tbuckley/cabot-search huggingface dataset:
A human tumor necrosis factor p75 receptor agonist stimulates in vitro T cell proliferation but does not produce inflammation or shock in the baboon.
Authors: M B Welborn, K Van Zee, P D Edwards, J H Pruitt, A Kaibara, J N Vauthey, M Rogy, W L Castleman, S F Lowry, J S Kenney, D Stüber, U Ettlin, B Wipf, H Loetscher, E M Copeland, W Lesslauer, L L Moldawer
Journal: The Journal of Experimental Medicine (1996)

Tumor necrosis factor (TNF) is a potentially useful adjunct to anticancer therapies. However, the clinical utility of TNF has been limited by generalized toxicity and hypotension. Recently, studies have begun to dissect the individual proinflammatory and immunologic responses that result from TNF binding to its two cellular receptors, p55 and p75, in an attempt to develop TNF receptor agonists with reduced systemic toxicity. To evaluate a p75 receptor selective TNF mutant (p75TNF), TNF and p75TNF were administered to healthy anesthetized baboons. Intravenous infusion of the p75TNF produced none of the hemodynamic changes seen after the infusion of TNF. Infusion of p75TNF also failed to induce the plasma appearance of interleukins 6 and 8. However, p75TNF enhanced in vitro baboon thymocyte proliferation to concanavalin A, and infusion of p75TNF resulted in increased soluble p55 and p75 receptor plasma concentrations. Local skin necrosis and tissue neutrophil infiltration were seen after subcutaneous injections of TNF and p55TNF. Subcutaneous injection of p75TNF did not result in skin necrosis but did result in a modest dermal infiltration of lymphocytes and macrophages. The findings suggest that p75TNF may stimulate T cell proliferation without the systemic and local toxicity seen with TNF.
What is the optimal means of preparing the endometrium in frozen–thawed embryo transfer cycles? A systematic review and meta-analysis
Authors: Eva R. Groenewoud, Astrid E.P. Cantineau, Boudewijn J. Kollen, Nick S. Macklon, Ben J. Cohlen
Journal: Human Reproduction Update (2013)

BACKGROUND Frozen-thawed embryo transfer (FET) enables surplus embryos derived from IVF or IVF-ICSI treatment to be stored and transferred at a later date. In recent years the number of FET cycles performed has increased due to transferring fewer embryos per transfer and improved laboratory techniques. Currently, there is little consensus on the most effective method of endometrium preparation prior to FET. METHODS Using both MEDLINE and EMBASE database a systematic review and meta-analysis of literature was performed. Case-series, case-control studies and articles in languages other than English, Dutch or Spanish were excluded. Those studies comparing clinical and ongoing pregnancy rates as well as live birth rates in (i) true natural cycle FET (NC-FET) versus modified NC-FET, (ii) NC-FET versus artificial cycle FET (AC-FET), (iii) AC-FET versus artificial with GnRH agonist cycle FET and (iv) NC-FET versus artificial with GnRH agonist cycle FET were included. Forest plots were constructed and relative risks or odds ratios were calculated. RESULTS A total of 43 publications were selected for critical appraisal and 20 articles were included in the final review. For all comparisons, no differences in the clinical pregnancy rate, ongoing pregnancy rate or live birth rate could be found. Based on information provided in the articles no conclusions could be drawn with regard to cancellation rates. CONCLUSIONS Based on the current literature it is not possible to identify one method of endometrium preparation in FET as being more effective than another. Therefore, all of the current methods of endometrial preparation appear to be equally successful in terms of ongoing pregnancy rate. However, in some comparisons predominantly retrospective studies were included leaving these comparisons subject to selection and publication bias. Also patients' preferences as well as cost-efficiency were not addressed in any of the included studies. Therefore, prospective randomized studies addressing these issues are needed.
Ubiquitin‐specific protease 7 accelerates p14ARF degradation by deubiquitinating thyroid hormone receptor‐interacting protein 12 and promotes hepatocellular carcinoma progression
Authors: Jia‐Bin Cai, Guo‐Ming Shi, Zhao‐Ru Dong, Ai‐Wu Ke, Hong‐Hui Ma, Qiang Gao, Zao‐Zhuo Shen, Xiao‐Yong Huang, Hao Chen, Ding‐Dang Yu, Li‐Xin Liu, Peng‐Fei Zhang, Chi Zhang, Mei‐Yu Hu, Liu‐Xiao Yang, Ying‐Hong Shi, Xiao‐Ying Wang, Zhen‐Bin Ding, Shuang‐Jian Qiu, Hui‐Chuan Sun, Jian Zhou, Yujiang G. Shi, Jia Fan
Journal: Hepatology (2014)

