Differential involvement of gp130 signalling pathways in modulating tobacco carcinogen-induced lung tumourigenesis.

Interleukin (IL)-6 family cytokines signal exclusively via the gp130 coreceptor, and are implicated in smoking-associated lung cancer, the most lethal cancer worldwide. However, the role of gp130 signalling pathways in transducing the carcinogenic effects of tobacco-related compounds is ill-defined. Here, we report that lung tumourigenesis induced by the potent tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (Nicotine-derived Nitrosamine Ketone; NNK) is suppressed in gp130(F/F) knock-in mice characterized by the contrasting gp130-dependant hypoactivation of extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) and phosphatidylinositol 3-kinase/Akt, and hyperactivation of signal transducer and activator of transcription (STAT)3 signalling cascades. Specifically, in response to NNK, the absolute number and size of lung lesions in gp130(F/F) mice were significantly reduced compared with gp130(+/+) littermate controls, and associated with lower cellular proliferation without any alteration to the level of apoptosis in gp130(F/F) lung tumours. At the molecular level, reduced activation of ERK MAPK, but not Akt, was observed in lung tumours of gp130(F/F) mice, and corresponded with impaired expression of several tumour suppressor genes (for example, Trp53, Tsc2). Notably, STAT3 was not activated in the lungs of gp130(+/+) mice by NNK, and genetic normalization of STAT3 activation in gp130(F/F):Stat3(-/+) mice had no effect on NNK-induced tumourigenesis. The expression of tumour suppressor genes was reduced in tumours from current versus never-smoking lung cancer patients, and in vitro pharmacological inhibition of ERK MAPK signalling in human lung cancer cells abrogated NNK-induced downmodulation of tumour suppressor gene expression. Among IL-6 cytokine family members, IL-6 gene expression was specifically upregulated by NNK in vitro and in vivo, and inversely correlated with tumour suppressor gene expression. Collectively, our data reveal that a key molecular mechanism by which NNK promotes tumour cell proliferation during tobacco carcinogen-induced lung carcinogenesis is via upregulation of IL-6 and the preferential usage of gp130-dependant ERK MAPK signalling to downmodulate tumour suppressor gene expression.

Preliminary studies on the use of ultra-low-volume applications of malathion for control of Aedes simpsoni.

In view of the threat of additional yellow fever epidemics in East Africa and recent successes in the use of malathion applied by the ultra-low-volume technique against insect vectors, field trials were initiated in November 1968 to test the efficacy of this method against Aedes simpsoni. Results of these trials show that in areas where Musa ensetta is the principal breeding site, the application of 20.2 US fl oz/acre (1474 ml/ha) of malathion was capable of reducing vector populations 93%-100%. Comparable applications of 6 US fl oz/acre (438 ml/ha) reduced populations by 76% and 89%. Since this study did not conclusively demonstrate that the 6 US fl oz/acre dosage rate was sufficient to obtain maximum population reduction, further studies should be initiated to obtain information on the optimal dosage to be employed against this species.Under the conditions of these trials, the use of a light, single-engined aircraft equipped with a rotary atomizer spray system and capable of operation from improvised fields was shown to be feasible against this vector species. It was further demonstrated that the canopy formed by M. ensetta does not present an impossible barrier to the penetration of the spray droplets produced by the ULV application technique.Observations made on the application methodology and on the biology of A. simpsoni show the versatility of this species and the need for further studies on the integration of spray applications with the peak activity periods of the insect.