Evaluation of the oral antimitotic agent (ABT-751) in dogs with lymphoma

Background

ABT‐751 is a novel orally available antimitotic agent that targets microtubule polymerization. This mechanism may suggest potential activity in canine lymphoma.

Objective

Determine a maximum tolerated dose for ABT‐751, and assess long‐term tolerability and activity in canine lymphoma.

Animals

Thirty dogs with newly diagnosed (n = 19) or relapsed (n = 11) non‐Hodgkin's lymphoma.

Methods

Dogs (n = 11) were enrolled in a rapid dose escalation study to define the maximum tolerated dose. Upon definition of a maximally tolerated dose, a cohort expansion of 19 dogs allowed verification of long‐term tolerability and assessment of activity. Study endpoints in the cohort expansion included chronic tolerability, response rate, response duration, and time to progression. Additional endpoints included serum pharmacokinetics, lymph node drug concentrations, and changes in circulating endothelial cells.

Results

The maximum tolerated dose of ABT‐751 was 350 mg/m² PO q24h. Dose‐limiting toxicities included vomiting and diarrhea, which resolved with a schedule adjustment to 350 mg/m² PO q48h. ABT‐751 was consistently detected in lymphoma tissue samples from dogs treated at or above the maximum tolerated dose. In the cohort expansion, objective responses were seen in 3/15 (20%) dogs with a response duration ranging from 21 to 111 days. Decreases in circulating endothelial cells were seen in 10 dogs at day 7 (2 responding dogs and 8 nonresponding dogs).

Conclusion

ABT‐751 was well tolerated at 350   mg/m² PO q24h for 7 days and then q48h thereafter. Activity of ABT‐751 suggested a rationale for additional studies of ABT‐751 as part of a combination chemotherapy protocol for lymphoma or other canine cancers.     

Comparison of thoracic radiographs and single breath-hold helical CT for detection of pulmonary nodules in dogs with metastatic neoplasia

Imaging studies in people indicate that x-ray computed tomography (CT) is a more sensitive technique than thoracic radiography for the detection of pulmonary metastasic neoplasia. Systematic studies comparing CT and thoracic radiographic techniques in veterinary patients have not been performed. The present retrospective study was designed to directly compare the efficacy of these 2 techniques in detecting pulmonary nodules in dogs. Eighteen dogs with histologically confirmed pulmonary metastatic neoplasia had contemporaneous thoracic radiographs and pulmonary CT scans compared. Quantitative analyses included estimation of pulmonary nodule size, number, and lobar distribution on thoracic radiographs and CT images. Only 9% of CT-detected pulmonary nodules were identified on thoracic radiographs (P < .003). The lower size threshold was approximately 1 mm to detect pulmonary nodules on CT images and 7-9 mm to reliably detect nodules on radiographs (P < .0001). Additionally, pulmonary nodules were detected in a significantly greater number of lung lobes using CT as compared with thoracic radiographs (P < .0001). These data indicate that CT is significantly more sensitive than thoracic radiography for detecting soft-tissue nodules in dogs. As such, thoracic CT should be considered in any patient with neoplasia that has potential for pulmonary metastasis to more reliably stage the disease, particularly when accurate characterization of the extent and distribution of pulmonary metastatic disease affects therapeutic planning.     

Evaluation of peripheral blood neutrophil function in tumor‐bearing dogs

Background: Peripheral blood neutrophils of untreated human cancer patients have been shown to have normal, increased, and decreased phagocytic activity, killing capacity, and/or oxidative burst activities. Objectives: The objectives of this study were to evaluate oxidative burst and phagocytic activities of peripheral blood neutrophils from tumor‐bearing dogs before therapy and compare them with neutrophil function of healthy control dogs. Methods: Heparinized whole blood was obtained from dogs with high‐grade lymphoma (n=23), sarcoma (n=13), or carcinoma (n=11), and healthy control dogs (n=11) for flow cytometric evaluation of oxidative burst and phagocytic activities. Percentage of bursting cells and amount of oxidative burst activity were determined after stimulation with phorbol 12‐myristate 13‐acetate (PMA) or Escherichia coli. Percentage of phagocytic cells and amount of phagocytic activity were determined after incubation with fluorescent E. coli. Results: Compared with control dogs, dogs with sarcoma (P=.004) and carcinoma (P=.05) had a lower percentage of neutrophils exhibiting oxidative burst activity after stimulation with PMA. Phagocytic activity was significantly lower in dogs with sarcomas compared with control dogs (P<.0001) and dogs with lymphoma (P=.01). Conclusions: Untreated carcinomas and sarcomas in dogs may suppress the percentage of neutrophils capable of oxidative burst when stimulated by PMA. Furthermore, sarcomas also may suppress the amount of phagocytic activity per neutrophil. Until further studies can be performed, the clinical significance of these findings is unknown.     

功能性食品在抗癌症方面的应用

所谓功能性食品就是指在满足基本的营养需要的同时还能够发挥额外的生理作用,如预防或延迟慢性疾病的发作等。过去数十年的研究已经发现了大量的可以防止细胞氧化的营养物质。这些水果和蔬菜中的成分能够作为抗氧化剂清除体内的有害的能引起疾病的自由基。功能性食品在抗癌症方面有着广阔的应用前景。     

Handling time and predation behaviour by the crab, Cancer pagurus, preying on cultured scallop, Pecten maximus

We investigated handling time, persistence time and shell‐breaking techniques by crab, Cancer pagurus (L.) (13–15 cm carapace width), offered cultured scallops, Pecten maximus(L.), within the recommended release size for bottom culture. Three shell height groups were used: 50–55, 60–65 and 70–75 mm. The results showed that the crabs managed to open scallops from all the three size groups. The median handling time in the 50–55 mm group (788 s) was significantly different from the median handling time of the 60–65 mm (2482 s) and 70–75 mm (2980 s) groups. The median persistence time increased significantly with each scallop size, from 89 s in the 50–55 mm group to 97 s in the 60–65 mm and 125 s in the 70–75 mm group. We observed a change in the shell‐breaking techniques from a dominance of smashed scallops in the 50–55 mm group to more punched and chipped scallops in the 60–65 and 70–75 mm groups. The shift in predation behaviour when crabs were offered 50–55 mm scallops compared with the larger groups is discussed in relation to strategies in the release of scallops to seabed cultures.     

