tbuckley/cabot-search huggingface dataset:
Cyclosporine A-induced nitration of tyrosine 34 MnSOD in endothelial cells: role of mitochondrial superoxide
Authors: Mariano Redondo-Horcajo, Natalia Romero, Pablo Martínez-Acedo, Antonio Martínez-Ruiz, Celia Quijano, Catia F. Lourenço, Nieves Movilla, Jose Antonio Enríquez, Fernando Rodríguez-Pascual, Eduardo Rial, Rafael Radi, Jesús Vázquez, Santiago Lamas
Journal: Cardiovascular Research (2010)

Cyclosporine A (CsA) has represented a fundamental therapeutic weapon in immunosupression for the past three decades. However, its clinical use is not devoid of side effects, among which hypertension and vascular injury represent a major drawback. Endothelial cells are able to generate reactive oxygen and nitrogen species upon exposure to CsA, including formation of peroxynitrite. This may result in endothelial cell toxicity and increased tyrosine nitration. We have now studied the subcellular origin of superoxide formation in endothelial cells treated with CsA and the biochemical consequences for the function of mitochondrial enzymes. By using electron spin resonance and endothelial cells lacking functional mitochondria, we showed that superoxide anion is generated in mitochondria. This was associated with an effect of CsA on bioenergetic parameters: increased mitochondrial membrane potential and inhibition of cellular respiration. In addition, CsA inhibited the activity of the mitochondrial enzymes aconitase and manganese superoxide dismutase (MnSOD). The use of murine lung endothelial cells deficient in endothelial nitric oxide synthase (eNOS) and NOS/peroxynitrite inhibitors allowed us to establish that the presence of eNOS and concomitant NO synthesis and peroxynitrite formation were essential for CsA induced nitration and inhibition of MnSOD activity. As the latter has been shown to become inactivated by nitration, we sought to identify this modification by mass spectrometry analysis. We found that CsA induced specific MnSOD tyrosine 34 nitration both in the recombinant protein and in endothelial cells overexpressing MnSOD. We propose that CsA induced endothelial damage may be related to increased mitochondrial superoxide formation and subsequent peroxynitrite-dependent nitroxidative damage, specifically targeting MnSOD. The inactivation of this key antioxidant enzyme by tyrosine nitration represents a pathophysiological cellular mechanism contributing to self-perpetuation and amplification of CsA-related vascular toxicity.
Ganetespib (STA-9090), a Nongeldanamycin HSP90 Inhibitor, Has Potent Antitumor Activity in <i>In Vitro</i> and <i>In Vivo</i> Models of Non–Small Cell Lung Cancer
Authors: Takeshi Shimamura, Samanthi A. Perera, Kevin P. Foley, Jim Sang, Scott J. Rodig, Takayo Inoue, Liang Chen, Danan Li, Julian Carretero, Yu-Chen Li, Papiya Sinha, Christopher D. Carey, Christa L. Borgman, John-Paul Jimenez, Matthew Meyerson, Weiwen Ying, James Barsoum, Kwok-Kin Wong, Geoffrey I. Shapiro
Journal: Clinical Cancer Research (2012)

