tbuckley/cabot-search huggingface dataset:
Occupational Trichloroethylene Exposure and Renal Carcinoma Risk: Evidence of Genetic Susceptibility by Reductive Metabolism Gene Variants
Authors: Lee E. Moore, Paolo Boffetta, Sara Karami, Paul Brennan, Patricia S. Stewart, Rayjean Hung, David Zaridze, Vsevolod Matveev, Vladimir Janout, Helena Kollarova, Vladimir Bencko, Marie Navratilova, Neonila Szeszenia-Dabrowska, Dana Mates, Jan Gromiec, Ivana Holcatova, Maria Merino, Stephen Chanock, Wong-Ho Chow, Nathaniel Rothman
Journal: Cancer Research (2010)

Abstract Trichloroethylene (TCE) is a suspected renal carcinogen. TCE-associated renal genotoxicity occurs predominantly through glutathione S-transferase (GST) conjugation and bioactivation by renal cysteine β-lyase (CCBL1). We conducted a case-control study in Central Europe (1,097 cases and 1,476 controls) specifically designed to assess risk associated with occupational exposure to TCE through analysis of detailed job histories. All jobs were coded for organic/chlorinated solvent and TCE exposure (ever/never) as well as the frequency and intensity of exposure based on detailed occupational questionnaires, specialized questionnaires, and expert assessments. Increased risk was observed among subjects ever TCE exposed [odds ratio (OR) = 1.63; 95% confidence interval (95% CI), 1.04–2.54]. Exposure-response trends were observed among subjects above and below the median exposure [average intensity (OR = 1.38; 95% CI, 0.81–2.35; OR = 2.34; 95% CI, 1.05–5.21; Ptrend = 0.02)]. A significant association was found among TCE-exposed subjects with at least one intact GSTT1 allele (active genotype; OR = 1.88; 95% CI, 1.06–3.33) but not among subjects with two deleted alleles (null genotype; OR = 0.93; 95% CI, 0.35–2.44; Pinteraction = 0.18). Similar associations for all exposure metrics including average intensity were observed among GSTT1-active subjects (OR = 1.56; 95% CI, 0.79–3.10; OR = 2.77; 95% CI, 1.01–7.58; Ptrend = 0.02) but not among GSTT1 nulls (OR = 0.81; 95% CI, 0.24-2.72; OR = 1.16; 95% CI, 0.27–5.04; Ptrend = 1.00; Pinteraction = 0.34). Further evidence of heterogeneity was seen among TCE-exposed subjects with ≥1 minor allele of several CCBL1-tagging single nucleotide polymorphisms: rs2293968, rs2280841, rs2259043, and rs941960. These findings provide the strongest evidence to date that TCE exposure is associated with increased renal cancer risk, particularly among individuals carrying polymorphisms in genes that are important in the reductive metabolism of this chemical, and provides biological plausibility of the association in humans. Cancer Res; 70(16); 6527–36. ©2010 AACR.
Surgical Strategy for Liver Cancers in the Era of Effective Chemotherapy
Authors: Junichi Shindoh, Ahmed Kaseb, Jean-Nicolas Vauthey
Journal: Liver Cancer (2013)

