tbuckley/cabot-search huggingface dataset:
Avoiding unnecessary surgery in irritable bowel syndrome
Authors: G. F Longstreth
Journal: Gut (2007)

Protecting patients with IBS from the risks and costs of unnecessary surgery

Surgery has no role in treating irritable bowel syndrome (IBS), the prototypic functional bowel disorder.1 Nevertheless, since Ryle2 reported a high appendectomy rate in such patients nearly 80 years ago, descriptive case series, population-based studies and comparisons of patients with IBS with subjects without IBS and patients with inflammatory bowel disease3–8 have shown that patients with IBS are predisposed to surgery. In two large groups of patients with IBS, cholecystectomy and hysterectomy, which are mainly elective procedures, were increased threefold and twofold, respectively, and the primarily emergency operation, appendectomy, was also increased twofold.5,7 Other abdominopelvic operations, especially colon resection, are also increased,7 as is back surgery.5 Much of this increased surgery must be unnecessary, and high surgical rates have been reported from the UK, Western Europe, Scandinavia, North America, Latin America and South Africa. The association of IBS with normal appendiceal pathology after urgent appendectomy, as reported by investigators from Taiwan in this issue,9 ( see page 655 ) further emphasises the worldwide importance of avoiding unnecessary surgery in IBS.

How much surgery is unnecessary on patients with IBS and the reasons for this problem are difficult to ascertain from studies that are retrospective and lack information on surgical pathology. Furthermore, unlike appendicitis, gallstones and uterine pathology are often asymptomatic and are not life threatening, so their documentation does not necessarily mean that surgery was needed. If hysterectomy is performed for dysfunctional uterine bleeding and chronic pelvic pain (CPP), consistent elimination of bleeding with variable pain relief complicates assessment of the overall benefit. Nevertheless, the available data identify preoperative misdiagnosis of the aetiology of pain as a major reason for increased abdominopelvic surgery in patients with IBS. The prospective study by …
Aberrant WNT/β-catenin signaling in parathyroid carcinoma
Authors: Jessica Svedlund, Maria Aurén, Magnus Sundström, Henning Dralle, Göran Åkerström, Peyman Björklund, Gunnar Westin
Journal: Molecular Cancer (2010)

Abstract Background Parathyroid carcinoma (PC) is a very rare malignancy with a high tendency to recur locally, and recurrent disease is difficult to eradicate. In most western European countries and United States, these malignant neoplasms cause less than 1% of the cases with primary hyperparathyroidism, whereas incidence as high as 5% have been reported from Italy, Japan, and India. The molecular etiology of PC is poorly understood. Results The APC (adenomatous polyposis coli) tumor suppressor gene was inactivated by DNA methylation in five analyzed PCs, as determined by RT-PCR, Western blotting, and quantitative bisulfite pyrosequencing analyses. This was accompanied by accumulation of stabilized active nonphosphorylated β-catenin, strongly suggesting aberrant activation of the WNT/β-catenin signaling pathway in these tumors. Treatment of a primary PC cell culture with the DNA hypomethylating agent 5-aza-2'-deoxycytidine (decitabine, Dacogen(r)) induced APC expression, reduced active nonphosphorylated β-catenin, inhibited cell growth, and caused apoptosis. Conclusion Aberrant WNT/β-catenin signaling by lost expression and DNA methylation of APC, and accumulation of active nonphosphorylated β-catenin was observed in the analyzed PCs. We suggest that adjuvant epigenetic therapy should be considered as an additional option in the treatment of patients with recurrent or metastatic parathyroid carcinoma.
Chronic obstructive pulmonary disease * 1: Susceptibility factors for COPD the genotype-environment interaction
Authors: A J Sandford
Journal: Thorax (2002)

Genetic factors including α<sub>1</sub>-antitrypsin deficiency are important in COPD. Candidate gene association studies in COPD are reviewed. Efforts to identify interactions between genetic factors and environmental determinants such as smoking may lead to improved understanding of the pathogenesis of the disease.
Modulation of Renal Apical Organic Anion Transporter 4 Function by Two PDZ Domain–Containing Proteins
Authors: Hiroki Miyazaki, Naohiko Anzai, Sophapun Ekaratanawong, Takeshi Sakata, Ho Jung Shin, Promsuk Jutabha, Taku Hirata, Xin He, Hiroshi Nonoguchi, Kimio Tomita, Yoshikatsu Kanai, Hitoshi Endou
Journal: Journal of the American Society of Nephrology (2005)

