tbuckley/cabot-search huggingface dataset:
Abstract 4088: Methylselenic acid inhibits the soluble and cell-surface bound NKG2D-ligand ULBP2 in melanoma
Authors: Franziska K. Uhlenbrock, Michael Hagemann Jensen, Stephanie Kehlet, Lars Andresen, Søren Skov
Journal: Cancer Research (2014)

Abstract The secretion of the soluble NKG2D-ligand ULBP2 is a marker for poor prognosis in several types of cancer. NKG2D-ligands are normally directed to the cell surface of stressed, inflamed or pre-cancer cells and serve as targets for immune effector cells expressing the NKG2D receptor. The soluble NKG2D-ligands are devastating due to their chronic activation and thereby desensitization of NKG2D expressing immune effector cells. In fact this leads to severely compromised immune activation governing cancer development. The present study describes that methylselenic acid (MSA) is able to inhibit soluble ULBP2 in different primary melanoma cell lines. Moreover, MSA actively suppressed ULBP2 both from constitutively expressing tumors and after induction by HDAC-inhibitors. In the attempt to elucidate the mechanism of inhibition, real-time qPCR experiments were performed. MSA activated the promoter and the transcription of the ULBP2 gene at a level similar to HDAC-inhibitors. These findings strongly indicate that ULBP2 is post-transcriptional regulated. Selective blocking of ULBP2 from melanomas or other cancers that produces soluble immune suppressive ULBP2 is thus a new treatment strategy that also has the potential to be used in combination with existing treatment regimens. Citation Format: Franziska K. Uhlenbrock, Michael Hagemann Jensen, Stephanie Kehlet, Lars Andresen, Søren Skov. Methylselenic acid inhibits the soluble and cell-surface bound NKG2D-ligand ULBP2 in melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4088. doi:10.1158/1538-7445.AM2014-4088
Registration of drugs for treating cancer and HIV infection: a plea to carry out phase 3 trials before admission to the market
Authors: P P Koopmans
Journal: BMJ (1995)

Drugs for cancer and HIV infection tend to be admitted to the market on the basis of results from phase 2 trials. Assessing the benefit-risk balance with phase 2 trials often is difficult--the effect of the drug is usually temporary; the correlation between response or improvement of clinical measurements and the patient's wellbeing is often poor; and the side effects of drugs for these fatal diseases are serious. Therefore, although sometimes difficult to conduct, comparative trials that use standard treatment, placebos, or best supportive care remain the cornerstone for reliably assessing the benefit-risk balance.
Oestradiol ameliorates monocrotaline pulmonary hypertension<i>via</i>NO, prostacyclin and endothelin-1 pathways
Authors: Ping Yuan, Wen-Hui Wu, Lan Gao, Ze-Qi Zheng, Dong Liu, Han-Ying Mei, Zhuo-Li Zhang, Zhi-Cheng Jing
Journal: European Respiratory Journal (2012)

Pulmonary hypertension continues to be a serious clinical problem with high mortality. As oestrogen is a potential vasodilator of the pulmonary circulation, this study examined the mechanisms by which 17β-oestradiol improves monocrotaline (MCT)-induced pulmonary hypertension. Female Sprague–Dawley rats underwent bilateral ovariectomy or sham operations. The rats received MCT (50 mg·kg −1 ) and were treated with 17β-oestradiol (1 mg·kg −1 per day) for either 5 weeks or only from week 4 to week 5. Plasma 17β-oestradiol concentrations were decreased in sham-operated, MCT-treated rats when compared with sham-operated rats (17.7±4.7 versus 50.3±15.4 pg·mL −1 ; p=0.029). The 17β-oestradiol anabolic enzyme cytochrome P450 (CYP)-19 was decreased by MCT treatment, while the catabolic enzymes CYP-1A1 and -1B1 were increased. Ovariectomised and MCT-treated rats had more severe pulmonary hypertension. 17β-oestradiol suppressed pulmonary arterial smooth muscle cell proliferation and macrophage infiltration, and enhanced apoptosis by increasing nitric oxide (NO) and prostacyclin (prostaglandin (PG)I 2 ) levels and reducing endothelin (ET)-1 levels. Phosphoinositide-3-kinase (PI3K) and Akt phosphorylations were markedly increased, but were inhibited by 17β-oestradiol treatment in rats with pulmonary hypertension. Oestrogen deficiency may aggravate development of pulmonary hypertension. 17β-oestradiol improved pulmonary hypertension via activation of the PI3K/Akt pathway to regulate NO, PGI 2 and ET-1 expression.
Improved Survival in Metastatic Colorectal Cancer Is Associated With Adoption of Hepatic Resection and Improved Chemotherapy
Authors: Scott Kopetz, George J. Chang, Michael J. Overman, Cathy Eng, Daniel J. Sargent, David W. Larson, Axel Grothey, Jean-Nicolas Vauthey, David M. Nagorney, Robert R. McWilliams
Journal: Journal of Clinical Oncology (2009)