Bacterial septicaemia in prerecruit edible crabs,Cancer pagurus L.

Juvenile edible crabs, Cancer pagurus L., were surveyed from Mumbles Head and Oxwich Bay in South Wales, UK, and the number of heterotrophic bacteria and vibrios in the hemolymph was determined. The percentage of crabs with hemolymph containing bacteria was variable over the survey with higher numbers of animals affected in summer than in winter. Post‐moult crabs contained significantly higher numbers of heterotrophic bacteria in the hemolymph than pre‐ and intermoult animals. Crabs with cuticular damage to the gills also had significantly higher numbers of bacteria in the hemolymph. Crabs were found to have a high prevalence of infection by the dinoflagellate, Hematodinium. Such animals had significantly fewer bacteria in the blood in comparison with Hematodinium‐free animals. Of the 463 crabs surveyed, only 3 individuals had hemolymph containing 2000 + CFU mL^?1. Based on 16S rRNA gene sequences, two of these crabs contained a Vibrio pectenicida‐like isolate, while the other had a mixed assemblage of vibrios. Although 59% of the crabs surveyed had culturable bacteria in the hemolymph, the majority only had small numbers (<2000 CFU mL^?1), suggesting that such infections may be of limited importance to the sustainability of the crab fishery in this region.     

Rock crab predation of juvenile sea scallops: the functional response and its implications for bottom culture

The functional response describes how consumption rate of individual predators changes as prey density changes, and can have important implications for the bottom culture of scallops. We examined (i) the functional response of rock crabs (Cancer irroratus) preying on juvenile sea scallops (Placopecten magellanicus); (ii) the effect of substrate type and scallop size on the functional response; and (iii) the underlying behavioural mechanisms of observed functional responses. Specifically, we quantified predation rate and behaviours, such as the proportion of time spent searching for prey, encounter rate between predators and prey and the outcomes of encounters, when individual rock crabs were offered a range of scallop density (2–50 or 11–111 scallops m⁻²) and two size classes of scallops (∼ ∼25 and ∼ ∼35 mm shell height) on two different substrate types (“glass-bottom” and “granule”). We found that crab predation rate on small juvenile scallops increased at a decelerating rate with prey density to a plateau at high prey density on both substrates, indicating a hyperbolic (type II) functional response. Crab predation rate on large juvenile scallops was independent of prey density (i.e., no functional response evident), suggesting that crabs were at their satiation level. Prey density did not influence any behaviour except encounter rate on small juvenile scallops, which increased as prey density increased. Substrate type influenced crab predation: maximum predation rate of crabs on small juvenile scallops and encounter rate with either size of juvenile scallops was lower on granule than on glass-bottom. Our results in the laboratory suggest that crabs could potentially be swamped if scallops are seeded at a high density in the field. However, many factors in the field may influence the functional response. For example, the presence of multiple prey types may lead to sigmoid functional responses, while the presence of many crab individuals may lead to aggregation of crabs in areas of high prey density.     

Risk assessment of pesticide residues in South African raw wheat

The presence of pesticide residues in wheat produced and imported in South Africa was determined and their health risks assessed. Pesticides were detected in all local (median = 1, range: 1–3, n = 71) and imported (median = 1, range: 1–6, n = 13) samples. Multiple pesticides (>1 pesticide) were detected in about 30% local samples and 39% imported samples. Eight different pesticides were detected in total. The most frequently detected pesticides were mercaptothion (99%), permethrin (19%) and chlorpyrifos (17%). Nine (11%) samples exceeded the EU wheat MRL for permethrin (0.05 mg/kg) which included 7 (10%) local samples and 2 (15%) imported samples. The highest fenitrothion level (0.65 mg/kg) corresponds to an intake that was below but near the estimated short-term safety threshold. The results call for an investigation into the levels of pesticide residues in cereal-based food and for tighter regulation and regular monitoring by government and industry.     

piRNA在癌症上的研究进展

piRNAs(piwi-interacting RNAs)是一类新型的长约30 nt的非编码单链小RNAs,参与生殖细胞的发育,抑制DNA的自我复制,维持生殖DNA的完整。但是,对piRNAs与疾病的关系研究目前相对较少。主要综述了其对癌症调控作用的最新研究进展。     

Potent Skin Cancer Chemopreventing Activity of Some Novel Semi-synthetic Cembranoids from Marine Sources

In the course of our continuing research in development and evaluation of novel skin cancer chemopreventive agents from marine sources, five semi-synthetic cembranoids derived from the marine natural product sarcophine, isolated from the soft coral Sarcophyton glaucum, were synthesized and shown to exhibit a remarkable chemopreventive activity in the in-vitro Epstein Barr Virus Early Antigen (EBV-EA) activation assay. These compounds were assayed in vivo using the two-stage carcinogenesis test of mouse skin tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator, and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter by topical administration. They showed potent inhibition of both percentage incidence of skin tumor as well as the multiplicity of skin tumors per mouse compared to untreated controls.