tbuckley/cabot-search huggingface dataset:
Effect of Maternal and Postweaning Folic Acid Supplementation on Mammary Tumor Risk in the Offspring
Authors: Anna Ly, Hanna Lee, Jianmin Chen, Karen K. Y. Sie, Richard Renlund, Alan Medline, Kyoung-Jin Sohn, Ruth Croxford, Lilian U. Thompson, Young-In Kim
Journal: Cancer Research (2010)

Abstract Intrauterine and early life exposure to folic acid has significantly increased in North America owing to folic acid fortification, widespread supplemental use, and periconceptional supplementation. We investigated the effects of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring. Female rats were placed on a control or folic acid–supplemented diet prior to mating and during pregnancy and lactation. At weaning, female pups from each maternal diet group were randomized to the control or supplemented diet and mammary tumors were induced with 7,12 dimethylbenz[a]anthracene at puberty. At necropsy, mammary tumor parameters, genomic DNA methylation, and DNA methyltransferase activity were determined in the offspring. Both maternal and postweaning folic acid supplementation significantly increased the risk of mammary adenocarcinomas in the offspring (OR = 2.1, 95% CI 1.2–3.8, P = 0.008 and OR = 1.9, 95% CI 1.1–3.3, P = 0.03, respectively). Maternal folic acid supplementation also significantly accelerated the rate of mammary adenocarcinoma appearance (P = 0.002) and increased the multiplicity of mammary adenocarcinomas (P = 0.008) in the offspring. Maternal, but not postweaning, folic acid supplementation significantly reduced global DNA methylation (P = 0.03), whereas postweaning, but not maternal, folic acid supplementation significantly decreased DNA methyltransferase activity (P = 0.05) in nonneoplastic mammary glands of the offspring. Our findings suggest that a high intrauterine and postweaning dietary exposure to folic acid may increase the risk of mammary tumors in the offspring. Further, they suggest that this tumor-promoting effect may be mediated in part by altered DNA methylation and DNMT activity. Cancer Res; 71(3); 988–97. ©2010 AACR.
Lipid peroxidation, antioxidants and cardiovascular disease: how should we move forward?
Authors: B Halliwell
Journal: Cardiovascular Research (2000)

Time for primary review 27 days. 

It is widely agreed that increased consumption of fruits, grains and vegetables, decreased intake of saturated fats, a moderate degree of exercise and perhaps judicious consumption of red wine or other alcoholic beverages (or even tea) would improve the cardiovascular health of the populations in most developed and ‘near-developed’ countries [1–8]. Fruits, grains, teas, vegetables and red wines are rich in antioxidants (ascorbate, tocopherols, tocotrienols, flavonoids, other phenols and carotenoids are among the antioxidants found in various plants consumed by humans; reviewed in [9]), and so it is widely thought that antioxidants make an important contribution to this cardiovascular protective effect [9–14]. This assumption is logical, because there is good evidence that oxidative damage contributes to the pathology of atherosclerosis and vascular dysfunction generally, and that free radicals are involved in myocardial ischemia-reperfusion injury [9,15–20]. However, intervention trials with vitamin E that assess clinical end-points are giving a confused picture [21–23]. Indeed, foods and beverages derived from plants are chemically complex, and cardiovascular protective effects could also arise from many other components or mixtures of components present, including fibre, immunostimulatory agents, monounsaturated fatty acids, agents that modulate cholesterol synthesis, B-vitamins, folic acid, agents modulating nitric oxide production, and even the humble ethanol molecule itself [2,3,5,6,14,24–29].

One obvious way to assess the contribution of antioxidants to the cardiovascular protective effects of the above diets is to conduct intervention trials with single antioxidants, or combinations of a few antioxidants. For example the intervention trials with β-carotene convincingly demolished the concept that this carotenoid is an important anti-cancer agent in humans, at least in smokers [30]. Hence high plasma levels of β-carotene are negatively associated with cancer incidence because both are a consequence of eating a good diet; β-carotene is not …
Treatment of rosacea with 1% metronidazole cream. A double-blind study
Authors: P.GAMBORG NIELSEN
Journal: British Journal of Dermatology (1983)

