Miracle-dz/UniFAR-FTUs huggingface dataset:
Global DNA hypomethylation in leukocytes associated with glioma risk

Global DNA hypomethylation in leukocytes has been associated with increased risk for a variety of cancers. However, the role of leukocyte global DNA hypomethylation in glioma development, if any, is largely unknown. To define this role, we performed a case-control study with 390 glioma patients and 390 controls with no known cancer. Levels of 5-methylcytosine (5-mC%), a marker for global DNA methylation, were measured in leukocyte DNA. Overall, median levels of 5-mC% were significantly lower in glioma cases than in controls (3.45 vs 3.82, P=0.001). Levels of 5-mC% differed significantly by age and sex among controls and by tumor subtype and grade among glioma cases. In multivariate analysis, lower levels of 5-mC% were associated with a 1.31-fold increased risk of glioma (odds ratio = 1.31, 95% confidence interval = 1.10-1.41). A significant dose-response trend was observed in quartile analysis (P=0.001). In an analysis further stratified by clinical characteristics at baseline, the association between lower levels of 5-mC% and glioma risk was evident only among younger participants (age <52 years), women, and those with aggressive tumor characteristics, such as glioblastoma subtype, high tumor grade (grade III or IV), and absence of IDH1 mutation. Our findings indicate that global DNA hypomethylation in leukocytes may contribute to the development of glioma and that the association is affected by age, sex, and tumor aggressiveness.
Relaxation Response and Resiliency Training and Its Effect on Healthcare Resource Utilization

Background Poor psychological and physical resilience in response to stress drives a great deal of health care utilization. Mind-body interventions can reduce stress and build resiliency. The rationale for this study is therefore to estimate the effect of mind-body interventions on healthcare utilization. Objective Estimate the effect of mind body training, specifically, the Relaxation Response Resiliency Program (3RP) on healthcare utilization. Design Retrospective controlled cohort observational study. Setting: Major US Academic Health Network. Sample: All patients receiving 3RP at the MGH Benson-Henry Institute from 1/12/2006 to 7/1/2014 (n = 4452), controls (n = 13149) followed for a median of 4.2 years (.85–8.4 yrs). Measurements: Utilization as measured by billable encounters/year (be/yr) stratified by encounter type: clinical, imaging, laboratory and procedural, by class of chief complaint: e.g., Cardiovascular, and by site of care delivery, e.g., Emergency Department. Subgroup analysis by propensity score matched pre-intervention utilization rate. Results At one year, total utilization for the intervention group decreased by 43% [53.5 to 30.5 be/yr] (p <0.0001). Clinical encounters decreased by 41.9% [40 to 23.2 be/yr], imaging by 50.3% [11.5 to 5.7 be/yr], lab encounters by 43.5% [9.8 to 5.6], and procedures by 21.4% [2.2 to 1.7 be/yr], all p < 0.01. The intervention group’s Emergency department (ED) visits decreased from 3.6 to 1.7/year (p<0.0001) and Hospital and Urgent care visits converged with the controls. Subgroup analysis (identically matched initial utilization rates—Intervention group: high utilizing controls) showed the intervention group significantly reduced utilization relative to the control group by: 18.3% across all functional categories, 24.7% across all site categories and 25.3% across all clinical categories. Conclusion Mind body interventions such as 3RP have the potential to substantially reduce healthcare utilization at relatively low cost and thus can serve as key components in any population health and health care delivery system.
Evaluation of Cytotoxic Potentials of Some Isoindole-1,3-Dione Derivatives on HeLa, C6 and A549 Cancer Cell Lines.

