tbuckley/cabot-search huggingface dataset:
<b>Diethylstilbestrol (DES)-Stimulated Hormonal Toxicity is Mediated by ER</b> α <b> Alteration of Target Gene Methylation Patterns and Epigenetic Modifiers ( <i>DNMT3A</i> , <i>MBD2</i> , and <i>HDAC2</i> ) in the Mouse Seminal Vesicle </b>
Authors: Yin Li, Katherine J. Hamilton, Anne Y. Lai, Katherine A. Burns, Leping Li, Paul A. Wade, Kenneth S. Korach
Journal: Environmental Health Perspectives (2013)

Background: Diethylstilbestrol (DES) is a synthetic estrogen associated with adverse effects on reproductive organs. DES-induced toxicity of the mouse seminal vesicle (SV) is mediated by estrogen receptor α (ERα), which alters expression of seminal vesicle secretory protein IV (Svs4) and lactoferrin (Ltf) genes.Objectives: We examined a role for nuclear receptor activity in association with DNA methylation and altered gene expression.Methods: We used the neonatal DES exposure mouse model to examine DNA methylation patterns via bisulfite conversion sequencing in SVs of wild-type (WT) and ERα-knockout (αERKO) mice.Results: The DNA methylation status at four specific CpGs (–160, –237, –306, and –367) in the Svs4 gene promoter changed during mouse development from methylated to unmethylated, and DES prevented this change at 10 weeks of age in WT SV. At two specific CpGs (–449 and –459) of the Ltf gene promoter, DES altered the methylation status from methylated to unmethylated. Alterations in DNA methylation of Svs4 and Ltf were not observed in αERKO SVs, suggesting that changes of methylation status at these CpGs are ERα dependent. The methylation status was associated with the level of gene expression. In addition, gene expression of three epigenetic modifiers—DNMT3A, MBD2, and HDAC2—increased in the SV of DES-exposed WT mice.Conclusion: DES-induced hormonal toxicity resulted from altered gene expression of Svs4 and Ltf associated with changes in DNA methylation that were mediated by ERα. Alterations in gene expression of DNMT3A, MBD2, and HDAC2 in DES-exposed male mice may be involved in mediating the changes in methylation status in the SV.Citation: Li Y, Hamilton KJ, Lai AY, Burns KA, Li L, Wade PA, Korach KS. 2014. Diethylstilbestrol (DES)-stimulated hormonal toxicity is mediated by ERα alteration of target gene methylation patterns and epigenetic modifiers (DNMT3A, MBD2, and HDAC2) in the mouse seminal vesicle. Environ Health Perspect 122:262–268; http://dx.doi.org/10.1289/ehp.1307351
Marker molecules of human endometrial differentiation can be hormonally regulated under in-vitro conditions as in-vivo
Authors: I Classen-Linke
Journal: Human Reproduction Update (1998)

An established cell culture system of isolated human endometrial stromal and epithelial cells has been used to study the effects of oestrogen and progesterone, as well as their antagonists, upon endometrial cells. Normal hormonal regulation in vivo was investigated simultaneously in endometrial tissue samples taken at different phases of the menstrual cycle. Several marker molecules analysed by immunohistochemistry appeared to depend strongly on endocrine regulation and could be traced in culture. Immunohistochemically, basic parameters of cell biology were identified in vitro, e.g. cell proliferation (Ki-67), adhesion molecules (β3 integrin) and paracrine factors (leukaemia inhibitory factor). The most reliable parameters to assess hormonal influences were oestrogen and progesterone receptor molecules. Immunohistochemical localization could be improved by molecular biological analysis using RT-PCR. In the presence of oestrogen, a significant expression of hormone receptors was also shown by RT-PCR, and withdrawal of oestrogens and addition of gestagen, i.e. medroxyprogesterone acetate, caused receptor downregulation. Addition of the anti-oestrogen ICI 182.780 to cell-culture medium significantly decreased the synthesis of progesterone receptors. Keywords:endometrial cell culture/marker molecules/oestradiol/oestradiol antagonist/progestin
Killing of Resistant Cancer Cells with Low Bak by a Combination of an Antimesothelin Immunotoxin and a TRAIL Receptor 2 Agonist Antibody
Authors: Xing Du, Laiman Xiang, Crystal Mackall, Ira Pastan
