New approaches for modelling cancer mechanisms in the mouse

Mouse models of human cancer are vital to our understanding of the neoplastic process, and to advances in both basic and clinical research. Indeed, models of many of the major human tumours are now available and are subject to constant revision to more faithfully recapitulate human disease. Despite these advances, it is important to recognize that limitations do exist to the current range of models. The principal approach to modelling has relied upon the use of constitutive gene knockouts, which can often result in embryonic lethality, can potentially be affected by developmental compensation, and which do not mimic the sporadic development of a tumour expanding from a single cell in an otherwise normal environment. Furthermore, simple knockouts are usually designed to lead to loss of protein function, whereas a subset of cancer-causing mutations clearly results in gain of function. These drawbacks are well recognized and this review describes some of the approaches used to address these issues. Key amongst these is the development of conditional alleles that precisely mimic the mutations found in vivo, and which can be spatially and tissue-specifically controlled using 'smart' systems such as the tetracycline system and Cre-Lox technology. Examples of genes being manipulated in this way include Ki-Ras, Myc, and p53. These new developments in modelling mean that any mutant allele can potentially be turned on or off, or over- or under-expressed, in any tissue at any stage of the life-cycle of the mouse. This will no doubt lead to ever more accurate and powerful mouse models to dissect the genetic pathways that lead to cancer.     

Mycobacterium avium ssp. paratuberculosis recombinant heat shock protein 70 interaction with different bovine antigen-presenting cells

Abstract Heat shock proteins (Hsp) can deliver antigen into the major histocompatibility complex class I presentation pathway of antigen-presenting cells (APC), a process called cross priming, thus stimulating antigen-specific CD8+ T-cell reactions. Hsp were shown to elicit proinflammatory responses in APC. Both processes require interaction of Hsp with APC via specific receptors. This study describes the interaction of recombinant Hsp70 (rHsp70) of Mycobacterium avium subspecies paratuberculosis with bovine peripheral blood mononuclear cells that was restricted to CD14+ cells. Characterized monocyte-derived macrophages, monocyte-derived dendritic cells (DC) and BoMac, an immortalized bovine macrophage cell line, were used to investigate the interaction of rHsp70 with different bovine APC. Saturation of immature DC with high concentrations of rHsp70 is demonstrated, and it was found that interaction of rHsp70 with DC was related to the maturation stage of the DC. Involvement of CD91 as a cellular receptor for rHsp70 was demonstrated; however, competition studies with immature DC demonstrated that other receptors exist on bovine APC. These data suggest that rHsp70-based vaccines may be useful for the successful immunization of cattle.     

Movement detection at the ankle following stroke is poor

This study assessed whether sense of movement is impaired at the ankle in persons post-stroke who are able to walk independently. Eleven chronic post-stroke subjects (> 4 months post stroke) who were ambulatory with or without walking aids and living within the community, and 10 healthy age-matched control subjects volunteered to participate. Proprioceptive acuity at the ankle, measured by sense of movement, was tested at three velocities, 0.1, 0.5, and 2.5 deg/sec, in random order. In addition, ankle range of motion and the distance that subjects walked in 6 minutes were assessed. Stroke subjects were significantly poorer (p < 0.001) at detecting movement at the affected ankle compared with either the unaffected ankle or with the control group at each of the velocities tested. Six out of 11 stroke subjects demonstrated significant impairment in movement detection compared to controls. The usual primary impairments following stroke are loss of strength and loss of co-ordination. However, reduced proprioceptive acuity at the affected ankle may also contribute to a person's ability to position and load the foot during walking. This could explain the moderate relationship found between proprioceptive acuity and walking endurance in persons following stroke (Spearman's rho = 0.63 to 0.77).     

Pulmonary toxicity,hepatic, and extrahepatic metabolism of 2-methylnaphthalene in mice

Male mice ($\text{C57BL}\text{6J}$) were injected once ip with 0.1, 1, 100, 200, 400, 600, 800, or 1000 mg/kg of 2-methylnaphthalene dissolved in corn oil. After 24 hr, the animals were killed and the lungs, livers, and kidneys were prepared for light microscopy. In addition, some lungs were subjected to scanning and transmission electron microscopy. A dose of 200 mg/kg produced a bronchiolar necrosis which affected the nonciliated bronchiolar (Clara) cell; the parenchymal cells remained unaffected. At higher doses of 2-methylnaphthalene (800 mg/kg), in addition to the damaged Clara cell, severe damage to the upper respiratory tract was noted. No liver or kidney pathology was detected by light microscopy in animals treated with the highest dose. No cellular damage was noted in any organ at doses less than 200 mg/kg. Forty-eight hours after a dose of 200–1000 mg/kg of 2-methylnaphthalene, less pulmonary damage was detected by light microscopy. The metabolism of 2-methylnaphthalene was investigated in hepatic, pulmonary, and renal microsomes from $\text{C57BL}\text{6J}$ mice. Lung and liver microsomes produced three isomeric dihydrodiols of 2-methylnaphthalene as well as other monohydroxylated metabolites. Only trace amounts of these metabolites were produced by the kidney.     

Multifocal follicular carcinoma of thyroid following radiotherapy for Hodgkin's disease

A 21-year-old white male developed multifocal follicular carcinoma of the thyroid gland 17 years after receiving neck irradiation (3000 rad) for Hodgkin''s disease. The tumour was unique in that follicular carcinoma has not previously been reported as having a multifocal origin, even after high dose radiotherapy.