Risk of HCC: Genetic heterogeneity and complex genetics

Hepatocellular carcinoma (HCC) is a common form of cancer that arises from hepatocytes and whose risk may be affected by several known environmental factors, including hepatitis viruses, alcohol, cigarette smoking, and others. Rare monogenic syndromes, such as alpha1-antitrypsin deficiency, glycogen storage disease type I, hemochromatosis, acute intermittent and cutanea tarda porphyria, as well as hereditary tyrosinemia type I are associated with a high risk of HCC. Several common conditions or diseases inherited as polygenic traits e.g. autoimmune hepatitis, type 2 diabetes, a family history of HCC, hypothyroidism, and non-alcoholic steatohepatitis also show an increased risk of HCC compared to the general population. Overall, the genetic susceptibility to HCC is characterized by a genetic heterogeneity; a high individual risk of HCC may thus be caused by several unlinked single gene defects, whose carriers are rare in the general population, or by more common conditions inherited by complex genetics

Propagation and amplification of tide at the Bransfield and Gerlache Straits, northwestern Antarctic Peninsula

The propagation and amplification of the tide at the Gerlache and Bransfield Straits, northwestern side of the Antarctic Peninsula, was studied by analysis of thirteen series of direct sea level measurements. Harmonic analysis was performed to obtain the amplitudes and phases of the M_2, S_2, O_1 and K_1 tidal constituents. Based on the computed harmonic constants, cotidal and corange charts of these main constituents were prepared. The M_2 cotidal lines are parallel to the coast and show predominantly southeastward propagation, except at the western side of the Trinity Peninsula, where the M_2 wave pivots to enter the Bransfield Strait from the Weddell Sea and turns southwestward. M_2 amplitudes present a southwestward decrease. S_2 cotidal lines are normal to the Antarctic Peninsula coast and show southwestward propagation. S_2 corange lines increase eastward from the Gerlache Strait to the Antarctic Strait. O_1 and K_1 cotidal lines are also normal to the Antarctic Peninsula coast. Diurnal amplitudes are alike in the study area except at the northwestern side of the Antarctic Strait where they present a maximum gradient. Amplitudes of the main tidal constituents are higher in the northwestern Weddell Sea than at the northwestern side of the peninsula. This fact explains the maximum tidal amplitudes observed at the Antarctic Strait in comparison to the Bransfield Strait

A 5'-region polymorphism modulates promoter activity of the tumor suppressor gene MFSD2A

<p>Abstract</p> <p>Background</p> <p>The MFSD2A gene maps within a linkage disequilibrium block containing the MYCL1-<it>EcoRI </it>polymorphism associated with prognosis and survival in lung cancer patients. Survival discrepancies between Asians and Caucasians point to ethnic differences in allelic frequencies of the functional genetic variations.</p> <p>Results</p> <p>Analysis of three single-nucleotide polymorphisms (SNPs) mapping in the MFSD2A 5'-regulatory region using a luciferase reporter system showed that SNP rs12072037, in linkage disequilibrium with the MYCL1-<it>EcoRI </it>polymorphism and polymorphic in Asians but not in Caucasians, modulated transcriptional activity of the MFSD2A promoter in cell lines expressing AHR and ARNT transcription factors, which potentially bind to the SNP site.</p> <p>Conclusion</p> <p>SNP rs12072037 modulates MFSD2A promoter activity and thus might affect MFSD2A levels in normal lung and in lung tumors, representing a candidate ethnically specific genetic factor underlying the association between the MYCL1 locus and lung cancer patients' survival.</p

A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

Genome-wide association; Survival; COVID-19Asociación de todo el genoma; Supervivencia; COVID-19Associació de tot el genoma; Supervivència; COVID-19The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10−8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10−8). A total of 113 variants were associated with survival at P-value < 1.0 × 10−5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways.Istituto Buddista Italiano Soka Gakkai funded A.R.’s and F.C.’s project “PAT-COVID: Host genetics and pathogenetic mechanisms of COVID-19” with the 8 × 1000 funds (ID n. 2020-226 2016_RIC_3), that, in part, included the present study. We also thank the generous contribution of Banca Intesa San Paolo to R.A. The funding organisations had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript

One-dimensional tidal model of the Ría San Julián, Argentina

Se implementó un modelo numérico unidimensional para sistemas de canales interconectados con el fin de simular la hidrodinámica de la marea de la ría San Julián, Argentina. En posiciones prefijadas dentro del sistema se pronosticaron la altura de la superficie libre y los caudales, utilizando un método implícito en diferencias finitas. Los resultados de la simulación numérica se compararon con mediciones de campo, y se obtuvo una correlación satisfactoria entre marea y corrientes predichas y observadas.A one-dimensional numerical model for a system of interconnected channels was implemented to simulate the tidal hydraulics of the Ría San Julián, Argentina. Free surface displacement and discharge were computed from predetermined locations throughout the system using an implicit, finite-difference technique. The results of the numerical simulation were compared with field measurements, and a satisfactory correlation was obtained between observed and predicted tides and currents.Este documento es bilingüe: español-inglésFacultad de Ciencias Naturales y Muse

Major milestones in translational oncology.

