tbuckley/cabot-search huggingface dataset:
Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells
Authors: Michael Lotz, Dominique Gütle, Sabrina Walther, Sandrine Ménard, Christian Bogdan, Mathias W. Hornef
Journal: The Journal of Experimental Medicine (2006)

The role of innate immune recognition by intestinal epithelial cells (IECs) in vivo is ill-defined. Here, we used highly enriched primary IECs to analyze Toll-like receptor (TLR) signaling and mechanisms that prevent inappropriate stimulation by the colonizing microflora. Although the lipopolysaccharide (LPS) receptor complex TLR4/MD-2 was present in fetal, neonatal, and adult IECs, LPS-induced nuclear factor κB (NF-κB) activation and chemokine (macrophage inflammatory protein 2 [MIP-2]) secretion was only detected in fetal IECs. Fetal intestinal macrophages, in contrast, were constitutively nonresponsive to LPS. Acquisition of LPS resistance was paralleled by a spontaneous activation of IECs shortly after birth as illustrated by phosphorylation of IκB-α and nuclear translocation of NF-κB p65 in situ as well as transcriptional activation of MIP-2. Importantly, the spontaneous IEC activation occurred in vaginally born mice but not in neonates delivered by Caesarean section or in TLR4-deficient mice, which together with local endotoxin measurements identified LPS as stimulatory agent. The postnatal loss of LPS responsiveness of IECs was associated with a posttranscriptional down-regulation of the interleukin 1 receptor–associated kinase 1, which was essential for epithelial TLR4 signaling in vitro. Thus, unlike intestinal macrophages, IECs acquire TLR tolerance immediately after birth by exposure to exogenous endotoxin to facilitate microbial colonization and the development of a stable intestinal host–microbe homeostasis.
Molecular basis of endothelial dysfunction in sepsis
Authors: Kirsten Peters, Ronald E Unger, Joachim Brunner, C James Kirkpatrick
Journal: Cardiovascular Research (2003)

Sepsis is one of the major causes of mortality in critically ill patients and develops as a result of the host response to infection. A complex network of events is set into motion in the body by the infection and results in the pathogenesis of sepsis. This review article focuses on the molecular mechanisms and components involved in the pathogenesis of sepsis with a major emphasis on the endothelium. This includes sepsis-inducing bacterial components (e.g. endotoxins), cellular targets of these molecules and their responses, host reactions, intracellular and cytokine networks, individual susceptibility and new therapeutic targets in sepsis treatment.
Clinical Evaluation of Defibrillation Testing in an Unselected Population of 2,120 Consecutive Patients Undergoing First Implantable Cardioverter-Defibrillator Implant
Authors: Michele Brignole, Eraldo Occhetta, Maria Grazia Bongiorni, Alessandro Proclemer, Stefano Favale, Saverio Iacopino, Leonardo Calò, Antonello Vado, Gianfranco Buja, Giosuè Mascioli, Fabio Quartieri, Massimo Tritto, Umberto Parravicini, Antonio Castro, Corrado Tomasi, Giovanni Quinto Villani, Matteo Giuseppe D'Acri, Catherine Klersy, Maurizio Gasparini
Journal: Journal of the American College of Cardiology (2012)
Natural selection of K13 mutants of Plasmodium falciparum in response to artemisinin combination therapies in Thailand
Authors: C. Putaporntip, N. Kuamsab, R. Kosuwin, W. Tantiwattanasub, P. Vejakama, T. Sueblinvong, S. Seethamchai, S. Jongwutiwes, A.L. Hughes
Journal: Clinical Microbiology and Infection (2015)
Validation of SAG/RBX2/ROC2 E3 Ubiquitin Ligase as an Anticancer and Radiosensitizing Target
Authors: Lijun Jia, Jie Yang, Xinbao Hao, Min Zheng, Hongbin He, Xiufang Xiong, Liang Xu, Yi Sun
Journal: Clinical Cancer Research (2010)