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Many solid tumors express cell surface mesothelin making them attractive targets for antibody-based therapies of cancer. SS1P [antimesothelin(Fv)PE38] is a recombinant immunotoxin (RIT) that has potent cytotoxic activity on several cancer cell lines and clinical activity in mesothelioma patients. Pancreatic cancers express mesothelin and are known to be resistant to most chemotherapeutic agents. The goal of this study is to treat pancreatic cancer with RIT by targeting mesothelin. Experimental Design: We measured the cytotoxic activity of an antimesothelin immunotoxin on pancreatic cancer cells. We also measured the levels of several pro- and antiapoptotic proteins, as well as the ability of TNF-related apoptosis-inducing ligand (TRAIL) or the anti-TRAIL receptor 2 agonist antibody (HGS-ETR2) to kill pancreatic cells, and the cytotoxic activity of the two agents together in cell culture and against tumors in mice. Results: In two pancreatic cancer cell lines, immunotoxin treatment inhibited protein synthesis but did not produce significant cell death. The resistant lines had low levels of the proapoptotic protein Bak. Increasing Bak expression enhanced the sensitivity to immunotoxins, whereas Bak knockdown diminished it. We also found that combining immunotoxin with TRAIL or HGS-ETR2 caused synergistic cell death, and together triggered caspase-8 recruitment and activation, Bid cleavage and Bax activation. Combining SS1P with HGS-ETR2 also acted synergistically to decrease tumor burden in a mouse model. Conclusion: Our data show that low Bak can cause cancer cells to be resistant to immunotoxin treatment and that combining immunotoxin with TRAIL or a TRAIL agonist antibody can overcome resistance. Clin Cancer Res; 17(18); 5926–34. ©2011 AACR.
Antitumor effects of hydrogen peroxide in vivo
Authors: CF Nathan, ZA Cohn
Journal: The Journal of Experimental Medicine (1981)

Glucose oxidase, covalently coupled to polystyrene microspheres (GOL), produced H(2)0(2) at an average rate of 3.6 nmol/min per 10(9) beads under standard assay conditions. Injection of 1.3 × 10(10) to 1.1 × 10(11) GOL i.p. prolonged the survival of mice by 27 percent after injection of 10(6) P388 lymphoma cells in the same site, consistent with destruction of 97.6 percent of the tumor cells. Placing mice for several hours in 100 percent O(2), the probable rate-limiting substrate for GOL, afforded a 42 percent prolongation of survival from P388 lymphoma, consistent with destruction of 99.6 percent of the tumor cells. When the P388 inoculum was 10(5), 10(4), or 10(3) cells, GOL led to long-term survival (presumed cure) of 23 percent, 77 percent, and 92 percent of the mice, respectively, consistent with reduction of the injected tumor dose to less than 10 cells. Subcutaneous growth of 10(5) P388 cells (approximately 300 lethal dose to 50 percent of mice) was suppressed in 83 percent of mice by admixture of GOL with the tumor cell inoculum. GOL alone had no effect against a more peroxide-resistant tumor, P815 mastocytoma. However, P815 cell glutathione reductase could be inhibited in vivo by well-tolerated doses of the antitumor agent, 1,3-bis(2-chloroethyl)- 1-nitrosourea (BCNU). BCNU alone cured few mice with P815. Together, BCNU and GOL apparently cured 86 percent of mice injected with 10(6) P815 cells i.p. The protective effect of GOL was abolished by boiling it to inactivate the enzyme, by co-injection of catalase coupled to latex beads, or by delaying the injection of tumor cells for 3 h, by which time the beads had formed aggregates. Soluble glucose oxidase, in doses threefold higher than that bound to GOL, had no detectable antitumor effect. A single injection of preformed H(2)0(2) readily killed P388 cells in the peritoneal cavity, but only at doses nearly lethal to the mice. In contrast, GOL had very little toxicity, as judged by the normal appearance of the mice for over 400 d, gross and microscopic findings at autopsy, and various blood tests. GOL injected i.p. remained in the peritoneal cavity, where it was gradually organized into granulomata by macrophages, without generalized inflammation. Thus, an H(2)0(2)-generating system confined to the tumor bed exerted clear- cut antitumor effects with little toxicity to the host.