Systemic chemotherapy is the only option for advanced and/or disseminated disease in patients with hepatocellular carcinoma (HCC). For decades, various systemic therapies have been explored for the treatment of advanced HCC. Nevertheless, no satisfactory results have been obtained in cytotoxic chemotherapy so far. However, with the recent introduction of effective chemotherapy agents including sorafenib, the role of systemic therapy for the treatment of HCC is changing. The goals of systemic therapy include prolongation of survival with stabilization of disease progression and, in selected patients, downsizing of primarily unresectable tumors. In the era of effective chemotherapy, patients with advanced HCC should be managed with individualized approaches to optimize outcome.
The Parietal Epithelial Cell
Authors: Bart Smeets, Nathalie A.J.M. Te Loeke, Henry B.P.M. Dijkman, Mark L.M. Steenbergen, Joost F.M. Lensen, Mark P.V. Begieneman, Toin H. van Kuppevelt, Jack F.M. Wetzels, Eric J. Steenbergen
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Focal segmental glomerulosclerosis (FSGS) is a hallmark of progressive renal disease. Podocyte injury and loss have been proposed as the critical events that lead to FSGS. In the present study, the authors have examined the development of FSGS in Thy-1.1 transgenic (tg) mice, with emphasis on the podocyte and parietal epithelial cell (PEC). Thy-1.1 tg mice express the Thy-1.1 antigen on podocytes. Injection of anti-Thy-1.1 mAb induces an acute albuminuria and development of FSGS lesions that resemble human collapsing FSGS. The authors studied FSGS lesions at days 1, 3, 6, 7, 10, 14, and 21, in relation to changes in the expression of specific markers for normal podocytes (WT-1, synaptopodin, ASD33, and the Thy-1.1 antigen), for mouse PEC (CD10), for activated podocytes (desmin), for macrophages (CD68), and for proliferation (Ki-67). The composition of the extracellular matrix (ECM) that forms tuft adhesions or scars was studied using mAb against collagen IV α2 and α4 chains and antibodies directed against different heparan sulfate species. The first change observed was severe PEC injury at day 1, which increased in time, and resulted in denuded segments of Bowman's capsule at days 6 and 7. Podocytes showed foot process effacement and microvillous transformation. There was no evidence of podocyte loss or denudation of the GBM. Podocytes became hypertrophic at day 3, with decreased expression of ASD33 and synaptopodin and normal expression of WT-1 and Thy-1.1. Podocyte bridges were formed by attachment of hypertrophic podocytes to PEC and podocyte apposition against denuded segments of Bowman's capsule. At day 6, there was a marked proliferation of epithelial cells in Bowman's space. These proliferating cells were negative for desmin and all podocyte markers, but stained for CD10, and thus appeared to be PEC. The staining properties of the early adhesions were identical to that of Bowman's capsule, suggesting that the ECM in the adhesions was produced by PEC. In conclusion, the authors propose the following sequence of events leading to FSGS lesions in the Thy1.1 tg mice: (1) PEC damage and denudation of Bowman's capsule segments; (2) podocyte hypertrophy and bridging; and (3) PEC proliferation with ECM production.
Structural and kinetic basis for heightened immunogenicity of T cell vaccines
Authors: Ji-Li Chen, Guillaume Stewart-Jones, Giovanna Bossi, Nikolai M. Lissin, Linda Wooldridge, Ed Man Lik Choi, Gerhard Held, P. Rod Dunbar, Robert M. Esnouf, Malkit Sami, Jonathan M. Boulter, Pierre Rizkallah, Christoph Renner, Andrew Sewell, P. Anton van der Merwe, Bent K. Jakobsen, Gillian Griffiths, E. Yvonne Jones, Vincenzo Cerundolo
Journal: The Journal of Experimental Medicine (2005)

Analogue peptides with enhanced binding affinity to major histocompatibility class (MHC) I molecules are currently being used in cancer patients to elicit stronger T cell responses. However, it remains unclear as to how alterations of anchor residues may affect T cell receptor (TCR) recognition. We correlate functional, thermodynamic, and structural parameters of TCR–peptide–MHC binding and demonstrate the effect of anchor residue modifications of the human histocompatibility leukocyte antigens (HLA)–A2 tumor epitope NY–ESO-1157–165–SLLMWITQC on TCR recognition. The crystal structure of the wild-type peptide complexed with a specific TCR shows that TCR binding centers on two prominent, sequential, peptide sidechains, methionine–tryptophan. Cysteine-to-valine substitution at peptide position 9, while optimizing peptide binding to the MHC, repositions the peptide main chain and generates subtly enhanced interactions between the analogue peptide and the TCR. Binding analyses confirm tighter binding of the analogue peptide to HLA–A2 and improved soluble TCR binding. Recognition of analogue peptide stimulates faster polarization of lytic granules to the immunological synapse, reduces dependence on CD8 binding, and induces greater numbers of cross-reactive cytotoxic T lymphocyte to SLLMWITQC. These results provide important insights into heightened immunogenicity of analogue peptides and highlight the importance of incorporating structural data into the process of rational optimization of superagonist peptides for clinical trials.
Vision and cognition: Drawing the line
Authors: Andrew Hollingworth, John M. Henderson
Journal: Behavioral and Brain Sciences (1999)

Pylyshyn defends a distinction between early visual perception and cognitive processing. But exactly where should the line between vision and cognition be drawn? Our research on object identification suggests that the construction of an object's visual description is isolated from contextually derived expectations. Moreover, the matching of constructed descriptions to stored descriptions appears to be similarly isolated.
Docetaxel in combination with mitoxantrone and granulocyte colony-stimulating factor as front-line chemotherapy in metastatic breast cancer: A multicenter phase II study
Authors: A. Alexopoulos, C. Kouroussis, N. Malamos, S. Kakolyris, K. Kalbakis, C. Kosmas, D. Mavroudis, S. Agelaki, J. Vlachonicolis, E. Sarra, G. Rigatos, V. Georgoulias
Journal: Annals of Oncology (2001)
Gender Differences in the Renal Response to Renin-Angiotensin System Blockade
Authors: Judith A. Miller, David Z. Cherney, John A. Duncan, Vesta Lai, Kevin D. Burns, Christopher R.J. Kennedy, Joseph Zimpelmann, Wei Gao, Daniel C. Cattran, James W. Scholey
Journal: Journal of the American Society of Nephrology (2006)