Abstract Purpose: We describe the anticancer activity of ganetespib, a novel non-geldanamycin heat shock protein 90 (HSP90) inhibitor, in non-small cell lung cancer (NSCLC) models. Experimental Design: The activity of ganetespib was compared with that of the geldanamycin 17-AAG in biochemical assays, cell lines, and xenografts, and evaluated in an ERBB2 YVMA-driven mouse lung adenocarcinoma model. Results: Ganetespib blocked the ability of HSP90 to bind to biotinylated geldanamycin and disrupted the association of HSP90 with its cochaperone, p23, more potently than 17-AAG. In genomically defined NSCLC cell lines, ganetespib caused depletion of receptor tyrosine kinases, extinguishing of downstream signaling, inhibition of proliferation and induction of apoptosis with IC50 values ranging 2 to 30 nmol/L, substantially lower than those required for 17-AAG (20–3,500 nmol/L). Ganetespib was also approximately 20-fold more potent in isogenic Ba/F3 pro-B cells rendered IL-3 independent by expression of EGFR and ERBB2 mutants. In mice bearing NCI-H1975 (EGFR L858R/T790M) xenografts, ganetespib was rapidly eliminated from plasma and normal tissues but was maintained in tumor with t1/2 58.3 hours, supporting once-weekly dosing experiments, in which ganetespib produced greater tumor growth inhibition than 17-AAG. However, after a single dose, reexpression of mutant EGFR occurred by 72 hours, correlating with reversal of antiproliferative and proapoptotic effects. Consecutive day dosing resulted in xenograft regressions, accompanied by more sustained pharmacodynamic effects. Ganetespib also showed activity against mouse lung adenocarcinomas driven by oncogenic ERBB2 YVMA. Conclusions: Ganetespib has greater potency than 17-AAG and potential efficacy against several NSCLC subsets, including those harboring EGFR or ERBB2 mutation. Clin Cancer Res; 18(18); 4973–85. ©2012 AACR.
Cutaneous Structural and Biochemical Correlates of Foot Complications in High-Risk Diabetes
Authors: Abd A. Tahrani, Wei Zeng, Jayadave Shakher, Milan K. Piya, Sharon Hughes, Kiran Dubb, Martin J. Stevens
Journal: Diabetes Care (2012)

Impairment of skin quality may contribute to diabetic foot ulceration (DFU). Our goal was to determine whether high-risk patients exhibited specific skin structural and metabolic deficits that could predispose to foot complications.A total of 46 patients comprising 9 diabetic control subjects, 16 with diabetic peripheral neuropathy (DPN) alone, and 21 with recurrent DFUs (including 9 with Charcot neuroarthropathy [CNA]) were recruited and compared with 14 nondiabetic control (NDC) subjects. DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI). Skin punch biopsies (3 mm) were performed on upper and lower leg skin for measurements of intraepidermal nerve fiber density (IENFD), structural analysis, type 1 procollagen abundance, tissue degrading matrix metalloproteinases (MMPs), and poly(ADP-ribose) (PAR) immunoreactivity.MNSI scores were comparable across DPN groups. IENFD was decreased by diabetes and DPN but did not differ between neuropathic groups. Skin structural deficit scores were elevated in all neuropathic subjects, particularly in the DFU group. Type 1 procollagen abundance was reduced in DFU subjects 387 ± 256 units (mean ± 1 SD) compared with NDC subjects (715 ± 100, P < 0.001). MMP-1 and MMP-2 were activated by diabetes. PAR immunoreactivity was increased in DFU (particularly in the CNA group; P < 0.01) compared with other DPN subjects.Increased PAR, reduced type 1 procollagen abundance, and impaired skin structure are associated with foot complications in diabetes. The potential of therapies that improve skin quality to reduce DFU needs to be investigated.
Small- and Large-Fiber Involvement in Early Diabetic Neuropathy: A Study With the Medial Plantar Response and Sensory Thresholds
Authors: David M Levy, R Ralph Abraham, Raju M Abraham
Journal: Diabetes Care (1987)

