Origin of renal cell carcinomas

[Abstract] Cancer is a heritable disorder of somatic cells: environment and heredity are both important in the carcinogenic process. The primal force is the “two hits” of Knudson’s hypothesis, which has proved true for many tumours, including renal cell carcinoma. Knudson et al. [1, 2] recognised that familial forms of cancer might hold the key to the identification of important regulatory elements known as tumour-suppressor genes. Their observations (i.e., that retinoblastoma tend to be multifocal in familial cases and unifocal in sporadic presentation) led them to propose a two-hit theory of carcinogenesis. Furthermore, Knudson postulated that patients with the familial form of the cancer would be born with one mutant allele and that all cells in that organ or tissue would be at risk, accounting for early onset and the multifocal nature of the disease. In contrast, sporadic tumours would develop only if a mutation occurred in both alleles within the same cell, and, as each event would be expected to occur with low frequency, most tumours would develop late in life and in a unifocal manner [3, 4]. The kidney is affected in a variety of inherited cancer syndromes. For most of them, both the oncogene/tumour-suppressor gene involved and the respective germline mutations have been identified. Each of the inherited syndromes predisposes to distinct types of renal carcinoma. Families with hereditary predisposition to cancer continue to provide a unique opportunity for the identification and characterisation of genes involved in carcinogenesis. A surprising number of genetic syndromes predispose to the development of renal cell carcinoma, and genes associated with five of these syndromes have been already identified: VHL, MET, FH, BHD and HRPT2. Few cancers have as many different types of genetic predisposition as renal cancer, although to date only a small proportion of renal cell cancers can be explained by genetic predisposition

Cyclooxygenase-2 (COX-2): a molecular target in prostate cancer

[Abstract] Epidemiological studies provided the first evidence that COX may be involved in the pathogenesis of cancer. In the process of carcinogenesis and in the route of intracellular signalling during carcinogenesis, COX-2 expression may be a universal phenomenon. In general, COX-2 is up-regulated throughout the tumorigenic process, from early hyperplasia to metastatic disease. COX-2 has been reported to be constitutively overexpressed in a variety of malignancies and is frequently constitutively elevated in prostate carcinoma. COX-2 was consistently overexpressed in premalignant lesions such as prostatic intraepithelial neoplasia, and carcinoma. Cases are described with evolution of proliferative inflammatory atrophy of the prostate and prostate carcinoma. The increase of evidence implicating COX-2 in cancer has stimulated clinical trials to investigate the efficacy of selective COX-2 inhibitors in individuals at risk for human cancer. Regarding prostate carcinoma there is much direct or indirect evidence to support the use of COX-2 inhibitors in this disease. Trials using these drugs in familial adenomatous polyposis (FAP) and other patients with a high risk of colorectal carcinoma are ongoing

Validity and reliability of the new Basic Functional Assessment protocol (BFA)

The global evaluation of motion patterns can examine the synchrony of neuromuscular control, range of motion, strength, resistance, balance and coordination needed to complete the movement. Visual assessments are commonly used to detect risk factors. However, it is essential to define standardized field-based tests that can evaluate with accuracy. The aims of the study were to design a protocol to evaluate fundamental motor patterns (FMP), and to analyze the validity and reliability of an instrument created to provide information about the quality of movement in FMP. Five tasks were selected: Overhead Squat (OHS); Hurdle Step (HS); Forward Step Down (FSD); Shoulder Mobility (SM); Active Stretching Leg Raise (ASLR). A list of variables was created for the evaluation of each task. Ten qualified judges assessed the validity of the instrument, while six external observers performed inter-intra reliability. The results show that the instrument is valid according to the experts’ opinion; however, the reliability shows values below those established. Thus, the instrument was considered unreliable, so it is recommended to repeat the reliability process by performing more training sessions for the external observers. The present study creates the basic functional assessment (BFA), a new protocol which comprises five tasks and an instrument to evaluate FMP

Synthesis, structure, and photophysical properties of platinum(II) (N, C, N) pincer complexes derived from purine nucleobases

The synthesis of a series of Pt{κ3-N,C,N′-[L]}X (X = Cl, RC≡C) pincer complexes derived from purine and purine nucleosides is reported. In these complexes, the 6-phenylpurine skeleton provides the N,C-cyclometalated fragment, whereas an amine, imine, or pyridine substituent of the phenyl ring supplies the additional N′-coordination point to the pincer complex. The purine N,C-fragment has two coordination positions with the metal (N1 and N7), but the formation of the platinum complexes is totally regioselective. Coordination through the N7 position leads to the thermodynamically favored [6.5]-Pt{κ3-N7,C,N′-[L]}X complexes. However, the coordination through the N1 position is preferred by the amino derivatives, leading to the isomeric kinetic [5.5]-Pt{κ3-N1,C,N′-[L]}X complexes. Extension of the reported methodology to complexes having both pincer and acetylide ligands derived from nucleosides allows the preparation of novel heteroleptic bis-nucleoside compounds that could be regarded as organometallic models of Pt-induced interstrand cross-link. Complexes having amine or pyridine arms are green phosphorescence emitters upon photoexcitation at low concentrations in CH2Cl2 solution and in poly(methyl methacrylate) (PMMA) films. They undergo self-quenching at high concentrations due to molecular aggregation. The presence of intermolecular π–π stacking and weak Pt···Pt interactions was also observed in the solid state by X-ray diffraction analysis