Impact of the increasing use of immunosuppressants in Crohn's disease on the need for intestinal surgery
Authors: J Cosnes
Journal: Gut (2005)

Immunosuppressants are now used much earlier in the course of Crohn's disease; however their effect on the natural history of the disease, especially on the need for surgery, is not known. The aim of this study was to assess the evolution of the need for surgery in Crohn's disease during the last 25 years.The medical charts of 2573 patients were reviewed retrospectively. The use of immunosuppressants (azathioprine or methotrexate), the need for intestinal resection, and the occurrence of intestinal complications were assessed using Kaplan-Meier analysis in five consecutive cohorts of patients defined by the date of diagnosis of Crohn's disease (1978-82; 1983-87; 1988-92; 1993-97; 1998-2002).In 565 patients seen in the authors' unit within the first three months after diagnosis, characteristics of Crohn's disease at diagnosis did not differ from one cohort to another. The five year cumulative probability to receive immunosuppressants increased from 0 in the 1978-82 cohort to 0.13, 0.25, 0.25, and 0.56 in the 1983-87, 1988-92, 1993-97, and 1998-2002 cohorts, respectively (p<0.001). Concomitantly, the cumulative risk of intestinal resection remained unchanged (from 0.35 to 0.34 at five years; p=0.81). The cumulative risk of developing a stricturing or a penetrating intestinal complication remained also unchanged. Similar results were obtained in the 2008 patients seen during the same period who were referred to us more than three months after diagnosis.Although immunosuppressants have been used more frequently over the last 25 years, there was no significant decrease of the need for surgery, or of intestinal complications of Crohn's disease.
Maternal mortality in adolescents compared with women of other ages: evidence from 144 countries
Authors: Andrea Nove, Zoë Matthews, Sarah Neal, Alma Virginia Camacho
Journal: The Lancet Global Health (2014)

Background Adolescents are often noted to have an increased risk of death during pregnancy or childbirth compared with older women, but the ex isting evidence is inconsistent and in many cases contradictory.We aimed to quantify the risk of maternal death in adolescents by estimating maternal mortality ratios for women aged 15-19 years by country, region, and worldwide, and to compare these ratios with those for women in other 5-year age groups.Methods We used data from 144 countries and territories (65 with vital registration data and 79 with nationally representative survey data) to calculate the proportion of maternal deaths among deaths of females of reproductive age (PMDF) for each 5-year age group from 15-19 to 45-49 years.We adjusted these estimates to take into account under-reporting of maternal deaths, and deaths during pregnancy from non-maternal causes.We then applied the adjusted PMDFs to the most reliable age-specifi c estimates of deaths and livebirths to derive age-specifi c maternal mortality ratios. FindingsThe aggregated data show a J-shaped curve for the age distribution of maternal mortality, with a slightly increased risk of mortality in adolescents compared with women aged 20-24 years (maternal mortality ratio 260 [uncertainty 100-410] vs 190 [120-260] maternal deaths per 100 000 livebirths for all 144 countries combined), and the highest risk in women older than 30 years.Analysis for individual countries showed substantial heterogeneity; some showed a clear J-shaped curve, whereas in others adolescents had a slightly lower maternal mortality ratio than women in their early 20s.No obvious groupings were apparent in terms of economic development, demographic characteristics, or geographical region for countries with these diff erent age patterns.Interpretation Our fi ndings suggest that the excess mortality risk to adolescent mothers might be less than previously believed, and in most countries the adolescent maternal mortality ratio is low compared with women older than 30 years.However, these fi ndings should not divert focus away from eff orts to reduce adolescent pregnancy, which are central to the promotion of women's educational, social, and economic development.