Small- and large-fiber function in diabetic neuropathy was studied in 68 patients (mean age 45.4 ± 12.9 yr; 27 type I and 41 type II diabetics) with psychophysical tests of vibration and thermal sensation and neurophysiological measurements, including the medial plantar sensory action potential (MPSAP). Thermal sensitivity at the dorsolateral aspect of the foot (Pfizer thermal tester) correlated significantly with vibration thresholds (Somedic vibrameter) at three sites in the foot and two in the hand. Forty patients had normal sensory thresholds, but 18 of these lacked an MPSAP. Smaller groups had a single abnormal sensory threshold: 12 (18%) had an abnormal vibration threshold, and 24 (35%) had abnormal thermal sensitivity; 8 of the former group and 17 of the latter group lacked an MPSAP response. Only 8 (12%) had both abnormal vibration and thermal sensation (6 without an MPSAP). Fifteen of the 17 symptomatic patients had lost the MPSAP, but there was no consistent pattern of sensory loss. In this relatively young group of diabetics, more patients showed absent MPSAP responses than an abnormality in either sensory test on its own. The MPSAP is frequently absent in patients with no abnormalities in psychophysical tests of peripheral large-fiber function (vibration sensation) and small-fiber function (thermal sensitivity).
Erratum. Predictive Low-Glucose Insulin Suspension Reduces Duration of Nocturnal Hypoglycemia in Children Without Increasing Ketosis. Diabetes Care 2015;38:1197–1204
Authors: Bruce A. Buckingham, Dan Raghinaru, Fraser Cameron, B. Wayne Bequette, H. Peter Chase, David M. Maahs, Robert Slover, R. Paul Wadwa, Darrell M. Wilson, Trang Ly, Tandy Aye, Irene Hramiak, Cheril Clarson, Robert Stein, Patricia H. Gallego, John Lum, Judy Sibayan, Craig Kollman, Roy W. Beck
Journal: Diabetes Care (2015)
Treatment of relapsed acute myeloid leukemia with idarubicin and intermediate-dose cytarabine.
Authors: J L Harousseau, J Reiffers, P Hurteloup, N Milpied, H Guy, F Rigal-Huguet, T Facon, P Dufour, N Ifrah
Journal: Journal of Clinical Oncology (1989)

High-dose cytarabine (HDARA-C) is an effective but toxic treatment for acute myeloid leukemia (AML). In order to reduce the incidence of severe complications noted with HDARA-C-containing regimens, we used a combination of intravenous (IV) idarubicin (IDARUB) at optimal dosage and cytarabine (ARA-C) at intermediate dosage. Thirty-five patients aged 23 to 78 years (median, 56) with AML in first relapse received IDARUB, 8 mg/m2/d for five days, and ARA-C, 1 g/m2 every 12 hours for six doses. Of the 35 patients, 21 achieved a complete remission (CR), four had a partial remission (PR), four died in aplasia, and six were nonresponders. The only factor influencing the CR rate was the duration of the first CR (35% for patients relapsing before 16 months v 83% for patients relapsing after 16 months, P = .003). Mucositis was the most significant extrahematologic side effect. Diarrhea, skin toxicity, and hepatic disturbances were rare and mild. There was no cerebellar toxicity, even in 25 patients greater than 50 years of age. This regimen is effective and well tolerated even in elderly patients, and could be used either as induction or consolidation therapy for the treatment of AML.
Roles of gall bladder emptying and intestinal transit in the pathogenesis of octreotide induced gall bladder stones.
Authors: S H Hussaini, S P Pereira, M J Veysey, C Kennedy, P Jenkins, G M Murphy, J A Wass, R H Dowling
Journal: Gut (1996)

Octreotide treatment of acromegalic patients increases the % deoxycholic acid conjugates and the cholesterol saturation of gall bladder bile, and induces gall stone formation.To study the roles of gall bladder emptying and intestinal transit in these phenomena.Gall bladder emptying and mouth to caecum transit was measured in (a) control subjects and acromegalic patients given saline or 50 micrograms of octreotide, and (b) acromegalic patients taking long term octreotide. In the second group, large bowel transit was also measured.A single dose of octreotide inhibited meal stimulated gall bladder emptying, the ejection fraction falling from mean (SEM) 66.0 (2.3)% to 7.0 (5.3)% in controls (p < 0.001); from 72.5 (2.1) to 16.6 (5.1)% in untreated acromegalic patients (p < 0.001), and to 30.4 (9.5)% in acromegalic patients taking long term octreotide (p < 0.001 v untreated acromegalic group). Octreotide prolonged mouth to caecum transit time, from 112 (15) min to 237 (13) min in controls (p < 0.001), from 170 (13) min to 282 (11) min in untreated acromegalic patients (p < 0.001), and to 247 (10) min in acromegalic patients taking long term octreotide (p < 0.001 v untreated acromegalic patients). The mean large bowel transit in octreotide untreated compared with treated acromegalic patients remained unchanged (40 (6) h v 47 (6) h).Prolongation of intestinal transit and impaired gall bladder emptying may contribute to lithogenic changes in bile composition and gall stone formation in patients receiving long term octreotide.
Higher pulmonary artery pressure in children than in adults upon fast ascent to high altitude
Authors: S. Kriemler, C. Jansen, A. Linka, A. Kessel-Schaefer, M. Zehnder, T. Schurmann, M. Kohler, K. Bloch, H. P. Brunner-La Rocca
Journal: European Respiratory Journal (2008)