Competing endogenous rna networks as biomarkers in neurodegenerative diseases

Protein aggregation is classically considered the main cause of neuronal death in neurodegenerative diseases (NDDs). However, increasing evidence suggests that alteration of RNA metabolism is a key factor in the etiopathogenesis of these complex disorders. Non-coding RNAs are the major contributor to the human transcriptome and are particularly abundant in the central nervous system, where they have been proposed to be involved in the onset and development of NDDs. Interestingly, some ncRNAs (such as lncRNAs, circRNAs and pseudogenes) share a common functionality in their ability to regulate gene expression by modulating miRNAs in a phenomenon known as the competing endogenous RNA mechanism. Moreover, ncRNAs are found in body fluids where their presence and concentration could serve as potential non-invasive biomarkers of NDDs. In this review, we summarize the ceRNA networks described in Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis and spinocerebellar ataxia type 7, and discuss their potential as biomarkers of these NDDs. Although numerous studies have been carried out, further research is needed to validate these complex interactions between RNAs and the alterations in RNA editing that could provide specific ceRNET profiles for neurodegenerative disorders, paving the way to a better understanding of these diseases

The Star Formation History and the spatial distribution of stellar populations in the Ursa Minor Dwarf Spheroidal Galaxy

As a part of a project devoted to the study of the Ursa Minor dSph, the star formation history of the galaxy is presented in this paper. The analysis uses wide field photometry, encompassing about 1deg x 1deg (the total covered area being 0.75 deg^2), which samples the galaxy out to its tidal radius. Derivation of the SFH has been performed using the synthetic partial model technique. The resulting SFH shows that Ursa Minor hosts a predominantly old stellar population, with virtually all the stars formed earlier than 10 Gyr ago and 90% of them formed earlier than 13 Gyr ago. Nevertheless, Ursa Minor color-magnitude diagram shows several stars above the main, old turn-off forming a blue-plume (BP). If these stars were genuine, main-sequence stars, Ursa Minor would have maintained a low star formation rate extending up to 2 Gyr ago. However, several indications (relative amount and spatial distribution of BP stars and difficulty to retain processed gas) play against this possibility. In such context, the most reliable hypothesis is that BP stars are blue-stragglers originating in the old population, Ursa Minor hence remaining the only Milky Way dSph satellite to host a pure old stellar population. A marginally significant age gradient is detected, in the sense that stars in outer regions are slightly younger, in average. The distance of Ursa Minor, has been calculated using the magnitude of the horizontal-branch and a calibration based on Hipparcos data of main sequence sub-dwarfs. We estimated a distance d=76+/-4 Kpc, which is slightly larger than previous estimates. From the RGB color, we estimate a metallicity [Fe/H]=-1.9+/-0.2, in agreement with a previous spectroscopic determination. No metallicity gradients have been detected across the galaxy.Comment: 28 pages,3 tables, 10 figures, Accepted for publication in Astronomical Journa

The VVV Templates Project Towards an automated classification of VVV light-curves: I. Building a database of stellar variability in the near-infrared

Context. The Vista Variables in the Vía Láctea (VVV) ESO Public Survey is a variability survey of the Milky Way bulge and an adjacent section of the disk carried out from 2010 on ESO Visible and Infrared Survey Telescope for Astronomy (VISTA). The VVV

Cost-effectiveness analysis of umeclidinium bromide/vilanterol 62.5/25 mcg versus tiotropium/olodaterol 5/5 mcg in symptomatic patients with chronic obstructive pulmonary disease: A Spanish National Healthcare System perspective

Background: A head-to-head study demonstrated the superiority of once-daily umeclidinium bromide/vilanterol (UMEC/VI) 62.5/25 mcg on trough forced expiratory volume in 1 s (FEV1) versus once-daily tiotropium/olodaterol (TIO/OLO) 5/5 mcg in symptomatic patients with chronic obstructive pulmonary disease (COPD). This analysis evaluated the cost effectiveness of UMEC/VI versus TIO/OLO from a Spanish National Healthcare System perspective, using data from this study and Spanish literature. Methods: This analysis was conducted from the perspective of the Spanish National Healthcare System with a 3-year horizon as base case. A disease progression model using a linked risk equation approach was used to estimate disease progression and associated healthcare costs, and quality-adjusted life years (QALYs). The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study was used to develop the statistical risk equations for clinical endpoints, and costs were calculated using a health state approach (by dyspnea severity). Utilities for QALY calculation were estimated using patient baseline characteristics within a regression fit to Spanish observational data. Treatment effect, expressed as change from baseline in FEV1 was obtained from the head-to-head study and used in the model (UMEC/VI minus TIO/OLO difference: + 52 mL [95% confidence interval: 28, 77]). Baseline patient characteristics were sourced from Spanish literature or the head-to-head study if unavailable. A scenario analysis using only the intent-to-treat (ITT) population from the head-to-head study, and sensitivity analyses (including probabilistic sensitivity analyses), were conducted. Direct healthcare costs (2017 Euro) were obtained from Spanish sources and costs and benefits were discounted at 3% per annum. Results: UMEC/VI was associated with small improvements in QALYs (+ 0.029) over a 3-year time horizon, compared with TIO/OLO, alongside cost savings of €393/patient. The ITT scenario analysis and sensitivity analyses had similar results. All probabilistic simulations resulted in UMEC/VI being less costly and more effective than TIO/OLO. Conclusion: UMEC/VI dominated TIO/OLO (more effective and less expensive). These results may aid payers and decision-makers in Spain when making judgements on which long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) treatments can be considered cost effective in Spain.This study was funded by GSK (study number HO-17-17500). The funders of the study had a role in study design, data analysis, data interpretation, and writing of the report. Data analysis was conducted by ICON Health Economics and funded by GSK. No funding was provided to employees of ICON Health Economics for manuscript developmen