snu-aidas/HVMap-dataset huggingface dataset:
The role of oral antidiabetic agents: why and when to use an early-phase insulin secretion agent in Type II diabetes mellitus

Abstract Evidence obtained in the 1990's strongly supports the notion that glycaemic control is important not only in Type I (insulin-dependent), but also in Type II (non-insulin-dependent) diabetes mellitus. Although measurement of HbA1c is the standard for assessing the effect of glucose control in the occurrence and prevention of diabetic sequelae, more recent evidence indicates that other glucose parameters are also important. Postchallenge and postprandial hyperglycaemic peaks seem to be prospective determinants of vascular damage in early Type II diabetes. Currently, there is no overall accepted standard approach for the pharmacological management of Type II diabetes. The United Kingdom Prospective Diabetes Study has shown that reaching a near-normal glycaemic target is critically important and the pharmacotherapy of this progressive disease is difficult. Loss of endogenous insulin secretion has been substantiated to cause the progression of Type II diabetes in the United Kingdom Prospective Diabetes Study. Early insulinization, however, was not advantageous over other forms of therapy. The advent of polypharmacy in recent years has greatly strengthened the treatment of this disease. This synergy has been extended of late with the development of early-phase insulin secretion agents. Two such agents, nateglinide and repaglinide, can be used to reduce mealtime glucose excursions and HbA1c as monotherapy, and in combination with metformin; their antidiabetic potential is similar to the combination treatment with glibenclamide and metformin. Additional substantiation of their long-term effect on improving life expectancy and reducing diabetic complications in Type II diabetic patients is now required.
On the origins of ultra-fine anaphase bridges.

Comment on: Chan KL, Palmai-Pallag T, Ying S, Hickson ID. Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nat Cell Biol 2009; 11:753-60.
Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3'-kinase/Akt pathway signaling.

PURPOSE Tyrosine kinase (TK) inhibitors are emerging as a promising new approach to the treatment of HER overexpressing tumors, however optimal use of these agents awaits further definition of the downstream signaling pathways that mediate their effects. We reported previously that both EGFR- and Her2-overexpressing tumors are sensitive to the new EGFR-selective TK inhibitor gefitinib (ZD1839, "Iressa"), and sensitivity to this agent correlated with its ability to down-regulate Akt. However, EGFR-overexpressing MDA-468 cells, which lack PTEN function, are resistant to ZD1839, and ZD1839 is unable to down-regulate Akt activity in these cells. EXPERIMENTAL DESIGN To study the role of PTEN function, we generated MDA468 cells with tet-inducible PTEN expression. RESULTS We show here that the resistance of MDA-468 cells to ZD1839 is attributable to EGFR-independent constitutive Akt activation caused by loss of PTEN function in these cells. Reconstitution of PTEN function through tet-inducible expression restores ZD1839 sensitivity to these cells and reestablishes EGFR-stimulated Akt signaling. Although restoration of PTEN function to tumors is difficult to implement clinically, much of the effects of PTEN loss are attributable to overactive PI3K/Akt pathway signaling, and this overactivity can be modulated by pharmacologic approaches. We show here that pharmacologic down-regulation of constitutive PI3K/Akt pathway signaling using the PI3K inhibitor LY294002 similarly restores EGFR-stimulated Akt signaling and sensitizes MDA-468 cells to ZD1839. CONCLUSIONS Sensitivity to ZD1839 requires intact growth factor receptor-stimulated Akt signaling activity. PTEN loss leads to uncoupling of this signaling pathway and results in ZD1839 resistance, which can be reversed with reintroduction of PTEN or pharmacologic down-regulation of constitutive PI3K/Akt pathway activity. These data have important predictive and therapeutic clinical implications.
Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial.

BACKGROUND Type 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, and report here our 12-month results. METHODS For this phase 2, randomised, placebo-controlled, clinical trial, we enrolled patients with recent-onset type 1 diabetes, aged 12-35 years, and with a peak C-peptide of 0.4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used a computer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks of size three or six and stratified by study site) to receive either 6.5 mg/kg ATG or placebo over a course of four days. All participants were masked and initially managed by an unmasked drug management team, which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetes management throughout the remainder of the study, participants received diabetes management from an independent, masked study physician and nurse educator. The primary endpoint was the baseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance test from baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of an on-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov, number NCT00515099. FINDINGS Between Sept 10, 2007, and June 1, 2011, we screened 154 individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve of -0.195 pmol/mL (95% CI -0.292 to -0.098) and those in the placebo group had a mean change of -0.239 pmol/mL (-0.361 to -0.118) in the placebo group (p=0.591). All except one participant in the ATG group had both cytokine release syndrome and serum sickness, which was associated with a transient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group, with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and the ratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter. ATG-treated patients had 159 grade 3-4 adverse events, many associated with T-cell depletion, compared with 13 in the placebo group, but we detected no between-group difference in incidence of infectious diseases. INTERPRETATION Our findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. Generalised T-cell depletion in the absence of specific depletion of effector memory T cells and preservation of regulatory T cells seems to be an ineffective treatment for type 1 diabetes.
The nucleosome family: dynamic and growing.

