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Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.

Background: Vitamin A deficiency, iodine deficiency, and protein-energy malnutrition are prevalent malnutrition issues that disproportionately affect low-income countries and pose significant risks to the health and development of children and adolescents. This study offers a detailed examination of these deficiencies' prevalence trends and gender and regional variations using Global Burden of Disease Study data from 1990 to 2019. It also assesses the specific impact on various age groups, providing essential insights for targeted health interventions and policy-making., Methods: Data spanning from 1990 to 2019 on Vitamin A deficiency, iodine deficiency, and protein-energy malnutrition were extracted from the 2019 Global Burden of Disease Study. Age-Standardized Incidence Rates (ASR) were computed by gender, region, and etiology, utilizing the estimated annual percentage change (EAPC) to assess temporal trends., Results: In 2019, Central Sub-Saharan Africa had the highest prevalence of Vitamin A deficiency, particularly among males, and iodine deficiency peaked in the same region for both genders. South Asia had the highest incidence of protein-energy malnutrition for both genders. Regions with a low Socio-Demographic Index (SDI) showed lower ASR for these deficiencies. Notably, Cameroon, Equatorial Guinea, and Maldives recorded the highest ASR for vitamin A deficiency, iodine deficiency, and protein-energy malnutrition, respectively. The declining ASR trend for vitamin A deficiency, especially among males, suggests effective interventions. East Asia saw a significant increase in iodine deficiency ASR from 1990 to 2019, particularly among women, requiring targeted interventions. The rising ASR of protein-energy malnutrition in several regions, especially among men, raises concerns. Vitamin A deficiency primarily affected children and adolescents, iodine deficiency predominantly impacted adolescents and young adults, and protein-energy malnutrition was chiefly observed among children under 5 years old. These findings underscore the necessity for tailored interventions considering age-specific nutritional needs and challenges., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ji, Zhou, Zhao, Chen and Su.)

Prostate cancer has a heterogeneous prognosis. Most previous studies have focused on the identification of prognostic biomarkers in the prostate cancer tumor. However, it is increasingly recognized that the tumor microenvironment contributes to prostate cancer aggressiveness and progression. We therefore examined whole transcriptome expression of the prostate stroma and associations with aggressive and lethal prostate cancer. We performed RNA sequencing (Illumina TruSeq Exome Capture) of 272 tumor-adjacent and 120 benign-adjacent macrodissected prostate stromal samples from 293 men with prostate cancer from the Health Professionals Follow-up Study and Physicians' Health Study. We performed differential expression analysis comparing gene expression and pathways by Gleason score and lethal outcome. We also tested a previously developed stromal gene signature of Gleason score in these datasets. Comparing high- with low-Gleason score cancers, 26 genes (P < 0.001) and 12 pathways (FDR < 0.20) were significantly differentially expressed in tumor-adjacent stroma, including pathways related to stroma composition remodeling and DNA repair, with 73 genes and 65 pathways significant in benign-adjacent stroma. Comparing lethal with nonlethal prostate cancer, 11 genes were differentially expressed in tumor-adjacent and 15 genes in benign-adjacent stroma, and pathways involved in inflammatory response were differentially enriched in both tumor and benign-adjacent stroma. In addition, our previously identified Gleason stromal gene signature was validated to be associated with Gleason score in these data. Implications: Our study uncovers stroma-specific genes and pathways that are differentially enriched with high Gleason score and lethal prostate cancer, demonstrating that the molecular investigation of the tumor microenvironment can provide additional information about prostate cancer prognosis., (©2022 American Association for Cancer Research.)