tbuckley/cabot-search huggingface dataset:
Local microcirculatory reflexes and afferent signalling in response to gastric acid challenge
Authors: P Holzer
Journal: Gut (2000)

The gastrointestinal tract is innervated by extrinsic primary afferent neurones which arise from two different sources. Spinal afferents originate in the dorsal root ganglia whereas vagal afferents have their cell bodies in the nodose ganglia.1 Most of the spinal afferents which supply the stomach and intestine of rodents contain neuropeptides such as calcitonin gene related peptide (CGRP) and the tachykinins, substance P and neurokinin A as their chemical messengers.2 In terms of modality, these neurones are to a considerable extent nociceptive afferents and are thought to serve tissue homeostasis in a dual manner. On the one hand, afferent neurones convey information to the central nervous system and thus lead to the sensations of discomfort and pain and elicit autonomic and endocrine reactions. On the other hand, peptidergic afferent neurones can release vasoactive neuropeptides from their peripheral endings and thus enhance the resistance of the tissue to injury and aid the repair of damaged tissue.3 4 This latter function is borne out by the abundance of CGRP and substance P containing axons around arterioles in the rat gastric submucosa.5 

The overall aim of our studies has been to elucidate the role of afferent neurones in the vascular regulation of the stomach …
Structural assignment of novel and immunodominant antigenic sites in the neutralizing antibody response of CBA/Ca mice to influenza hemagglutinin.
Authors: C A Smith, B C Barnett, D B Thomas, F Temoltzin-Palacios
Journal: The Journal of Experimental Medicine (1991)

Information on the antigenic structure of influenza hemagglutinin (HA) has been deduced previously from sequence analyses of laboratory mutant viruses selected, in vitro, with neutralizing monoclonal antibody (mAb) established exclusively from BALB/c (H-2d) mice; and there has been no attempt to investigate the influence of host genetic background, or natural route of infection, on the protective antibody repertoire. CBA/Ca mice are extremely sensitive to X31 virus infection, and in the present study a structural analysis was made of the antibody repertoire, by direct sequencing of the HA genes of laboratory mutant viruses selected, in ovo with mAb from CBA/Ca mice primed by natural infection with X31 virus at two different infectious doses. Single nucleotide substitutions in the HA genes of mutant viruses identified both novel and immunodominant antigenic sites on the HA1 subunit: a majority of mAbs, from different donors, were of the IgG2a isotype and were specific for HA1 158 Gly. In addition, novel laboratory mutants were obtained containing substitutions in the HA1 subunit that had not been reported previously for H3 subtype viruses, either natural variants or laboratory mutants, at residues: HA1 62 Ile----Arg; HA1 165 Asn----Ser (resulting in the loss of a N-glycosylation site); and HA1 273 Pro----Leu. Our findings suggest that host genetic background and/or a natural route of infection may be significant factors in the selection of different and distinct neutralizing antibody responses to influenza HA and therefore be of some relevance in our further understanding of the immune pressure for antigenic drift, and the immunogenic features of a protective antigen.
Emerging Molecular Targets for the Treatment of Nonalcoholic Fatty Liver Disease
Authors: Giovanni Musso, Roberto Gambino, Maurizio Cassader
Journal: Annual Review of Medicine (2010)

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of significant ethanol consumption, viral infection, or other specific causes of liver disease. Currently the most common chronic liver disease, affecting 30% of the Western world, NAFLD may progress to cirrhosis and end-stage liver disease and may increase the risk of developing diabetes and cardiovascular disease. Although its pathogenesis is unclear, NAFLD is tightly associated with insulin resistance and the metabolic syndrome. No established treatment exists, and current research is targeting new molecular mechanisms that underlie NAFLD and associated cardiometabolic disorders. This review discusses some of these emerging molecular mechanisms and their therapeutic implications for the treatment of NAFLD: microRNAs, incretin analogs/antagonists, liver-specific thyromimetics, AMP-activated protein kinase activators, and nuclear receptors farnesoid X receptor and pregane X receptor.
Prodromal irritable bowel syndrome doubles disease lat ency length in crohn's disease and increases it by a third in coeliac disease: natural history or tunnel vision?
Authors: S. M. Barratt, J. S. Leeds, K. Robinson, A. J. Lobo, M. E. Mcalindon, D. S. Sanders
Journal: Gut (2011)