The response of pulmonary artery pressure to high altitude has not been studied in children. It is also not known whether the individual response is hereditary. Therefore, the response of pulmonary artery pressure to high altitude was measured in pre-pubertal children in comparison to that in their biological fathers. Echocardiography was performed at 450 m and over 3 days at 3,450 m. Systolic pulmonary artery pressure was estimated from the pressure gradient of tricuspid regurgitation. The increase in pulmonary artery pressure in children was greater than that in adults at day 1 of high altitude (15.5±9.1 <i>versus</i> 7.9±6.4 mmHg), but returned to adult levels on day 2. The increase in pulmonary artery pressure from low to high altitude of each child correlated with that in the father. Pre-pubertal children transiently develop greater pulmonary hypertension than their fathers when exposed to high altitude. The individual response of pulmonary pressure to high altitude seems to be at least partly hereditary.
Dynamic strength of the quadriceps muscle and sports activity
Authors: T Hahn, A Foldspang, T Ingemann-Hansen
Journal: British Journal of Sports Medicine (1999)

The study objectives were to examine the dynamic strength of the quadriceps muscle in athletes, and investigate its association with participation in sport. The study comprised 168 active competitive non-pregnant athletes, aged 14-24 years. The dynamic strength of their quadriceps muscle was measured, and they answered a questionnaire about sports activity and occupation. The dynamic strength of the quadriceps muscle was significantly higher in men than in women, and was positively associated with body weight, years of jogging, years of soccer, and weekly hours of basketball. In conclusion, the dynamic strength of the quadriceps muscle seems to be associated with sports activity. The results suggest sport specific adaptation, which may reflect high levels of running and jumping activity.
A case of exacerbation of ulcerative colitis induced by combination therapy with PEG-interferon -2b and ribavirin
Authors: T Watanabe, M Inoue, K Harada, N Homma, M Uchida, N Ogata, R Funada, K Hasegawa, K Soga, K Shibasaki
Journal: Gut (2006)

A 55 year old man with chronic hepatitis C presented with diarrhoea and bloody stools in July 2003. Colonoscopic examination showed redness and oedematous mucosa in the rectum and ulcerative colitis was suspected. Biopsy of the lesion confirmed the diagnosis and treatment was initiated with mesalazine (5-ASA 2250 mg/day). However, he showed short term improvement and mesalazine was discontinued. He was treated with percutaneous radiofrequency ablation therapy (RFA)(Cool-tip) for adenomatous hyperplasia in S5 of the liver in December 2004. After providing consent to treatment with interferon (IFN), the patient underwent combination therapy with PEG-IFNα-2b (100 mg/week) and ribavirin (800 mg/day) for chronic hepatitis C. Liver biopsy and blood biochemistry revealed chronic active hepatitis C virus (HCV) F3/A2, genotype 1b, liver injury associated with HCV, aspartate aminotransferase (AST) 109 IU/l, alanine aminotransferase (ALT) 126 IU/l, and HCV RNA 3400.0 KIU/ml (by reverse transcription nested polymerase chain reaction, high range method).

One …
Serum Uric Acid in Essential Hypertension: An Indicator of Renal Vascular Involvement
Authors: FRANZ H. MESSERLI
Journal: Annals of Internal Medicine (1980)

