The impact of induction therapy on mortality and treated rejection in cardiac transplantation: A retrospective study.

BACKGROUND: Evidence regarding the utility of routine induction therapy on outcomes is not clear. This study aims to evaluate whether induction therapy is associated with a reduced risk of treated rejection and improved overall survival. METHODS: We retrospectively analyzed all adult patients (age ≥ 18 years) that are included in the UNOS database who underwent heart transplantation between 2000 and 2017. Patients with prior transplants and dual organ transplants were excluded. 34,361 patients were included in the final analysis. We assessed the impact of induction therapy with T cell depleting agents (TC-DA), IL2 receptor antagonists (IL2R antagonist) and compared that to no induction therapy using Cox regression models adjusted for propensity scores. The primary outcome measure was all-cause mortality, whereas treated rejection at one year was analyzed as a secondary outcome measure (available in 77% of patients). RESULTS: A total of 52% of the cohort did not receive any induction therapy. A total of 27% received IL2R antagonist and the rest received TC-DA. Median age of the recipients was 55 (IQR: 46-62) years. A total of 25% of the population were women and 39% were supported on left ventricular assist device therapy at the time of transplantation. Median follow-up was 4.2 (IQR: 1.1-8.5) years with 32% reported mortality. Multivariate analysis with propensity score adjustment showed that TC-DA induction did not have any effect on mortality (HR = 0.98, 95% CI 0.93-1.03, p = 0.48). However, IL2R antagonist was associated with a modestly increased risk of all-cause mortality compared to no induction (HR = 1.06, 95% CI 1.01-1.11, p = 0.02, respectively). A total of 25% of patients were found to have treated rejection at one year, TC-DA induction was associated with reduced odds of rejection at one year (OR = 0.82, 95% CI 0.76-0.88, p < 0.001). However, induction with IL2R antagonist was not found to have a significant impact (OR = 1.03, 95% CI 0.96-1.11, p = 0.36). CONCLUSIONS: Compared to no induction therapy, induction with TC-DA was associated with reduction in risk of treated rejection at 1 year with no effect on mortality and IL2R antagonist was associated with a small but statistically significant increase in mortality without any impact on risk of rejection.

Evaluation of pet owner preferences for operative sterilization techniques in female dogs within the veterinary community.

OBJECTIVE: To describe pet owner preferences within the veterinary community when choosing operative techniques for canine spay. STUDY DESIGN: Prospective survey. SAMPLE POPULATION: 1234 respondents from 5 veterinary university teaching hospitals in North America. METHODS: An electronic survey was distributed to faculty, students, and staff that currently are or previously were dog owners. Responses were analyzed to determine what spay technique respondents would choose for their own dogs. Surgical options offered included open celiotomy, 2-port (TP) laparoscopy, single-port (SP) laparoscopy, and natural orifice transluminal endoscopic surgery (NOTES). RESULTS: TP laparoscopic ovariectomy (OVE) was the most popular choice, followed by SP laparoscopic OVE; NOTES was the least popular technique when all surgical options were available. If only minimally invasive surgeries were offered, 0.3% of respondents would refuse surgery. Nearly half (48%) of respondents were willing to spend between $100 and $200 more for a minimally invasive OVE than for an open celiotomy. CONCLUSION: Minimally invasive OVE is an acceptable operative approach to those in the veterinary community. Additional study is required to correlate these findings with the general veterinary client population.

Outcome in cats with benign ureteral obstructions treated by means of ureteral stenting versus ureterotomy.

OBJECTIVE To evaluate the outcome for cats with benign ureteral obstructions treated by means of ureteral stenting and to compare the outcome for these cats with outcome for a historical cohort of cats treated by means of ureterotomy only. DESIGN Prospective study with historical cohort. ANIMALS 62 client-owned cats with benign ureteral obstructions, including 26 cats treated with ureteral stenting and 36 cats previously treated with ureterotomy. PROCEDURES Data were recorded prospectively (ureteral stent cases) or collected retrospectively from the medical records (ureterotomy cases), and results were compared. RESULTS Cats treated with ureteral stents had significantly greater decreases in BUN and serum creatinine concentrations 1 day after surgery and at hospital discharge, compared with values for cats that underwent ureterotomy. Six cats in the ureteral stent group developed abdominal effusion after surgery, and cats in this group were significantly more likely to develop abdominal effusion when a ureterotomy was performed than when it was not. Cats that developed abdominal effusion after surgery were significantly less likely to survive to hospital discharge. Cats that underwent ureteral stenting were significantly more likely to have resolution of azotemia prior to hospital discharge than were cats that underwent ureterotomy alone. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that cats with benign ureteral obstructions treated with ureteral stenting were more likely to have resolution of azotemia prior to hospital discharge, compared with cats undergoing ureterotomy alone. Results of ureteral stenting were encouraging, but further investigation is warranted.

GPCR Signaling Mediates Tumor Metastasis via PI3Kß.

Inappropriate activation of PI3K signaling has been implicated strongly in human cancer. Although studies on the role of PI3K signaling in breast tumorigenesis and progression have focused most intensively on PI3Kα, a role for PI3Kß has begun to emerge. The PI3Kß isoform is unique among class IA PI3K enzymes in that it is activated by both receptor tyrosine kinases and G-protein-coupled receptors (GPCR). In previous work, we identified a mutation that specifically abolishes PI3Kß binding to Gßγ (p110(526KK-DD)). Expression of this mutant in p110ß-silenced breast cancer cells inhibits multiple steps of the metastatic cascade in vitro and in vivo and causes a cell autonomous defect in invadopodial matrix degradation. Our results identify a novel link between GPCRs and PI3Kß in mediating metastasis, suggesting that disruption of this link might offer a novel therapeutic target to prevent the development of metastatic disease. Cancer Res; 76(10); 2944-53. ©2016 AACR.

G protein-coupled receptor-mediated activation of p110ß by Gßγ is required for cellular transformation and invasiveness.

Synergistic activation by heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) and receptor tyrosine kinases distinguishes p110ß from other class IA phosphoinositide 3-kinases (PI3Ks). Activation of p110ß is specifically implicated in various physiological and pathophysiological processes, such as the growth of tumors deficient in phosphatase and tensin homolog deleted from chromosome 10 (PTEN). To determine the specific contribution of GPCR signaling to p110ß-dependent functions, we identified the site in p110ß that binds to the Gßγ subunit of G proteins. Mutation of this site eliminated Gßγ-dependent activation of PI3Kß (a dimer of p110ß and the p85 regulatory subunit) in vitro and in cells, without affecting basal activity or phosphotyrosine peptide-mediated activation. Disrupting the p110ß-Gßγ interaction by mutation or with a cell-permeable peptide inhibitor blocked the transforming capacity of PI3Kß in fibroblasts and reduced the proliferation, chemotaxis, and invasiveness of PTEN-null tumor cells in culture. Our data suggest that specifically targeting GPCR signaling to PI3Kß could provide a therapeutic approach for tumors that depend on p110ß for growth and metastasis.