tbuckley/cabot-search huggingface dataset:
Flagellin Perception Varies Quantitatively in Arabidopsis thaliana and Its Relatives
Authors: M. M. Vetter, I. Kronholm, F. He, H. Haweker, M. Reymond, J. Bergelson, S. Robatzek, J. de Meaux
Journal: Molecular Biology and Evolution (2012)

Much is known about the evolution of plant immunity components directed against specific pathogen strains: They show pervasive functional variation and have the potential to coevolve with pathogen populations. However, plants are effectively protected against most microbes by generalist immunity components that detect conserved pathogen-associated molecular patterns (PAMPs) and control the onset of PAMP-triggered immunity. In Arabidopsis thaliana, the receptor kinase flagellin sensing 2 (FLS2) confers recognition of bacterial flagellin (flg22) and activates a manifold defense response. To decipher the evolution of this system, we performed functional assays across a large set of A. thaliana genotypes and Brassicaceae relatives. We reveal extensive variation in flg22 perception, most of which results from changes in protein abundance. The observed variation correlates with both the severity of elicited defense responses and bacterial proliferation. We analyzed nucleotide variation segregating at FLS2 in A. thaliana and detected a pattern of variation suggestive of the rapid fixation of a novel adaptive allele. However, our study also shows that evolution at the receptor locus alone does not explain the evolution of flagellin perception; instead, components common to pathways downstream of PAMP perception likely contribute to the observed quantitative variation. Within and among close relatives, PAMP perception evolves quantitatively, which contrasts with the changes in recognition typically associated with the evolution of R genes.
Is Human Hibernation Possible?
Authors: Cheng Chi Lee
Journal: Annual Review of Medicine (2008)

The induction of hypometabolism in cells and organs to reduce ischemia damage holds enormous clinical promise in diverse fields, including treatment of stroke and heart attack. However, the thought that humans can undergo a severe hypometabolic state analogous to hibernation borders on science fiction. Some mammals can enter a severe hypothermic state during hibernation in which metabolic activity is extremely low, and yet full viability is restored when the animal arouses from such a state. To date, the underlying mechanism for hibernation or similar behaviors remains an enigma. The beneficial effect of hypothermia, which reduces cellular metabolic demands, has many well-established clinical applications. However, severe hypothermia induced by clinical drugs is extremely difficult and is associated with dramatically increased rates of cardiac arrest for nonhibernators. The recent discovery of a biomolecule, 5′-AMP, which allows nonhibernating mammals to rapidly and safely enter severe hypothermia could remove this impediment and enable the wide adoption of hypothermia as a routine clinical tool.
Fat or Fit: What Is More Important?
Authors: Vojtech Hainer, Hermann Toplak, Vladimír Stich
Journal: Diabetes Care (2009)

The prevalence of obesity is increasing worldwide, and obesity represents one of the major health hazards (1). Obesity was shown to be linked to an increased mortality and morbidity. However, obesity is often associated with modifications of physical activity level. Physical activity level itself affects the health status of the individual and thus may be a confounding variable in the obesity-mortality/morbidity relationship. Understanding the role of physical activity in the development of obesity-associated health hazards appears crucial for effective treatment of obesity and prevention of its complications.

A large number of prospective studies have paid attention to the relationship between adiposity (i.e., degree of overweight/obesity) and mortality or morbidity. In the classic Framingham Heart Study (2), the degree of obesity predicted the incidence of cardiovascular disease. In the Harvard Alumni Health Study (3), men with the highest BMI (>26.0 kg/m2) had the highest risk of mortality. The Nurses Health Study (4) shows the lowest all-cause mortality and morbidity rates in subjects with the lowest BMI. The British Regional Heart Study (5) found an elevated all-cause mortality in men with BMI  30 kg/m2. A German study in obese subjects did show an elevated risk of all-cause mortality in obese subjects when compared with individuals with the lowest BMI, but, interestingly, did not find a difference in mortality rates between grossly obese (32 < BMI < 40 kg/m2) and overweight/moderately obese (25 < BMI < 32 kg/m2) patients (6). Abdominal fat distribution characterized by a higher waist-to-hip and waist-to-thigh ratio increases the risk of mortality not only among obese (BMI ≥30.0 kg/m2), but also among normal-weight (BMI 18.5–24.9 kg/m2) young and middle-aged adults (7). Measures of abdominal adiposity strongly and positively predict mortality, independent of BMI, among both white and black adults (8 …
Factor V Leiden, Prothrombin 20210 Gene Variant, and Risk of Myocardial Infarction
Authors: Mae B. Hultin, Roger C. Grimson
Journal: Circulation (1999)

