tbuckley/cabot-search huggingface dataset:
High prevalence of Helicobacter pylori infection in cohabiting children. Epidemiology of a cluster, with special emphasis on molecular typing.
Authors: P Vincent, F Gottrand, P Pernes, M O Husson, M Lecomte-Houcke, D Turck, H Leclerc
Journal: Gut (1994)

Intrafamilial cases of infection with the same strain of Helicobacter pylori (H pylori) have been reported but these clusters were too small to distinguish between person to person spread or coinfection from a common environmental source. To gain more information on the mode of transmission of H pylori, an epidemiological survey with bacterial strain differentiation by restriction endonuclease analysis of chromosomal DNA was carried out in an institution of 117 children with encephalopathy (aged 3.5 to 19 years). All children with antibodies against H pylori had gastroscopy to obtain gastric biopsy specimens. The prevalence of infection (confirmed histologically or microbiologically, or both) was 38% (45/117), and rose to 67% in one of the five sections of the institution. H pylori was isolated in 34/45 cases, and 22 different strains were found of which five strains were present in more than one child. Up to seven children were infected by the same strain, five of them were living in the same section. Analysis of the characteristics of infected children showed the predominant role of living conditions and the period of time cohabiting in this unexpectedly high prevalence of H pylori infection in children living in good sanitary conditions.
Inhibition of Rho-associated coiled-coil containing protein kinase enhances the activation of epidermal growth factor receptor in pancreatic cancer cells
Authors: Masanori Nakashima, Seiji Adachi, Ichiro Yasuda, Takahiro Yamauchi, Junji Kawaguchi, Toshimasa Hanamatsu, Takashi Yoshioka, Yukio Okano, Yoshinobu Hirose, Osamu Kozawa, Hisataka Moriwaki
Journal: Molecular Cancer (2011)

Rho-associated coiled-coil containing protein kinase (Rho-kinase/ROCK) is involved in various cellular functions including cell proliferation, and is generally considered to be oncogenic, while some studies show that ROCK functions as a negative regulator of cancer progression. As a result, the precise role of ROCK remains controversial. We have previously reported that Rho-kinase/ROCK negatively regulates epidermal growth factor (EGF)-induced cell proliferation in SW480 colon cancer cells. In the present study, we investigated the role of ROCK in EGF receptor (EGFR) signaling in the pancreatic cancer cell lines, Panc1, KP3 and AsPc1.In these cells, Y27632, a specific ROCK inhibitor, enhanced EGF-induced BrdU incorporation. The blockade of EGF stimulation utilizing anti-EGFR-neutralizing antibodies suppressed Panc1 cell proliferation. EGF induced RhoA activity, as well as the phosphorylation of cofilin and myosin light chain (MLC), both targets of ROCK signaling, and Y27632 suppressed both of these processes, indicating that the phosphorylation of cofilin and MLC by EGF occurs through ROCK in Panc1 cells. EGF-induced phosphorylation of EGFR at tyrosine residues was augmented when the cells were pretreated with Y27632 or were subjected to gene silencing using ROCK-siRNA. We also obtained similar results using transforming growth factor-α. In addition, EGF-induced phosphorylation of p44/p42 mitogen-activated protein kinase and Akt were also enhanced by Y27632 or ROCK-siRNA. Moreover, an immunofluorescence microscope study revealed that pretreatment with Y27632 delayed EGF-induced internalization of EGFR. Taken together, these data indicate that ROCK functions to switch off EGFR signaling by promoting the internalization of the EGFR.While EGF first stimulates the activation of the EGFR and subsequently increases cancer cell proliferation, EGF concurrently induces the activation of ROCK, which then turns off the activated EGFR pathway via a negative feedback system.
M40 Tackling Poor Attendance To Tuberculosis Clinic - Who, Why And What Can Be Done
Authors: E. Denneny, S. Black, Y. Bogle, V. Macavei, T. O'Shaughnessy, V. White, H. Kunst, N. Jayasekera
Journal: Thorax (2014)