Purpose Fluorouracil/leucovorin as the sole therapy for metastatic colorectal cancer (CRC) provides an overall survival of 8 to 12 months. With an increase in surgical resections of metastatic disease and development of new chemotherapies, indirect evidence suggests that outcomes for patients are improving in the general population, although the incremental gain has not yet been quantified. Methods We performed a retrospective review of patients newly diagnosed with metastatic CRC treated at two academic centers from 1990 through 2006. Landmark analysis evaluated the association of diagnosis year and liver resection with overall survival. Additional survival analysis of the Surveillance Epidemiology and End Results (SEER) database evaluated a similar population from 1990 through 2005. Results Two thousand four hundred seventy patients with metastatic CRC at diagnosis received their primary treatment at the two institutions during this time period. Median overall survival for those patients diagnosed from 1990 to 1997 was 14.2 months, which increased to 18.0, 18.6, and 29.3 months for patients diagnosed in 1998 to 2000, 2001 to 2003, and 2004 to 2006, respectively. Likewise, 5-year overall survival increased from 9.1% in the earliest time period to 19.2% in 2001 to 2003. Improved outcomes from 1998 to 2004 were a result of an increase in hepatic resection, which was performed in 20% of the patients. Improvements from 2004 to 2006 were temporally associated with increased utilization of new chemotherapeutics. In the SEER registry, overall survival for the 49,459 identified patients also increased in the most recent time period. Conclusion Profound improvements in outcome in metastatic CRC seem to be associated with the sequential increase in the use of hepatic resection in selected patients (1998 to 2006) and advancements in medical therapy (2004 to 2006).
Sphingosine-1-phosphate and modulation of vascular tone
Authors: Junsuke Igarashi, Thomas Michel
Journal: Cardiovascular Research (2009)

Sphingosine-1-phosphate (S1P) is a phosphorylated product of sphingosine, the core structure of the class of lipids termed sphingolipids. S1P is a naturally occurring lipid metabolite, and usually is present at a concentration of a few 100 nanomolar in human sera. S1P has been found to exert a diverse set of physiological and pathophysiological responses in mammalian tissues through the activation of heterotrimeric G-proteins that in turn modulate the activity of various downstream effecter molecules. In blood vessels, vascular endothelial cells and smooth muscle cells express specific receptors for S1P that modulate vascular tone. This article will provide a brief overview of S1P metabolism in the vasculature and will discuss some of the pathways whereby S1P regulates intracellular signal transduction pathways in endothelial and smooth muscle cells, leading to the activation of both vasorelaxation and vasoconstriction responses.
Juvenile xanthogranulomas with inconspicuous or absent foam cells and giant cells
Authors: Philip E. Shapiro, David N. Silvers, Ruth K. Treiber, Philip H. Cooper, Lawrence D. True, Raffaele Lattes
Journal: Journal of the American Academy of Dermatology (1991)

We report 17 cases of juvenile xanthogranuloma in which foam cells and Touton giant cells are absent or inconspicuous and mitoses may be numerous. We report 17 cases of juvenile xanthogranuloma in which foam cells and Touton giant cells are absent or inconspicuous and mitoses may be numerous.
Rapid changes in the prevalence of obesity and known diabetes in an adult Norwegian population. The Nord-Trøndelag Health Surveys: 1984-1986 and 1995-1997.
Authors: K Midthjell, O Krüger, J Holmen, A Tverdal, T Claudi, A Bjørndal, P Magnus
Journal: Diabetes Care (1999)