Human organic anion transporter 4 (OAT4) is an apical organic anion/dicarboxylate exchanger in the renal proximal tubules and mediates high-affinity transport of steroid sulfates such as estrone-3-sulfate (E1S) and dehydroepiandrosterone sulfate. Here, two multivalent PDZ (PSD-95/Discs Large/ZO-1) proteins PDZK1 and NHERF1 were examined as interactors of OAT4 by a yeast two-hybrid assay. These interactions require the extreme C-terminal region of OAT4 and the first and fourth PDZ domains of PDZK1 and the first PDZ domain of NHERF1. These interactions were confirmed by surface plasmon resonance assays (K(D): 36 nM, 1.2 microM, and 41.7 microM, respectively). In vitro binding assays and co-immunoprecipitation studies revealed that the OAT4 wild-type but not a mutant lacking the PDZ motif interacted directly with both PDZK1 and NHERF1. OAT4, PDZK1, and NHERF1 proteins were shown to be localized at the apical membrane of renal proximal tubules. The association with PDZK1 or NHERF1 enhanced OAT4-mediated E1S transport activities in HEK293 cells (1.2- to 1.4-fold), and the deletion of the OAT4 C-terminal PDZ motif abolished this effect. The augmentation of the transport activity was accompanied by alteration in V(max) of E(1)S transport via OAT4 and was associated with the increased surface expression level of OAT4 protein. This study indicates that the functional activity of OAT4 is modulated through the PDZ interaction with the network of PDZK1 and NHERF1 and suggests that OAT4 is involved in the regulated apical organic anion handling in the renal proximal tubules, provided by the PDZ scaffold.
Low-Dose Transdermal Testosterone Therapy Improves Angina Threshold in Men With Chronic Stable Angina
Authors: Katherine M. English, Richard P. Steeds, T. Hugh Jones, Michael J. Diver, Kevin S. Channer
Journal: Circulation (2000)

Background —Experimental studies suggest that androgens induce coronary vasodilatation. We performed this pilot project to examine the clinical effects of long-term low-dose androgens in men with angina. Methods and Results —Forty-six men with stable angina completed a 2-week, single-blind placebo run-in, followed by double-blind randomization to 5 mg testosterone daily by transdermal patch or matching placebo for 12 weeks, in addition to their current medication. Time to 1-mm ST-segment depression on treadmill exercise testing and hormone levels were measured and quality of life was assessed by SF-36 at baseline and after 4 and 12 weeks of treatment. Active treatment resulted in a 2-fold increase in androgen levels and an increase in time to 1-mm ST-segment depression from (mean±SEM) 309±27 seconds at baseline to 343±26 seconds after 4 weeks and to 361±22 seconds after 12 weeks. This change was statistically significant compared with that seen in the placebo group (from 266±25 seconds at baseline to 284±23 seconds after 4 weeks and to 292±24 seconds after 12 weeks; P =0.02 between the 2 groups by ANCOVA). The magnitude of the response was greater in those with lower baseline levels of bioavailable testosterone ( r =−0.455, P &lt;0.05). There were no significant changes in prostate specific antigen, hemoglobin, lipids, or coagulation profiles during the study. There were significant improvements in pain perception ( P =0.026) and role limitation resulting from physical problems ( P =0.024) in the testosterone-treated group. Conclusions —Low-dose supplemental testosterone treatment in men with chronic stable angina reduces exercise-induced myocardial ischemia.
Features Predicting Sentinel Lymph Node Positivity in Merkel Cell Carcinoma
Authors: Jennifer L. Schwartz, Kent A. Griffith, Lori Lowe, Sandra L. Wong, Scott A. McLean, Douglas R. Fullen, Christopher D. Lao, James A. Hayman, Carol R. Bradford, Riley S. Rees, Timothy M. Johnson, Christopher K. Bichakjian
Journal: Journal of Clinical Oncology (2011)