We measured glomerular filtration rate, renal and systemic hemodynamics, and intravascular volume in normotensive subjects and in borderline and established essential hypertensive patients classified according to serum uric acid level. Renal blood flow was lower and renal vascular and total peripheral resistances were increased in patients with high uric acid levels (p < 0.02). Serum uric acid concentration correlated inversely with renal blood flow/m2 body surface area (r = -0.45, p < 0.001) and directly with renal vascular (r = 0.41, p < 0.001) and total (r = 0.38, p < 0.001) resistance. Cardiac output, heart rate, and intravascular volume as well as glomerular filtration rate showed no uric-acid-dependent pattern. Mild asymptomatic hyperuricemia, therefore, was associated with decreased renal blood flow without affecting glomerular filtration rate. Increased renal vascular and total peripheral resistances reflecting renal and systemic hypertensive vascular disease paralleled the rising serum uric acid levels. These data suggest that heretofore unexplained hyperuricemia in patients with essential hypertension most likely reflects early renal vascular involvement, specifically, nephrosclerosis.
Long-Standing Sulfonylurea Therapy After Pubertal Relapse of Neonatal Diabetes in a Case of Uniparental Paternal Isodisomy of Chromosome 6
Authors: Ulf Schimmel
Journal: Diabetes Care (2008)

Approximately 30% of cases of transient (relapsing) neonatal diabetes can be diagnosed by identifying anomalies of chromosome 6 (6q24). At the time of relapse of diabetes, β-cell function appears to be intact and β-cells able to secrete insulin while exhibiting a specific defect of insulin secretion after glucose stimulation similar to that in patients with mutations of the ATP-sensitive K+ channel (1,2,3). However, in contrast with patients with mutations of the ATP-sensitive K+ channel, 6q24 patients are usually treated with insulin or diet alone and not with oral agents (4).

We report on a patient with uniparental paternal isodisomy of chromosome 6 (UPD6) with good-to-fair glycemic control during long-standing sulfonylurea therapy started after diabetes relapsed at …
54 CANNABINOID RECEPTOR 2 PROTECTS AGAINST ALCOHOL-INDUCED STEATOSIS BY REGULATING KUPFFER CELL POLARIZATION
Authors: F. Teixeira-Clerc, A. Louvet, M.-N. Chobert, V. Deveaux, A. Zimmer, A. Mallat, S. Lotersztajn
Journal: Journal of Hepatology (2011)
Improved Effector Functions of a Therapeutic Monoclonal Lewis Y-Specific Antibody by Glycoform Engineering
Authors: Manfred Schuster, Pablo Umana, Claudia Ferrara, Peter Brünker, Christian Gerdes, Günter Waxenecker, Susanne Wiederkum, Cornelia Schwager, Hans Loibner, Gottfried Himmler, Geert C. Mudde
Journal: Cancer Research (2005)

