tbuckley/cabot-search huggingface dataset:
Endotoxin-Induced Mortality Is Related to Increased Oxidative Stress and End-Organ Dysfunction, Not Refractory Hypotension, in Heme Oxygenase-1–Deficient Mice
Authors: Philippe Wiesel, Anand P. Patel, Nicole DiFonzo, Pooja B. Marria, Chäng U. Sim, Andrea Pellacani, Koji Maemura, Brian W. LeBlanc, Kathryn Marino, Claire M. Doerschuk, Shaw-Fang Yet, Mu-En Lee, Mark A. Perrella
Journal: Circulation (2000)

Heme oxygenase (HO)-1 is an enzyme that degrades heme to generate CO (a vasodilatory gas), iron, and the potent antioxidant bilirubin. A disease process characterized by decreases in vascular tone and increases in oxidative stress is endotoxic shock. Moreover, HO-1 is markedly induced in multiple organs after the administration of endotoxin (lipopolysaccharide [LPS]) to mice.To determine the role of HO-1 in endotoxemia, we administered LPS to mice that were wild-type (+/+), heterozygous (+/-), or homozygous null (-/-) for targeted disruption of HO-1. LPS produced a similar induction of HO-1 mRNA and protein in HO-1(+/+) and HO-1(+/-) mice, whereas HO-1(-/-) mice showed no HO-1 expression. Four hours after LPS, systolic blood pressure (SBP) decreased in all the groups. However, SBP was significantly higher in HO-1(-/-) mice (121+/-5 mm Hg) after 24 hours, compared with HO-1(+/+) (96+/-7 mm Hg) and HO-1(+/-) (89+/-13 mm Hg) mice. A sustained increase in endothelin-1 contributed to this SBP response. Even though SBP was higher, mortality was increased in HO-1(-/-) mice, and they exhibited hepatic and renal dysfunction that was not present in HO-1(+/+) and HO-1(+/-) mice. The end-organ damage and death in HO-1(-/-) mice was related to increased oxidative stress.These data suggest that the increased mortality during endotoxemia in HO-1(-/-) mice is related to increased oxidative stress and end-organ (renal and hepatic) damage, not to refractory hypotension.
Enhanced glucocorticoid‐induced leucine zipper in dendritic cells induces allergen‐specific regulatory <scp>CD</scp>4<sup>+</sup><scp>T</scp>‐cells in respiratory allergies
Authors: S. Karaki, G. Garcia, C. Tcherakian, F. Capel, T. Tran, M. Pallardy, M. Humbert, D. Emilie, V. Godot
Journal: Allergy (2014)

Abstract Background Respiratory allergies rely on a defect of IL ‐10‐secreting regulatory CD 4 + T ‐cells ( IL ‐10‐ T regs ) leading to excessive T h2‐biased immune responses to allergens. According to clinical data, the restoration of allergen‐specific IL ‐10‐ T regs is required to control respiratory allergies and cure patients. The discovery of mechanisms involved in the generation of IL ‐10‐ T regs will thus help to provide effective treatments. We previously demonstrated that dendritic cells ( DC s) expressing high levels of the glucocorticoid‐induced leucine zipper protein ( GILZ ) generate antigen‐specific IL ‐10‐ T regs . Objective We suspect a defective expression of GILZ in the DC s of respiratory allergic patients and speculate that increasing its expression might restore immune tolerance against allergens through the induction of IL ‐10‐ T regs . Methods We assessed GILZ expression in blood DC s of patients and healthy nonallergic donors by qPCR . We compared the ability of patients' DC s to induce allergen‐specific IL ‐10‐ T regs before and after an in vivo up‐regulation of GILZ expression by steroid administration, steroids being inducers of GILZ . Results We report lower levels of GILZ in DC s of respiratory allergic patients that return to normal levels after steroid administration. We show that patients' DC s with increased levels of GILZ generate allergen‐specific IL ‐10‐ T regs again. We further confirm unequivocally that GILZ is required in patients' DC s to activate these IL ‐10‐ T regs . Conclusion This proof of concept study shows that the re‐establishment of GILZ expression in patients' DC s to normal levels restores their capacity to activate allergen‐specific IL ‐10‐ T regs . We thus highlight the up‐regulation of GILZ in DC s as a new interventional approach to restore the immune tolerance to allergens.
Prognostic significance of the allelic loss of the BRCA1 gene in colorectal cancer
Authors: J M Garcia
Journal: Gut (2003)