Sensitive to apoptosis gene (SAG; also known as RBX2 or ROC2) was originally cloned as a redox-inducible antioxidant protein and was later characterized as a RING component of SCF E3 ubiquitin ligases. SAG overexpression inhibits apoptosis induced by many stimuli both in vitro and in vivo. SAG mRNA was overexpressed in human lung tumor tissues with a correlation to poor patient survival. To investigate whether SAG serves as an anticancer target, we determined the effect of SAG silencing on cell proliferation, survival, and radiosensitivity.SAG protein expression in human tumors was evaluated by immunohistochemical staining using tumor tissue arrays. SAG expression in cancer cells was knocked down by siRNA silencing. The anticancer effects of SAG silencing were evaluated by in vitro assays for cell growth and survival and by an in vivo orthotopic xenograft tumor model. Radiosensitization by SAG silencing of human cancer cells was determined by clonogenic survival assay. Apoptosis induction was evaluated by fluorescence-activated cell sorting analysis, caspase-3 activation assay, and Western blotting of apoptosis-associated proteins.SAG was overexpressed in multiple human tumor tissues compared with their normal counterparts. SAG silencing selectively inhibited cancer cell proliferation, suppressed in vivo tumor growth, and sensitized radiation-resistant cancer cells to radiation. Mechanistically, SAG silencing induced apoptosis with accumulation of NOXA, whereas SAG overexpression reduced NOXA levels and shortened NOXA protein half-life.The findings showed that SAG E3 ubiquitin ligase plays an essential role in cancer cell proliferation and tumor growth and may serve as a promising anticancer and radiosensitizing target.
Image‐Predicated Sorting of Adherent Cells Using Photopatterned Hydrogels
Authors: Joseph Kovac, Ylaine Gerardin, Joel Voldman
Journal: Advanced Healthcare Materials (2012)

Using photopatterned hydrogels and selective cell encapsulation, populations of adherent cells are examined using microscopy and sorted into viable sub-populations predicated on their imaged phenotypes. The inexpensive method utilizes commercial reagents and equipment available in many labs, making image-predicated cell sorting an accessible technique for a large number of individual labs.
Synopsis of a Roundtable on Validating Novel Therapeutics for Multiple Myeloma
Authors: William Dalton, Kenneth C. Anderson
Journal: Clinical Cancer Research (2006)

With the identification of new molecular targets and pathways, many new therapeutic approaches are being identified for potential application in the treatment of multiple myeloma. New chemical compounds and biologics have been developed against molecular targets with substantial scientific evidence that these targets are involved in myeloma development, progression, or relapse. To safely and rapidly bring these advances to bear on the disease, new preclinical models in cells and animals need to be established, as well as prioritization and standardization in current preclinical and clinical validation. An experts' roundtable was convened in November 2005 to discuss shortcomings in current preclinical models and discuss what models are needed to best validate therapeutics and combinations of therapies for multiple myeloma.This exciting event brought together experts in compound validation, preclinical development, and experts in multiple myeloma from academic institutions and the pharmaceutical and biotechnology industries. The goals were to evaluate an algorithm for therapeutic validation and discuss in vitro modeling for target discovery, animal models for preclinical development, and models for testing drug combinations.
Caloric Sweetener Consumption and Dyslipidemia Among US Adults
Authors: Jean A. Welsh, Andrea Sharma, Jerome L. Abramson, Viola Vaccarino, Cathleen Gillespie, Miriam Benedicta Vos
Journal: JAMA (2010)

Dietary carbohydrates have been associated with dyslipidemia, a lipid profile known to increase cardiovascular disease risk. Added sugars (caloric sweeteners used as ingredients in processed or prepared foods) are an increasing and potentially modifiable component in the US diet. No known studies have examined the association between the consumption of added sugars and lipid measures.To assess the association between consumption of added sugars and blood lipid levels in US adults.Cross-sectional study among US adults (n = 6113) from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. Respondents were grouped by intake of added sugars using limits specified in dietary recommendations (< 5% [reference group], 5%-<10%, 10%-<17.5%, 17.5%-<25%, and > or = 25% of total calories). Linear regression was used to estimate adjusted mean lipid levels. Logistic regression was used to determine adjusted odds ratios of dyslipidemia. Interactions between added sugars and sex were evaluated.Adjusted mean high-density lipoprotein cholesterol (HDL-C), geometric mean triglycerides, and mean low-density lipoprotein cholesterol (LDL-C) levels and adjusted odds ratios of dyslipidemia, including low HDL-C levels (< 40 mg/dL for men; < 50 mg/dL for women), high triglyceride levels (> or = 150 mg/dL), high LDL-C levels (> or = 130 mg/dL), or high ratio of triglycerides to HDL-C (> 3.8). Results were weighted to be representative of the US population.A mean of 15.8% of consumed calories was from added sugars. Among participants consuming less than 5%, 5% to less than 17.5%, 17.5% to less than 25%, and 25% or greater of total energy as added sugars, adjusted mean HDL-C levels were, respectively, 58.7, 57.5, 53.7, 51.0, and 47.7 mg/dL (P < .001 for linear trend), geometric mean triglyceride levels were 105, 102, 111, 113, and 114 mg/dL (P < .001 for linear trend), and LDL-C levels modified by sex were 116, 115, 118, 121, and 123 mg/dL among women (P = .047 for linear trend). There were no significant trends in LDL-C levels among men. Among higher consumers (> or = 10% added sugars) the odds of low HDL-C levels were 50% to more than 300% greater compared with the reference group (< 5% added sugars).In this study, there was a statistically significant correlation between dietary added sugars and blood lipid levels among US adults.
Pseudoprogression after high-dose busulfan-thiotepa with autologous stem cell transplantation and radiation therapy in children with brain tumors: Impact on survival
Authors: Laura Negretti, Pierre Blanchard, Dominique Couanet, Virginie Kieffer, Gisele Goma, Jean Louis Habrand, Frédéric Dhermain, Dominique Valteau-Couanet, Jacques Grill, Christelle Dufour
Journal: Neuro-Oncology (2012)

