Miracle-dz/UniFAR-FTUs huggingface dataset:
Antioxidant Treatment Improves Cardiac Dysfunction in a Murine Model of Premature Aging

Abstract: Bmal1-(brain and muscle ARNT-like protein-1) deficient (Bmal1−/−) mice prematurely age because of an increased reactive oxygen species (ROS) production. These mice also show a decline in cardiac function with age. We investigated whether an antioxidant treatment can ameliorate the declining cardiac function in prematurely aged Bmal1−/− mice. Male Bmal1−/− and wild-type (Bmal1+/+) mice were exposed for 15 weeks to a high fat and high cholesterol diet with or without the antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL; 5 mmol/L; in drinking water during the last 10 weeks). Echocardiographic analysis revealed that TEMPOL treatment of Bmal1−/− mice normalized cardiac function, as evidenced by a decrease in left ventricular diastolic and systolic internal diameters, and by an increase in fractional shortening and ejection fraction. The antioxidant did not affect cardiac function in Bmal1+/+ mice. Although TEMPOL did not influence cardiac ROS levels in Bmal1−/− mice, it significantly protected Bmal1−/− cardiac telomeres from oxidation, as evidenced by a reduction in the telomere damage score (0.11 ± 0.012% vs. 0.16 ± 0.015%; P = 0.028). Thus, antioxidant treatment normalized cardiac function of Bmal1−/− mice, probably in part by scavenging ROS.
Biallelic expression of the H19 and IGF2 genes in human testicular germ cell tumors.

BACKGROUND Genomic imprinting, resulting in the nonequivalence of expression of homologue genes depending on their parental origin, is an important determinant of the developmental potential of embryonic cells. The expression of two genes, one termed H19 and the other IGF2, has been found to be necessary for proper embryonal development in humans. Both the murine and human H19 and IGF2 genes are normally characterized by monoallelic expression. PURPOSE Because testicular germ cell tumors of adults originate from an early germ cell and, to a certain extent, mimic normal embryonal development, we investigated the patterns of allelic expression of the H19 and IGF2 genes in these tumors to determine if genomic imprinting, or a disturbance of it, is involved in their pathogenesis. METHODS Specimens of normal tissue and tumor tissue were obtained from 20 patients with testicular germ cell tumors; 10 of the patients had seminomas and 10 had nonseminomatous germ cell tumors. To determine if there was heterozygosity of the Alu I and Apa I restriction site polymorphism in the H19 and IGF2 genes, respectively, DNA was isolated from cells of the peripheral blood of these patients, then subjected to polymerase chain reaction (PCR) amplification, restriction enzyme digestion, and electrophoresis in agarose gels. If heterozygosity was determined, a similar analysis was performed on complementary DNA (cDNA) obtained from matched tumor RNA by reverse transcription and subsequent PCR amplification (RT-PCR). If monoallelic expression was found, matched tumor DNA was studied for possible deletions. RESULTS Tumor samples from 14 of 20 and 11 of 20 patients were informative for allelic expression patterns of the H19 and IGF2 genes, respectively. Analysis of the products of RT-PCR showed biallelic expression of the H19 gene in 12 testicular germ cell tumors (patients numbered 6, 8-13, 15, 16, and 18-20) and of the IGF2 gene in 10 testicular germ cell tumors (patients numbered 1, 3, 6, 8-13, and 15-20). The three remaining tumors (patients numbered 2, 4, and 5) had lost the nonexpressed allele. CONCLUSIONS In contrast to normally developing embryos, testicular germ cell tumors show a consistent expression of both parental alleles of the H19 and IGF2 genes. IMPLICATIONS Testicular germ cell tumors of adults may develop from precursor cells in which the imprinting has been either erased or subjected to a consistent relaxation of its effect.
Individual differences in response to regular physical activity.

