tbuckley/cabot-search huggingface dataset:
Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial
Authors: P. Gringras, C. Gamble, A. P. Jones, L. Wiggs, P. R. Williamson, A. Sutcliffe, P. Montgomery, W. P. Whitehouse, I. Choonara, T. Allport, A. Edmond, R. Appleton
Journal: BMJ (2012)

Immune cells rely on the transcription factor NFAT5 to adapt to hypertonic stress. The hypertonicity-dependent role of NFAT5 in T cells in vivo remains unclear because mouse models of NFAT5 deficiency have produced substantially different T cell phenotypes. In this study, we analyzed the T cell compartment in NFAT5-null and T cell-specific NFAT5 knockout mice. We found that NFAT5-null mice had constitutive, pronounced hypernatremia and suffered a severe immunodeficiency, with T cell lymphopenia, altered CD8 naive/memory homeostasis, and inability to reject allogeneic tumors. By contrast, T cell-specific NFAT5 knockout mice had normal plasma tonicity, rejected allogeneic tumors, and exhibited only a mild, low-penetrance memory bias in CD8 cells. Notably, when T cells from these mice were cultured ex vivo in hypernatremic media, they exhibited features found in NFAT5-null mice, with pronounced naive/memory imbalance and impaired homeostatic survival in response to IL-7, as well as a severe inhibition of their mitogen-induced proliferation. By analyzing surface receptors whose expression might be affected in NFAT5-deficient cells, we identified CD24 as a novel NFAT5 target induced by hypertonicity both in vitro and in vivo, and required to sustain T cell expansion under osmostress. NFAT5 bound to the <i>Cd24</i> promoter in response to hypertonicity facilitated the local derepression of chromatin and enhanced the expression of CD24 mRNA and protein. Altogether, our results indicate that the systemic hypernatremia of NFAT5-null mice is a major contributor to their immunodeficiency, and highlight the role of NFAT5 and CD24 in the homeostasis of T cells under osmostress in vivo.
Re: Per-Uno Malmström, Richard J. Sylvester, David E. Crawford, et al. An Individual Patient Data Meta-Analysis of the Long-Term Outcome of Randomised Studies Comparing Intravesical Mitomycin C versus Bacillus Calmette-Guérin for Non–Muscle-Invasive Bladder Cancer. Eur Urol 2009;56:247–56
Authors: Donald Lamm, Andreas Böhle, Joan Palou, Raj Persad, Maurizio Brausi, Marc Colombel, Hideyuki Akaza, Roger Buckley
Journal: European Urology (2009)
MAEBL Is Essential for Malarial Sporozoite Infection of the Mosquito Salivary Gland
Authors: Tohru Kariu, Masao Yuda, Kazuhiko Yano, Yasuo Chinzei
Journal: The Journal of Experimental Medicine (2002)

Malarial sporozoites mature in the oocysts formed in the mosquito midgut wall and then selectively invade the salivary glands, where they wait to be transmitted to the vertebrate host via mosquito bite. Invasion into the salivary gland has been thought to be mediated by specific ligand–receptor interactions, but the molecules involved in these interactions remain unknown. MAEBL is a single transmembrane-like protein that is structurally related to merozoite adhesive proteins. We found MAEBL of the rodent malaria parasite, Plasmodium berghei, to be specifically produced by the sporozoites in the oocyst and localized in their micronemes, which are secretory organelles involved in malarial parasite invasion into the host cell. A targeted disruption experiment of the P. berghei MAEBL gene revealed that it was essential for sporozoite infection of the salivary gland and was involved in the attachment to the salivary gland surface. In contrast, the disruption of the MAEBL gene did not affect sporozoite motility in vitro nor infectivity to the vertebrate host. These results suggest that P. berghei MAEBL is a sporozoite attachment protein that participates in specific binding to and infection of the mosquito salivary gland.
Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours.
Authors: R Arnold, M E Trautmann, W Creutzfeldt, R Benning, M Benning, C Neuhaus, R Jurgensen, K Stein, H Schafer, C Bruns, H J Dennler
Journal: Gut (1996)