Evidence suggests that gender differences exist in renin-angiotensin system (RAS) function. It was hypothesized that women may differ also in their response to RAS blockade. The renal and peripheral hemodynamic responses to incremental dosages of an angiotensin receptor blocker and the degree of angiotensin II (AngII) insensitivity achieved during 8 wk were examined in men and women. Participants were 30 young healthy men (n = 15; mean age 27 +/- 2) and women (n = 15; mean age 28 +/- 2) who were on a controlled sodium and protein diet for 1 wk before each study. The humoral, renal, and systemic response to incremental dosages of irbesartan (75 mg for 4 wk, then 150 mg for 4 wk) was assessed, as was the pressor response to AngII (3 ng/kg per min), at 2-wk intervals. AngII type 1 receptor expression in skin biopsies was assessed at baseline and after 8 wk by a real-time PCR protocol. Men and women both exhibited significant declines in BP. Women achieved significantly reduced AngII sensitivity compared with men at lower dosages, showing no pressor response at 4 wk of 75 mg/d irbesartan, whereas men continued to exhibit a pressor response at 4 wk of 150 mg/d. Receptor expression at baseline did not differ between men and women but by 8 wk was significantly decreased in women and unchanged in men. Our findings indicate that men may require larger dosages of angiotensin receptor blocker than do women and that the BP response cannot be used as a surrogate marker for adequate RAS blockade of the renal microvasculature.
MGL1 promotes adipose tissue inflammation and insulin resistance by regulating 7/4hi monocytes in obesity
Authors: Daniel J. Westcott, Jennifer B. DelProposto, Lynn M. Geletka, Tianyi Wang, Kanakadurga Singer, Alan R. Saltiel, Carey N. Lumeng
Journal: The Journal of Experimental Medicine (2009)

Adipose tissue macrophages (ATMs) play a critical role in obesity-induced inflammation and insulin resistance. Distinct subtypes of ATMs have been identified that differentially express macrophage galactose-type C-type lectin 1 (MGL1/CD301), a marker of alternatively activated macrophages. To evaluate if MGL1 is required for the anti-inflammatory function of resident (type 2) MGL1+ ATMs, we examined the effects of diet-induced obesity (DIO) on inflammation and metabolism in Mgl1−/− mice. We found that Mgl1 is not required for the trafficking of type 2 ATMs to adipose tissue. Surprisingly, obese Mgl1−/− mice were protected from glucose intolerance, insulin resistance, and steatosis despite having more visceral fat. This protection was caused by a significant decrease in inflammatory (type 1) CD11c+ ATMs in the visceral adipose tissue of Mgl1−/− mice. MGL1 was expressed specifically in 7/4hi inflammatory monocytes in the blood and obese Mgl1−/− mice had lower levels of 7/4hi monocytes. Mgl1−/− monocytes had decreased half-life after adoptive transfer and demonstrated decreased adhesion to adipocytes indicating a role for MGL1 in the regulation of monocyte function. This study identifies MGL1 as a novel regulator of inflammatory monocyte trafficking to adipose tissue in response to DIO.
Adverse Reactions to Tetanus Toxoid
Authors: Robert L. Jacobs
Journal: JAMA (1982)

A retrospective review of 740 charts of patients with a history of adverse reaction to tetanus toxoid immunization was undertaken. The most common reactions, by history, were local edema and tenderness (33%), fever (15%), and anaphylactoid response (33%). Three patients who had a vesicular eruption at the immunization site were found to have delayed hypersensitivity to mercury. Thirty percent of the patients had received tetanus toxoid within one year and 55% within five years of evaluation. Reactive responses to immediate skin tests were exceedingly rare (less than 1%). None of the challenge patients suffered an adverse reaction.
Research outputs in respiratory medicine
Authors: I Rippon
Journal: Thorax (2004)