Merkel cell carcinoma (MCC) is a relatively rare, potentially aggressive cutaneous malignancy. We examined the clinical and histologic features of primary MCC that may correlate with the probability of a positive sentinel lymph node (SLN).Ninety-five patients with MCC who underwent SLN biopsy at the University of Michigan were identified. SLN biopsy was performed on 97 primary tumors, and an SLN was identified in 93 instances. These were reviewed for clinical and histologic features and associated SLN positivity. Univariate associations between these characteristics and a positive SLN were tested for by using either the χ(2) or the Fisher's exact test. A backward elimination algorithm was used to help create a best multiple variable model to explain a positive SLN.SLN positivity was significantly associated with the clinical size of the lesion, greatest horizontal histologic dimension, tumor thickness, mitotic rate, and histologic growth pattern. Two competing multivariate models were generated to predict a positive SLN. The histologic growth pattern was present in both models and combined with either tumor thickness or mitotic rate.Increasing clinical size, increasing tumor thickness, increasing mitotic rate, and infiltrative tumor growth pattern were significantly associated with a greater likelihood of a positive SLN. By using the growth pattern and tumor thickness model, no subgroup of patients was predicted to have a lower than 15% to 20% likelihood of a positive SLN. This suggests that all patients presenting with MCC without clinical evidence of regional lymph node disease should be considered for SLN biopsy.
Genome-Wide Survey of Natural Selection on Functional, Structural, and Network Properties of Polymorphic Sites in Saccharomyces paradoxus
Authors: A. Vishnoi, P. Sethupathy, D. Simola, J. B. Plotkin, S. Hannenhalli
Journal: Molecular Biology and Evolution (2011)

To characterize the genetic basis of phenotypic evolution, numerous studies have identified individual genes that have likely evolved under natural selection. However, phenotypic changes may represent the cumulative effect of similar evolutionary forces acting on functionally related groups of genes. Phylogenetic analyses of divergent yeast species have identified functional groups of genes that have evolved at significantly different rates, suggestive of differential selection on the functional properties. However, due to environmental heterogeneity over long evolutionary timescales, selection operating within a single lineage may be dramatically different, and it is not detectable via interspecific comparisons alone. Moreover, interspecific studies typically quantify selection on protein-coding regions using the D(n)/D(s) ratio, which cannot be extended easily to study selection on noncoding regions or synonymous sites. The population genetic-based analysis of selection operating within a single lineage ameliorates these limitations.We investigated selection on several properties associated with genes, promoters, or polymorphic sites, by analyzing the derived allele frequency spectrum of single nucleotide polymorphisms (SNPs) in 28 strains of Saccharomyces paradoxus. We found evidence for significant differential selection between many functionally relevant categories of SNPs, underscoring the utility of function-centric approaches for discovering signatures of natural selection. When comparable, our findings are largely consistent with previous studies based on interspecific comparisons, with one notable exception: our study finds that mutations from an ancient amino acid to a relatively new amino acid are selectively disfavored, whereas interspecific comparisons have found selection against ancient amino acids. Several of our findings have not been addressed through prior interspecific studies: we find that synonymous mutations from preferred to unpreferred codons are selected against and that synonymous SNPs in the linker regions of proteins are relatively less constrained than those within protein domains.We present the first global survey of selection acting on various functional properties in S. paradoxus. We found that selection pressures previously detected over long evolutionary timescales have also shaped the evolution of S. paradoxus. Importantly, we also make novel discoveries untenable via conventional interspecific analyses.
Phase III Trial of Carboplatin and Paclitaxel With or Without Sorafenib in Metastatic Melanoma
Authors: Keith T. Flaherty, Sandra J. Lee, Fengmin Zhao, Lynn M. Schuchter, Lawrence Flaherty, Richard Kefford, Michael B. Atkins, Philip Leming, John M. Kirkwood
Journal: Journal of Clinical Oncology (2012)