Survival at the intermediate stage of colorectal cancer (CRC) is less predictable than in the early and advanced stages. Several genetic markers possibly involved in growth and progression of CRC can be used for prognosis.This study investigated the proportion of allelic loss (loss of heterozygosity (LOH)) at the BRCA1 locus in sporadic CRC and its value in patient prognosis.A total of 314 patients were investigated for LOH at the BRCA1 locus using polymerase chain reaction by means of three intragenic polymorphic microsatellite markers. Allelic losses were compared with clinicopathological characteristics of patients, recurrence rate, disease free survival (DFS), and overall survival.Twenty six patients were excluded because of microsatellite instability. Of the remaining 288 cases, 244 (84.7%) were informative, with 97 (39.8%) patients bearing BRCA1 LOH. Recurrence rate was higher in patients with LOH (p=0.0003), and DFS was 73.3% (SEM 5.7) at five years in patients without LOH, and 49.2% (7.1) in cases with positive allelic loss (p=0.0004). Retention of alleles at the BRCA1 locus was associated with a favourable DFS in stages I and II (p<0.05). The presence of LOH was also significantly associated with short overall survival (p=0.02). Multivariate analysis in the complete series showed that stage (p=0.006) and lymph node metastases (> or =4 nodes, p=0.0001; 1-3 nodes, p=0.038) were independent prognostic factors. However, multivariate study by stages revealed that BRCA1 LOH was an independent prognostic factor in stages I and II (p=0.001).BRCA1 LOH is a molecular alteration present in CRC, with unfavourable repercussions for overall survival, that could be considered as an outstanding independent prognostic factor in stages I and II.
Anticancer Therapies Combining Antiangiogenic and Tumor Cell Cytotoxic Effects Reduce the Tumor Stem-Like Cell Fraction in Glioma Xenograft Tumors
Authors: Chris Folkins, Shan Man, Ping Xu, Yuval Shaked, Daniel J. Hicklin, Robert S. Kerbel
Journal: Cancer Research (2007)

Abstract Vascular endothelial cells have been identified as a critical component of the neural stem cell niche, raising the possibility that brain tumor stem-like cells (TSLC) may also rely on signaling interactions with nearby tumor vasculature to maintain their stem-like state. The disruption of such a TSLC vascular niche by an antiangiogenic therapy could result in loss of stemness characteristics associated with intrinsic drug resistance and, thus, preferentially sensitize TSLC to the effects of chemotherapy. Considering these possibilities, we investigated the impact of antiangiogenic anticancer therapy on the TSLC fraction of glioma tumors. Athymic nude mice bearing s.c. tumor xenografts of the C6 rat glioma cell line were treated with either a targeted antiangiogenic agent, antiangiogenic schedules of low-dose metronomic chemotherapy, combination therapies of antiangiogenic agents and chemotherapy, or, for the purpose of comparison, a conventional cytotoxic schedule of maximum tolerated dose chemotherapy using cyclophosphamide. Targeted antiangiogenic therapy or cytotoxic chemotherapy did not reduce the fraction of tumor sphere-forming units (SFU) in the tumor, whereas all treatment groups that combined both antiangiogenic and cytotoxic drug effects caused a significant reduction in SFU. This work highlights the possibility that selective eradication of TSLC may be achieved by targeting the tumor microenvironment (and potentially a supportive TSLC niche) rather than the TSLC directly. Furthermore, this work suggests a possible novel effect of antiangiogenic therapy, namely, as a chemosensitizer of TSLC, and thus represents a possible new mechanism to explain the ability of antiangiogenic therapy to enhance the efficacy of chemotherapy. [Cancer Res 2007;67(8):3560–4]
Nicotinic Acetylcholine Receptors and Nicotinic Cholinergic Mechanisms of the Central Nervous System
Authors: John A. Dani, Daniel Bertrand
Journal: The Annual Review of Pharmacology and Toxicology (2006)