Doggen et al 1 reported a case-control study assessing the effect of factor V Leiden and the prothrombin 20210 gene variant on the risk of myocardial infarction in men.The authors stated in their conclusions that "the 20210 G3 A variant of prothrombin is associated with an increased risk of myocardial infarction" and that "the combined presence of major cardiovascular risk factors and carriership of a coagulation defect increases the risk considerably."A review of their data in Tables 1 through 4 leads us to conclude that neither claim is supported by statistical significance.In Table 2, the prevalence of the prothrombin variant in cases (1.8%) is not significantly different from the prevalence in controls (1.2%) by the 2 test, with an OR of 1.5 and a CI (0.6 -3.8) that includes unity.A larger study would be required to prove that an OR of 1.5 is truly increased.The likelihood that this OR of 1.5 is not significantly different from 1.0 is also suggested by the fact that it is based on the unexpected finding of a lower prevalence of the variant in the controls (1.2%) than in the general population(2%) rather than a higher prevalence in the cases.The second conclusion, that a coagulation defect added to the effect of a metabolic defect, also does not stand up to scrutiny of the data.In Table 3, the ORs of 6.1 and 3.3, with their overlapping CIs of 3.0 -12.5 and 2.5-4.2,respectively, indicate that smoking increased the risk of myocardial infarction, with or without a coagulation defect, but do not prove that factor V Leiden or the prothrombin variant significantly added to the risk.Without access to the original data, we cannot calculate the P value for this comparison of age-adjusted ORs, but the wide overlap of the CIs suggests that a significant difference between the 2 ORs was not found.Similar observations apply to the subset analyses of the effect of obesity and hypertension in Table 4.Only the pooled data for any "metabolic defect" and any coagulation defect, shown in Table 3, appear possibly to have achieved statistical significance.The authors should have explicitly stated the presence or absence of statistical significance for each of the comparisons of risk that they published in Tables 1 through 4, a minimum of 23 comparisons, for which a P value of Ͻ0.05 may be found at least once by chance.We conclude that the authors have not proven that the prothrombin 20210 gene variant, in the absence of factor V Leiden, increases the risk of myocardial infarction.
Role of Hypoxia-Inducible Factor 1 in Gastric Cancer Cell Growth, Angiogenesis, and Vessel Maturation
Authors: O. Stoeltzing, M. F. McCarty, J. S. Wey, F. Fan, W. Liu, A. Belcheva, C. D. Bucana, G. L. Semenza, L. M. Ellis
Journal: JNCI Journal of the National Cancer Institute (2004)

