Purpose: Recombinant Listeria vaccines induce tumor-specific T-cell responses that eliminate established tumors and prevent metastatic disease in murine cancer models. We used dogs with HER2/neu þ appendicular osteosarcoma, a well-recognized spontaneous model for pediatric osteosarcoma, to determine whether a highly attenuated, recombinant Listeria monocytogenes expressing a chimeric human HER2/neu fusion protein (ADXS31-164) could safely induce HER2/neu-specific immunity and prevent metastatic disease. Experimental Design: Eighteen dogs that underwent limb amputation or salvage surgery and adjuvant chemotherapy were enrolled in a phase I dose escalation clinical trial and received either 2 Â 10 8 , 5 Â 10 8 , 1 Â 10 9 , or 3.3 Â 10 9 CFU of ADXS31-164 intravenously every 3 weeks for 3 administrations.Results: Only low-grade, transient toxicities were observed. ADXS31-164 broke peripheral tolerance and induced antigenspecific IFNg responses against the intracellular domain of HER2/neu in 15 of 18 dogs within 6 months of treatment. Furthermore, ADXS31-164 reduced the incidence of metastatic disease and significantly increased duration of survival time and 1-, 2-, and 3-year survival rates when compared with a historical control group with HER2/neu þ appendicular osteosarcoma treated with amputation and chemotherapy alone.Conclusions: These findings demonstrate that ADXS31-164 administered in the setting of minimal residual disease can induce HER2/neu-specific immunity and may reduce the incidence of metastatic disease and prolong overall survival in a clinically relevant, spontaneous, large animal model of cancer. These findings, therefore, have important translational relevance for children with osteosarcoma and adults with other HER2/neu þ cancers.

Background Angiotensin‐converting enzyme 2 (ACE2) is a homologue of angiotensin‐converting enzyme (ACE) and produces angiotensin peptides (APs), such as angiotensin 1‐9 and 1‐7 that are vasodilatory and natriuretic, and act to counterbalance angiotensin II. Hypothesis Evidence of ACE2 can be found in tissues and plasma of dogs. Equilibrium concentrations of renin angiotensin aldosterone system (RAAS) APs differ in dogs with heart disease compared to healthy dogs and recombinant human ACE2 (rhACE2) alters relative concentrations of APs. Animals Forty‐nine dogs with and 34 dogs without heart disease. Methods Immunohistochemistry and assays for tissue and plasma ACE2 activity and equilibrium concentrations of plasma RAAS APs were performed. Results Immunolabeling for ACE2 was present in kidney and myocardial tissue. Median plasma ACE2 activity was significantly increased in dogs with congestive heart failure (CHF; 6.9 mU/mg; interquartile range [IQR], 5.1‐12.1) as compared to control (2.2 mU/mg; IQR, 1.8‐3.0; P = .0003). Plasma equilibrium analysis of RAAS APs identified significant increases in the median concentrations of beneficial APs, such as angiotensin 1‐7, in dogs with CHF (486.7 pg/mL; IQR, 214.2‐1168) as compared to those with preclinical disease (41.0 pg/mL; IQR, 27.4‐45.1; P < .0001) or control (11.4 pg/mL; IQR, 7.1‐25.3; P = .01). Incubation of plasma samples from dogs with CHF with rhACE2 increased beneficial APs, such as angiotensin 1‐9 (preincubation, 10.3 pg/mL; IQR, 4.4‐37.2; postincubation, 2431 pg/mL; IQR, 1355‐3037; P = .02), while simultaneously decreasing maladaptive APs, such as angiotensin II (preincubation, 53.4 pg/mL; IQR, 28.6‐226.4; postincubation, 2.4 pg/mL; IQR, 0.50‐5.8; P = .02). Conclusions and Clinical Importance Recognition of the ACE2 system expands the conventional view of the RAAS in the dog and represents an important potential therapeutic target.