Translational oncology represents a bridge between basic research and clinical practice in cancer medicine. Today, translational research in oncology benefits from an abundance of knowledge resulting from genome-scale studies regarding the molecular pathways involved in tumorigenesis. In this Forum article, we highlight the state of the art of translational oncology in five major cancer types. We illustrate the use of molecular profiling to subtype colorectal cancer for both diagnosis and treatment, and summarize the results of a nationwide screening program for ovarian cancer based on detection of a tumor biomarker in serum. Additionally, we discuss how circulating tumor DNA can be assayed to safely monitor breast cancer over the course of treatment, and report on how therapy with immune checkpoint inhibitors is proving effective in advanced lung cancer. Finally, we summarize efforts to use molecular profiling of prostate cancer biopsy specimens to support treatment decisions. Despite encouraging early successes, we cannot disregard the complex genetics of individual susceptibility to cancer nor the enormous complexity of the somatic changes observed in tumors, which urge particular attention to the development of personalized therapies

Mouse Genome-Wide Association Mapping Needs Linkage Analysis to Avoid False-Positive Loci

We carried out genome-wide association (GWA) studies in inbred mouse strains characterized for their lung tumor susceptibility phenotypes (spontaneous or urethane-induced) with panels of 12,959 (13K) or 138,793 (140K) single-nucleotide polymorphisms (SNPs). Above the statistical thresholds, we detected only SNP rs3681853 on Chromosome 5, two SNPs in the pulmonary adenoma susceptibility 1 (Pas1) locus, and SNP rs4174648 on Chromosome 16 for spontaneous tumor incidence, urethane-induced tumor incidence, and urethane-induced tumor multiplicity, respectively, with the 13K SNP panel, but only the Pas1 locus with the 140K SNP panel. Haplotype analysis carried out in the latter panel detected four additional loci. Loci reported in previous GWA studies failed to replicate. Genome-wide genetic linkage analysis in urethane-treated (BALB/c×C3H/He)F2, (BALB/c×SWR/J)F2, and (A/J×C3H/He)F2 mice showed that Pas1, but none of the other loci detected previously or herein by GWA, had a significant effect. The Lasc1 gene, identified by GWA as a functional element (Nat. Genet., 38:888–95, 2006), showed no genetic effects in the two independent intercross mouse populations containing both alleles, nor was it expressed in mouse normal lung or lung tumors. Our results indicate that GWA studies in mouse inbred strains can suffer a high rate of false-positive results and that such an approach should be used in conjunction with classical linkage mapping in genetic crosses

Correlation between FIX genotype and pharmacokinetics of Nonacog alpha according to a multicentre Italian study

Pharmacokinetic (PK) studies on recombinant FIX concentrate, Nonacog alpha, were conducted with different sampling time designs which gave rise to not complete and homogenous outcomes. In addition, patient's FIX genotype/PK relationship has never been investigated

Persistencia de vientos superficiales del cuadrante este en estaciones costeras de la Patagonia

Martin, Paula Beatriz. Servicio de Hidrografía Naval. Buenos Aires, Argentina.Serio, Leonardo Ariel. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Recursos Naturales y Ambiente. Cátedra de Climatología y Fenología Agrícolas. Buenos Aires, Argentina.Pescio, A. Servicio de Hidrografía Naval. Buenos Aires, Argentina.Dragani, W. Servicio de Hidrografía Naval. Buenos Aires, Argentina.87-97La explotación y el transporte de petróleo son actividades muy importantes para el desarrollo económico de la sociedad industrial moderna. Sin embargo, estas actividades exponen a las costas patagónicas a riesgos de sufrir contaminación por hidrocarburos. En caso de ocurrir algún derrame de petróleo en el mar, el viento actúa como agente de dispersión y advección, por lo que conocer las características de la deriva del derrame bajo las condiciones específicas de viento permite adoptar medidas para reducir sus impactos. El objetivo de este trabajo es estudiar el comportamiento general del viento en localidades costeras de la región Patagónica y, en particular, las situaciones de persistencia de vientos con componente Este. Se utilizaron 23 años de datos horarios de intensidad y dirección del viento del período 1991-2013, de 6 estaciones meteorológicas ubicadas en la zona costera de la región Patagónica. Si bien las direcciones con componente Este suelen ser las menos frecuentes en la región (menores al 25%), constituyen los casos más importantes para este estudio. Debido a esto, se realizó el análisis de la persistencia de la dirección del viento a fin de poder determinar la cantidad de horas consecutivas en que éstos soplan de la misma dirección, poniendo especial énfasis en los vientos con componente Este. En las 6 localidades se encontraron casos de al menos 80 horas consecutivas de viento proveniente desde esas direcciones. El caso más extenso se prolongó por 9 días. Para los casos de mayor persistencia en cada estación meteorológica, se identificó el momento de ocurrencia de la mayor intensidad de viento y se analizó la situación sinóptica asociada. Se concluye que las regiones estudiadas están sujetas a la posibilidad de ocurrencia de eventos sinópticos en los cuales el viento puede soplar persistentemente hacia tierra, con intensidades de moderadas a fuerte, durante períodos que pueden superar los 5 días de duración. Dichos eventos son los más indeseables desde el punto de vista de la contaminación costera y deberían ser considerados para el diseño de planes de contingencia