Hypoxia-inducible factor 1 (HIF-1), a heterodimer comprising the oxygen-regulated subunit, HIF-1alpha, and HIF-1beta, mediates transcription of the gene for vascular endothelial growth factor (VEGF). Overexpression of HIF-1alpha is associated with tumor angiogenesis and tumor cell proliferation and invasion. We examined the effects of inhibiting HIF-1alpha activity on angiogenesis and human gastric cancer growth in vivo.Human gastric cancer TMK-1 cells were stably transfected with pHIF-1alphaDN, an expression plasmid encoding a dominant-negative form of HIF-1alpha that dimerizes with endogenous HIF-1beta to produce HIF-1 complexes that cannot activate transcription, or with the empty expression vector (pCEP4). Two clones of pHIF-1alphaDN-transfected cells, DN2 and DN3, were tested in all experiments. We used an enzyme-linked immunosorbent assay to measure VEGF secretion by transfected cells cultured in hypoxic (1% O2) or nonhypoxic (20% O2) conditions. We used subcutaneous and orthotopic mouse tumor models to examine the growth of tumors derived from injected pHIF-1alphaDN-or pCEP4-transfected cells. Tumor cell proliferation, vessel area (a measure of functional vascular volume), and tumor endothelial cell association with pericyte-like cells (a measure of vessel maturation) were analyzed by immunohistochemical or immunofluorescent staining. All statistical tests were two-sided.DN2 cells and DN3 cells secreted less VEGF than pCEP4-transfected TMK-1 cells when cultured in nonhypoxic or hypoxic conditions (e.g., DN2 versus pCEP4 in nonhypoxic conditions: 645 pg of VEGF/10(6) cells versus 1591 pg of VEGF/10(6) cells, difference = 946 pg of VEGF/10(6) cells [95% confidence interval [CI] = 640 to 1251 pg of VEGF/10(6) cells; P =.006]; DN2 versus pCEP4 in hypoxic conditions: 785 pg of VEGF/10(6) cells versus 2807 pg of VEGF/10(6) cells, difference = 2022 pg of VEGF/10(6) cells [95% CI = 1871 to 2152 pg of VEGF/10(6) cells; P<.001]). In the subcutaneous tumor model, tumors derived from DN2 or DN3 cells had lower final volumes, weights, and vessel areas, less tumor endothelial cell association with desmin-positive cells, and fewer proliferating tumor cells than tumors derived from pCEP4-transfected cells. In the orthotopic tumor model, tumors derived from DN2 cells had smaller volumes and less vessel area and maturation than tumors derived from pCEP4-transfected cells.Inhibition of HIF-1alpha activity impairs gastric tumor growth, angiogenesis, and vessel maturation.
Inflammation: friend or foe of muscle remodelling in COPD?
Authors: R. C. J. Langen, A. M. W. J. Schols
Journal: European Respiratory Journal (2007)

n enhanced systemic inflammatory response is a typical feature of chronic diseases, including chronic obstructive pulmonary disease (COPD), cancer, rheumatoid arthritis and chronic heart failure.The pattern and degree of systemic cytokine elevation is remarkably comparable among these conditions, despite different primary organ pathology.Interestingly, these diseases share skeletal muscle weakness and wasting as a common phenomenon in the disease course, and experimental studies using different acute and chronic disease models have clearly implicated cytokinemediated effects, particularly of tumour necrosis factor (TNF)-a, on muscle contractility and muscle atrophy and regeneration.
Injury rates, types, mechanisms and risk factors in female youth ice hockey
Authors: Melissa D Decloe, Willem H Meeuwisse, Brent E Hagel, Carolyn A Emery
Journal: British Journal of Sports Medicine (2013)

Background The objectives of this cohort study were to examine the rate, types, mechanisms and risk factors for injury in female youth (ages 9–17) ice hockey players in the Girls Hockey Calgary Association. Methods The main outcome was ice hockey injury, defined as any injury occurring during the 2008/2009 season that required medical attention, and/or removal from a session and/or missing a subsequent session. Potential risk factors included age group, level of play, previous injury, ice hockey experience, physical activity level, weight, height, position of play and menarche. Incidence rate ratios (IRR) were estimated with Poisson Regression adjusted for cluster (team). Exposure data were collected for every session for each participating player. Results Twenty-eight teams (n=324) from Atom (ages 9–10), PeeWee (11–12), Bantam (13–14) and Midget (15–17) participated with 53 reported injuries. The overall injury rate was 1.9 injuries/1000 player-hours (95% CI 1.4 to 2.7). Previous injury (IRR=2.7, 95% CI 1.7 to 4.3), games (IRR=2.1, 95% CI 1.1 to 4.2), menarche (PeeWee) (IRR=4.1, 95% CI 1.0 to 16.8) were significant risk factors. In Midget, the more elite divisions were associated with a lower injury risk (A-IRR=0.2, 95% CI 0.1 to 0.5) (AAA-IRR=0.5, 95% CI 0.2 to 0.9). Conclusions Injury rates were lower in this study than previously found in male youth and women's ice hockey populations. Previous injury and game play as risk factors are consistent with the literature. Menarche as a risk factor is a new finding in this study. This research will inform future studies of the development of injury prevention strategies in this population.
Immunoglobulin G (IgG), IgG1, and IgG2 determinations from endoscopic biopsy specimens in control, Crohn's disease, and ulcerative colitis subjects.
Authors: J Ruthlein, M Ibe, W Burghardt, J Mossner, I O Auer
Journal: Gut (1992)