BACKGROUND Norcantharimides are known as norcantharidine derivatives and contain an isoindole skeleton structure. Isoindole derivatives have positively effect on inflammatory pathologies including cancers. OBJECTIVE Considering this information, firstly, isoindole derivatives containing different functional groups 4-13 have been synthesized from 2-alkyl/aryl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione. METHODS For the synthesis of all compounds, 2-alkyl/aryl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione was used as the starting compound. The syntheses were based on two main reactions: Ene-reaction of singlet oxygen and epoxidation. Second, their anticancer activities were evaluated against HeLa, C6 and A549 cancer cell lines by the BrdU assay. RESULTS Anticancer activities of synthesized compounds (4-13) and 5-FU (5-Florouracil) against HeLa, C6 and A549 cells were investigated at four concentrations (100, 50, 25 and 5 µM). IC50 values of compounds 4-13 were calculated for all cancer cell lines. The investigated compounds showed an anticancer activity against the cancer cell lines depending on doses. Compound 7 containing azide and silyl ether exhibited higher inhibitory activity than the other compounds and 5-FU against A549 cancer cell lines (IC50 =19.41± 0.01 µM). Compounds 9 and 11 were determined to exhibit cell-selective activity against HeLa cancer cell lines. Compound 11 had higher activity than the positive control at 100 µM concentration against the C6 cancer cell lines. CONCLUSION According to the results found, isoindole derivatives 7, 9, and 11 might be good potential anticancer agents for the treatment of cervical and glioma cancer due to their antiproliferative properties, having less cytotoxic effects on healthy cells. In addition, compound 7 could be used in in vivo studies of all three cancer cell lines (C6, HeLa, and A549).
Passive sampling of pesticides and polychlorinated biphenyls along the Quequén Grande River watershed, Argentina

Water monitoring is of great importance, especially for water bodies in agricultural or industrial areas. Grab sampling is a widely used technique for aquatic monitoring but represents only a snapshot of the contaminant levels at a specific point in time. Passive sampling, on the other hand, is an integrative technique that provides an average concentration of contaminants representative of its deployment period. Thus, the current contamination by organochlorine pesticides, polychlorinated biphenyls (PCBs), and some currently used pesticides was assessed along the Quequén Grande River watershed (Argentina) using the integrative silicone rubber passive sampling technique in a year‐long study. Silicone rubber samplers were deployed at 6 sampling sites selected according to different land uses (agricultural–livestock production, agricultural and urban activities) during 3 periods in 2014 and 2015. The organochlorine pesticides were dominated by endosulfan (sum of α‐, β‐endosulfan, endosulfan sulfate = 0.15–23.4 ng/L). The highest endosulfan levels were registered during the pesticide application period (December–March), exceeding the international water quality guidelines for protecting freshwater biota (3 ng/L). Compared with previous reports, no reductions in endosulfan levels were observed at the Quequén Grande River watershed. These results would suggest the illegal use of remaining stocks because water sampling was carried out after endosulfan was banned in Argentina. Chlorpyrifos was the second major pesticide found in water (0.02–4.3 ng/L), associated with its widespread usage on soybean crops. A reduction in levels of legacy pesticides (heptachlors, DDTs, dieldrin, and chlordanes) was evident compared with previous reports from 2007. Levels of PCBs were very low, indicating that probably only minor diffuse sources were still available along the Quequén Grande River watershed. Environ Toxicol Chem 2019;38:340–349. © 2018 SETAC
Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes.