<h3>Introduction</h3> Previous studies report that patients with Coeliac Disease and Inflammatory Bowel Disease (IBD) (Crohn9s Disease (CD) and Ulcerative Colitis (UC)) experience a latency period (a period between the onset of symptoms and correct diagnosis). Irritable Bowel Syndrome (IBS) is more prevalent in Coeliac Disease and IBD. We aimed to determine the prevalence of prodromal IBS (P-IBS) during such latency periods and the impact P-IBS has, if any, on latency period duration. <h3>Methods</h3> 683 histologically proven age and sex matched patients (Coeliac n=225, 26% male, mean disease duration 8 years; UC n=228, 43% male, mean disease duration 16.5 years; CD n=230, 28% male, mean disease duration 15.5 years) completed a postal survey. Patients were asked to recall if they perceived a 'latency period' and whether they had been diagnosed with IBS by a physician during this period. Responses were validated by medical records. <h3>Results</h3> 100/225 (44%) of Coeliac patients reported a latency (mean length 13.2 years.) Of these 100 patients 67 (67%) had P-IBS. Mean latency length in P-IBS Coeliac Disease was 10 years versus 7 years without (p=0.046). In IBD overall 326/458 (71%) reported a latency (mean length 4.99 years) of which 106 (32%) had P- IBS. Mean latency length in P-IBS IBD was 3 years versus 1.5 years without (p=0.01). In UC 110/228 (48%) reported a latency (mean length 2.89 years) of which 42 (38%) had P-IBS. There was no difference in mean latency length in P-IBS UC versus those without, both 1 year in length (p=ns). In CD 216/230 (94%) reported a latency (mean length 6.15 years) of which 64 (29%) had P-IBS CD. Mean latency length in P-IBS CD was 4 years versus 2 years without (p=0.018). <h3>Conclusion</h3> When present, the duration of latency in patients with Coeliac Disease is significantly longer and more often characterised by P-IBS than patients with IBD. In both Coeliac Disease and CD P-IBS increases the duration of the latency period, significantly so in CD. This delay may (1) reflect inherent diagnostic difficulties of symptoms attributed to small bowel pathology (2) suggest that IBS forms part of the natural history of Coeliac Disease and CD (3) demonstrate that once a diagnosis of IBS is reached physicians are more likely to attribute ongoing symptoms to refractory IBS and not to an underlying small bowel inflammatory process, such as Coeliac Disease or IBD.
Targeting Fibroblast Growth Factor Receptor Signaling Inhibits Prostate Cancer Progression
Authors: Shu Feng, Longjiang Shao, Wendong Yu, Paul Gavine, Michael Ittmann
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Extensive correlative studies in human prostate cancer as well as studies in vitro and in mouse models indicate that fibroblast growth factor receptor (FGFR) signaling plays an important role in prostate cancer progression. In this study, we used a probe compound for an FGFR inhibitor, which potently inhibits FGFR-1–3 and significantly inhibits FGFR-4. The purpose of this study is to determine whether targeting FGFR signaling from all four FGFRs will have in vitro activities consistent with inhibition of tumor progression and will inhibit tumor progression in vivo. Experimental Design: Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation in vitro was also evaluated in prostate cancer cell lines. Finally, the impact of AZ8010 on tumor progression in vivo was evaluated using a VCaP xenograft model. Results: AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nmol/L, which is an achievable in vivo concentration. This results in marked inhibition of extracellular signal–regulated kinase (ERK) phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all prostate cancer cell lines tested. Treatment in vivo completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors. Conclusions: Targeting FGFR signaling is a promising new approach to treating aggressive prostate cancer. Clin Cancer Res; 18(14); 3880–8. ©2012 AACR.
Obesity in Survivors of Childhood Acute Lymphoblastic Leukemia and Lymphoma
Authors: Bassem I. Razzouk, Susan R. Rose, Suradej Hongeng, Dana Wallace, Matthew P. Smeltzer, Margie Zacher, Ching-Hon Pui, Melissa M. Hudson
Journal: Journal of Clinical Oncology (2007)

