tbuckley/cabot-search huggingface dataset:
Prognostic Significance of AMPK Activation and Therapeutic Effects of Metformin in Hepatocellular Carcinoma
Authors: Longyi Zheng, Wen Yang, Fuquan Wu, Chao Wang, Lexing Yu, Liang Tang, Bijun Qiu, Yuqiong Li, Linna Guo, Mengchao Wu, Gensheng Feng, Dajin Zou, Hongyang Wang
Journal: Clinical Cancer Research (2013)

The AMP-activated protein kinase (AMPK) serves as an energy sensor in eukaryotic cells and occupies a central role in linking metabolism and cancer development. However, the phosphorylation status of AMPK and its therapeutic value in human hepatocellular carcinoma (HCC) remain unclear.The phosphorylation status of AMPK (Thr172) was determined by immunoblotting and immunostaining in specimens from 273 patients with HCC (including 253 patients with hepatitis B virus -related HCC). Kaplan-Meier survival analysis was used to determine the correlation with prognosis. The effects of therapeutic metformin/AMPK activation were assessed in cultured human HCC cell lines and primary HCC cells in vitro and in xenograft tumors model in vivo. To define the mechanisms of anticancer effects of metformin, we examined its influence on AMPK activation and NF-κB pathway.AMPK is dysfunctional in patients with HCC, and low p-AMPK staining is correlated with aggressive clinicopathologic features and poor prognosis. Activation of AMPK by metformin not only inhibited HCC cells growth in vitro and in vivo, but also augmented cisplatin-induced growth inhibition in HCC cells. Knockdown of AMPKα expression can greatly decrease the inhibitory effect of metformin, indicating that AMPK activation is required for the anticancer action of metformin. Mechanistically, metformin/AMPK activation inhibited NF-κB signaling through upregulation of IκBα. Activation of NF-κB signaling by ectopic expression of P65 or overexpression of an undegradable mutant form of IκBα attenuated the anticancer effects of metformin.These results present novel insight into a critical role of AMPK in HCC progression. Anticancer effects of therapeutic metformin/AMPK activation unravel metformin's potential in treatment of HCC.
The Four Faces of Autophagy: Implications for Cancer Therapy
Authors: David A. Gewirtz
Journal: Cancer Research (2014)

It is generally thought that autophagy has two primary and opposing functions in tumor cells in response to stress induced by chemotherapy or radiation. One is the cytoprotective function that can in theory be inhibited for therapeutic advantage by sensitizing the cells to these treatment modalities. The other is the cytotoxic function that is generally not observed with conventional treatment modalities, but that may function to promote tumor cell killing either alone or in association with apoptosis. In this commentary/review, we advance the premise that autophagy is actually populated by at least two additional players. One we have termed the nonprotective form of autophagy, where the cell is apparently carrying out autophagy-mediated degradative functions, but where autophagy inhibition does not lead to perceptible alterations in drug or radiation sensitivity. The other is what we now term the cytostatic form of autophagy in that its activation results in prolonged growth inhibition as well as reduced clonogenic survival (loss of reproductive capacity) but in the absence of actual loss of cell viability through apoptosis or necrosis; however, as is the case with cytototoxic autophagy, inhibition of cytostatic autophagy protects the tumor cell from the agent (drugs or radiation) that promotes the autophagic response. In view of current clinical efforts to exploit autophagy inhibition as a therapeutic strategy for sensitization of malignancies to chemotherapy and radiation, it is critical to recognize that if chemotherapy and/or radiation actually promote autophagy in patient tumors, the autophagy is not of necessity cytoprotective in function.
Systemic lupus erythematosus in a multiethnic US cohort (LUMINA): XXIV. Cytotoxic treatment is an additional risk factor for the development of symptomatic osteonecrosis in lupus patients: results of a nested matched case-control study
Authors: J Calvo-Alen
Journal: Annals of the Rheumatic Diseases (2005)

