tbuckley/cabot-search huggingface dataset:
The Hepatocyte Protein Synthesis Defect Induced by Galactosamine Involves Hypomethylation of Ribosomal Rna
Authors: Gary A. Clawson, Julie Sesno, Kathy Milam, Yan-Fel Wang, Caroline Gabriel
Journal: Hepatology (1990)

d–galactosamine produces an early defect in protein synthesis, independent of its effects on RNA synthcsis. Here we show that the defect in protein synthesis is inherent in purified ribosomal subunits in vitro. Furthere, galactosamine treatment is associated with an 85% decrease in methylation of ribosomal RNA, involving all sites (2′–0–ronpse and base positions), intact ribosomes from galactosamine–treated animals can be methylated to a greater extent than control ribosomes and in vitro methylation restores their funtional capacity. Statistical analyes of these data, along with those with a number of other hepatotoxins, reveal a correlation coefficent of r = 0.95 (p &lt; 0.003) between protein synthetic capacity and ribosomal RNA methylaiton, and linear regression accounts for more than 90% of the observed variation. In contrast, no relationship was found between nucleolar RNA methylation and protein synthetic capacity. A relationship of borderline statistical significance was found between messenger RNA methylaiton and protein synthetic capacity, but it does not appear consistent with results obtained after CCI 4 intoxication. These results lend strong support ot the notion that methylation status of ribosomal RNA is an important control for protein synthesis in quiscent hepatocytes and that net hypomethylation is a common responses to such divergent hepatotoxins as CCI 4 , ethionine and d–galactosamine. (Hepatology 1990;11:428-434.)
Growth in utero and during childhood among women who develop coronary heart disease: longitudinal study
Authors: T Forsen, J G Eriksson, J Tuomilehto, C Osmond, D J P Barker
Journal: BMJ (1999)

<h3>Abstract</h3> <b>Objective:</b> To examine whether women who develop coronary heart disease have different patterns of fetal and childhood growth from men in the same cohort who develop the disease. <b>Design:</b> Follow up study of women whose body size at birth was recorded and who had an average of 10 measurements of height and weight during childhood. <b>Setting:</b> Helsinki, Finland. <b>Subjects:</b> 3447 women who were born in Helsinki University Central Hospital during 1924-33 and who went to school in Helsinki. <b>Main outcome measures:</b> Hazard ratios for hospital admission for or death from coronary heart disease. Results Coronary heart disease among women was associated with low birth weight (P=0.08 after adjustment for gestation, P=0.007 after adjustment for placental weight) and was more strongly associated with short body length at birth (P=0.001 and P&gt;0.0001, respectively). The hazard ratio for women developing coronary heart disease increased by 10.2% (95% confidence interval 4.3 to 15.7) for each cm decrease in length at birth. The effect of short length at birth was greatest in women whose height "caught up" after birth so that as girls they were tall. Such girls tended to have tall mothers. In contrast, men in the same cohort who developed the disease were thin at birth rather than short, showed "catch up" growth in weight rather than height, and their mothers tended to be overweight rather than tall. <b>Conclusions:</b> Coronary heart disease among both women and men reflects poor prenatal nutrition and consequent small body size at birth combined with improved postnatal nutrition and "catch up" growth in childhood. The disease is associated with reductions in those aspects of body proportions at birth that distinguish the two sexes—short body length in women and thinness in men. <h3>Key messages</h3> Coronary heart disease in women is associated with low birth weight but more strongly with short body length at birth Among men in the same cohort coronary heart disease is also associated with low birth weight but more strongly with thinness at birth In the whole cohort body proportions at birth differed in the two sexes: the girls were short and the boys were thin These differences may reflect intrinsic sex differences in rates of fetal growth at similar levels of maternal nutrition The slower fetal growth of females may underlie their lower rates of coronary heart disease
Gene Promoter Methylation in Prostate Tumor–Associated Stromal Cells
Authors: Jeffrey A. Hanson, John W. Gillespie, Amelia Grover, Michael A. Tangrea, Rodrigo F. Chuaqui, Michael R. Emmert-Buck, Joseph A. Tangrea, Stephen K. Libutti, W. Marston Linehan, Karen G. Woodson
Journal: JNCI Journal of the National Cancer Institute (2006)