Ever since the discovery of the nucleosome in 1974, scientists have stumbled upon discrete particles in which DNA is wrapped around histone complexes of different stoichiometries: octasomes, hexasomes, tetrasomes, "split" half-nucleosomes, and, recently, bona fide hemisomes. Do all these particles exist in vivo? Under what conditions? What is their physiological significance in the complex DNA transactions in the eukaryotic nucleus? What are their dynamics? This review summarizes research spanning more than three decades and provides a new meaning to the term "nucleosome. " The nucleosome can no longer be viewed as a single static entity: rather, it is a family of particles differing in their structural and dynamic properties, leading to different functionalities.
Association between serum corin levels and risk of acute myocardial infarction.

BACKGROUND Accumulating evidence has indicated that corin plays critical roles in regulating salt-water balance, blood pressure and cardiac function by activating natriuretic peptides. The present case-control study was designed to evaluate the association of serum soluble corin with acute myocardial infarction (AMI). METHODS We enrolled 856 consecutive AMI patients and 856 control subjects and explored the possible relation between serum corin levels and AMI risk using logistic regression model. RESULTS Patients with AMI had higher BMI, were less physically active, and were more likely to have histories of hypertension, diabetes, hyperlipidemia and smoking compared with the controls. Serum levels of corin were remarkably reduced in AMI patients (825±263pg/ml) compared with those in healthy controls (1246±425pg/ml). Odds ratios of ST elevation (STEMI) and non-ST elevation myocardial infarction (NSTEMI) were significantly decreased with the increasing levels of serum corin in both men and women (P for trend, <0.001) after adjustment for body mass index, hypertension, diabetes, hyperlipidemia, smoking, and physical activity. CONCLUSIONS Our study demonstrates that serum levels of corin are significantly decreased in AMI patients, and it is inversely associated with the incidences of STEMI and NSTEMI in both men and women.
SEROSURVEY FOR FELINE LEUKEMIA VIRUS AND LENTIVIRUSES IN CAPTIVE SMALL NEOTROPIC FELIDS IN SÃO PAULO STATE, BRAZIL

Abstract Feline leukemia virus (FeLV), Gammaretrovirus, and feline immunodeficiency virus, a Lentivirus, are members of the family Retroviridae, and may establish persistent infections in the domestic cat (Felis catus). Cytoproliferative and cytosuppressive disorders may result from infection with these viruses. Morbidity and mortality rates are high in domestic cats worldwide. Infection of endangered neotropic small felids with these viruses could be devastating. To investigate the prevalence of FeLV and feline lentiviruses in neotropic small felids kept in captivity in São Paulo state, Brazil, serum samples from 104 animals belonging to the species Leopardus pardalis, Leopardus tigrinus, Leopardus wiedii, Herpailurus yaguarondi, and Oncifelis geoffroyi were tested for FeLV and feline lentiviruses by commercially available immunoassays. All results were negative, suggesting that retrovirus infection is not an important clinical problem in these populations. Because domestic cats in São Paulo city are naturally infected with these pathogens, and feral cats are commonly found in zoologic facilities in Brazil, preventive measures should be taken to avoid transmission of retroviruses to naive populations of wild and captive neotropic felids in Brazil.
Comparing the metabolism of quercetin in rats, mice and gerbils

Several species of rodents are used to investigate the metabolism of quercetin in vivo. However, it is unclear whether they are a proper animal model. Thus, we compared the metabolism of quercetin in Wistar rats (rats), Balb/c mice (mice) and Mongolian gerbils (gerbils). We determined the levels of quercetin metabolites, quercetin-3-glucuronide (Q3G), quercetin-3′-sulfate (Q3′S) and methyl-quercetin isorhamnetin (IH), in the plasma, lungs and livers of three species of animals by high-performance liquid chromatography after acute and/or chronic quercetin administration. The metabolic enzyme activities in the intestinal mucosal membrane and liver were also investigated. First, we found that after acute quercetin administration, the Q3′S level was the highest in gerbils. However, after long-term supplementation (20 weeks), Q3G was the dominant metabolite in the plasma, lungs and livers followed by IH and Q3′S in all animals, although the gerbils still had a higher Q3′S conversion ratio. The average concentrations of total quercetin concentration in the plasma of gerbils were the highest in both short- and long-term studies. The activities of uridine 5′-diphosphate-glucuronosyltransferase, phenolsulfotransferase and catechol-O-methyltransferase were induced by quercetin in a dose- and tissue-dependent manner in all animals. Taken together, in general, after long-term supplementation the metabolism of quercetin is similar in all animals and is comparable to that of humans. However, the accumulation of quercetin and Q3′S conversion ratio in gerbils are higher than those in the other animals.
Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells

