tbuckley/cabot-search huggingface dataset:
Bile acid induced colonic irritation stimulates intracolonic nitric oxide release in humans.
Authors: F Casellas, M Mourelle, M Papo, F Guarner, M Antolin, J R Armengol, J R Malagelada
Journal: Gut (1996)

AIM--To measure the intracolonic release of nitric oxide end products (nitrates plus nitrites) and eicosanoids in response to intraluminal irritation with deoxycholic acid (DCA). PATIENTS--Seven patients with irritable bowel syndrome. METHODS--The left colon was perfused with a solution with or without 3 mM deoxycholic acid. Aspirates were assayed for eicosanoids by specific radioimmuno-assay, and for nitrates plus nitrites by the Griess reaction. To confirm that stimulated colonic mucosa can produce nitric oxide (NO), ancillary studies were performed in vitro using samples of normal mucosa obtained from five surgically resected colons. Samples were incubated for 30 minutes in Kreb9s solution, 3 mM DCA or DCA with 1 mM L-nitro-arginine-methyl-ester (L-NAME) to inhibit the NO synthase. Finally, NO synthase activity was measured in five samples of human colonic mucosa. RESULTS--Intracolonic release of nitrates plus nitrites was basally undetectable in six of seven patients. Bile acid considerably increased the release of prostaglandin E2 and nitrates plus nitrites (p &lt; 0.01). By contrast, no increase in thromboxane and leukotriene was seen. In vitro mucosal incubation with DCA increased the production of NO synthase products, which was blocked by L-NAME. Activity of Ca+2 independent NO synthase was detectable in four of five samples of human colonic mucosa. CONCLUSION--The human colonic mucosa responds to bile acid induced irritation by a surge in NO generation via NO synthase.
Pathology of the pancreas
Authors: A. Price
Journal: Gut (1988)

report by Shorrock et aP who, although observing a stimulatory effect of De-Nol in vitro, failed to detect a similar increase in HCO3 secretion in man.In Konturek's paper2 significant results were obtained with drug concentrations of at least 10 mg/ml, but in Shorrock's experiment 10 mg/ml was still an ineffective dose.We have recently treated 10 patients with endo- scopic duodenitis (but devoid of gastric abnormalities and with normal basal values of bicarbonate secretion) with De-Nol 600 mg bid for four weeks.Basal alkaline secretion was determined, by Feldman's method, before treatment and 10 hours after the last dose of the drug.No significant changes in gastric bicarbonate output was observed.A comparison of our results with Konturek's and Shorrock's findings seems to indicate that the stimulatory activity (if any) of therapeutic doses of De-Nol on gastric alkaline secretion in man is transient.Thus, as stated by Rees,4 this effect appears to have little relevance to the ulcer healing properties of colloidal bismuth.
Promise and Pitfalls of Heavy-Particle Therapy
Authors: Timur Mitin, Anthony L. Zietman
Journal: Journal of Clinical Oncology (2014)

Proton beam therapy, the most common form of heavy-particle radiation therapy, is not a new invention, but it has gained considerable public attention because of the high cost of installing and operating the rapidly increasing number of treatment centers. This article reviews the physical properties of proton beam therapy and focuses on the up-to-date clinical evidence comparing proton beam therapy with the more standard and widely available radiation therapy treatment alternatives. In a cost-conscious era of health care, the hypothetical benefits of proton beam therapy will have to be supported by demonstrable clinical gains. Proton beam therapy represents, through its scale and its cost, a battleground for the policy debate around managing expensive technology in modern medicine.
Lymphocytic gastritis: a newly described entity: a retrospective endoscopic and histological study.
Authors: J Haot, L Hamichi, L Wallez, P Mainguet
Journal: Gut (1988)