Gene expression can be silenced through the methylation of specific sites in the promoter region. This mechanism of gene silencing has an important role in the carcinogenesis of prostate and other cancers. Although tumor-associated stromal cells also exhibit changes in gene expression, promoter methylation has not been described in these cells.Tumor epithelia, tumor-associated stroma and normal epithelia, and stroma adjacent to tumor tissues were isolated from whole-mount prostatectomy specimens (two per patient) of patients (n = 5) with localized prostate cancer and from normal epithelia and stroma from benign prostate hyperplasia specimens (two per patient) from men (n = 5) without prostate cancer by using laser capture microdissection or expression microdissection. The methylation status of three genes important in prostate carcinogenesis, GSTP1, RARbeta2, and CD44, were evaluated using quantitative methylation-sensitive polymerase chain reaction.GSTP1 and RARbeta2 were methylated in the tumor epithelium of all five prostate cancer patients and in the tumor-associated stroma in four of the five patients. CD44 was methylated in the tumor epithelium from four of the five patients but not in the tumor stroma. GSTP1 and RARbeta2 were methylated in normal epithelium of two and four patients, respectively, and in normal stroma of one and two patients, respectively, that were isolated from regions adjacent to the tumors and may have resulted from a tumor-field effect; CD44 methylation was not observed in normal epithelium or stroma. In contrast, normal epithelia and stroma from benign prostate hyperplasia specimens showed no promoter methylation in GSTP1, RARbeta2, or CD44.The observation of promoter methylation in the non-neoplastic cells of the prostate tumor microenvironment may advance our understanding of prostate cancer development and progression and lead to new diagnostic and prognostic markers and therapeutic targets.
Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer
Authors: Rodrigo Dienstmann, Amita Patnaik, Rocio Garcia-Carbonero, Andrés Cervantes, Marta Benavent, Susana Roselló, Bastiaan B.J. Tops, Rachel S. van der Post, Guillem Argilés, Niels J.Ø. Skartved, Ulla H. Hansen, Rikke Hald, Mikkel W. Pedersen, Michael Kragh, Ivan D. Horak, Stephan Braun, Eric Van Cutsem, Anthony W. Tolcher, Josep Tabernero
Journal: Cancer Discovery (2015)

Tumor growth in the context of EGFR inhibitor resistance may remain EGFR-dependent and is mediated by mechanisms including compensatory ligand upregulation and de novo gene alterations. Sym004 is a two-antibody mixture targeting nonoverlapping EGFR epitopes. In preclinical models, Sym004 causes significant EGFR internalization and degradation, which translates into superior growth inhibition in the presence of ligands. In this phase I trial, we observed grade 3 skin toxicity and hypomagnesemia as mechanism-based dose-limiting events during dose escalation. In dose-expansion cohorts of 9 and 12 mg/kg of Sym004 weekly, patients with metastatic colorectal cancer and acquired EGFR inhibitor resistance were enrolled; 17 of 39 patients (44%) had tumor shrinkage, with 5 patients (13%) achieving partial response. Pharmacodynamic studies confirmed marked Sym004-induced EGFR downmodulation. MET gene amplification emerged in 1 patient during Sym004 treatment, and a partial response was seen in a patient with EGFR(S492R) mutation that is predictive of cetuximab resistance.Potent EGFR downmodulation with Sym004 in patients with metastatic colorectal cancer and acquired resistance to cetuximab/panitumumab translates into significant antitumor activity and validates the preclinical hypothesis that a proportion of tumors remains dependent on EGFR signaling. Further clinical development and expanded correlative analyses of response patterns with secondary RAS/EGFR mutations are warranted.
Bedtime Dosing of Antihypertensive Medications Reduces Cardiovascular Risk in CKD
Authors: Ramón C. Hermida, Diana E. Ayala, Artemio Mojón, José R. Fernández
Journal: Journal of the American Society of Nephrology (2011)

Time of ingestion of hypertension medications can affect circadian patterns of BP, but whether this translates into an effect on clinical outcomes is unknown. Here, in an open-label trial, we randomly assigned 661 patients with CKD either to take all prescribed hypertension medications upon awakening or to take at least one of them at bedtime. We measured 48-hour ambulatory BP at baseline and 3 months after any adjustment in treatment or, at the least, annually. After a median follow-up of 5.4 years, patients who took at least one BP-lowering medication at bedtime had an adjusted risk for total cardiovascular events (a composite of death, myocardial infarction, angina pectoris, revascularization, heart failure, arterial occlusion of lower extremities, occlusion of the retinal artery, and stroke) that was approximately one-third that of patients who took all medications upon awakening (adjusted HR 0.31; 95% CI 0.21 to 0.46; P < 0.001). Bedtime dosing demonstrated a similar significant reduction in risk for a composite outcome of cardiovascular death, myocardial infarction, and stroke (adjusted HR 0.28; 95% CI 0.13 to 0.61; P < 0.001). Furthermore, patients on bedtime treatment had a significantly lower mean sleep-time BP and a greater proportion demonstrated control of their ambulatory BP (56% versus 45%, P = 0.003). Each 5-mmHg decrease in mean sleep-time systolic BP was associated with a 14% reduction in the risk for cardiovascular events during follow-up (P < 0.001). In conclusion, among patients with CKD and hypertension, taking at least one antihypertensive medication at bedtime improves control of BP and reduces the risk for cardiovascular events.
SURFACE TENSION OF THE BLOOD SERUM OF THE DOG AFTER UPPER GASTROINTESTINAL TRACT OBSTRUCTION
Authors: Russell L. Haden, Thomas G. Orr
Journal: The Journal of Experimental Medicine (1926)