<b>Background:</b> There is currently little information regarding how much the distribution of research activity in respiratory medicine reflects the interests of its clinicians and scientists, the disease burden in any country, or the availability of funding. <b>Methods:</b> A total of 81 419 respiratory medicine publications identified in the Science Citation Index for the years 1996–2001 were assigned to 14 subject areas (mainly based on title words) and to 15 OECD countries. Outputs were compared with a nation’s disease burdens and, for the UK, the sources of research funding were investigated. <b>Results and conclusions:</b> Overall, Finland, Canada, Spain and the UK had the greatest relative commitment to respiratory medicine research expressed as a ratio of their share of world biomedical research. The largest subject areas were asthma, lung cancer, and paediatric lung disease, each with over 1400 papers published per year. Australia and Canada led in relative commitment to sleep research and Sweden and Finland led in research on asthma. Australia and the UK produced significant numbers of publications on cystic fibrosis (CF) but Finland produced few. The Netherlands has a strong output on chronic obstructive pulmonary disease (COPD), France and the UK on diffuse parenchymal lung disease (DPLD), and Finland dominated occupational lung disease research but had few publications on HIV/AIDS where Spain proportionately produced most. Finland and Australia had strong outputs in paediatric lung disease research. For most subject areas the research output of a country correlated poorly with disease burden. In the UK, lung cancer research appeared unduly low in relation to the number of deaths and COPD outputs were low compared with those for asthma. However, correlations were positive for the burden of CF and pulmonary complications of HIV/AIDS which explains, for example, the low outputs in these subject areas from Finland. The strong performance in CF research in the UK is likely to reflect significant charitable funding, while sleep research, pulmonary circulatory disease, and DPLD had little stated external funding or sponsorship.
Validity of the inexpensive Stepping Meter in counting steps in free living conditions: a pilot study
Authors: K De Cocker, G Cardon, I De Bourdeaudhuij
Journal: British Journal of Sports Medicine (2006)

Objectives: To evaluate if inexpensive Stepping Meters are valid in counting steps in adults in free living conditions. Methods: For six days, 35 healthy volunteers wore a criterion Yamax Digiwalker and five Stepping Meters every day until all 973 pedometers had been tested. Steps were recorded daily, and the differences between counts from the Digiwalker and the Stepping Meter were expressed as a percentage of the valid value of the Digiwalker step counts. The criterion used to determine if a Stepping Meter was valid was a maximum deviation of 10% from the Digiwalker step counts. Results: A total of 252 (25.9%) Stepping Meters met the criterion, whereas 74.1% made an overestimation or underestimation of more than 10%. In more than one third (36.6%) of the invalid Stepping Meters, the deviation was greater than 50%. Most (64.8%) of the invalid pedometers overestimated the actual steps taken. Conclusions: Inexpensive Stepping Meters cannot be used in community interventions as they will give participants the wrong message.
825-4 Effect of fosinopril and pravastatin on carotid intima-Media-thickness in microalbuminuric subjects without hypertension or hypercholesterolemia
Authors: Folkert W Asselbergs, Andries J Smit, Gilles F.H Diercks, Arie M van Roon, Ad J van Boven, Hans L Hillege, Paul E de Jong, Dirk J van Veldhuisen, Wiek H van Gilst
Journal: Journal of the American College of Cardiology (2004)
cAMP-Mediated Vascular Protection in an Orthotopic Rat Lung Transplant Model
Authors: Yoshifumi Naka, Dilip K. Roy, Hui Liao, Nepal C. Chowdhury, Robert E. Michler, Mehmet C. Oz, David J. Pinsky
Journal: Circulation Research (1996)

Prostaglandin E 1 (PGE 1 ) is often added to the donor pulmonary flush solution to enhance clinical lung preservation for transplantation. Although PGE 1 is thought to act as a pulmonary vasodilator during the harvest period, the precise mechanism(s) of action whereby PGE 1 enhances lung preservation is unknown. Because cAMP levels decline in endothelial and vascular smooth muscle cells exposed to hypoxia, we hypothesized that a PGE 1 -mediated increase in cAMP levels within the preserved lungs might improve pulmonary vascular homeostasis following lung transplantation. Rat lungs demonstrated a time-dependent decline in cAMP levels during hypothermic storage, with cAMP levels significantly increased by PGE 1 supplementation (≈2-fold by 6 hours, P &lt;.0005). To test whether augmenting cAMP levels may enhance lung preservation, experiments were performed using an orthotopic rat left lung transplant model. Compared with controls, supplementing the preservation solution with the membrane-permeable cAMP analogue dibutyryl-cAMP resulted in dose-dependent preservation enhancement, marked by reduced pulmonary vascular resistance (6.0-fold, P &lt;.01), improved arterial oxygenation (3.0-fold, P &lt;.01), reduced graft neutrophil infiltration (1.5-fold, P &lt;.05), and improved recipient survival (7.0-fold, P &lt;.005). Similar preservation enhancement was observed with another cAMP analogue (8-bromo-cAMP) or the phosphodiesterase inhibitor indolidan. Stimulating the cAMP second messenger system by PGE 1 supplementation resulted in marked hemodynamic benefits and improved recipient survival, in parallel with reduced graft neutrophil infiltration, vascular permeability, and platelet deposition. These beneficial effects of PGE 1 were abrogated by simultaneous administration of the cAMP-dependent protein kinase antagonist Rp-cAMPS. Although an arterial vasodilator (minoxidil) resulted in significant pulmonary vasodilation during harvest, it lacked other nonvasodilating effects of PGE 1 and resulted in poor preservation. These data show that harvest vasodilation by itself is insufficient to enhance lung preservation and that PGE 1 enhances lung preservation by stimulating the cAMP-dependent protein kinase and promoting nonvasodilatory mechanisms of pulmonary protection.
Activation of cardiac and smooth muscle-specific genes in primary human cells after forced expression of human myocardin
Authors: J VANTUYN, S KNAANSHANZER, M VANDEWATERING, M DEGRAAF, A VANDERLAARSE, M SCHALIJ, E VANDERWALL, A DEVRIES, D ATSMA
Journal: Cardiovascular Research (2005)

