tbuckley/cabot-search huggingface dataset:
Differences in gastric mechanosensory function after repeated ramp distensions in non-consulters with dyspepsia and healthy controls
Authors: G Holtmann
Journal: Gut (2000)

<h3>BACKGROUND</h3> Abnormal visceral mechano- sensory function has been reported in 50% of non-ulcer (functional) dyspepsia patients. However, only a minority of subjects with functional dyspepsia ever seek medical attention. Whether factors promoting health care seeking behaviour explain visceral hypersensitivity is unknown. Decreased rectal thresholds following sigmoid mechanical stimulation have been observed in irritable bowel but this mechanism has not been evaluated in functional dyspepsia. <h3>AIMS</h3> To compare visceral mechanosensory function in healthy asymptomatic subjects and non-consulters with chronic unexplained dyspepsia. <h3>METHODS</h3> Forty two volunteers were recruited: 10 had a history of chronic or recurrent upper abdominal pain or discomfort as assessed by a standardised questionnaire, and <i>Helicobacter pylori</i>status was determined (ELISA and <sup>13</sup>C urea breath test). Eight <i>H pylori</i> negative, currently asymptomatic dyspeptic subjects who were non-consulters and eight asymptomatic age and sex matched <i>H pylori</i>negative controls were enrolled. With a barostat bag in the proximal part of the stomach, visceral perception thresholds were determined by random tracking. Thereafter, standardised ramp distensions were performed (2 mm Hg increments, duration of each pressure step 30 seconds, maximum pressure 35 mm Hg (or occurrence of pain)) and tracking of sensory thresholds and ramp distension repeated every 30 minutes for a total of two hours. <h3>RESULTS</h3> Overall, thresholds for first perception were significantly lower in dyspeptic subjects compared with asymptomatic controls (12.5 (0.6) mm Hg<i>v</i> 17.5 (1.0) mm Hg; p&lt;0.02). After repeated ramp distensions, thresholds for first perception significantly increased by 3.6 (0.7) mm Hg in healthy subjects compared with 0.1 (1.4) mm Hg in subjects with dyspepsia (p&lt;0.05 dyspeptics<i>v</i> controls). <h3>CONCLUSIONS</h3> (1) Repeated mechanical stimulation increases visceral sensory thresholds in asymptomatic subjects while thresholds remain unchanged in dyspeptics. (2) Visceral hyperalgesia occurs in dyspeptic subjects who are not health care seekers.
Molecular Evolution of Cadherin-Related Neuronal Receptor/Protocadherin α (CNR/Pcdhα) Gene Cluster in Mus musculus Subspecies
Authors: Yusuke Taguchi, Tsuyoshi Koide, Toshihiko Shiroishi, Takeshi Yagi
Journal: Molecular Biology and Evolution (2005)

