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Summary Every year gastric cancer accounts for nearly 1 million new cases and more than 720 000 deaths worldwide. Prognosis is dismal because most patients are diagnosed with advanced disease; as such, gastric cancer outcomes will benefit from better methods for identification of at-risk individuals that can be targeted for early detection. One approach to targeting high-risk populations is to identify individuals who are genetically predisposed to gastric cancer, as up to 15% of all patients report family history of the disease. On the basis of clinical manifestations, three gastric cancer syndromes have been described, but the diagnosis of some of these syndromes is suboptimal and could benefit from genetic information. Over the past decade, genome-wide association and next-generation sequencing studies have identified several low penetrance variants and high-risk genes, considerably increasing our understanding of inherited gastric cancer predisposition. From these studies, PALB2 has emerged as a new familial gastric cancer gene. Furthermore, genetic analyses in patients with sporadic gastric cancer suggest that more than 10% of all cases have pathogenic mutations, a finding of great importance for cancer aetiology. In this Review, we summarise the role of genetics in gastric cancer aetiology and the implications of genetics findings for the prevention of this malignancy.

The p53 inhibitor MDMX is overexpressed in the vast majority of patients with AML; however, a causative role of MDMX in leukemogenesis has not yet been investigated. Mdmx transgenic mice (Mdmx-Tg) displayed increased number, proliferation and competitive advantage of hematopoietic stem cells compared to WT littermates. Crossing Mdmx-Tg with preleukemic mouse models representing frequent alterations in human AML, we generated three distinct compound models. We found that Mdmx overexpression triggered progression of each of the different chronic/asymptomatic preleukemic conditions to overt AML, and thereby markedly shortened survival. RNA sequencing revealed that Mdmx overexpression exerted this function through activation of Wnt/b-Catenin signaling in pre-LSC. Mechanistically, we found that MDMX bound CK1a, a canonical degrader of b-Catenin, and led to accumulation and nuclear translocation of b-Catenin. WNT/b-Catenin inhibitors or exogenous overexpression of CK1a were both effective in reversing Mdmx-induced pre-LSC properties, and showed further synergism in combination with MDMX inhibitor treatment. Competitive advantage and accumulation of b-Catenin upon Mdmx overexpression were still seen upon crossing into a p53-/- background, demonstrating that Mdmx-driven WNT/b-Catenin activation and its functional consequences are, at least part, independent of p53. Lastly, upregulation of WNT/b-Catenin pathways correlated with MDMX overexpression in large cohorts of patients with MDS and was associated with increased risk of progression to AML and poor survival. Our work identifies MDMX overexpression as a pervasive preleukemic-to-AML switch mechanism effective in different genetically-driven disease subtypes, and reveals WNT/b-Catenin as a novel, non-canonical p53-independent MDMX-driven pathway with therapeutic potential for progression prevention and cancer interception.

The Llanos foreland basin of Colombia is the country's most prolific oil producer, with the most known oil fields found in normal fault traps created during flexure of the foreland basin. The objective of the study is to evaluate the potential of stratigraphic traps in the Late Eocene-Early Miocene Carbonera Formation, a 400-1800 m-thick reservoir unit with numerous traps related to unfaulted, sand-prone fluvial deposits. We integrated 700 km2 of 3D seismic data with eight wells near the ~8600 bcd Cubiro field in the central area of the Llanos foreland. Interpretations of well logs and stratal slices through multi-attribute and iso-frequency amplitude cubes show that the Carbonera Formation contains tectonically-controlled, sinuous channel belts seen on seismic lines as strong, high-amplitude, concave reflections with variable width-to-depth ratio. Well logs through the Carbonera Formation record two regressive-transgressive cycles with greater preservation of non-reservoir, shaly transgressive deposits within the intermediate Carbonera members 5 and 3, and sandy, lowstand deposits in the lower and uppermost Carbonera members 7 and 1, respectively. Seismic and gamma-ray facies analyses allowed the distinction of prospective, sand-rich point bars, scrolls, and basal lag deposits from non-prospective, mud-rich abandoned channels. Stratal slices within the Carbonera Formation show changes from Late Eocene-Early Oligocene, northeast-flowing channel belts of a main axial fluvial system -proposed to be the proto-Meta River-, to a Late Oligocene southeast-flowing tributary channels interpreted as a result of eastward flexural migration, enhanced accommodation from loading of the Eastern Cordillera and a shift from an underfilled to overfilled foreland basin.