Eighty‐one patients with rosacea were treated with either i % metronidazole cream or the cream base as a placebo for two months. The trial was performed double‐blind, and the patients were assessed once each month. The variates studied were: (i) overall clinical assessment, (2) lesion counts, (3) degree of erythema, (4) independent photographic evaluation, and (5) patient's opinion. Four patients dropped out of the trial (one treated with metronidazole, three with placebo). In all the variates, 1% metronidazole cream proved to be significantly more effective than placebo.
PTU-210 Young patients with PR bleeding: flexible sigmoidoscopy or colonoscopy?: Abstract PTU-210 Table 1
Authors: J Dyson, A Reddy
Journal: Gut (2012)

Vitamin D deficiency is common and associated with higher risk for and unfavourable outcome of many diseases. Limited data exist on genetic determinants of serum 25(OH)D concentration. In a cohort of the LURIC study (n=2974, median 25(OH)D concentration 15.5 ng/ml), we tested the hypothesis that variants (SNPs, n=244) of several genes (n=15) involved in different aspects of skin pigmentation, including melanosomal biogenesis (ATP7A, DTNBP1, BLOC1S5, PLDN, PMEL), melanosomal transport within melanocytes (RAB27A, MYO5A, MLPH); or various melanocyte signaling pathways (MC1R, MITF, PAX3, SOX10, DKK1, RACK1, CNR1) are predictive of serum 25(OH)D levels. Eleven SNPs located in 6 genes were associated (p&lt;0.05) with low or high serum 25(OH)D levels, 3 out of these 11 SNPs reached the aimed significance level after correction for multiple comparisons (FDR). In the linear regression model adjusted for sex, body mass index (BMI), year of birth and month of blood sample rs7565264 (MLPH), rs10932949 (PAX3), and rs9328451 (BLOC1S5) showed a significant association with 25(OH)D. The combined impact on variation of 25(OH)D serum levels (coefficient of determination (R<sup>2</sup>)) for the 11 SNPs was 1.6% and for the 3 SNPs after FDR 0.3%. In Cox Regression we identified rs2292881 (MLPH) as having a significant association (advantage) with overall survival. Kaplan-Meier analysis did not show any significant impact of individual SNPs on overall survival. In conclusion, these results shed new light on the role of sunlight, skin pigmentation and vitamin D for human evolution.
Gli1, downregulated in colorectal cancers, inhibits proliferation of colon cancer cells involving Wnt signalling activation
Authors: T Akiyoshi
Journal: Gut (2005)

Early events in the progression of 90% of sporadic colorectal cancers depend on constitutive activation of Wnt signalling. Recent data also indicate a close association between the Hedgehog (Hh) and Wnt pathways in colonic epithelial cell differentiation.To investigate whether expression of Gli1, a transactivator of Hh signalling, can suppress Wnt signalling and inhibit proliferation of human colorectal cancer cells.Gli1 and nuclear beta-catenin expression were examined in a series of 40 human colorectal cancers by immunohistochemistry. We quantified Gli1 and nuclear beta-catenin staining as markers of Hh and Wnt pathway activation, respectively. Two human colon cancer cell lines, SW480 and HCT116, with mutations in APC and beta-catenin, respectively, were used. The effects of Gli1 overexpression on Wnt transcriptional activity, beta-catenin subcellular distribution, and proliferation in these cells were analysed.Nuclear accumulation of beta-catenin and the Gli1 staining level were inversely associated in the 40 human colorectal cancers. Wnt transcriptional activity was reduced in Gli1 transfected cells. These effects were observed even in Gli1 transfected cells cotransfected with mutated beta-catenin. Furthermore, nuclear accumulation of beta-catenin was diminished compared with that in empty vector transfected cells, and downregulated transcription of c-Myc was observed in Gli1 transfected cells. Proliferation of Gli1 transfected cells was also significantly suppressed compared with that in empty vector transfected cells.Our data suggest that Gli1 plays an inhibitory role in the development of colorectal cancer involving Wnt signalling, even in cases with the stabilising mutation of beta-catenin.
Autoimmune Diabetes Not Requiring Insulin at Diagnosis (Latent Autoimmune Diabetes of the Adult)
Authors: Paolo Pozzilli, Umberto Di Mario
Journal: Diabetes Care (2001)