A long-standing hypothesis on tumorigenesis is that cell division failure, generating genetically unstable tetraploid cells, facilitates the development of aneuploid malignancies. Here we test this idea by transiently blocking cytokinesis in p53-null (p53-/-) mouse mammary epithelial cells (MMECs), enabling the isolation of diploid and tetraploid cultures. The tetraploid cells had an increase in the frequency of whole-chromosome mis-segregation and chromosomal rearrangements. Only the tetraploid cells were transformed in vitro after exposure to a carcinogen. Furthermore, in the absence of carcinogen, only the tetraploid cells gave rise to malignant mammary epithelial cancers when transplanted subcutaneously into nude mice. These tumours all contained numerous non-reciprocal translocations and an 8–30-fold amplification of a chromosomal region containing a cluster of matrix metalloproteinase (MMP) genes. MMP overexpression is linked to mammary tumours in humans and animal models. Thus, tetraploidy enhances the frequency of chromosomal alterations and promotes tumour development in p53-/- MMECs.
Cold-related respiratory symptoms in the general population.

INTRODUCTION Cold-related respiratory symptoms are common among northern populations, especially among people suffering from respiratory diseases. However, the prevalence of such symptoms in the general population and the threshold temperatures at which the symptoms start to emerge are poorly known. OBJECTIVES The present study determined the prevalence and threshold temperatures of self-reported respiratory symptoms related to cold, separately for healthy people and those with respiratory disease. MATERIALS AND METHODS Six thousand five hundred ninety-one men and women aged 25 years-74 years from the national FINRISK study were queried about cold-related respiratory symptoms. The results were expressed as age-adjusted prevalence figures and coefficients from multivariate regressions. RESULTS Cold-related respiratory symptoms were more often reported by people with asthma (men 69%/women 78%) and by subjects with chronic bronchitis (65%/76%) than the healthy subjects (18%/21%). A binomial regression showed an increase of symptom prevalence by age and excesses of 4%, 50% and 21% units because of female sex, asthma and chronic bronchitis, respectively. The reported threshold temperature for cold-related symptoms was -14 degrees C for males and -15 degrees C for females, and it showed some increase by age (0 degrees C-5 degrees C), asthma (2 degrees C) and chronic bronchitis (3 degrees C). The threshold temperature for mucus production was exceptional as it decreased by age (2 degrees C-5 degrees C) and asthma (2 degrees C). The effects of smoking and education were marginal. CONCLUSION Cold-related respiratory symptoms are common in patients with chronic respiratory diseases, but they start to emerge at relatively low temperatures. In a cold climate, the cold-related symptoms may have an impact on the health-related quality of life.
Carvedilol for children and adolescents with heart failure: a randomized controlled trial.

