Genetic analysis of the RNASEL gene in hereditary, familial, and sporadic prostate cancer.

PURPOSE: The RNASEL gene has been proposed as a candidate gene for the HPC1 locus through a positional cloning and candidate gene approach. Cosegregation between the truncating mutation E265X and disease in a hereditary prostate cancer (HPC) family and association between prostate cancer risk and the common missense variant R462Q has been reported. To additionally evaluate the possible role of RNASEL in susceptibility to prostate cancer risk, we performed a comprehensive genetic analysis of sequence variants in RNASEL in the Swedish population. EXPERIMENTAL DESIGN: Using 1624 prostate cancer cases and 801 unaffected controls, the truncating mutation E265X and five common sequence variants, including the two missense mutations R462Q and D541E, were evaluated for association between genotypes/haplotypes and prostate cancer risk. RESULTS: The prevalence of E265X carriers among unaffected controls and prostate cancer patients was almost identical (1.9 and 1.8% in controls and cases, respectively), and evidence for segregation of E265X with disease was not observed within any HPC family. Overall, the analyses of common sequence variants provided limited evidence for association with prostate cancer risk. We found a marginally significant inverse association between the missense mutation D541E and sporadic prostate cancer risk (odds ratio, 0.77; 95% confidence interval, 0.59-1.00) and reduced risk of prostate cancer in carriers of two different haplotypes being completely discordant. CONCLUSIONS: Considering the high quality in genotyping and the size of this study, these results provide solid evidence against a major role of RNASEL in prostate cancer etiology in Sweden.     

Human kallikrein 6 (hK6): a new potential serum biomarker for diagnosis and prognosis of ovarian carcinoma.

PURPOSE: The discovery of new ovarian cancer biomarkers that are suitable for early disease diagnosis and prognosis may ultimately lead to improved patient management and outcomes. PATIENTS AND METHODS: We measured, by immunoassay, human kallikrein 6 (hK6) concentration in serum of 97 apparently healthy women, 141 women with benign abdominal diseases, and 146 women with histologically proven primary ovarian carcinoma. We then calculated the diagnostic sensitivity and specificity of this test and examined the association of serum hK6 concentration with various clinicopathologic variables and patient survival. RESULTS: Serum hK6 concentration between normal and benign disease patients was not different (mean, 2.9 and 3.1 micro g/L, respectively). However, hK6 in presurgical serum of ovarian cancer patients was highly elevated (mean, 6.8 micro g/L; P <.001). Serum hK6 decreased after surgery (to a mean of 3.9 micro g/L) in 68% of patients. The diagnostic sensitivity of serum hK6 at 90% and 95% specificity is 52% and 47%, respectively, in the whole patient population. For early stage disease (stage I or II), sensitivity is approximately 21% to 26%. When combined with CA-125, at 90% specificity, sensitivity increases to 72% (for all patients) and to 42% in stage I or II disease. Serum hK6 concentration correlates moderately with CA-125 and is higher in patients with late-stage, higher-grade disease and in patients with serous histotype. Preoperative serum hK6 concentration is a powerful predictor of disease-free and overall survival in both univariate and multivariate analyses. CONCLUSIONS: Serum hK6 concentration seems to be a new biomarker for ovarian carcinoma and may have value for disease diagnosis and prognosis.     

Trends in cervical squamous cell carcinoma incidence in 13 European countries: changing risk and the effects of screening.

Despite there being sufficient evidence for the effectiveness of screening by cytology in preventing cancer of the cervix uteri, screening policies vary widely among European countries, and incidence is increasing in younger women. This study analyzes trends in squamous cell carcinoma (SCC) of the cervix uteri in 13 European countries to evaluate effectiveness of screening against a background of changing risk. Age-period-cohort models were fitted and period and cohort effects were estimated; these were considered as primarily indicative of screening interventions and changing etiology, respectively. A unique set of estimates was derived by fixing age slopes to one of several plausible age curves under the assumption that the relation between age and cervical cancer incidence is biologically determined. There were period-specific declines in cervical SCC in several countries, with the largest decreases seen in northern Europe. A pattern emerged across Europe of escalating risk in successive generations born after 1930. In the western European countries, a decrease followed by a stabilization of risk by cohort was accompanied by period-specific declines. In southern Europe, stable period, but increasing cohort trends, were observed. Substantial changes have occurred in cervical SCC incidence in Europe and well-organized screening programs have been highly effective in reducing the incidence of cervical SCC. Screening and changing sexual mores largely explain the changing period- and cohort-specific patterns, respectively. The increasing risk in recent cohorts is of obvious concern particularly in countries where no screening programs are in place. Further investigation of the effectiveness of opportunistic screening is warranted as is the observation of differing risk patterns in young cohorts in countries with relatively similar societal structures.     

