Clinicopathologic Characterization of Prostatic Cancer in Dogs.

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.

Re-examining poikilocytosis in goats: prevalence, type and association with age and disease.

Background: Domestic goats (Capra aegagrus hircus) are a food, fiber and companion animal. Abnormal erythrocyte shapes (poikilocytes) are considered normal in young goats, but their association with disease is not well described. Likewise, there is little information on the significance of poikilocytosis in adult goats. Objective: The objective of this study was to investigate the prevalence, severity and type of poikilocytosis in young and adult goats and its association with age, sex, breed, laboratory results, and underlying disease. Methods: We retrospectively examined clinical and laboratory data from 1254 goats presented at the University of California-Davis Veterinary Medical Teaching Hospital from 1997 to 2019. We analyzed 313 blood smears from goats with moderate or marked (MOD-MKD) poikilocytosis on initial blood smear evaluation. Number and type of poikilocytes per 1000 red blood cells (RBCs) were enumerated. Laboratory values and primary disease categories were compared with the severity and type of poikilocytosis. Results: Kids (<6 mos) and juveniles (>6 mos to <1 year) had a higher prevalence of MOD-MKD poikilocytosis (95/210, 45.2% kids; 27/59, 45.8% juveniles) than adult goats (≥1 year; 190/982, 19.3%) (p < 0.001). Kids had a higher percentage of elliptocytes, dacryocytes, and schistocytes and a lower percentage of polygonal and spiculated RBCs than juvenile and adult goats (p < 0.001). Of goats with MOD-MKD (vs NONE-SLIGHT) poikilocytosis, kids had lower HGB and MCH, and higher RDW (p ≤ 0.02); juveniles and adult goats had lower HCT, MCV, MCH, and albumin concentration (p ≤ 0.01), and all age groups had lower total CO2 concentration and higher PLT counts (p < 0.03). Adult goats with MOD-MKD poikilocytosis also had higher BUN:Cr ratios (p = 0.005). Gastrointestinal parasitism, Johne's disease, diarrhea/enteritis, lice, hepatic disease and renal disease (but not urolithiasis) were significantly associated with MOD-MKD poikilocytosis (p < 0.001). Goats with hepatic and renal disease had a higher prevalence and percentage of spiculated cells (p = 0.001). Goats with Johne's disease had a higher prevalence of polygonal cells (93.3%) and dacryocytes (66.7%) than other diseases, and elliptocytes predominated in a higher proportion (36.0%) of adult goats with GI parasitism vs other diseases (p < 0.05). Conclusion: These findings suggest that iron deficiency is an important pathophysiologic mechanism of poikilocytosis in juvenile and adult goats, and possibly in kids, whether due to iron-restricted erythropoiesis, chronic hemorrhage, functional iron deficiency, or a combination of these mechanisms. Further investigation into the detection and monitoring of iron deficiency and the value of poikilocytosis as a diagnostic marker of iron status in goats is warranted.

Pesticides and Bladder Cancer: Mechanisms Leading to Anti-Cancer Drug Chemoresistance and New Chemosensitization Strategies.

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-ß, STAT3) and chemoresistance (drug efflux, DNA repair, and apoptosis resistance) and potential therapeutic tactics to counter these pesticide-induced affects.

Androgen receptor transcriptional activity is required for heregulin-1ß-mediated nuclear localization of the HER3/ErbB3 receptor tyrosine kinase.

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-1ß (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.

Molecular Similarities and Differences between Canine Prostate Cancer and Human Prostate Cancer Variants.

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.

Amikacin disaggregates platelet clumps in EDTA blood samples from cats and dogs when added postcollection.

BACKGROUND: Pseudothrombocytopenia may lead to the erroneous diagnosis of thrombocytopenia, resulting in unnecessary testing and treatment. The addition of exogenous substances to blood samples prior to collection has been shown to mitigate platelet (PLT) clumps in blood samples. Postcollection additives aiming to disaggregate PLT clumps have been largely unexplored. OBJECTIVES: We aimed to determine if the addition of amikacin to blood samples postcollection aids in the disaggregation of PLT clumps in cats and dogs. METHODS: For this prospective study, EDTA-collected blood samples from 28 cats and 17 dogs were obtained from a hospital population at UC Davis Veterinary Medical Teaching Hospital. Samples had PLT clumps detected on blood smears and thrombocytopenia per analyzer count. Amikacin was added to samples postcollection, and an additional CBC was performed. Flow cytometry was performed to assess PLT-fibrinogen binding in amikacin-treated aliquots. RESULTS: PLT-clumped samples treated with amikacin significantly increased PLT numbers by 134% and decreased mean platelet volume (MPV) values by 14% (P ≤ 0.0001) in cats, and increased PLT numbers by 32% (P = 0.04) and increased MPV values by 9% (P = 0.02) in dogs. Mean cell volume (MCV) slightly increased (<4%) for both species. No other CBC parameters were substantially affected by the addition of amikacin. Flow cytometry showed decreased PLT-fibrinogen binding in the majority of cats but was not significant (P > 0.05). CONCLUSIONS: Adding amikacin to PLT-clumped blood samples postcollection may be a convenient solution for pseudothrombocytopenia in cats and dogs. Future studies are needed to elucidate the mechanism of amikacin and its effectiveness under different storage conditions. This is the first reported use of amikacin postcollection to disaggregate PLT clumps in blood samples from animals.