Type 1 diabetes is caused by the immune-mediated destruction of islet insulin-secreting β-cells. This chronic destructive process is associated with both cellular and humoral immune changes in the peripheral blood that can be detected months or even years before the onset of clinical diabetes. Throughout this prediabetic period, metabolic changes, including altered glucose tolerance and reduced insulin secretion, deteriorate at variable rates and eventually result in clinical diabetes. A fraction of individuals with humoral immunological changes have clinical diabetes that initially is not insulin-requiring. The onset of diabetes in these patients is usually in adult life, and because their diabetes is at least initially not insulin-requiring, they appear clinically to be affected by type 2 diabetes. Such patients probably have the same disease process as patients with type 1 diabetes in that they have similar HLA genetic susceptibility as well as autoantibodies to islet antigens, low insulin secretion, and a higher rate of progression to insulin dependency. These patients are defined as being affected by an autoimmune type of diabetes not requiring insulin at diagnosis, which is also named latent autoimmune diabetes of the adult (LADA). Special attention should be paid to diagnose such patients because therapy may influence the speed of progression toward insulin dependency, and in this respect, efforts should be made to protect residual C-peptide secretion. LADA can serve as a model for designing new strategies for prevention of type 1 diabetes but also as a target group for prevention in its own right.
Methotrexate resistance in relation to treatment outcome in childhood acute lymphoblastic leukemia
Authors: Anna Wojtuszkiewicz, Godefridus J. Peters, Nicole L. van Woerden, Boas Dubbelman, Gabriele Escherich, Kjeld Schmiegelow, Edwin Sonneveld, Rob Pieters, Peter M. van de Ven, Gerrit Jansen, Yehuda G. Assaraf, Gertjan J. L. Kaspers, Jacqueline Cloos
Journal: Journal of Hematology & Oncology (2015)

Methotrexate (MTX) eradicates leukemic cells by disrupting de novo nucleotide biosynthesis and DNA replication, resulting in cell death. Since its introduction in 1947, MTX-containing chemotherapeutic regimens have proven instrumental in achieving curative effects in acute lymphoblastic leukemia (ALL). However, drug resistance phenomena pose major obstacles to efficacious ALL chemotherapy. Moreover, clinically relevant molecular mechanisms underlying chemoresistance remain largely obscure. Several alterations in MTX metabolism, leading to impaired accumulation of this cytotoxic agent in tumor cells, have been classified as determinants of MTX resistance. However, the relation between MTX resistance and long-term clinical outcome of ALL has not been shown previously.We have collected clinical data for 235 childhood ALL patients, for whom samples taken at the time of diagnosis were also broadly characterized with respect to MTX resistance. This included measurement of concentrations of MTX polyglutamates in leukemic cells, mRNA expression of enzymes involved in MTX metabolism (FPGS, FPGH, RFC, DHFR, and TS), MTX sensitivity as determined by the TS inhibition assay, and FPGS activity.Herein we demonstrate that higher accumulation of long-chain polyglutamates of MTX is strongly associated with better overall (10-year OS: 90.6 vs 64.1%, P = 0.008) and event-free survival (10-year EFS: 81.2 vs 57.6%, P = 0.029) of ALL patients. In addition, we assessed both the association of several MTX resistance-related parameters determined in vitro with treatment outcome as well as clinical characteristics of pediatric ALL patients treated with MTX-containing combination chemotherapy. High MTX sensitivity was associated with DNA hyperdiploid ALL (P < 0.001), which was linked with increased MTX accumulation (P = 0.03) and elevated reduced folate carrier (RFC) expression (P = 0.049) in this subset of ALL patients. TEL-AML1 fusion was associated with increased MTX resistance (P = 0.023). Moreover, a low accumulation of MTX polyglutamates was observed in MLL-rearranged and TEL-AML1 rearranged ALL (P < 0.05).These findings emphasize the central role of MTX in ALL treatment thereby expanding our understanding of the molecular basis of clinical differences in treatment response between ALL individuals. In particular, the identification of patients that are potentially resistant to MTX at diagnosis may allow for tailoring novel treatment strategies to individual leukemia patients.
Endocrine Effects of Tamoxifen Plus Exemestane in Postmenopausal Women with Breast Cancer
Authors: Richard R. Love, Paul R. Hutson, Thomas C. Havighurst, James F. Cleary
Journal: Clinical Cancer Research (2005)

