CHK1 expression in gastric cancer is modulated by p53 and RB1/E2F1: Implications in chemo/radiotherapy response

Radiation has a limited but relevant role in the adjuvant therapy of gastric cancer (GC) patients. Since Chk1 plays a critical function in cellular response to genotoxic agents, we aimed to analyze the role of Chk1 in GC as a biomarker for radiotherapy resistance. We analyzed Chk1 expression in AGS and MKN45 human GC cell lines by RT-QPCR and WB and in a small cohort of human patient’s samples. We demonstrated that Chk1 overexpression specifically increases resistance to radiation in GC cells. Accordingly, abrogation of Chk1 activity with UCN-01 and its expression with shChk1 increased sensitivity to bleomycin and radiation. Furthermore, when we assessed Chk1 expression in human samples, we found a correlation between nuclear Chk1 accumulation and a decrease in progression free survival. Moreover, using a luciferase assay we found that Chk1’s expression is controlled by p53 and RB/E2F1 at the transcriptional level. Additionally, we present preliminary data suggesting a posttranscriptional regulation mechanism, involving miR-195 and miR-503, which are inversely correlated with expression of Chk1 in radioresistant cells. In conclusion, Chk1/microRNA axis is involved in resistance to radiation in GC, and suggests Chk1 as a potential tool for optimal stratification of patients susceptible to receive adjuvant radiotherapy after surgeryThis work was supported by Instituto de Salud Carlos III–Fondo de Investigación Sanitaria (PS09/1988 to ISP; PI11-00949, pI014-1495 and Feder Funds to RP); Comunidad Autónoma de Madrid-Universidad Autónoma de Madrid (CCG10-UAM/BIO-5871 to ISP); Fundación Leticia Castillejo Castillo and Ministerio de Ciencia e Innovación (SAF2012-30862 to RSP), Spain

Lab-on-a-chip platforms based on highly sensitive nanophotonic Si biosensors for single nucleotide DNA testing

In order to solve the drawbacks of sensitivity and portability in optical biosensors we have developed ultrasensitive and miniaturized photonic silicon sensors able to be integrated in a "lab-on-a-chip" microsystem platform. The sensors are integrated Mach-Zehnder interferometers based on TIR optical waveguides (Si/SiO2/Si3N4) of micro/nanodimensions. We have applied this biosensor for DNA testing and for detection of single nucleotide polymorphisms at BRCA-1 gene, involved in breast cancer development, without target labeling. The oligonucleotide probe is immobilized by covalent attachment to the sensor surface through silanization procedures. The hybridization was performed for different DNA target concentrations showing a lowest detection limit at 10 pM. Additionally, we have detected the hybridization of different concentrations of DNA target with two mismatching bases corresponding to a mutation of the BRCA-1 gene. Following the way of the lab-on-a-chip microsystem, integration with the microfluidics has been achieved by using a novel fabrication method of 3-D embedded microchannels using the polymer SU-8 as structural material. The optofluidic chip shows good performances for biosensing

Role of Sterile Neutrino Warm Dark Matter in Rhenium and Tritium Beta Decays

Sterile neutrinos with mass in the range of one to a few keV are important as extensions of the Standard Model of particle physics and are serious dark matter (DM) candidates. This DM mass scale (warm DM) is in agreement with both cosmological and galactic observations. We study the role of a keV sterile neutrino through its mixing with a light active neutrino in Rhenium 187 and Tritium beta decays. We pinpoint the energy spectrum of the beta particle, 0 < T_e < (Q_{beta} - m_s), as the region where a sterile neutrino could be detected and where its mass m_s could be measured. This energy region is at least 1 keV away rom the region suitable to measure the mass of the light active neutrino, located near the endpoint Q_{beta} . The emission of a keV sterile neutrino in a beta decay could show up as a small kink in the spectrum of the emitted beta particle. With this in view, we perform a careful calculation of the Rhenium and Tritium beta spectra and estimate the size of this perturbation by means of the dimensionless ratio R of the sterile neutrino to the active neutrino contributions. We comment on the possibility of searching for sterile neutrino signatures in two experiments which are currently running at present, MARE and KATRIN, focused on the Rhenium 187 and Tritium beta decays respectively.Comment: 16 pages, 10 figures. Version to appear in Nucl. Phys. B. Results and conclusions unchange

Robustness of Cooperation in the Evolutionary Prisoner's Dilemma on Complex Networks

Recent studies on the evolutionary dynamics of the Prisoner's Dilemma game in scale-free networks have demonstrated that the heterogeneity of the network interconnections enhances the evolutionary success of cooperation. In this paper we address the issue of how the characterization of the asymptotic states of the evolutionary dynamics depends on the initial concentration of cooperators. We find that the measure and the connectedness properties of the set of nodes where cooperation reaches fixation is largely independent of initial conditions, in contrast with the behavior of both the set of nodes where defection is fixed, and the fluctuating nodes. We also check for the robustness of these results when varying the degree heterogeneity along a one-parametric family of networks interpolating between the class of Erdos-Renyi graphs and the Barabasi-Albert networks.Comment: 18 pages, 6 figures, revised version accepted for publication in New Journal of Physics (2007

SC83288 is a clinical development candidate for the treatment of severe malaria

Severe malaria is a life-threatening complication of an infection with the protozoan parasite Plasmodium falciparum, which requires immediate treatment. Safety and efficacy concerns with currently used drugs accentuate the need for new chemotherapeutic options against severe malaria. Here we describe a medicinal chemistry program starting from amicarbalide that led to two compounds with optimized pharmacological and antiparasitic properties. SC81458 and the clinical development candidate, SC83288, are fast-acting compounds that can cure a P. falciparum infection in a humanized NOD/SCID mouse model system. Detailed preclinical pharmacokinetic and toxicological studies reveal no observable drawbacks. Ultra-deep sequencing of resistant parasites identifies the sarco/endoplasmic reticulum Ca(2+) transporting PfATP6 as a putative determinant of resistance to SC81458 and SC83288. Features, such as fast parasite killing, good safety margin, a potentially novel mode of action and a distinct chemotype support the clinical development of SC83288, as an intravenous application for the treatment of severe malaria