We evaluated the long-term effects of treatment on the body mass index (BMI) of children with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma who received one of three CNS-directed therapies: intrathecal methotrexate with intravenous high-dose methotrexate (1 g/m2), intrathecal methotrexate with 18 Gy cranial radiation, or intrathecal methotrexate with 24 Gy cranial radiation.Between 1979 and 1984, 456 children with newly diagnosed ALL and lymphoma were enrolled onto a single protocol at St Jude Children's Research Hospital (Memphis, TN). The heights and weights of 422 of the children were measured at diagnosis, during treatment, at the end of therapy, and approximately every 6 to 12 months thereafter. Patients who had attained their adult height at the time of analysis (n = 248) were placed in weight categories based on their BMI, BMI percentile, or weight-for-length percentile depending on age.The overall percentage of survivors who were overweight or obese approximated rates prevalent in the general population of the United States. Young age (< 6 years) and overweight/obesity at diagnosis were the best predictors of obesity at adult height. The rate of BMI increase did not differ significantly between children who received radiation and those who did not, nor between patients who received 18 or 24 Gy of cranial radiation.BMI weight category at diagnosis, rather than type of CNS treatment received, predicted adult weight in long-term survivors of childhood hematologic malignancies.
Methylation-Associated Silencing of the <b> <i>Heat Shock Protein 47</i> </b> Gene in Human Neuroblastoma
Authors: Qiwei Yang, Shuqing Liu, Yufeng Tian, Chiler Hasan, Donna Kersey, Helen R. Salwen, Alexandre Chlenski, Elizabeth J. Perlman, Susan L. Cohn
Journal: Cancer Research (2004)

Abstract Hypermethylation of gene promoter CpG islands is a frequent mechanism for gene inactivation in a variety of human cancers, including neuroblastoma (NB). We demonstrated recently that treatment with the demethylating agent 5′-aza-2′-deoxycytidine (5-Aza-dC) significantly inhibited NB growth in vivo. In an effort to identify the genes and biological pathways that are responsible for the impaired NB tumor growth observed after treatment with 5-Aza-dC, we performed genome-wide gene expression analysis of control and treated NBL-W-S NB cells. We found ≥3-fold changes in expression of 44 genes that play roles in angiogenesis, apoptosis, cell adhesion, transcriptional regulation, and signal transduction. The gene encoding heat shock protein 47 (Hsp47), a collagen-specific molecular chaperon, was up-regulated &amp;gt;80-fold after 5-Aza-dC treatment. Expression studies confirmed that Hsp47 is silenced in a subset of NB cell lines and tumors. We also show that silencing of Hsp47 in NB cells is associated with aberrant methylation of promoter CpG islands and that Hsp47 expression can be restored after treatment with 5-Aza-dC. A strong correlation between Hsp47 and collagen type I and IV expression was seen in NB cells. Interestingly, tumorigenicity was inversely correlated with the level of collagen expression in NB cell lines, and higher levels of collagen were detected in mature NB tumors that are associated with favorable outcome compared with undifferentiated, advanced-stage NBs. Our studies support a role for Hsp47 in the regulation of collagen type I and IV production in NB cells and suggest that the level of collagen expression may influence NB tumor phenotype.
Bone Morphogenetic Protein 4 Promotes Pulmonary Vascular Remodeling in Hypoxic Pulmonary Hypertension
Authors: David B. Frank, Amir Abtahi, D.J. Yamaguchi, Suzanne Manning, Yu Shyr, Ambra Pozzi, H. Scott Baldwin, Joyce E. Johnson, Mark P. de Caestecker
Journal: Circulation Research (2005)

We show that 1 of the type II bone morphogenetic protein (BMP) receptor ligands, BMP4, is widely expressed in the adult mouse lung and is upregulated in hypoxia-induced pulmonary hypertension (PH). Furthermore, heterozygous null Bmp4 lacZ/+ mice are protected from the development of hypoxia-induced PH, vascular smooth muscle cell proliferation, and vascular remodeling. This is associated with a reduction in hypoxia-induced Smad1/5/8 phosphorylation and Id1 expression in the pulmonary vasculature. In addition, pulmonary microvascular endothelial cells secrete BMP4 in response to hypoxia and promote proliferation and migration of vascular smooth muscle cells in a BMP4-dependent fashion. These findings indicate that BMP4 plays a dominant role in regulating BMP signaling in the hypoxic pulmonary vasculature and suggest that endothelium-derived BMP4 plays a direct, paracrine role in promoting smooth muscle proliferation and remodeling in hypoxic PH.
Stearoyl-CoA Desaturase 1 Is a Novel Molecular Therapeutic Target for Clear Cell Renal Cell Carcinoma
Authors: Christina A. von Roemeling, Laura A. Marlow, Johnny J. Wei, Simon J. Cooper, Thomas R. Caulfield, Kevin Wu, Winston W. Tan, Han W. Tun, John A. Copland
Journal: Clinical Cancer Research (2013)