The prognosis for hepatocellular carcinoma (HCC) remains dismal in terms of overall survival (OS), and its molecular pathogenesis has not been completely defined. Here, we report that expression of deubiquitylase ubiquitin‐specific protease 7 (USP7) is higher in human HCC tissues than in matched peritumoral tissues. Ectopic USP7 expression promotes growth of HCC cells in vivo and in vitro . Mechanistically, USP7 overexpression fosters HCC cell growth by forming a complex with and stabilizing thyroid hormone receptor‐interacting protein 12 (TRIP12), which induces constitutive p14 ARF ubiquitination. Clinically, USP7 overexpression is significantly correlated with a malignant phenotype, including larger tumor size, multiple tumor, poor differentiation, elevated alpha‐fetoprotein, and microvascular invasion. Moreover, overexpression of USP7 and/or TRIP12 correlates with shorter OS and higher cumulative recurrence rates of HCC. Conclusion : USP7 stabilizes TRIP12 by deubiquitination, thus constitutively inactivating p14 ARF and promoting HCC progression. This represents a novel marker for predicting prognosis and a potential therapeutic target for HCC. (H epatology 2015;61:1603‐1614)
Predictive Value of <i>XRCC1</i> Gene Polymorphisms on Platinum-Based Chemotherapy in Advanced Non–Small Cell Lung Cancer Patients: A Systematic Review and Meta-analysis
Authors: Junjie Wu, Jie Liu, Yuhao Zhou, Jun Ying, Houdong Zou, Shicheng Guo, Lei Wang, Naiqing Zhao, Jianjun Hu, Daru Lu, Li Jin, Qiang Li, Jiu-Cun Wang
Journal: Clinical Cancer Research (2012)

Published data have shown conflicting results about the relationship between X-ray repair cross-complementing group 1 (XRCC1) gene polymorphisms (Arg399Gln and Arg194Trp) and clinical outcome of platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). A meta-analysis is needed to provide a systematic review of the published findings.We conducted a systematic review and meta-analysis to evaluate the predictive value of XRCC1 gene polymorphisms on clinical outcome up to October 1, 2010. The quality of each study was scored on the basis of predefined criteria.A total of 13 eligible follow-up studies met all the inclusion criteria. The XRCC1194Trp allele was found to be significantly associated with a favorable response rate relative to 194Arg [Trp vs. Arg: OR, 1.88; 95% confidence interval (CI), 1.48-2.38]. XRCC1399Gln was less favorably associated with both response rate (Gln vs. Arg: OR, 0.67; 95% CI, 0.52-0.87) and overall survival (Gln vs. Arg: HR, 1.30; 95% CI, 1.04-1.63) than 399Arg in analyses using all available studies; but these associations became insignificant when only high-quality studies were used.These findings suggest a predictive role for XRCC1 gene polymorphisms in clinical outcome. However, the role of 399Gln could be considered controversial because its impact on clinical outcome was insignificant in high-quality studies. These findings show the importance of establishing suitable criteria, including genetic epidemiologic, phenotypic, and clinical criteria, to improve quality control of study design and methods in pharmacogenomic studies related to XRCC1 gene polymorphism.
Molecular Pathways: <i>Fumarate Hydratase</i>-Deficient Kidney Cancer—Targeting the Warburg Effect in Cancer
Authors: W. Marston Linehan, Tracey A. Rouault
Journal: Clinical Cancer Research (2013)

