Tumor stem cells and implications for the immunotherapy of cancer

Passive, active and adoptive immunotherapy of human cancers and leukemias raise a renewed interest strengthened by the availability of purified biological substances such as IL2, interferon, thymic hormones and by some recent favourable therapeutic results which have demonstrated the possibility of obtaining objective tumor regressions by immunotherapy. Analysis of results of chemotherapy shows that only 8 human cancers and malignant hemopathies are curable at an advanced diffuse stage of disease. These cancers are characterized by the rarity or absence of late metastases (more than 3-4 years after initial diagnosis). Cure may be considered as complete with a high probability if disease free status is maintained for 3 years. This finding suggests the absence of tumor stem cells capable to produce late metastases. Other cancers are not chemocurable at an advanced systemic stage. In most of them late metastases (greater than 4 years after diagnosis) are observed. A model of organization of malignant tumors based on the distinction between primitive tumor stem cells which are rarely or exceptionally in cycle and protected by a specific microenvironment and committed tumor stem cells is proposed. According to this model, only cancers and/or metastases and malignant hemopathies containing but committed tumor stem cells would be chemocurable. Analysis of a trial of adjuvant therapy of breast cancer with poly A: poly U shows the possibility of immunotherapy to prevent the development of late metastases, independently of hormonal status in contrast with standard adjuvant chemotherapy which is only active on early micrometastases in premenopausal women.(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment of Neotrombicula autumnalis dermatitis in dogs using two topical permethrin-pyriproxyfen combinations

Few data are available in the literature on the dermatological consequences and treatment of Neotrombicula autumnalis infestation in dogs and cats. In this study, 15 dogs naturally infested with Neotrombicula were affected with moderate to severe pruritic dermatitis. The dermatitis resolved with successful treatment of the parasitic infestation. In 14 dogs, treatment using a topical permethrin-pyriproxyfen combination (pump-spray or 'line-on') was effective within one to three weeks. Two applications were necessary in four dogs. Careful follow-up was conducted in all cases. Statistical analysis was performed to assess the impact of treatment on the parasite population and clinical signs over the three-week study period.     

Prospective study of bacterial overgrowth syndrome in eight dogs

Eight dogs with cutaneous lesions, clinical signs and cytological findings compatible with bacterial overgrowth syndrome were compared with four healthy dogs. The affected dogs were treated for 28 days with 30 mg/kg/day cephalexin. The results showed that the syndrome was a superficial cutaneous disorder characterised by marked pruritus, greasy seborrhoea, offensive odour, erythema, lichenification, hyperpigmentation, excoriations and alopecia involving principally the ventral aspect of the body, but no papules, pustules, epidermal collarettes or crusts; it was caused by overgrowths of Staphylococcus intermedius all over the body surface. Histopathological findings included a superficial, perivascular, hyperplastic and spongiotic dermatitis with a mixed inflammatory infiltrate, but no lesions suggestive of a true pyoderma. In the affected dogs, anti-staphylococcal immunoglobulin G levels were high, but anti-staphylococcal immunoglobulin E levels were low, suggesting that staphylococcal hypersensitivity is not the underlying pathogenic process. The antibiotic treatment improved the condition of all the dogs, but five of the eight had an underlying allergic skin disease.     

Botulinum neurotoxin is shielded by NTNHA in an interlocked complex

Botulinum neurotoxins (BoNTs) are highly poisonous substances that are also effective medicines. Accidental BoNT poisoning often occurs through ingestion of Clostridium botulinum-contaminated food. Here, we present the crystal structure of a BoNT in complex with a clostridial nontoxic nonhemagglutinin (NTNHA) protein at 2.7 angstroms. Biochemical and functional studies show that NTNHA provides large and multivalent binding interfaces to protect BoNT from gastrointestinal degradation. Moreover, the structure highlights key residues in BoNT that regulate complex assembly in a pH-dependent manner. Collectively, our findings define the molecular mechanisms by which NTNHA shields BoNT in the hostile gastrointestinal environment and releases it upon entry into the circulation. These results will assist in the design of small molecules for inhibiting oral BoNT intoxication and of delivery vehicles for oral administration of biologics.     

Thymomas in rabbits: clinical evaluation, diagnosis, and treatment

Thymomas are rarely recorded in rabbits, and the literature includes comparatively few cases. Medical records were reviewed to identify all pet rabbits in which a mediastinal mass was diagnosed between Feb 2007 and Jan 2010. Signalment, history, clinical signs, diagnostic work-up (including laboratory data, diagnostic imaging, and ultrasound-guided fine-needle aspiration of the mediastinal mass), treatment modalities, survival time, and histologic findings were evaluated. Cytologic and/or histopathologic examinations revealed thymomas in all rabbits with mediastinal masses (n=13). Rabbits with thymomas showed clinical signs of dyspnea (76.9%), exercise intolerance (53.9%), and bilateral exophthalmos (46.2%). In seven rabbits the thymoma was removed surgically. Two rabbits were treated conservatively, and four rabbits were euthanized because of their poor clinical condition. The two rabbits that underwent surgery were euthanized 6 mo and 34 mo later. Mediastinal masses in rabbits appear to be more common than previously believed and consist primarily of thymomas rather than thymic lymphomas. Cytology of samples collected by ultrasound-guided fine-needle aspiration is an accurate diagnostic tool for the identification of thymomas in rabbits. Due to a high rate of perioperative mortality, intensive perioperative care and the provision of a low-stress environment are recommended for a successful thoracotomy.     