PURPOSE The purpose of this review was to address the question of interindividual variation in responsiveness to regular exercise training and to define the contributions of age, sex, race, and pretraining phenotype level to this variability. METHODS A literature review was conducted of the studies reporting interindividual variation in responsiveness to standardized and controlled exercise-training programs, and included an analysis of the contribution of age, sex, race, and initial phenotype values to the heterogeneity in VO(2max), high-density lipoprotein (HDL)-C and submaximal exercise, heart rate (HR), and systolic blood pressure (SBP) training responses in subjects from the HERITAGE Family Study. RESULTS Several studies have shown marked individual differences in responsiveness to exercise training. For example, VO(2max) responses to standardized training programs have ranged from almost no gain up to 100% increase in large groups of sedentary individuals. A similar pattern of heterogeneity has been observed for other phenotypes. Data from the HERITAGE Family Study show that age, sex, and race have little impact on interindividual differences in training responses. On the other hand, the initial level of a phenotype is a major determinant of training response for some traits, such as submaximal exercise heart rate and blood pressure (BP) but has only a minor effect on others (e.g., VO(2max), HDL-C). The contribution of familial factors (shared environment and genetic factors) is supported by data on significant familial aggregation of training response phenotypes. CONCLUSIONS There is strong evidence for considerable heterogeneity in the responsiveness to regular physical activity. Age, sex, and ethnic origin are not major determinants of human responses to regular physical activity, whereas the pretraining level of a phenotype has a considerable impact in some cases. Familial factors also contribute significantly to variability in training response.
APF530 versus ondansetron, each in a guideline-recommended three-drug regimen, for the prevention of chemotherapy-induced nausea and vomiting due to anthracycline plus cyclophosphamide–based highly emetogenic chemotherapy regimens: a post hoc subgroup analysis of the Phase III randomized MAGIC trial

Background APF530, a novel extended-release granisetron injection, was superior to ondansetron in a guideline-recommended three-drug regimen in preventing delayed-phase chemotherapy-induced nausea and vomiting (CINV) among patients receiving highly emetogenic chemotherapy (HEC) in the double-blind Phase III Modified Absorption of Granisetron In the prevention of CINV (MAGIC) trial. Patients and methods This MAGIC post hoc analysis evaluated CINV prevention efficacy and safety of APF530 versus ondansetron, each with fosaprepitant and dexamethasone, in patient subgroup receiving an anthracycline plus cyclophosphamide (AC) regimen. Patients were randomized 1:1 to APF530 500 mg subcutaneously (granisetron 10 mg) or ondansetron 0.15 mg/kg intravenously (IV) (≤16 mg); stratification was by planned cisplatin ≥50 mg/m2 (yes/no). Patients were to receive fosaprepitant 150 mg IV and dexamethasone 12 mg IV on day 1, then dexamethasone 8 mg orally once daily on day 2 and twice daily on days 3 and 4. Patients were mostly younger females (APF530 arm, mean age 54.1 years, female, 99.3%; ondansetron arm, 53.8 years, female 98.3%). The primary end point was delayed-phase (>24–120 hours) complete response (CR). Results APF530 versus ondansetron regimens achieved numerically better CINV control in delayed and overall (0–120 hours) phases for CR, complete control, total response, rescue medication use, and proportion with no nausea. APF530 trends are consistent with the overall population, although not statistically superior given the underpowered AC subgroup analysis. The APF530 regimen in this population was generally well tolerated, with safety comparable to that of the overall population. Conclusion APF530 plus fosaprepitant and dexamethasone effectively prevented CINV among patients receiving AC-based HEC, a large subgroup in whom CINV control has traditionally been challenging.
QUALITATIVE AND QUANTITATIVE DETERMINATION OF A HUMIC MODEL COMPOUND IN MICROBIAL CULTURES BY CYCLIC VOLTAMMETRY

The humic model compound, anthraquinone–2,6–disulfonate (AQDS), was characterized and measured in microbial cultures by cyclic voltammetry (CV). Under the experimental conditions, the formal reduction potential (E°´) of the couple AQDS/AHQDS– was found to be of –0.520 V vs. SCE (standard calomel electrode) at pH value of 7.0. Control experiments showed that there were no interferences of the culture medium or the microbial consortium on the quantitative determination of the quinone. The linear equation E°´ = –0.294 – 0.032 pH was found, showing that the pH used (7.0–7.8) did not affect significantly the AQDS determination by CV and AHQDS– was the predominant hydroquinone formed. A calibration curve was obtained by plotting current response versus AQDS concentration with a linear correlation (r = 0.999) from 0.2 to 10 mM of AQDS. This technique was applied in a denitrifying culture to establish kinetic profiles for AHQDS– formation coupled to acetate and p–cresol oxidation. CV results showed that organic matter oxidation by the denitrifying sludge was stoichiometrically associated to AQDS reduction into AHQDS–. CV was shown to be a useful tool for monitoring oxidation/reduction processes of quinones occurring in complex microbial media.
In vitro model for DNA double‐strand break repair analysis in breast cancer reveals cell type–specific associations with age and prognosis