After obstruction of the upper gastrointestinal tract the surface tension of the blood serum of the dog shows no marked change. There is a tendency of the time-drop to increase 24 hours after operation. There is no characteristic course of the time-drop.
Prospective Study of Serum Vitamin D and Cancer Mortality in the United States
Authors: D. M. Freedman, A. C. Looker, S.-C. Chang, B. I. Graubard
Journal: JNCI Journal of the National Cancer Institute (2007)

BackgroundVitamin D has been hypothesized to reduce cancer mortality through its effects on incidence and/or survival. Epidemiologic studies of the association of 25-hydroxyvitamin D [25(OH)D] and the risk of cancer, however, have been largely limited to incident cancers at a few sites.
Enhancing Citizen Engagement in Cancer Screening Through Deliberative Democracy
Authors: L. Rychetnik, S. M. Carter, J. Abelson, H. Thornton, A. Barratt, V. A. Entwistle, G. Mackenzie, G. Salkeld, P. Glasziou
Journal: JNCI Journal of the National Cancer Institute (2013)

Cancer screening is widely practiced and participation is promoted by various social, technical, and commercial drivers, but there are growing concerns about the emerging harms, risks, and costs of cancer screening. Deliberative democracy methods engage citizens in dialogue on substantial and complex problems: especially when evidence and values are important and people need time to understand and consider the relevant issues. Information derived from such deliberations can provide important guidance to cancer screening policies: citizens' values are made explicit, revealing what really matters to people and why. Policy makers can see what informed, rather than uninformed, citizens would decide on the provision of services and information on cancer screening. Caveats can be elicited to guide changes to existing policies and practices. Policies that take account of citizens' opinions through a deliberative democracy process can be considered more legitimate, justifiable, and feasible than those that don't.
Surgeons' and occupational health departments' awareness of guidelines on post-exposure prophylaxis for staff exposed to HIV: telephone survey
Authors: S E Duff, C K M Wong, R E May
Journal: BMJ (1999)

Surgeons face the occupational risk of parenteral transmission of infection, in particular with HIV, percutaneous exposure to which carries an estimated risk of transmission of 0.3%.1–3 This risk may be reduced by antiretroviral prophylactic treatment.4 The UK Department of Health issued guidelines on post-exposure prophylaxis in June 1997.5 We assessed whether the guidelines had been implemented and whether surgeons were aware of them in the South and West health region. We conducted a telephone survey of all the occupational health departments and on-duty general surgical and orthopaedic registrar grade surgical trainees in the South and West region. Separate sets of questions were used for occupational health departments and surgical trainees (box). #### Survey questions ##### To both groups
Dietary Fiber Intake and Risk of Colorectal Cancer
Authors: Yikyung Park, David J. Hunter, Donna Spiegelman, Leif Bergkvist, Franco Berrino, Piet A. van den Brandt, Julie E. Buring, Graham A. Colditz, Jo L. Freudenheim, Charles S. Fuchs, Edward Giovannucci, R. Alexandra Goldbohm, Saxon Graham, Lisa Harnack, Anne M. Hartman, David R. Jacobs, Ikuko Kato, Vittorio Krogh, Michael F. Leitzmann, Marjorie L. McCullough, Anthony B. Miller, Pirjo Pietinen, Thomas E. Rohan, Arthur Schatzkin, Walter C. Willett, Alicja Wolk, Anne Zeleniuch-Jacquotte, Shumin M. Zhang, Stephanie A. Smith-Warner
Journal: JAMA (2005)