Antiproliferative treatment of patients with metastatic endocrine gastroenteropancreatic tumours (GEP) is based mainly on chemotherapeutic protocols whereby drug toxicity is a major handicap. Octreotide is the first choice in the control of hormone mediated symptoms. From retrospective and a few prospective studies it has been suggested that octreotide exhibits antiproliferative properties. The prospective German Sandostatin multicentre phase II trial investigated the effects of 200 micrograms octreotide thrice daily for one year on tumour growth and endocrine abnormalities in 103 patients. Octreotide treatment was continued in those patients responding to the drug until tumour progression occurred. In 28 of those with tumour progression during 200 micrograms thrice daily octreotide dose was increased to 500 micrograms thrice daily. The study sample consisted of 52 patients with computed tomography confirmed tumour progression and 13 patients with stable disease before octreotide treatment, whereas no preobservation period was available in 38 patients. Nineteen patients (36.5%) with computed tomography confirmed tumour progression experienced stabilisation of tumour growth lasting for at least three months. Median duration of stable disease was 18 months. At month 12, stable disease continued in 12 patients, declined after 24 months to nine patients, and after 36 months to five patients. Tumour regression has not been seen in this or other subgroups. In the subgroup with stable disease before octreotide, stable disease continued in 53.8% of patients over 12 months. Increase of octreotide dose to 500 micrograms thrice daily did not influence progression seen during the lower dose with the exception of one patient in whom tumour progression changed to stable disease. No association of tumour size response and patients9 characteristics could be detected. The results suggest that octreotide inhibits tumour growth in patients with metastasised endocrine GEP tumours. The antiproliferative effect is, at least in some patients, longlasting. Currently, octreotide can only be recommended as an antiproliferative drug if patients with clearly progressive disease show stabilisation after treatment for three to six months.
Colorectal cancer: a tale of two sides or a continuum?: Figure 1
Authors: Mai Yamauchi, Paul Lochhead, Teppei Morikawa, Curtis Huttenhower, Andrew T Chan, Edward Giovannucci, Charles Fuchs, Shuji Ogino
Journal: Gut (2012)

Colorectal cancer comprises a heterogeneous group of diseases that arise through varying molecular carcinogenic pathways, involving complex interactions between tumour cells and the host microenvironment.1 2 It has long been appreciated that developmental and physiological differences exist between anatomic segments of the colorectum, and that colorectal cancers occur with distinctly different frequencies at different subsites.3 While approaches to surgical and adjuvant therapy have set rectal cancer as a separate entity, colon cancers still tend to get grouped together.

In the 1980s, epidemiological and molecular data suggested that cancers arising at different subsites may be biologically disparate, implying different cancer aetiologies or evolutions. These observations prompted the suggestion that the proximal and distal colon should be considered separately in aetiological studies, with the splenic flexure as a demarcation point.3 This dichotomisation has been propagated by subsequent clinical, translational and epidemiological studies,4–10 while evolving molecular data have galvanised and lent further support to the two-colon concept.11–14 It remains uncertain, however, whether the splenic flexure represents a genuine or arbitrary divide in the aetiological spectrum of colon cancers. Notably, our recent study,15 demonstrating that the frequencies of key tumour molecular features change gradually along the length of the colon (rather than abruptly at the splenic flexure), challenges the current two-colon paradigm. The aim of this article is to review data relevant to the current concept of distinct molecular pathogeneses for proximal versus distal colon cancers, to describe the impact of our recent findings and to discuss the implications for future research.

### Historical overture

There are incontrovertible differences between the ontogeny, morphology, biochemistry and physiology of the proximal and distal colon.11–14 Furthermore, gross macroscopic differences are well described between proximal and distal colorectal tumours.9 11–14 In …
The Impact of Genomics on Drug Discovery
Authors: C. Debouck, B. Metcalf
Journal: The Annual Review of Pharmacology and Toxicology (2000)

High-throughput gene sequencing has revolutionized the process used to identify novel molecular targets for drug discovery. Thousands of new gene sequences have been generated but only a limited number of these can be converted into validated targets likely to be involved in disease. We describe here some of the approaches used at SmithKline Beecham to select and validate novel targets. These include the identification of selective tissue gene product expression, such as for cathepsin K, a novel osteoclast-specific cysteine protease. We also describe the discovery and functional characterization of novel members of the G-protein coupled receptor superfamily and their pairing with natural ligands. Lastly, we discuss the promises of gene microarrays and proteomics, developing technologies that allow the parallel analyses of tissue expression patterns of thousands of genes or proteins, respectively.
Distribution of maternal immunoglobulins in the mouse uterus and embryo in the days after implantation.
Authors: O Bernard, M A Ripoche, D Bennett
Journal: The Journal of Experimental Medicine (1977)