Previous interpretation of 2D and 3D seismic reflection data have shown widespread, direct hydrocarbon indicators from deep-water successions of the eastern Colombian Basin (ECB) and adjacent South Caribbean deformed belt (SCDB) that suggest the presence of an extensive - but poorly defined - petroleum system. We integrate Rock-Eval analysis, seismic interpretation, and 1D/2D thermal and basin modeling to better understand the origin of gas chimneys and bright spots identified in the ECB. Our dataset consists of 36 Rock-Eval samples of Coniacian to Santonian source rocks from the DSDP well sites 153, 151, and 146 located in the Beata Ridge tied to a 270 km-long composite 2D seismic line covering the ECB. Rock-Eval analyses reveal intervals of immature source rocks containing 1) kerogen types II and III, 2) an average TOC of 3.17% with a maximum TOC of 11.4%, 3) an average HI of 241, and 4) an average OI of 124. Seismic interpretation reveals: 1) wedging of post-Coniacian, organic-rich successions from the Beata Ridge (35–73 m) towards the ECB (500–1700 m); 2) Late Cretaceous to Eocene slow sedimentation rate of 38 m/my, followed by faster Oligocene to Recent sedimentation rate of 149 m/my from the Magdalena River; and 3) Late Oligocene to Recent thrusting and propagation of the SCDB. Thermal and basin modeling show: 1) mature source rocks in the SCDB and ECB; 2) Miocene to Pliocene reservoir and seal rocks related to deltaic and turbiditic sandstone, and mass transport deposits of the Magdalena Fan; 3) trap formation since the Late Oligocene related to thrust front structures, compaction folds, and stratigraphic traps, 4) hydrocarbon expulsion since Pliocene times, 5) vertical and lateral migration in the SCDB and vertical, up-dip migration in the ECB, and 6) hydrocarbon accumulation and preservation may be affected by remobilization due to biodegradation and trap breaching.

The Central Costa Rica Deformed Belt (CCRDB) is a diffuse faulting area that represents the western border of the Panama Microplate. Using the Markov Chain – Monte Carlo method and under three scenarios of the spatial distribution of the CCRDB, we analyzed the inter-seismic crustal deformation in Costa Rica and its surroundings based on the results of the Global Navigation Satellite System (GNSS) observations for Costa Rica, Nicaragua, and Panama. We assumed that the observed inter-seismic crustal deformation on the surface is a result of the kinematic effects of the rigid tectonic blocks motion, the elastic deformation due to the block interface interactions and the internal strain inside of the tectonic blocks. Assuming that the seismic moment in the subduction and inland interfaces is accumulated only as an elastic strain and is then released co-seismically, the resulting seismic moment accumulated rates reflect the capacity for producing earthquakes Mw > 8 along the Cocos Plate convergence and earthquakes Mw > 7 along the inland interfaces. Although these are the values that the modeling outputs, limited historical data suggests that this earthquake potential might be overestimated, but the historical seismicity in Costa Rica is still short for disesteeming higher earthquake potential levels.

Leukemia stem cells (LSCs) are resistant to current therapies used to treat chronic myeloid leukemia (CML). Abraham et al. (2016) have identified a molecular network critical for CML LSC survival and propose that simultaneously targeting two of their major transcriptional regulators, p53 and c-Myc, may facilitate their eradication.

