ERCC1 expression and RAD51B activity correlate with cell cycle response to platinum drug treatment not DNA repair

Background: The H69CIS200 and H69OX400 cell lines are novel models of low-level platinum-drug resistance. Resistance was not associated with increased cellular glutathione or decreased accumulation of platinum, rather the resistant cell lines have a cell cycle alteration allowing them to rapidly proliferate post drug treatment. Results: A decrease in ERCC1 protein expression and an increase in RAD51B foci activity was observed in association with the platinum induced cell cycle arrest but these changes did not correlate with resistance or altered DNA repair capacity. The H69 cells and resistant cell lines have a p53 mutation and consequently decrease expression of p21 in response to platinum drug treatment, promoting progression of the cell cycle instead of increasing p21 to maintain the arrest. Conclusion: Decreased ERCC1 protein and increased RAD51B foci may in part be mediating the maintenance of the cell cycle arrest in the sensitive cells. Resistance in the H69CIS200 and H69OX400 cells may therefore involve the regulation of ERCC1 and RAD51B independent of their roles in DNA repair. The novel mechanism of platinum resistance in the H69CIS200 and H69OX400 cells demonstrates the multifactorial nature of platinum resistance which can occur independently of alterations in DNA repair capacity and changes in ERCC1

Differential susceptibility to obesity between male, female and ovariectomized female mice

All authors are with the Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas, USABackground: The prevalence of obesity has increased dramatically. A direct comparison in the predisposition to obesity between males, premenopausal females, and postmenopausal females with various caloric intakes has not been made. To determine the effects of sex and ovarian hormones on the susceptibility to obesity, we conducted laboratory studies with mice. To eliminate confounders that can alter body weight gain, such as age and food consumption; we used mice with the same age and controlled the amount of calories they consumed. -- Methods: We determined sex-specific susceptibility to obesity between male, non-ovariectomized female, and ovariectomized female mice. To compare susceptibility to gaining body weight between males and females, animals from each sex were exposed to either a 30% calorie-restricted, low-fat (5% fat), or high-fat (35% fat) diet regimen. To establish the role of ovarian hormones in weight gain, the ovaries were surgically removed from additional female mice, and then were exposed to the diets described above. Percent body fat and percent lean mass in the mice were determined by dual energy x-ray absorptiometry (DEXA). -- Results: In all three diet categories, male mice had a greater propensity of gaining body weight than female mice. However, ovariectomy eliminated the protection of female mice to gaining weight; in fact, ovariectomized female mice mimicked male mice in their susceptibility to weight gain. In summary, results show that male mice are more likely to become obese than female mice and that the protection against obesity in female mice is eliminated by ovariectomy. -- Conclusion: Understanding metabolic differences between males and females may allow the discovery of better preventive and treatment strategies for diseases associated with body weight such as cancer and cardiovascular disease.Nutritional [email protected]

Early Predictors of Employment Status One Year Post Injury in Individuals with Traumatic Brain Injury in Europe

Sustaining a traumatic brain injury (TBI) often affects the individual's ability to work, reducing employment rates post-injury across all severities of TBI. The objective of this multi-country study was to assess the most relevant early predictors of employment status in individuals after TBI at one-year post-injury in European countries. Using a prospective longitudinal non-randomized observational cohort (The Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) project), data was collected between December 2014-2019 from 63 trauma centers in 18 European countries. The 1015 individuals who took part in this study were potential labor market participants, admitted to a hospital and enrolled within 24 h of injury with a clinical TBI diagnosis and indication for a computed tomography (CT) scan, and followed up at one year. Results from a binomial logistic regression showed that older age, status of part-time employment or unemployment at time of injury, premorbid psychiatric problems, and higher injury severity (as measured with higher Injury severity score (ISS), lower Glasgow Coma Scale (GCS), and longer length of stay (LOS) in hospital) were associated with higher unemployment probability at one-year after injury. The study strengthens evidence for age, employment at time of injury, premorbid psychiatric problems, ISS, GCS, and LOS as important predictors for employment status one-year post-TBI across Europe

Astrocytic Ion Dynamics: Implications for Potassium Buffering and Liquid Flow

We review modeling of astrocyte ion dynamics with a specific focus on the implications of so-called spatial potassium buffering, where excess potassium in the extracellular space (ECS) is transported away to prevent pathological neural spiking. The recently introduced Kirchoff-Nernst-Planck (KNP) scheme for modeling ion dynamics in astrocytes (and brain tissue in general) is outlined and used to study such spatial buffering. We next describe how the ion dynamics of astrocytes may regulate microscopic liquid flow by osmotic effects and how such microscopic flow can be linked to whole-brain macroscopic flow. We thus include the key elements in a putative multiscale theory with astrocytes linking neural activity on a microscopic scale to macroscopic fluid flow.Comment: 27 pages, 7 figure

Comparison of air displacement plethysmography to hydrostatic weighing for estimating total body density in children

