A xenogeneic melanoma-antigen-enhanced allogeneic tumor cell vaccine (ATCV) is an appealing strategy for anti-cancer immunotherapy due to its relative ease of production, and the theoretical possibility that presentation of a multiplex of antigens along with a xenogeneic antigen would result in cross-reaction between the xenogeneic homologs and self-molecules, breaking tolerance and ultimately resulting in a clinically relevant immune response. In this study, we evaluated the efficacy of such a strategy using a xenogeneic melanoma differentiation antigen, human glycoprotein 100 (hgp100) in the context of a phase II clinical trial utilizing spontaneously arising melanoma in pet dogs. Our results demonstrate that the approach was well tolerated and resulted in an overall response rate (complete and partial response) of 17% and a tumor control rate (complete and partial response and stable disease of >6 weeks duration) of 35%. Dogs that had evidence of tumor control had significantly longer survival times than dogs that did not experience control. Delayed type hypersensitivity (DTH) to 17CM98 canine melanoma cells used in the whole cell vaccine was enhanced by ATCV and correlated with clinical response. In vitro cytotoxicity was enhanced by ATCV, but did not correlate with clinical response. Additionally, anti-hgp100 antibodies were elicited in response to ATCV in the majority of patients tested; however, this also did not correlate with clinical response. This approach, along with further elucidation of the mechanisms of tumor protection after xenogeneic immunization, may allow the development of more rational vaccines. This trial also further demonstrates the utility of spontaneous tumors in companion animals as a valid translational model for the evaluation of novel vaccine therapies.
The effect of orally administered insulin-like growth factor-I (IGF-I) on small intestinal structure and function was studied in 5-day-old colostrum-deprived piglets. Human recombinant IGF-I (3.5 mg ⋅ kg−1 ⋅ day−1) or control vehicle was given orogastrically for 4 days. Body weights, jejunal and ileal mucosa wet and dry weights, and serum IGF-I levels were similar in the two groups. Small intestinal villus height and crypt depth and jejunal enterocyte microvillar dimensions were also similar between groups. Oral IGF-I produced higher rates of jejunal ion transport because of increased basal Na+ absorption. Short-circuit current responses to mucosal addition ofd-glucose andl-alanine and net transepithelial absorption of 3- O-methylglucose were increased by IGF-I. Carrier-mediated uptake ofd-glucose per milligram in everted jejunal sleeves was greater in IGF-I-treated piglets because of a significantly greater maximal rate of uptake. We conclude that rates of net Na+ and Na+-dependent nutrient absorption are enhanced in piglets treated with oral IGF-I, and this effect is independent of changes in mucosal mass or surface area.
Mechanisms responsible for increased jejunal transport rates observed in tissues treated with orally administered insulin-like growth factor-I (IGF-I) were studied in 5-day-old colostrum-deprived piglets. Human recombinant IGF-I (3.5 mg. kg(-1). day(-1)) or control vehicle was given orogastrically for 4 days. Disaccharidase activity, fructose uptake, and Na+-glucose cotransporter SGLT-1 protein abundance were similar between groups. Oral IGF-I produced greater rates of enterocyte Na+-K+-ATPase activity with no significant differences in Na+-K+-ATPase abundance. Cellular mechanisms responsible for transport changes were studied in Ussing chambers. In control tissues, the presence of IGF-I in mucosal solutions increased basal short-circuit current (I(sc)), potential difference, D-glucose-stimulated I(sc), and Na+-K+-ATPase activity; these changes were abolished by preincubation of tissues with wortmannin, a phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor. The results suggest that the effect of IGF-I on jejunal ion and nutrient transport involves activation of PI 3-kinase and stimulation of Na+-K+-ATPase activity in enterocytes.
A 2-year-old Holstein heifer with a swollen brisket, jugular vein distention, muffled heart sounds, tachycardia, and free gas bloat was examined. Thymic lymphosarcoma was suspected based on a negative agar gel immunodiffusion test for bovine leukemia virus, presence of atypical lymphocytes in pleural fluid, and detection of a mass in the thoracic inlet. Right-sided cardiac catheterization was performed, and markedly increased jugular venous pressures (41 m m Hg) hymic lymphosarcoma, juvenile multicentric lympho-T sarcoma, and cutaneous lymphosarcoma are 3 sporadic forms of bovine lymphosarcoma that are not associated with bovine leukemia virus (BLV) infection.' Thymic lymphosarcoma produces clinical signs related to an anterior mediastinal mass, such as cervical and submandibular edema, bilateral jugular vein distention, and varying degrees of ruminal tympany, as well as dyspnea, anorexia, and weight loss.',' The clinical signs of thymic lymphosarcoma can therefore be difficult to differentiate from right-sided heart failure (RSHF). In this report, we describe the clinical and pathological findings in a heifer with thymic lymphosarcoma. Thoracocentesis, ultrasonography, electrocardiography, cardiac catheterization, and immunohistochemical staining pennitted detailed characterization and classification of this case. Case DescriptionA 2-year-old Holstein heifer was examined because of a 6-day history of a swollen brisket, anorexia, and free gas bloat. The heifer had been previously treated for bloat by oral-ruminal passage of a stomach tube and intraruminal administration of liquid fat and magnesium hydroxide. A magnet (PO), procaine penicillin G (IM), and ceftiofur sodium (IM) (doses unknown) had also been administered for treatment of suspected traumatic reticulopericarditis.The heifer appeared depressed and had bilateral abdominal distention. Rectal temperature and respiratory rate were within normal limits, while the pulse rate was increased (1 05 beatshinute). The heart and lung sounds were difficult to auscultate over the entire left side of the thorax, but could be heard normally over the right side of the thorax. Pitting edema extended from the thoracic inlet to the ramus of the mandible, and both jugular veins were greatly distended. Edema and venous distention were not evident caudal to the brisket. Palpation of the brisket revealed a 10-cm diameter, firm mass that extended deep into the thoracic inlet. The mass was fixed in place and surrounded by a markedly edematous subcutis, and the cervical skin was cold to the touch. Palpation per rectum revealed ruminal gas distention and a gravid uterus of approximately 7 months gestation. The feces were dark green and contained frank blood and mucus. A 3-cm diameter stomach tube was easily passed into the mmen and a large volume of gas released with subsequent decrease in abdominal distention.The heifer had a normal blood leukocyte count (9,000 cells/pL; normal, 4,000 to 12,000 cells/pL), normal lymphocyte count (3,150 cells/pL; normal, 2,500 to 7,500 cells/pL),...
Agents that enhance intestinal glutamine transport may be useful under conditions in which intestinal mucosal function is compromised. Here we examined whether oral administration of insulin-like growth factor (IGF-I) stimulates absorption of L-glutamine in piglet intestine. Colostrum-deprived piglets received human recombinant IGF-I (3.5 mg/kg/day) or vehicle orogastrically every 8 hr for four days after birth. Piglets were killed on day 5 and the proximal jejunum was removed. Basal electrical parameters and L-glutamine-stimulated changes in short-circuit current were measured in muscle-stripped tissues, and rates of L-glutamine uptake were measured in everted jejunal sleeves. Oral IGF-I had no effect on jejunal mucosal mass. Short-circuit current responses to mucosal addition of 10 mM L-glutamine were increased by oral IGF-I. Total and carrier-mediated uptakes of L-glutamine per milligram were greater in tissues from IGF-I-treated piglets due to a significantly greater maximal rate of uptake (Jmax). Thus, oral administration of IGF-I stimulates Na+-dependent glutamine absorption in piglet small intestine, an effect that is independent of changes in intestinal mucosal mass.
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