<h3>Introduction</h3> Despite efforts to improve Tuberculosis (TB) services, disease rates remain high (UK national average 14.4 per 100,000). We believe one of the ongoing challenges is engaging patients in attending outpatient clinics for care. However, there is no current UK data evaluating poor attendance to TB clinic. <h3>Aim</h3> To identify reasons for patient's not attending TB clinic, in order to implement service improvements and increase patient engagement. <h3>Methods</h3> We conducted a prospective study reviewing the number of Did Not Attends (DNAs) to our TB clinic over a six-week period (April to June 2014). We evaluated data, usually obtained from patients who are contacted after they DNA, and cross referenced this with the trust electronic database. Data obtained included patient demographics, stage of TB treatment, route of referral, reasons for non-attendance and accessibility to clinic. <h3>Results</h3> 63 of 385 patients (16% - 42 males, 21 females) did not attend their TB clinic appointments compared to 15% for non-TB respiratory appointments in this time. 64% were contactable (25 males, 15 females). Median age was 32 (range 17–78 years), which included 16 ethnicities and seven languages. 62.5% were follow-up appointments and 37.5% were new. 27.5% had TB previously. Stage of TB treatment included: completed (17.5%), current (25%), none (57.5%). Referral route included GP (40%), hospital (32.5%) and contact tracing (27.5%). 59% were aware of their appointment but were unable to attend due to other engagements. 41% stated they had not received a letter informing them of their appointment, 13% of these patients had relocated to another area and not updated their address. 8% of patients highlighted problems with transport leading to difficulties accessing the clinic. <h3>Conclusions</h3> Communication to inform patients about appointments needs to be improved by both the referring and TB service. Utilising information technology and community links may improve patient education and therefore engagement with services. Experiencing the patient's journey will highlight further areas for development.
DO SPECIES LACKING A GALL BLADDER POSSESS ITS FUNCTIONAL EQUIVALENT?
Authors: Philip D. McMaster
Journal: The Journal of Experimental Medicine (1922)

In a previous paper the point has been brought out that the influence of the gall bladder upon the bile differs entirely from that of the ducts, the one organ acting to concentrate the secretion markedly and the other to dilute it slightly. The question arises, in species lacking a gall bladder, whether the concentrating function of this organ will be found lodged in the ducts. To test the point, observations have been made upon the mouse and rat, since these animals though so nearly related have, the mouse, a gall bladder and the rat, none. The normal bile was first studied. Both animals were found to secrete larger quantities than do cats and dogs, but less than the guinea pig and rabbit. Methods were worked out for the quantitation of the pigment which was used as the index to changes in concentration. Bladder bile of the mouse was regularly found to be more concentrated than that collected from the common duct of the same animal. The bile collecting during stasis regularly showed a great increase in pigment content, such as in other species is brought about by the action of the gall bladder. In the rat, on the other hand, stasis bile never became more concentrated in pigment than the normal. The gall bladder, then, is not only absent from the rat in form, but in one at least of its important functions. That its other obvious function-that of a reservoir-cannot be assumed in the rat by the ducts would seem to be indicated, not only by the small size of these channels, but by the recent observation of Mann that the tonus of the sphincter of Oddi is almost negligible in the rat, in contradistinction to animals which possess a gall bladder. It is an interesting fact that the bile of the rat, which as has been said, undergoes no condensation of bulk after leaving the liver, contains on the average eight times as much pigment as does the liver bile of the mouse which is submitted to concentration. Whether it is correspondingly strong in substances useful for digestion, and therefore ab initio requires no concentration, is a matter upon which little can be said at present. However, in this connection the fact that the bulk of bile secreted per gram of liver weight is identical in both animals may be significant. Although this output is the same, the mouse liver when compared with the body weight (1 to 14.6) is relatively larger than that of the rat (1 to 21.7), so that the mouse secretes somewhat more bile per 100 gm. of body weight. This bile as it comes from the liver is but one-eighth as strong at least in pigment as rat bile, but the concentrating activity of the gall bladder is so great that the products yielded to the intestine may become not dissimilar.
The prognostic role of TGF-β signaling pathway in breast cancer patients
Authors: E.M. de Kruijf, T.J.A. Dekker, L.J.A.C. Hawinkels, H. Putter, V.T.H.B.M. Smit, J.R. Kroep, P.J.K. Kuppen, C.J.H. van de Velde, P. ten Dijke, R.A.E.M. Tollenaar, W.E. Mesker
Journal: Annals of Oncology (2012)
Suicide Prodrugs Activated by Thymidylate Synthase: Rationale for Treatment and Noninvasive Imaging of Tumors with Deoxyuridine Analogues
Authors: Jerry M. Collins, Raymond W. Klecker, Aspandiar G. Katki
Journal: Clinical Cancer Research (1999)