Abstract Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for development of cutaneous and uterine leiomyomas and an aggressive form of type II papillary kidney cancer. HLRCC is characterized by germline mutation of the tricarboxylic acid (TCA) cycle enzyme, fumarate hydratase (FH). FH-deficient kidney cancer is characterized by impaired oxidative phosphorylation and a metabolic shift to aerobic glycolysis, a form of metabolic reprogramming referred to as the Warburg effect. Increased glycolysis generates ATP needed for increased cell proliferation. In FH-deficient kidney cancer, levels of AMP-activated protein kinase (AMPK), a cellular energy sensor, are decreased resulting in diminished p53 levels, decreased expression of the iron importer, DMT1, leading to low cellular iron levels, and to enhanced fatty acid synthesis by diminishing phosphorylation of acetyl CoA carboxylase, a rate-limiting step for fatty acid synthesis. Increased fumarate and decreased iron levels in FH-deficient kidney cancer cells inactivate prolyl hydroxylases, leading to stabilization of hypoxia-inducible factor (HIF)-1α and increased expression of genes such as VEGF and glucose transporter 1 (GLUT1) to provide fuel needed for rapid growth demands. Several therapeutic approaches for targeting the metabolic basis of FH-deficient kidney cancer are under development or are being evaluated in clinical trials, including the use of agents such as metformin, which would reverse the inactivation of AMPK, approaches to inhibit glucose transport, lactate dehydrogenase A (LDHA), the antioxidant response pathway, the heme oxygenase pathway, and approaches to target the tumor vasculature and glucose transport with agents such as bevacizumab and erlotinib. These same types of metabolic shifts, to aerobic glycolysis with decreased oxidative phosphorylation, have been found in a wide variety of other cancer types. Targeting the metabolic basis of a rare cancer such as FH-deficient kidney cancer will hopefully provide insights into the development of effective forms of therapies for other, more common forms of cancer. Clin Cancer Res; 19(13); 3345–52. ©2013 AACR.
Dietary fructo-oligosaccharides and lactulose inhibit intestinal colonisation but stimulate translocation of salmonella in rats
Authors: I M J Bovee-Oudenhoven
Journal: Gut (2003)

It is frequently assumed that dietary non-digestible carbohydrates improve host resistance to intestinal infections by stimulating the protective gut microflora. However, compelling scientific evidence from in vivo infection studies is lacking. Therefore, we studied the effect of several non-digestible carbohydrates on the resistance of rats to Salmonella enteritidis infection.Rats (n=8 per group) were fed "humanised" purified diets containing 4% lactulose, fructo-oligosaccharides (FOS), resistant starch, wheat fibre, or cellulose. After an adaptation period of 2 weeks the animals were orally infected with S enteritidis. Supplement induced changes in faecal biochemical and microbiological parameters were studied before infection. Colonisation of salmonella was determined by studying the faecal excretion of this pathogen and translocation by analysis of urinary nitric oxide metabolites over time and classical organ cultures. Intestinal mucosal myeloperoxidase activity was determined to quantify intestinal inflammation after infection.Despite stimulation of intestinal lactobacilli and bifidobacteria and inhibition of salmonella colonisation, FOS and lactulose significantly enhanced translocation of this pathogen. These supplements also increased cytotoxicity of faecal water and faecal mucin excretion, which may reflect mucosal irritation. In addition, caecal and colonic, but not ileal, mucosal myeloperoxidase activity was increased in infected rats fed FOS and lactulose. In contrast, cellulose, wheat fibre, and resistant starch did not affect the resistance to salmonella.In contrast to most expectations, FOS and lactulose impair the resistance of rats to intestinal salmonella infection. Obviously, stimulation of the endogenous lactobacilli and bifidobacteria is no guarantee of improved host defence against intestinal infections.
LDLs Impair Vasomotor Function of the Coronary Microcirculation
Authors: Travis W. Hein, Lih Kuo
Journal: Circulation Research (1998)

