P53 is known to modulate metabolism and FDXR is required for steroidogenesis. Given that FDXR is a target/regulator of p53, the FDXR–p53 axis may play a unique role in lipid metabolism. Here, we found that expression of ABCA1, a cholesterol-efflux pump, was suppressed by loss of FDXR and/or p53, leading to activation of master lipogenic regulators SREBP1/2. Accordingly, lipid droplets, cholesterol, and triglycerides were increased by loss of FDXR or p53, which were further increased by loss of both FDXR and p53. To explore the biological significance of the FDXR–p53 axis, we generated a cohort of mice deficient in Fdxr and/or Trp53. We found that Fdxr^+/−, Trp53^+/−, and Fdxr^+/−;Trp53^+/− mice had a short life span and were prone to spontaneous tumors and liver steatosis. Moreover, the levels of serum cholesterol and triglycerides were significantly increased in Fdxr^+/− and Trp53^+/− mice, which were further increased in Fdxr^+/−;Trp53^+/− mice. Interestingly, loss of Fdxr but not p53 led to accumulation of serum low-density lipoprotein. Together, our findings reveal that the FDXR–p53 axis plays a critical role in lipid homeostasis and tumor suppression.

Multiple risk factors have been associated with bladder cancer. This review focuses on pesticide exposure, as it is not currently known whether agricultural products have a direct or indirect effect on bladder cancer, despite recent reports demonstrating a strong correlation. While it is known that pesticide exposure is associated with an increased risk of bladder cancer in humans and dogs, the mechanism(s) by which specific pesticides cause bladder cancer initiation or progression is unknown. In this narrative review, we discuss what is currently known about pesticide exposure and the link to bladder cancer. This review highlights multiple pathways modulated by pesticide exposure with direct links to bladder cancer oncogenesis/metastasis (MMP-2, TGF-β, STAT3) and chemoresistance (drug efflux, DNA repair, and apoptosis resistance) and potential therapeutic tactics to counter these pesticide-induced affects.

Background Detection of urinary casts is difficult due to their intermittent presence and deterioration in urine samples. Objective To compare the performance of the IDEXX SediVue Dx^® Urine Sediment Analyzer (SediVue) with manual microscopy for the detection of urinary casts. We hypothesized that the SediVue analyzer would perform similarly to manual microscopy in cast detection. Animals Four hundred forty‐three samples from 420 dogs from a hospital population. Methods This is a prospective, cross‐sectional study. For SediVue analysis (software version [SW] 1.0.1.3), uncentrifuged urine was pipetted into a disposable cartridge. Seventy images were captured and processed by an onboard algorithm. For manual microscopy, urine was centrifuged to obtain sediment. Any cast identified by either method was considered a positive result (>0/low‐power field [LPF]). SediVue images were evaluated if casts were detected by either methodology. A revised sensitivity and specificity were calculated after image review and when using a threshold of >1 cast/LPF. Results The sensitivity of the SediVue analysis for the detection of urinary casts was 53.7% (43.85%‐63.35%), and specificity was 86.0% (81.78%‐89.51%). After image review, the revised sensitivity/specificity was 52.0% (42.89%‐61.02%) and 90.6% (86.81%‐93.54%), respectively. When using a more clinically relevant threshold of >1/LPF, the sensitivity was 52.6% (35.82%‐69.02%) and specificity was 99.3% (97.85%‐99.85%). Conclusions and Clinical Importance The SediVue provides moderate agreement to manual methodology for detection of casts in urine.

Dogs are one of few species that naturally develop prostate cancer (PCa), which clinically resembles aggressive, advanced PCa in humans. Moreover, PCa-tumor samples from dogs are often androgen receptor (AR)-negative and may enrich our understanding of AR-indifferent PCa in humans, a highly lethal subset of PCa for which few treatment modalities are available This narrative review discusses the molecular similarities between dog PCa and specific human-PCa variants, underscoring the possibilities of using the dog as a novel pre-clinical animal model for human PCa, resulting in new therapies and diagnostics that may benefit both species.

Clinicopathologic data in dogs with prostate cancer (PCa) may aid in the differentiation between tumor types and subsequent treatment decisions; however, these data are often unreported. Demographic, clinicopathologic, cytologic, histologic and survival data from dogs with primary prostatic adenocarcinoma (PRAD) (n = 56) and primary prostatic transitional cell carcinoma (P-TCC) (n = 74) were acquired from a tertiary veterinary teaching hospital from 1992 to 2022. Red blood cell distribution width (RDW) to albumin ratio (RAR) was evaluated for diagnostic utility in differentiating between PRAD and P-TCC. Sections from PRAD tumors (n = 50) were stained for androgen receptor (AR) expression, and laboratory data were compared between AR positive (AR+) and AR negative (AR−) groups. RDW was increased in PRAD, while albumin was decreased (p < 0.05). P-TCC was associated with Melamed-Wolinska bodies (MWB) and necrosis on cytology (p < 0.05). RAR had acceptable diagnostic utility in the differentiation of PCa tumors (AUC = 0.7; p < 0.05). Survival rates and metastases were equivocal. AR+ and AR− PRAD tumors did not differ in clinicopathologic data or survival (p > 0.05). In conclusion, hypoalbuminemia was significantly associated with PRAD and decreased survival, while MWB and necrosis were significantly associated with P-TCC on cytology. These clinicopathologic data may help clinicians differentiate between these tumors ante mortem to guide appropriate treatment and intervention.

Prostate cancer is initially regulated by the androgen receptor (AR), a ligand-activated, transcription factor, and is in a hormone-dependent state (hormone-sensitive prostate cancer (HSPC)), but eventually becomes androgen-refractory (castration-resistant prostate cancer (CRPC)) because of mechanisms that bypass the AR, including by activation of ErbB3, a member of the epidermal growth factor receptor family. ErbB3 is synthesized in the cytoplasm and transported to the plasma membrane for ligand binding and dimerization, where it regulates downstream signaling, but nuclear forms are reported. Here, we demonstrate in prostatectomy samples that ErbB3 nuclear localization is observed in malignant, but not benign prostate, and that cytoplasmic (but not nuclear) ErbB3 correlated positively with AR expression but negatively with AR transcriptional activity. In support of the latter, androgen depletion upregulated cytoplasmic, but not nuclear ErbB3, while in vivo studies showed that castration suppressed ErbB3 nuclear localization in HSPC, but not CRPC tumors. In vitro treatment with the ErbB3 ligand heregulin-1β (HRG) induced ErbB3 nuclear localization, which was androgen-regulated in HSPC but not in CRPC. In turn, HRG upregulated AR transcriptional activity in CRPC but not in HSPC cells. Positive correlation between ErbB3 and AR expression was demonstrated in AR-null PC-3 cells where stable transfection of AR restored HRG-induced ErbB3 nuclear transport, while AR knockdown in LNCaP reduced cytoplasmic ErbB3. Mutations of ErbB3's kinase domain did not affect its localization but was responsible for cell viability in CRPC cells. Taken together, we conclude that AR expression regulated ErbB3 expression, its transcriptional activity suppressed ErbB3 nuclear translocation, and HRG binding to ErbB3 promoted it.