Most tumors are resistant to therapy by thymidylate synthase (TS) inhibitors due to their high levels of TS. Instead of inhibiting TS, we hypothesized that it was possible to use this enzyme to activate suicide prodrugs (deoxyuridine analogues) to more toxic species (thymidine analogues). Tumors with high levels of TS could be particularly sensitive to deoxyuridine analogues because they would be more efficient in producing the toxic methylated species. Furthermore, the accumulation of methylated species within tumors could be visualized externally if a tracer dose of the deoxyuridine analogue was tagged with an isotope, preferably a positron emitter, such as 18F. Higher accumulation of isotope indicates higher activity of TS and lower sensitivity of the tumor to TS inhibitors, but perhaps more sensitivity to therapy with deoxyuridine analogues as suicide prodrugs. 2′-F-ara-deoxyuridine (FAU) was used as a prototype to demonstrate these concepts experimentally. FAU readily entered cells and was phosphorylated, methylated, and subsequently incorporated into cellular DNA. Among different cell lines, FAU produced varying degrees of growth inhibition. Greater DNA incorporation ( e.g ., for CEM and U-937 cells) was reflected as increased toxicity. FAU produced less DNA incorporation in Raji or L1210 cells, and growth rate was minimally decreased. As the first demonstration that cells with high levels of TS activity can be more vulnerable to therapy than cells with low TS activity, this preliminary work suggests a new therapeutic approach for common human tumors that were previously resistant. Furthermore, it appears that the TS activity of tumors could be noninvasively imaged in situ by tracer doses of [18F]FAU and that this phenotypic information could guide patient therapy.
Signaling through Raf-1 in the neovasculature and target validation by nanoparticles.
Authors: Kishore K Wary
Journal: Molecular Cancer (2003)

A recent study demonstrated that vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) activate Raf-1 kinase in an experimental neovasculature system. The study showed that bFGF and VEGF activate p21-activated protein kinase-1 (PAK-1) and Src kinase, respectively. PAK-1 and Src kinases phosphorylate specific serine and tyrosine residues within the activation loop of Raf-1 kinase. Their findings further suggest that phosphorylation at these sites protects endothelial cells from apoptosis induced by both intrinsic and extrinsic factors. The tumor neovasculature provides specific molecular markers or "zip codes". This group of investigators has previously shown that nanosphere-aided targeting of the neovasculature with mutant Raf-1 causes regression of the tumor vasculature. Thus, nanoparticles coated with "zip code"-specific homing biomolecules may be useful for delivering anti-angiogenic molecules that can induce tumor regression.
Chronic Intestinal Failure After Crohn Disease
Authors: Undine A. Gerlach, Georgios Vrakas, Srikanth Reddy, Daniel C. Baumgar, Peter Neuhaus, Peter J. Friend, Andreas Pascher, Anil Vaidya
Journal: JAMA Surgery (2014)

Because of the severity of disease and additional surgery, Crohn disease (CD) may result in intestinal failure (IF) and dependency on home parenteral nutrition (HPN). Defining the indication and timing for intestinal transplantation (ITx) is challenging.To determine the limitations of conventional surgery and to facilitate the decision making for transplantation.Data were collected prospectively and obtained by retrospective review of medical records from all patients with CD who were assessed for ITx in Oxford, United Kingdom, and Berlin, Germany, from October 10, 2003, through July 31, 2013. Patients were considered suitable for ITx if a diagnosis of irreversible IF was established and life-threatening complications under HPN were unresolvable. Twenty patients with CD and IF, established on HPN, were evaluated for ITx. The mean (SD) age at CD onset was 17.8 (9.8) years. On first diagnosis, most patients had a stricturing CD. By the time of referral, most had a combination of stricturing and fistulizing disease.New scoring system: a modification of the American Gastroenterology Association guidelines for ITx. Modifications are related to CD-specific issues that potentially lead to a poorer outcome and are based on the findings of the study to determine the expected benefit from ITx.A scoring system that would alert the physician to the severity of the patient's CD and trigger early referral for ITx. This system may translate into better long-term outcomes for patients with CD. In addition, the Karnofsky performance status score was used to compare pretransplantation and posttransplantation outcomes.Ten patients underwent ITx, 4 were on the waiting list, and 4 were unavailable for follow-up. One patient was taken off the waiting list because of severe deterioration. One patient underwent conventional stricturoplasty and did not need transplantation. Among the transplant recipients, 17 (85%) had a stoma or enterocutaneous fistula, and the mean (SD) residual bowel length was 71.5 (38) cm. A total of 80% of transplant recipients had life-threatening catheter infections, and 13 (65%) had a significant decrease in the estimated glomerular filtration rate. At a mean (SD) follow-up of 27.6 (36.1) months for transplant recipients, the patient and graft survival is 80%, and their Karnofsky performance status score increased by a mean of 18.6%.Intestinal transplantation is a suitable treatment option for patients with CD and IF. It should be considered before any additional attempts at conventional surgery, which may cause eligible patients to miss this opportunity through perioperative complications. The suggested scoring system enables the physician to identify patients who may benefit from transplantation before HPN-associated secondary organ failure.
Response to Letter Regarding Article, “Remote Ischemic Preconditioning in Human Coronary Artery Bypass Surgery: From Promise to Disappointment?”
Authors: Robert S. Bonser, Ishtiaq A. Rahman, Jorge G. Mascaro, Rick P. Steeds, John N. Townend, Michael P. Frenneaux, Peter Nightingale, Peter Gosling, Peter Townsend, David Green
Journal: Circulation (2011)