BACKGROUND Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown. The current study investigated metformin-induced GLP-1 secretion and its contribution to the overall glucose-lowering effect of metformin and underlying mechanisms in patients with type 2 diabetes. METHODS Twelve patients with type 2 diabetes were included in this placebo-controlled, double-blinded study. On 4 separate days, the patients received metformin (1,500 mg) or placebo suspended in a liquid meal, with subsequent i.v. infusion of the GLP-1 receptor antagonist exendin9-39 (Ex9-39) or saline. During 240 minutes, blood was sampled. The direct effect of metformin on GLP-1 secretion was tested ex vivo in human ileal and colonic tissue with and without dorsomorphin-induced inhibiting of the AMPK activity. RESULTS Metformin increased postprandial GLP-1 secretion compared with placebo (P = 0.014), and the postprandial glucose excursions were significantly smaller after metformin + saline compared with metformin + Ex9-39 (P = 0.004). Ex vivo metformin acutely increased GLP-1 secretion (colonic tissue, P < 0.01; ileal tissue, P < 0.05), but the effect was abolished by inhibition of AMPK activity. CONCLUSIONS Metformin has a direct and AMPK-dependent effect on GLP-1-secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to metformin's glucose-lowering effect and mode of action. TRIAL REGISTRATION NCT02050074 (https://clinicaltrials.gov/ct2/show/NCT02050074). FUNDING This study received grants from the A.P. Møller Foundation, the Novo Nordisk Foundation, the Danish Medical Association research grant, the Australian Research Council, the National Health and Medical Research Council, and Pfizer Inc.
Seasonality of cardiovascular risk factors: an analysis including over 230 000 participants in 15 countries

Objective To assess the seasonality of cardiovascular risk factors (CVRF) in a large set of population-based studies. Methods Cross-sectional data from 24 population-based studies from 15 countries, with a total sample size of 237 979 subjects. CVRFs included Body Mass Index (BMI) and waist circumference; systolic (SBP) and diastolic (DBP) blood pressure; total, high (HDL) and low (LDL) density lipoprotein cholesterol; triglycerides and glucose levels. Within each study, all data were adjusted for age, gender and current smoking. For blood pressure, lipids and glucose levels, further adjustments on BMI and drug treatment were performed. Results In the Northern and Southern Hemispheres, CVRFs levels tended to be higher in winter and lower in summer months. These patterns were observed for most studies. In the Northern Hemisphere, the estimated seasonal variations were 0.26 kg/m2 for BMI, 0.6 cm for waist circumference, 2.9 mm Hg for SBP, 1.4 mm Hg for DBP, 0.02 mmol/L for triglycerides, 0.10 mmol/L for total cholesterol, 0.01 mmol/L for HDL cholesterol, 0.11 mmol/L for LDL cholesterol, and 0.07 mmol/L for glycaemia. Similar results were obtained when the analysis was restricted to studies collecting fasting blood samples. Similar seasonal variations were found for most CVRFs in the Southern Hemisphere, with the exception of waist circumference, HDL, and LDL cholesterol. Conclusions CVRFs show a seasonal pattern characterised by higher levels in winter, and lower levels in summer. This pattern could contribute to the seasonality of CV mortality.
Position-invariant letter identification is a key component of any universal model of reading

Abstract A universal property of visual word identification is position-invariant letter identification, such that the letter “A” is coded in the same way in CAT and ACT. This should provide a fundamental constraint on theories of word identification, and, indeed, it inspired some of the theories that Frost has criticized. I show how the spatial coding scheme of Colin Davis (2010) can, in principle, account for contrasting transposed letter (TL) priming effects, and at the same time, position-invariant letter identification.
Alterations in the lipid profiles and circulating liver enzymes in individuals infected by Schistosoma mansoni.

INTRODUCTION Portal hypertension and periportal fibrosis commonly occur in severe Schistosoma mansoni infection. Changes in lipid profile and elevated levels of circulating liver enzymes have also been described in infected individuals. The present study sought to assess the alterations in laboratory parameters associated with liver disorder in individuals infected by S. mansoni who visited a private routine laboratory service. Levels of circulating liver enzymes (gamma-glutamyl transferase [γ-GT], aspartate transaminase [AST], alanine transaminase [ALT], and alkaline phosphatase [ALP]) and a lipid panel (total cholesterol [COL], high-density lipoprotein [HDL], low-density lipoprotein [LDL], very low-density lipoprotein [VLDL], and triglycerides [TRI]) were evaluated in both infected and non-infected individuals and relative risk was used to measure associations. METHODS Data were collected for analysis from a total of 1,078 cases identified in 379,600 individuals who submitted samples to the Datalab Laboratory (Salvador, Bahia) between 2004 and 2008. RESULTS S. mansoni infection led to increased circulating levels of γ-GT in both women and men, AST (women), and ALP (men). S. mansoni infection was a protective factor against increased levels of TRI, CHO, and VLDL for individuals aged 19 years or older. The results of our analysis indicate that alterations in lipid metabolism and circulating liver enzymes in asymptomatic S. mansoni-infected individuals might be attributed to eggs lodged in the hepatic sinusoids. CONCLUSIONS Parasitological testing for S. mansoni should be indicated in endemic areas when this pattern of alterations is detected.
Molecular Characterization and Tissue Distribution of Mitochondrial Ca2+ -Dependent Solute Carrier Protein during Prevention of Diapause by HCl Treatment in the Silkworm, Bombyx mori