BackgroundTreatment targeted to achieve reduction in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) improves outcomes in human congestive heart failure (CHF) patients.HypothesisA pre‐specified therapeutic algorithm that increased diuretic or pimobendan usage will reduce plasma NT‐proBNP concentrations in dogs with CHF secondary to myxomatous mitral valve disease (MMVD).AnimalsTwenty‐six dogs with clinically stable CHF secondary to MMVD.MethodsProspective, controlled before‐and‐after study. Dogs were examined up to 3 times over 21 days. Treatment was prescribed based on NT‐proBNP as follows: <1500 pmol/L at baseline, no treatment adjustment at any point during the study (group 1); ≥1500 pmol/L and creatinine ≤3.0 mg/dL at baseline or SC visits, treatment escalated according to the algorithm (group 2); ≥1500 pmol/L at baseline, no treatment adjustment (group 3).ResultsN‐terminal pro‐B‐type natriuretic peptide decreased significantly in group 2 (mean change = −1736 pmol/L (95% CI, −804 to −2668), P < .001) but not in groups 1 or 3 (623 pmol/L [–631 to 1877 pmol/L], P = .14 and 685 pmol/L [–304 to 1068 pmol/L], P = .46, respectively). Serum BUN and creatinine did not change significantly between visit 0 and visit 2 in group 1 (median = 23 mg/dL [range 13‐32] versus 19 mg/dL [12‐38], P = .72 and 1.15 mg/dL [0.70‐1.40] versus 0.95 mg/dL [0.70‐1.10], P = .10, respectively) or group 2 (28 mg/dL [18‐87] versus 43.5 mg/dL [21‐160], P = .092 and 1.10 mg/dL [0.90‐2.50] versus 1.55 mg/dL [0.90‐3.30], P = .062, respectively).Conclusions and Clinical ImportanceUse of this treatment escalation algorithm allows effective targeting of treatment for CHF in dogs against an objective criterion.

Zika virus and the critical need for yellow fever vaccines have recently emphasized the poignant need for a One Health paradigm shift at all levels of academic, corporate, food production, lawmaking, public policy, and research systems. oAdditionally, the world must soon feed the projected 9 billion people expected to populate its surface without causing further global destruction. Many scientists and One Health advocates believe that a One Health approach and application is the planet's 'Ray of Hope' for the future because they see as unsustainable our current ways of doing business in professional 'silos'. In addition to human, veterinary and environmental health specialists joining hands, we need anthropologists, chemists, ecologists, educators, engineers, private industry, social scientists, etc. to all work in interactive One Health systems and thinking. This will require conjoined concerted effort. Over the past decade there has been increasing recognition of just how much can be learned at the interface of human, animal, environmental and plant domains. From heart transplants to management of psychiatric disorders to prosthetic limbs, cancer treatments and vaccine development, tremendous knowledge can be gained when we create opportunities for trans-professional interactions of researchers and clinicians. This presentation will share a very brief historic context for global efforts to resurrect this very old concept, give an update on current happenings in the One Health 'movement' and give examples of how One Health thinking is advancing comparative medicine and translational research.

Nine adult Asiatic black bears (Ursus thibetanus) previously rescued from illegal bile farming in Vietnam were examined via abdominal ultrasound and exploratory laparoscopy for liver and gall bladder pathology. Three bears demonstrated notable gall bladder pathology, and minimally invasive cholecystectomies were performed using an open laparoscopic access approach, standard 10 to 12 mmHg carbon dioxide pneumoperitoneum and a four-port technique. A single bear required insertion of an additional 5 mm port and use of a flexible liver retractor due to the presence of extensive adhesions between the gall bladder and quadrate and left and right medial liver lobes. The cystic duct was dissected free and this and the cystic artery were ligated by means of extracorporeal tied Meltzer knot sutures. The gall bladder was dissected free of the liver by blunt and sharp dissection, aided by 3.8 MHz monopolar radiosurgery. Bears that have had open abdominal cholecystectomies are reported as taking four to six weeks before a return to normal activity postoperatively. In contrast, these bears demonstrated rapid unremarkable healing, and were allowed unrestricted access to outside enclosures to climb trees, swim and interact normally with other bears within seven days of surgery.