Androgen receptor in breast cancer and its clinical implication.

Breast cancer is a heterogeneous group of diseases characterized by diverse subtypes. Currently, the classification of breast cancer is based on the status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). In addition to these receptors, the presence of the androgen receptor (AR) in breast cancer cells adds a layer of complexity to our understanding of the disease. The role of AR in breast cancer is intricate, as it can alter diverse signaling pathways in the presence of different hormone receptors (HRs). This complex interplay between signaling pathways affects patient outcomes and prognosis, and the presence of AR has a significant effect. While AR positivity is common in breast cancer, the efficacy of utilizing AR blockade as a monotherapy has been limited, demonstrating only modest results. To address this challenge, substantial efforts have been directed toward comprehending the intricacies of AR's role and pathways in breast cancer development in the hope of understanding its utility as a biomarker or drug target. Multiple ongoing clinical trials are currently investigating combination treatments involving AR inhibitors and other agents to disrupt oncogenic signaling pathways and their crosstalk. Particularly in the context of triple-negative breast cancer (TNBC), where targeted therapeutic options are lacking, extensive research efforts have been dedicated to exploring the potential of AR-related interventions. This review aims to provide an overview of the various breast cancer subtypes with AR signaling mechanisms, and ongoing clinical trials that hold the potential to reshape future clinical approaches.

CDK4/6 Inhibitor Resistance in Hormone Receptor-Positive Metastatic Breast Cancer: Translational Research, Clinical Trials, and Future Directions.

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.

CCR3 plays a role in murine age-related cognitive changes and T-cell infiltration into the brain.

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.

Preoperative sarcopenia is a negative predictor for enhanced postoperative recovery after pancreaticoduodenectomy.

PURPOSE: Sarcopenia is common in pancreatic cancer patients. Considering the growing adoption of standardized protocols for enhanced recovery after surgery (ERAS), we examined the clinical impact of sarcopenia in pancreaticoduodenectomy (PD) patients in a 5-day accelerated ERAS program, termed the Whipple Accelerated Recovery Pathway. METHODS: A retrospective review was conducted of patients undergoing PD from 2017 through 2020 on the ERAS pathway. Preoperative computerized tomographic scans taken within 45 days before surgery were analyzed to determine psoas muscle cross-sectional area (PMA) at the third lumbar vertebral body. Sarcopenia was defined as the lowest quartile of PMA respective to gender. Outcome measures were compared between patients with or without sarcopenia. RESULTS: In this 333-patient cohort, 252 (75.7%) patients had final pathology revealing pancreatic or periampullary cancer. The median age was 66.7 years (16.4-88.4 years) with a 161:172 male to female ratio. Sarcopenia correlated with delayed tolerance of oral intake (OR 2.2; 95%CI 1.1-4.3, P = 0.03), increased complication rates (OR 4.3; 95%CI 2.2-8.5, P < 0.01), and longer hospital length of stay (LOS) (P < 0.05). Preoperative albumin levels, BMI, and history of pancreatitis were also found to correlate with LOS (P < 0.05). Multivariate regression analysis found low PMA, BMI, and male gender to be independent predictors of increased LOS (P < 0.05). CONCLUSION: Sarcopenia correlated with increased LOS and postoperative complications in ERAS patients after PD. Sarcopenia can be used to predict poor candidates for ERAS protocols who may require an alternative recovery protocol, promoting a clinical tier-based approach to ERAS for pancreatic surgery.

Obesity in early onset breast cancer in African American patients.

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.

Differential regulation of the Drosophila sleep homeostat by circadian and arousal inputs.

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.