OBJECTIVE: To determine whether changes in mean BMI and the prevalence of obesity in a total adult population during a short (11-year) period were associated with changes in the prevalence of diabetes. RESEARCH DESIGN AND METHODS: This study involved cross-sectional surveys of all inhabitants aged &amp;gt; or = 20 years of the county of Nord-Trøndelag from 1984 to 1986 (n = 85,100) and from 1995 to 1997 (n = 92,434). Attendance rates were 88.1 and 71.3%, respectively, and 90.0% in an additional survey of people aged 13-19 years from 1995 to 1997 (n = 9,593). Main outcome measures were age-specific mean BMI for the diabetic and nondiabetic subgroups and the prevalence of obesity and diabetes. For comparison, mean BMIs from 18 of 19 Norwegian counties for the group aged 40-42 years were examined. RESULTS: Mean BMI increased from 27.2 to 29.0 kg/m2 in the diabetic population and from 25.1 to 26.3 kg/m2 in the nondiabetic population. The BMI distribution curve shifted to the right, but homogeneity was also reduced. A comparison with other Norwegian counties indicated that this increase occurred during the last 6 years between the surveys. The prevalence of obesity (BMI &amp;gt; or = 30 kg/m2) increased from 7.5 to 14% in nondiabetic men and from 13 to 18% in nondiabetic women. The increase was particularly great in men aged &amp;lt; 60 years and in women aged &amp;lt; 50 years. The overall prevalence of known diabetes increased between the two surveys (from 2.9 to 3.2%) but only in men. The largest increase was observed in the corresponding younger sex and age-groups. CONCLUSIONS: A substantial increase in mean BMI and the prevalence of obesity occurred in the younger age-groups at the same time as an increase in the prevalence of diabetes. A greater increase in diabetes prevalence in this ethnically stable Western European population may follow if effective primary preventive strategies are not undertaken.
Predictive value for progression to tuberculosis by IGRA and TST in immigrant contacts
Authors: S. V. Kik, W. P. J. Franken, M. Mensen, F. G. J. Cobelens, M. Kamphorst, S. M. Arend, C. Erkens, A. Gebhard, M. W. Borgdorff, S. Verver
Journal: European Respiratory Journal (2009)

The authors determined the positive predictive value (PPV) for progression to tuberculosis (TB) of two interferon-γ release assays (IGRAs), QuantiFERON-TB® Gold In-tube (QFT-GIT) and T-SPOT. TB ®, and the tuberculin skin test (TST) in immigrants contacts. Immigrant close contacts of sputum smear-positive TB patients were included when aged ≥16 yrs and their TST result was ≥5 mm 0 or 3 months after diagnosis of the index patient. Contacts were followed for the next 2 yrs for development of TB disease. Of 339 immigrant contacts with TST ≥5 mm, 324 and 299 had valid results of QFT-GIT and T-SPOT. TB ®, respectively. Nine contacts developed active TB. One patient had not been tested with TST, while another patient had not been tested with QFT-GIT and T-SPOT. TB ®. The PPV for progression to TB during this period was 9/288 = 3.1% (95% CI 1.3–5.0%) for TST ≥10 mm, 7/184 = 3.8% (95% CI 1.7–5.9%) for TST ≥15 mm, 5/178 = 2.8% (95% CI 1.0–4.6%) for QFT-GIT and 6/181 = 3.3% (95% CI 1.3–5.3%) for T-SPOT. TB ®. Sensitivity was 100%, 88%, 63% and 75%, respectively. The predictive values of QFT-GIT, T-SPOT. TB ® and TST for progression to TB disease among immigrant close contacts were comparable.
Vitamin D Supplementation and the Effects on Glucose Metabolism During Pregnancy: A Randomized Controlled Trial
Authors: Constance Yap, N. Wah Cheung, Jenny E. Gunton, Neil Athayde, Craig F. Munns, Anna Duke, Mark McLean
Journal: Diabetes Care (2014)

Vitamin D deficiency in pregnancy is associated with an increased risk of gestational diabetes mellitus (GDM) and neonatal vitamin D deficiency. We conducted a double-blind, randomized controlled trial of low-dose (LD) versus high-dose (HD) vitamin D supplementation to investigate the effects of vitamin D supplementation on glucose metabolism during pregnancy.Women with plasma 25-hydroxyvitamin D (25OHD) levels <32 ng/mL before 20 weeks' gestation were randomized to oral vitamin D3 at 5,000 IU daily (HD) (n = 89) or the recommended pregnancy dose of 400 IU daily (LD) (n = 90) until delivery. The primary end point was maternal glucose levels on oral glucose tolerance test (OGTT) at 26-28 weeks' gestation. Secondary end points included neonatal 25OHD, obstetric and other neonatal outcomes, and maternal homeostasis model assessment of insulin resistance. Analysis was by intention to treat.There was no difference in maternal glucose levels on OGTT. Twelve LD women (13%) developed GDM versus seven (8%) HD women (P = 0.25). Neonatal cord 25OHD was higher in HD offspring (46 ± 11 vs. 29 ± 12 ng/mL, P < 0.001), and deficiency was more common in LD offspring (24 vs. 10%, P = 0.06). Post hoc analysis in LD women showed an inverse relationship between pretreatment 25OHD and both fasting and 2-h blood glucose level on OGTT (both P < 0.001). Baseline 25OHD remained an independent predictor after multiple regression analysis.HD vitamin D supplementation commencing at a mean of 14 weeks' gestation does not improve glucose levels in pregnancy. However, in women with baseline levels <32 ng/mL, 5,000 IU per day was well tolerated and highly effective at preventing neonatal vitamin D deficiency.
Stage classification and prognosis: an intersection of medicine, quantum physics and religion?
Authors: F. C. Detterbeck
Journal: Thorax (2011)

