In mammalian cells, glycogen synthase kinase-3 (GSK-3) exists as two homologs, GSK-3alpha and GSK-3beta, encoded by independent genes, which share similar kinase domains but differ substantially in their termini. Here, we describe the generation of an allelic series of mouse embryonic stem cell (ESC) lines with 0-4 functional GSK-3 alleles and examine GSK-3-isoform function in Wnt/beta-catenin signaling. No compensatory upregulation in GSK-3 protein levels or activity was detected in cells lacking either GSK-3alpha or GSK-3beta, and Wnt/beta-catenin signaling was normal. Only in cells lacking three or all four of the alleles was a gene-dosage effect on beta-catenin/TCF-mediated transcription observed. Indeed, GSK-3alpha/beta double-knockout ESCs displayed hyperactivated Wnt/beta-catenin signaling and were severely compromised in their ability to differentiate, but could be rescued to normality by re-expression of functional GSK-3. The rheostatic regulation of GSK-3 highlights the importance of considering the contributions of both homologs when studying GSK-3 functions in mammalian systems.

Lymphoma is the most common hematopoietic tumour in dogs and is remarkably similar to the human disease. Tumour biomarker discovery is providing new tools for diagnostics and predicting therapeutic response and clinical outcome. MicroRNAs are small non-coding RNAs that participate in post-transcriptional gene regulation and their aberrant expression can impact genes involved in cancer. The aim of this study was to characterize microRNA expression in lymph nodes and plasma from dogs with multicentric B or T cell lymphoma compared to healthy control dogs. We further compared expression between lymph nodes and corresponding plasma samples and assessed changes in expression at relapse compared to time of diagnosis. Lastly, we investigated microRNAs for association with clinical outcome in patients treated with CHOP chemotherapy. A customized PCR array was utilized to profile 38 canine target microRNAs. Quantification was performed using real time RT-qPCR and relative expression was determined by the delta-delta Ct method. In lymph nodes, there were 16 microRNAs with significantly altered expression for B cell lymphoma and 9 for T cell lymphoma. In plasma, there were 15 microRNAs altered for B cell lymphoma and 3 for T cell lymphoma. The majority of microRNAs did not have correlated expression between lymph node and plasma and only 8 microRNAs were significantly different between diagnosis and relapse. For B cell lymphoma, 8 microRNAs had differential expression in the non-remission group compared to dogs that completed CHOP in complete remission. Four of these microRNAs were also altered in patients that died prior to one-year. Kaplan-Meier survival curves for high versus low microRNA expression revealed that 10 microRNAs were correlated with progression-free survival and 3 with overall survival. This study highlights microRNAs of interest for canine multicentric lymphoma. Future goals include development of microRNA panels that may be useful as biomarkers with the intent to provide improved outcome prediction to veterinary cancer patients.

No abstract

This is a report from the first phase of a longitudinal study of the ways young adults imagine their future lives. The future possible selves of 223 18- and 19-year-old adults were examined using the Anticipated Life History measure (ALH), a psychological instrument prompting participants to describe their future life course from their 21st birthday until their death. When the ALH narratives were coded for presence/absence of life events, female participants were more likely to predict career choice, marriage, children, divorce, and death of spouse than their male counterparts; when coded for psychological qualities, female participants demonstrated greater psychological complexity and awareness of future life role choices and conflicts. Participants with lower SES wrote ALH narratives with fewer altruistic acts, less awareness of life role complexity, and fewer anticipated conflicts and their resolutions than those with higher SES.

No abstract

Measurement of thrombin generation using CAT appears to be repeatable in healthy dogs, and samples are stable for at least 12 months when stored at -80°C. Direct venipuncture sampling is recommended for CAT. Low indices of individuality suggest that subject-based reference intervals are more suitable when interpreting CAT results.

Previously, we have shown that Copenhagen (Cop) rats are highly resistant to the induction of putative preneoplastic, glutathione 5-transferase 7-7-(GST 7-7) positive liver lesions following treatment with a modified resistant hepatocyte (RH) protocol. The objective of this study was to determine If resistance Is Inherited In a dominant or recessive manner and to derive an estimate of the number of genetic loci Involved. We crossed male and female Cop rats with F344 rats to produce F1 offspring. Backcross rats were generated using female F1 rats and either Cop or F344 males, resulting In B1c and B1f generations, respectively. The male rats from all these crosses were Initiated with dlethylnltrosamine (200 mglkg) at 7 to 8 weeks of age and were promoted 3 weeks later with the RH protocol (2-acetylamlnofluorene and a two-thirds partial hepatectomy). The rats were sacrificed 3 weeks after the partial hepatectomy and their livers were sectioned and stained for aST 7-7-positlve lesions. The susceptibility of F1 rats was In between Cop and F344 rats, having 21.7% % 2.0% (mean % SEM) of their liver volume occupied by lesions versus 4.2% % 0.8% for Cop and 53.0% % 5.8% for F344 rats. As expected, B1c rats had a volume of liver occupied by lesions that was In between the F1 and Cop rats at 13.5% % 1.6%. Surprisingly, B1f rats were similar to B1c rats In their resistance (9.1% % 2.1%). These results point to a complex, polygenic Inheritance pattern that can be explained by a minimum of four loci, one of which shows recessive epistasis.

OBJECTIVE To determine the effectiveness of metronomic cyclophosphamide (MC) chemotherapy (primary treatment of interest) with adjuvant meloxicam administration as maintenance treatment for dogs with appendicular osteosarcoma following limb amputation and carboplatin chemotherapy. DESIGN Retrospective case series with nested cohort study. ANIMALS 39 dogs with a histologic diagnosis of appendicular osteosarcoma that underwent limb amputation and completed carboplatin chemotherapy from January 2011 through December 2015. PROCEDURES Dogs were grouped by whether carboplatin chemotherapy had been followed with or without MC chemotherapy (15 mg/m, PO, q 24 h) and meloxicam (0.1 mg/kg [0.045 mg/lb], PO, q 24 h). The Breslow rank test was used to assess whether MC chemotherapy was associated with overall survival time (OST) and disease progression-free time (PFT) after limb amputation. RESULTS 19 dogs received carboplatin and MC chemotherapy, and 20 dogs received only carboplatin chemotherapy. No differences were identified between these groups regarding age, reproductive status, body weight, serum alkaline phosphatase activity, tumor location, or histologic grade or subtype of osteosarcoma. Median duration of MC chemotherapy for dogs in the carboplatin-MC group was 94 days (range, 7 to 586 days); this treatment was discontinued for 11 (58%) dogs when cystitis developed. Overall, 11 (28%) dogs survived to the time of analysis, for a median follow-up period of 450 days (range, 204 to 1,400 days). No difference in median PFT or OST was identified between the 2 groups. CONCLUSIONS AND CLINICAL RELEVANCE Maintenance MC chemotherapy following limb amputation and completed carboplatin chemotherapy was associated with no increase in PFT or OST in dogs with appendicular osteosarcoma. Cystitis was common in MC-treated dogs, and prophylactic treatment such as furosemide administration could be considered to reduce the incidence of cystitis in such dogs.