Estrogenic activity, race/ethnicity, and Indigenous American ancestry among San Francisco Bay Area women.

Estrogens play a significant role in breast cancer development and are not only produced endogenously, but are also mimicked by estrogen-like compounds from environmental exposures. We evaluated associations between estrogenic (E) activity, demographic factors and breast cancer risk factors in Non-Latina Black (NLB), Non-Latina White (NLW), and Latina women. We examined the association between E activity and Indigenous American (IA) ancestry in Latina women. Total E activity was measured with a bioassay in plasma samples of 503 women who served as controls in the San Francisco Bay Area Breast Cancer Study. In the univariate model that included all women with race/ethnicity as the independent predictor, Latinas had 13% lower E activity (p = 0.239) and NLBs had 35% higher activity (p = 0.04) compared to NLWs. In the multivariable model that adjusted for demographic factors, Latinas continued to show lower E activity levels (26%, p = 0.026), but the difference between NLBs and NLWs was no longer statistically significant (p = 0.431). An inverse association was observed between E activity and IA ancestry among Latina women (50% lower in 0% vs. 100% European ancestry, p = 0.027) consistent with our previously reported association between IA ancestry and breast cancer risk. These findings suggest that endogenous estrogens and exogenous estrogen-like compounds that act on the estrogen receptor and modulate E activity may partially explain racial/ethnic differences in breast cancer risk

Individual variations in serum melatonin levels through time: Implications for epidemiologic studies

Melatonin, a marker for the circadian rhythm with serum levels peaking between 2AM and 5AM, is hypothesized to possess anti-cancer properties, making it a mechanistic candidate for the probable carcinogenic effect of circadian rhythm disruption. In order to weigh epidemiologic evidence on the association of melatonin with cancer, we must first understand the laboratory and biological sources of variability in melatonin levels measured in samples. Participants for this methodological study were men enrolled in the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO). We measured serum melatonin levels over a five year period in 97 individuals to test if melatonin levels are steady over time. The Pearson correlation coefficient between two measures separated by 1 year was 0.87, while the correlation between two measures separated by 5 years was to 0.70. In an additional cross-sectional study of 292 individuals, we used Analysis of Variance to identify differences in melatonin levels between different lifestyle and environmental characteristics. Serum melatonin levels were slightly higher in samples collected from 130 individuals during the winter, (6.36±0.59 pg/ml) than in samples collected from 119 individuals during the summer (4.83±0.62 pg/ml). Serum melatonin levels were lowest in current smokers (3.02±1.25 pg/ml, p = 0.007) compared to never (6.66±0.66 pg/ml) and former (5.59±0.50 pg/ml) smokers whereas BMI did not significantly affect serum melatonin levels in this study. In conclusion, the high 5 year correlation of melatonin levels implies that single measurements may be used to detect population level associations between melatonin and risk of cancer. Furthermore, our results reiterate the need to record season of sample collection, and individual characteristics in order to maximize study power and prevent confounding

MiR-155 has a protective role in the development of non-alcoholic hepatosteatosis in mice

Hepatic steatosis is a global epidemic that is thought to contribute to the pathogenesis of type 2 diabetes. MicroRNAs (miRs) are regulators that can functionally integrate a range of metabolic and inflammatory pathways in liver. We aimed to investigate the functional role of miR-155 in hepatic steatosis. Male C57BL/6 wild-type (WT) and miR-155−/− mice were fed either normal chow or high fat diet (HFD) for 6 months then lipid levels, metabolic and inflammatory parameters were assessed in livers and serum of the mice. Mice lacking endogenous miR-155 that were fed HFD for 6 months developed increased hepatic steatosis compared to WT controls. This was associated with increased liver weight and serum VLDL/LDL cholesterol and alanine transaminase (ALT) levels, as well as increased hepatic expression of genes involved in glucose regulation (Pck1, Cebpa), fatty acid uptake (Cd36) and lipid metabolism (Fasn, Fabp4, Lpl, Abcd2, Pla2g7). Using miRNA target prediction algorithms and the microarray transcriptomic profile of miR-155−/− livers, we identified and validated that Nr1h3 (LXRα) as a direct miR-155 target gene that is potentially responsible for the liver phenotype of miR-155−/− mice. Together these data indicate that miR-155 plays a pivotal role regulating lipid metabolism in liver and that its deregulation may lead to hepatic steatosis in patients with diabetes