Estimating prognosis is an important part of caring for patients with cancer. However, predicting prognosis is complicated and depends on many factors. Simply amassing more data alone is not the answer; we have to learn to intellectually manage the inherent complexity and uncertainty if we are to make progress.
MicroRNA-223 regulates Glut4 expression and cardiomyocyte glucose metabolism
Authors: Han Lu, Rachel J. Buchan, Stuart A. Cook
Journal: Cardiovascular Research (2010)

MicroRNAs (miRNAs) are important for cardiac function and tissue metabolism. The aim of the present study is to investigate the role(s) of miRNAs in the insulin-resistant heart. Left ventricular biopsies were collected from patients with or without type 2 diabetes and from patients with left ventricular dysfunction. Quantitative miRNA expression analyses of 155 miRNAs revealed that miR-223 was consistently upregulated in the insulin-resistant heart. We assessed the effects of miR-223 on glucose metabolism in neonatal rat cardiomyocytes where adenoviral-mediated overexpression of miR-223 increased glucose uptake. Using in silico miRNA target prediction programs, we prioritized candidate miR-223 target genes, but observed no effect of miR-223 on myocyte enhancer factor 2c or insulin-like growth factor 1 receptor, and an unexpected miR-223-induced increase in nuclear factor IA. We next examined the effects of miR-223 on insulin signalling and glucose transport proteins. Neither phosphoinositide 3-kinase (PI3K) signalling nor AMP kinase activity was affected by miR-223 overexpression, whereas glucose transporter 4 (Glut4) protein expression was increased. miR-223 overexpression-induced Glut4 protein expression in cardiomyocytes was necessary and sufficient for increased glucose uptake as demonstrated by siRNA knockdown of Glut4. Loss-of-function studies in vivo, using a synthetic miR-223 inhibitor, confirmed the effect of miR-223 on Glut4. These data demonstrate a role for miR-223 in Glut4 regulation and glucose metabolism in the heart, reveal the pleiotropic effects of miRNAs across tissues, and show that miRNAs can upregulate target genes in terminally differentiated cardiomyocytes.
Lower-Extremity Amputation in People With Diabetes: Epidemiology and Prevention
Authors: Diane E Bild, Joseph V Selby, Pomeroy Sinnock, Warren S Browner, Paula Braveman, Jonathon A Showstack
Journal: Diabetes Care (1989)

The age-adjusted rate of lower-extremity amputation (LEA) in the diabetic population is ∼15 times that of the nondiabetic population. Over 50,000 LEAs were performed on individuals with diabetes in the United States in 1985. Among individuals with diabetes, peripheral neuropathy and peripheral vascular disease (PVD) are major predisposing factors for LEA. Lack of adequate foot care and infection are additional risk factors. Several large clinical centers have experienced a 44–85% reduction in the rate of amputations among individuals with diabetes after the implementation of improved foot-careprograms. Programs to reduce amputations among people with diabetes in primarycare settings should identify those at high risk; clinically evaluate individuals to determine specific risk status; ensure appropriate preventive therapy, treatment for foot problems, and follow-up; provide patient education;and, when necessary, refer patients to specialists, including health-care professionals for diagnostic and therapeutic interventions and shoe fitters for proper footwear. Programs should monitor and evaluate their activities andoutcomes. Many issues related to the etiology and prevention of LEAs requirefurther research.
Validation of a predictive rule for the management of community-acquired pneumonia
Authors: A. Capelastegui, P. P. España, J. M. Quintana, I. Areitio, I. Gorordo, M. Egurrola, A. Bilbao
Journal: European Respiratory Journal (2005)

