Synthetic oleanane triterpenoids (SOTs) are small molecules with broad anticancer properties. A recently developed SOT, 1‐[2‐cyano‐3,12‐dioxooleana‐1,9(11)‐dien‐28‐oyl]‐4(‐pyridin‐2‐yl)‐1H‐imidazole (CDDO‐2P‐Im or ‘2P‐Im’), exhibits enhanced activity and improved pharmacokinetics over CDDO‐Im, a previous generation SOT. However, the mechanisms leading to these properties are not defined. Here, we show the synergy of 2P‐Im and the proteasome inhibitor ixazomib in human multiple myeloma (MM) cells and 2P‐Im activity in a murine model of plasmacytoma. RNA sequencing and quantitative reverse transcription PCR revealed the upregulation of the unfolded protein response (UPR) in MM cells upon 2P‐lm treatment, implicating the activation of the UPR as a key step in 2P‐Im‐induced apoptosis. Supporting this hypothesis, the deletion of genes encoding either protein kinase R‐like endoplasmic reticulum kinase (PERK) or DNA damage‐inducible transcript 3 protein (DDIT3; also known as CHOP) impaired the MM response to 2P‐Im, as did treatment with ISRIB, integrated stress response inhibitor, which inhibits UPR signaling downstream of PERK. Finally, both drug affinity responsive target stability and thermal shift assays demonstrated direct binding of 2P‐Im to endoplasmic reticulum chaperone BiP (GRP78/BiP), a stress‐inducible key signaling molecule of the UPR. These data reveal GRP78/BiP as a novel target of SOTs, and specifically of 2P‐Im, and suggest the potential broader utility of this class of small molecules as modulators of the UPR.

Male infertility is a growing global concern with increasing prevalence in both developing and developed nations. While many associations between environmental factors and male infertility have been explored, the relationship between sleep deprivation and male infertility remains underexplored. This narrative review examines the reported effects of sleep deprivation on the Hypothalamic––Gonadal (HPG) axis, Hypothalamic–Pituitary–Adrenal (HPA) axis, oxidative stress, and testicular function, and their consequential effects on male infertility. Disruption of the HPG axis results in altered follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, leading to fluctuation in testosterone levels, negatively affecting spermatogenesis and other critical reproductive processes. Activation of the HPA axis, often due to stress, elevates cortisol levels, which, in turn, suppresses gonadotropin-releasing hormone (GnRH), impairing reproductive function. Reactive oxidative species (ROS) accumulate in periods of oxidative stress and have been shown to damage sperm and reduce their quality. The blood–testis barrier (BTB) is disrupted in states of sleep deprivation, leading to decreased sperm quality. A literature review was conducted using PubMed and Google Scholar to assess peer-reviewed studies from 1990 to 2024, revealing a complex interplay between sleep deprivation and male reproductive dysfunction. While existing studies support a link between sleep disturbances and hormonal dysregulation, further research is needed to establish causal relationships and identify potential therapeutic interventions. Addressing sleep deprivation may represent a modifiable factor in improving male fertility outcomes.

Male infertility is a growing global concern with increasing prevalence in both developing and developed nations. While many associations between environmental factors and male infertility have been explored, the relationship between sleep deprivation and male infertility remains underexplored. This narrative review examines the reported effects of sleep deprivation on the Hypothalamic-Pituitary-Gonadal (HPG) axis, Hypothalamic-Pituitary-Adrenal (HPA) axis, oxidative stress, and testicular function, and their consequential effects on male infertility. Disruption of the HPG axis results in altered FSH and LH levels, leading to fluctuation in testosterone levels, negatively affecting spermatogenesis and other critical reproductive processes. Activation of the HPA axis, often due to stress, elevates cortisol levels, which, in turn, suppresses gonadotropin-releasing hormone (GnRH), impairing reproductive function. Reactive oxidative species accumulate in periods of oxidative stress and have been shown to damage sperm and reduce their quality. The blood-testis-barrier (BTB) is disrupted in states of sleep deprivation, leading to decreased sperm quality. A literature review was conducted using PubMed and Google Scholar to assess peer-reviewed studies from 1990 to 2024, revealing a complex interplay between sleep deprivation and male reproductive dysfunction. While existing studies support a link between sleep disturbances and hormonal dysregulation, further research is needed to establish causal relationships and identify potential therapeutic interventions. Addressing sleep deprivation may represent a modifiable factor in improving male fertility outcomes.

Introduction: Paragangliomas of the urinary bladder (PUBs) are rare neuroendocrine tumors, representing less than 0.06% of all bladder neoplasms. While most are functional and associated with catecholamine excess, approximately 15% are non‐functional, often presenting asymptomatically and discovered incidentally. Due to their rarity, standardized management guidelines are lacking. Case Presentation: We report a 57‐year‐old female evaluated for ureterolithiasis who was incidentally found to have a 1.5 cm posterior bladder lesion. Biopsy confirmed paraganglioma. Functional studies, including plasma and urinary metanephrines, were negative, establishing a non‐functional tumor. DOTATATE PET/CT and genetic testing excluded metastasis and hereditary syndromes. At planned transurethral resection, no residual lesion was identified, and pathology was benign. The patient remains asymptomatic on follow‐up. Conclusion: This case illustrates the diagnostic challenges of non‐functional PUBs and emphasizes the importance of multidisciplinary evaluation and vigilant follow‐up in the absence of standardized management strategies.

Purpose: Prostate-specific antigen (PSA) value interpretation following primary focal cryotherapy (PFC) for prostate cancer remains a challenge. The purpose of this study is to determine significance of cryoprobe density (CPD), defined as number of cryoprobes divided by preoperative prostate volume (mL), on PSA following PFC.Materials and Methods: A total of 109 patients who underwent primary focal therapy with at least 3 follow-ups within a year were included from an Institutional Review Board (IRB)-approved PCa database (IRB No. s18-01661) from July 2010 to October 2019. A Spearman correlation coefficient was used to assess associations between CPD and PSA nadir as well as percent PSA reduction from baseline PSA to posttreatment PSA nadir. We then assessed predictors of a PSA nadir ≥2.0 ng/mL, ≥1.0 ng/mL, as well as biochemical recurrence using multivariate logistic regression model.Results: A total of 109 patients with median follow-up of 78 (60–102) months were included. Median CPD was 0.12 (0.083–0.15). A total of 28 patients (26%) had a PSA nadir ≥2 ng/mL and 60 (55%) had a PSA nadir ≥1.0 ng/mL with median PSA nadir being 1.2 (0.6–2.1) ng/mL. There was a negative correlation between CPD and PSA nadir value (rho=-0.389, p<0.0001). Percent PSA reduction was positively correlated with CPD (rho=0.307, p=0.001). CPD was a significant predictor of PSA nadir value of ≥1.0 ng/mL and ≥2.0 on univariate analysis but not multivariate. CPD was not associated with biochemical recurrence.Conclusion: Results from this study demonstrate a correlation between CPD and PSA outcomes following PFC. Findings from this study may aid in better understanding of the behavior of PSA behavior following PFC.