Miracle-dz/UniFAR-FTUs huggingface dataset:
Cell-Cycle Gene Expression in Lovastatin-Induced Medulloblastoma Apoptosis

Background: 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a key rate-limiting enzyme in the mevalonate pathway, which generates precursors both for cholesterol biosynthesis and for the production of nonsteroidal mevalonate derivatives that are involved in a number of growth-regulatory processes. We have reported that lovastatin, a competitive inhibitor of HMG-CoA reductase, not only inhibits medulloblastoma proliferation in vitro, but also induces near-complete cell death via apoptosis. The mechanism of this phenomenon is unclear. Possible involvement of changes in expression of certain cell-cycle related genes led us to study some of them in more detail. Methods: Medulloblastoma cell lines were exposed in vitro to lovastatin, and the effects of gene expression changes were studied using RT-PCR, antisense oligonucleotide, DNA electrophoresis and Western blotting analysis. Results: 1) Levels of total Ras gene mRNA and individual Ras gene mRNA are stable in lovastatin treatment in all examined medulloblastoma cell lines. 2) Blocking c-myc gene over-expression does not enhance medulloblastoma cell sensitivity to lovastatin. 3) Following lovastatin treatment, p16 expression exhibits no change, but pronounced increases of p27 KIP1 protein are observed in all examined cell lines. Lovastatin induces pronounced increases of p21WAF1 protein only in Daoy and UW228, but not in D283 Med and D341 Med. 4) Following lovastatin treatment, increased p53 protein is detected only in D341 Med, and bax protein is unchanged in all cell lines. Conclusion: Lovastatin-induced growth inhibition and apoptosis in medulloblastoma are not dependent on the regulation of Ras and c-myc gene expression, but may be mediated by p27KIP1 gene expression. Lovastatin-induced apoptosis in medulloblastoma is probably p53 independent, but p53 and p21WAF1 gene expression may also mediate anti-proliferative effects of lovastatin on specific medulloblastoma cell lines.
Regulation of Dioxin Receptor Function by Omeprazole*

The intracellular dioxin (aryl hydrocarbon) receptor mediates signal transduction by dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) and related environmental pollutants and functions as a ligand-activated transcription factor. In this study we have examined the effects on dioxin receptor function of a potentially novel ligand, omeprazole, which is widely clinically used as a gastric anti-ulcer drug. In primary human hepatocytes omeprazole potently induced cytochrome P4501A1 mRNA expression, whereas this effect was not detected in mouse primary hepatocytes. In human hepatoma cells omeprazole was found to induce transcription of reporter genes via the xenobiotic response element that is recognized by the ligand-activated dioxin receptor. In contrast, the human dioxin receptor was not activated by omeprazole upon expression in a receptor-deficient mouse hepatoma cell line. In a reconstituted yeast (Saccharomyces cerevisiae) model system, however, both the mouse and human dioxin receptors were potently activated by omeprazole. Although omeprazole failed to displace dioxin in in vitro ligand binding assays, a residue within the ligand binding domain that is critical for dioxin binding in vitro was also critical for omeprazole responsiveness in vivo. Consistent with this observation, both omeprazole and dioxin responsiveness of the dioxin receptor was inhibited in mutant yeast cells expressing low levels of the molecular chaperone hsp90 that is critical for ligand binding activity. The sulfoxide group that is essential for formation of a planar conversion product of omeprazole was found to be critical for dioxin receptor activation. Taken together, these data suggest that omeprazole represents a precursor for a novel class of dioxin receptor agonists that are bona fide dioxin receptor ligands but generated in a strictly species-specific manner.
MinIAttention: attention management in minimal invasive surgery using an IoT synchronization approach

Laparoscopy and endoscopy have revolutionized the state of the art in surgical health care. Still, the associated higher complexity of the operating procedure leads to suboptimal or even erroneous surgical outcomes of minimal invasive surgery (MIS). Our work aims at evaluating and reducing MIS surgeons' cognitive load by observing their bio features and linking them to their psycho physiological triggers. In this way, we aim at detecting the current cognitive load and attention of surgeons to give them unobtrusive feedback when detecting suboptimal levels of cognitive load.
Duloxetine for the management of diabetic peripheral neuropathic pain: evaluation of functional outcomes.