We thank Dr Heling et al for their interest in our article. 1Their letter raises the question of whether pain is a prerequisite for remote ischemic preconditioning (RIPC), and reflects on the utility of RIPC as a protective adjunct in the anesthetized patient, particularly when volatile anesthetic agents are used.][4] The single-blinded coronary artery bypass grafting studies 3,4 suggested a promising major reduction in troponin release.We developed a scrupulous double-blinding technique to avoid inadvertent bias and applied an identical RIPC stimulus.Similar fractions of patients received volatile anesthetics and preoperative statins in the reported study as in its predecessors.Disappointingly, perhaps, we did not find differences in troponin release, and we were unable to establish any differences in postoperative cardiac function between RIPC and placebo.We thus concluded that RIPC, with the stimulus used, failed to fulfill its promise in myocardial protection in the setting of coronary artery surgery performed on bypass with cardioplegic arrest.Nevertheless, by adding the query sign in the title and considering caveats within the discussion, we did not exclude an RIPC benefit in other situations, including higher-risk patients, a different RIPC stimulus mass, or within cardiac conditions in which the potential for myocardial necrosis rather than reversible injury was likely to be higher, such as ST-elevation myocardial infarction.The ST-elevation myocardial infarction trial cited by Heling et al studied primary percutaneous intervention in patients with or without RIPC. 5The protective effect of RIPC was demonstrable, but modest.Myocardial salvage index was higher, but troponin levels were not different.Benefit was maximal in patients with left anterior descending artery infarction and vessel occlusion.Clinical patient outcome, major adverse cardiovascular events, final infarct size, and 30-day left ventricular ejection fraction were not different.We do not dispute that RIPC may ultimately be found to have a clinical role in a variety of clinical scenarios, and we view the data on nociception with interest.However, the clinical size of the effect appears smaller than suggested by experimental studies, and any true clinical benefit needs to be established by appropriately sized randomized trials.
A 10th of GPs on consortium boards are also on boards of private firms
Authors: A. O'Dowd
Journal: BMJ (2011)

A survey of almost half of all primary care trusts in England has shown that one in 10 GPs on the boards of the new commissioning consortiums are on boards of private firms.

Doctors’ leaders are concerned about possible conflicts of interests that GPs in consortiums might have over commissioning care for patients through services that might be on offer from private companies in which they have a role.

A survey by Pulse magazine collected data under the Freedom of Information Act, which included results from 73 primary care trusts about the pathfinder consortiums in their areas that are piloting the NHS reforms that will give consortiums …
Integrative analysis for finding genes and networks involved in diabetes and other complex diseases
Authors: Regine Bergholdt, Zenia M Størling, Kasper Lage, E Olof Karlberg, Páll Í Ólason, Mogens Aalund, Jørn Nerup, Søren Brunak, Christopher T Workman, Flemming Pociot
Journal: Genome biology (2007)

