Resistin potentiates chemoresistance and stemness of breast cancer cells: Implications for racially disparate therapeutic outcomes.

Breast cancer (BC) continues to be the most frequently diagnosed cancer in American women, which disproportionately affects women of African-American (AA) descent. Previously, we reported greater serum levels of resistin in AA BC patients relative to Caucasian-American (CA) patients, and established its role in growth and aggressiveness of breast tumor cells. Here we have investigated the role of resistin in BC-chemoresistance. MDA-MB-231 and MDA-MB-468 BC cells of CA and AA origin, respectively, were incubated with resistin prior to doxorubicin treatment. Our data suggest that resistin conferred chemoresistance to both BC cell lines; however, the effect on AA cells was more profound. Furthermore, the resistin-induced doxorubicin-resistance was shown to occur due to suppression of apoptosis. Resistin treatment also affected the stemness of BC cells, as suggested by reduced cell surface expression of CD24, induced expression of CD44 and ALDH1, and increased capability of cells to form mammospheres. Mechanistic studies revealed that resistin-induced chemoresistance, apoptosis and stemness of BC cells were mediated through STAT3 activation. Taken together, our findings provide novel insight into the role of resistin in BC biology, and strengthen its role in racially disparate clinical outcomes.

United Kingdom health research analyses and the benefits of shared data.

BACKGROUND: To allow research organisations to co-ordinate activity to the benefit of national and international funding strategies requires assessment of the funding landscape; this, in turn, relies on a consistent approach for comparing expenditure on research. Here, we discuss the impact and benefits of the United Kingdom's Health Research Classification System (HRCS) in national landscaping analysis of health research and the pros and cons of performing large-scale funding analyses. METHODS: The first United Kingdom health research analysis (2004/2005) brought together the 11 largest public and charity funders of health research to develop the HRCS and use this categorisation to examine United Kingdom health research. The analysis was revisited in 2009/2010 and again in 2014. The most recent quinquennial analysis in 2014 compiled data from 64 United Kingdom research organisations, accounting for 91% of all public/charitable health research funding in the United Kingdom. The three analyses summarise the United Kingdom's health research expenditure in 2004/2005, 2009/2010 and 2014, and can be used to identify changes in research activity and disease focus over this 10 year period. RESULTS: The 2004/2005 analysis provided a baseline for future reporting and evidence for a United Kingdom Government review that recommended the co-ordination of United Kingdom health research should be strengthened to accelerate the translation of basic research into clinical and economic benefits. Through the second and third analyses, we observed strategic prioritisation of certain health research activities and disease areas, with a strong trend toward increased funding for more translational research, and increases in specific areas such as research on prevention. CONCLUSIONS: The use of HRCS in the United Kingdom to analyse the research landscape has provided benefit both to individual participatory funders and in coordinating initiatives at a national level. A modest amount of data for each project is sufficient for a nationwide assessment of health research funding, but achieving coverage of the United Kingdom portfolio relies on sourcing these details from a large number of individual funding agencies. The effort needed to compile this data could be minimised if funders routinely shared or published this information in a standard and accessible way. The United Kingdom approach to landscaping analyses could be readily adapted to suit other groups or nations, and global availability of research funding data would support better national and international coordination of health research.

Resistin and interleukin-6 exhibit racially-disparate expression in breast cancer patients, display molecular association and promote growth and aggressiveness of tumor cells through STAT3 activation.

African-American (AA) women with breast cancer (BC) are diagnosed with more aggressive disease, have higher risk of recurrence and poorer prognosis as compared to Caucasian American (CA) women. Therefore, it is imperative to define the factors associated with such disparities to reduce the unequal burden of cancer. Emerging data suggest that inherent differences exist in the tumor microenvironment of AA and CA BC patients, however, its molecular bases and functional impact have remained poorly understood. Here, we conducted cytokine profiling in serum samples from AA and CA BC patients and identified resistin and IL-6 to be the most differentially-expressed cytokines with relative greater expression in AA patients. Resistin and IL-6 exhibited positive correlation in serum levels and treatment of BC cells with resistin led to enhanced production of IL-6. Moreover, resistin also enhanced the expression and phosphorylation of STAT3, and treatment of BC cells with IL-6-neutralizing antibody prior to resistin stimulation abolished STAT3 phosphorylation. In addition, resistin promoted growth and aggressiveness of BC cells, and these effects were mediated through STAT3 activation. Together, these findings suggest a crucial role of resistin, IL-6 and STAT3 in BC racial disparity.