OBJECTIVE To assess the effectiveness of duloxetine, compared with placebo, on patient-reported health outcomes over a 12-week period, in the management of diabetic peripheral neuropathic pain (DPNP). METHODS The results were pooled from three 12-week multicenter, double-blind studies. In study 1 (N = 457), patients with DPNP were randomly assigned to treatment with duloxetine 20 mg once daily (QD), 60 mg QD, 60 mg twice daily (BID), or placebo. In studies 2 (N = 334) and 3 (N = 348), patients with DPNP were randomly assigned to treatment with duloxetine 60 mg QD, 60 mg BID, or placebo. Patient-reported functional outcomes were measured by the Short Form 36 (SF-36), the interference portion of the Brief Pain Inventory (BPI), and EuroQol 5D Health Questionnaire (EQ-5D). Results for all functional outcomes from the intent-to-treat and completer populations are discussed. RESULTS In the SF-36 health survey and the BPI interference, duloxetine 60 mg QD and 60 mg BID were significantly superior to placebo in all the domains (P <or= 0.03). In the analysis of the EQ-5D, duloxetine 60 mg QD (P = 0.004) and 60 mg BID (P < 0.001) were significantly better than placebo on all items. CONCLUSIONS Acute treatment with duloxetine was associated with significant improvement in functional outcomes in persons with DPNP.
Pharmacokinetics, Pharmacodynamics, and Safety of Ticagrelor in Volunteers With Severe Renal Impairment

Ticagrelor, a P2Y12 receptor antagonist, is approved in the European Union and the US for the prevention of thrombotic events in patients with acute coronary syndromes. Renal dysfunction potentially affects drug disposition. Ticagrelor pharmacokinetics, pharmacodynamics, and safety in renal impairment were assessed. A single 180‐mg ticagrelor dose was administered to volunteers with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min) and normal renal function (CrCL ≥ 80 mL/min; n = 10/group). Severe renal impairment did not significantly affect ticagrelor's pharmacokinetics, pharmacodynamics, or safety. Ticagrelor absorption and AR‐C124910XX (active metabolite) formation were rapid. In renally impaired volunteers, ticagrelor mean maximum concentration (Cmax) and area under the plasma concentration‐time curve from zero to infinity were 20% lower and for AR‐C124910XX was 17% higher versus normal volunteers. Ticagrelor systemic exposure was low in 3 volunteers (CrCL < 20 mL/min), but data were variable. Onset and offset of final‐extent inhibition of platelet aggregation were comparable in both groups. Inhibition of platelet aggregation parameters and profiles were similar between groups, indicating that platelet sensitivity to ticagrelor was not affected by severe renal impairment. Ticagrelor was well tolerated in both groups with few adverse events. No ticagrelor dose adjustment is required for renally impaired patients.
Retrospective study on the benefits of combined Memantine and cholinEsterase inhibitor treatMent in AGEd Patients affected with Alzheimer's Disease: the MEMAGE study.