Abstract —Oxidized LDLs (Ox-LDLs) inhibit endothelium-dependent dilation of isolated conduit arteries in a manner comparable to the impairment demonstrated in atherosclerotic vessels. However, it is not known whether the microvessels, which do not develop atherosclerotic lesions, are susceptible to Ox-LDL. Since endothelial release of NO plays an important role in vasodilation and since its dysfunction associated with atherosclerosis has been shown to extend into the coronary microcirculation, we hypothesized that Ox-LDLs impair endothelium-dependent vasodilation of coronary arterioles by reducing the synthesis and/or release of NO. To test this hypothesis, porcine subepicardial vessels (50 to 100 μm) were isolated, cannulated, and pressurized to 60 cm H 2 O without flow for in vitro study. Isolated vessels developed basal tone and dilated in a dose-dependent manner to the endothelium-dependent vasodilators serotonin, ATP, and ionomycin. These vasodilatory responses were inhibited by the NO synthase inhibitor N G -monomethyl- l -arginine and were subsequently reversed by extraluminal administration of the NO precursor l -arginine (3 mmol/L), suggesting the involvement of NO in these vasomotor responses. Intraluminal incubation of the vessels with native LDL (N-LDL) or Ox-LDL (1 mg protein/mL) significantly attenuated dilations to serotonin, ATP, and ionomycin. Ox-LDL produced more severe inhibition than did N-LDL, and the inhibitory effect was comparable to that of N G -monomethyl- l -arginine. The inhibitory effects of N-LDL and Ox-LDL were reversed by exogenous l -arginine (3 mmol/L) and were prevented by sodium dihydroxybenzene disulfonate (Tiron), a cell-permeable superoxide scavenger. In contrast, administration of the cell-impermeable superoxide scavenger superoxide dismutase prevented the inhibitory effect of N-LDL but not of Ox-LDL. In addition, the inhibitory effects of LDL were not restored by d -arginine or by removal of intraluminal LDL. Neither N-LDL nor Ox-LDL altered endothelium-independent vasodilation to sodium nitroprusside. These results indicate that coronary arterioles are susceptible to LDLs that specifically impair endothelium-dependent vasodilation by reducing NO synthesis. It is suggested that the initiation of superoxide anion production and the subsequent l -arginine deficiency may be responsible for the detrimental effect of LDL.
Effects of L-Carnitine Supplementation in Maintenance Hemodialysis Patients
Authors: Jean-Marc Hurot, Michel Cucherat, Margaret Haugh, Denis Fouque
Journal: Journal of the American Society of Nephrology (2002)

There are many causes for carnitine depletion during maintenance hemodialysis. Supplementation with L-carnitine in animals has been associated with improvement in some abnormalities also present in chronic renal failure. However, it is still controversial whether restoring plasma or tissue carnitine will correct clinical or biologic symptoms observed in maintenance hemodialysis. A systematic review is here performed to determine the effects of L-carnitine in maintenance hemodialysis patients. Eighty-three prospective trials were identified from 1978 to 1999 in which L-carnitine was randomly allocated in 21 trials. Change in serum triglycerides, cholesterol fractions, hemoglobin levels, erythropoietin dose, and other symptoms (muscle function, exercise capacity, and quality of life) were examined. A total of 482 patients in 18 trials were considered for analysis. There was no effect of L-carnitine on triglycerides, total cholesterol, or any of its fractions. Before the erythropoietin (EPO) era, L-carnitine treatment was associated with improved hemoglobin (P < 0.01) and with a decreased EPO dose (P < 0.01) and improved resistance to EPO when patients routinely received EPO. Muscle function, exercise capacity, and quality of life could not be reliably assessed because of the noncombinable nature of end points and the limited number of trials. In conclusion, L-carnitine cannot be recommended for treating the dyslipidemia of maintenance hemodialysis patients. By contrast, this review suggests a promising effect of L-carnitine on anemia management. The route of L-carnitine administration should be evaluated because there is no evidence as to the most efficient method of administration in maintenance hemodialysis.
<i>PIK3CA</i> and <i>PTEN</i> Mutations in Uterine Endometrioid Carcinoma and Complex Atypical Hyperplasia
Authors: Monica Prasad Hayes, Hong Wang, Rosanny Espinal-Witter, Wayne Douglas, Garron J. Solomon, Suzanne J. Baker, Lora Hedrick Ellenson
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The tumor suppressor PTEN gene and the PIK3CA oncogene are frequently mutated in uterine endometrioid carcinoma (UEC). PTEN mutations are also common in complex atypical hyperplasia (CAH), the precursor lesion of UEC. The status of PIK3CA has not yet been explored in CAH. In this study, we evaluated both CAH and UEC for PTEN and PIK3CA mutations. Experimental Design: Neoplastic tissue was microdissected, and DNA was extracted from 29 cases of CAH. DNA was available from 44 UEC cases previously characterized for PTEN mutations. Direct DNA sequencing of exons 9 and 20 of the PIK3CA gene was done on all 73 cases. In addition, CAH cases were analyzed for PTEN mutations. Statistical analyses were done using the Fisher's exact test. Results: Two (7%) of 29 CAH and 17 (39%) of 44 UEC cases contained a PIK3CA mutation (P = 0.003). Fourteen (48%) of 29 CAH cases had a PTEN mutation, but none contained both a PTEN and PIK3CA mutation. Twenty-five (57%) of 44 UEC cases had a PTEN mutation, and 12 (48%) of these 25 cases also contained a PIK3CA mutation. Coexistent PIK3CA and PTEN mutations were significantly correlated with UEC compared with CAH (P = 0.002), but the association in UEC did not reach statistical significance (P = 0.21). Conclusions: PIK3CA is the most commonly mutated oncogene in UEC; however, mutations are uncommon in CAH. Thus, mutations in PIK3CA, unlike PTEN mutations, are associated with invasion. These findings suggest that mutations in PIK3CA may serve as a marker of invasion with potential clinical use. Furthermore, PIK3CA and PTEN mutations may play distinct roles in endometrial tumorigenesis.
Drug Therapy in Alcoholism
Authors: BENJAMIN KISSIN, MILTON M. GROSS
Journal: American Journal of Psychiatry (1968)