Children with a brain tumor treated with high-dose busulfan-thiotepa with autologous stem cell transplantation (ASCT) and radiation therapy (RT) often experience radiographic changes during follow-up. The purpose of the study was to identify the incidence, time course, risk factors, and clinical outcome of this complication. From May 1988 through May 2007, 110 patients (median age, 3.6 years; range, 1 month to 15.3 years) with a brain tumor had received 1 course of high-dose busulfan-thiotepa with stem cell rescue, followed or preceded by RT as part of their treatment. All MRI follow-up examinations were systematically reviewed. Twenty-three patients (21%) developed neuroradiological abnormalities at a median time of 9.2 months (range, 5.6-17.3 months) after ASCT. All contrast-enhancing lesions appeared in patients who had received RT after ASCT and were localized inside the 50-55Gy isodoses. They disappeared in 14 of 23 patients after a median time of 8 months (range, 3-17 months), leaving microcalcifications in some cases. The presence of MRI abnormalities was an independent prognostic factor for overall survival in the multivariate analysis (hazard ratio, 0.12; 95% confidence interval [CI], 0.04-0.33), with a 5-year overall survival rate of 84% among patients with MRI abnormalities (95% CI, 62-94), compared with 27% (95% CI, 19-37) among those without lesions. MRI-detectable pseudoprogression is a common early finding in children treated with high-dose busulfan-thiotepa followed by radiation therapy and is correlated with a better outcome.
Diabetic Retinopathy and Neuropathy
Authors: Zachary T. Bloomgarden
Journal: Diabetes Care (2005)

This is the seventh in a series of articles on presentations at the American Diabetes Association Annual Meeting, Orlando, Florida, 4–8 June 2004.