Lymphocytic gastritis is a histopathological entity characterised by the accumulation of small lymphocytes in the surface and foveolar epithelium. In order to investigate the correlation between endoscopy and histology in this condition, 192 observations selected on the basis of a presumed diagnosis of erosive or varioliform gastritis were reviewed. Ninety two instances corresponded to lymphocytic gastritis, while 100 did not show any particular microscopic feature and were labelled non-specific gastritis. There was a good correlation (48 of 58) between the diagnosis of the so-called varioliform gastritis and the histological evidence of lymphocytic gastritis. The correlation was even better when nodules, erosions, and enlarged folds were considered. Lymphocytic gastritis has a typical endoscopical appearance consisting of nodules, erosions, and large folds predominating in the gastric body. This contrasts with non-specific gastritis, which affects the antrum and produces erosions on a flat mucosa.
Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2
Authors: P. Seemann
Journal: Journal of Clinical Investigation (2005)

Here we describe 2 mutations in growth and differentiation factor 5 (GDF5) that alter receptor-binding affinities. They cause brachydactyly type A2 (L441P) and symphalangism (R438L), conditions previously associated with mutations in the GDF5 receptor bone morphogenetic protein receptor type 1b (BMPR1B) and the BMP antagonist NOGGIN, respectively. We expressed the mutant proteins in limb bud micromass culture and treated ATDC5 and C2C12 cells with recombinant GDF5. Our results indicated that the L441P mutant is almost inactive. The R438L mutant, in contrast, showed increased biological activity when compared with WT GDF5. Biosensor interaction analyses revealed loss of binding to BMPR1A and BMPR1B ectodomains for the L441P mutant, whereas the R438L mutant showed normal binding to BMPR1B but increased binding to BMPR1A, the receptor normally activated by BMP2. The binding to NOGGIN was normal for both mutants. Thus, the brachydactyly type A2 phenotype (L441P) is caused by inhibition of the ligand-receptor interaction, whereas the symphalangism phenotype (R438L) is caused by a loss of receptor-binding specificity, resulting in a gain of function by the acquisition of BMP2-like properties. The presented experiments have identified some of the main determinants of GDF5 receptor-binding specificity in vivo and open new prospects for generating antagonists and superagonists of GDF5.
A winter’s tale
Authors: Liam Farrell
Journal: BMJ (2008)

It must be tough being an emperor penguin; not only are you being constantly harassed by film crews, who love the fact that you can’t fly away or strafe them with guano, but Morgan Freeman is always popping up from behind an iceberg and global warming is increasingly degrading your breeding grounds and food supplies.

And global warming is no picnic for general practitioners either; it has irrevocably altered the aesthetic of wintertime home visits, a cherished part of general practice since the day …
Quantitative <i>In situ</i> Analysis of β-Catenin Expression in Breast Cancer Shows Decreased Expression Is Associated with Poor Outcome
Authors: Marisa Dolled-Filhart, Anthony McCabe, Jennifer Giltnane, Melissa Cregger, Robert L. Camp, David L. Rimm
Journal: Cancer Research (2006)

Abstract The role of β-catenin in breast cancer and its prognostic value is controversial. The prognostic value had been assessed previously in a series of nonquantitative immunohistochemical studies with conflicting results. In efforts to clarify the relationship between β-catenin protein expression and breast cancer prognosis, we have assessed a retrospective 600 case cohort of breast cancer tumors from the Yale Pathology archives on tissue microarrays. They were assessed using automated quantitative analysis (AQUA) with a series of array-embedded cell lines for which the β-catenin concentration was standardized by an ELISA assay. The expression levels of the standard clinical markers HER2, estrogen receptor (ER), progesterone receptor (PR), and Ki-67 were also assessed on the same cohort. X-tile software was used to select optimal protein concentration cutpoints and to evaluate the outcome using a training set and a validation set. We found that low-level expression of membranous β-catenin is associated with significantly worse outcome (38% versus 76%, 10-year survival, validation set log-rank P = 0.0016). Multivariate analysis of this marker, assessed in a proportional hazards model with tumor size, age, node status, nuclear grade, ER, PR, HER2, and Ki-67, is still highly significant with a hazard ratio of 6.8 (P &amp;lt; 0.0001, 95% confidence interval, 3.1-15.1). These results suggest that loss of β-catenin expression at the membrane, as assessed by objective quantitative analysis methods, may be useful as a prognostic marker or may be part of a useful algorithm for prognosis in breast cancer. (Cancer Res 2006; 66(10): 5487-94)
Maintenance Therapy Comes of Age for Non–Small-Cell Lung Cancer, but at What Cost?
Authors: Frances A. Shepherd
Journal: Journal of Clinical Oncology (2011)