Spanish Abstract: Se realizaron multiples simulaciones del proceso de captacion de agua en el sumidero Tipo B de las Empresas Publicas de Medellin (EPM E.S.P.), a partir de un modelo hidrodinamico tridimensional (Ansys – CFX). Se utilizo un dominio virtual de una via de 3.0 m de ancho y 5.30 m de largo, variando los caudales de entrada de 50 a 250 l/s, la pendiente longitudinal de 0.1 a 10% y la pendiente transversal de 0 a 5%, generando 105 casos simulados. Los resultados del modelo numerico se compararon con aproximaciones empiricas que representan el proceso de captacion en sumideros de reja de fondo, logrando correlaciones satisfactorias. El caudal total captado, se desagrego en el caudal captado por los mecanismos frontal y lateral y se definieron diferentes coeficientes de descarga tipo vertedero y orificio para el caudal captado frontalmente y tipo vertedero para el caudal captado lateralmente. Ademas, se propone un umbral de potencia unitaria del flujo de aproximacion en la reja analizada, para identificar si el proceso de captacion frontal es tipo vertedero u orificio. Estos coeficientes fueron evaluados en una segunda reja (Tipo A de EPM E.S.P.), ajustandose notablemente a los modelos empiricos disponibles. English Abstract: Multiple simulations of water catchment process were carried out in the Type B grate stablished by Empresas Publicas de Medellin (EPM E.S.P.), using a three-dimensional hydrodynamic model (Ansys – CFX). A highway virtual domain of 3.0 m wide and 5.3 m long was used, changing the input flow values from 50 to 250 l/s, the longitudinal slope from 0.1 to 10% and the transverse slope from 0 to 5%, generating 105 cases. The results of the numerical model were compared with empirical approachs which represent the catchment process in a grate, obtaining satisfactory correlations. The total captured flow was separated in the flow captured by frontal and side mechanisms and several discharge coefficients were defined, such as weir and orifice type for frontal flow and weir type for lateral flow. Furthermore, in order to identify if the front catchment process is weir or orifice type, a unitary power threshold for the approximation flow in the analyzed grate was proposed. These coefficients were evaluated in a second grate (EPM E.S.P. Type A), adjusting remarkably to the available empirical models.

ResumenObjetivoProceder a un análisis descriptivo de los pacientes a quienes se les realizaron embolizaciones de colaterales por vía percutánea.Materiales y métodosSe revisaron las historias clínicas de 27 pacientes entre febrero de 2004 y marzo de 2012. Se hace una descripción de las variables analizadas.ResultadosEn el período descrito se efectuó la embolización percutánea de 33 colaterales en 27 pacientes. La edad promedio al momento del procedimiento fue de 53 meses (1-143 meses). Al 68% se les había realizado previamente cirugía de Glenn o de Fontan, al 8% fístula Blalock-Taussig y al 24% otros procedimientos quirúrgicos. En el 76% de los casos el vaso embolizado fue una colateral venovenosa, y en el 24% restante, una colateral aortopulmonar. Los dispositivos mecánicos fueron los más utilizados (coils y plug vascular). El Amplatzer Vascular Plug se usó para embolizar colaterales de mayor tamaño. Se obtuvo la oclusión inmediata en el 92% de los casos. No hubo mortalidad asociada con los procedimientos.Discusión y conclusionesLa embolización de colaterales por vía percutánea es un procedimiento seguro y con alta tasa de eficacia. Los dispositivos utilizados mostraron ser igualmente efectivos.AbstractObjectiveTo perform a descriptive analysis of patients who underwent percutaneous embolization of collateral vessels.Materials and methodsWe reviewed the medical records of 27 patients between February 2004 and March 2012, and made a description of the variables analyzed.ResultsIn the period described, percutaneous embolization of 33 collateral vessels was performed in 27 patients. The mean age at the time of the procedure was 53 months (1-143 months). 68% had previously undergone Glenn or Fontan surgery, 8% Blalock-Taussig shunt and 24% other surgical procedures. In 76% of cases the vessel embolized was a venovenous collateral and in the remaining 24% an aortopulmonary collateral. Mechanical devices were most commonly used (coils and vascular plug). The Amplatzer Vascular Plug was used to embolize larger collateral vessels. Immediate occlusion was obtained in 92% of cases. There was no mortality associated with the procedures.Discussion and conclusionsPercutaneous embolization is a safe procedure with high success rate. The devices used were shown to be equally effective.