Dysfunction of homologous recombination is a common denominator of changes associated with breast cancer–predisposing mutations. In our previous work, we identified a functional signature in peripheral blood lymphocytes from women who were predisposed that indicated a shift from homologous recombination to alternative, error‐prone DNA double‐strand break (DSB) repair pathways. To capture both hereditary and nonhereditary factors, we newly established a protocol for isolation and ex vivo analysis of epithelial cells, epithelialmesenchymal transition cells (EMTs), and fibroblasts from breast cancer specimens (147 patients). By applying a fluorescence‐based test system, we analyzed the error‐prone DSB repair pathway microhomology‐mediated end joininginthese tumor‐derivedcell types and peripheral blood lymphocytes. Inparallel, we investigated DNA lesion processing by quantitative immunofluorescence microscopy of histone H2AX phosphorylated on Ser139 focus after radiomimetic treatment. Our study reveals elevated histone H2AX phosphorylated on Ser139 damage removal in epithelial cells, not EMTs, and poly(ADP‐ribose)polymerase inhibitor sensitivities, which suggested a DSB repair pathway shift with increasing patient age. Of interest, we found elevated microhomology‐mediated end joining in EMTs, not epithelial cells, from patients who received a treatment recommendation of adjuvant chemotherapy, that is, those with high‐risk tumors. Our discoveries of altered DSB repair activities in cells may serve as a method to further classify breast cancer to predict responsiveness to adjuvant chemotherapy and/or therapeutics that target DSB repair‐dysfunctional tumors. —Deniz, M. , Kaufmann, J., Stahl, A. , Gundelach, T. , Janni, W. , Hoffmann, I. , Keimling, M. , Hampp, S. , Ihle, M. , Wiesmüller, L. In vitro model for DNA double‐strand break repair analysis in breast cancer reveals cell type–specific associations with age and prognosis. FASEB J. 30, 3786–3799 (2016) www.fasebj. org
Automated Cerebral Infarct Volume Measurement in Follow-up Noncontrast CT Scans of Patients with Acute Ischemic Stroke

BACKGROUND AND PURPOSE: Cerebral infarct volume as observed in follow-up CT is an important radiologic outcome measure of the effectiveness of treatment of patients with acute ischemic stroke. However, manual measurement of CIV is time-consuming and operator-dependent. The purpose of this study was to develop and evaluate a robust automated measurement of the CIV. MATERIALS AND METHODS: The CIV in early follow-up CT images of 34 consecutive patients with acute ischemic stroke was segmented with an automated intensity-based region-growing algorithm, which includes partial volume effect correction near the skull, midline determination, and ventricle and hemorrhage exclusion. Two observers manually delineated the CIV. Interobserver variability of the manual assessments and the accuracy of the automated method were evaluated by using the Pearson correlation, Bland-Altman analysis, and Dice coefficients. The accuracy was defined as the correlation with the manual assessment as a reference standard. RESULTS: The Pearson correlation for the automated method compared with the reference standard was similar to the manual correlation (R = 0.98). The accuracy of the automated method was excellent with a mean difference of 0.5 mL with limits of agreement of −38.0–39.1 mL, which were more consistent than the interobserver variability of the 2 observers (−40.9–44.1 mL). However, the Dice coefficients were higher for the manual delineation. CONCLUSIONS: The automated method showed a strong correlation and accuracy with the manual reference measurement. This approach has the potential to become the standard in assessing the infarct volume as a secondary outcome measure for evaluating the effectiveness of treatment.
Bi-directional associations between healthy lifestyles and mood disorders in young adults: The Childhood Determinants of Adult Health Study

Background Healthy lifestyles prevent cardiovascular disease and are increasingly recognized in relation to mental health but longitudinal studies are limited. We examined bi-directional associations between mood disorders and healthy lifestyles in a cohort followed for 5 years. Method Participants were aged 26–36 years at baseline (2004–2006) and 31–41 years at follow-up (2009–2011). At follow-up, lifetime mood disorders (depression or dysthymia) were retrospectively diagnosed with the Composite International Diagnostic Interview. A five-item lifestyle score (comprising body mass index, non-smoking, alcohol consumption, leisure time physical activity and healthy diet) was measured at both time points. Linear and log multinomial regression determined if mood disorder before baseline predicted changes in lifestyle (n = 1041). Log binomial regression estimated whether lifestyle at baseline predicted new episodes of mood disorder (n = 1233). Covariates included age, sex, socio-economic position, parental and marital status, social support, major life events, cardiovascular disease history, and self-rated physical and mental health. Results A history of mood disorder before baseline predicted unfavourable trajectories of lifestyle over follow-up, including somewhat lower risk of improvement [relative risk (RR) 0.76, 95% confidence interval (CI) 0.56–1.03] and greater risk of worsening (RR 1.46, 95% CI 0.99–2.15) of lifestyle independent of confounding factors. Higher lifestyle scores at baseline were associated with a 22% (RR 0.76, 95% CI 0.61–0.95) reduced risk of first episodes of mood disorder, independent of confounding factors. Conclusions Healthy lifestyles and mood disorders are closely related. Our results suggest that healthy lifestyles may not only reduce cardiovascular disease but also promote mental health.
Differential free fatty acid receptor-1 (FFAR1/GPR40) signalling is associated with gene expression or gelatinase granule release in bovine neutrophils