Abstract Purpose: In some specific circumstances, combined hormonal therapies for breast cancer seem to be more effective than single maneuvers. In two laboratory mammary cancer models, the combination of the aromatase inactivator exemestane plus tamoxifen gives a higher response rate than is found with either agent alone. To evaluate the endocrine effects of the combination of exemestane and tamoxifen, we studied 33 postmenopausal women disease-free following primary treatments for breast cancer who were taking tamoxifen for at least 3 months. Design: After observation for symptoms on tamoxifen for 4 weeks, blood samples were taken and patients were begun additionally on exemestane 25 mg p.o. qd. Eight weeks later, blood samples were again taken, and exemestane was discontinued. Results: A decrease in alkaline phosphatase was found with exemestane treatment (P = 0.06), whereas no change in osteocalcin level was observed. A decrease in high-density lipoprotein cholesterol level was found (P = 0.0025), whereas total cholesterol, low-density lipoprotein cholesterol and triglyceride levels showed no changes with exemestane treatment. Estradiol, estrone, and estrone sulfate levels decreased to immeasurable or very low levels with exemestane treatment (all P &amp;lt; 0.001). No significant changes in frequencies of common drug-associated side effects, such as vasomotor symptoms or weight change, were found. Conclusions: Based on the absence of adverse endocrine effects with the addition of exemestane to tamoxifen therapy observed in this study, further clinical evaluation of the efficacy of this combination is warranted.
Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes
Authors: Wei Jiang, Xiaqiong Wang, Benhua Zeng, Lei Liu, Aubry Tardivel, Hong Wei, Jiahuai Han, H. Robson MacDonald, Jurg Tschopp, Zhigang Tian, Rongbin Zhou
Journal: The Journal of Experimental Medicine (2013)

NOD2 functions as an intracellular sensor for microbial pathogen and plays an important role in epithelial defense. The loss-of-function mutation of NOD2 is strongly associated with human Crohn's disease (CD). However, the mechanisms of how NOD2 maintains the intestinal homeostasis and regulates the susceptibility of CD are still unclear. Here we found that the numbers of intestinal intraepithelial lymphocytes (IELs) were reduced significantly in Nod2(-/-) mice and the residual IELs displayed reduced proliferation and increased apoptosis. Further study showed that NOD2 signaling maintained IELs via recognition of gut microbiota and IL-15 production. Notably, recovery of IELs by adoptive transfer could reduce the susceptibility of Nod2(-/-) mice to the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Our results demonstrate that recognition of gut microbiota by NOD2 is important to maintain the homeostasis of IELs and provide a clue that may link NOD2 variation to the impaired innate immunity and higher susceptibility in CD.
Remodeling of myocyte dimensions in hypertrophic and atrophic rat hearts.
Authors: S E Campbell, B Korecky, K Rakusan
Journal: Circulation Research (1991)

Changes in hemodynamic load cause alterations in cardiac myocyte size, with regional variations in myocyte size distribution possible within the ventricular wall. We studied regional changes in cellular dimensions and their distribution in two models of cardiac hypertrophy and in cardiac atrophy in the rat. Combined volume-pressure overload was produced by 3,3',5-triiodo-L-thyronine (T3) treatment; atrophy was produced by heterotopic isotransplantation. Our previous data from long-term pressure overload after aortic constriction were used for comparison. Isolated ventricular myocytes were obtained after in vitro coronary perfusion with collagenase. Cell volume and its distribution were determined; cell length was directly measured by image analysis, and cross-sectional area was estimated from the cell volume/cell length ratio, assuming a cylindrical model. Myocyte hypertrophy resulting from hyperthyroidism and aortic constriction was primarily due to increased cross-sectional area. In both cases, the relative response was greater in the right ventricle than in the left ventricle. Within the left ventricle, epimyocardial myocytes enlarged the most. Aortic constriction and T3 treatment predominantly increased the size of smaller myocytes. Heterogeneity in myocyte size increased after constriction but remained relatively unaffected after T3 treatment. Atrophy of left ventricular myocytes was due to a proportional decrease in cell length and cross-sectional area, with the greatest decrease in the left ventricular endomyocardium. Atrophy predominantly affected larger myocytes, resulting in a more homogeneous overall population of smaller myocytes. We conclude that various alterations in load lead to diverse remodeling in the myocyte population throughout the ventricular wall. In general, smaller myocytes show the highest growth potential, whereas larger myocytes exhibit the highest potential to atrophy.
Clinical and radiographic disease course of hand osteoarthritis and determinants of outcome after 6 years
Authors: J. Bijsterbosch, I. Watt, I. Meulenbelt, F. R. Rosendaal, T. W. J. Huizinga, M. Kloppenburg
Journal: Annals of the Rheumatic Diseases (2010)

