Surgical Treatment of Recurrent Rectal Prolapse in an Adult Female Black-crested Mangabey (Lophocebus aterrimus) by Colopexy.

A 13-y-old, multiparous female black-crested mangabey (Lophocebus aterrimus) underwent surgical treatment for chronically recurring rectal prolapse by laparotomy and subsequent colopexy. Initially, a laparoscopic approach was attempted but was converted to an open approach after intraabdominal adhesions were noted. The colopexy was performed through a ventral midline incision, with no complications intraoperatively or postoperatively. The predisposing factors responsible for the development of this condition likely were related to pelvic floor weakness due to multiple past pregnancies. Transport-associated stressors likely contributed to the acute worsening of this patient's condition. Rectal prolapse is a common condition in laboratory-housed NHP. This case report describes an effective surgical treatment for recurring or otherwise nonreducible rectal prolapse in these species.

Correction of biapical radial deformities by use of bi-level hinged circular external fixation and distraction osteogenesis in 13 dogs.

OBJECTIVES: To describe clinical, radiographic, and computed tomographic (CT) assessment of biapical deformities of the radius in dogs and evaluate the effectiveness of their management by use of bilevel hinged circular external fixation frames. STUDY DESIGN: Prospective, non-randomized cohort study. ANIMALS: Dogs (N = 26: 13 with 14 limbs operated, 13 controls). METHODS: CT scans of the forelimbs were performed and CT-based polymer replicas prepared. Rotation within the elbow joint, varus of the proximal portion of the radius, radial torsion, valgus of the distal portion of the radius, procurvatum, and rotation within the carpal joint were measured on radiographs, on polymer replicas, and on CT scans. Bilevel hinged circular external fixation frames were assembled on polymer replicas and identical frames were placed on dogs. Torsion was corrected acutely and angulation was corrected progressively. Functional outcome was assessed subjectively. RESULTS: Buckling was present preoperatively in operated limbs. Mean (± SD) varus of the proximal portion of the radius was 36 ± 8°, valgus of the distal portion of the radius was 32 ± 5°, external radial torsion was 35 ± 6°, procurvatum was 41 ± 10°, and medial translation was 44 ± 11 mm. Treatment duration was 80 ± 24 days. Buckling was not observed after surgery. Lameness scores improved in all dogs (P < .001). CONCLUSIONS: The forelimbs of dogs with severe biapical radial deformities buckle and have increased radial head rotation and radial torsion. Biapical radial deformities can be managed with proximal and distal radial osteotomies and bilevel hinged circular external fixation.

Comparison of surgical site infection rates in clean and clean-contaminated wounds in dogs and cats after minimally invasive versus open surgery: 179 cases (2007-2008).

OBJECTIVE: To report and compare the surgical site infection (SSI) rates for clean and clean-contaminated procedures performed by either a minimally invasive surgical or open surgical approach in a large population of dogs and cats. DESIGN: Prospective case series. ANIMALS: 179 patients (dogs and cats) undergoing minimally invasive abdominal or thoracic surgery. PROCEDURES: Case information from all animals that underwent minimally invasive abdominal or thoracic surgery was prospectively collected and compared with an existing database of the same information collected from 379 patients undergoing laparotomy or thoracotomy via an open surgical approach. For both groups, an SSI was defined as any surgical wound in which purulent discharge was observed within 14 days after the procedure. Follow-up for all patients was obtained by direct examination or telephone interviews. RESULTS: Overall SSI rate in the minimally invasive surgery (MIS) group was 1.7% and in the open surgery (OS) group was 5.5%. On univariate analysis, there was a significantly lower SSI rate in the MIS group, compared with the SSI rate for the OS group. On multivariable logistic regression analysis, this difference appeared to be a result of the fact that surgery times were longer (median, 105 vs 75 minutes) and hair was clipped ≥ 4 hours prior to surgery for more animals (23% vs 11 %) in the OS group, compared with the MIS group. CONCLUSIONS AND CLINICAL RELEVANCE: MIS may be associated with a lower SSI rate, compared with OS, but confounding factors such as differences in surgery time and preoperative preparation contributed in part to this finding. As such, surgical approach cannot be categorized as an independent risk factor for SSIs in small animals until further studies are performed.

The small heat shock protein HspB2 is a novel anti-apoptotic protein that inhibits apical caspase activation in the extrinsic apoptotic pathway.

Members of the conserved small heat shock protein (sHSP) family, such as αB-crystallin and Hsp27, are constitutively expressed in diverse malignancies and have been linked to several hallmark features of cancer including apoptosis resistance. In contrast, the sHSP HspB2/MKBP, which shares an intergenic promoter with αB-crystallin, was discovered as a chaperone of the myotonic dystrophy protein kinase and has not been previously implicated in apoptosis regulation. Here we describe a new function for HspB2 as a novel inhibitor of apical caspase activation in the extrinsic apoptotic pathway. Specifically, we demonstrate that HspB2 is expressed in a subset of human breast cancer cell lines and that ectopic expression of HspB2 in breast cancer cells confers resistance to apoptosis induced by both TRAIL and TNF-α. We also show that HspB2 inhibits the extrinsic apoptotic pathway by suppressing apical caspases-8 and 10 activation, thereby blocking downstream apoptotic events, such as Bid cleavage and caspase-3 activation. Consistent with these in vitro effects, HspB2 attenuates the anti-tumor activity of TRAIL in an orthotopic xenograft model of breast cancer. Collectively, our results reveal a novel function of HspB2 as an anti-apoptotic protein that negatively regulates apical caspase activation in the extrinsic apoptotic pathway.

