Genomic Characterization of Polyps in Familial Adenomatous Polyposis Patients and Identification of Candidate Chemopreventive Drugs

Familial adenomatous polyposis (FAP) is an autosomal dominant disease characterized by APC germline mutations and the development of hundreds to thousands of premalignant adenomas in the gastrointestinal tract at a young age. If left untreated, these patients inevitably develop colon cancer (CRC) and small bowel tumors. We performed exome sequencing of samples from 12 FAP patients to characterize adenomas and to identify candidate genes of adenoma development that may serve as potential targets for chemoprevention drug development. From each patient, a blood and at least one polyp were sequenced with a total of 25 polyps analyzed. In some cases, normal mucosa samples were also sequenced. We characterized point mutations, insertions, deletions and chromosomal allelic imbalance. In addition, we performed RNA sequencing of 8 polyps and 4 normal mucosa samples from the colon and small bowel of 2 additional FAP patients. Somatic APC truncating mutations and loss of chromosome 5q were recurrent across polyps, although we found no recurrent intra-patient somatic APC point mutations, indicating intra-patient polyp heterogeneity. Oncogenic driver events such as activating KRAS mutations were identified in multiple polyps. Further, analysis of mutation allele fractions suggests that several of the polyps studied are multi-clonal in nature. Excluding the known genes APC and KRAS, 50 candidate genes were identified that are putatively involved in the early development of CRC. These genes could play a role in future chemoprevention strategies. Most of these genes have been previously associated with CRC. In addition, a gene fusion in PTEN was detected and a novel, recurrent REG3A fusion was identified in duodenum polyps. The WNT signaling pathway, aberrant in 92% of CRCs, was recurrently altered in 80% of polyps. We identified colon and duodenum gene expression signatures of FAP patients and screened them against drug-induced signatures using our Cancer in-silico Drug Discovery (CiDD) software. CiDD identified Celecoxib, a COX-2 inhibitor that has already been clinically tested as a chemopreventive drug, providing validity to our drug development approach. CiDD also identified a novel candidate compound, TTNPB, which targets the Retinoid pathway as a potential drug for chemopreventive treatment of FAP patients

Orientability of vector bundles over real flag manifolds

We investigate the orientability of a class of vector bundles over flag manifolds of real semi-simple Lie groups, which include the tangent bundle and also stable bundles of certain gradient flows. Closed formulas, in terms of roots, are provided.Comment: 26 page

Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma

Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases. Our findings reveal that: (a) nearly all PDAC samples harbor potentially targetable neoantigens; (b) T cells are present but generally show a reduced activation signature; and (c) markers of efficient antigen presentation are associated with a reduced signature of markers characterizing cytotoxic T cells. These findings suggest that despite the presence of tumor specific neoepitopes, T cell activation is actively suppressed in PDAC. Further, we identify iNOS as a potential mediator of immune suppression that might be actionable using pharmacological avenues

Critical behavior of a Ginzburg-Landau model with additive quenched noise

We address a mean-field zero-temperature Ginzburg-Landau, or \phi^4, model subjected to quenched additive noise, which has been used recently as a framework for analyzing collective effects induced by diversity. We first make use of a self-consistent theory to calculate the phase diagram of the system, predicting the onset of an order-disorder critical transition at a critical value {\sigma}c of the quenched noise intensity \sigma, with critical exponents that follow Landau theory of thermal phase transitions. We subsequently perform a numerical integration of the system's dynamical variables in order to compare the analytical results (valid in the thermodynamic limit and associated to the ground state of the global Lyapunov potential) with the stationary state of the (finite size) system. In the region of the parameter space where metastability is absent (and therefore the stationary state coincide with the ground state of the Lyapunov potential), a finite-size scaling analysis of the order parameter fluctuations suggests that the magnetic susceptibility diverges quadratically in the vicinity of the transition, what constitutes a violation of the fluctuation-dissipation relation. We derive an effective Hamiltonian and accordingly argue that its functional form does not allow to straightforwardly relate the order parameter fluctuations to the linear response of the system, at odds with equilibrium theory. In the region of the parameter space where the system is susceptible to have a large number of metastable states (and therefore the stationary state does not necessarily correspond to the ground state of the global Lyapunov potential), we numerically find a phase diagram that strongly depends on the initial conditions of the dynamical variables.Comment: 8 figure

Antiretroviral Drug Use in a Cohort of HIV-Uninfected Women in the United States: HIV Prevention Trials Network 064

Antiretroviral (ARV) drug use was analyzed in HIV-uninfected women in an observational cohort study conducted in 10 urban and periurban communities in the United States with high rates of poverty and HIV infection. Plasma samples collected in 2009–2010 were tested for the presence of 16 ARV drugs. ARV drugs were detected in samples from 39 (2%) of 1,806 participants: 27/181 (15%) in Baltimore, MD and 12/179 (7%) in Bronx, NY. The ARV drugs detected included different combinations of non-nucleoside reverse transcriptase inhibitors and protease inhibitors (1–4 drugs/sample). These data were analyzed in the context of self-reported data on ARV drug use. None of the 39 women who had ARV drugs detected reported ARV drug use at any study visit. Further research is needed to evaluate ARV drug use by HIV-uninfected individuals

Responses and Differences in Tolerance to Water Shortage under Climatic Dryness Conditions in Seedlings from Quercus spp. and Andalusian Q. ilex Populations