An Eastern Cooperative Oncology Group Study. J Clin Oncol 3:373-378, 1985 4. Moertel CG, Frytak S, Hahn RG, et al: Therapy of locally unresectable pancreatic carcinoma: A randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads 5-fluorouracil), and high dose radiation 5-flurouracil—The Gastrointestinal Tumor Study Group. Cancer 48:1705-1710, 1981 5. Gastrointestinal Tumor Study Group: Treatment of locally unresectable carcinoma of the pancreas: Comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy. J Natl Cancer Inst 80:751-755, 1988 6. Conroy T, Desseigne F, Ychou M, et al: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364:1817-1825, 2011 7. Huguet F, Andre T, Hammel P, et al: Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol 25:326-331, 2007 8. Huguet F, Girard N, Guerche CS, et al: Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: A qualitative systematic review. J Clin Oncol 27:2269-2277, 2009 9. Crane CH, Varadhachary GR, Yordy JS, et al: Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4 (Dpc4) immunostaining with pattern of disease progression. J Clin Oncol 29:3037-3043, 2011 10. Jones S, Zhang X, Parsons DW, et al: Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:18011806, 2008 11. Philip PA, Mooney M, Jaffe D, et al: Consensus report of the National Cancer Institute Clinical Trials Planning Meeting on pancreas cancer treatment. J Clin Oncol 27:5660-5669, 2009
EWS/FLI1 Regulates Tumor Angiogenesis in Ewing's Sarcoma via Suppression of Thrombospondins
Authors: Gary Potikyan, Rupert O.V. Savene, Julie M. Gaulden, Kelly A. France, Zhichao Zhou, Eugenie S. Kleinerman, Stephen L. Lessnick, Christopher T. Denny
Journal: Cancer Research (2007)

Suppression of the expression of antiangiogenic factors has been closely associated with multiple malignancies. Thrombospondins 1 and 2 are members of a family of angiogenic inhibitors that are regulated by several oncogenes. In this study, we investigate the role of thrombospondins in Ewing's sarcoma and their regulation by EWS/ETS fusion oncoproteins. We show that the EWS/FLI1 fusion suppresses the expression of thrombospondins in both NIH3T3 fibroblasts and Ewing's sarcoma tumor-derived cell lines. This regulation depends on an intact EWS/FLI1 DNA-binding domain and may involve direct interactions between EWS/FLI1 and thrombospondin promoter regions. Forced expression of thrombospondins in Ewing's sarcoma cell lines inhibited the rate of tumor formation in vivo and markedly decreased the number of microvessels present in the tumors. These findings suggest that thrombospondins play a biologically significant role in tumor vascularization in Ewing's sarcoma and suggest potential therapeutic strategies for future therapeutic intervention.
Jejunal mucosal gamma glutamyl transferase activity in coeliac disease.
Authors: M J Fairman, B B Scott, C Toothill, M S Losowsky
Journal: Gut (1977)

In view of data suggesting that deficiency of gamma glutamyl transferase (GGT) may be the primary abnormality in the small-intestinal mucosa of patients with coeliac disease, this enzyme was measured in mucosal biopsies from coeliac patients at different stages of treatment. Activity was only slightly reduced in only one of nine well-treated patients, suggesting that deficiency of this enzyme has no primary role in the aetiology of coeliac disease.
Hormone-mediated down-regulation of hepatic glutathione synthesis in the rat.
Authors: S C Lu, J Kuhlenkamp, C Garcia-Ruiz, N Kaplowitz
Journal: Journal of Clinical Investigation (1991)