First case of sterility associated with sex chromosomal abnormalities in a jenny

Chromosomal abnormalities are one of the main causes of genetic infertility in horses. Currently, their detection rate is rising due to the use of new diagnostic tools employing molecular markers linked to the sex chromosome pair. Despite genetic similarities, there are no previous reports of sterility associated with chromosomal abnormalities in the domestic donkey (Equus asinus). Hereby, we determined the presence of a chromosomal mosaicism in a female donkey with reproductive problems using molecular methodologies developed for horses. A two-and- a- half- year- old jenny characterized by morphological abnormalities of the reproductive tract was cytogenetically analysed using conventional and fluorescent techniques and a group of microsatellite markers (short tandem repeat, STR). At the same time, five ultrasound measures of the reproductive tract were taken and compared with eight contemporary jennies of the same breed. After slaughter, morphological examinations showed that the case study had a blind vaginal vestibule defining an empty pouch that covered the entrance of the cervical os. Histopathological studies demonstrated that this abnormal structure was compatible with a remnant hymen. Molecular markers, STR and fluorescent in situ hybridization determinations revealed that the animal was a 62, XX/61,X mosaic and, therefore, the first case of chromosomal abnormalities in the sex pair reported in donkeys.Instituto de Genética Veterinari

Energy loss of protons and deuterons at low energies in Pd polycrystalline thin films

We have investigated experimentally and by computer simulations the energy loss  distributions of low energy (E <10 keV) protons and deuterons transmitted through  polycrystalline palladium thin flms. In contrast with previous experiments on various transition metals we find that the stopping power of Pd is proportional to the ion velocity. Data of protons and deuterons are coincident within the experimental uncertainties, showing the absence of an isotopic effect on the stopping power of Pd in this energy range. The experimental results were analyzed and compared with Monte Carlo computer simulations and previous theoretical models. The dference in the velocity dependence of the energy loss of hydrogen ions in Pd with respect to other transition metals (Cu, Ag and Au) is explained by a theoretical analysis based on the properties of the d-electron bands of those elements.Fil: Celedón, C.. Comisión Nacional de Energía Atómica. Gerencia del Area de Energía Nuclear. Instituto Balseiro; Argentina. Comisión Nacional de Energía Atómica. Gerencia del Area de Investigación y Aplicaciones No Nucleares. Gerencia de Física (Centro Atómico Bariloche); ArgentinaFil: Sanchez, Esteban Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Gerencia del Area de Investigación y Aplicaciones No Nucleares. Gerencia de Física (Centro Atómico Bariloche); Argentina. Comisión Nacional de Energía Atómica. Gerencia del Area de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Moreno, Mario Sergio Jesus. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Gerencia del Area de Investigación y Aplicaciones No Nucleares. Gerencia de Física (Centro Atómico Bariloche); Argentina. Comisión Nacional de Energía Atómica. Gerencia del Area de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Arista, Nestor Ricardo. Comisión Nacional de Energía Atómica. Gerencia del Area de Investigación y Aplicaciones No Nucleares. Gerencia de Física (Centro Atómico Bariloche); Argentina. Comisión Nacional de Energía Atómica. Gerencia del Area de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Uribe, J. D.. Universidad Técnica Federico Santa María. Departamento de Física. Laboratorio de Colisiones Atómicas; ChileFil: Mery, M.. Universidad Técnica Federico Santa María. Departamento de Física. Laboratorio de Colisiones Atómicas; ChileFil: Valdés, J. E.. Universidad Técnica Federico Santa María. Departamento de Física. Laboratorio de Colisiones Atómicas; ChileFil: Vargas, P.. Universidad Técnica Federico Santa María. Departamento de Física. Laboratorio de Colisiones Atómicas; Chil

Use of an experimental model to evaluate infection resistance of meshes in abdominal wall surgery

Background: Staphylococcal species are the most common organisms causing prosthetic mesh infections, however, infections due to rapidly growing mycobacteria are increasing. This study evaluates the resistance of biomaterial for abdominal wall prostheses against the development of postoperative infection in a rat model. Material and methods: In 75 rats, we intramuscularly implanted three different types of prostheses: (1) low-density polypropylene monofilament mesh (PMM), (2) high-density PMM, and (3) a composite prosthesis composed of low-density PMM and a nonporous hydrophilic film. Meshes were inoculated with a suspension containing 108 colony-forming units of Staphylococcus aureus, Staphylococcus epidermidis, Mycobacterium fortuitum, or Mycobacterium abscessus before wound closure. Animals were sacrificed on the eighth day postoperatively for clinical evaluation, and the implants were removed for bacteriologic analyses. Results: Prostheses infected with S aureus showed a higher bacterial viability, worse integration, and clinical outcome compared with infection by other bacteria. Composite prostheses showed a higher number of viable colonies of both M fortuitum and Staphylococcus spp., with poorer integration in host tissue. However, when the composite prosthesis was infected with M abscessus, a lower number of viable bacteria were isolated and a better integration was observed compared with infection by other bacteria. Conclusions: Considering M abscessus, a smaller collagen-free contact surface shows better resistance to infection, however, depending on the type of bacteria, prostheses with a large surface, and covered with collagen shows reduced resistance to infection, worse integration, and worse clinical outcome. (C) 2016 Elsevier Inc. All rights reserved.Peer reviewe