CONTEXT Although beta-blockers improve symptoms and survival in adults with heart failure, little is known about these medications in children and adolescents. OBJECTIVE To prospectively evaluate the effects of carvedilol in children and adolescents with symptomatic systemic ventricular systolic dysfunction. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized, double-blind, placebo-controlled study of 161 children and adolescents with symptomatic systolic heart failure from 26 US centers. In addition to treatment with conventional heart failure medications, patients were assigned to receive placebo or carvedilol. Enrollment began in June 2000 and the last dose was given in May 2005 (each patient received medication for 8 months). INTERVENTIONS Patients were randomized in a 1:1:1 ratio to twice-daily dosing with placebo, low-dose carvedilol (0.2 mg/kg per dose if weight <62.5 kg or 12.5 mg per dose if weight > or =62.5 kg), or high-dose carvedilol (0.4 mg/kg per dose if weight <62.5 kg or 25 mg per dose if weight > or =62.5 kg) and were stratified according to whether each patient's systemic ventricle was a left ventricle or not. MAIN OUTCOME MEASURES The primary outcome was a composite measure of heart failure outcomes in patients receiving carvedilol (low- and high-dose combined) vs placebo. Secondary efficacy variables included individual components of this composite, echocardiographic measures, and plasma b-type natriuretic peptide levels. RESULTS There was no statistically significant difference between groups for the composite end point based on the percentage of patients who improved, worsened, or were unchanged. Among 54 patients assigned to placebo, 30 improved (56%), 16 worsened (30%), and 8 were unchanged (15%); among 103 patients assigned to carvedilol, 58 improved (56%), 25 worsened (24%), and 20 were unchanged (19%). The rates of worsening were lower than expected. The odds ratio for worsened outcome for patients in the combined carvedilol group vs the placebo group was 0.79 (95% CI, 0.36-1.59; P = .47). A prespecified subgroup analysis noted significant interaction between treatment and ventricular morphology (P = .02), indicating a possible differential effect of treatment between patients with a systemic left ventricle (beneficial trend) and those whose systemic ventricle was not a left ventricle (nonbeneficial trend). CONCLUSIONS These preliminary results suggest that carvedilol does not significantly improve clinical heart failure outcomes in children and adolescents with symptomatic systolic heart failure. However, given the lower than expected event rates, the trial may have been underpowered. There may be a differential effect of carvedilol in children and adolescents based on ventricular morphology. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00052026.
The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm arising from the mesothelial cells lining the parietal pleura and it exhibits poor prognosis. Although there has been significant progress in MPM treatment, development of more efficient therapeutic approaches is needed. BMAL1 is a core component of the circadian clock machinery and its constitutive overexpression in MPM has been reported. Here, we demonstrate that BMAL1 may serve as a molecular target for MPM. The majority of MPM cell lines and a subset of MPM clinical specimens expressed higher levels of BMAL1 compared to a nontumorigenic mesothelial cell line (MeT-5A) and normal parietal pleural specimens, respectively. A serum shock induced a rhythmical BMAL1 expression change in MeT-5A but not in ACC-MESO-1, suggesting that the circadian rhythm pathway is deregulated in MPM cells. BMAL1 knockdown suppressed proliferation and anchorage-dependent and independent clonal growth in two MPM cell lines (ACC-MESO-1 and H290) but not in MeT-5A. Notably, BMAL1 depletion resulted in cell cycle disruption with a substantial increase in apoptotic and polyploidy cell population in association with downregulation of Wee1, cyclin B and p21(WAF1/CIP1) and upregulation of cyclin E expression. BMAL1 knockdown induced mitotic catastrophe as denoted by disruption of cell cycle regulators and induction of drastic morphological changes including micronucleation and multiple nuclei in ACC-MESO-1 cells that expressed the highest level of BMAL1. Taken together, these findings indicate that BMAL1 has a critical role in MPM and could serve as an attractive therapeutic target for MPM.
Mechanism and Regulation of DNA-Protein Crosslink Repair by the DNA-Dependent Metalloprotease SPRTN

Covalent DNA-protein crosslinks (DPCs) are toxic DNA lesions that interfere with essential chromatin transactions, such as replication and transcription. Little was known about DPC-specific repair mechanisms until the recent identification of a DPC-processing protease in yeast. The existence of a DPC protease in higher eukaryotes is inferred from data in Xenopus laevis egg extracts, but its identity remains elusive. Here we identify the metalloprotease SPRTN as the DPC protease acting in metazoans. Loss of SPRTN results in failure to repair DPCs and hypersensitivity to DPC-inducing agents. SPRTN accomplishes DPC processing through a unique DNA-induced protease activity, which is controlled by several sophisticated regulatory mechanisms. Cellular, biochemical, and structural studies define a DNA switch triggering its protease activity, a ubiquitin switch controlling SPRTN chromatin accessibility, and regulatory autocatalytic cleavage. Our data also provide a molecular explanation on how SPRTN deficiency causes the premature aging and cancer predisposition disorder Ruijs-Aalfs syndrome.
'Zero is not good for me': implications of infertility in Ghana.

BACKGROUND Given the high value placed on children in sub-Saharan Africa, previous research suggests that infertility increases the risk of psychological distress and marital conflict, encourages risky sexual behavior and deprives infertile individuals and couples of an important source of economic and social capital. This paper explores the implications of infertility for women in Ghana, West Africa. METHODS Semi-structured interview data collected from 107 women (aged 21-48 years, mean 33 years) seeking treatment in gynecological and obstetric clinics in Accra, Ghana, are analyzed. Based on iterative open coding of the interviews, the focus of the analysis is on mental health, marital instability, social interaction and gendered experiences. RESULTS Infertile women report facing severe social stigma, marital strain and a range of mental health difficulties. Many women feel that they shoulder a disproportionate share of the blame for infertility and, by extension, face greater social consequences than male partners for difficulties conceiving. Women who do not self-identify as infertile corroborate these findings, asserting that the social consequences of infertility are severe, particularly for women. CONCLUSIONS Infertility in Ghana has important consequences for social interactions, marital stability and mental health. These consequences are not perceived to be shared equally by Ghanaian men.