Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51.

BACKGROUND: Chemotherapy is a standard therapeutic regimen to treat triple-negative breast cancer (TNBC); however, chemotherapy alone does not result in significant improvement and often leads to drug resistance in patients. In contrast, combination therapy has proven to be an effective strategy for TNBC treatment. Whether metformin enhances the anticancer effects of cisplatin and prevents cisplatin resistance in TNBC cells has not been reported. METHODS: Cell viability, wounding healing, and invasion assays were performed on Hs 578T and MDA-MB-231 human TNBC cell lines to demonstrate the anticancer effects of combined cisplatin and metformin treatment compared to treatment with cisplatin alone. Western blotting and immunofluorescence were used to determine the expression of RAD51 and gamma-H2AX. In an in vivo 4T1 murine breast cancer model, a synergistic anticancer effect of metformin and cisplatin was observed. RESULTS: Cisplatin combined with metformin decreased cell viability and metastatic effect more than cisplatin alone. Metformin suppressed cisplatin-mediated RAD51 upregulation by decreasing RAD51 protein stability and increasing its ubiquitination. In contrast, cisplatin increased RAD51 expression in an ERK-dependent manner. In addition, metformin also increased cisplatin-induced phosphorylation of γ-H2AX. Overexpression of RAD51 blocked the metformin-induced inhibition of cell migration and invasion, while RAD51 knockdown enhanced cisplatin activity. Moreover, the combination of metformin and cisplatin exhibited a synergistic anticancer effect in an orthotopic murine model of 4T1 breast cancer in vivo. CONCLUSIONS: Metformin enhances anticancer effect of cisplatin by downregulating RAD51 expression, which represents a novel therapeutic target in TNBC management.

Assessing preschool children's physical activity: how many days of accelerometry measurement.

The purpose of this study was to determine the minimum number of days of accelerometry required to estimate accurately MVPA and total PA in 3- to 5-year-old children. The study examined these metrics for all days, weekdays, and in-school activities. Study participants were 204 children attending 22 preschools who wore accelerometers for at least 6 hr per day for up to 12 days during most waking hours. The primary analysis considered the intraclass correlation coefficient (ICC) for each metric to estimate the number of days required to attain a specified reliability. The ICC estimates are 0.81 for MVPA-all days, 0.78 for total PA-all days, 0.83 for MVPA weekdays, 0.80 for total PA-weekdays, 0.81 for in-school MVPA, and 0.84 for in-school total PA. We recommend a full seven days of measurement whenever possible, but researchers can achieve acceptable reliability with fewer days, as indicated by the Spearman-Brown prophecy: 3-4 days for any weekday measure and 5-6 days for the all-days measures.

The myokine meteorin-like (metrnl) improves glucose tolerance in both skeletal muscle cells and mice by targeting AMPKα2.

Meteorin-like (metrnl) is a recently identified adipomyokine that beneficially affects glucose metabolism; however, its underlying mechanism of action is not completely understood. We here show that the level of metrnl increases in vitro under electrical pulse stimulation and in vivo in exercised mice, suggesting that metrnl is secreted during muscle contractions. In addition, metrnl increases glucose uptake via the calcium-dependent AMPKα2 pathway in skeletal muscle cells and increases the phosphorylation of HDAC5, a transcriptional repressor of GLUT4, in an AMPKα2-dependent manner. Phosphorylated HDAC5 interacts with 14-3-3 proteins and sequesters them in the cytoplasm, resulting in the activation of GLUT4 transcription. An intraperitoneal injection of recombinant metrnl improved glucose tolerance in mice with high-fat-diet-induced obesity or type 2 diabetes, but not in AMPK ß1ß2 muscle-specific null mice. Metrnl improves glucose metabolism via AMPKα2 and is a promising therapeutic candidate for glucose-related diseases such as type 2 diabetes.

Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients.