We have developed an integrative analysis method combining genetic interactions, identified using type 1 diabetes genome scan data, and a high-confidence human protein interaction network. Resulting networks were ranked by the significance of the enrichment of proteins from interacting regions. We identified a number of new protein network modules and novel candidate genes/proteins for type 1 diabetes. We propose this type of integrative analysis as a general method for the elucidation of genes and networks involved in diabetes and other complex diseases.
Patients With Type 3 Severe von Willebrand Disease Are Not Protected Against Atherosclerosis
Authors: A. Šrámek, P. Bucciarelli, A.B. Federici, P.M. Mannucci, V. De Rosa, G. Castaman, M. Morfini, M.G. Mazzucconi, A. Rocino, M. Schiavoni, F.A. Scaraggi, J.H.C. Reiber, F.R. Rosendaal
Journal: Circulation (2004)

The results of a number of studies in pigs and mice suggest that absence of von Willebrand factor (vWF) protects against the development of atherosclerosis. We studied whether patients with a complete deficiency of vWF (type 3 von Willebrand disease [vWD]) develop fewer atherosclerotic vessel wall changes than healthy controls.This study included 47 individuals with type 3 vWD and 84 healthy controls. Early atherosclerotic changes were assessed by measuring the thickness of the intima-media in the carotid and femoral arteries by B-mode ultrasonography. Advanced atherosclerotic changes were quantified by summing the maximal thickness of atherosclerotic plaques in the carotid and femoral arteries and were expressed as a plaque score. Established risk factors were determined to adjust for possible differences between the groups. We found no substantial difference in intima-media thickness between vWD patients and controls (adjusted difference for carotid artery 0.007 mm, 95% CI -0.022 to 0.036 mm; femoral artery 0.069 mm, 95% CI -0.056 to 0.19 mm). Similar proportions of patients and controls had atherosclerotic plaques (19% and 17%, respectively). No difference was found in the plaque score between groups (adjusted difference -0.22 mm, 95% CI -0.69 to 0.26). Among vWD patients, we found no effect of treatment with vWF concentrates on intima-media thickness or plaque score.The results of this study indicate that vWF does not play a substantial role in human atherogenesis.
Inflammation-Induced NFATc1–STAT3 Transcription Complex Promotes Pancreatic Cancer Initiation by <i>Kras</i>G12D
Authors: Sandra Baumgart, Nai-Ming Chen, Jens T. Siveke, Alexander König, Jin-San Zhang, Shiv K. Singh, Elmar Wolf, Marek Bartkuhn, Irene Esposito, Elisabeth Heßmann, Johanna Reinecke, Julius Nikorowitsch, Marius Brunner, Garima Singh, Martin E. Fernandez-Zapico, Thomas Smyrk, William R. Bamlet, Martin Eilers, Albrecht Neesse, Thomas M. Gress, Daniel D. Billadeau, David Tuveson, Raul Urrutia, Volker Ellenrieder
Journal: Cancer Discovery (2014)

Abstract Cancer-associated inflammation is a molecular key feature in pancreatic ductal adenocarcinoma. Oncogenic KRAS in conjunction with persistent inflammation is known to accelerate carcinogenesis, although the underlying mechanisms remain poorly understood. Here, we outline a novel pathway whereby the transcription factors NFATc1 and STAT3 cooperate in pancreatic epithelial cells to promote KrasG12D-driven carcinogenesis. NFATc1 activation is induced by inflammation and itself accelerates inflammation-induced carcinogenesis in KrasG12D mice, whereas genetic or pharmacologic ablation of NFATc1 attenuates this effect. Mechanistically, NFATc1 complexes with STAT3 for enhancer–promoter communications at jointly regulated genes involved in oncogenesis, for example, Cyclin, EGFR and WNT family members. The NFATc1–STAT3 cooperativity is operative in pancreatitis-mediated carcinogenesis as well as in established human pancreatic cancer. Together, these studies unravel new mechanisms of inflammatory-driven pancreatic carcinogenesis and suggest beneficial effects of chemopreventive strategies using drugs that are currently available for targeting these factors in clinical trials. Significance: Our study points to the existence of an oncogenic NFATc1–STAT3 cooperativity that mechanistically links inflammation with pancreatic cancer initiation and progression. Because NFATc1–STAT3 nucleoprotein complexes control the expression of gene networks at the intersection of inflammation and cancer, our study has significant relevance for potentially managing pancreatic cancer and other inflammatory-driven malignancies. Cancer Discov; 4(6); 688–701. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 621