The aim of the present study was to produce glycosylation variants of the therapeutic Lewis Y-specific humanized IgG1 antibody IGN311 to enhance cell-killing effector function. This was achieved via genetic engineering of the glycosylation machinery of the antibody-producing host. Antibody genes were transiently cotransfected with acetyl-glycosaminyltransferase-III genes into human embryonic kidney-EBV nuclear antigen cells. A control wild-type antibody, IGN311wt, was expressed in the same host using identical expression vectors, but without cotransfection of genes for acetyl-glycosaminyltransferase-III expression. Both expression products were purified to homogeneity and characterized. The glyco-engineered expression product (IGN312-Glyco-I) showed a remarkably homogenous N-linked glycosylation pattern consisting of one major hybrid-type, non-fucosylated and agalactosylated form carrying a bisecting GlcNAc-group. Wild-type expression product (IGN311wt) on the other hand was glycosylated by a multitude of different core-fucosylated complex-type structures of variable degrees of galactosylation. Target affinity of the glyco-engineered antibody as well as heavy and light chain assembly were not affected by acetyl-glycosaminyltransferase-III expression. In vitro experiments showed a approximately 10-fold increase of antibody-dependent cellular cytotoxicity of the glyco-engineered antibody using different Lewis Y-positive target cancer cell lines (SK-BR-3, SK-BR-5, OVCAR-3, and Kato-III). Complement-mediated cytotoxicity of IGN312-Glyco-I was 0.4-fold reduced using SK-BR-5 as target cell line. The reduction of complement activation could be prevented and even converted into a slight increase of activity by using a different molecular-biological approach directing the glycosylation towards increased levels of complex N-linked oligosaccharides of bisected, non-fucosylated type, as a result of cotransfection of mannosidase II together with acetyl-glycosaminyltransferase-III.
Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus
Authors: Yi Lu, Veronique Vitart, Kathryn P Burdon, Chiea Chuen Khor, Yelena Bykhovskaya, Alireza Mirshahi, Alex W Hewitt, Demelza Koehn, Pirro G Hysi, Wishal D Ramdas, Tanja Zeller, Eranga N Vithana, Belinda K Cornes, Wan-Ting Tay, E Shyong Tai, Ching-Yu Cheng, Jianjun Liu, Jia-Nee Foo, Seang Mei Saw, Gudmar Thorleifsson, Kari Stefansson, David P Dimasi, Richard A Mills, Jenny Mountain, Wei Ang, René Hoehn, Virginie J M Verhoeven, Franz Grus, Roger Wolfs, Raphaële Castagne, Karl J Lackner, Henriët Springelkamp, Jian Yang, Fridbert Jonasson, Dexter Y L Leung, Li J Chen, Clement C Y Tham, Igor Rudan, Zoran Vatavuk, Caroline Hayward, Jane Gibson, Angela J Cree, Alex MacLeod, Sarah Ennis, Ozren Polasek, Harry Campbell, James F Wilson, Ananth C Viswanathan, Brian Fleck, Xiaohui Li, David Siscovick, Kent D Taylor, Jerome I Rotter, Seyhan Yazar, Megan Ulmer, Jun Li, Brian L Yaspan, Ayse B Ozel, Julia E Richards, Sayoko E Moroi, Jonathan L Haines, Jae H Kang, Louis R Pasquale, R Rand Allingham, Allison Ashley-Koch, Paul Mitchell, Jie Jin Wang, Alan F Wright, Craig Pennell, Timothy D Spector, Terri L Young, Caroline C W Klaver, Nicholas G Martin, Grant W Montgomery, Michael G Anderson, Tin Aung, Colin E Willoughby, Janey L Wiggs, Chi P Pang, Unnur Thorsteinsdottir, Andrew J Lotery, Christopher J Hammond, Cornelia M van Duijn, Michael A Hauser, Yaron S Rabinowitz, Norbert Pfeiffer, David A Mackey, Jamie E Craig, Stuart Macgregor, Tien Y Wong
Journal: Nature Genetics (2013)
Gene Expression Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma
Authors: Hu-Liang Jia, Qing-Hai Ye, Lun-Xiu Qin, Anuradha Budhu, Marshonna Forgues, Yidong Chen, Yin-Kun Liu, Hui-Chuan Sun, Lu Wang, Hong-Zhou Lu, Fang Shen, Zhao-You Tang, Xin Wei Wang
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Hepatocellular carcinoma (HCC), a common cancer worldwide, has a dismal outcome partly due to the poor identification of early-stage HCC. Currently, one third of HCC patients present with low serum α-fetoprotein (AFP) levels, the only clinically available diagnostic marker for HCC. The aim of this study was to identify new diagnostic molecular markers for HCC, especially for individuals with low serum AFP. Experimental Design: We used the microarray technique to determine the expression profiles of 218 HCC specimens from patients with either high or low serum AFP. From the microarray study, we selected five candidate genes (i.e., GPC3, PEG10, MDK, SERPINI1, and QP-C), which were overexpressed in HCCs. Using quantitative real-time PCR analyses, we validated the expression of these five genes in 50 AFP-normal and 8 AFP-positive HCC specimens and 36 cirrhotic noncancerous hepatic specimens, which include 52 independent specimens not used in microarray analysis. Results: A significant increase in the expression of the five candidate genes could be detected in most of the HCC samples, including those with normal serum AFP and small tumors. GPC3, MDK, and SERPINI1 encode known serum proteins. Consistently, a significant increase in serum midkine, encoded by MDK, was associated with HCC patients, including those with normal serum AFP. Using prediction analysis of microarray, we showed that a combined score of these five genes can accurately classify noncancerous hepatic tissues (100%) and HCC (71%). Conclusions: We suggest that a diagnostic signature approach using a combined score of these five biomarkers rather than a single marker may improve the prediction accuracy of HCC patients, including those with normal serum AFP and smaller-sized tumors.