<b>Background:</b> Osteonecrosis is common in systemic lupus erythematosus (SLE) and often disabling. The role of glucocorticoids in its development is well known. <b>Objective:</b> To explore other possible risk factors for osteonecrosis in SLE. <b>Methods:</b> A nested matched case–control study undertaken in the context of a large, longitudinal, multiethnic lupus cohort (LUMINA), currently formed of 571 SLE patients meeting American College of Rheumatology criteria. All those developing symptomatic osteonecrosis after the diagnosis of SLE were considered cases. Two controls matched for age, disease duration, ethnicity, and centre were selected for each case. Cases and controls were compared by univariable analyses using selected variables. Variables with p&lt;0.10 and those thought clinically relevant were entered into conditional logistic regression models including either the average dose or the highest dose of glucocorticoids, with osteonecrosis as the dependent variable. <b>Results:</b> 32 cases were identified and 59 matched controls selected (in five cases only one control could be found). By univariable analyses, both groups were largely comparable for socioeconomic-demographic, clinical, and laboratory variables. Cases were less exposed to hydroxychloroquine (as assessed by the percentage of exposure time) (p = 0.026), used higher doses of glucocorticoids (average and highest doses) (p = 0.011 and 0.001, respectively), and received cytotoxic drugs more often (p = 0.015). In the multivariable analyses only cytotoxic drug use (both models) and the highest dose of glucocorticoids remained associated with the occurrence of osteonecrosis. <b>Conclusions:</b> Cytotoxic drug use is a risk factor for the development of symptomatic osteonecrosis in SLE patients, along with glucocorticoids. No definite protective factors were identified.
Diet and Sex Hormones in Girls: Findings From a Randomized Controlled Clinical Trial
Authors: J. F. Dorgan, S. A. Hunsberger, R. P. McMahon, P. O. Kwiterovich, R. M. Lauer, L. Van Horn, N. L. Lasser, V. J. Stevens, L. A. Friedman, J. A. Yanovski, S. F. Greenhut, D. W. Chandler, F. A. Franklin, B. A. Barton, D. W. Buckman, L. G. Snetselaar, B. H. Patterson, A. Schatzkin, P. R. Taylor
Journal: JNCI Journal of the National Cancer Institute (2003)

Results of several studies have suggested that diet during adolescence may influence the risk of breast cancer in adulthood. We evaluated whether an intervention to lower fat intake among adolescent girls altered their serum concentrations of sex hormones that, in adults, are related to breast cancer development.We conducted an ancillary hormone study among 286 of the 301 girls who participated between 1988 and 1997 in the Dietary Intervention Study in Children, in which healthy, prepubertal, 8- to 10-year-olds with elevated low-density lipoprotein cholesterol were randomly assigned to usual care or to a behavioral intervention that promoted a low-fat diet. Median time on the intervention was 7 years. Blood samples collected before randomization and at the year 1, year 3, year 5, and last visits were assayed to determine the girls' serum levels of sex hormones. All P values are two-sided.At the year 5 visit, girls in the intervention group had 29.8% (95% confidence interval [CI] = 5.4% to 47.9%; P =.02) lower estradiol, 30.2% (95% CI = 7.0% to 47.7%; P =.02) lower non-sex hormone binding globulin-bound estradiol, 20.7% (95% CI = 4.7% to 34.0%; P =.02) lower estrone, and 28.7% (95% CI = 5.1% to 46.5%; P =.02) lower estrone sulfate levels during the follicular phase of the menstrual cycle and 27.2% (95% CI = 5.7% to 53.1%; P =.01) higher testosterone levels during the luteal phase of the menstrual cycle than did girls in the usual care group. At the last visit, the luteal phase progesterone level was 52.9% (95% CI = 20.0% to 72.3%) lower for girls in the intervention group than for girls in the usual care group (P =.007).Modest reductions in fat intake during puberty are associated with changes in sex hormone concentrations that are consistent with alterations in the function of the hypothalamic-pituitary-ovarian axis. Whether these changes influence breast cancer risk is currently unknown.
Functional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers
Authors: I. Aurich, L. P Mueller, H. Aurich, J. Luetzkendorf, K. Tisljar, M. M Dollinger, W. Schormann, J. Walldorf, J. G Hengstler, W. E Fleig, B. Christ
Journal: Gut (2006)

<b>Aims:</b> At present, clinical success of hepatocyte transplantation as an alternative to whole liver transplantation is hampered by the limited availability of suitable donor organs for the isolation of transplantable hepatocytes. Hence, novel cell sources are required to deliver hepatocytes of adequate quality for clinical use. Mesenchymal stem cells (MSCs) from human bone marrow may have the potential to differentiate into hepatocytes in vitro and in vivo. <b>Methods:</b> Isolated MSCs were selected by density gradient centrifugation and plastic adherence, differentiated in the presence of human hepatocyte growth medium and transplanted in immunodeficient Pfp/Rag2 mice. <b>Results:</b> Here, we demonstrate that human MSCs gain in vitro the characteristic morphology and function of hepatocytes in response to specified growth factors. Specifically, preconditioned MSCs store glycogen, synthesise urea and feature the active hepatocyte-specific gene promoter of phosphoenolpyruvate carboxykinase (PCK1). After transplantation into livers of immunodeficient mice, preconditioned MSCs engraft predominantly in the periportal portion of the liver lobule. In situ, the cells continue to store glycogen and express PCK1, connexin32, albumin and the human hepatocyte-specific antigen HepPar1, indicating that the transplanted cells retain prominent qualities of hepatocytes after their regional integration. <b>Conclusion:</b> MSCs derived from human bone marrow may serve as a novel source for the propagation of hepatocyte-like cells suitable for cell therapy in liver diseases.
Differential Expression of Individual UT-A Urea Transporter Isoforms in Rat Kidney
Authors: SERENA M. BAGNASCO, TAO PENG, YUSHI NAKAYAMA, JEFF M. SANDS
Journal: Journal of the American Society of Nephrology (2000)

