The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

Evidence for structural discordance in the inverted metamorphic sequence of Sikkim himalaya: Towards resolving the main central thrust controversy

Inverted, metamorphism in the Himalayas is closely associated with the Main Central Thrust (MCT). In the western Himalayas, the Main Central Thrust conventionally separates high grade metamorphic rocks of the Higher Himalayan Crystalline Sequence (HHCS) from unmetamorphosed rocks of the Inner sedimentary Belt. In the eastern Himalayas, the Inner sedimentary Belt is absent, and the HHCS and meta-sedimentary Lesser Himalayan Sequence (LHS) apparently form a continuous Barrovian metamorphic sequence, leading to confusion about the precise location of the MCT. In this study, it is demonstrated that migmatitic gneisses of the sillimanite zone in the higher structural levels of the HHCS are multiply deformed, with two phases of penetrative fabric formation (S 1HHCS and S2HHCS) followed by third folding event associated with a spaced, NW-SE trending, north-east dipping foliation (S 3HHCS). The underlying LHS schists (kyanite zone and lower) are also multiply deformed, with the bedding S0 being isoclinally folded (F1LHS), and subsequently refolded (F2LHS and F 3LHS). The contact zone between, the HHCS and LHS is characterized by ductile, top-to-the southwest shearing and stabilization of a pervasive foliation that is consistently oriented NW-SE and dips northeast. This foliation is parallel to the S3HHCS foliation in the HHCS, and the S 2LHS in the LHS. Early lineations in the HHCS and LHS also show different dispersions across the contact shear zone, implying that pre-thrusting orientations of the two units were distinct. The contact shear zone is therefore interpreted to be a plane of structural discordance, shows a shear sense consistent with thrust movement and is associated with mineral growth during Barrovian metamorphism. It may well be considered to represent the MCT in this region

Autocyclized and oxidized forms of SCR7 induce cancer cell death by inhibiting nonhomologous DNA end joining in a Ligase IV dependent manner

International audienceNonhomologous DNA end joining (NHEJ) is the major DNA double-strand break (DSB) repair pathway in mammals. Previously, we have described a small molecule inhibitor, SCR7, which can inhibit NHEJ in a Ligase IV-dependent manner. Administration of SCR7 within the cells resulted in the accumulation of DNA breaks, cell death, and inhibition of tumor growth in mice. In the present study, we report that parental SCR7, which is unstable, can be autocyclized into a stable form. Both parental SCR7 and cyclized SCR7 possess the same molecular weight (334.09) and molecular formula (C18H14N4OS), whereas its oxidized form, SCR7-pyrazine, possesses a different molecular formula (C18H12N4OS), molecular weight (332.07), and structure. While cyclized form of SCR7 showed robust inhibition of NHEJ in vitro, both forms exhibited efficient cytotoxicity. Cyclized and oxidized forms of SCR7 inhibited DNA end joining catalyzed by Ligase IV, whereas their impact was minimal on Ligase III, Ligase I, and T4 DNA Ligase-mediated joining. Importantly, both forms inhibited V(D)J recombination, although the effect was more pronounced for SCR7-cyclized. Both forms blocked NHEJ in a Ligase IV-dependent manner leading to the accumulation of DSBs within the cells. Although cytotoxicity due to SCR7-cyclized was Ligase IV specific, the pyrazine form exhibited nonspecific cytotoxicity at higher concentrations in Ligase IV-null cells. Finally, we demonstrate that both forms can potentiate the effect of radiation. Thus, we report that cyclized and oxidized forms of SCR7 can inhibit NHEJ in a Ligase IV-dependent manner, although SCR7-pyrazine is less specific to Ligase IV inside the cell