Acute exacerbations of chronic inflammatory bowel disease (ulcerative colitis and Crohn9s disease) are characterised by an increase in immunoglobulin G (IgG) positive cells in the mucosa, whereas uninflamed mucosa of inflammatory bowel disease patients displays only moderately increased or normal numbers of these cells. Previous data suggest that acute exacerbations of ulcerative colitis and Crohn9s disease can be distinguished by different IgG subclass expression of mucosal immunocytes and a different IgG subclass production pattern of lamina propria lymphocytes. A procedure to obtain enough intestinal mononuclear cells from biopsy specimens to measure in vitro IgG and IgG1 production in control subjects and various patient groups has been established. IgG2 could be measured in Crohn9s disease and ulcerative colitis only, as the concentrations in control subjects were below the sensitivity of the ELISA method. We found that IgG and IgG1 production correlated with the degree of local inflammation in both diseases, even in slightly inflamed mucosa, compared with control subjects. The proportion of IgG1 subclass was significantly increased in severely inflamed mucosa of both ulcerative colitis and Crohn9s disease patients. A major difference between Crohn9s disease and ulcerative colitis mucosa is apparent in mild or no inflammation. In Crohn9s disease mucosa in remission, the IgG1/IgG ratio is comparable with that in controls, yet ulcerative colitis mucosa still displays significantly increased proportions of IgG1. In addition, the IgG2/IgG ratio is 0.12 in ulcerative colitis and 0.19 in Crohn9s disease patients. The results show the dependence of local IgG and IgG1 production on the degree of inflammation and that an increase in subclass IgG1 in ulcerative colitis is present at all stages, including remission. These findings support the hypothesis that different immunoregulatory mechanisms are involved in Crohn9s disease and ulcerative colitis. Environmental stimuli or genetic background may be responsible for the observed differences.
Bone Morphogenetic Protein Signaling Suppresses Tumorigenesis at Gastric Epithelial Transition Zones in Mice
Authors: Sylvia A. Bleuming, Xi C. He, Liudmila L. Kodach, James C. Hardwick, Frieda A. Koopman, Fiebo J. ten Kate, Sander J.H. van Deventer, Daniel W. Hommes, Maikel P. Peppelenbosch, G. Johan Offerhaus, Linheng Li, Gijs R. van den Brink
Journal: Cancer Research (2007)

Abstract Bone morphogenetic protein (BMP) signaling is known to suppress oncogenesis in the small and large intestine of mice and humans. We examined the role of Bmpr1a signaling in the stomach. On conditional inactivation of Bmpr1a, mice developed neoplastic lesions specifically in the squamocolumnar and gastrointestinal transition zones. We hypothesized that the regulation of epithelial cell fate may be less well defined in these junctional zones than in the adjacent epithelium and found that the mucosa at the squamocolumnar junction in mice shows a lack of differentiated fundic gland cell types and that foveolar cells at the gastrointestinal junctional zone lack expression of the foveolar cell marker Muc5ac. Precursor cell proliferation in both transition zones was higher than in the surrounding epithelium. Our data show that BMP signaling through Bmpr1a suppresses tumorigenesis at gastric epithelial junctional zones that are distinct from the adjacent gastric epithelium in both cellular differentiation and proliferation. [Cancer Res 2007;67(17):8149–55]
Mage-A Cancer/Testis Antigens Inhibit p53 Function by Blocking Its Interaction with Chromatin
Authors: Lynnette Marcar, Nicola J. MacLaine, Ted R. Hupp, David W. Meek
Journal: Cancer Research (2010)