Inconsistent findings from observational studies have continued the controversy over the effects of dietary fiber on colorectal cancer.To evaluate the association between dietary fiber intake and risk of colorectal cancer.From 13 prospective cohort studies included in the Pooling Project of Prospective Studies of Diet and Cancer, 725,628 men and women were followed up for 6 to 20 years across studies. Study- and sex-specific relative risks (RRs) were estimated with the Cox proportional hazards model and were subsequently pooled using a random-effects model.Incident colorectal cancer.During 6 to 20 years of follow-up across studies, 8081 colorectal cancer cases were identified. For comparison of the highest vs lowest study- and sex-specific quintile of dietary fiber intake, a significant inverse association was found in the age-adjusted model (pooled RR = 0.84; 95% confidence interval [CI], 0.77-0.92). However, the association was attenuated and no longer statistically significant after adjusting for other risk factors (pooled multivariate RR = 0.94; 95% CI, 0.86-1.03). In categorical analyses compared with dietary fiber intake of 10 to <15 g/d, the pooled multivariate RR was 1.18 (95% CI, 1.05-1.31) for less than 10 g/d (11% of the overall study population); and RR, 1.00 (95% CI, 0.85-1.17) for 30 or more g/d. Fiber intake from cereals, fruits, and vegetables was not associated with risk of colorectal cancer. The pooled multivariate RRs comparing the highest vs lowest study- and sex-specific quintile of dietary fiber intake were 1.00 (95% CI, 0.90-1.11) for colon cancer and 0.85 (95% CI, 0.72-1.01) for rectal cancer (P for common effects by tumor site = .07).In this large pooled analysis, dietary fiber intake was inversely associated with risk of colorectal cancer in age-adjusted analyses. However, after accounting for other dietary risk factors, high dietary fiber intake was not associated with a reduced risk of colorectal cancer.
Genetic variation in the GDF5 region is associated with osteoarthritis, height, hip axis length and fracture risk: the Rotterdam study
Authors: R B A Vaes, F Rivadeneira, J M Kerkhof, A Hofman, H A P Pols, A G Uitterlinden, J B J van Meurs
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Background:</h3> A polymorphism (rs143383; T to C) near the <i>GDF5</i> gene has been associated with height and osteoarthritis (OA), but debate exists about whether its primary biological action is directed to cartilage or bone. <h3>Objective:</h3> To study the association between genetic variation in the <i>GDF5</i> region and radiographic osteoarthritis (ROA) susceptibility, height, bone size parameters and fracture risk in a large population-based cohort of Caucasian elderly subjects. <h3>Methods:</h3> 6365 men and women had genotype data available. ROA was defined as a Kellgren/Lawrence (K/L) score ⩾2 for hand, knee and hip joints. CTX-II levels, height, bone mineral density (BMD), bone size and fracture risk were also assessed. <h3>Results:</h3> rs143383 and three highly correlated single nucleotide polymorphisms (SNPs) in the <i>GDF5</i> region were found to be independently associated with OA, height, bone size and fracture risk in women. Women with homozygotes for the rs143383 C allele had a 37% lower risk for hand OA (p = 8×10<sup>−6</sup>) and a 28% lower risk for knee OA (p = 0.003). In addition, they were 1.1 cm taller (p = 0.001), had a larger hip axis length (HAL) (p = 4×10<sup>−4</sup>) and had a 29% increased risk of incident non-vertebral fractures (p = 0.02). No associations with hip OA or BMD were detected. No associations were found in men. <h3>Conclusion:</h3> This population-based study shows that <i>GDF5</i> gene variants are associated with hand OA, knee OA and fracture risk in elderly women. It also replicates previous association between <i>GDF5</i> variation and height. Furthermore, our findings for HAL suggest that <i>GDF5</i> action is primarily directed to the long bones, rather than the axial skeleton.
Gefitinib Reverses TRAIL Resistance in Human Bladder Cancer Cell Lines via Inhibition of AKT-Mediated X-Linked Inhibitor of Apoptosis Protein Expression
Authors: Marissa Shrader, Maria Simona Pino, Laura Lashinger, Menashe Bar-Eli, Liana Adam, Colin P.N. Dinney, David J. McConkey
Journal: Cancer Research (2007)