The CURB-65 score (Confusion, Urea &gt;7 mmol·L −1 , Respiratory rate ≥30·min −1 , low Blood pressure, and age ≥65 yrs) has been proposed as a tool for augmenting clinical judgement for stratifying patients with community-acquired pneumonia (CAP) into different management groups. The six-point CURB-65 score was retrospectively applied in a prospective, consecutive cohort of adult patients with a diagnosis of CAP seen in the emergency department of a 400-bed teaching hospital from March 1, 2000 to February 29, 2004. A total of 1,100 inpatients and 676 outpatients were included. The 30-day mortality rate in the entire cohort increased directly with increasing CURB-65 score: 0, 1.1, 7.6, 21, 41.9 and 60% for CURB-65 scores of 0, 1, 2, 3, 4, and 5, respectively. The score was also significantly associated with the need for mechanical ventilation and rate of hospital admission in the entire cohort, and with duration of hospital stay among inpatients. The CURB-65 score (Confusion, Urea &gt;7 mmol·L −1 , Respiratory rate ≥30·min −1 , low Blood pressure, and age ≥65 yrs), and a simpler CRB-65 score that omits the blood urea measurement, helps classify patients with community-acquired pneumonia into different groups according to the mortality risk and significantly correlates with community-acquired pneumonia management key points. The new score can also be used as a severity adjustment measure.
Abnormal stimulation of the thyrotrophin receptor during gestation
Authors: P. Rodien
Journal: Human Reproduction Update (2004)

Pregnancy induces physiological alterations in thyroid function which may make difficult the interpretation of results of thyroid hormone measurement. A state of hyperstimulation of the thyroid gland is common in early pregnancy. In a few cases, thyroid hormone values will deviate from the normal range, which corresponds to the gestational transient thyrotoxicosis. This syndrome is closely associated with hyperemesis gravidarum. The relationship between the two syndromes, demonstrated by epidemiological studies, has been illustrated by an exceptional case of familial recurrent gestational thyrotoxicosis presenting as hyperemesis gravidarum due to hypersensitivity of the thyrotrophin receptor to hCG. However, the exact mechanisms of hyperemesis gravidarum have not yet been identified. Gestational transient thyrotoxicosis has to be distinguished from Graves' disease, because the latter is associated with potential maternal and fetal complications when thyrotoxicosis is not controlled, whereas the former has usually a favourable outcome. The existence of other cases of thyroid hypersensitivity or hCG endowed with abnormal thyrotrophic activity is suspected. They may be identified only by assessment of the thyroid function in cases of hyperemesis gravidarum. The identification of these cases would be helpful to understand the mechanisms of specificity of glycoprotein hormone receptors.
Antecedent Hyperglycemia Is Associated With an Increased Risk of Neutropenic Infections During Bone Marrow Transplantation
Authors: Rachel L. Derr, Victoria C. Hsiao, Christopher D. Saudek
Journal: Diabetes Care (2008)

To use bone marrow transplantation (BMT) as a model for testing the association between hyperglycemia and infection.This cohort study included 382 adults (6.5% with diabetes) who had no evidence of infection before neutropenia during BMT. Mean glucose was calculated from central laboratory and bedside measurements taken before neutropenia; the primary outcome was neutropenic infections.Eighty-four patients (22%) developed at least one neutropenic infection, including 51 patients (13%) with bloodstream infections. In patients who did not receive glucocorticoids during neutropenia, each 10 mg/dl increase in mean preneutropenia glucose was associated with an odds ratio of 1.08 (95% CI 0.98-1.19) (P = 0.14) for any infection and 1.15 (1.03-1.28) (P = 0.01) for bloodstream infections, after adjusting for age, sex, race, year, cancer diagnosis, transplant type, and total glucocorticoid dose before neutropenia. In those who received glucocorticoids during neutropenia (n = 71), the adjusted odds ratio associated with a 10 mg/dl increase in mean glucose was 1.21 (1.09-1.34) (P < 0.0001) for any infection and 1.24 (1.11-1.38) (P < 0.0001) for bloodstream infections. There was no association between mean glycemia and long length of hospital stay, critical status designation, or mortality.In a BMT population highly susceptible to infection, there was a continuous positive association between mean antecedent glycemia and later infection risk, particularly in patients who received glucocorticoids while neutropenic. Tight glycemic control during BMT and glucocorticoid treatment may reduce infections.