Abstract. The rat renal urea transporter UT-A includes four mRNA isoforms: UT-A1, UT-A2, UT-A3, and UT-A4. This study detected by rapid amplification of cDNA ends (RACE), primer extension, and ribonuclease protection assay (RPA) a single transcription start site for UT-A1, UT-A3, and UT-A4, distinct from the one for UT-A2 and identified by 3′-RACE new transcripts of UT-A1, UT-A2, and UT-A3, characterized by alternative 3′ untranslated sequences (UTR). Expression of an alternative 3′UTR resulted in UT-A1 and UT-A2 transcripts that are approximately 400 bp shorter than the original cDNA. These mRNA isoforms (UT-A1b and UT-A2b) were present in low abundance in the inner medulla. Expression of an alternative 3′UTR for UT-A3 resulted in a 3.5 kb transcript (UT-A3b), which is 1.5 kb longer than the original UT-A3 cDNA. UT-A3b mRNA was easily detected by Northern hybridization in the inner medulla. This study examined whether different states of hydration induce homogeneous changes in mRNA expression of individual UT-A isoforms in the kidney. Analysis of UT-A1, UT-A1b, UT-A2, UT-A2b, UT-A3, and UT-A3b mRNA expression in rat kidney revealed that water deprivation markedly increases the relative abundance of UT-A2, UT-A2b, UT-A3, and UT-A3b mRNA in renal inner medulla, whereas UT-A1 and UT-A1b remain almost unchanged. The conclusion is that differential expression of individual UT-A mRNA isoforms occurs in the kidney and probably involves multiple regulatory mechanisms.
(6) Idiopathic oedema
Authors: E.M. Saihan, R.R.M. Harman
Journal: British Journal of Dermatology (1977)

Journal Article (6) Idiopathic oedema Get access E.M. Saihan, E.M. Saihan Bristol Royal Infirmary Search for other works by this author on: Oxford Academic Google Scholar R.R.M. Harman R.R.M. Harman Bristol Royal Infirmary Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 97, Issue s15, 1 December 1977, Pages 32–33, https://doi.org/10.1111/j.1365-2133.1977.tb14314.x Published: 01 December 1977
Alcohol and its effects on sprint and middle distance running.
Authors: L McNaughton, D Preece
Journal: British Journal of Sports Medicine (1986)

Alcohol has been used as an aid to performance for a considerable period of time in many athletic endeavours. Five sprinters and five middle distance athletes were tested to determine whether differing levels of alcohol (0.01 mg X ml-1, 0.05 mg X ml-1 and 0.10 mg X ml-1) had differing effects upon performance times in the 100 m, 200 m, 400 m, 800 m and 1500 m events. Blood alcohol concentration (BAC) was estimated from breath alcohol concentration (BrAC) using a hand held Drager Alcotest 7310 and a Borkenstein Breathalyser. Alcohol affected all but the 100 m event to varying degrees. In the 200 m the performance decreased when the level of intoxication increased. This was not the case in the 400 m which showed a difference between the two lower levels of alcohol consumption (0.01 mg X ml-1 to 0.05 mg X ml-1) but not between the 0.05 mg X ml-1 and 0.10 mg X ml-1. In the middle distance events the 800 m was most adversely affected. We concluded that alcohol is not an ergogenic aid in so much that it does not improve performance. In the 100 m events, performance remained stable. More research in this area is warranted.
Multifactorial basis for coronary collateralization: a complex adaptive response to ischemia
Authors: Judy R Kersten, Paul S Pagel, William M Chilian, David C Warltier
Journal: Cardiovascular Research (1999)