Subtypes of neuronal nicotinic acetylcholine receptors (nAChRs) are constructed from numerous subunit combinations that compose channel-receptor complexes with varied functional and pharmacological characteristics. Structural and functional diversity and the broad presynaptic, postsynaptic, and nonsynaptic locations of nAChRs underlie their mainly modulatory roles throughout the mammalian brain. Presynaptic and preterminal nicotinic receptors enhance neurotransmitter release, postsynaptic nAChRs contribute a small minority of fast excitatory transmission, and nonsynaptic nAChRs modulate many neurotransmitter systems by influencing neuronal excitability. Nicotinic receptors have roles in development and synaptic plasticity, and nicotinic mechanisms participate in learning, memory, and attention. Decline, disruption, or alterations of nicotinic cholinergic mechanisms contribute to dysfunctions such as epilepsy, schizophrenia, Parkinson's disease, autism, dementia with Lewy bodies, Alzheimer's disease, and addiction.
FURTHER IMPLICATION OF MURINE LEUKEMIA-LIKE VIRUS IN THE DISORDERS OF NZB MICE
Authors: Robert C. Mellors, Tadao Aoki, Robert J. Huebner
Journal: The Journal of Experimental Medicine (1969)

Further evidence implicating murine leukemia-like virus in the disorders of NZB mice was afforded by a study of antigens associated with murine leukemia virus (MuLV). MuLV group antigens were prevalent in extracts of spleen, kidney, and, to a lesser extent, thymus throughout a substantial portion of the life span of NZB mice as well as in extracts of lymphomas and sarcomas indigenous to the strain. G (Gross) soluble antigen, type-specific antigen, was first detected in plasma of untreated NZB mice at 3 months of age. G soluble antigen production increased thereafter in line with age, with 50% of reactions becoming positive at 5.3 months and 100% at 7 to 9 months. From months 3 to 9, the time-response curve for positive conversion of direct antiglobulin (Coombs) tests in untreated NZB mice corresponded closely to that for G soluble antigen production. Beyond the 9th month, G soluble antigen underwent elimination from the plasma of NZB mice, with positive reactions reduced to 50% at 13.3 months and to 0% at 18 months. G natural antibody was first detected in the serum of NZB mice at about 10 months of age and increased thereafter in line with age. The curves for G antibody production and G soluble antigen elimination bore a reciprocal relation to each other with crossover at 50% response occurring at 13.3 months. Significant proteinuria, a functional manifestation of membranous glomerulonephritis, became increasingly prevalent in female NZB mice as G soluble antigen was eliminated from plasma. Cumulative mortality of female NZB mice, mainly attributable to renal glomerular disease, increased in phase with G antibody production. MuLV group antigens were identified in the glomerular lesions by the immunofluorescence method. Positive conversion of direct antiglobulin tests was significantly delayed by vaccinating baby NZB mice with formaldehyde-inactivated cell-free filtrates of older NZB mouse spleens. The plasmas of vaccinated NZB mice with negative direct antiglobulin reactions at 4 to 7 months were likewise negative when tested for G soluble antigen. The 50% response time for G antibody production in the vaccinated NZB mice occurred at 7.3 months, that is, 6 months earlier than in untreated NZB mice. The collective findings implicate murine leukemia-like virus in the etiology of autoimmune hemolytic disease and membranous glomerulonephritis, as well as malignant lymphoma, of NZB mice and suggest that virus-specified cell-surface and soluble antigen is a factor in the immunopathogenesis of the renal disease and possibly also the autoimmune hemolytic disease.
Does body posture affect the incidence and mechanism of gastro-oesophageal reflux?
Authors: N Freidin, R K Mittal, R W McCallum
Journal: Gut (1991)

We studied eight patients with gastro-oesophageal reflux disease to compare the frequency and mechanism of reflux in the upright and supine positions. Simultaneous oesophageal manometry and pH studies were performed on two separate days in each subject in the fasting and postprandial periods. The frequency of reflux tended to be higher in the upright position. The most prevalent mechanism of reflux in either position was transient relaxation of the lower oesophageal sphincter. The frequency of transient lower oesophageal sphincter relaxation was higher in the upright than in the supine position. There was no difference in the total reflux time, acid clearance time, and number of reflux episodes lasting longer than five minutes in the two positions. We suggest that daytime reflux (upright) may be as important as night time (supine) reflux in the pathogenesis of reflux oesophagitis and needs to be considered when treating patients with reflux disease.
Mesenchymal Stem Cells Arrest Intervertebral Disc Degeneration Through Chondrocytic Differentiation and Stimulation of Endogenous Cells
Authors: Fan Yang, Victor YL Leung, Keith DK Luk, Danny Chan, Kenneth MC Cheung
Journal: Molecular Therapy (2009)