BACKGROUND Combined therapy of memantine and acetylcholinesterase inhibitors (AChEIs) in patients with Alzheimer's disease (AD) may be associated with higher benefits than either monotherapy. OBJECTIVE This retrospective multicentric study conducted in seven Italian Ambulatory Centers for Dementia assessed the efficacy and safety of memantine 20 mg/day administered for 6 months in addition to an AChEI in AD patients with worsened cognitive functions and behavioral disorders. METHODS A total number of 240 patients (61.7% of women, 38.3% men, mean age 77.9 ± 7.32 years old) who had started treatment with the combination therapy were recruited. At baseline (T0), Month 3 (T1), and Month 6 (T2), cognitive functions were assessed by Mini-Mental State Examination (MMSE), functional dependence by activities of daily living (ADL) and instrumental ADL, behavioral disturbances by the Neuropsychiatric Inventory (NPI), and comorbidities by Cumulative Illness Rating Scale. Adverse events were reported during the study. RESULTS MMSE total score significantly increased at Month 6 (p = 0.029 versus month 3) and IADL total score significantly decreased from baseline to endpoint (p = 0.033). There were no significant changes from baseline in mean ADL, despite significant improvements in NPI total score. The mean MMSE total score significantly increased with the combination donepezil + memantine compared to rivastigmine + memantine. The adverse events profile was in line with the expected range of the drugs studied and concomitant therapies. Overall, 17 patients discontinued treatment in the observation time. CONCLUSION Combined treatment with memantine and AChEIs was effective in patients with AD, particularly in slowing cognitive impairment and preventing the onset of agitation and aggression in elderly AD patients.
Localization of the Insertion Site and Pathotype Determination of the Locus of Enterocyte Effacement of Shiga Toxin-Producing Escherichia coli Strains

ABSTRACT Of 220 Shiga toxin-producing Escherichia coli (STEC) strains collected in central France from healthy cattle, food samples, and asymptomatic children, 12 possessed the eae gene included in the locus of enterocyte effacement (LEE) pathogenicity island. Based on gene typing, we observed 7 different eae espA espB tir pathotypes among the 12 STEC strains and described the new espAβv variant. As previously observed, the O157 serogroup is associated with eaeγ, O26 is associated with eaeβ, and O103 is associated with eaeε. However, the unexpected eaeζ allele was detected in 5 of the 12 isolates. PCR amplification and pulsed-field gel electrophoresis using the I-CeuI endonuclease followed by Southern hybridization indicated that the LEE was inserted in the vicinity of the selC (three isolates), pheU (two isolates), or pheV (six isolates) tRNA gene. Six isolates harbored two or three of these tRNA loci altered by the insertion of integrase genes (CP4-int and/or int-phe), suggesting the insertion of additional foreign DNA fragments at these sites. In spite of great genetic diversity of LEE pathotypes and LEE insertion sites, bovine strains harbor alleles of LEE genes that are frequently found in clinical STEC strains isolated from outbreaks and sporadic cases around the world, underscoring the potential risk of the bovine strains on human health.
Increased level of circulating U2 small nuclear RNA fragments indicates metastasis in melanoma patients

Abstract Background: Melanoma is the most aggressive skin cancer and, despite recent advances in therapy, about 20% of the patients die of their disease. Early relapse detection and monitoring of therapy response are crucial for efficient treatment of advanced melanoma. Thus, there is a need for blood-based biomarkers in melanoma management. Serum-derived U2 small nuclear RNA fragments (RNU2-1f) were previously shown to be blood-based biomarkers for gastrointestinal and gynecologic malignancies. Here we examined whether RNU2-1f may also serve as diagnostic biomarker in advanced melanoma. Methods: Circulating RNU2-1f levels were quantified by comparative reverse transcription PCR in a training cohort of patients with metastatic melanoma (n=33, thereof regionally metastasized to skin and lymph nodes, n=23, and distantly metastasized, n=10) vs. patients with benign naevi (n=16) vs. healthy controls (n=39). Results were validated in an independent patient cohort with distant metastasis (n=16) vs. controls (n=18). Results: Circulating RNU2-1f levels in the training cohort were significantly increased in serum of regionally and distantly metastatic patients, compared with patients with benign naevi or healthy controls (p<0.0001) and allowed accurate detection of regional (AUC 0.80) as well as distant (AUC 0.84) metastasis. In the validation cohort, increased RNU2-1f levels were confirmed and enabled highly specific detection of distant metastasis (sensitivity 81%, specificity 100%, AUC 0.94). Conclusions: This is the first report to suggest a blood-based snRNA serving as a diagnostic biomarker for melanoma metastasis. Our data provide a rationale for further defining clinical utility of circulating RNU2-1f in metastasis detection in the management of melanoma patients at risk of relapse and/or with advanced disease.
TATA‐binding protein promotes the selective formation of UV‐induced (6‐4)‐photoproducts and modulates DNA repair in the TATA box