Purpose The primary objective of this study was to determine whether carboplatin, paclitaxel, and sorafenib (CPS) improve overall survival (OS) compared with carboplatin and paclitaxel (CP) in chemotherapy-naive patients with metastatic melanoma. Patients and Methods In this double-blind, randomized, placebo-controlled phase III study, all patients received carboplatin at area under the [concentration-time] curve 6 and paclitaxel 225 mg/m 2 intravenously once every 21 days with random assignment to sorafenib 400 mg orally twice per day on days 2 through 19 every 21 days or placebo. The primary end point was OS, and secondary end points included progression-free survival, objective tumor response, and toxicity. Results In all, 823 patients were enrolled over 34 months. At final analysis, the median OS was 11.3 months (95% CI, 9.8 to 12.2 months) for CP and 11.1 months (95% CI, 10.3 to 12.3 months) for CPS; the difference in the OS distribution was not statistically significant by the stratified log-rank test, stratified on American Joint Committee on Cancer (AJCC) stage, Eastern Cooperative Oncology Group (ECOG) performance status, and prior therapy (P = .878). Median progression-free survival was 4.9 months for CPS and 4.2 months for CP (P = .092, stratified log-rank test). Response rate was 20% for CPS and 18% for CP (P = .427). More patients on the CPS arm had grade 3 or higher toxicities (84% v 78%; P = .027), with increased rash, hand-foot syndrome, and thrombocytopenia accounting for most of the difference. Conclusion Sorafenib does not improve OS when given in combination with CP for chemotherapy-naive patients with metastatic melanoma. This study establishes benchmark end points for the CP regimen in first-line therapy of metastatic melanoma.
THE INFLUENCE OF DIET ON IRON ABSORPTION
Authors: D. Mark Hegsted, Clement A. Finch, Thomas D. Kinney
Journal: The Journal of Experimental Medicine (1952)

The response of rats, chicks, mice, and guinea pigs to two diets containing various amounts of iron has been compared. With diets composed chiefly of corn grits animals of all these species absorb and store considerably more iron than those with normal diets of the same iron content. If sufficient iron is added to a normal diet, all species will absorb large amounts of iron. However, there appear to be great species differences in the level of iron which must be fed to cause the increase in absorption. Chicks and mice appear to have less effective control over iron absorption on high iron diets. Attention is called to large individual differences in ability to control iron absorption under the conditions of these experiments.
LG 30435, a new potential antiasthmatic agent
Authors: F Berti, L Daffonchio, F Magni, C Omini, G Rossoni, A Subissi
Journal: European Respiratory Journal (1989)

LG 30435 is a new quarternary phenothiazine derivative with H1-antihistaminic and antimuscarinic properties. The ability of LG 30435 to prevent changes in respiratory mechanics, induced by different mediators and the immunological reaction, was monitored together with biological and radioimmunological determination of circulating thromboxane-A2 (TxA2) in anaesthetized guinea-pigs. LG 30435 dose-dependently reduces the bronchoconstriction and TxA2 generation caused by different stimuli such as histamine, acetylcholine, leukotriene C4 (LTC4) and PAF-acether. In addition i.v. and aerosol administration of LG 30435 causes a dose-dependent reduction of the increase in airway resistance and TxA2 generation induced by ovalbumin challenge in actively sensitized animals. LG 30435 infused at different concentrations through the isolated guinea-pig lungs inhibits the TxB2 generation caused by different anaphylactic mediators, but not by arachidonic acid. These data, which further substantiate the bronchodilator activity of LG 30435 against a variety of stimuli and demonstrate its protective properties on lung anaphylaxis, suggest that this compound has a potential therapeutic value in the treatment of asthma.
Differential Effects of Drug-Eluting Stents on Local Endothelium-Dependent Coronary Vasomotion
Authors: Michalis I. Hamilos, Miodrag Ostojic, Branko Beleslin, Dragan Sagic, Ljubco Mangovski, Sinisa Stojkovic, Milan Nedeljkovic, Dejan Orlic, Bratislav Milosavljevic, Dragan Topic, Nevena Karanovic, William Wijns
Journal: Journal of the American College of Cardiology (2008)
Functions of the fibrinolytic system in human ito cells and its control by basic fibroblast and platelet-derived growth factor
Authors: Gabriella Fibbi, Marco Pucci, Cecilia Grappone, Giulia Pellegrini, Renata Salzano, Alessandro Casini, Stefano Milani, Mario Del Rosso
Journal: Hepatology (1999)