The distribution of maternal immunoglobulins in the mouse uterus and embryo in the days after implantation has been studied on sections incubated with sheep Fab anti-mouse immunoglobulins labeled with peroxidase. At the time of implantation the blastocyst is already surrounded by immunoglobulins that are also present in the blastocoel and early endoderm; uterine glands contain large amounts of immunoglobulins. Later, immunoglobulins are concentrated in the vacuolated endoderm, then the visceral yolk sac and the embryonic gut. They are also present in the various cavities of the embryo. Trophoblast cells progressively contain increasing amounts of immunoglobulins. In the decidua, immunoglobulins coat the cells and also occasionally appear as cytoplasmic granules. The early presence of maternal immunoglobulins may represent the transfer of serum proteins as a means of nutrition for the embryo. It is also very likely to have an immunological significance in the protection of the embryo.
Carotid Endarterectomy and Prevention of Cerebral Ischemia in Symptomatic Carotid Stenosis
Authors: Marc R. Mayberg
Journal: JAMA (1991)

<h3>Objective.</h3> —To determine whether carotid endarterectomy provides protection against subsequent cerebral ischemia in men with ischemic symptoms in the distribution of significant (&gt;50%) ipsilateral internal carotid artery stenosis. <h3>Design.</h3> —Prospective, randomized, multicenter trial. <h3>Setting.</h3> —Sixteen university-affiliated Veterans Affairs medical centers. <h3>Patients.</h3> —Men who presented within 120 days of onset of symptoms that were consistent with transient ischemic attacks, transient monocular blindness, or recent small completed strokes between July 1988 and February 1991. Among 5000 patients screened, 189 individuals were randomized with angiographic internal carotid artery stenosis greater than 50% ipsilateral to the presenting symptoms. Forty-eight eligible patients who refused entry were followed up outside of the trial. <h3>Outcome Measures.</h3> —Cerebral infarction or crescendo transient ischemic attacks in the vascular distribution of the original symptoms or death within 30 days of randomization. <h3>Intervention.</h3> —Carotid endarterectomy plus the best medical care (n = 91) vs the best medical care alone (n=98). <h3>Results.</h3> —At a mean follow-up of 11.9 months, there was a significant reduction in stroke or crescendo transient ischemic attacks in patients who received carotid endarterectomy (7.7%) compared with nonsurgical patients (19.4%), or an absolute risk reduction of 11.7% (<i>P</i>=.011). The benefit of surgery was more profound in patients with internal carotid artery stenosis greater than 70% (absolute risk reduction, 17.7%;<i>P</i>=.004). The benefit of surgery was apparent within 2 months after randomization, and only one stroke was noted in the surgical group beyond the 30-day perioperative period. <h3>Conclusions.</h3> —For a selected cohort of men with symptoms of cerebral or retinal ischemia in the distribution of a high-grade internal carotid artery stenosis, carotid endarterectomy can effectively reduce the risk of subsequent ipsilateral cerebral ischemia. The risk of cerebral ischemia in this subgroup of patients is considerably higher than previously estimated. (<i>JAMA</i>. 1991;266:3289-3294)
Defibrillator Implantation Without Induction of Ventricular Fibrillation
Authors: Anne B. Curtis
Journal: Circulation (2007)

n increasing number of cardiac electrophysiologists are fortunate not to have endured the challenges of implanting monophasic waveform cardioverterdefibrillators (ICDs).With early technology, ICDs were routinely tested during the implantation procedure and then again before discharge, with a not-infrequent need for system revisions.With transvenous, high-output devices and biphasic shocks, the number of patients who have an inadequate defibrillation safety margin (DSM) has become so small that questions have been raised about the need for testing at all.However, given the fact that ICDs are designed to be potentially lifesaving, it is incumbent on physicians to obtain a high level of assurance that the device will work as designed if needed.It also should be noted that all clinical trials of ICD therapy for the prevention of sudden cardiac death incorporated testing for the adequacy of the DSM.
Sexual problems among married ileostomists. Survey conducted by The Ileostomy Association of Great Britain and Ireland.
Authors: W R Burnham, J E Lennard-Jones, B N Brooke
Journal: Gut (1977)