Holger Gerhardt (Goteborg, Sweden) discussed pericytes and vascular stability in the diabetic retina, noting that these cells cover most of the endothelium and are present during the development of normal new blood vessels, while proliferative retinopathy classically shows “pericyte drop out” as an early pathological marker. It has been hypothesized that endothelial dysfunction leads to capillary occlusion and regression, causing ischemia, to which neovascularization with subsequent proliferative retinopathy is a response. In this schema, pericyte drop out may occur either before or after the stage of endothelial dysfunction. A number of markers can be used for characterizing pericytes. Mice that do not express platelet-derived growth factor (PDGF)-β have severe diffuse bleeding and die early in the neonatal period. There is diffuse pericyte loss in these mice, suggesting PDGF-β to be an important growth factor for the cells. An endothelium-specific PDGF-β knockout displays a variety of phenotypes with variable degrees of pericyte loss, with areas of pericyte-covered vessels and areas lacking pericytes and with severe retinopathy localized to the areas lacking pericytes. Gerhardt suggested that pericyte drop out is therefore sufficient to cause capillary occlusion and regression, leading to retinal ischemia. Why, though, he asked, is there a proliferative response rather than normal development of well-behaved new vessels repairing the region of ischemia, and how does retinal normal vascular development differ from that seen in neovascularization? The normal advancing vascular sprout extends “tip cells,” which appear to guide the development of the vasculature, following paths produced by astrocytes, which produce vascular endothelial growth factor (VEGF)-α in areas of hypoxia, with astrocyte VEGF-α downregulated after it becomes covered by new vessels. In the developing retina, the VEGF receptor (R)2 …
Aerobic Exercise Decreases Chronic Allergic Lung Inflammation and Airway Remodeling in Mice
Authors: Rodolfo P. Vieira, Renata C. Claudino, Anna Cecília S. Duarte, Ângela B. G. Santos, Adenir Perini, Hugo C. C. Faria Neto, Thais Mauad, Mílton A. Martins, Marisa Dolhnikoff, Celso R. F. Carvalho
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Aerobic conditioning improves exercise capacity and decreases symptoms in patients with asthma. However, its benefits in the context of allergic airway inflammation are poorly understood.To evaluate the effects of two intensities of aerobic exercise on airway inflammation and remodeling in a model of chronic allergic lung inflammation.Mice were subjected to chronic ovalbumin (OVA) sensitization and to 4 weeks of low (OVA+Low) or moderate (OVA+Mod) exercise training in a treadmill. Airway inflammation and remodeling and expression of helper T-cell type 1 and 2 cytokines were evaluated.OVA-induced allergic airway inflammation and remodeling were characterized by an increase in collagen (288%), elastic fiber (56%), smooth muscle (380%), and epithelial (402%) contents (P < 0.001) when compared with the control group. OVA+Low and OVA+Mod groups presented a decrease in bronchoalveolar lavage fluid eosinophils (respectively, 84 and 75%; P < 0.01) and airway walls (respectively, 94 and 58%; P < 0.001) when compared with the OVA group. OVA+Low and OVA+Mod groups also presented a reduction in the number of peribronchial inflammatory cells expressing IL-4 (respectively, 85 and 75%; P < 0.01) and IL-5 (respectively, 88 and 89%; P < 0.01) when compared with the OVA group. Aerobic conditioning did not change the expression of either IFN-gamma or IL-2 by inflammatory cells or plasma levels of IgE or IgG1. OVA+Low and OVA+Mod groups presented an increase in the expression of IL-10 (P < 0.001). Low and moderate aerobic conditioning also reduced airway remodeling in OVA-sensitized mice when compared with the OVA group.We concluded that low and moderate aerobic exercise decreases airway inflammation and remodeling in a murine model of asthma.
Fibroblasts as Host Cells in Latent Leishmaniosis
Authors: Christian Bogdan, Norbert Donhauser, Reinhard Döring, Martin Röllinghoff, Andreas Diefenbach, Michael G. Rittig
Journal: The Journal of Experimental Medicine (2000)

Intracellular parasites are known to persist lifelong in mammalian hosts after the clinical cure of the disease, but the mechanisms of persistence are poorly understood. Here, we show by confocal laser microscopy that in the draining lymph nodes of mice that had healed a cutaneous infection with Leishmania major, 40% of the persisting parasites were associated with fibroblasts forming the reticular meshwork of the lymph nodes. In vitro, both promastigotes and amastigotes of L. major infected primary skin or lymph node fibroblasts. Compared with macrophages, cytokine-activated fibroblasts had a reduced ability to express type 2 nitric oxide synthase and to kill intracellular L. major. These data identify fibroblasts as an important host cell for Leishmania during the chronic phase of infection and suggest that they might serve as safe targets for the parasites in clinically latent disease.
Type 2 Diabetes and 10-Year Risk of Dementia and Cognitive Impairment Among Older Mexican Americans
Authors: Elizabeth R. Mayeda, Mary N. Haan, Alka M. Kanaya, Kristine Yaffe, John Neuhaus
Journal: Diabetes Care (2013)

Type 2 diabetes has been linked with increased risk of dementia and cognitive impairment among older adults and with premature mortality in young and middle-aged adults. No studies have evaluated the association between diabetes and dementia among Mexican Americans, a population with a high burden of diabetes. We evaluated the association of diabetes with incidence of dementia and cognitive impairment without dementia (CIND) among older Mexican Americans while accounting for competing risk from death.This study included 1,617 participants 60-98 years of age from the Sacramento Area Latino Study on Aging followed up to 10 years from 1998. We evaluated the association between diabetes and dementia/CIND with competing risk regression models.Participants free of dementia/CIND at baseline (n = 1,617) were followed annually up to 10 years. There were 677 (41.9%) participants with diabetes, 159 (9.8%) incident dementia/CIND cases, and 361 (22.3%) deaths. Treated and untreated diabetes (hazard ratio 2.12 [95% CI 1.65-2.73] and 2.15 [1.58-2.95]) and dementia/CIND (2.48 [1.75-3.51]) were associated with an increased risk of death. In models adjusted for competing risk of death, those with treated and untreated diabetes had an increased risk of dementia/CIND (2.05 [1.41-2.97] and 1.55 [0.93-2.58]) compared with those without diabetes.These findings provide evidence that the association between type 2 diabetes and dementia/CIND among Mexican Americans remains strong after accounting for competing risk of mortality. Treatments that modify risk of death among those with diabetes may change future dementia risk.
THE IN VIVO FORMATION AND FATE OF ANTIGEN-ANTIBODY COMPLEXES FORMED BY FRAGMENTS AND POLYPEPTIDE CHAINS OF RABBIT γG-ANTIBODIES
Authors: Hans L. Spiegelberg, William O. Weigle
Journal: The Journal of Experimental Medicine (1966)