Drug therapy for alcoholism covers three major areas: chronic alcoholism, acute alcohal intoxication, and the withdrawal syndrome. No drug therapy has yet been proven of significant value in long-term treatment; however, preliminary studies are encouraging. The treatment of acute alcohol intoxication may include sedatives or glucose administration, depending on the episode. The value of paraldehyde and chlordiazepoxide in the management of the withdrawal syndrome appears to be well established. The authors suggest that the efficacy of these drugs in the acute toxic states may be related to the restoration of normal REM and Delta sleep.
Cholesterol supplementation prevents necrosis and inflammation but enhances fibrosis in alcoholic liver disease in the rat
Authors: A A Nanji, A Rahemtulla, T Daly, S Khwaja, L Miao, S Zhao, S R Tahan
Journal: Hepatology (1997)

Based on studies that show a role for the low-density lipoprotein (LDL)-receptor in arachidonic acid delivery and eicosanoid synthesis in macrophages, the present study investigated the effect of cholesterol supplementation on pathological changes and thromboxane (TX) synthesis in alcoholic liver injury. Male Wistar rats were intragastrically fed ethanol with either corn oil or fish oil for 1 month. Control rats received isocaloric amounts of dextrose instead of ethanol. An additional group of rats fed either ethanol or dextrose with fish oil or corn oil were supplemented with 1% cholesterol. At the time of killing, all rats had the following evaluated: liver histopathology, lipid peroxidation, liver and plasma thromboxane levels, plasma endotoxin and messenger RNA (mRNA) levels of LDL-receptor, tumor necrosis factor alpha (TNF-alpha), cyclooxygenase (Cox)-1 and -2, and transforming growth factor beta (TGF-beta). Rats fed ethanol with either fish oil or corn oil developed fatty liver, necrosis, inflammation, and central vein collagen deposition. Cholesterol supplementation enhanced the degree of fibrosis but prevented necrosis and inflammation. These alterations in pathological changes by cholesterol were accompanied by absent TNF-alpha and Cox-2 mRNAs, decreased thromboxane levels, decreased lipid peroxidation, and increased TGF-beta mRNA. Cholesterol enrichment of the diet thus decreases proinflammatory components, but enhances fibrosis in ethanol-fed rats.
Increased risk of left sided colon cancer in patients with diverticular disease.
Authors: T Stefansson, A Ekbom, P Sparen, L Pahlman
Journal: Gut (1993)

Certain similar epidemiological characteristics suggest a common aetiology for colon cancer and diverticulosis of the colon. The hypothesis that patients with diverticulosis are at increased risk of developing colon cancer was tested in a retrospective, population based, cohort study in Sweden. A total of 7159 patients (2478 men and 4681 women) who had been given a hospital discharge diagnosis of diverticulosis or diverticulitis of the colon between 1965 and 1983 were followed up during 1985 by means of record linkage procedures. After excluding the first 2 years of follow up, there was not a significant increase in risk (SIR) overall for colon cancer (SIR = 1.2; 95% confidence intervals (CI) 0.9, 1.6) or for rectal cancer (SIR = 1.1; 95% CI 0.7, 1.7). The observed number of right sided colon cancers was as expected (SIR = 0.9; 95% CI 0.5, 1.5). In contrast, an increased risk of left sided colon cancer was found both overall (SIR = 1.8; 95% CI 1.1, 2.7) and consistently in men and women as well as in different age groups. This risk increased the longer the follow up (p value for trend < 0.001). These results do not support the hypothesis of a common aetiology in diverticular disease and colonic cancer but suggest a causal relationship between diverticular disease and cancer of the left colon.