Pericardial effusion in a dog due to T-cell lymphoma of granular lymphocyte type.

Pericardial effusions in dogs are most often diagnosed as haemorrhagic and idiopathic. Pericardial effusions secondary to an underlying neoplastic process are infrequently diagnosed, as neoplastic cells are rarely observed in a sample of the effusion. In the present report, we describe a 9-year-old dog with pericardial effusion due to T-cell lymphoma of granular lymphocyte type. Immunophenotyping and molecular clonality PCR were performed to confirm the cytologic diagnosis. To our knowledge, this is the first report of pericardial effusion in a dog due to T-cell lymphoma of granular lymphocyte type.

Optimization of eIF4E-Binding Peptide Pep8 to Disrupt the RBM38-eIF4E Complex for Induction of p53 and Tumor Suppression.

Interaction of RNA-binding protein RBM38 with eIF4E on p53 mRNA is known to suppress p53 mRNA translation, which can be disrupted by an 8-amino acid peptide (Pep8-YPYAASPA) derived from RBM38, leading to induction of p53 and tumor suppression. Here, we rationally designed multiple Pep8 derivatives and screened for their binding affinities towards eIF4E in silico. We showed that several key residues within Pep8 are necessary for its structure and function. We identified a shortened 7-amino acid peptide (Pep7-PSAASPV) that has the highest affinity towards eIF4E and is the most potent inducer of p53 expression. We found that iRGD is an effective vehicle to deliver Pep7 inside of cells for induction of p53 expression and growth suppression as compared to other cell penetrating peptides (Penetratin and Pep-1). We found that peptide cyclization enhances Pep8 affinity for eIF4E, induction of p53 and tumor cell growth suppression. We also found that the ability of Pep7 to induce p53 expression and growth suppression is conserved in cells derived from canine osteosarcoma, a spontaneous tumor model frequently used for testing the feasibility of a therapeutic agent for human cancer. Moreover, we showed that both human and canine osteosarcoma cells, which are notoriously resistant to radiation therapy, were sensitized by Pep7 to radiation-induced growth suppression and cell death. Together, our data suggest that Pep7 may be explored to sensitize tumors to radiation therapy.

Ferredoxin reductase and p53 are necessary for lipid homeostasis and tumor suppression through the ABCA1-SREBP pathway.

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.

A novel bone marrow-sparing treatment for primary erythrocytosis in a cat: Onion powder.

Primary erythrocytosis (PE) is a rare myeloproliferative neoplasm in cats resulting in the overproduction of erythrocytes. Current treatment modalities include repeated phlebotomy and chemotherapeutic drugs. These treatments may not be well tolerated by the cat and can present safety and financial challenges to owners. Because of the rarity of PE, prospective studies for new treatment options are difficult to perform. This case report describes the novel use of onion powder in an attempt to produce Heinz body-induced erythrocyte destruction in order to decrease total erythrocyte mass and normalize the hematocrit in a cat with PE. To our knowledge, the use of onion powder in the treatment of PE in cats has never been described before and may have potential as a safe, low-cost, and highly accessible alternative treatment for this rare disease.

Canine leishmaniasis in Northern California-A case report.

A 3-year-old dog was referred to the Veterinary Medical Teaching Hospital of the University of California-Davis for further evaluation of episodes of epistaxis of 1-year duration and peripheral lymphadenopathy. The patient had a history of atopic dermatitis with no travel history outside of California. Hyperglobulinemia with a polyclonal gammopathy was noted on serum protein electrophoresis. Microscopic evaluation of a bone marrow aspirate sample revealed many free and intra-cellular amastigotes of Leishmania sp. that was further confirmed by qPCR as L infantum. This is, to the best of our knowledge, the first reported case of canine leishmaniasis in the state of California. The patient is believed to have been vertically infected from the dam who is from Serbia and remained subclinical until presentation. Because the clinical progression of leishmaniasis is variable, it is important that precautions be discussed with owners acquiring puppies with dams from endemic regions of leishmaniasis to prevent zoonotic exposure in states where competent vectors are present.

Comparison of IDEXX SediVue Dx® urine sediment analyzer to manual microscopy for detection of casts in canine urine.

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.