Angiogenesis and vasculogenesis are adaptive responses of the coronary collateral circulation to myocardial ischemia. This review focuses on the concerted action of growth factors, growth factor receptors, extracellular matrix, and inflammatory cellular responses to regulate angiogenesis and vasculogenesis in response to myocardial ischemia and alterations in shear stress. Therapeutic angiogenesis represents a novel approach to increase myocardial perfusion in patients with coronary artery disease and provides an opportunity to further clarify the mechanisms that regulate collateral development. Impairment of angiogenic adaptive responses to ischemia during disease states is an important subject for future investigation.
Short Preoperative Treatment With Erlotinib Inhibits Tumor Cell Proliferation in Hormone Receptor–Positive Breast Cancers
Authors: Marta Guix, Nara de Matos Granja, Ingrid Meszoely, Theresa B. Adkins, Bobbye M. Wieman, Kerek E. Frierson, Violeta Sanchez, Melinda E. Sanders, Ana M. Grau, Ingrid A. Mayer, Gary Pestano, Yu Shyr, Senthil Muthuswamy, Benjamin Calvo, Helen Krontiras, Ian E. Krop, Mark C. Kelley, Carlos L. Arteaga
Journal: Journal of Clinical Oncology (2008)

To administer the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to patients with operable untreated breast cancer during the immediate preoperative period and to measure an antiproliferative and/or a proapoptotic effect in the post-therapy specimen and determine a biomarker profile associated with evidence of erlotinib-mediated cellular activity.Newly diagnosed patients with stages I to IIIA invasive breast cancer were treated with erlotinib 150 mg/d orally for 6 to 14 days until the day before surgery. Erlotinib plasma levels were measured by tandem mass spectrometry the day of surgery. Drug-induced changes in tumor cell proliferation and apoptosis were assessed by Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling analysis, respectively, in biopsies from the pretherapy and surgical specimens. Biopsies were also evaluated for P-EGFR, P-HER-2, P-MAPK, P-Akt, P-S6, and S118 P-ER alpha.In drug-sensitive PC9 xenografts, 5 days of treatment with erlotinib were enough to induce a maximal inhibition of cell proliferation and induction of apoptosis. Forty-one patients completed preoperative treatment with erlotinib. Grade <or= 2 rash and diarrhea were the main toxicities. Erlotinib inhibited tumor cell proliferation (Ki67), P-EGFR, and P-HER-2. The inhibition of proliferation occurred in estrogen receptor (ER) -positive but not in human epidermal growth factor receptor 2 (HER-2) -positive or triple-negative cancers. Treatment was associated with a significant reduction of P-MAPK, P-Akt, P-S6, and S118 P-ER alpha in hormone receptor-positive cancers.A presurgical approach to evaluate cellular responses to new drugs is feasible in breast cancer. EGFR inhibitors are worthy of testing against ER-positive breast cancers but are unlikely to have clinical activity against HER-2-positive or triple-negative breast cancers.
Cardiac Allograft Vasculopathy Progression Associated With Intraplaque Neovascularization
Authors: Yasuhiro Ichibori, Daisaku Nakatani, Yasushi Sakata, Kouichi Tachibana, Takashi Akasaka, Shunsuke Saito, Norihide Fukushima, Yoshiki Sawa, Shinsuke Nanto, Issei Komuro
Journal: Journal of the American College of Cardiology (2013)
Endothelial Dysfunction Contributes to Renal Function–Associated Cardiovascular Mortality in a Population with Mild Renal Insufficiency
Authors: Frank Stam, Coen van Guldener, Annemarie Becker, Jacqueline M. Dekker, Robert J. Heine, Lex M. Bouter, Coen D.A. Stehouwer
Journal: Journal of the American Society of Nephrology (2005)

Mildly impaired renal function is associated with cardiovascular morbidity and mortality. There are indications that endothelial dysfunction and/or chronic inflammation, which play an important role in atherothrombosis, are present in early stages of renal insufficiency. This study investigated whether and to which extent endothelial dysfunction and inflammation were related to renal function and contributed to renal function-associated cardiovascular mortality in a population-based cohort (n = 613), aged 50 to 75 yr, that was followed with a median duration of 12.5 yr. During follow-up, 192 individuals died (67 of cardiovascular causes). At baseline, renal function was estimated with serum creatinine, the Cockcroft-Gault formula, and the Modification of Diet in Renal Disease equation of GFR (eGFR). Endothelial function was estimated by plasma von Willebrand factor, soluble vascular cell adhesion molecule-1, and the urinary albumin-creatinine ratio. Inflammatory activity was estimated by plasma C-reactive protein and soluble intercellular adhesion molecule-1. Renal function was mildly impaired (mean eGFR 68 +/- 12 ml/min per 1.73 m(2)) and independently associated with von Willebrand factor (standardized beta -0.09; 95% confidence interval [CI] -0.18 to -0.002; P < 0.05), soluble vascular cell adhesion molecule-1 (standardized beta -0.14; 95% CI -0.22 to -0.05; P < 0.01), and albumin-creatinine ratio (standardized beta -0.15; 95% CI -0.23 to -0.08; P < 0.001) but not with markers of inflammatory activity. Renal function was inversely associated with cardiovascular and all-cause mortality. The relative risk for cardiovascular mortality but not all-cause mortality associated with renal function decreased from 1.22 to 1.12 per 5 ml/min per 1.73 m(2) decrease of eGFR after adjustment for markers of endothelial dysfunction. In conclusion, endothelial dysfunction was related to renal function and contributed to the excess in cardiovascular mortality in this population-based cohort with mild renal insufficiency.
Effects of Glutathione-S-Transferase M1, T1, and P1 on Childhood Lung Function Growth
Authors: Frank D. Gilliland, W. James Gauderman, Hita Vora, Edward Rappaport, Louis Dubeau
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