DNA‐damage formation and repair are coupled to the structure and accessibility of DNA in chromatin. DNA damage may compromise protein binding, thereby affecting function. We have studied the effect of TATA‐binding protein (TBP) on damage formation by ultraviolet light and on DNA repair by photolyase and nucleotide excision repair in yeast and in vitro. In vivo, selective and enhanced formation of (6‐4)‐photoproducts (6‐4PPs) was found within the TATA boxes of the active SNR6 and GAL10 genes, engaged in transcription initiation by RNA polymerase III and RNA polymerase II, respectively. Cyclobutane pyrimidine dimers (CPDs) were generated at the edge and outside of the TATA boxes, and in the inactive promoters. The same selective and enhanced 6‐4PP formation was observed in a TBP–TATA complex in vitro at sites where crystal structures revealed bent DNA. We conclude that similar DNA distortions occur in vivo when TBP is part of the initiation complexes. Repair analysis by photolyase revealed inhibition of CPD repair at the edge of the TATA box in the active SNR6 promoter in vitro, but not in the GAL10 TATA box or in the inactive SNR6 promoter. Nucleotide excision repair was not inhibited, but preferentially repaired the 6‐4PPs. We conclude that TBP can remain bound to damaged promoters and that nucleotide excision repair is the predominant pathway to remove UV damage in active TATA boxes.
Historical Institutionalism in comparative politics

This article provides an overview of recent developments in historical institutionalism. First, it reviews some distinctions that are commonly drawn between the ihistoricali and the irational choicei variants of institutionalism and shows that there are more points of tangency than typically assumed. However, differences remain in how scholars in the two traditions approach empirical problems. The contrast of rational choiceis emphasis on institutions as coordination mechanisms that generate or sustain equilibria versus historical institutionalismis emphasis on how institutions emerge from and are embedded in concrete temporal processes serves as the foundation for the second half of the essay, which assesses our progress in understanding institutional formation and change. Drawing on insights from recent historical institutional work on icritical juncturesi and on ipolicy feedbacks,i the article proposes a way of thinking about institutional evolution and path dependency that provides an alternative to equilibrium and other approaches that separate the analysis of institutional stability from that of institutional change.
An Autonomic Cloud Application Placement Tool Based on Cost Criteria

The cloud computing ecosystem comprises hundreds of providers, offering diverse computing services, incompatible APIs, and significantly different pricing models. Cloud application management platforms hide the heterogeneity of the services and APIs, allowing, to varying degrees, portability between providers. These tools remove technical barriers to switching providers, but they do not provide a mechanism for evaluating the cost effectiveness of switching.This paper presents a decision support system, working within cloud application management platforms, that evaluates the costs of a customer's applications using resources from different cloud service providers. The system (1) generalizes and normalizes multiple cloud pricing models and (2) gathers pricing data from cloud providers. These, in conjunction with the application resource consumption model, allow the cloud pricing module to estimate a price for the application for each cloud provider.To demonstrate this, our cloud pricing module has been integrated with the SlipStream multi-cloud application management platform, allowing its users to optimize their choice of provider(s).
Emotional Distress and Substance Abuse as Risk Factors for Suicide Attempts