The mouse cadherin-related neuronal receptor/protocadherin (CNR/Pcdh) gene clusters are located on chromosome 18. We sequenced single-nucleotide polymorphisms (SNPs) of the CNR/Pcdhα-coding region among 12 wild-derived and four laboratory strains; these included the four major subspecies groups of Mus musculus: domesticus, musculus, castaneus, and bactrianus. We detected 883 coding SNPs (cSNPs) in the CNR/Pcdhα variable exons and three in the constant exons. Among all the cSNPs, 586 synonymous (silent) and 297 nonsynonymous (amino acid exchanged) substitutions were found; therefore, the Ka/Ks ratio (nonsynonymous substitutions per synonymous substitution) was 0.51. The synonymous cSNPs were relatively concentrated in the first and fifth extracellular cadherin domain-encoding regions (ECs) of CNR/Pcdhα. These regions have high nucleotide homology among the CNR/Pcdhα paralogs, suggesting that gene conversion events in synonymous and homologous regions of the CNR/Pcdhα cluster are related to the generation of cSNPs. A phylogenetic analysis revealed gene conversion events in the EC1 and EC5 regions. Assuming that the common sequences between rat and mouse are ancestral, the GC content of the third codon position has increased in the EC1 and EC5 regions, although biased substitutions from GC to AT were detected in all the codon positions. In addition, nonsynonymous substitutions were extremely high (11 of 13, Ka/Ks ratio 5.5) in the laboratory mouse strains. The artificial environment of laboratory mice may allow positive selection for nonsynonymous amino acid variations in CNR/Pcdhα during inbreeding. In this study, we analyzed the direction of cSNP generation, and concluded that subspecies-specific nucleotide substitutions and region-restricted gene conversion events may have contributed to the generation of genetic variations in the CNR/Pcdh genes within and between species.
Preliminary phase II results of selinexor, an oral selective inhibitor of nuclear export in patients with heavily pretreated gynecological cancers.
Authors: Ignace Vergote, Bente Lund, Hanne Havsteen, Zaza Ujmajuridze, Karin Leunen, Charlotte Aaquist Haslund, Trine Juhler-Noettrup, Henrik Roed, Tami Rashal, Anne L. Kranich, Yosef Landesman, Jean-Richard Saint-Martin, Robert Carlson, Sharon Shacham, Michael Kauffman, Mansoor Raza Mirza
Journal: Journal of Clinical Oncology (2015)

5565 Background: Multiple tumour suppressor proteins (TSPs) are altered in ovarian (OC), endometrial (EC) & cervical (CC) cancers, including p53, BRCA1/2, CDKN2A & pRB. Selinexor, an oral first in class, inhibitor of XPO1 mediated nuclear export, results in nuclear retention and activation of multiple TSPs. Selinexor has anti-cancer activity in preclinical models of CC & platinum-resistant OC & in a phase I clinical study. This phase II trial explores the efficacy & tolerability of Selinexor in patients (pts) with advanced/metastatic incurable OC, EC & CC. Methods: Pts with ≥ 1 line of prior therapy were treated with single agent oral S using Simons two-stage design (NCT02025985). The primary endpoint is disease-control-rate (DCR = PR+SD ≥ 12weeks [wk]). Other endpoints are ORR, PFS, safety, & tolerability. Three treatment schedules (50 mg/m2 twice-weekly (BIW); 35 mg/m2 BIW; & 50 mg/m2 QW in 4-wk cycles) are evaluated. The three cohorts (OC, EC & CC) are evaluated independently for response by RECIST 1.1 after 6 & 12 wks, then every 8 wks. Results: All three cohorts have passed efficacy response rates for Simon analysis & proceeded to stage two. 30 OC (Median age [MA] 63, ECOG 0/1: 16/14, median 5.5 (1–11) prior treatment regimens [PTR]), 15 EC (MA 69, ECOG 0/1: 8/7, median 2 (1–5) PTR) & 18 CC (MA 55.5, ECOG 0/1: 13/5, median 3 (1–8) PTR) heavily pre-treated pts have been enrolled. No Grade 4 toxicities have been seen. Grade 3 drug related adverse events (AEs) include: Nausea (13%), Thrombocytopenia (13%), Vomiting (11%), & Fatigue (10%). Commonly reported Grade 1/2 drug related AEs for all three cohorts include: Nausea (54%), Vomiting (5%), Fatigue (32%), & Anorexia (25%). Dose reductions occurred in 30 % of pts. DCR in evaluable pts: OC: 36%; EC: 64%; CC: 28%. ORR in evaluable pts: OC: 9%; EC: 18%; CC 7%. Conclusions: The initial phase 2 data demonstrate meaningful single-agent anti-tumor activity of Selinexor in all three heavily pretreated gynaecological malignancies. Some pts required dose reduction of Selinexor due to fatigue & anorexia. The most tolerable dosing regimen will be selected for phase III trials. The trial continues to enrol pts. Updated data will be presented. Clinical trial information: NCT02025985.
Oral application of bacterial lysate in infancy decreases the risk of atopic dermatitis in children with 1 atopic parent in a randomized, placebo-controlled trial
Authors: Susanne Lau, Kerstin Gerhold, Kurt Zimmermann, Charlotte W. Ockeloen, Siri Rossberg, Petra Wagner, Claudia Sulser, Rita Bunikowski, Imke Witt, Juliane Wauer, John Beschorner, Georg Menke, Eckard Hamelmann, Ulrich Wahn
Journal: Journal of Allergy and Clinical Immunology (2012)
Salt loading induces redistribution of the plasmalemmal Na/K-ATPase in proximal tubule cells
Authors: Sankaridrug M. Periyasamy, Jiang Liu, Feras Tanta, Besher Kabak, Brent Wakefield, Deepak Malhotra, David J. Kennedy, Alaa Nadoor, Olga V. Fedorova, William Gunning, Zijian Xie, Alexei Y. Bagrov, Joseph I. Shapiro
Journal: Kidney International (2005)
Heterozygous lipoprotein lipase deficiency due to a missense mutation as the cause of impaired triglyceride tolerance with multiple lipoprotein abnormalities.
Authors: G Miesenböck, B Hölzl, B Föger, E Brandstätter, B Paulweber, F Sandhofer, J R Patsch
Journal: Journal of Clinical Investigation (1993)