Abstract Purpose: We set out to identify Stearoyl-CoA desaturase 1 (SCD1) as a novel molecular target in clear cell renal cell carcinoma (ccRCC) and examine its role in tumor cell growth and viability in vitro and in vivo independently as well as in combination with current U.S. Food and Drug Administration (FDA)-approved regimens. Experimental Design: Patient normal and ccRCC tissue samples and cell lines were examined for SCD1 expression. Genetic knockdown models and targeted inhibition of SCD1 through use of a small molecule inhibitor, A939572, were analyzed for growth, apoptosis, and alterations in gene expression using gene array analysis. Therapeutic models of synergy were evaluated utilizing pharmacologic inhibition of SCD1 with the tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, and the mTOR inhibitor temsirolimus. Results: Our studies identify increased SCD1 expression in all stages of ccRCC. Both genetic knockdown and pharmacologic inhibition of SCD1 decreased tumor cell proliferation and induced apoptosis in vitro and in vivo. Upon gene array, quantitative real-time PCR, and protein analysis of A939572-treated or SCD1 lentiviral knockdown samples, induction of endoplasmic reticulum stress response signaling was observed, providing mechanistic insight for SCD1 activity in ccRCC. Furthermore, combinatorial application of A939572 with temsirolimus synergistically inhibited tumor growth in vitro and in vivo. Conclusions: Increased SCD1 expression supports ccRCC viability and therefore we propose it as a novel molecular target for therapy either independently or in combination with an mTOR inhibitor for patients whose disease cannot be remedied with surgical intervention, such as in cases of advanced or metastatic disease. Clin Cancer Res; 19(9); 2368–80. ©2013 AACR.
THE INTRARENAL PRESSURE DURING EXPERIMENTAL RENAL HYPERTENSION
Authors: H. G. Swann, J. M. Prine, Victor Moore, R. D. Rice
Journal: The Journal of Experimental Medicine (1952)

The intrarenal interstitial pressure was measured during the course of experimental renal hypertension in dogs. In perinephritic hypertension, produced by wrapping the kidney in a cellophane bag, the intrarenal pressure rose slowly from the normal value of 25 mm. Hg to a final level of about 60 mm. Hg. Strong pressure pulsations were observed in the renal parenchyma during this type of hypertension. In the hypertension following partial occlusion of the renal artery, the intrarenal pressure remained approximately normal, except in malignant hypertension when it tended to decline to about 9 mm. Hg. The hypertension of perinephritis is interpreted as a consequence of renal ischemia, the high intrarenal pressure, produced by the constricting fibrotic hull, acting to reduce the effective perfusion pressure of the kidney. The two experimental hypertensions herein examined are considered as examples of influent resistance hypertensions and effluent resistance hypertensions, the former being due to renal arterial or arteriolar resistance and the latter due to renal venous resistance, specifically at the arcuate-interlobar junction. The application of this concept to renal hypertensive disease in man is discussed.
Rhinovirus vaccination: the case in favour
Authors: G.G.U. Rohde
Journal: European Respiratory Journal (2010)

Respiratory viruses have been shown to be important respiratory pathogens. The majority of upper respiratory tract infections and most uncomplicated cases of acute tracheobronchitis are due to respiratory viral infections 1. Moreover, respiratory viruses play an important role as infective triggers of acute exacerbations of chronic respiratory diseases such as asthma 2–5 and chronic obstructive pulmonary disease (COPD) 6–8. Human rhinoviruses (HRVs) were by far the most frequent respiratory viruses detected in most of the studies cited. Hence, HRVs can be considered as very important respiratory pathogens in upper and lower respiratory tract infections. In particular, the role of HRVs in exacerbations of asthma and COPD makes them an important therapeutic target. …
Cytochrome P450 and Vascular Homeostasis
Authors: Ingrid Fleming
Journal: Circulation Research (2001)