During liver fibrogenesis, hepatic stellate cells (HSC) proliferate and migrate under the influence of growth factors, including platelet-derived growth factor (PDGF) and basic-fibroblast growth factor (b-FGF). The plasminogen activation system regulates extracellular matrix (ECM) catabolism and cell movement. We evaluated the expression and biological functions of the plasminogen activation system in human HSC and its interaction with PDGF and b-FGF. Urokinase-plasminogen activator receptors (u-PAR) were measured by radioligand binding, cell cross-linking, immunoassay, and RNAse protection assay. u-PA and plasminogen activator inhibitors (PAIs) expression and activities were analyzed by zymography, immunoassay, and RNase protection assay. Cell migration and proliferation, studied in Boyden chambers and by microscopic counting, were evaluated after the addition of PDGF, b-FGF, and blockade with anti-u-PA, anti-u-PAR antibodies, and antisense oligodeoxynucleotides (aODN) against u-PAR mRNA. We have shown that HSC produce u-PAR, u-PA, and PAI-1. PDGF and b-FGF up-regulate u-PA and u-PAR, but not PAI-1, and exogenous addition of u-PA stimulates HSC proliferation, chemotaxis, and chemoinvasion. Inhibition of u-PA/u-PAR with antibodies against u-PA or u-PAR and with u-PAR aODN inhibit the proliferative, chemotactic, and chemoinvasive activity of PDGF and b-FGF. These findings indicate that u-PA and u-PAR are required for the mitogenic and chemoinvasive activity of PDGF and b-FGF on HSC.
Genetic Architecture Underlying Variation in Extent and Remodeling of the Collateral Circulation
Authors: Shiliang Wang, Hua Zhang, Xuming Dai, Robert Sealock, James E. Faber
Journal: Circulation Research (2010)

Rationale: Collaterals are arteriole-to-arteriole anastomoses that connect adjacent arterial trees. They lessen ischemic tissue injury by serving as endogenous bypass vessels when the trunk of 1 tree becomes narrowed by vascular disease. The number and diameter (“extent”) of native (preexisting) collaterals, plus their amount of lumen enlargement (growth/remodeling) in occlusive disease, show remarkably wide variation among inbred mouse strains (eg, C57BL/6 and BALB/c), resulting in large differences in tissue injury in models of occlusive disease. Evidence suggests similar large differences exist among healthy humans. Objective: To identify candidate loci responsible for genetic-dependent collateral variation. Methods and Results: Cerebral collateral number and diameter were determined in 221 C57BL/6×BALB/c F2 progeny, followed by linkage analysis to identify quantitative trait loci (QTL) for collateral number and diameter. Four QTL were obtained for collateral number, including epistasis between 2 loci. A QTL that was identical to the strongest QTL for collateral number on chromosome 7 (logarithm of the odds [LOD]=29, effect size=37%) was also mapped for collateral diameter (LOD=17, effect size=30%). Chromosome substitution strain analysis confirmed this locus. We also obtained a unique QTL on chromosome 11 for collateral remodeling after middle cerebral artery occlusion. Association mapping within the chromosome 7 QTL interval using collateral traits measured for 15 inbred strains delineated 172-kbp ( P =0.00002) and 290-kbp ( P =0.0004) regions on chromosome 7 containing 2 and 7 candidate genes, respectively. Conclusions: We conclude that collateral extent and remodeling are unique, highly heritable complex traits, with 1 QTL predominantly affecting native collateral number and diameter.
Hepatitis B virus protein preS2 potentially promotes HCC development via its transcriptional activation of hTERT
Authors: F Luan, H Liu, L Gao, J Liu, Z Sun, Y Ju, N Hou, C Guo, X Liang, L Zhang, W Sun, C Ma
Journal: Gut (2009)

<h3>Backgrounds and aims:</h3> Telomerase is significantly reactivated in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). Our previous studies showed that the transactivation unit of HBV surface (S) gene, preS2, could upregulate human telomerase reverse transcriptase (hTERT) expression and telomerase activity of HepG2 cells. Here, we aim to explore the functions, and the underlying mechanisms, of this preS2-mediated hTERT upregulation during HCC development. <h3>Methods:</h3> An antisense blocking assay was performed on HBV-integrated HepG2.2.15 cells. The expression of hTERT was examined in clinical samples to test the role of the preS2-mediated hTERT upregulation in HCC development in vivo. In order to explore the mechanisms of preS2-mediated hTERT upregulation, co-transfection, reporter assays and electrophoretic mobility shift assays (EMSA) were performed. <h3>Results:</h3> Blocking preS2 expression reduced hTERT expression, telomerase activity, cell proliferation and tumorigenicity of HepG2.2.15. A region located between −349 and −329 bp upstream of the transcription initiation site of hTERT was identified as responsible for the preS2-mediated effect. preS2 interacted with the preS2-responsible region (PRR) and activated the hTERT promoter. Importantly, hTERT was also highly expressed in preS2-positive human HCC samples. All these findings strongly suggest that preS2 may promote HCC development via hTERT activation. <h3>Conclusions:</h3> HBV protein preS2 upregulates hTERT via the PRR element in promoting HCC development.