One output arm of the sleep homeostat in Drosophila appears to be a group of neurons with projections to the dorsal fan-shaped body (dFB neurons) of the central complex in the brain. However, neurons that regulate the sleep homeostat remain poorly understood. Using neurogenetic approaches combined with Ca2+ imaging, we characterized synaptic connections between dFB neurons and distinct sets of upstream sleep-regulatory neurons. One group of the sleep-promoting upstream neurons is a set of circadian pacemaker neurons that activates dFB neurons via direct glutaminergic excitatory synaptic connections. Opposing this population, a group of arousal-promoting neurons downregulates dFB axonal output with dopamine. Co-activating these two inputs leads to frequent shifts between sleep and wake states. We also show that dFB neurons release the neurotransmitter GABA and inhibit octopaminergic arousal neurons. We propose that dFB neurons integrate synaptic inputs from distinct sets of upstream sleep-promoting circadian clock neurons, and arousal neurons.

Targeting immune-mediated, age-related, biology has the potential to be a transformative therapeutic strategy. However, the redundant nature of the multiple cytokines that change with aging requires identification of a master downstream regulator to successfully exert therapeutic efficacy. Here, we discovered CCR3 as a prime candidate, and inhibition of CCR3 has pro-cognitive benefits in mice, but these benefits are not driven by an obvious direct action on central nervous system (CNS)-resident cells. Instead, CCR3-expressing T cells in the periphery that are modulated in aging inhibit infiltration of these T cells across the blood-brain barrier and reduce neuroinflammation. The axis of CCR3-expressing T cells influencing crosstalk from periphery to brain provides a therapeutically tractable link. These findings indicate the broad therapeutic potential of CCR3 inhibition in a spectrum of neuroinflammatory diseases of aging.

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e19020 Background: The rate of obesity in adults is 34% in the city of Philadelphia, with rates being highest among non-Hispanic blacks and Hispanics. We sought to evaluate how BMI varies by age and race/ethnicity at time of initial encounter for a breast cancer (BC) diagnosis (dx), and investigate factors predictive of BMI change in the first 2 years of dx. Methods: We identified 1,833 patients (pts) in our electronic medical record, (1/2015-present), who had a BC dx at their first hospital or ambulatory encounter using ICD-10 code C50.X, and had BMI recorded at baseline (BL) (6 mo pre-and up to 3 mo post), at 1 yr +/- 3 mo and 2 yr +/- 6 mo. We summarized demographic data (age, gender, marital status, race/ethnicity) with mean and standard deviation for continuous variables and with count and percentage for categorical variables. Descriptive statistics were summarized by 3-level BMI categories: underweight/normal (≤ 24.9), overweight (25 to 29.9), and obese (>30) and compared with ANOVA test, Chi-square-test or Fisher’s exact test as appropriate. Mixed effect regression analysis was conducted to adjust for the effects of time (i.e., BL, 1 yr, 2 yr), gender, race/ethnicity and the interaction of time and race and ethnicity in estimating mean BMI. We calculated the mean change of BMI between the BL and later time points by race/ethnicity. The significance level of all tests was set a priori to the 0.05 level. Results: 99.4% of pts were female; mean age was 63 yrs; White (60 %), Black/AA (27 %). By BMI category, we did not observe a substantial difference in the mean age of dx and gender (p = 0.18 for age and p = 0.55 for gender). We observed a substantial difference in race/ethnicity among BMI categories (p < .0001); the highest percentage of obese pts were Black/AA. In the mixed effect model, the reference level was set as a white female with an average (avg) systolic blood pressure of 137.8. The estimated avg BL BMI of this reference group was 28.8. We observed that among Asian/Pacific Islander (API) pts the avg BL BMI is lower by 3.5 ( p < .0001) and among female Black/AA pts the avg BL BMI is higher by 2.6 ( p < .0001) compared to reference group. No significant change was noted in mean BMI between BL and 1 yr for any race and ethnicity group, and only the Hispanic/Latino group had a declining trend for change in BMI between BL and 2 yr (estimate: -1.9; 95% CI: -5.9, 2.1). Conclusions: In our cohort, Black/AA pts likely have higher BL BMI and API pts likely have lower BL BMI compared to White pts. We found no significant difference in change of BMI by race and ethnicity group during the first 2 years from an initial encounter for a BC dx.

Obesity is a modifiable risk factor in breast cancer patients and is predictive of disease outcomes in early-onset breast cancer survivors. The purpose of this review is to summarize the current evidence in the association between early-onset breast cancer and obesity, specifically in African-American women. Reviewing the molecular mechanisms and social determinants of disease in this population can provide a foundation for future interventions in prevention, detection, and treatment aiming at improving outcomes for young breast cancer patients.

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The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains a challenge, limiting their long-term efficacy. Understanding the complex mechanisms driving resistance is crucial for the development of novel therapeutic strategies and the improvement of patient outcomes. Translational research efforts, such as preclinical models and biomarker studies, offer valuable insight into resistance mechanisms and may guide the identification of novel combination therapies. This review paper aims to outline the reported mechanisms underlying CDK4/6 inhibitor resistance, drawing insights from both clinical data and translational research in order to help direct the future of treatment for hormone receptor-positive metastatic breast cancer.

The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains a challenge, limiting their long-term efficacy. Understanding the complex mechanisms driving resistance is crucial for the development of novel therapeutic strategies and improvement of patient outcomes. Translational research efforts, such as preclinical models and biomarker studies, offer valuable insight into resistance mechanisms and may guide the identification of novel combination therapies. This review paper aims to outline the reported mechanisms underlying CDK4/6 inhibitor resistance, drawing insights from both clinical data and translational research in order to help direct the future of treatment for hormone receptor positive metastatic breast cancer.