Aspirin sensitizes cancer cells to TRAIL-induced apoptosis by reducing survivin levels.

PURPOSE: Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic antibodies targeting its receptors are promising cancer therapies because of their tumor selectivity, many tumors are resistant to TRAIL-based therapies. We examined whether the nonsteroidal anti-inflammatory drug aspirin sensitized cancer cells to TRAIL agonists in vitro and in vivo and investigated the underlying mechanism. EXPERIMENTAL DESIGN: The effects of aspirin on sensitivity to TRAIL agonists and expression of apoptosis regulators was determined in human breast cancer cell lines and xenograft tumors. The specific role of survivin depletion in the TRAIL-sensitizing effects of aspirin was determined by silencing survivin. RESULTS: Aspirin sensitized human breast cancer cells, but not untransformed human mammary epithelial cells, to TRAIL-induced caspase activation and apoptosis by a cyclooxygenase-2-independent mechanism. Aspirin also sensitized breast cancer cells to apoptosis induced by a human agonistic TRAIL receptor-2 monoclonal antibody (lexatumumab). Aspirin treatment led to G1 cell cycle arrest and a robust reduction in the levels of the antiapoptotic protein survivin by inducing its proteasomal degradation, but did not affect the levels of many other apoptosis regulators. Silencing survivin with small interfering RNAs sensitized breast cancer cells to TRAIL-induced apoptosis, underscoring the functional role of survivin depletion in the TRAIL-sensitizing actions of aspirin. Moreover, aspirin acted synergistically with TRAIL to promote apoptosis and reduce tumor burden in an orthotopic breast cancer xenograft model. CONCLUSIONS: Aspirin sensitizes transformed breast epithelial cells to TRAIL-based therapies in vitro and in vivo by a novel mechanism involving survivin depletion. These findings provide the first in vivo evidence for the therapeutic utility of this combination.

The small heat shock protein alpha B-crystallin is a novel inhibitor of TRAIL-induced apoptosis that suppresses the activation of caspase-3.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor alpha family of cytokines that preferentially induces apoptosis in transformed cells, making it a promising cancer therapy. However, many neoplasms are resistant to TRAIL-induced apoptosis by mechanisms that are poorly understood. We demonstrate that the expression of the small heat shock protein alpha B-crystallin (but not other heat shock proteins or apoptosis-regulating proteins) correlates with TRAIL resistance in a panel of human cancer cell lines. Stable expression of wild-type alpha B-crystallin, but not a pseudophosphorylation mutant impaired in its assembly and chaperone function, protects cancer cells from TRAIL-induced caspase-3 activation and apoptosis in vitro. Furthermore, selective inhibition of alpha B-crystallin expression by RNA interference sensitizes cancer cells to TRAIL. In addition, wild-type alpha B-crystallin promotes xenograft tumor growth and inhibits TRAIL-induced apoptosis in vivo in nude mice, whereas a pseudophosphorylation alpha B-crystallin mutant impaired in its anti-apoptotic function inhibits xenograft tumor growth. Collectively, these findings indicate that alpha B-crystallin is a novel regulator of TRAIL-induced apoptosis and tumor growth. Moreover, these results demonstrate that targeted inhibition of alpha B-crystallin promotes TRAIL-induced apoptosis, thereby suggesting a novel strategy to overcome TRAIL resistance in cancer.

Peroxisome proliferator-activated receptor gamma agonists promote TRAIL-induced apoptosis by reducing survivin levels via cyclin D3 repression and cell cycle arrest.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapy that preferentially induces apoptosis in cancer cells. However, many neoplasms are resistant to TRAIL by mechanisms that are poorly understood. Here we demonstrate that human breast cancer cells, but not normal mammary epithelial cells, are dramatically sensitized to TRAIL-induced apoptosis and caspase activation by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists of the thiazolidinedione (TZD) class. Although TZDs do not significantly alter the expression of components of the TRAIL signaling pathway, they profoundly reduce protein levels of cyclin D3, but not other D-type cyclins, by decreasing cyclin D3 mRNA levels and by inducing its proteasomal degradation. Importantly, both TRAIL sensitization and reduction in cyclin D3 protein levels induced by TZDs are likely PPARgamma-independent because a dominant negative mutant of PPARgamma did not antagonize these effects of TZDs, nor were they affected by the expression levels of PPARgamma. TZDs also inhibit G(1) to S cell cycle progression. Furthermore, silencing cyclin D3 by RNA interference inhibits S phase entry and sensitizes breast cancer cells to TRAIL, indicating a key role for cyclin D3 repression in these events. G(1) cell cycle arrest sensitizes breast cancer cells to TRAIL at least in part by reducing levels of the anti-apoptotic protein survivin: ectopic expression of survivin partially suppresses apoptosis induced by TRAIL and TZDs. We also demonstrate for the first time that TZDs promote TRAIL-induced apoptosis of breast cancer in vivo, suggesting that this combination may be an effective therapy for cancer.