Abstract In a previous study, we found that the small-molecule epidermal growth factor receptor (EGFR) inhibitor gefitinib (ZD1839, Iressa) blocked cell proliferation at biologically relevant concentrations in approximately one third (6 of 17) of human bladder cancer cell lines examined. Here, we studied the effects of gefitinib on apoptosis in a representative subset of the same panel of cells. The drug had modest effects on DNA fragmentation as a single agent at concentrations that produced strong growth inhibition (≤1 μmol/L) and also failed to promote apoptosis induced by conventional chemotherapeutic agents (gemcitabine and paclitaxel). However, gefitinib did interact with recombinant human tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) to induce high levels of apoptosis in gefitinib-responsive but not gefitinib-unresponsive lines. The molecular mechanisms involved down-regulation of active AKT and X-linked inhibitor of apoptosis protein (XIAP) expression and were mimicked by chemical inhibitors of the phosphatidylinositol 3-kinase/AKT pathway but not of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase/ERK pathway. Furthermore, direct small interfering RNA–mediated knockdown of AKT resulted in down-regulation of XIAP and TRAIL sensitization, and knockdown of XIAP itself was sufficient to reverse TRAIL resistance. Together, our results show that EGFR pathway activation limits TRAIL-induced apoptosis via an AKT- and XIAP-dependent mechanism in EGFR-dependent human bladder cancer cells, providing the conceptual framework for a further evaluation of the combination in relevant preclinical in vivo models. [Cancer Res 2007;67(4):1430–5]
IL-1R–MyD88 signaling in keratinocyte transformation and carcinogenesis
Authors: Christophe Cataisson, Rosalba Salcedo, Shakeeb Hakim, B. Andrea Moffitt, Lisa Wright, Ming Yi, Robert Stephens, Ren-Ming Dai, Lyudmila Lyakh, Dominik Schenten, H. Stuart Yuspa, Giorgio Trinchieri
Journal: The Journal of Experimental Medicine (2012)

Constitutively active RAS plays a central role in the development of human cancer and is sufficient to induce tumors in two-stage skin carcinogenesis. RAS-mediated tumor formation is commonly associated with up-regulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. In this study, we report that mice lacking IL-1R or MyD88 are less sensitive to topical skin carcinogenesis than their respective wild-type (WT) controls. MyD88−/− or IL-1R−/− keratinocytes expressing oncogenic RAS are hyperproliferative and fail to up-regulate proinflammatory genes or down-regulate differentiation markers characteristic of RAS-expressing WT keratinocytes. Although RAS-expressing MyD88−/− keratinocytes form only a few small tumors in orthotopic grafts, IL-1R–deficient RAS-expressing keratinocytes retain the ability to form tumors in orthotopic grafts. Using both genetic and pharmacological approaches, we find that the differentiation and proinflammatory effects of oncogenic RAS in keratinocytes require the establishment of an autocrine loop through IL-1α, IL-1R, and MyD88 leading to phosphorylation of IκBα and NF-κB activation. Blocking IL-1α–mediated NF-κB activation in RAS-expressing WT keratinocytes reverses the differentiation defect and inhibits proinflammatory gene expression. Collectively, these results demonstrate that MyD88 exerts a cell-intrinsic function in RAS-mediated transformation of keratinocytes.
Anti-vitronectin antibodies enhance anti-Thy-1-induced proteinuria in PVG/c, but not in Wistar rats.
Authors: M G Van Dixhoorn, D Salazar-Exaire, T Sato, M R Daha, R J Quigg, J A Bruijn, W G Couser, E De Heer
Journal: Journal of the American Society of Nephrology (1998)

Injection of rats with mouse monoclonal IgG2a anti-Thy1.1 antibodies (ER4G) results in rapid development of proteinuria in Wistar rats, reaching average values of 160 mg/24 h on day 3 after antibody administration. In contrast, no overt proteinuria was observed in PVG/c+ rats (maximum, 40 mg/24 h on day 3). This study investigates whether differences in the inactivation of C5b-9 complexes in the glomerulus by complement inhibitors are responsible for the differences in proteinuria between the two rat strains. Regardless of the presence of proteinuria, an increased expression of Crry by mesangial cells (MC) was observed within 24 h after injection of ER4G in both Wistar and PVG/c+ rats. Double-label immunofluorescence using goat anti-mouse Ig antibodies demonstrated an expression of Crry exclusively on MC. Furthermore, Crry colocalized with C5b-9 complexes on MC, as detected by a monoclonal antibody against the rat C5b-9 neo-antigen. In PVG/c+ rats, C5b-9 complexes persisted in the mesangial area for at least 7 d and colocalized immediately (within 1 h) and homogeneously with vitronectin. However, in proteinuric Wistar rats, C5b-9 complexes disappeared from the glomerular mesangium within 6 d. In these rats, mesangial colocalization of C5b-9 with vitronectin could only occasionally be detected. Pretreatment of PVG/c+ rats with antibodies against vitronectin, followed by administration of ER4G, resulted in the immediate development of proteinuria (maximum, 119 mg/24 h on day 3; P < 0.05), whereas Wistar rats did not become more proteinuric. This study provides evidence that differences in susceptibility of PVG/c+ and Wistar rats to complement-mediated damage of the glomerulus may be related to the degree of inactivation of C5b-9 complexes by complement regulatory factors.