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Conceptual models of carcinogenesis typically consist of an evolutionary sequence of heritable changes in genes controlling proliferation, apoptosis, and senescence. We propose that these steps are necessary but not sufficient to produce invasive breast cancer because intraductal tumour growth is also constrained by hypoxia and acidosis that develop as cells proliferate into the lumen and away from the underlying vessels. This requires evolution of glycolytic and acid-resistant phenotypes that, we hypothesise, is critical for emergence of invasive cancer. Mathematical models demonstrate severe hypoxia and acidosis in regions of intraductal tumours more than 100 microm from the basement membrane. Subsequent evolution of glycolytic and acid-resistant phenotypes leads to invasive proliferation. Multicellular spheroids recapitulating ductal carcinoma in situ (DCIS) microenvironmental conditions demonstrate upregulated glucose transporter 1 (GLUT1) as adaptation to hypoxia followed by growth into normoxic regions in qualitative agreement with model predictions. Clinical specimens of DCIS exhibit periluminal distribution of GLUT-1 and Na(+)/H(+) exchanger (NHE) indicating transcriptional activation by hypoxia and clusters of the same phenotype in the peripheral, presumably normoxic regions similar to the pattern predicted by the models and observed in spheroids. Upregulated GLUT-1 and NHE-1 were observed in microinvasive foci and adjacent intraductal cells. Adaptation to hypoxia and acidosis may represent key events in transition from in situ to invasive cancer. [ABSTRACT FROM AUTHOR]

Two-week average NO2 concentrations were measured in Amsterdam (NL), Huddersfield (UK) and Prague (CZ) at 80 sites in each study area, to assess small area spatial variation, using a tube type and a badge type passive sampler. The badges appeared to be less robustthan the tubes. The lower detection limit for tubes and badges was 3.7 and 0.91 mu g/m3, respectively for fortnightly measurements. Accuracy of the samplers was determined with reference methods (chemiluminescence). The mean ratio of the concentration measured by diffusion tube over that by the reference method was 1.16, 1.03 and 0.77 in Amsterdam, Huddersfield and Prague, respectively. Standardizing the badges for the results obtained in Amsterdam, the relative meanratio of the concentration measured by the badges over that by the reference method was 0.95 and 0.58 in Huddersfield and Prague, respectively. NO2 concentrations measured by the two designs did not differ significantly. Mean NO2 concentrations were 36,26 and 22 mu g/m3 in Amsterdam, Huddersfield and Prague, respectively. The precision of duplicate tubes and badges was 8% and 11% respectively. Both samplers are suitable for determining real variation in small area NO2 concentrations in the ranges which occurred. It is concluded that low-cost, simple NO2 passive samplers can provide reliable information about variation in NO2 concentrations within urban or rural areas on a small spatial scale. Based on its robustness and its precision, tubes were preferred over badges. [ABSTRACT FROM AUTHOR]