Our present work characterized the role of hormone-mediated signal transduction pathways in regulating hepatic reduced glutathione (GSH) synthesis. Cholera toxin, dibutyryl cAMP (DBcAMP), and glucagon inhibited GSH synthesis in cultured hepatocytes by 25-43%. Cellular cAMP levels exhibited a lower threshold for stimulation of the GSH efflux than inhibition of its synthesis. The effect of DBcAMP was independent of the type of sulfur amino acid precursor and cellular ATP levels and unassociated with increased GSH mixed disulfide formation or altered GSH/oxidized glutathione ratio. In liver cytosols, addition of DBcAMP and cAMP-dependent protein kinase (A-kinase) inhibited GSH synthesis from substrates (cysteine, ATP, glutamate, and glycine) by approximately 20% which was prevented by the A-kinase inhibitor. However, if only substrates of the second step in GSH synthesis were used (gamma-glutamylcysteine, glycine, and ATP), DBcAMP and A-kinase exerted no inhibitory effect. Phenylephrine, vasopressin, and phorbol ester also inhibited GSH synthesis in cultured cells by approximately 20%, and depleted cell GSH independent of the type of sulfur amino acid precursor. Cellular cysteine level was unchanged despite the significant fall in GSH after glucagon or phenylephrine treatment. Pretreatment with either staurosporine, C-kinase inhibitor, or calmidazolium, a calmodulin inhibitor, partially prevented but, together, completely prevented the inhibitory effect of phenylephrine. The same combination had no effect on the inhibitory effect of glucagon. The effects of hormones were confirmed in both the intact perfused liver and after in vivo administration. Thus, two classes of hormones acting through distinct signal transduction pathways may down-regulate hepatic GSH synthesis by phosphorylation of gamma-glutamylcysteine synthetase.
Abstract 4784: Genetic alterations in premalignant nasopharyngeal epithelium support stable EBV infection.
Authors: George Sai-Wah Tsao, Anna CM Tsang, Elaine YL Yip, W Deng, Annie LM Cheung, KW Lo
Journal: Cancer Research (2013)

Abstract EBV infection is closely associated with nasopharyngeal carcinoma. Early events involved in the establishment of EBV infection in premalignant nasopharyngeal epithelium are largely undefined. We have established multiple immortalized nasopharygeal epithelial cells as premalignant cell models for EBV infection. We observed that nasopharyngeal epithelial cells immortalized by combined actions of telomerase and cyclin D1 or knocking down p16 could support stable EBV infection. Furthermore, we observed that EBV infection commonly induces growth inhibition and senescence in infected nasopharyngeal epithelial cells. Overexpression of cyclin D1 suppresses the growth inhibition and support EBV infection. Furthermore cyclin D1 expression confers resistance to differentiation induction in immortalized nasopharyngeal epithelial cells. EBV infection is closely associated with undifferentiated nasopharyngeal carcinoma. We observed that cyclin D1 overexpression is common in premalignant nasopharyngeal epithelium and co-exist with EBV infection shown by EBER staining. All these showed that cyclin D1 overexpression or suppression of the p16 activation support EBV infection establishment in premalignant nasopharyngeal epithelium which has been postulated to be an important and early event in NPC development. Citation Format: George Sai-Wah Tsao, Anna CM Tsang, Elaine YL Yip, W Deng, Annie LM Cheung, KW Lo. Genetic alterations in premalignant nasopharyngeal epithelium support stable EBV infection. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4784. doi:10.1158/1538-7445.AM2013-4784 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
The generality of specificity: Some lessons from audiovisual speech
Authors: Lawrence D. Rosenblum, Michael S. Gordon
Journal: Behavioral and Brain Sciences (2001)

The global array might prove to be an important and even necessary concept for explaining some multi-modal phenomena from the specificational perspective. However, we suspect that specification exists in energy arrays detectable by single or multiple sensory systems. We argue for a more general modality-neutral perspective and review results from recent research on audiovisual speech perception.
Immune–endothelial–nerve interaction: an explanation for the failure of the gastrointestinal system in systemic sclerosis?
Authors: Marco Matucci-Cerinic, László Czirják
Journal: Annals of the Rheumatic Diseases (2009)