The Ileostomy Association of Great Britain and Ireland has conducted a survey to assess the incidence and nature of sexual problems among a one in 10 sample of its membership. The analysis was restricted to married ileostomists; of those aged up to 45 years at the time of operation 16% had married and 23% had had children after the operation. The majority had adapted well to the ileostomy, and this appeared true also for the spouse. However, 12% of those who replied ascribed marital tension, unhappiness, or even separation, to the presence of the stoma. There was no evidence of sexual dysfunction from the construction of an ileostomy without rectal excision. After rectal excision nearly one-third of men reported sexual dysfunction, the frequency and severity of which was related to the age at operation. Up to the age of 45, one of 88 men developed complete erectile impotence and 17 partial dysfunction; over this age five of 30 men developed complete and 11 partial erectile impotence. One-third of women reported some dyspareunia after rectal excision.
Portal branch ligation with a continuous hepatocyte growth factor supply makes extensive hepatectomy possible in cirrhotic rats
Authors: Toshimi Kaido, Akira Yoshikawa, Shin-ichi Seto, Shoji Yamaoka, Maki Sato, Takehisa Ishii, Masayuki Imamura
Journal: Hepatology (1998)

In a cirrhotic liver, the regenerative ability and specific functions are so impaired that excessive resection easily complicates postoperative liver dysfunction, which frequently leads to life-threatening multiple-organ failure. Hepatocyte growth factor (HGF), first identified as the most potent stimulator of DNA synthesis in primary hepatocytes, not only stimulates liver regeneration, but also accelerates hepatic function, improves fibrosis, and protects liver cells against injury. Therefore, we investigated the efficacy of preoperative portal branch ligation (PBL) (which can induce compensatory hypertrophy of the unaffected lobes) combined with a continuous HGF supply in the performance of extensive hepatectomy in cirrhotic rats. Cirrhosis was induced by intraperitoneal injections of dimethylnitrosamine (DMN) three times per week for 3 weeks. Five days after the last injection, when 70% hepatectomy is lethal, the rats underwent portal ligation of the left lateral and median branches (corresponding to approximately 70% of the total volume of the liver). Simultaneously, they were continuously treated with either recombinant human HGF (rhHGF) or vehicle from an intraperitoneally implanted osmotic pump. Four days after the portal ligation, the occluded lobes were resected. The HGF treatment rapidly increased both the wet weight of the unoccluded lobes and the hepatocellular DNA synthesis. The blood chemical analysis indicated that HGF significantly suppressed the posthepatectomy liver dysfunction. Most importantly, the HGF treatment markedly improved the survival rate of the rats at 48 hours after the major hepatectomy. In conclusion, PBL combined with a continuous HGF supply makes extensive hepatectomy possible in cirrhotic rats, mainly by promoting the hypertrophy of the unaffected lobes.
Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase–dependent manner
Authors: Anje Cauwels, Emmanuel S. Buys, Robrecht Thoonen, Lisa Geary, Joris Delanghe, Sruti Shiva, Peter Brouckaert
Journal: The Journal of Experimental Medicine (2009)

Nitrite (NO2−), previously viewed as a physiologically inert metabolite and biomarker of the endogenous vasodilator NO, was recently identified as an important biological NO reservoir in vasculature and tissues, where it contributes to hypoxic signaling, vasodilation, and cytoprotection after ischemia–reperfusion injury. Reduction of nitrite to NO may occur enzymatically at low pH and oxygen tension by deoxyhemoglobin, deoxymyoglobin, xanthine oxidase, mitochondrial complexes, or NO synthase (NOS). We show that nitrite treatment, in sharp contrast with the worsening effect of NOS inhibition, significantly attenuates hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue infarction, and mortality in a mouse shock model induced by a lethal tumor necrosis factor challenge. Mechanistically, nitrite-dependent protection was not associated with inhibition of mitochondrial complex I activity, as previously demonstrated for ischemia–reperfusion, but was largely abolished in mice deficient for the soluble guanylate cyclase (sGC) α1 subunit, one of the principal intracellular NO receptors and signal transducers in the cardiovasculature. Nitrite could also provide protection against toxicity induced by Gram-negative lipopolysaccharide, although higher doses were required. In conclusion, we show that nitrite can protect against toxicity in shock via sGC-dependent signaling, which may include hypoxic vasodilation necessary to maintain microcirculation and organ function, and cardioprotection.
GENETICS OF RESTRICTED ANTIBODIES TO STREPTOCOCCAL GROUP POLYSACCHARIDES IN MICE
Authors: Matthias Cramer, Dietmar G. Braun
Journal: The Journal of Experimental Medicine (1974)