Degenerative disc disease (DDD) is a common disease which affects millions of people. Autograft of the bone marrow derived mesenchymal stem cells (BMSCs) have been shown to have the ability to arrest degeneration in rabbit and canine intervertebral discs. In this study, we have used the mouse model to investigate the mechanism of degeneration arrest. BMSC from Egfp transgenic mice were injected into the degenerated murine intervertebral discs induced by annular puncture. We found that BMSC could arrest the progressive degeneration of the discs with significant regeneration of the nucleus pulposus (NP). In the regeneration, expression of proteoglycan genes were upregulated and extracellular matrix (ECM) progressively accumulated in the NP after BMSC injection. Combined in situ hybridization and immunohistochemistry revealed that BMSC underwent chondrocytic differentiation in the regeneration process. Interestingly, BMSC-induced an increase of endogenous notochordal cells in NP and expression of chondrocytic markers. In this study, we have firstly shown that the BMSC could arrest the degeneration of the murine notochordal NP and contribute to the augmentation of the ECM in the NP by both autonomous differentiation and stimulatory action on endogenous cells. Degenerative disc disease (DDD) is a common disease which affects millions of people. Autograft of the bone marrow derived mesenchymal stem cells (BMSCs) have been shown to have the ability to arrest degeneration in rabbit and canine intervertebral discs. In this study, we have used the mouse model to investigate the mechanism of degeneration arrest. BMSC from Egfp transgenic mice were injected into the degenerated murine intervertebral discs induced by annular puncture. We found that BMSC could arrest the progressive degeneration of the discs with significant regeneration of the nucleus pulposus (NP). In the regeneration, expression of proteoglycan genes were upregulated and extracellular matrix (ECM) progressively accumulated in the NP after BMSC injection. Combined in situ hybridization and immunohistochemistry revealed that BMSC underwent chondrocytic differentiation in the regeneration process. Interestingly, BMSC-induced an increase of endogenous notochordal cells in NP and expression of chondrocytic markers. In this study, we have firstly shown that the BMSC could arrest the degeneration of the murine notochordal NP and contribute to the augmentation of the ECM in the NP by both autonomous differentiation and stimulatory action on endogenous cells.
Triptolide Inhibits Bcr-Abl Transcription and Induces Apoptosis in STI571-resistant Chronic Myelogenous Leukemia Cells Harboring T315I Mutation
Authors: Xianping Shi, Yanli Jin, Chao Cheng, Hui Zhang, Waiyi Zou, Qin Zheng, Zhongzheng Lu, Qi Chen, Yingrong Lai, Jingxuan Pan
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Resistance to STI571 is an emerging problem for patients with chronic myelogenous leukemia (CML). Mutation in the kinase domain of Bcr-Abl is the predominant mechanism of the acquired resistance to STI571. In the present study, we investigated the effect of triptolide on cell survival or apoptosis in CML cells bearing Bcr-Abl-T315I or wild-type Bcr-Abl. Experimental Design: CML cell lines (KBM5 versus KBM5-T315I, BaF3-Bcr-Abl versus BaF3-Bcr-Abl-T315I) and primary cells from CML patients with clinical resistance to STI571 were treated with triptolide, and analyzed in terms of growth, apoptosis, and signal transduction. Nude mouse xenograft model was also used to evaluate the antitumor activity. Results: Triptolide potently down-regulated the mRNA and protein levels of Bcr-Abl independently of the caspase or proteosome activation in CML cells. It induced mitochondrial-dependent apoptosis in Bcr-Abl-T315I CML cells and primary cells from CML patients with clinical resistance to STI571. Additionally, triptolide inhibited the growth of STI571-sensitive KBM5 and STI571-resistant KBM5-T315I CML cells in nude mouse xenografts. Triptolide also down-regulated the expression of survivin, Mcl-1, and Akt in CML cells, which suggests that it may have multiple targets. Conclusions: These findings suggest that triptolide is a promising agent to overcome STI571-resistant CML cells, and warrant a clinical trial of triptolide derivatives for CML with Bcr-Abl-T315I mutation.
Composition of the adult digestive tract bacterial microbiome based on seven mouth surfaces, tonsils, throat and stool samples
Authors: Nicola Segata, Susan Kinder Haake, Peter Mannon, Katherine P Lemon, Levi Waldron, Dirk Gevers, Curtis Huttenhower, Jacques Izard
Journal: Genome biology (2012)