In this issue, Kawaguchi et al 1 ( see page 710 ) report the occurrence of antimuscarinic 3 receptor (M3R) antibodies correlating with gastrointestinal involvement and severe dysmotility in systemic sclerosis (SSc). Contractility of the gastrointestinal system is controlled, in the myenteric plexus, by the autonomic nervous systems—sympathetic and parasympathetic—that are both essentially sustained by cholinergic transmission. The data reported by Kawaguchi et al 1 might suggest that these antibodies impair enteric cholinergic neurotransmission, thus fostering enteric dysmotility in SSc. Clearly, this report focuses interest on the role that the immune system, with the production of autoantibodies, may play in generating the dysmotility of the gastrointestinal system in SSc. It is also important to focus attention on the technical details. It is well known that the technique for antibody detection is critical and may lead to controversial results, as already shown in Sjogren syndrome.2 This aspect is even more important because these antibodies are found in high titres in Sjogren syndrome,3 4 remarking the absence of a connective tissue disease control group in the study by Kawaguchi et al .1

Howe et al 5 have previously shown the presence of circulating antibodies to myenteric neurons in SSc, with a positive correlation with the presence of Raynaud’s phenomenon but not with gastrointestinal involvement. Moreover, Eaker et al 6 have injected antimyenteric neuronal antibodies separated from SSc serum into an immunosuppressed rat model (with chronic indwelling intestinal electrodes to measure intestinal myoelectric activity) to observe the effects on intestinal motility. A prolongation in activity front duration and interval and a disruption were seen after SSc antibody injections. The authors hypothesised that these antibodies could account for the gastrointestinal …
Methods for the de-identification of electronic health records for genomic research
Authors: Khaled El Emam
Journal: Genome Medicine (2011)

Electronic health records are increasingly being linked to DNA repositories and used as a source of clinical information for genomic research. Privacy legislation in many jurisdictions, and most research ethics boards, require that either personal health information is de-identified or that patient consent or authorization is sought before the data are disclosed for secondary purposes. Here, I discuss how de-identification has been applied in current genomic research projects. Recent metrics and methods that can be used to ensure that the risk of re-identification is low and that disclosures are compliant with privacy legislation and regulations (such as the Health Insurance Portability and Accountability Act Privacy Rule) are reviewed. Although these methods can protect against the known approaches for re-identification, residual risks and specific challenges for genomic research are also discussed.
Fanning the flames: inflammation in cardiovascular diseases
Authors: Peter Libby
Journal: Cardiovascular Research (2015)

Leucocytes have occupied centre stage as protagonists in host defences and inflammatory diseases since the era of the 19th century pioneers including Virchow, Cohnheim, and Metchnikoff.1 These investigators helped establish the scientific basis of modern medicine through their careful morphologic observation, experimental manipulations, and deductive reasoning. The romance of the white corpuscle achieved popular culture status in the beginning of the 20th century, as reflected by George Bernard Shaw's exhortation to ‘stimulate the phagocytes’ in his 1906 play ‘The Doctor's Dilemma’.2

Application of the tools of biochemistry and cell biology enabled fleshing out the functions of phagocytes in the 20th century. Such studies discovered the ability of leucocytes to produce reactive oxygen species (ROS), lipid mediators, peptides, and cytokines, as well as granular constituents including plentiful proteinases. This potent armamentarium equips leucocytes to fight invaders, or when turned against the host, to produce or promote disease.

The field of leucocyte biology has flourished during the last several decades. We now possess detailed knowledge of the way in which various leucocyte sub-classes enter, tarry within, and exit the vasculature and tissue compartments ( Figure 1 ). We have learned what signals beckon these cells to extravasate and delineated detailed mechanisms by which they do so. Leucocytes not only enter tissues but persist within them in response to specific signals, and may in some cases emigrate, each step subject to regulation by various interesting mechanisms and paths. 



Figure 1 
( A ) This panel shows a simplified ‘life cycle’ of neutrophil responding to an acute inflammatory or injurious stimulus. The role of the neutrophil typically plays out in a matter of hours. The neutrophil can exercise functions intravascularly, in interstitial spaces, in walled-off collections (abscesses), or within the parenchyma of a tissue. After recruitment and activation, neutrophils release many …