Antisense Suppression of Pygopus2 Results in Growth Arrest of Epithelial Ovarian Cancer
Authors: Cathy M. Popadiuk, Jieying Xiong, Malcolm G. Wells, Phillip G. Andrews, Kweku Dankwa, Kensuke Hirasawa, Blue B. Lake, Kenneth R. Kao
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The Pygopus proteins are critical elements of the canonical Wnt/β-catenin transcriptional complex. In epithelial ovarian cancer, constitutively active Wnt signaling is restricted to one (endometrioid) tumor subtype. The purpose of this study was to determine the level of expression and growth requirements of human Pygopus2 (hPygo2) protein in epithelial ovarian cancer. Experimental Design: Expression and subcellular localization of hPygo2 was determined in epithelial ovarian cancer cell lines and tumors using Northern blot, immunoblot, and immunofluorescence. Immunohistochemistry was done on 125 archived patient epithelial ovarian cancer tumors representing all epithelial ovarian cancer subtypes. T-cell factor–dependent transcription levels were determined in epithelial ovarian cancer cells using TOPflash/FOPflash in vivo assays. Phosphorothioated antisense oligonucleotides were transfected into cell lines and growth assayed by cell counting, anchorage-independent colony formation on soft agar, and xenografting into severe combined immunodeficient mice. Results: All six epithelial ovarian cancer cell lines and 82% of the patient samples overexpressed nuclear hPygo2 compared with control cells and benign disease. Depletion of hPygo2 by antisense oligonucleotides in both Wnt-active (TOV-112D) and Wnt-inactive serous (OVCAR-3, SKOV-3) and clear cell (TOV-21G) carcinoma cell lines halted growth, assessed using tissue culture, anchorage-independent, and xenograft assays. Conclusions: hPygo2 is unexpectedly widely expressed in, and required in the absence of, Wnt signaling for malignant growth of epithelial ovarian cancer, the deadliest gynecologic malignancy. These findings strongly suggest that inhibition of hPygo2 may be of therapeutic benefit for treating this disease.
Associations Between Dietary Fiber and Inflammation, Hepatic Function, and Risk of Type 2 Diabetes in Older Men
Authors: S. Goya Wannamethee, Peter H. Whincup, Mary C. Thomas, Naveed Sattar
Journal: Diabetes Care (2009)

OBJECTIVE To examine the relationship between dietary fiber and the risk of type 2 diabetes in older men and the role of hepatic and inflammatory markers. RESEARCH DESIGN AND METHODS The study was performed prospectively and included 3,428 nondiabetic men (age 60–79 years) followed up for 7 years, during which there were 162 incident cases of type 2 diabetes. RESULTS Low total dietary fiber (lowest quartile ≤20 g/day) was associated with increased risk of diabetes after adjustment for total calorie intake and potential confounders (relative risk −1.47 [95% CI 1.03–2.11]). This increased risk was seen separately for both low cereal and low vegetable fiber intake. Dietary fiber was inversely associated with inflammatory markers (C-reactive protein, interleukin-6) and with tissue plasminogen activator and γ-glutamyl transferase. Adjustment for these markers attenuated the increased risk (1.28 [0.88–1.86]). CONCLUSIONS Dietary fiber is associated with reduced diabetes risk, which may be partly explained by inflammatory markers and hepatic fat deposition.
Hypothesis: troponin degradation is one of the factors responsible for deterioration of left ventricular function in heart failure
Authors: A van der Laarse
Journal: Cardiovascular Research (2002)

A hypothesis is presented that explains one of the mechanisms by which a heart starts to fail. The hypothesis is that myocardial function of an overloaded or otherwise stressed heart may become impaired by cellular troponin degradation in vital cardiomyocytes. The troponins (I, T and C) regulate actin–myosin interaction, thereby controlling contraction and relaxation. Troponins have been shown to be targets of activated calpain I. This enzyme, that is activated by elevated intracellular Ca2+ concentrations, such as occurs during ischemia, degrades troponins, leading to impaired interaction between actin and myosin and, thereby, less contractile force. Several reports about troponin degradation in viable myocardium support this hypothesis. Also, results are discussed that demonstrate the presence of immunoreactive troponin fragments in plasma under conditions in which myocardial necrosis can be excluded or is unlikely. The hypothesis implicates that release of troponin and/or troponin degradation products is not specific for necrotic myocardium but may occur from viable myocardium as well. To test this hypothesis, several lines of research are suggested. If the hypothesis is not rejected in the near future, the concept that a positive troponin test reflects 'even microscopic zones of myocardial necrosis' as used by the Joint ESC/ACC Committee for the Redefinition of Myocardial Infarction [The Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. Myocardial infarction redefined—A consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. Eur Heart J 2000;21:1502–1513], should be withdrawn.
Identification of Persons at High Risk for Type 2 Diabetes Mellitus: Do We Need the Oral Glucose Tolerance Test?