To clarify the molecular mechanism of prevention of entry into diapause in Bombyx mori by HCl treatment, we biochemically analyzed mitochondrial Ca2+ -dependent solute carrier protein (MCSC) in diapause eggs treated with HCl solution. Our previous studies revealed that HCl treatment causes Ca2+ to efflux from diapause eggs. Therefore, we attempted to analyze MCSC, which is known to associate with Ca2+ . The isolated cDNA of B. mori MCSC (BmMCSC) had an open reading flame (ORF) of 667 amino acid residues, and the ORF contained two EF-hand calcium-binding domains and three characteristic features of the mitochondrial solute carrier superfamily. The gene expression level of BmMCSC increased by HCl treatment. A Ca2+ binding assay indicated that recombinant BmMCSC (rBmMCSC) shows an affinity with Ca2 + . The distribution of BmMCSC was investigated with an immunohistochemical technique using antisera against BmMCSC in diapause eggs and HCl-treated diapause eggs. BmMCSC was localized in serosa cells in both eggs. These data may suggest that BmMCSC is activated by intracellular Ca2+ or efflux Ca2+ by HCl treatment, and that it plays a role in the molecular mechanisms of artificial diapause prevention or the breaking of diapause in the silkworm.
Madelung’s disease – progressive, excessive, and symmetrical deposition of adipose tissue in the subcutaneous layer: case report and literature review

Madelung’s disease is a rare disorder described for the first time in the year 1846 by Brodie. It is characterized by the occurrence of progressive, excessive, and symmetrical deposits of adipose tissue in the subcutaneous layer. Most often, these changes concern the neck, the nape of the neck, arms, and upper back, giving the patients a specific, pseudoathletic appearance. Madelung’s disease is also known as multiple symmetrical lipomatosis, benign symmetrical lipomatosis, and Launois-Bensaude syndrome. The most commonly affected ones are men who drink alcohol in excessive amounts. The fat masses emerging in the course of the disease are painless but can lead to adverse repercussions. Patients may experience dysphagia, dysphonia, difficulty in breathing, and limited mobility of the neck. The reasons for the willingness to take up treatment are also often esthetic reasons. The disease is usually accompanied by numerous metabolic disorders. The etiology of the disease has not been sufficiently explained so far, which creates diagnostic and therapeutic difficulties. Currently used treatment is limited to surgical resection of the resulting lesions or liposuction. Unfortunately, the effectiveness of these activities is limited. Most patients experience recurrence after treatment. This paper discusses the essence of Madelung’s disease, numerous aspects of etiology, the manner of diagnosis, and treatment based on current literature data.
Uncertainties associated with assessing Ontario uranium miners’ exposure to radon daughters