BACKGROUND AND OBJECTIVE: Despite the belief that cytochrome P450 (CYP) 2D6 alone is responsible for the metabolism of risperidone, several studies suggest that CYP3A may be involved. The aim of this study was to evaluate the effect of itraconazole, a CYP3A inhibitor, on the plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients in relation to CYP2D6 genotype. METHODS: Nineteen schizophrenic patients treated with 2 to 8 mg/d of risperidone received 200 mg/d of itraconazole for a week. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured immediately before and after itraconazole treatment, as well as at 1 week after itraconazole treatment was stopped, together with clinical assessment by use of the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale and the Brief Psychiatric Rating Scale. RESULTS: Dose-normalized plasma concentrations of risperidone and 9-hydroxyrisperidone before itraconazole treatment (0.9 +/- 0.8 ng.mL(-1).mg(-1) and 6.9 +/- 3.3 ng.mL(-1).mg(-1), respectively) were significantly elevated after itraconazole treatment (1.6 +/- 1.3 ng.mL(-1).mg(-1) and 11.3 +/- 4.5 ng.mL(-1).mg(-1)) and decreased 1 week after its discontinuation (1.0 +/- 0.8 ng.mL(-1).mg(-1) and 7.2 +/- 3.7 ng.mL(-1).mg(-1)) (P < .01). However, the ratio of risperidone/9-hydroxyrisperidone, an index of CYP2D6 activity, did not differ before itraconazole treatment (0.14 +/- 0.13), after itraconazole treatment (0.15 +/- 0.13), and 1 week after discontinuation (0.14 +/- 0.13) (P > .05). Itraconazole increased the concentrations of risperidone by 69% (P < .001) and 75% (P < .01) in CYP2D6 extensive and poor metabolizers, respectively. In addition, the active moiety (risperidone plus 9-hydroxyrisperidone) also increased similarly, by 71% (P < .001) and 73% (P < .05), respectively, with itraconazole, without a significant difference between CYP2D6 genotypes. The scores on the Brief Psychiatric Rating Scale decreased significantly but only by 6% after itraconazole treatment (P < .05); however, the scores on the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale were not changed. CONCLUSIONS: Our results provide in vivo evidence of the involvement of CYP3A in the disposition of risperidone and 9-hydroxyrisperidone. In addition to CYP2D6, treatment with CYP3A inhibitor(s) including itraconazole may influence clinical symptoms and risperidone side effects.

Convergent validity of pedometer and accelerometer estimates of moderate-to-vigorous physical activity of youth.

BACKGROUND: Pedometer step-frequency thresholds (120 steps·min-1, SPM) corresponding to moderate-to vigorous intensity physical activity (MVPA) have been proposed for youth. Pedometers now have internal mechanisms to record time spent at or above a user-specified SPM. If pedometers provide comparable MVPA (P-MVPA) estimates to those from accelerometry, this would have broad application for research and the general public. The purpose of this study was to examine the convergent validity of P-MVPA to accelerometer-MVPA for youth. METHODS: Youth (N = 149, average 8.6 years, range 5 to 14 years, 60 girls) wore an accelerometer (5-sec epochs) and a pedometer for an average of 5.7 ± 0.8 hours·day-1. The following accelerometer cutpoints were used to compare P-MVPA: Treuth (TR), Mattocks (MT), Evenson (EV), Puyau (PU), and Freedson (FR) child equation. Comparisons between MVPA estimates were performed using Bland-Altman plots and paired t tests. RESULTS: Overall, P-MVPA was 24.6 min ± 16.7 vs. TR 25.2 min ± 16.2, MT 18.8 min ± 13.3, EV 36.9 min ± 21.0, PU 22.7 min ± 15.1, and FR 50.4 min ± 25.5. Age-specific comparisons indicated for 10 to 14 year-olds MT, PU, and TR were not significantly different from P-MVPA; for the younger children (5-8 year- olds) P-MVPA consistently underestimated MVPA. CONCLUSIONS: Pedometer-determined MVPA provided comparable estimates of MVPA for older children (10-14 year-olds). Additional work is required to establish age appropriate SPM thresholds for younger children.

Convergent Validity of Pedometer and Accelerometer Estimates of Moderate-to-Vigorous Physical Activity of Youth.

