abiraterone acetate (Yonsa)

CRISPR/Cas9 screening revealed BIRC6-AS1/BIRC6 mediates abiraterone resistance via NHEJ pathway-dependent A20 degradation in prostate cancer.

Li Lan L, An Xue-Ni XN, Ruan Yong-Tong YT, Yang Rong R et al.

Abiraterone acetate is a standard-of-care therapy for prostate cancer (PCa). However, resistance frequently emerges, often characterized by the progression to AR-independent phenotypes. Employing a genome-wide CRISPR/Cas9 library screening strategy, we identified 523 long non-coding RNAs (lncRNAs) and 2,183 protein-coding genes as potential candidates associated with abiraterone resistance. Notably, a pair of sense-antisense genes, BIRC6-AS1/BIRC6, was identified as a significant contributor to abiraterone resistance, serving as a critical survival factor in AR-independent contexts. BIRC6-AS1 depletion led to a reduction in both the mRNA and protein levels of BIRC6. Moreover, depletion of either BIRC6-AS1 or BIRC6 enhanced the sensitivity of PCa cells to abiraterone in both in vitro and in vivo settings. Further investigation revealed that BIRC6-AS1 stabilized the mRNA of BIRC6 through interaction with ILF2. Suppression of either BIRC6-AS1 or BIRC6 attenuated non-homologous end joining (NHEJ) repair activity, resulting in the disassembly of 53BP1 foci at DNA damage sites and an increased accumulation of DNA damage, thereby exposing a vulnerability in AR-independent resistant cells. Mechanistically, BIRC6 interacted with A20 and facilitated the K48-linked ubiquitination and subsequent degradation of A20 at the K337 residue. Additionally, A20 knockdown effectively reversed the abiraterone sensitivity induced by BIRC6-AS1 depletion. Collectively, our study provides a landscape of lncRNAs and protein-coding genes associated with abiraterone resistance and suggests that targeting the BIRC6-AS1/BIRC6 axis represents a potential therapeutic strategy to eradicate AR-independent resistant tumors in prostate cancer.

Advancements and future directions in transforming therapies of prostate cancer.

Zhao Jinge J, Tang Bo B, Zeng Hao H, Wei Qiang Q

The treatment landscape for advanced prostate cancer (PCa) has significantly evolved in recent years, marked by the introduction of several novel therapies. Targeting the androgen receptor (AR) remains a cornerstone of treatment, with drugs, such as abiraterone and next-generation antiandrogens, providing substantial benefits. Poly (ADP-ribose) polymerase (PARP) inhibitors, both as monotherapies and in combination with other agents, have demonstrated promise, particularly for patients with deoxyribonucleic acid (DNA) repair defects. While immunotherapy has historically shown limited efficacy in the treatment of PCa, recent findings from the CONTACT‑02 study suggest a potential breakthrough, demonstrating improved patient outcomes with the combined use of atezolizumab and cabozantinib. Additionally, emerging therapies targeting cyclin-dependent kinases 4 and 6 (CDK4/6), the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, and epigenetic modifications offer new treatment possibilities. These advancements, coupled with ongoing research into combination therapies and novel drug targets, hold the potential to further enhance outcomes for patients with advanced PCa. This article review summarizes the latest transformative therapies in PCa care.

Correction: p-Coumaric Acid Attenuates Lead Acetate-induced Neurotoxicity in Rats by Improving Behavioral Dysfunction and Suppressing Oxidative Stress, Neuroinflammation, Apoptosis, and Plasticity-related Molecular Alterations.

Karaarslan Tuba T, Bolat Merve M, Bolat İsmail İ, Orhan Betul B et al.

Effects of neutral detergent fiber content and its source on growth performance, rumen characteristics, digestibility, and methane concentrations in Hanwoo heifers.

Cho Hyunjin H, Jeong Sinyong S, Kang Kyewon K, Lee Mingyung M et al.

This study investigated the effects of neutral detergent fiber (NDF) content and NDF source (forage- or concentrate-derived) on growth performance, rumen characteristics, nutrient digestibility, and methane (CH4) concentrations in growing Hanwoo heifers. Thirty heifers (296 ± 25.7 kg body weight [BW]; 10 months old) were blocked by BW and assigned to three treatments: high forage-to-concentrate ratio (42.5:57.5) with high-energy concentrate (HFHC), low forage-to-concentrate ratio (30:70) with low-energy concentrate (LFLC), and low forage-to-concentrate ratio (30:70) with high-energy concentrate (LFHC). NDF-level effects were assessed by contrasting HFHC and LFLC with LFHC, whereas the NDF-source contrast compared HFHC with LFLC at similar total NDF levels. Dry matter intake (DMI) was recorded daily and BW every four weeks. Rumen fluid and fecal samples were collected, and CH4 concentrations measured, after 12 weeks. Average daily gain (ADG) and feed conversion ratio were unaffected by NDF level or source (P > 0.05), whereas DMI tended to increase with lower NDF (P = 0.099). Lower NDF reduced NDF digestibility and increased total volatile fatty acid concentration (P < 0.05), decreased acetate proportion and acetate-to-propionate ratio, and increased propionate and butyrate proportions (P < 0.001). NDF source did not affect nutrient digestibility (P > 0.05). In the NDF-source contrast, LFLC had lower acetate and propionate and higher butyrate proportions than HFHC (P < 0.05). Lower NDF also decreased CH4 concentration per DMI and ADG (P < 0.05). LFLC had lower CH4 concentration per ADG than HFHC, whereas CH4 concentration per DMI did not differ. Dietary NDF level was associated with broader changes in ruminal fermentation, NDF digestibility, and CH4 concentration per DMI and ADG, whereas NDF source had more limited effects, primarily on VFA proportions and CH4 concentration per ADG. Neither NDF level nor source significantly affected growth performance in growing Hanwoo heifers.