Increased fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) uptake in childhood CNS tumors is correlated with malignancy grade: a study with FDG positron emission tomography/magnetic resonance imaging coregistration and image fusion.

PURPOSE Positron emission tomography (PET) has been used in grading of CNS tumors in adults, whereas studies of children have been limited. PATIENTS AND METHODS Nineteen boys and 19 girls (median age, 8 years) with primary CNS tumors were studied prospectively by fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) PET with (n = 16) or without (n = 22) H(2)(15)O-PET before therapy. Image processing included coregistration to magnetic resonance imaging (MRI) in all patients. The FDG uptake in tumors was semiquantitatively calculated by a region-of-interest-based tumor hotspot/brain index. Eight tumors without histologic confirmation were classified as WHO grade 1 based on location, MRI, and clinical course (22 to 42 months). Results Four grade 4 tumors had a mean index of 4.27 +/- 0.5, four grade 3 tumors had a mean index of 2.47 +/- 1.07, 10 grade 2 tumors had a mean index of 1.34 +/- 0.73, and eight of 12 grade 1 tumors had a mean index of -0.31 +/- 0.59. Eight patients with no histologic confirmation had a mean index of 1.04. For these 34 tumors, FDG uptake was positively correlated with malignancy grading (n = 34; r = 0.72; P < .01), as for the 26 histologically classified tumors (n = 26; r = 0.89; P < .01). The choroid plexus papilloma (n = 1) and the pilocytic astrocytomas (n = 3) had a mean index of 3.26 (n = 38; r = 0.57; P < .01). H(2)(15)O-uptake showed no correlation with malignancy. Digitally performed PET/MRI coregistration increased information on tumor characterization in 90% of cases. CONCLUSION FDG PET of the brain with MRI coregistration can be used to obtain a more specific diagnosis with respect to malignancy grading. Improved PET/MRI imaging of the benign hypermetabolic tumors is needed to optimize clinical use.     

Automated multicolor mesoscopic imaging for the 3-dimensional reconstruction of fluorescent biomarker distribution in large tissue specimens

Research in translational medicine often requires high-resolution characterization techniques to visualize or quantify the fluorescent probes. For example, drug delivery systems contain fluorescent molecules enabling in vitro and in vivo tracing to determine biodistribution or plasma disappearance. Albeit fluorescence imaging systems with sufficient resolution exist, the sample preparation is typically too complex to image a whole organism of the size of a mouse. This article established a mesoscopic imaging technique utilizing a commercially available cryo-microtome and an in-house built episcopic imaging add-on to perform imaging during serial sectioning. Here we demonstrate that our automated red, green, blue (RGB) and fluorescence mesoscope can generate sequential block-face and 3-dimensional anatomical images at variable thickness with high quality of 6 µm × 6 µm pixel size. In addition, this mesoscope features a numerical aperture of 0.10 and a field-of-view of up to 21.6 mm × 27 mm × 25 mm (width, height, depth).     

Changes in socioeconomic differentials in old age life expectancy in four Nordic countries: the impact of educational expansion and education-specific mortality

Overall progress in life expectancy (LE) depends increasingly on survival in older ages. The birth cohorts now reaching old age have experienced considerable educational expansion, which is a driving force for the social change and social inequality. Thus, this study examines changes in old age LE by educational attainment in the Nordic countries and aims to find out to what extent the change in national LEs is attributable to education-specific mortality and the shifting educational composition. We used national register data comprising total 65 + populations in Denmark, Finland, Norway and Sweden to create period life tables stratified by five-year age groups (65–90 +), sex and educational attainment. Difference in LE between 2001 and 2015 was decomposed into the contributions of mortality changes within each educational group and changes in educational composition. Increasing LE at all ages and in all educational groups coincided with persistent and growing educational inequalities in all countries. Most of the gains in LE at age 65 could be attributed to decreased mortality (63–90%), especially among those with low education, the largest educational group in most countries. The proportion of the increase in LE attributable to improved education was 10–37%, with the highest contributions recorded for women in Norway and Sweden. The rising educational levels in the Nordic countries still carry potential for further gains in national LEs. However, the educational expansion has contributed to uneven gains in LE between education groups, which poses a risk for the future increase of inequalities in LE.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10433-022-00698-y.