Abstract The p53 tumor suppressor plays a major protective role in tumor prevention by coordinating changes in gene expression that lead to the elimination of cancer cells. Mage-A proteins comprise a family of metastasis-associated transcriptional regulators that potently inhibit p53 function. Here, we show that Mage-A interacts with 3 distinct peptides each of which is located within the DNA binding surface of the core domain of p53 and encompasses amino acids that are critical for site-specific DNA binding. These data suggest that Mage-A may block the association of p53 with its cognate sites in chromatin. Consistent with this idea, silencing of Mage-A expression leads to upregulation of several p53-responsive genes in a p53-dependent manner and stimulates by several fold the interaction of p53 with the p21, MDM2, and PUMA promoters. Notably, these effects can occur in the absence of genotoxic stress, leading in a p53-dependent manner, to cell-cycle delay and increased cell death. These data reveal a novel mechanism by which Mage-A proteins may suppress the p53 transcriptional program during tumor development and highlight the p53/Mage-A interaction as a prospective therapeutic target. Cancer Res; 70(24); 10362–70. ©2010 AACR.
Zoom Zoom: Racing CARs for Multiple Myeloma
Authors: Marcela V. Maus, Carl H. June
Journal: Clinical Cancer Research (2013)

Chimeric antigen receptors redirect T cells to surface antigens. Discovery and validation of appropriate target antigens expand the possible indications for chimeric-antigen receptor (CAR)-T cells. B-cell maturation antigen (BCMA) is expressed only on mature B cells and plasma cells and promotes their survival. BCMA is a promising target for CAR-T cells in multiple myeloma.
The long‐acting β2‐agonist salmeterol xinafoate: effects on airway inflammation in asthma
Authors: J A Roberts, P Bradding, K M Britten, A F Walls, S Wilson, C Gratziou, S T Holgate, P H Howarth
Journal: European Respiratory Journal (1999)

Salmeterol xinafoate is an inhaled long-acting beta2-adrenoceptor agonist recently introduced for the treatment of asthma. Both in vitro and animal studies suggest that it may have anti-inflammatory activities of benefit in this disease. To assess this directly, the effects of 6 weeks' treatment with salmeterol on indices of clinical activity, airway dysfunction and inflammation in subjects with stable atopic asthma were investigated. In a double blind study, asthmatic patients were randomized to 6 weeks' treatment with either salmeterol 50 microg twice daily (n=14) or placebo (n=12). They underwent bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsy immediately before starting treatment and again after 6 weeks. Treatment with salmeterol improved clinical indices of asthma activity, but there were no changes in BAL differential cell counts or mediator levels, and no change in T-cell numbers or activation status. In the biopsy specimens there were no changes in numbers of inflammatory cells, sub-basement membrane collagen deposition or mast cell degranulation. Regular treatment with salmeterol improves clinical indices of asthma but has no effect on the underlying inflammatory process. These findings strengthen guideline recommendations that long-acting beta2-agonists should not be prescribed as sole antiasthma medication.
Pleurodesis: state of the art
Authors: F Rodriguez-Panadero, VB Antony
Journal: European Respiratory Journal (1997)

Pleurodesis aims to achieve a symphysis between parietal and visceral pleural surfaces, in order to prevent accumulation of fluid or air in the pleural space. Its major indications are malignant effusions and pneumothorax, and a re-expandable lung is essential for the success of the technique. Moreover, expectation of a reasonably long survival is important before attempting pleurodesis. A successful lung re-expansion is unlikely if the pleural pressure falls more than 20 cmH2O x L(-1) of fluid removed, because there is a central bronchial obstruction or the lung is trapped by tumour and/or fibrin. Pleural fluid pH (&lt;7.20) is a good indicator of the presence of trapped lung; moreover, a successful pleurodesis is less likely when pH is low, and this parameter is also a good predictor for survival of the patients. Among the many sclerosing agents that have been used for pleurodesis, talc has achieved the best results, with an average success rate of approximately 90%. The cellular and biochemical mechanisms involved in pleurodesis may be specific to the agent used, however, they may all follow a common final pathway leading to activation of the pleural coagulation cascade, the appearance of fibrin networks, and the proliferation of fibroblasts. The details of these mechanisms are still unclear and need to be further elaborated.