We identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cancer relative to normal human tissues. RT112 bladder cancer cells, endogenously expressing CYP1A1, were selectively chemosensitive to ICT2700, whereas EJ138 bladder cells that do not express CYP1A1 were significantly less responsive. Introduction of CYP1A1 into EJ138 cells resulted in 75-fold increased chemosensitivity to ICT2700 relative to wild-type EJ138. Negligible chemosensitivity was observed in ICT2700 in EJ138 cells expressing CYP1A2 or with exposure of EJ138 cells to CYP1B1- or CYP3A4-generated metabolites of ICT2700. Chemosensitivity to ICT2700 was also negated in EJ138-CYP1A1 cells by the CYP1 inhibitor alpha-naphthoflavone. Furthermore, ICT2700 did not induce expression of the AhR-regulated CYP1 family, indicating that constitutive CYP1A1 expression is sufficient for activation of ICT2700. Consistent with the selective activity by CYP1A1 was a time and concentration-dependent increase in gamma-H2AX protein expression, indicative of DNA damage, associated with the activation of ICT2700 in RT112 but not EJ138 cells. In mice-bearing CYP1A1-positive and negative isogenic tumors, ICT2700 administration resulted in an antitumor response only in the CYP1A1-expressing tumor model. This antitumor response was associated with detection of the CYP1A1-activated metabolite in tumors but not in the liver. Our findings support the further development of ICT2700 as a tumor-selective treatment for human bladder cancers.

Historical evidence documents mass migration from Ireland to London during the period of the Great Irish Famine of 1845-52. The rural Irish were reliant on a restricted diet based on potatoes but maize, a C(4) plant, was imported from the United States of America in 1846-47 to mitigate against Famine. In London, Irish migrants joined a population with a more varied diet. To investigate and characterize their diet, carbon and nitrogen isotope ratios were obtained from bone collagen of 119 and hair keratin of six individuals from Lukin Street cemetery, Tower Hamlets (1843-54), and bone collagen of 20 individuals from the cemetery at Kilkenny Union Workhouse in Ireland (1847-51). A comparison of the results with other contemporaneous English populations suggests that Londoners may have elevated delta(15) N compared with their contemporaries in other cities. In comparison, the Irish group have lower delta(15) N. Hair analysis combined with bone collagen allows the reconstruction of perimortem dietary changes. Three children aged 5-15 years from Kilkenny have bone collagen delta(13) C values that indicate consumption of maize (C(4)). As maize was only imported into Ireland in quantity from late 1846 and 1847, these results demonstrate relatively rapid bone collagen turnover in children and highlight the importance of age-related bone turnover rates, and the impact the age of the individual can have on studies of short-term dietary change or recent migration. Stable light isotope data in this study are consistent with the epigraphic and documentary evidence for the presence of migrants within the London cemetery.

OBJECTIVE: To describe the growth pattern from birth to 2 years of UK-born white British and Pakistani infants. DESIGN: Birth cohort. SETTING: Bradford, UK. PARTICIPANTS: 314 white British boys, 383 Pakistani boys, 328 white British girls and 409 Pakistani girls. MAIN OUTCOME MEASURES: Weight and length trajectories based on repeat measurements from birth to 2 years. RESULTS: Linear spline multilevel models for weight and length with knot points at 4 and 9 months fitted the data well. At birth Pakistani boys were 210 g lighter (95% CI -290 to -120) and 0.5 cm shorter (-1.04 to 0.02) and Pakistani girls were 180 g lighter (-260 to -100) and 0.5 cm shorter (-0.91 to -0.03) than white British boys and girls, respectively. Pakistani infants gained length faster than white British infants between 0 and 4 months (+0.3 cm/month (0.1 to 0.5) for boys and +0.4 cm/month (0.2 to 0.6) for girls) and gained more weight per month between 9 and 24 months (+10 g/month (0 to 30) for boys and +30 g/month (20 to 40) for girls). Adjustment for maternal height attenuated ethnic differences in weight and length at birth, but not in postnatal growth. Adjustment for other confounders did not explain differences in any outcomes. CONCLUSIONS: Pakistani infants were lighter and had shorter predicted mean length at birth than white British infants, but gained weight and length quicker in infancy. By age 2 years both ethnic groups had similar weight, but Pakistani infants were on average taller than white British infants.

PURPOSE: Cytochrome P450 2W1 (CYP2W1) is a monooxygenase detected in 30% of colon cancers, whereas its expression in nontransformed adult tissues is absent, rendering it a tumor-specific drug target for development of novel colon cancer chemotherapy. Previously, we have identified duocarmycin synthetic derivatives as CYP2W1 substrates. In this study, we investigated whether two of these compounds, ICT2705 and ICT2706, could be activated by CYP2W1 into potent antitumor agents. EXPERIMENTAL DESIGN: The cytotoxic activity of ICT2705 and ICT2706 in vitro was tested in colon cancer cell lines expressing CYP2W1, and in vivo studies with ICT2706 were conducted on severe combined immunodeficient mice bearing CYP2W1-positive colon cancer xenografts. RESULTS: Cells expressing CYP2W1 suffer rapid loss of viability following treatment with ICT2705 and ICT2706, whereas the CYP2W1-positive human colon cancer xenografts display arrested growth in the mice treated with ICT2706. The specific cytotoxic metabolite generated by CYP2W1 metabolism of ICT2706 was identified in vitro. The cytotoxic events were accompanied by an accumulation of phosphorylated H2A.X histone, indicating DNA damage as a mechanism for cancer cell toxicity. This cytotoxic effect is most likely propagated by a bystander killing mechanism shown in colon cancer cells. Pharmacokinetic analysis of ICT2706 in mice identified higher concentration of the compound in tumor than in plasma, indicating preferential accumulation of drug in the target tissue. CONCLUSION: Our findings suggest a novel approach for treatment of colon cancer that uses a locoregional activation of systemically inactive prodrug by the tumor-specific activator enzyme CYP2W1.

Examination of three frozen bodies, a 13-y-old girl and a girl and boy aged 4 to 5 y, separately entombed near the Andean summit of Volcan Llullaillaco, Argentina, sheds new light on human sacrifice as a central part of the Imperial Inca capacocha rite, described by chroniclers writing after the Spanish conquest. The high-resolution diachronic data presented here, obtained directly from scalp hair, implies escalating coca and alcohol ingestion in the lead-up to death. These data, combined with archaeological and radiological evidence, deepen our understanding of the circumstances and context of final placement on the mountain top. We argue that the individuals were treated differently according to their age, status, and ritual role. Finally, we relate our findings to questions of consent, coercion, and/or compliance, and the controversial issues of ideological justification and strategies of social control and political legitimation pursued by the expansionist Inca state before European contact.

We identified human visual field maps, LO1 and LO2, in object-selective lateral occipital cortex. Using transcranial magnetic stimulation (TMS), we assessed the functions of these maps in the perception of orientation and shape. TMS of LO1 disrupted orientation, but not shape, discrimination, whereas TMS of LO2 disrupted shape, but not orientation, discrimination. This double dissociation suggests that specialized and independent processing of different visual attributes occurs in LO1 and LO2.