Analyzing differences in tolerance to drought in Quercus spp., and the characterization of these responses at the species and individual population level, are imperative for the selection of resilient elite genotypes in reforestation programs. The main objective of this work was to evaluate differences in the response and tolerance to water shortage under in five Quercus spp. and five Andalusian Q. ilex populations at the inter- and intraspecies level. Six-month-old seedlings grown in perlite were subjected to drought treatments by withholding water for 28 days under mean 37 °C temperature, 28 W m-2 solar irradiance, and 41% humidity. The use of perlite as the substrate enabled the establishment of severe drought stress with reduction in water availability from 73% (field capacity) to 28% (dryness), corresponding to matric potentials of 0 and −30 kPa. Damage symptoms, mortality rate, leaf water content, photosynthetic, and biochemical parameters (amino acids, sugars, phenolics, and pigments) were determined. At the phenotypic level, based on damage symptoms and mortality, Q. ilex behaved as the most drought tolerant species. Drought caused a significant decrease in leaf fluorescence, photosynthesis rate, and stomatal conductance in all Quercus spp. analyzed, being less pronounced in Q. ilex. There were not differences between irrigated and non-irrigated Q. ilex seedlings in the content of sugar and photosynthetic pigments, while the total amino acid and phenolic content significantly increased under drought conditions. As a response to drought, living Q. ilex seedlings adjust stomata opening and gas exchange, and keep hydrated, photosynthetically active, and metabolically competent. At the population level, based on damage symptoms, mortality, and physiological parameters, the eastern Andalusian populations were more tolerant than the western ones. These observations inform the basis for the selection of resilient genotypes to be used in breeding and reforestation programs

COMPARACIÓN DE DOS TÉCNICAS PARADETERMINAR LA DIGESTIBILIDAD PROTEICADE INSUMOS YALIMENTOS COMERCIALES PARA CANINOS

El objetivo del estudio fue comparar el método de digestibilidad proteica aparente in vivo en ratas con el método alternativo in vitro con pepsina, así como determinar el grado de correlación entre ambosmétodos. Para ello, se determinó la digestibilidad proteica de tres insumos utilizados en la elaboración de alimentos comerciales para perros (torta de soya, harina de carne y harina de pollo), tres alimentos comerciales para cachorros (C1, C2 yC3); tres alimentos comerciales para perros adultos (A1,A2 yA3); y un control que fue caseinato de sodio. Para la prueba in vivo se utilizaron 60 ratas albinas de laboratorio (Rattus norvegicus) de 23 días de edad ypara la prueba in vitro se utilizó el método de la pepsina estandarizado en el Laboratorio deNutrición de la Facultad deMedicina Veterinaria de la UNMSM. El coeficiente de correlación entre ambos fue de 0.94 y la regresión fue: Y, in vivo = 11.037 + 0.804 (X, in vitro), siendo la digestibilidad proteica in vitro estadísticamentemayor que la digestibilidad aparente in vivo (p< 0.05). Se concluye que existe una alta correlación entre los métodos empleados para medir la digestibilidad proteica de insumos y alimentos usados en la alimentación canina.The aim of this study was to compare the in vivo apparent protein digestibility method in rats and the in vitro pepsin digestibility method as well as their level of correlation. Three protein sources used in commercial dog foods (soybean meal, meat meal, and chicken meal), three commercial adult dog foods (A1, A2, and A3), three commercial puppy foods (C1, C2, and C3), and sodium caseinate as a control groupwere evaluated. For the in vivo assay, 60 twenty-three-day-old albino laboratory rats (Rattus norvegicus) were used and for the in vitromethod the standardized pepsin method used at the Nutrition Laboratory, Faculty of Veterinary Medicine, UNMSM was evaluated. The correlation coefficient between the in vivo and in vitro methods was 0.94, whereas the in vitro digestibility was statistically higher than the in vivo digestibility (p<0.05). The regression equation was Y, in vivo = 11.037 + 0.804 (X, in vitro). It was concluded that there is a high correlation between both protein digestibilitymethods when assessing protein sources and commercial dog foods

In Situ neutron diffraction study of effect of hydrogen on deformation mechanisms in austenitic and duplex steels

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Stomatal Development and Conductance of a Tropical Forage Legume Are Regulated by Elevated [CO2] Under Moderate Warming

The opening and closing of stomata are controlled by the integration of environmental and endogenous signals. Here, we show the effects of combining elevated atmospheric carbon dioxide concentration (eCO2; 600 μmol mol-1) and warming (+2°C) on stomatal properties and their consequence to plant function in a Stylosanthes capitata Vogel (C3) tropical pasture. The eCO2 treatment alone reduced stomatal density, stomatal index, and stomatal conductance (gs), resulting in reduced transpiration, increased leaf temperature, and leading to maintenance of soil moisture during the growing season. Increased CO2 concentration inside leaves stimulated photosynthesis, starch content levels, water use efficiency, and PSII photochemistry. Under warming, plants developed leaves with smaller stomata on both leaf surfaces; however, we did not see effects of warming on stomatal conductance, transpiration, or leaf water status. Warming alone enhanced PSII photochemistry and photosynthesis, and likely starch exports from chloroplasts. Under the combination of warming and eCO2, leaf temperature was higher than that of leaves from the warming or eCO2 treatments. Thus, warming counterbalanced the effects of CO2 on transpiration and soil water content but not on stomatal functioning, which was independent of temperature treatment. Under warming, and in combination with eCO2, leaves also produced more carotenoids and a more efficient heat and fluorescence dissipation. Our combined results suggest that control on stomatal opening under eCO2 was not changed by a warmer environment; however, their combination significantly improved whole-plant functioning