Germline pathogenic variants in the E-cadherin gene (CDH1) are strongly associated with the development of hereditary diffuse gastric cancer. There is a paucity of data to guide risk assessment and management of families with hereditary diffuse gastric cancer that do not carry a CDH1 pathogenic variant, making it difficult to make informed decisions about surveillance and risk-reducing surgery. We aimed to identify new candidate genes associated with predisposition to hereditary diffuse gastric cancer in affected families without pathogenic CDH1 variants.We did whole-exome sequencing on DNA extracted from the blood of 39 individuals (28 individuals diagnosed with hereditary diffuse gastric cancer and 11 unaffected first-degree relatives) in 22 families without pathogenic CDH1 variants. Genes with loss-of-function variants were prioritised using gene-interaction analysis to identify clusters of genes that could be involved in predisposition to hereditary diffuse gastric cancer.Protein-affecting germline variants were identified in probands from six families with hereditary diffuse gastric cancer; variants were found in genes known to predispose to cancer and in lesser-studied DNA repair genes. A frameshift deletion in PALB2 was found in one member of a family with a history of gastric and breast cancer. Two different MSH2 variants were identified in two unrelated affected individuals, including one frameshift insertion and one previously described start-codon loss. One family had a unique combination of variants in the DNA repair genes ATR and NBN. Two variants in the DNA repair gene RECQL5 were identified in two unrelated families: one missense variant and a splice-acceptor variant.The results of this study suggest a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants. We also identified new candidate genes associated with disease risk in these families.UK Medical Research Council (Sackler programme), European Research Council under the European Union's Seventh Framework Programme (2007-13), National Institute for Health Research Cambridge Biomedical Research Centre, Experimental Cancer Medicine Centres, and Cancer Research UK.

The case for identifying rare, disease-associated germline variants rather than undertaking larger genome-wide association (GWA) studies for common variants is increasingly being advocated. I agree with the importance of identifying rare variation in human disease, but believe more thought needs to be put into the limitations of such enterprises before advocating a dramatic departure from the GWA approach. In this paper, I discuss some of the main challenges in identifying rare disease variants with modest effects in disease, including: the over optimistic expectations about their effects; the need for very large studies needed to prove, beyond doubt, statistical associations; the problems associated with private variants, including the need for functional studies; the difficulties in prioritization of candidates for further validation and the issues related to the accurate estimation of the risk associated with individual rare variants. The rare variant approach is very promising, but it remains largely untested in comparison with the proven and successful GWA approach. Both strategies must continue to be pursued in parallel and their advantages and pitfalls must be considered without excessive scepticism or expectation.

BACKGROUND and AIMS: We report a patient of Indian descent with parental consanguinity, who developed 10 carcinomas and 35 adenomatous polyps at age 23 and duodenal adenocarcinoma at age 25. He also had dysmorphic features, mental retardation, and café-au-lait spots but no brain tumor. We aimed to establish his molecular diagnosis. METHODS: Germ-line screening for APC and MYH/MUTYH mutations was normal as was immunohistochemistry for MLH1 and MSH2 proteins. Investigation by array-comparative genomic hybridization revealed deletion of a small region on chromosome 7. Using polymerase chain reaction, this region was refined to a 400-kilobase deletion, which included exons 9-15 of the PMS2 gene, and all coding regions of oncomodulin, TRIAD3, and FSCN1. RESULTS: The deletion was confirmed as homozygous, and both parents were carriers. Immunohistochemistry showed absent PMS2 expression in all tumors and normal tissue. Most tumors showed microsatellite instability, more marked at dinucleotide than mononucleotide repeats. The tumors harbored no somatic mutations in APC, BRAF, AXIN2, or beta-catenin, but KRAS2 and TGFBR2 mutations were found. CONCLUSIONS: Our patient represents a novel phenotype for homozygous PMS2 mutation and perhaps the most severe colorectal cancer phenotype-in terms of numbers of malignancies at an early age-described to date. PMS2 mutations-and perhaps other homozygous mismatch repair mutations-should be considered in any patient presenting with multiple gastrointestinal tumors, since our patient could not be distinguished clinically from cases with attenuated familial adenomatous polyposis or MUTYH-associated polyposis.

We report the molecular characterization of three multiplex families and a sporadic case of juvenile Parkinsonism identified in the province of Antioquia (Colombia). Linkage and haplotype analysis using markers in 6q25.2-27 indicated that Parkinsonism in the pedigrees is linked to the parkin gene (maximum LOD-score of 3.85) but that they carry two different mutant haplotypes. Sequence analysis revealed a novel G to A transition in exon 6 at position 736 (G736A) of parkin. This change results in a non-conservative cysteine for tyrosine substitution. All affected individuals from two families were homozygous for this mutation, which was not detected in 100 normal controls. Patients from the family carrying the second haplotype and the sporadic case were homozygous for a GT insertion in exon 3. This mutation has been previously identified in French families with juvenile Parkinsonism. The concomitant presence of founder effects and allelic heterogeneity in Antioquia might relate to the founding admixture at the origin of this population.