An investigation of DEET-insensitivity in Aedes aegypti

N,N-Diethyl-m-toluamide (DEET) is one of the most effective and commonly used mosquito repellents. However, during laboratory trials a small proportion of mosquitoes are still attracted by human odours despite the presence of DEET. In this study behavioural assays identified Aedes aegypti females that were insensitive to DEET. The selection of either sensitive or insensitive groups of females with males of unknown sensitivity over several generations resulted in two populations with different proportions of insensitive females. Crossing experiments showed the ‘DEET-insensitivity’ trait to be dominant. In addition to the finding of heritable DEET-insensitivity, unselected culture mosquitoes were shown to change their sensitivity to DEET after brief pre-exposure to the repellent. Female mosquitoes that were sensitive to DEET when first tested became insensitive when retested. Electroantennography showed that mosquitoes that were insensitive to DEET had a reduced response to DEET compared with mosquitoes that were sensitive to it. This was the case both for culture mosquitoes displaying insensitivity to DEET after brief pre-exposure to it, and for the sensitive and insensitive lines selected for several generations. Single sensillum recordings of the selected lines identified DEET-sensitive sensilla in the sensitive line that did not respond to DEET in the insensitive line. This study suggests that behavioural insensitivity to DEET in Ae. aegypti is a genetically determined dominant trait, which can also be temporarily induced by pre-exposure, and resides in changes in sensillum function. These results highlight the necessity for careful monitoring of DEET-insensitivity in the field, and caution when designing laboratory methods for repellency assays

An investigation of DEET-insensitivity in Aedes aegypti

N,N-Diethyl-m-toluamide (DEET) is one of the most effective and commonly used mosquito repellents. However, during laboratory trials a small proportion of mosquitoes are still attracted by human odours despite the presence of DEET. In this study behavioural assays identified Aedes aegypti females that were insensitive to DEET. The selection of either sensitive or insensitive groups of females with males of unknown sensitivity over several generations resulted in two populations with different proportions of insensitive females. Crossing experiments showed the ‘DEET-insensitivity’ trait to be dominant. In addition to the finding of heritable DEET-insensitivity, unselected culture mosquitoes were shown to change their sensitivity to DEET after brief pre-exposure to the repellent. Female mosquitoes that were sensitive to DEET when first tested became insensitive when retested. Electroantennography showed that mosquitoes that were insensitive to DEET had a reduced response to DEET compared with mosquitoes that were sensitive to it. This was the case both for culture mosquitoes displaying insensitivity to DEET after brief pre-exposure to it, and for the sensitive and insensitive lines selected for several generations. Single sensillum recordings of the selected lines identified DEET-sensitive sensilla in the sensitive line that did not respond to DEET in the insensitive line. This study suggests that behavioural insensitivity to DEET in Ae. aegypti is a genetically determined dominant trait, which can also be temporarily induced by pre-exposure, and resides in changes in sensillum function. These results highlight the necessity for careful monitoring of DEET-insensitivity in the field, and caution when designing laboratory methods for repellency assays

Future direction of pathogenesis and treatment for rheumatic disorders

After the breakthrough in the treatment of rheumatoid arthritis and numerous related disorders with biological therapies targeting TNFa at the Kennedy Institute in London Millions of patients have tremendously benefitted. However, we cannot cure these diseases yet and have to search for additional therapeutic targets. Since it was shown that synovial fibroblasts (SF) are not only effector cells responding to inflammatory stimuli, but appear endogenously activated and potentially involved into spreading the disease [1], we searched for the epigenetic modifications leading to the activated phenotype of these cells. Epigenetics in its scientific definition “is the study of all heritable and potentially reversible changes in genome function that do not alter the nucleotide sequence within the DNA”, but might be considered in simpler terms as the regulation of gene expression. Epigenetic modifications include: Acetylation

Endogenous Sex Steroid Hormones, Lipid Subfractions, and Ectopic Adiposity in Asian Indians

Background: Estradiol, testosterone (T), and sex hormone binding globulin (SHBG) levels are associated with lipid subfractions in men and women. Our objective was to determine if associations are independent from adipose tissue area among Asian Indians. Methods: We used data from 42 women and 57 Asian Indian men who did not use exogenous steroids or lipid-lowering medications. Lipoprotein subfractions including low-density lipoprotein cholesterol (LDL), very low-density lipoprotein cholesterol (VLDL), and intermediate density lipoprotein (IDL) were assessed by ion mobility spectrometry. Intra-abdominal adiposity was assessed by computed tomography. Multivariable regression models estimated the association between sex hormones with lipoprotein subfractions before and after adjustment for adiposity. Results: Among women, lower logSHBG levels were associated with smaller logLDL particle size and higher logtriglycerides, logVLDL, and logIDL, although these associations were attenuated with adjustment for visceral adiposity in particular. Among women, lower logSHBG levels was significantly associated with lower logmedium LDL and logsmall LDL concentrations even after consideration of visceral and hepatic adiposity and insulin resistance as represented by the homeostasis model assessment of insulin resistance (HOMA-IR). Among men, lower logSHBG was also associated with smaller logLDL peak diameter size and higher logtriglycerides and logVLDL, even after adjustment for HOMA-IR and adiposity. Relationships between sex steroids and lipid subfractions were not significant among women. Among men, higher total testosterone was associated with higher logHDL and logLDL particle size, and lower logtriglycerides and logVLDL, but these associations were partially attenuated with adjustment for adiposity and HOMA-IR. Conclusions: Among Asian Indians, SHBG is associated with more favorable lipid subfraction concentrations, independent of hepatic and visceral fat.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140166/1/met.2015.0063.pd

The δ‐opioid receptor positive allosteric modulator BMS 986187 is a G‐protein‐biased allosteric agonist

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149355/1/bph14602.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149355/2/bph14602_am.pd