In 16 members of two Austrian families affected by a missense mutation at codon 188 of the lipoprotein lipase (LPL) gene (8 heterozygous and 8 normal subjects), carrier status for the mutation as determined by DNA analysis was related to LPL activity in postheparin plasma, to the magnitude of postprandial lipemia, and to concentration, composition, and size of the major lipoprotein classes of postabsorptive plasma. Carriers exhibited clearly reduced LPL activity, normal fasting triglycerides, but pronounced postprandial lipemia. The carriers' impaired triglyceride tolerance, as evident in the postprandial state of challenge only, was associated with a fasting lipoprotein constellation characterized by (a) enrichment of HDL2 with triglycerides, (b) reduced HDL2-cholesterol, (c) enrichment of VLDL and intermediate density lipoprotein (IDL) with cholesteryl esters, (d) elevated IDL levels, and (e) small-sized LDL. Within any given individual, the degrees of expression of these characteristics were quantitatively and continuously related with each other as well as with the magnitude of lipemia and with LPL activity.
Neuronal Activity Drives Localized Blood-Brain-Barrier Transport of Serum Insulin-like Growth Factor-I into the CNS
Authors: Takeshi Nishijima, Joaquin Piriz, Sylvie Duflot, Ana M. Fernandez, Gema Gaitan, Ulises Gomez-Pinedo, Jose M. Garcia Verdugo, Felix Leroy, Hideaki Soya, Angel Nuñez, Ignacio Torres-Aleman
Journal: Neuron (2010)
The synthesis and secretion of immunoglobulins by lymphoid cells in the sheep. The primary response to salmonella lipopolysaccharide.
Authors: L S English, E P Adams, B Morris
Journal: The Journal of Experimental Medicine (1976)

The primary response of the popliteal node to Salmonella lipopolysaccharide was studied in the sheep. All three classes of immunoglobulin IgG1, igG2, and IgM were produced by both free-floating cells in the lymph and by cells within the pymph node throughout the immune responce which extended over a period of at least 20 days.. Most of the immunoglobulins were found to be nonspecific for the antigen when tested by a binding assay. It was calculated from the binding assay that far more antigen-specific IgG molecules were produced than IgM molecules. The proportion of IgM and IgG1 which showed affinity for Salmonella organisms increased throughout the response. IgG2 had no affinity for the antigen until around 480 h after challenge. When a hemagglutination assay was used to measure antibody production, most of the specific antibody produced during the response was found to be IgM. Blast cells produced most of the immunoglobulin during the first 4 days of the response, and these cells were responsible for almost all of the IgM production. Differences were observed in the relative amounts of IgG and IgM produced by the cells within the node and by free-floating cells in the efferent lymph. The free-floating cells in lymph synthesized and secreted relatively more IgM and relatively less IgG than did cells within the lymph node. Both populations of cells, however, secreted much more IgG than IgM.
Central memory CD8+ T lymphocytes mediate lung allograft acceptance
Authors: Alexander Sasha Krupnick, Xue Lin, Wenjun Li, Ryuiji Higashikubo, Bernd H. Zinselmeyer, Hollyce Hartzler, Kelsey Toth, Jon H. Ritter, Mikhail Y. Berezin, Steven T. Wang, Mark J. Miller, Andrew E. Gelman, Daniel Kreisel
Journal: Journal of Clinical Investigation (2014)