BACKGROUND: The purpose of this study was to examine the accuracy of total body density and percent body fat (% fat) using air displacement plethysmography (ADP) and hydrostatic weighing (HW) in children. METHODS: Sixty-six male and female subjects (40 males: 12.4 ± 1.3 yrs, 47.4 ± 14.8 kg, 155.4 ± 11.9 cm, 19.3 ± 4.1 kg/m(2); 26 females: 12.0 ± 1.9 yrs, 41.4 ± 7.7 kg, 152.1 ± 8.9 cm, 17.7 ± 1.7 kg/m(2)) were tested using ADP and HW with ADP always preceding HW. Accuracy, precision, and bias were examined in ADP with HW serving as the criterion method. Lohman's equations that are child specific for age and gender were used to convert body density to % fat. Regression analysis determined the accuracy of ADP and potential bias between ADP and HW using Bland-Altman analysis. RESULTS: For the entire group (Y = 0.835x + 0.171, R(2 )= 0.84, SEE = 0.007 g/cm(3)) and for the males (Y = 0.837x + 0.174, R(2 )= 0.90, SEE = 0.006 g/cm(3)) the regression between total body density by HW and by ADP significantly deviated from the line of identity. However in females, the regression between total body density by HW and ADP did not significantly deviate from the line of identity (Y = 0.750x + 0.258, R(2 )= 0.55, SEE = 0.008 g/cm(3)). The regression between % fat by HW and ADP for the group (Y = 0.84x + 3.81, R(2 )= 0.83, SEE = 3.35 % fat) and for the males (Y = 0.84x + 3.25, R(2 )= 0.90, SEE = 3.00 % fat) significantly deviated from the line of identity. However, in females the regression between % fat by HW and ADP did not significantly deviate from the line of identity (Y = 0.81x + 5.17, R(2 )= 0.56, SEE = 3.80 % fat). Bland-Altman analysis revealed no bias between HW total body density and ADP total body density for the entire group (R = 0.-22; P = 0.08) or for females (R = 0.02; P = 0.92), however bias existed in males (R = -0.37; P ≤ 0.05). Bland-Altman analysis revealed no bias between HW and ADP % fat for the entire group (R = 0.21; P = 0.10) or in females (R = 0.10; P = 0.57), however bias was indicated for males by a significant correlation (R = 0.36; P ≤ 0.05), with ADP underestimating % fat at lower fat values and overestimating at the higher % fat values. CONCLUSION: A significant difference in total body density and % fat was observed between ADP and HW in children 10–15 years old with a potential gender difference being detected. Upon further investigation it was revealed that the study was inadequately powered, thus we recommend that larger studies that are appropriately powered be conducted to better understand this potential gender difference

Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule

Overexpression of Bcl-2 protein occurs via both t(14;18)-dependent and independent mechanisms and contributes to the survival and chemoresistance of non-Hodgkin lymphomas. HA14–1 is a nonpeptidic organic small molecule, which has been shown to inhibit the interaction of Bcl-2 with Bax, thereby interfering with the antiapoptotic function of Bcl-2. In this study, we sought to determine the in vitro efficacy of HA14–1 as a therapeutic agent for non-Hodgkin lymphomas expressing Bcl-2. Assessment of cell viability demonstrated that HA14–1 induced a dose- (IC50 = 10 μM) and time-dependent growth inhibition of a cell line (SudHL-4) derived from a t(14;18)-positive, Bcl-2-positive, non-Hodgkin lymphoma. HA14–1 effectively induced apoptosis via a caspase 3-mediated pathway but did not affect either the p38 MAPK or p44/42 MAPK pathways. Western blot analyses of Bcl-2 family proteins and other cell cycle-associated proteins were performed to determine the molecular sequelae of HA14–1-induced apoptosis. The results show down-regulation of Mcl-1 but up-regulation of p27kip1, Bad, Bcl-xL, and Bcl-2 proteins, without change in Bax levels during HA14–1-mediated apoptosis. Our findings further elucidate the cellular mechanisms accompanying Bcl-2 inhibition and demonstrate the potential of Bcl-2 inhibitors as therapeutic agents for the treatment of non-Hodgkin lymphomas

Translation and validation study of the Persian version of the Arthritis Impact Measurement Scales 2 (AIMS2) in patients with osteoarthritis of the knee

Background: The Arthritis Impact Measurement Scales 2 (AIMS2) has not been translated and validated for Persian-speaking patients with osteoarthritis of the knee. This was to provide a validated instrument to measure functional disability and health-related quality of life in patients with osteoarthritis of the knee in Iran. The aim of this study was to culturally adapt and validate the AIMS2 for Persian-speaking patients with osteoarthritis of the knee in Iran. Methods: A consecutive sample of patients with knee osteoarthritis were asked to complete the AIMS2, the Short Form Health Survey (SF-36) and four visual analog scales for pain, joint stiffness, patient's and physician's global assessment. Internal consistency and convergent validity were applied to examine psychometric properties of the AIMS2. In addition, 30 randomly selected patients were asked to complete the questionnaire two days later for the second time for test-retest reliability. Finally factor structure of the Persian AIMS2 was performed using the principal component factor analysis. Results: In all 230 patients were entered into the study. The mean (SD) age of the participants was 56.9 (8.7) years and the mean (SD) duration of disease was 7.2 (3.5) years. Cronbach's alpha coefficient and intraclass correlation coefficient (ICC) for the Persian AIMS2 scales ranged from 0.74 to 0.92 and 0.85 to 0.96, respectively. The correlation between most of the Persian AIMS2 scales and the physical and mental summary scores of the SF-36 and the visual analogue scales for pain, joint stiffness, patient's and physician's global assessment were statistically significant indicating a good convergent validity (p < 0.05). The results obtained from factor analysis indicated three latent factors that jointly accounted for 67.5% of the total variance. Conclusion: The results showed that the Persian AIMS2 had reasonably good internal consistency, test-retest reliability, and convergent validity in patients with osteoarthritis of the knee. It is simple and easy to use and now can be applied in the future studies in Iran. However, its sensitivity to change needs still to be studied.We wish to express our gratitude to physicians who co-operated in the selection of the patients and patients who gave their time to complete the questionnaires. This research was supported by Sport Medicine Research Center (SMRC), Tehran University of Medical Sciences; grant No 85-01-53-3579