Uncertainties in TDCR measurement revisited: Contribution of optical effects.

In the Triple to Double Coincidence Ratio method in Liquid Scintillation Counting, the detection efficiency is calculated from the value of a free parameter describing the intrinsic light yield of the counting system. This model is generally based on a Poisson distribution of the number of photoelectrons detected and the detection efficiency is obtained from the complement of the non-detection efficiency. In the classical free parameter model, the mean of the Poisson distribution, m, is a constant but some variability of this mean could be expected from optical effects due to internal reflections inside the LS source or from non-homogeneity of the detection efficiency of the photomultiplier tubes. Then, m becomes a random variable and the distribution of the photoelectrons becomes a compound Poisson distribution, with a random variable as mean value. This paper explores the implications of the variance of m, which were, to our knowledge, never considered previously in the uncertainty budget of TDCR measurements.

pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation.

In patients with von Hippel-Lindau (VHL) disease, renal cysts and clear cell renal cell carcinoma (ccRCC) arise from renal tubular epithelial cells containing biallelic inactivation of the VHL tumour suppressor gene. However, it is presumed that formation of renal cysts and their conversion to ccRCC involve additional genetic changes at other loci. Here, we show that cystic lesions in the kidneys of patients with VHL disease also demonstrate activation of the phosphatidylinositol-3-kinase (PI3K) pathway. Strikingly, combined conditional inactivation of Vhlh and the Pten tumour suppressor gene, which normally antagonises PI3K signalling, in the mouse kidney, elicits cyst formation after short latency, whereas inactivation of either tumour suppressor gene alone failed to produce such a phenotype. Interestingly, cells lining these cysts frequently lack a primary cilium, a microtubule-based cellular antenna important for suppression of uncontrolled kidney epithelial cell proliferation and cyst formation. Our results support a model in which the PTEN tumour suppressor protein cooperates with pVHL to suppress cyst development in the kidney.

Partition Coefficients and Diffusion Lengths of 222Rn in Some Polymers at Different Temperatures.

In this work, the partition coefficients K and diffusion lengths L D of radon in some polymers are experimentally determined for several temperatures in the range T = 5-31 °C. Some of the obtained values are compared to published data available for the given temperatures. It is shown that the temperature dependencies of the partition coefficients K ( T ) , the diffusion lengths L D ( T ) , and the permeabilities P ( T ) could be described analytically for the studied temperature range 5-31 °C. This allows estimation of these quantities in the given temperature range and quantitative description of the transport of radon in the studied polymers.

Testing and Calibration of CDs as Radon Detectors at Highly Variable Radon Concentrations and Temperatures.

The application of the compact disk (CD) method for radon measurements at mines, caves and other workplaces needs testing under highly variable exposure conditions. We present the results from a blind comparison of CDs exposed in the Laboratory of Natural Radiation (Saelices el Chico, Spain). During the exposure the temperature varied from 6.5 to 24.9 °C (average 12.6 °C) and the 222Rn activity concentrations varied from <10 Bq m-3 to 147 kBq m-3. Good correspondence was observed between the integrated 222Rn activity concentration determined by the reference instruments in the laboratory (122,500 ± 6100 kBq h m-3) and that assessed by analysis of the CDs at a depth 80 µm beneath the front surface (118,000 ± 12,000 kBq h m-3) and at a depth of 120 µm (106,000 ± 12,000 kBq h m-3). The theoretical modeling of the CD response under variable temperature and radon concentration suggested that the small bias is probably due to the time variation of the calibration factor because of the time variations of the temperature.

Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice.

The combinations of genetic alterations that cooperate with von Hippel-Lindau (VHL) mutation to cause clear cell renal cell carcinoma (ccRCC) remain poorly understood. We show that the TP53 tumour suppressor gene is mutated in approximately 9% of human ccRCCs. Combined deletion of Vhl and Trp53 in primary mouse embryo fibroblasts causes proliferative dysregulation and high rates of aneuploidy. Deletion of these genes in the epithelium of the kidney induces the formation of simple cysts, atypical cysts and neoplasms, and deletion in the epithelia of the genital urinary tract leads to dysplasia and tumour formation. Kidney cysts display a reduced frequency of primary cilia and atypical cysts and neoplasms exhibit a pro-proliferative signature including activation of mTORC1 and high expression of Myc, mimicking several cellular and molecular alterations seen in human ccRCC and its precursor lesions. As the majority of ccRCC is associated with functional inactivation of VHL, our findings suggest that for a subset of ccRCC, loss of p53 function represents a critical event in tumour development.

p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans.

Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours.

Combined VHLH and PTEN mutation causes genital tract cystadenoma and squamous metaplasia.

Patients with von Hippel-Lindau (VHL) disease develop tumors in a range of tissues, but existing mouse models of Vhlh mutation have failed to reproduce these lesions. Epididymal cystadenomas arise frequently in VHL patients, but VHL mutation alone is believed to be insufficient for tumor formation, implying a requirement for cooperating mutations in epididymal pathogenesis. Here we show that epididymal cystadenomas from VHL patients frequently also lack expression of the PTEN tumor suppressor and display activation of phosphatidylinositol 3-kinase (PI3K) pathway signaling. Strikingly, while conditional inactivation of either Vhlh or Pten in epithelia of the mouse genital tract fails to produce a tumor phenotype, their combined deletion causes benign genital tract tumors with regions of squamous metaplasia and cystadenoma. The latter are histologically identical to lesions found in VHL patients. Importantly, these lesions are characterized by expansion of basal stem cells, high levels of expression and activity of HIF1alpha and HIF2alpha, and dysregulation of PI3K signaling. Our studies suggest a model for cooperative tumor suppression in which inactivation of PTEN facilitates epididymal cystadenoma genesis initiated by loss of VHL.