To investigate the long-term clinical and radiographic disease course of hand osteoarthritis (OA) and determinants of outcome.Clinical and radiographic measures were obtained at baseline and after 6 years in 289 patients with hand OA (mean age 59.5 years, 83.0% women). Clinical outcomes were self-reported pain and functional limitations assessed with the Australian/Canadian Osteoarthritis Hand Index (AUSCAN). Poor clinical outcome was defined as a follow-up score not fulfilling the Patient Acceptable Symptom State. Radiographic outcome was assessed by osteophytes and joint space narrowing (JSN) on standardised hand radiographs using the Osteoarthritis Research Society International (OARSI) atlas. Radiographic progression was defined as a change in osteophytes or JSN, above the smallest detectable change. Change in outcome measures was calculated and baseline determinants for poor clinical outcome and radiographic progression were assessed using logistic regression analysis.Clinical change showed great variation, with half of the population reporting deterioration. Poor outcome in pain was related to high levels of functional limitations and a high number of painful joints at baseline. Poor outcome on functional limitations was related to high baseline pain levels. Radiographic progression was present in 52.5% of patients and associated with high baseline levels of pain, nodes, osteophytes and the presence of erosive OA and nodal OA. Clinical change and radiographic progression were not related.This study gives insight in the clinical and radiographic course of hand OA as well as determinants of outcome. These findings enable better patient information on prognosis. The relationship between clinical and radiographic outcome needs further investigation.
Caerulein induced pancreatitis
Authors: D J van Westerloo, N A Maris, M J Bruno, T van der Poll
Journal: Gut (2003)

We have read with interest the article by Frossard et al ( Gut2002;50:78–83 [OpenUrl][1][Abstract/FREE Full Text][2] ) entitled “Both thermal and non-thermal stress protect against caerulein induced pancreatitis and prevent trypsinogen activation in the pancreas”. We have a few comments with regard to the interpretation of the data that were obtained in this experiment. Previous experimental work by Frossard and others have implicated HSP70 as playing a protective role in caerulein induced acute pancreatitis. In the present study Frossard et al showed that thermal and non-thermal stress induced by injection of the β agonist isoproterenol upregulated HSP70 in the pancreas which is associated with amelioration of subsequently induced caerulein pancreatitis. The authors hypothesise that the protective effects on pancreatitis severity caused by thermal and non-thermal stress may by mediated by HSP70. We believe however that both heat shock stress and non-thermal stress can stimulate several other anti-inflammatory pathways which were not discussed in this study, all of which could be alternative explanations for the observations that were made. It is widely established that catecholamines, both endogenously released during heat shock stress or by injection of isoproterenol, can influence … [1]: {openurl}?query=rft.jtitle%253DGut%26rft.stitle%253DGut%26rft.issn%253D0017-5749%26rft.aulast%253DFrossard%26rft.auinit1%253DJ-L%26rft.volume%253D50%26rft.issue%253D1%26rft.spage%253D78%26rft.epage%253D83%26rft.atitle%253DBoth%2Bthermal%2Band%2Bnon-thermal%2Bstress%2Bprotect%2Bagainst%2Bcaerulein%2Binduced%2Bpancreatitis%2Band%2Bprevent%2Btrypsinogen%2Bactivation%2Bin%2Bthe%2Bpancreas%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fgut.50.1.78%26rft_id%253Dinfo%253Apmid%252F11772971%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=ABST&journalCode=gutjnl&resid=50/1/78&atom=%2Fgutjnl%2F52%2F3%2F452.2.atom
OKT3 and pulmonary capillary permeability.
Authors: P A Rowe, G M Rocker, A G Morgan, D J Shale
Journal: BMJ (1987)

regimen (cisplatin 20 mg/m2 days 1 to 5; bleomycin 30 mg days 1, 7, and 14; and vinblastine 10 mg days 1 and 2).The concentrations of tumour marker and an abdominal computed tomogram showed complete remission after three courses of chemotherapy (figure).Actinomycin-D Bleomycin Cisplatin