The Ontario uranium miners study is a large (n = 28 546) cohort with low levels of radon exposure relative to other uranium miner cohorts. Multiple methods were used over time to estimate annual occupational exposure to radon daughters including: mine-specific extrapolations by mining engineers, area sampling in limited areas of the mines combined with approximate working time and lastly, consistent exposure sampling in different locations of the mine combined with workers’ time cards. Nonetheless, estimating exposures involves assumptions that lead to some uncertainty in occupational exposure characterisation arising from the assessment approach and variability within workplace, over time and by individual. An evaluation of the total uncertainty associated with radon daughter exposure estimation in Ontario miners over time has not been conducted. The objective of this study was to identify the contributing sources and assess the total uncertainty associated with estimating occupational radon daughter exposure among underground Ontario uranium miners over the course of uranium mining. The five sources of radon daughter exposure uncertainty evaluated were: natural variations in radon concentration, estimation of working time, precision of the radon measurement method, unintended errors during sampling, and record keeping and transcription of exposure data. These sources were examined separately for the period 1958 to 1967 and then 1968 onward due to changes in radon daughter concentration measurement practices between these periods. The magnitude of uncertainty associated with each of these sources over time were determined by reviewing historical literature on uranium mining in Ontario as well as through expert advice. Using the root sum square method, the total radon daughter exposure uncertainty was found to be 53 to 67% in the earlier period of uranium mining from 1958 to 1967. This decreased to 31 to 39% for the period 1968 to 1996 with natural variations of radon daughter concentrations in mines accounting for the largest percentage of uncertainty. This assessment provides an initial step in understanding the effect of exposure uncertainty on risk estimates. The impact of this uncertainty on the dose-response relationship between radon exposure and cancer risk will be assessed in future work.
Reply to comparative risk‐adjusted mortality outcomes after primary surgery, radiotherapy, or androgen‐deprivation therapy for localized prostate cancer

I read with great interest the article by Cooperberg and coworkers studying survival rates in differently treated men with early prostate cancer. In this study, patients who underwent radical prostatectomy had a substantially decreased disease-specific mortality, particularly in the higher-risk groups, compared with those who were selected for radiation therapy or conservative management. Unlike Cooperberg et al., I do not consider it unlikely that unmeasured confounding, at least in part, accounted for the observed differences. It is conceivable that patients with a particularly adverse profile within the same risk category might have preferably been referred to external-beam radiotherapy, thus putting this treatment modality at a disadvantage. It is questionable whether this phenomenon is adequately covered by conventional prognostic factors because subjective clinical judgment is included. Selection in favor of surgery is a problem when different treatments for early prostate cancer are compared. Even careful risk adjustment will hardly be able to eliminate this effect completely. Otherwise, it would be difficult to justify randomized trials comparing radical prostatectomy and external-beam radiotherapy in this setting that the authors rightly called for.
Prokaryotic Soluble Overexpression and Purification of Human VEGF165 by Fusion to a Maltose Binding Protein Tag

Human vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis and plays a central role in the process of tumor growth and metastatic dissemination. Escherichia coli is one of the most common expression systems used for the production of recombinant proteins; however, expression of human VEGF in E. coli has proven difficult because the E. coli-expressed VEGF tends to be misfolded and forms inclusion bodies, resulting in poor solubility. In this study, we successfully produced semi-preparative amounts of soluble bioactive human VEGF165 (hVEGF). We created seven N-terminal fusion tag constructs with hexahistidine (His6), thioredoxin (Trx), glutathione S-transferase (GST), maltose-binding protein (MBP), N-utilization substance protein A (NusA), human protein disulfide isomerase (PDI), and the b'a' domain of PDI (PDIb'a'), and tested each construct for soluble overexpression in E. coli. We found that at 18°C, 92.8% of the MBP-tagged hVEGF to be soluble and that this tag significantly increased the protein's solubility. We successfully purified 0.8 mg of pure hVEGF per 500 mL cell culture. The purified hVEGF is stable after tag cleavage, contains very low levels of endotoxin, and is 97.6% pure. Using an Flk1+ mesodermal precursor cell (MPC) differentiation assay, we show that the purified hVEGF is not only bioactive but has similar bioactivity to hVEGF produced in mammalian cells. Previous reports on producing hVEGF in E. coli have all been based on refolding of the protein from inclusion bodies. To our knowledge, this is the first report on successfully expressing and purifying soluble hVEGF in E. coli.