Abstract Background To understand the relationship between our bacterial microbiome and health, it is essential to define the microbiome in the absence of disease. The digestive tract includes diverse habitats and hosts the human body's greatest bacterial density. We describe the bacterial community composition of ten digestive tract sites from more than 200 normal adults enrolled in the Human Microbiome Project, and metagenomically determined metabolic potentials of four representative sites. Results The microbiota of these diverse habitats formed four groups based on similar community compositions: buccal mucosa, keratinized gingiva, hard palate; saliva, tongue, tonsils, throat; sub- and supra-gingival plaques; and stool. Phyla initially identified from environmental samples were detected throughout this population, primarily TM7, SR1, and Synergistetes. Genera with pathogenic members were well-represented among this disease-free cohort. Tooth-associated communities were distinct, but not entirely dissimilar, from other oral surfaces. The Porphyromonadaceae, Veillonellaceae and Lachnospiraceae families were common to all sites, but the distributions of their genera varied significantly. Most metabolic processes were distributed widely throughout the digestive tract microbiota, with variations in metagenomic abundance between body habitats. These included shifts in sugar transporter types between the supragingival plaque, other oral surfaces, and stool; hydrogen and hydrogen sulfide production were also differentially distributed. Conclusions The microbiomes of ten digestive tract sites separated into four types based on composition. A core set of metabolic pathways was present across these diverse digestive tract habitats. These data provide a critical baseline for future studies investigating local and systemic diseases affecting human health.
The association between exaggeration in health related science news and academic press releases: retrospective observational study
Authors: P. Sumner, S. Vivian-Griffiths, J. Boivin, A. Williams, C. A. Venetis, A. Davies, J. Ogden, L. Whelan, B. Hughes, B. Dalton, F. Boy, C. D. Chambers
Journal: BMJ (2014)

To identify the source (press releases or news) of distortions, exaggerations, or changes to the main conclusions drawn from research that could potentially influence a reader's health related behaviour.Retrospective quantitative content analysis.Journal articles, press releases, and related news, with accompanying simulations.Press releases (n = 462) on biomedical and health related science issued by 20 leading UK universities in 2011, alongside their associated peer reviewed research papers and news stories (n = 668).Advice to readers to change behaviour, causal statements drawn from correlational research, and inference to humans from animal research that went beyond those in the associated peer reviewed papers.40% (95% confidence interval 33% to 46%) of the press releases contained exaggerated advice, 33% (26% to 40%) contained exaggerated causal claims, and 36% (28% to 46%) contained exaggerated inference to humans from animal research. When press releases contained such exaggeration, 58% (95% confidence interval 48% to 68%), 81% (70% to 93%), and 86% (77% to 95%) of news stories, respectively, contained similar exaggeration, compared with exaggeration rates of 17% (10% to 24%), 18% (9% to 27%), and 10% (0% to 19%) in news when the press releases were not exaggerated. Odds ratios for each category of analysis were 6.5 (95% confidence interval 3.5 to 12), 20 (7.6 to 51), and 56 (15 to 211). At the same time, there was little evidence that exaggeration in press releases increased the uptake of news.Exaggeration in news is strongly associated with exaggeration in press releases. Improving the accuracy of academic press releases could represent a key opportunity for reducing misleading health related news.
Malacia, inflammation and bronchoalveolar lavage culture in children with persistent respiratory symptoms
Authors: F. De Baets, I. De Schutter, C. Aarts, F. Haerynck, S. Van daele, E. De Wachter, A. Malfroot, P. Schelstraete
Journal: European Respiratory Journal (2011)

In children with persistent respiratory symptoms despite regular anti-asthma inhalation treatment, diagnostic investigations to exclude underlying disease are warranted. 124 children were prospectively enrolled, and 24-h oesophageal pH measurement and fibreoptic bronchoscopy with bronchoalveolar lavage (BAL) were performed. BAL fluid (BALF) was processed for neutrophil counting and bacterial culture. Inflammation of the respiratory mucosa was assessed. A structural abnormality of the central airways was found in 47% of subjects (40% females). In 19% of subjects, neither anatomical anomalies nor inflamed respiratory mucosa were observed, whereas in 64%, definite macroscopic mucosal inflammation was observed. Inflammation of the respiratory mucosa was associated with a significantly higher percentage of neutrophils in the BALF: median (interquartile range) 48 (14-82)% compared with 7 (0-16)% (p<0.025). A positive BALF culture was found in 62% of the infants with mucosal inflammation compared with 25% in the group without inflammation (p<0.016). 56% of the BALF samples were positive for bacterial culture. In children with persistent respiratory symptoms, nearly half have anatomical anomalies of the central airways. In 62% of the children with mucosal inflammation, a positive BAL culture and a significantly higher percentage of BALF neutrophils were detected.