The in vivo formation and subsequent fate of complexes formed between specific rabbit gammaG-antibody subunits and circulating protein antigens was studied in rabbits and guinea pigs. Subunits obtained from purified antibodies were injected immediately after an injection of antigen, and the elimination from the circulation of either I*-labeled gammaG-subunits or labeled antigen determined. In the absence of antigen, all gammaG-subunits which lack the Fc fragment were rapidly eliminated. In the presence of excess antigen, F (ab')(2), Fab and Fd fragments reacted with antigen and remained in the circulation as complexes which were eliminated at the same rate as the antigen. Fab hybrids containing a specific Fd fragment and a nonspecific L chain similarly reacted with antigen and remained in the circulation complexed to antigen. In contrast, L chains and Fab hybrids containing a specific L chain and a nonspecific Fd fragment did not react with antigen in vivo and were rapidly eliminated in both presence and absence of antigen. H chains remained in the circulation of rabbits in the absence of antigen, however, in the presence of antigen, more H chains which formed complexes with antigen remained in the intravascular space and were rapidly eliminated when the immune elimination of the antigen by the host occurred. Nonspecific H chains were rapidly eliminated from the circulaion of guinea pigs, whereas specific H chains remained in the circulation with the antigen. F (ab')(2) fragments formed complexes with antigen near antibody equivalence and in antibody excess which were rapidly eliminated, however, less effectively than complexes formed near antibody equivalence with intact gammaG. Complexes formed in antibody excess between Fab fragments and H chains remained in the circulation at all concentrations studied and were eliminated at the rate of antigen. The role of the Fc fragment in the immune elimination of antigen-antibody complexes is discussed.
Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors
Authors: R. Dienstmann, J. Rodon, A. Prat, J. Perez-Garcia, B. Adamo, E. Felip, J. Cortes, A.J. Iafrate, P. Nuciforo, J. Tabernero
Journal: Annals of Oncology (2013)
Reducing greenhouse emissions could cut global disease burden by 25%
Authors: A. O'Dowd
Journal: BMJ (2009)

Health policy makers must take climate change into consideration in their activities to help cut the burden of global disease, speakers at a conference have argued.

Countries that improve their environmental conditions could help to reduce the global disease burden by more than 25%, according to World Health Organization experts.

They have called for policy makers around the world to notice the serious impact that climate change is having on health.

At the WHO Climate Change Global Risks, Challenges, and Decisions conference in Copenhagen last week, speakers said that the health impact of climate change was critical …
Biological Esterification of Steroids*
Authors: Richard B. Hochberg
Journal: Endocrine Reviews (1998)

I. Introduction A. Obfuscating chemistry and the presumptive steroid acetates B. Sterol esters: substrates for the cholesterol side-chain cleavage enzyme II. Lipoidal Derivatives of Δ5-3β-Hydroxysteroids in the Adrenal and Ovary A. Endogenous steroid esters B. Biosynthetic esterification ofΔ 5-3β-hydroxy-steroids III. Lipoidal Derivatives of Steroids in Peripheral Tissues A. Esterification of steroid hormones B. Esterification of Δ5-3β-hydroxysteroids C. Endogenous esters of sex steroids D. Androsterone esters in breast cyst fluid IV. Lipoidal Derivatives Synthesized by Lecithin:Cholesterol Acyltransferase A. Blood B. Ovarian follicular fluid V. Steroid Esterases VI. Lipoidal Derivatives of Steroid Hormones in Insects VII. Biological Effects of Steroid Esterification A. Potent sex steroids B. Unique actions of the steroid esters in blood VIII. Conclusion