Memory T lymphocytes are commonly viewed as a major barrier for long-term survival of organ allografts and are thought to accelerate rejection responses due to their rapid infiltration into allografts, low threshold for activation, and ability to produce inflammatory mediators. Because memory T cells are usually associated with rejection, preclinical protocols have been developed to target this population in transplant recipients. Here, using a murine model, we found that costimulatory blockade–mediated lung allograft acceptance depended on the rapid infiltration of the graft by central memory CD8+ T cells (CD44hiCD62LhiCCR7+). Chemokine receptor signaling and alloantigen recognition were required for trafficking of these memory T cells to lung allografts. Intravital 2-photon imaging revealed that CCR7 expression on CD8+ T cells was critical for formation of stable synapses with antigen-presenting cells, resulting in IFN-γ production, which induced NO and downregulated alloimmune responses. Thus, we describe a critical role for CD8+ central memory T cells in lung allograft acceptance and highlight the need for tailored approaches for tolerance induction in the lung.
Tactics in theory of mind research
Authors: Jesse E. Purdy, Michael Domjan
Journal: Behavioral and Brain Sciences (1998)

Progress in the “theory of mind” debate would be better served at this point by abandoning the search for a perfect “critical experiment” and developing an incremental research program based on a systematic theory of “theory of mind.” Studies using the goggle procedure advocated by Heyes should dissociate the ability to see from possible behavioral artifacts of “blind” trainers.
C11ORF95-RELA FUSIONS DRIVE ONCOGENIC NF-KB SIGNALING IN EPENDYMOMA
Authors: R. Gilbertson, M. Parker, K. M. Mohankumar, C. Punchihewa, R. Weinlich, J. D. Dalton, Y. Li, R. Lee, R. G. Tatevossian, T. N. Phoenix, R. Thiruvenkatam, E. White, B. Tang, W. Orisme, K. Gupta, M. Rusch, X. Chen, Y. Li, P. Nagahawhatta, E. Hedlund, D. Finkelstein, G. Wu, S. Shurtleff, J. Easton, K. Boggs, D. Yergeau, B. Vadodaria, H. L. Mulder, J. Becksford, P. Gupta, R. Huether, J. Ma, G. Song, A. Gajjar, T. Merchant, F. Boop, A. A. Smith, L. Ding, C. Lu, K. Ochoa, D. Zhao, R. S. Fulton, L. L. Fulton, E. R. Mardis, R. K. Wilson, J. R. Downing, D. R. Green, J. Zhang, D. W. Ellison, R. J. Gilbertson
Journal: Neuro-Oncology (2014)

BACKGROUND: The nuclear factor-kB (NF-kB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-kB signaling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-kB activity in cancer. METHODS: To identify additional genetic alterations that drive ependymoma, we sequenced the whole genomes (WGS) of 41 tumours and matched normal blood, and the transcriptomes (RNAseq) of 77 tumours. The transforming significance of alterations were tested in mouse NSCs that we showed previously to be cells of origin of ependymoma. RESULTS: Here, we show that more than two thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-kB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-kB target genes, and rapidly transformed neural stem cells—the cell of origin of ependymoma—to form these tumours in mice. CONCLUSIONS: Our data identify the first highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.
Relationships between school indoor toluene and respiratory symptoms in children of five European countries (HESE study)
Authors: Marzia Simoni, Isabella Annesi-Maesano, Torben Sigsgaard, Gunilla Wieslander, Wenche Nystad, Mario Canciani, Piersante Sestini, Giovanni Viegi
Journal: European Respiratory Journal (2012)