Fatty acids have been recognized as regulators of immune function in addition to their known metabolic role. Long-chain fatty acids bind free fatty acid receptor (FFAR)-1/GPR40, which is expressed on bovine neutrophils, and increase responses such as granule release and gene expression. In this study, we investigated the molecular mechanisms governing the up-regulation of cyclooxygenase-2 (COX-2) and IL-8, as well as matrix metalloproteinase (MMP)-9 granule release in FFAR1/GPR40 agonist-stimulated neutrophils. Our results showed that natural (oleic and linoleic acid) and synthetic (GW9508) FFAR1/GPR40 agonists increased ERK1/2, p38 MAPK and Akt phosphorylation, and that the FFAR1/GPR40 antagonist GW1100 reduced these responses. We evaluated the levels of IκBα, a component of the classical activation pathway of the transcription factor NF-κB, and we observed IκBα reduction after stimulation with FFAR1/GPR40 agonists, an effect that was inhibited by GW1100 or the inhibitors UO126, SB203580 or LY294002. FFAR1/GPR40 agonists increased COX-2 and IL-8 expression, which was inhibited by GW1100 and an NF-κB inhibitor. Finally, the FFAR1/GPR40 agonist-induced MMP-9 granule release was reduced by GW1100 and UO126. In conclusion, FFAR1/GPR40 agonists differentially stimulate neutrophil functions; COX-2 and IL-8 are expressed after FFAR1/GPR40 activation via NF-κB, IκBα reduction is FFAR1/GPR40- and PI3K/MAPK-dependent, and MMP-9 granule release is FFAR1/GPR40- and ERK1/2-dependent.
The semitendinosus tendon regenerates after resection: A morphologic and MRI analysis in 6 patients after resection for anterior cruciate ligament reconstruction

Recently, the surprising observation has been made, supported by clinical and MRI findings, that the semitendinosus tendon can regenerate after being harvested in its whole length and thickness for anterior cruciate ligament reconstruction. We studied 6 patients with previous anterior cruciate ligament reconstruction, using a quadruple semitendinosus tendon autograft. In 5 of these, physical examination and MRI showed that the tendond had regenerated. In all 6 patients, the findings were documented macroscopically by open surgical exploration and in the 5 regenerated tendons, also morphologically by biopsies. Macroscopically, histologically and immunohistochemically the regenerated tendons closely resembled normal ones with focal scar-like areas. Our present findings and earlier studies show that full length and thickness harvesting of the semitendinosus tendon in most cases result in full-length tendon regeneration with tissue closely resembling the normal tendon.
Activated rat hepatic stellate cells influence Th1/Th2 profile in vitro.

