped based on their expression of stereotypic B cell receptors (BCRs), strongly suggesting that distinctive antigens are involved in the development of CLL. Unmutated CLLs, carrying Ig heavy chain variable (IGHV) genes in germline configuration, express low-affinity, poly-, and self-reactive BCRs. However, the antigenic specificity of CLLs with mutated IGHV-genes (M-CLL) remained elusive. In this study, we describe a new subset of M-CLL, expressing stereotypic BCRs highly specific for β-(1,6)-glucan, a major antigenic determinant of yeasts and filamentous fungi. β-(1,6)-glucan binding depended on both the stereotypic Ig heavy and light chains, as well as on a distinct amino acid in the IGHV-CDR3. Reversion of IGHV mutations to germline configuration reduced the affinity for β-(1,6)-glucan, indicating that these BCRs are indeed affinity-selected for their cognate antigen. Moreover, CLL cells expressing these stereotypic receptors proliferate in response to β-(1,6)-glucan. This study establishes a class of common pathogens as functional ligands for a subset of somatically mutated human B cell lymphomas.