Aim:  to assess whether indoor toluene may affect respiratory health in schoolchildren.  Methods : Health status and related risk factors were assessed through questionnaire in 628 children (mean age 10yrs) of five European countries: Sweden, Norway, Denmark, France, Italy (EU-funded HESE Study, Health Effects of School Environment). Measurements of pollutants were performed in 46 classrooms. Toluene was measured by active sampling using charcoal tubes.  Results : The levels of toluene were relatively low: median concentration was 4.57, significantly higher in France (12.12) than in the other four countries (range: 2.82 in Sweden to 5.09 µg/m 3  in Italy). Prevalence rates of dry cough at night and wheeze were respectively 35% (range: 17 in Sweden to 48% in Italy) and 13% (range: 10% in Northern countries to 18% in France). Multiple logistic regression, accounting for centre, gender, age, presence of asthma, passive smoking at home, other indoor pollutants (PM 10 , CO 2 , viable moulds) indicated toluene to be associated with higher risk of dry cough (OR 4.37, 95%CI 2.19-8.75 per 1 µg/m 3  increment) and wheeze (OR 3.24, 1.25-8.45). These associations were significant after further accounting for the fixed effect of the classroom.  Conclusion:  Although toluene levels in classrooms were relatively low, long-term exposure seems to be a risk factor for respiratory health of schoolchildren.
The role of high cell density in the promotion of neuroendocrine transdifferentiation of prostate cancer cells
Authors: Zuzana Pernicová, Eva Slabáková, Radek Fedr, Šárka Šimečková, Josef Jaroš, Tereza Suchánková, Jan Bouchal, Gvantsa Kharaishvili, Milan Král, Alois Kozubík, Karel Souček
Journal: Molecular Cancer (2014)

Tumor heterogeneity and the plasticity of cancer cells present challenges for effective clinical diagnosis and therapy. Such challenges are epitomized by neuroendocrine transdifferentiation (NED) and the emergence of neuroendocrine-like cancer cells in prostate tumors. This phenomenon frequently arises from androgen-depleted prostate adenocarcinoma and is associated with the development of castration-resistant prostate cancer and poor prognosis. In this study, we showed that NED was evoked in both androgen receptor (AR)-positive and AR-negative prostate epithelial cell lines by growing the cells to a high density. Androgen depletion and high-density cultivation were both associated with cell cycle arrest and deregulated expression of several cell cycle regulators, such as p27Kip1, members of the cyclin D protein family, and Cdk2. Dual inhibition of Cdk1 and Cdk2 using pharmacological inhibitor or RNAi led to modulation of the cell cycle and promotion of NED. We further demonstrated that the cyclic adenosine 3′, 5′-monophosphate (cAMP)-mediated pathway is activated in the high-density conditions. Importantly, inhibition of cAMP signaling using a specific inhibitor of adenylate cyclase, MDL-12330A, abolished the promotion of NED by high cell density. Taken together, our results imply a new relationship between cell cycle attenuation and promotion of NED and suggest high cell density as a trigger for cAMP signaling that can mediate reversible NED in prostate cancer cells.
Safety, Pharmacokinetic, and Antitumor Activity of SU11248, a Novel Oral Multitarget Tyrosine Kinase Inhibitor, in Patients With Cancer
Authors: Sandrine Faivre, Catherine Delbaldo, Karina Vera, Caroline Robert, Stéphanie Lozahic, Nathalie Lassau, Carlo Bello, Samuel Deprimo, Nicoletta Brega, Giorgio Massimini, Jean-Pierre Armand, Paul Scigalla, Eric Raymond
Journal: Journal of Clinical Oncology (2005)