BACKGROUND: Pedometer step-frequency thresholds (120 steps·min-1, SPM) corresponding to moderate-to-vigorous intensity physical activity (MVPA) have been proposed for youth. Pedometers now have internal mechanisms to record time spent at or above a user-specified SPM. If pedometers provide comparable MVPA (P-MVPA) estimates to those from accelerometry, this would have broad application for research and the general public. The purpose of this study was to examine the convergent validity of P-MVPA to accelerometer-MVPA for youth. METHODS: Youth (N = 149, average 8.6 years, range 5 to 14 years, 60 girls) wore an accelerometer (5-sec epochs) and a pedometer for an average of 5.7 ± 0.8 hours·day-1. The following accelerometer cutpoints were used to compare P-MVPA: Treuth (TR), Mattocks (MT), Evenson (EV), Puyau (PU), and Freedson (FR) child equation. Comparisons between MVPA estimates were performed using Bland-Altman plots and paired t tests. RESULTS: Overall, P-MVPA was 24.6 min ± 16.7 vs. TR 25.2 min ± 16.2, MT 18.8 min ± 13.3, EV 36.9 min ± 21.0, PU 22.7 min ± 15.1, and FR 50.4 min ± 25.5. Age-specific comparisons indicated for 10 to 14 year-olds MT, PU, and TR were not significantly different from P-MVPA; for the younger children (5-8 year- olds) P-MVPA consistently underestimated MVPA. CONCLUSIONS: Pedometer-determined MVPA provided comparable estimates of MVPA for older children (10-14 year-olds). Additional work is required to establish age appropriate SPM thresholds for younger children.

A study of the reliability and validity of the korean version of the penn alcohol craving scale for alcohol-dependent patients.

OBJECTIVE: The Penn Alcohol Craving Scale (PACS) is a stronger predictor of subsequent drinking and relapse of alcohol dependence that can be administered more quickly and easily than other craving scales. The goal of this study was to develop the Korean version of the Penn Alcohol Craving Scale (PACS-K). METHODS: To examine the psychometric properties of the PACS-K, responses were chosen from 80 patients admitted to a treatment facility for alcohol dependence. RESULTS: The PACS-K possesses good psychometric properties, as assessed by Cronbach's alpha estimates (Cronbach's alpha=0.91). The test-retest reliability of the PACS-K showed high correlation (p<0.01) when the retest interval was 1 day. When the validity of the PACS-K was investigated using correlation analysis with two other craving scales (the Obsessive Compulsive Drinking Scale (OCDS) and the Visual Analogue Scale (VAS), high correlations were obtained between total PACS scores and total OCDS scores, and between total PACS scores and VAS scores (p<0.01, respectively). CONCLUSION: The PACS-K is a reliable and valid measure of alcohol cravings, and it could be useful for predicting which individuals are at risk for subsequent relapse.

Association of functional opioid receptor genotypes with alcohol dependence in Koreans.

BACKGROUND: The functional polymorphism (A118G) of the mu-opioid receptor gene (OPRM1) is thought to have clinical significance in the treatment of alcohol dependence. This study compared Koreans with one or two copies of the A118G polymorphism seeking treatment for alcohol dependence with a group of non-alcohol-dependent controls. METHODS: Patients hospitalized for alcohol dependence (n = 112) and a group of non-alcohol-dependent controls (n = 140) were interviewed on aspects of drinking history and psychiatric history. Patients and controls were excluded if they met criteria for any other major psychiatric disorder. Participants were genotyped at the OPRM1 locus. RESULTS: The allele frequency of the Asp40 allele was 0.397 in the alcohol-dependent group, which is consistent with other literature demonstrating this polymorphism to be common in Asian populations. Within the alcohol-dependent subjects, being homozygous for the Asp40 allele was associated with more days drinking than those heterozygous or homozygous for the Asn40 allele. Differences in the allele frequencies between alcohol-dependent and non-alcohol-dependent controls were not significant. CONCLUSIONS: These results suggest that having one or two copies of the A118G allele is common among Koreans and may be an important genetic factor in the etiology of alcohol dependence and the frequency of alcohol consumption.