AIM To investigate the effects of activated rat hepatic stellate cells (HSCs) on rat Th1/Th2 profile in vitro. METHODS Growth and survival of activated HSCs and CD4(+) T lymphocytes cultured alone or together was assessed after 24 or 48 h. CD4(+) T lymphocytes were then cultured with or without activated HSCs for 24 or 48 h and the proportion of Th1 [interferon (IFN)-γ(+)] and Th2 [interleukin (IL)-4(+)] cells was assessed by flow cytometry. Th1 and Th2 cell apoptosis was assessed after 24 h of co-culture using a caspase-3 staining procedure. Differentiation rates of Th1 and Th2 cells from CD4(+) T lymphocytes that were positive for CD25 but did not express IFN-γ or IL-4 were also assessed after 48 h of co-culture with activated HSCs. Galectin-9 expression in HSCs was determined by immunofluorescence and Western blotting. ELISA was performed to assess galectin-9 secretion from activated HSCs. RESULTS Co-culture of CD4(+) T lymphocytes with activated rat HSCs for 48 h significantly reduced the proportion of Th1 cells compared to culture-alone conditions (-1.73% ± 0.71%; P < 0.05), whereas the proportion of Th2 cells was not altered; the Th1/Th2 ratio was significantly decreased (-0.44 ± 0.13; P < 0.05). In addition, the level of IFN-γ in Th1 cells was decreased (-65.71 ± 9.67; P < 0.01), whereas the level of IL-4 in Th2 cells was increased (82.79 ± 25.12; P < 0.05) by co-culturing, as measured by mean fluorescence intensity by flow cytometry. Apoptosis rates in Th1 (12.27% ± 0.99%; P < 0.01) and Th2 (1.71% ± 0.185%; P < 0.01) cells were increased 24 h after co-culturing with activated HSCs; the Th1 cell apoptosis rate was significantly higher than in Th2 cells (P < 0.01). Galectin-9 protein expression was significantly decreased in HSCs only 24 h after co-culturing (P < 0.05) but not after 48 h. Co-culture for 48 h significantly increased the differentiation of Th1 and Th2 cells; however, the increase in the proportion of Th2 cells was significantly higher than that of Th1 cells (1.85% ± 0.48%; P < 0.05). CONCLUSION Activated rat HSCs lower the Th1/Th2 profile, inhibiting the Th1 response and enhancing the Th2 response, and this may be a novel pathway for liver fibrogenesis.
Nonsteroidal anti-inflammatory drug hypersensitivity syndrome: a multicenter study. II. Basophil activation by nonsteroidal anti-inflammatory drugs and its impact on pathogenesis.

BACKGROUND Patients who are clinically hypersensitive to nonsteroidal anti-inflammatory drugs (NSAIDs) sometimes present basophil activation in vitro, and in 50% of cases a parallel response to release of sulfidoleukotrienes (cellular allergen stimulation test) is observed. These phenomena occur not only in clinically hypersensitive patients, but also in some healthy controls who tolerate NSAIDs. MATERIAL AND METHODS We studied 16 clinically hypersensitive patients, 22 controls tolerating NSAIDs, and 29 healthy blood donors (clinical NSAID status unknown) using 2 different basophil isolation techniques (buffy coat or plasma leukocytes). RESULTS In a population of 13 aspirin-tolerant healthy controls and 29 healthy blood donors, basophil activation with aspirin, diclofenac, and naproxen was analyzed at 4 different concentrations. The results in the 2 groups were quite similar in qualitative terms. Choosing a cutoff of 5% and a stimulation index >2, the proportion of positive results increased with the concentration. There were more positive results at all concentrations using the plasma leukocyte technique. CONCLUSIONS The most important finding of this study is that basophil activation by NSAIDs occurs not only in clinically hypersensitive patients but also, to a very variable extent and on an individual basis, in apparently normal healthy individuals who tolerate NSAIDs. The phenomenon is clearly dose-related, and hypersensitive patients seem to react to lower NSAID concentrations.
Risk Factors for Fecal and Urinary Incontinence After Childbirth: The Childbirth and Pelvic Symptoms Study

OBJECTIVE: To identify risk factors for postpartum FI and UI.METHODS: Secondary analysis of data from the CAPS study, which estimated the prevalence of postpartum FI and UI in primiparous women with clinically recognized anal sphincter tears after vaginal delivery, compared with women who delivered vaginally without recognized tears or by cesarean before labor. A total of 921 women were enrolled while in the hospital and 759 (82%) were interviewed by telephone 6 months postpartum. FI was assessed using the FISI and UI using the Medical, Epidemiological, and Social Aspects of Aging Questionnaire. FI risk factor analyses were conducted within each group, because of higher prevalence in the tear group. UI analyses were conducted with the groups combined.RESULTS: In women with sphincter tears, FI at 6 months was associated with white race (OR 6.1, 95% CI 1.3–29.4), antenatal UI (OR 2.2, CI 1.1–4.3), 4th versus 3rd degree tear (OR 2.0, CI 1.0–4.0), older age at delivery (OR 1.6 per 5 yr, CI 1.2–2.1), and higher body mass index (BMI) (OR 1.3 per 5 kg/m2, CI 1.0–1.7). No factors were associated with FI in the vaginal or cesarean control groups. Across all groups, risk factors for postpartum UI were antenatal UI (OR 3.5, CI 2.4–5.2), less education (OR 2.0, CI 1.4–2.8), and higher BMI (OR 1.2 per 5 kg/m2, CI 1.1–1.4); cesarean delivery was protective (OR 0.5, CI 0.3–0.9). CONCLUSIONS: Postpartum FI and UI are associated with few modifiable risk factors. However, the presence of antenatal UI and high BMI may help clinicians target at-risk women for early intervention.