The effects of glutathione-S-transferase (GST) M1, GSTT1, and GSTP1 genotypes on lung function growth were investigated in 1,940 children enrolled in the Children's Health Study as fourth graders (aged 8-11 years) in two cohorts during 1993 and 1996 and were followed annually over a 4-year period. Genotypes for GSTM1 and GSTT1 and GSTP1 codon 105 variants (ile105 and val105) were determined using DNA from buccal cell specimens. We used two-level regression models to estimate the effects of GSTM1, GSTT1, and GSTP1 genotypes on the adjusted annual average lung function growth. GSTM1 null was associated with deficits in annual growth rates for FVC (-0.21%; 95% confidence interval [CI], -0.40, -0.03) and FEV(1) (-0.27%; 95% CI, -0.50, -0.04). Children who were homozygous for the GSTP1 val105 allele had slower lung function growth (FVC -0.35%; 95% CI, -0.62, -0.07; and FEV(1) -0.34%; 95% CI, -0.68, 0.00) than children with one or more ile105 alleles. Children with asthma who were homozygous for the GSTP1 val105 allele had substantially larger deficits in FVC, FEV(1), and maximal mid-expiratory flow than children without asthma. The deficits in FVC and FEV(1) growth associated with both GSTM1 null and the GSTP1 val105 allele were largest and were statistically significant in non-Hispanic white children. We conclude that GSTM1 and GSTP1 genotypes are associated with lung function growth in school children.
Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis
Authors: Helga Westerlind, Marie-Rose Mellander, Francesca Bresso, Andreas Munch, Ferdinando Bonfiglio, Ghazaleh Assadi, Joseph Rafter, Matthias Hübenthal, Wolfgang Lieb, Henrik Källberg, Boel Brynedal, Leonid Padyukov, Jonas Halfvarson, Leif Törkvist, Jan Bjork, Anna Andreasson, Lars Agreus, Sven Almer, Stephan Miehlke, Ahmed Madisch, Bodil Ohlsson, Robert Löfberg, Rolf Hultcrantz, Andre Franke, Mauro D'Amato
Journal: Gut (2015)

Collagenous colitis (CC) is a major cause of chronic non-bloody diarrhoea, particularly in the elderly female population. The aetiology of CC is unknown, and still poor is the understanding of its pathogenesis. This possibly involves dysregulated inflammation and immune-mediated reactions in genetically predisposed individuals, but the contribution of genetic factors to CC is underinvestigated. We systematically tested immune-related genes known to impact the risk of several autoimmune diseases for their potential CC-predisposing role.Three independent cohorts of histologically confirmed CC cases (N=314) and controls (N=4299) from Sweden and Germany were included in a 2-step association analysis. Immunochip and targeted single nucleotide polymorphism (SNP) genotype data were produced, respectively, for discovery and replication purposes. Classical human leucocyte antigen (HLA) variants at 2-digit and 4-digit resolution were obtained via imputation from single marker genotypes. SNPs and HLA variants passing quality control filters were tested for association with CC with logistic regression adjusting for age, sex and country of origin.Forty-two markers gave rise to genome-wide significant association signals, all contained within the HLA region on chromosome 6 (best p=4.2×10-10 for SNP rs4143332). Among the HLA variants, most pronounced risk effects were observed for 8.1 haplotype alleles including DQ2.5, which was targeted and confirmed in the replication data set (p=2.3×10-11; OR=2.06; 95% CI (1.67 to 2.55) in the combined analysis).HLA genotype associates with CC, thus implicating HLA-related immune mechanisms in its pathogenesis.