The immune response of nine inbred and one outbred strain of mice to the streptococcal group A polysaccharide was investigated with respect to magnitude and restriction. Analytical isoelectric focusing served as a tool to estimate the degree of restriction of Group A polysaccharide-specific antibodies. It proved feasible to distinguish low and intermediate from high responder strains, and to delineate strain-specificity of isoelectric focusing spectra of the immune sera. For example, immune sera of BALB/c mice, restricted high responders, and of C57BL/6 mice, heterogeneous low responders, had distinct focusing properties. Responsiveness was a dominant autosomal genetic trait in C57BL/6 x BALB/c F(1) hybrid mice, irrespective of the maternal and the paternal genotype; the immune sera of these mice had their own, rather uniform isoelectric focusing spectra whereby structural genes of the low responder strain were expressed to predominant levels in 81% of the hybrids. Responsiveness in C57BL/6 x BALB/c F(2) progeny segregated into 79% high and 21% low responders, and showed no genetic linkage to the following characteristics: hair color, sex, H-2 type, and Ig allotype of the heavy chain. The isoelectric focusing properties of these immune sera indicated segregation into patterns like BALB/c mice (40%), F(1) hybrids (48%), and C57BL/6 mice (12%). Since this segregation is independent of any of the above criteria in these F(2) mice a regulatory gene(s) is postulated that controls the clonal pattern of the immune response.
Interactions Among Genetic Variants in Apoptosis Pathway Genes, Reflux Symptoms, Body Mass Index, and Smoking Indicate Two Distinct Etiologic Patterns of Esophageal Adenocarcinoma
Authors: Rihong Zhai, Feng Chen, Geoffrey Liu, Li Su, Matthew H. Kulke, Kofi Asomaning, Xihong Lin, Rebecca S. Heist, Norman S. Nishioka, Chau-Chyun Sheu, John C. Wain, David C. Christiani
Journal: Journal of Clinical Oncology (2010)

Apoptosis pathway, gastroesophageal reflux symptoms (reflux), higher body mass index (BMI), and tobacco smoking have been individually associated with esophageal adenocarcinoma (EA) development. However, how multiple factors jointly affect EA risk remains unclear.In total, 305 patients with EA and 339 age- and sex-matched controls were studied. High-order interactions among reflux, BMI, smoking, and functional polymorphisms in five apoptotic genes (FAS, FASL, IL1B, TP53BP, and BAT3) were investigated by entropy-based multifactor dimensionality reduction (MDR), classification and regression tree (CART), and traditional logistic regression (LR) models.In LR analysis, reflux, BMI, and smoking were significantly associated with EA risk, with reflux as the strongest individual factor. No individual single nucleotide polymorphism was associated with EA susceptibility. However, there was a two-way interaction between IL1B + 3954C>T and reflux (P = .008). In both CART and MDR analyses, reflux was also the strongest individual factor for EA risk. In individuals with reflux symptoms, CART analysis indicated that strongest interaction was among variant genotypes of IL1B + 3954C>T and BAT3S625P, higher BMI, and smoking (odds ratio [OR], 5.76; 95% CI, 2.48 to 13.38), a finding independently found using MDR analysis. In contrast, for participants without reflux symptoms, the strongest interaction was found between higher BMI and smoking (OR, 3.27; 95% CI, 1.88 to 5.68), also echoed by entropy-based MDR analysis.Although a history of reflux is an important risk for EA, multifactor interactions also play important roles in EA risk. Gene-environment interaction patterns differ between patients with and without reflux symptoms.
Performance of a new clinical grading system for chronic graft-versus-host disease: a multicenter study
Authors: Görgün Akpek, Stephanie J. Lee, Mary E. Flowers, Steven Z. Pavletic, Mukta Arora, Shing Lee, Steven Piantadosi, Katherine A. Guthrie, James C. Lynch, Alessandra Takatu, Mary M. Horowitz, Joseph H. Antin, Daniel J. Weisdorf, Paul J. Martin, Georgia B. Vogelsang
Journal: Blood (2003)