Authors: Michael P. Stern, Ken Williams, Steven M. Haffner
Journal: Annals of Internal Medicine (2002)

Background: The standard method of identifying persons at high risk for type 2 diabetes mellitus involves detection of impaired glucose tolerance, which requires a costly and inconvenient 2-hour oral glucose tolerance test. Because clinical trials have indicated that diabetes is preventable by using behavioral or pharmacologic interventions, less expensive methods of identifying high-risk persons are needed. Objective: To determine whether multivariable models are superior to glucose tolerance tests for identifying persons at high risk for diabetes mellitus. Design: Prospective cohort study. Setting: San Antonio, Texas. Participants: 1791 Mexican Americans and 1112 non-Hispanic whites without diabetes at baseline who were randomly selected from census tracts. Measurements: Medical history; body mass index; blood pressure; fasting and 2-hour plasma glucose levels; fasting serum total, low-density lipoprotein, and high-density lipoprotein cholesterol levels; and triglyceride level. Results: For prediction of 7.5-year incidence of type 2 diabetes, the area under the receiver-operating characteristic (ROC) curve for a multivariable model involving readily available clinical variables was significantly (P < 0.001) greater than the area under the ROC curve for the 2-hour glucose value alone (84.3% vs. 77.5%). Impaired glucose tolerance represents a single point on the latter curve. Adding the 2-hour glucose measurement to the multivariable model increased the area under its ROC curve, but only from 84.3% to 85.7%. Conclusion: Persons at high risk for diabetes mellitus are better identified by using a simple prediction model than by relying exclusively on the results of a 2-hour oral glucose tolerance test. Although adding the 2-hour glucose variable to the model enhanced prediction, the resulting slight improvement entails greater cost and inconvenience.
A novel inhaled corticosteroid ciclesonide significantly improves quality of life in patients with mild-to-moderate asthma
Authors: A. Nayak, B.L. Charous, A. Finn, W. Lumry, C. Crivera, J. Williams, S. Kundu, J. Fish, D. Banerji
Journal: Journal of Allergy and Clinical Immunology (2005)
Targeting Mitotic Exit Leads to Tumor Regression In Vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δ Phosphatase
Authors: Eusebio Manchado, María Guillamot, Guillermo de Cárcer, Manuel Eguren, Michelle Trickey, Irene García-Higuera, Sergio Moreno, Hiroyuki Yamano, Marta Cañamero, Marcos Malumbres
Journal: Cancer Cell (2010)
Early growth and coronary heart disease in later life: longitudinal study
Authors: J G Eriksson
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objective:</b> To determine how growth during infancy and childhood modifies the increased risk of coronary heart disease associated with small body size at birth. <b>Design:</b> Longitudinal study. <b>Setting:</b> Helsinki, Finland. <b>Subjects:</b> 4630 men who were born in the Helsinki University Hospital during 1934–44 and who attended child welfare clinics in the city. Each man had on average 18.0 (SD 9.5) measurements of height and weight between birth and age 12 years. <b>Main outcome measures:</b> Hospital admission or death from coronary heart disease. <b>Results:</b> Low birth weight and low ponderal index (birth weight/length<sup>3</sup>) were associated with increased risk of coronary heart disease. Low height, weight, and body mass index (weight/height<sup>2</sup>) at age 1 year also increased the risk. Hazard ratios fell progressively from 1.83 (95% confidence interval 1.28 to 2.60) in men whose body mass index at age 1 year was below 16 kg/m<sup>2</sup> to 1.00 in those whose body mass index was &gt;19 (P for trend=0.0004). After age 1 year, rapid gain in weight and body mass index increased the risk of coronary heart disease. This effect was confined, however, to men with a ponderal index &lt;26 at birth. In these men the hazard ratio associated with a one unit increase in standard deviation score for body mass index between ages 1 and 12 years was 1.27 (1.10 to 1.47; P=0.001). <b>Conclusion:</b> Irrespective of size at birth, low weight gain during infancy is associated with increased risk of coronary heart disease. After age 1 year, rapid weight gain is associated with further increase in risk, but only among boys who were thin at birth. In these boys the adverse effects of rapid weight gain on later coronary heart disease are already apparent at age 3 years. Improvements in fetal, infant, and child growth could lead to substantial reductions in the incidence of coronary heart disease. <h3>What is already known on this topic</h3> Coronary heart disease is associated with low birth weight One study has shown that irrespective of size at birth, low weight gain in infancy is also associated with increased risk of the disease among men Rapid weight gain after age 6 years is associated with further increase in risk <h3>What this study adds</h3> The association with low weight gain in infancy is confirmed The adverse effects of rapid childhood weight gain on risk of coronary heart disease are already apparent at age 3 years and occur only in boys who were thin at birth