Objective: Myocardin is a recently discovered transcriptional regulator of cardiac and smooth muscle development. Its ability to transactivate smooth muscle-specific genes has been firmly established in animal cells but its effect on heart muscle genes has been investigated less extensively and the consequences of ectopic myocardin expression in human cells are unknown. Methods: In this study, primary human mesenchymal stem cells and foreskin fibroblasts were transduced with human adenovirus vectors expressing the longest splice variant of the human myocardin gene (hAd5/F50.CMV.myocL) or with control vectors. One week later, the expression of muscle-restricted genes in these cells was analyzed by reverse transcription-polymerase chain reactions and immunofluorescence microscopy. Results: Forced expression of myocardin induced transcription of cardiac and smooth muscle genes in both cell types but did not lead to activation of skeletal muscle-specific genes. Double labeling experiments using monoclonal antibodies directed against striated (i.e. sarcomeric α-actin and sarcomeric α-actinin) and cardiac (i.e. natriuretic peptide precursor A) muscle-specific proteins together with a polyclonal antiserum specific for smooth muscle myosin heavy chain revealed that hAd5/F50.CMV.myocL-transduced cells co-express heart and smooth muscle-specific genes. Conclusions: These data indicate that the myocardin protein is a strong inducer of both smooth and cardiac muscle genes, but that additional factors are necessary to fully commit cells to either cardiac or smooth muscle cell fates.
Vascular Effects of Estrogen and Vitamin E Therapies in Postmenopausal Women
Authors: Kwang Kon Koh, Arnon Blum, Londa Hathaway, Rita Mincemoyer, Gyorgy Csako, Myron A. Waclawiw, Julio A. Panza, Richard O. Cannon
Journal: Circulation (1999)

Background —Estrogen and vitamin E therapies have been suggested to reduce cardiovascular risk, but comparison of the vascular effects of these therapies to determine mechanisms of potential benefit has not been performed in postmenopausal women. Methods and Results —In a double-blind, 3-period crossover study, we randomly assigned 28 healthy postmenopausal women to conjugated equine estrogens (CE) 0.625 mg/d, vitamin E 800 IU/d, and their combination, with measurements made before and after each 6-week treatment period. The ratio of LDL to HDL cholesterol and lipoprotein(a) decreased on therapies including CE but increased on vitamin E alone ( P &lt;0.001 and P =0.002, respectively, by ANOVA). Brachial artery flow–mediated dilation improved on all therapies (all P &lt;0.001 versus pretreatment values) and to a similar degree ( P =0.267 by ANOVA). No therapy improved the dilator response to nitroglycerin. CE lowered serum levels of cell adhesion molecules E-selectin, ICAM-1, and VCAM-1 (all P &lt;0.05 versus pretreatment values). Vitamin E had no significant effect on levels of these markers of inflammation ( P &lt;0.001 by ANOVA for E-selectin). CE alone or combined with vitamin E but not vitamin E alone lowered or showed a trend for lowering plasma levels of plasminogen activator inhibitor type-1 ( P =0.069 by ANOVA). Conclusions —Estrogen and vitamin E therapies similarly improved arterial endothelium-dependent vasodilator responsiveness consistent with increased nitric oxide in healthy postmenopausal women, despite divergent effects on atherogenic lipoproteins. However, only estrogen reduced markers of vascular disease.