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.

BackgroundA novel equine parvovirus (EqPV‐H) was recently discovered in the equine liver with Theiler's disease.ObjectivesTo determine the prevalence of EqPV‐H infection in naturally occurring Theiler's disease cases and in‐contact horses in the absence of historical equine biologic product administration.AnimalsTen cases of Theiler's disease from 6 separate properties were included in the study, based on the criteria of acute onset of clinical signs of liver failure with laboratory or histopathologic findings characteristic of Theiler's disease and no history of receiving an equine biologic product within the preceding 4 months. In addition, 37 in‐contact horses from 4 of the 6 properties were screened for EqPV‐H infection and hepatitis.MethodsIn prospective case series, cases were diagnosed with Theiler's disease by the attending veterinarian and were tested for EqPV‐H by PCR of liver or serum. In‐contact horses were assessed via serum chemistry and PCR at the attending veterinarian's discretion. Hepatitis was defined as serum gamma‐glutamyltransferase activity above reference interval. The association of EqPV‐H with hepatitis was determined by Fisher's exact test.ResultsNine of 10 (90%) Theiler's disease cases and 54% of tested in‐contact horses were EqPV‐H positive. Hepatitis was significantly associated with EqPV‐H infection (P = .036).Conclusions and Clinical ImportanceAlthough further study is required to identify EqPV‐H as the causative agent of Theiler's disease, EqPV‐H appears strongly associated with cases of fatal Theiler's disease and subclinical hepatitis in horses in contact with those cases. The prevalence of EqPV‐H infection on affected properties can be high.

Based on this case series, all teeth, and particularly the incisors, should be examined for signs of gingivitis and hypercementosis and subsequently radiographed for an early diagnosis and management. When compared with our hospital population, older geldings were more likely to be affected with cementoma formation and its accompanying resorptive process. Removal of clinically and radiographically affected teeth carries a good prognosis for improved quality of life.

Background: Implant-associated infections contribute to patient morbidity and health care costs. We hypothesized that

BackgroundEquine neuroborreliosis (NB), Lyme disease, is difficult to diagnose and has limited description in the literature.ObjectiveProvide a detailed description of clinical signs, diagnostic, and pathologic findings of horses with NB.AnimalsSixteen horses with histologically confirmed NB.MethodsRetrospective review of medical records at the University of Pennsylvania and via an ACVIM listserv query with inclusion criteria requiring possible exposure to Borrelia burgdorferi and histologic findings consistent with previous reports of NB without evidence of other disease.ResultsSixteen horses were identified, 12 of which had additional evidence of NB. Clinical signs were variable including muscle atrophy or weight loss (12), cranial nerve deficits (11), ataxia (10), changes in behavior (9), dysphagia (7), fasciculations (6), neck stiffness (6), episodic respiratory distress (5), uveitis (5), fever (2), joint effusion (2), and cardiac arrhythmias (1). Serologic analysis was positive for B. burgdorferi infection in 6/13 cases tested. CSF abnormalities were present in 8/13 cases tested, including xanthochromia (4/13), increased total protein (5/13; median: 91 mg/dL, range: 25–219 mg/dL), and a neutrophilic (6/13) or lymphocytic (2/13) pleocytosis (median: 25 nucleated cells/μL, range: 0–922 nucleated cells/μL). PCR on CSF for B. burgdorferi was negative in the 7 cases that were tested.Conclusion and Clinical ImportanceDiagnosis of equine NB is challenging due to variable clinical presentation and lack of sensitive and specific diagnostic tests. Negative serology and normal CSF analysis do not exclude the diagnosis of NB.

Tissue engineering holds great promise for the treatment of advanced intervertebral disc degeneration. However, assessment of in vivo integration and mechanical function of tissue-engineered disc replacements over the long term, in large animal models, will be necessary to advance clinical translation. To that end, we developed tissue-engineered, endplate-modified disc-like angle ply structures (eDAPS) sized for the rat caudal and goat cervical spines that recapitulate the hierarchical structure of the native disc. Here, we demonstrate functional maturation and integration of these eDAPS in a rat caudal disc replacement model, with compressive mechanical properties reaching native values after 20 weeks in vivo and evidence of functional integration under physiological loads. To further this therapy toward clinical translation, we implanted eDAPS sized for the human cervical disc space in a goat cervical disc replacement model. Our results demonstrate maintenance of eDAPS composition and structure up to 8 weeks in vivo in the goat cervical disc space and maturation of compressive mechanical properties to match native levels. These results demonstrate the translational feasibility of disc replacement with a tissue-engineered construct for the treatment of advanced disc degeneration.

Summary Cryptosporidium is a leading cause of diarrheal disease and an important contributor to early childhood mortality, malnutrition, and growth faltering. Older children in high endemicity regions appear resistant to infection, while previously unexposed adults remain susceptible. Experimental studies in humans and animals support the development of disease resistance, but we do not understand the mechanisms that underlie protective immunity to Cryptosporidium . Here, we derive an in vivo model of Cryptosporidium infection in immunocompetent C57BL/6 mice by isolating parasites from naturally infected wild mice. Similar to human cryptosporidiosis, this infection causes intestinal pathology, and interferon-γ controls early infection while T cells are critical for clearance. Importantly, mice that controlled a live infection were resistant to secondary challenge and vaccination with attenuated parasites provided protection equal to live infection. Both parasite and host are genetically tractable and this in vivo model will facilitate mechanistic investigation and rational vaccine design.

The bone marrow is an important site for the interrelated processes of hematopoiesis, granulopoiesis, erythropoiesis and lymphopoiesis. A wide variety of microbial challenges are associated with profound changes in this compartment that impact on hematopoietic differentiation and mobilization of a variety of cell types. This article reviews some of the key pathways that control BM homeostasis, the infectious and inflammatory processes that affect the BM, and how addressing the knowledge gaps in this area has the potential to widen our comprehension of immune homeostasis.