Purpose To establish the safety, pharmacokinetics, and recommended dose of sunitinib, a novel oral multitargeting tyrosine kinase inhibitor with antiangiogenic and antitumor properties, in patients with advanced malignancies. Patients and Methods Sunitinib was given orally for 4 weeks every 6 weeks. Results Twenty-eight patients received doses ranging from 15 to 59 mg/m 2 (ranging from 50 mg every other day to 150 mg/d). Dose-limiting toxicities reported at the maximum-tolerated doses ≥ 75 mg/d were reversible grade 3 fatigue, grade 3 hypertension, and grade 2 bullous skin toxicity. Therefore, the recommended dose was 50 mg/d. At this dose, the main adverse effects were sore mouth, edema, and thrombocytopenia. Hair discoloration and yellow coloration of the skin were observed at doses ≥ 50 mg/d. Pharmacokinetic data indicate that potentially active target plasma concentrations ≥ 50 ng/mL can be achieved with moderate interpatient variability and a long half-life compatible with a single daily dosing. Six objective responses were observed in three renal cell carcinomas, one neuroendocrine tumor, one stromal tumor, and one unknown primary adenocarcinoma patient. At higher doses (≥ 75 mg/d), tumor responses were often associated with reduced intratumoral vascularization and central tumor necrosis, eventually resulting in organ perforation or fistula. Conclusion At the dose of 50 mg/d (4 weeks on, 2 weeks off), sunitinib displays manageable toxicity. Antitumor activity supports further studies in patients with renal cell carcinoma, gastrointestinal, neuroendocrine, and stromal tumors. Future studies may consider including prospective imaging techniques such as high frequency ultrasound to monitor tumor density.
Negative regulators of cardiac hypertrophy
Authors: S HARDT
Journal: Cardiovascular Research (2004)

Throughout the past decade, much effort has been spent on deciphering the signaling pathways positively mediating cardiac hypertrophy. Recently, several endogenous molecules in the heart have been shown to negatively regulate cardiac hypertrophy. One group of these molecules is constitutively active at baseline, while molecules belonging to the second group serve as negative feedback regulators, which are activated in response to pathologic insults. Studies upon the negative regulators of cardiac hypertrophy may allow us to develop novel strategies to treat heart failure by mimicking the naturally preferred mechanisms to maintain homeostasis. In addition, the search for molecular targets of these negative regulators may allow us to identify novel positive mediators of hypertrophy. The aim of this article is to provide a brief overview of these newly identified negative regulators of cardiac hypertrophy.
Where are we now? And where are we going? A report from the Accelerate Brain Cancer Cure (ABC2) Low-grade Glioma Research Workshop
Authors: Jason T. Huse, Max Wallace, Kenneth D. Aldape, Mitchel S. Berger, Chetan Bettegowda, Daniel J. Brat, Daniel P. Cahill, Timothy Cloughesy, Daphne A. Haas-Kogan, Marco Marra, C. Ryan Miller, Sarah J. Nelson, Sofie R. Salama, Riccardo Soffietti, Patrick Y. Wen, Stephen Yip, Katharine Yen, Joseph F. Costello, Susan Chang
Journal: Neuro-Oncology (2013)

Diffuse gliomas consist of both low- and high-grade varieties, each with distinct morphological and biological features. The often extended periods of relative indolence exhibited by low-grade gliomas (LGG; WHO grade II) differ sharply from the aggressive, rapidly fatal clinical course of primary glioblastoma (GBM; WHO grade IV). Nevertheless, until recently, the molecular foundations underlying this stark biological contrast between glioma variants remained largely unknown. The discoveries of distinctive and highly recurrent genomic and epigenomic abnormalities in LGG have both informed a more accurate classification scheme and pointed to viable avenues for therapeutic development. As such, the field of neuro-oncology now seems poised to capitalize on these gains to achieve significant benefit for LGG patients. This report will briefly recount the proceedings of a workshop held in January 2013 and hosted by Accelerate Brain Cancer Cure (ABC(2)) on the subject of LGG. While much of the meeting covered recent insights into LGG biology, its focus remained on how best to advance the clinical management, whether by improved preclinical modeling, more effective targeted therapeutics and clinical trial design, or innovative imaging technology.