Development of an accelerometer-based multivariate model to predict free-living energy expenditure in a large military cohort.

This study developed a multivariate model to predict free-living energy expenditure (EE) in independent military cohorts. Two hundred and eighty-eight individuals (20.6 ± 3.9 years, 67.9 ± 12.0 kg, 1.71 ± 0.10 m) from 10 cohorts wore accelerometers during observation periods of 7 or 10 days. Accelerometer counts (PAC) were recorded at 1-minute epochs. Total energy expenditure (TEE) and physical activity energy expenditure (PAEE) were derived using the doubly labelled water technique. Data were reduced to n = 155 based on wear-time. Associations between PAC and EE were assessed using allometric modelling. Models were derived using multiple log-linear regression analysis and gender differences assessed using analysis of covariance. In all models PAC, height and body mass were related to TEE (P < 0.01). For models predicting TEE (r (2) = 0.65, SE = 462 kcal · d(-1) (13.0%)), PAC explained 4% of the variance. For models predicting PAEE (r (2) = 0.41, SE = 490 kcal · d(-1) (32.0%)), PAC accounted for 6% of the variance. Accelerometry increases the accuracy of EE estimation in military populations. However, the unique nature of military life means accurate prediction of individual free-living EE is highly dependent on anthropometric measurements.

An investigation of a novel three-dimensional activity monitor to predict free-living energy expenditure.

The aim of this study was to assess the capability of the 3dNX accelerometer to predict energy expenditure in two separate, free-living cohorts. Twenty-three adolescents and 14 young adults took a single dose of doubly labelled water and wore a 3dNX activity monitor during waking hours for a 10-day period while carrying out their normal routines. Multiple linear regression with backward elimination was used to establish the strength of the associations between various indices of energy expenditure, physical activity counts, and anthropometric variables. 3dNX output accounted for 27% and 35% of the variance in the total energy expenditure of the adolescent and young adult cohort, respectively. The explained variance increased to 78%, with a standard error of estimate of 7%, when 3dNX output was combined with body composition variables. The 3dNX accelerometer can be used to predict free-living daily energy expenditure with a standard error of estimate of 1.65 MJ in adolescents and 1.52 MJ in young adults. The inclusion of anthropometric variables reduces the error to approximately 1 MJ. Although it remains to cross-validate these models in other populations, early indications suggest that the 3dNX provides a useful method of predicting energy expenditure in free-living individuals.

Institution and validation of an observed structured assessment of technical skills (OSATS) for obstetrics and gynecology residents and faculty.

OBJECTIVE: This study was undertaken to further evaluate the construct validity of the observed structured assessment of technical skills (OSATS) by comparing resident scores to faculty scores. STUDY DESIGN: This study is a prospective blinded observational study. Four residents from each year (1-4) and 5 faculty members were examined. The OSATS examination was in the form of a dry laboratory with 10 stations: 4 laparoscopic and 6 open surgical skills. The sessions were videotaped and graded by the senior authors who used a task-specific checklist. The scoring of the videos was performed by the 2 senior authors blinded to the other examiners results. The examinations were videotaped, and the identity of the participants was blinded. The scores for each station were determined by adding all the numbers from the skills rating with a time score. Higher scores denote superior performance. Statistical analysis was performed with a nonparametric test (Kruskal-Wallis) for a total score with resident years divided into junior residents (first and second year), senior residents (third and fourth year), and faculty status as the independent variable. To determine the interrelater reliability between the 2 scores, the Kendall tau beta statistic was used. RESULTS: The results show definite trends for 7 stations, with junior residents performing the worst and faculty performing the best. This trend was statistically significant for 6 of the 10 stations. CONCLUSION: The OSATS examination has good construct validity that extends beyond residency to faculty.