Since the initial reports that renal cytochrome P450 (CYP) enzymes can metabolize arachidonic acid to substances which affect arterial tone, it has become increasingly clear that CYP enzymes expressed within the cardiovascular system play a crucial role in the modulation of vascular homeostasis. There is strong evidence suggesting that the activation of a CYP epoxygenase in endothelial cells is an essential step in nitric oxide and prostacyclin-independent vasodilatation of several vascular beds, particularly in the heart and kidney. A smooth muscle CYP ω-hydroxylase, on the other hand, generates a vasoconstrictor eicosanoid that is central to the myogenic response. Moreover, CYP epoxygenase and ω-hydroxylase products, as well as CYP-derived reactive oxygen species, are intracellular signal transduction molecules involved in several signaling cascades affecting numerous cellular processes, including vascular cell proliferation and angiogenesis. This review summarizes the vascular effects of epoxyeicosatrienoic acids and 20-hydroxyeicosatetraenoic acid, both of which are CYP-derived metabolites of arachidonic acid, endogenously generated within endothelial and vascular smooth muscle cells. Although the link between CYP expression/activity and cardiovascular disease is currently tentative, the evidence being accumulated to suggest that CYP pathways are altered in animal models of hypertension and atherosclerosis can no longer be ignored. The development of selective pharmacological tools is, however, a prerequisite for the analysis of the involvement of specific CYP isoforms in the regulation of vascular homeostasis in human subjects.
Suicide pacts and the internet
Authors: Sundararajan Rajagopal
Journal: BMJ (2004)

convincing evidence that this has any implications for subsequent morbidity let alone mortality.If we had serious concern over such effects, the best way to evaluate them would be by large cluster randomised trials of different vaccine formulations, or of standard vaccines given according to different schedules.We could contemplate such trials for reasons of overall direct as well as indirect effects.The standard vaccines change over time, and the most widely used timetable (BCG/oral polio vaccine at birth, DTP/OPV at 6, 10, and 14 weeks of age, measles after 9 months) was set 30 years ago at the start of the World Health Organization's expanded programme on immunisation as an optimal compromise considering the vaccines then in use, the disease risks then prevailing, and logistic considerations concerning paediatric clinic policies for children of that era.But much has changed-new vaccines and vaccine formulations, lowered disease risks (largely due to widespread vaccination), and changed child health regimens, which now include micronutrients in many countries.We may need to reconsider the optimal basic schedule for delivery of vaccines and other services to the world's children, and we need to evaluate them if possible with trials-not with observational studies with biased data.
Characterizing the Time Dependency of Human Mitochondrial DNA Mutation Rate Estimates
Authors: B. M. Henn, C. R. Gignoux, M. W. Feldman, J. L. Mountain
Journal: Molecular Biology and Evolution (2008)

Previous research has established a discrepancy of nearly an order of magnitude between pedigree-based and phylogeny-based (human vs. chimpanzee) estimates of the mitochondrial DNA (mtDNA) control region mutation rate. We characterize the time dependency of the human mitochondrial hypervariable region one mutation rate by generating 14 new phylogeny-based mutation rate estimates using within-human comparisons and archaeological dates. Rate estimates based on population events between 15,000 and 50,000 years ago are at least 2-fold lower than pedigree-based estimates. These within-human estimates are also higher than estimates generated from phylogeny-based human–chimpanzee comparisons. Our new estimates establish a rapid decay in evolutionary mutation rate between approximately 2,500 and 50,000 years ago and a slow decay from 50,000 to 6 Ma. We then extend this analysis to the mtDNA-coding region. Our within-human coding region mutation rate estimates display a similar, though less rapid, time-dependent decay. We explore the possibility that multiple hits explain the discrepancy between pedigree-based and phylogeny-based mutation rates. We conclude that whereas nucleotide substitution models incorporating multiple hits do provide a possible explanation for the discrepancy between pedigree-based and human–chimpanzee mutation rate estimates, they do not explain the rapid decline of within-human rate estimates. We propose that demographic processes such as serial bottlenecks prior to the Holocene could explain the difference between rates estimated before and after 15,000 years ago. Our findings suggest that human mtDNA estimates of dates of population and phylogenetic events should be adjusted in light of this time dependency of the mutation rate estimates.