Analysis of antimicrobial sales data of the main distributor in Quebec from 2016 to 2019: An estimate of usage in dairy cattle,horses, and small animals

Because antimicrobial usage (AMU) data are crucial in understanding and dealing with the threat that antimicrobial resistance (AMR) poses to global health, data of the sale of antimicrobials from 2016 to 2019 of CDMV Inc. — a major distributor of veterinary products in Canada — were collected and analyzed for the province of Quebec. The primary objective was to describe the evolution of AMU sales data for dairy cattle, small animals, and horses; a secondary objective was to determine effects of a new provincial regulation on antimicrobials of very high importance (in Quebec) on sales for dairy cattle. Results are described in milligrams of antimicrobials per kilogram of animal biomass (mg/PCU) for dairy cattle, small animals, and horses; intramammary products were analyzed for number of treatments per 100 cow-years; and results for dairy cattle were compared in Canadian-defined course doses for cattle (DCDbovCA) per 100 cow-years to a recent study for this species in Quebec. Between 2016 and 2019, there were decreased sales of Category 1 antimicrobials for all species included in the study (Category 1-VI for small animals). This reduction was even more apparent for dairy cattle, for which a 76% decrease occurred from 2018 to 2019 (1.7 to 0.4 mg/PCU). This marked reduction was attributed to the new regulation implemented in February 2019. Since a farm- and clinic-level AMU monitoring system has not yet been implemented in Quebec, analysis of CDMV Inc. sales enabled observations of temporal trends in AMU for dairy cattle, horses, and small animals. These temporal trends based on CDMV Inc. sales will be useful for making comparisons and validating trends derived from farm- and clinic-level data generated by a monitoring system.     

Evaluation of the expression of P-selectin, ICAM-1, and TNF-alpha in bacteria-free lesional skin of atopic dogs with low-to-mild inflammation

Canine atopic dermatitis (AD) is a pruritic skin condition that shares many clinical and pathophysiological features with its human counterpart. A major therapeutic challenge of AD is the control of the skin inflammatory process. A detailed knowledge of the pro-inflammatory molecules involved in cell recruitment in AD would allow for a better control of the disease. We thus have studied the protein expression of P-selectin, ICAM-1 and TNF-alpha in the lesional and non-lesional skin of atopic dogs that had been treated for bacterial infections. Despite a low-to-mild inflammatory process, P-selectin protein was clearly upregulated in the lesional skin areas when compared with non-lesional skin (four-fold average increase). This P-selectin upregulation was accompanied by signs of functional changes such as increased cell margination, and membrane-associated protein expression. Although the expression of ICAM-1 and TNF-alpha was not enhanced in the lesional versus the non-lesional skin, there was a trend towards a correlated upregulation of both molecules. Further studies will help elucidate the significance of the substantial overexpression of P-selectin in canine AD, in particular in a scenario where bacterial antigens are not contributing as pro-inflammatory stimuli.     

Nitrogen accumulation and partitioning in hail‐damaged soybeans 1

Hail damage to an experiment that was being used to investigate nitrogen (N) nutrition of soybeans [Glycine max (L.) Merr.] with ¹⁵N methodology provided a unique opportunity to study the effects of hail damage at the R3 stage of development on N uptake and partitioning through stage R5.8. Field plots were established on a silt loam soil (Typic Hapludol 1). Severely damaged (mean 72% leaf loss) and slightly damaged (mean 26% leaf loss) soybeans were compared for total reduced N and for ¹⁵N concentration in leaflets, petioles, stems, roots, pod walls, and seeds during the 28 days following the hailstrom. The concentration of total N and of ¹⁵N in all organs in both damage treatments declined significantly after the storm, but less in green leaflets (total N), and in green leaflets, green petioles, and pod walls (¹⁵N) of severely than of slightly damaged plants. Measurements on senesced leaflets and petioles showed that the concentration of ¹⁵N also decreased to a greater extent than that of the total N in these organs. This differential loss of ¹⁵N compared with total N suggests that the ¹⁵N was in a form that was less refractory than was the bulk tissue N, and provides evidence of separate mobile pools of N in the plant. Nitrogen budgets were calculated to compare the loss of N and ¹⁵N from abscising leaflets and petioles to the N accumulation of the damaged plants during podfill. These showed that loss from the leaflets and petioles contributed only 7% of the total N accumulated by the plants between R3 and R5.8. This study has exemplified the usefulness of ¹⁵N methodology in investigations of the nutrition and physiology of soybeans suffering leaf damage by hail.