Background: Both depression and hopelessness have been found to be closely related to suicide risk among adolescents and adults. Substance abuse has also been found to play a role in the suicide process with adults, but it is still unclear how much substance abuse influences suicide in adolescents. Method: The present study examined the relationship between substance abuse, emotional distress, and suicidal intent among 115 adolescent psychiatric inpatients who had attempted suicide. Results: Measures of emotional distress, as well as the measures of substance abuse, were significantly intercor-related. Correlations across domains (emotional distress versus substance abuse), however, varied by gender. Among adolescent females, both depression and hopelessness were significantly related to suicidal intent, whereas among adolescent males, only depression was related to suicidal intent. Also, alcohol abuse was significantly related to depression and hopelessness in adolescent males. Conclusions: Hopelessness may not be as useful an indicator of suicide risk among adolescent males as it is with adolescent females. Intervention and prevention programs designed for adolescent females should identify and address feelings of depression and hopelessness. New intervention and prevention programs may need to be developed for adolescent males.
Knowledge synthesis of smoking cessation among employed and unemployed young adults.

OBJECTIVES We synthesized evidence regarding effective strategies for smoking cessation among employed or unemployed young adults aged 18 to 24 years. METHODS For this knowledge synthesis, we used (1) a systematic review of the scientific literature, (2) a Delphi panel of experts, and (3) 6 focus groups of employed and unemployed young adult smokers. RESULTS Of 51 related studies, only 4 included employed and unemployed young adults in their samples (as opposed to students), and none focused solely on them. Using the Delphi process, 27 experts reached consensus on priorities for research, practice, and policy, emphasizing population engagement, recruitment, and innovative interventions. Key themes from focus groups were that interventions should be relevant to young adults, individual choice should be respected, and the positive aspects of quitting should be stressed. Despite having negative views on traditional smoking cessation methods, participants expressed optimism about being able to quit and proposed creative recommendations. CONCLUSIONS Our findings set an agenda for targeting research, improving practice, and informing policy for smoking cessation among young adults. We also demonstrate the value of using 3 complementary approaches: literature review, expert opinion, and target population perspectives.
Cognitive factors in source monitoring and auditory hallucinations

Background. In order to elucidate further the cognitive processes underlying auditory hallucinations, an experiment investigating delayed and immediate source monitoring for positive, negative and neutral verbal material was conducted with schizophrenic patients. Methods. Patients experiencing auditory hallucinations, patients not experiencing auditory hallucinations and normal subjects participated in a word association task, rating their responses for how much a self-generated thought was their own, how controllable and involuntary it was and their confidence in these ratings. A delayed source monitoring test in which subjects had to recall the source (self or experimenter) of the words from the association task was also administered. Results. Hallucinators showed a greater bias towards external attribution of their thoughts compared with both control groups for immediate attributions of source, but not for delayed attributions. Hallucinators showed a bias towards external attribution of emotional material for immediate source monitoring and all subjects showed a bias towards misattribution of positive material to an external source and negative material to an internal source for the delayed source monitoring task. Conclusions. These findings appear to be most consistent with theories proposing that hallucinations result from an external attributional bias for internal events. The implications of these results for research and practice are also discussed.
Is There Evidence of Brain White-Matter Abnormalities in Obsessive-Compulsive Disorder?: A Narrative Review

Objective: Although several studies have confirmed the occurrence of gray-matter abnormalities in obsessive-compulsive disorder (OCD), the literature on white matter in OCD is more limited. In this study, we reviewed the role of white-matter abnormalities in the pathophysiology of OCD. Method: We reviewed the PubMed studies investigating white-matter integrity in patients with OCD between 1980 and 2010. Results: Case studies of patients who developed obsessive-compulsive symptoms secondary to multiple sclerosis, cerebrovascular diseases, and paraneoplastic leucoencephalopathy and controlled studies of patients with OCD examined with neuroimaging techniques (eg, structural, diffusion, and spectroscopic magnetic resonance imaging) were all consistent with the existence of abnormalities in specific white-matter tracts (eg, internal capsule, cingulate bundle, and corpus callosum) of individuals with OCD. Conclusions: Our review emphasizes that the reported white-matter alterations in OCD complement the broader gray-matter abnormalities identified and may well suggest that OCD is associated with large-scale disruption in brain systems or networks, as opposed to being a consequence of disturbances in isolated brain regions.