Genomic Analyses across Six Cancer Types Identify Basal-like Breast Cancer as a Unique Molecular Entity

To improve our understanding of the biological relationships among different types of cancer, we have characterized variation in gene expression patterns in a set of 1,707 samples representing 6 human cancer types (breast, ovarian, brain, colorectal, lung adenocarcinoma and squamous cell lung cancer). In the unified dataset, breast tumors of the Basal-like subtype were found to represent a unique molecular entity as any other cancer type, including the rest of breast tumors, while showing striking similarities with squamous cell lung cancers. Moreover, gene signatures tracking various cancer- and stromal-related biological processes such as proliferation, hypoxia and immune activation were found expressed similarly in different proportions of tumors across the various cancer types. These data suggest that clinical trials focusing on tumors with common profiles and/or biomarker expression rather than their tissue of origin are warranted with a special focus on Basal-like breast cancer and squamous cell lung carcinoma

Early Pliocene climatic optimum, cooling and early glaciation deduced by terrestrial and marine environmental changes in SW Spain

The Pliocene is a key period in Earth's climate evolution, as it records the transition from warm and stable conditions to the colder and more variable glaciated climate of the Pleistocene. Simultaneously, climate became more seasonal in the Mediterranean area, and Mediterranean-type seasonal precipitation rhythm with summer drought established. These climatic changes presumably had significant impacts on terrestrial environments. However, the response of terrestrial environments to such climate changes is still not fully understood due to the lack of detailed studies dealing with this period of time. In this study, multiproxy analyses of continuous core sampling from La Matilla (SW Spain) shows detailed and continuous record of pollen, sand content and abundance of benthic foraminifer Bolivina spathulata to describe paleoenvironmental and paleoclimate trends during the early Pliocene. This record shows warmest, most humid climate conditions and highest riverine nutrient supply at ~ 4.35 Ma, coinciding with the Pliocene climatic optimum and high global sea level. A climate cooling and aridity trend occurred subsequently and a significant glaciation occurred at ~ 4.1–4.0 Ma, during a period known by very little terrestrial evidence of glaciation. Our multiproxy data thus indicate that terrestrial and marine environments were significantly variable during the early Pliocene and that major glaciation-like cooling occurred before the intensification of northern hemisphere glaciation at the beginning of the Pleistocene (~2.7 Ma). This major climate cooling and aridity maxima between 4.1 and 4.0 Ma is independently validated by a coeval sea-level drop (third order Za2 sequence boundary). This sea level drawdown is supported by enhanced coarse sedimentation and minima in riverine nutrient supply, showing paired vegetation and sea-level changes and thus a strong land-ocean relationship. This study also shows that long-term climatic trends were interrupted by orbital-scale cyclic climatic variability, with eccentricity, obliquity and precession acting as the main triggers controlling climate and environmental change in the area.Peer ReviewedPostprint (author's final draft

Pilot study of living donor liver transplantation for patients with HCC exceeding Milan criteria

BACKGROUND & AIMS: A subset of patients with hepatocellular carcinoma (HCC) beyond Milan criteria might obtain acceptable survival outcomes after liver transplantation. Living donor liver transplantation (LDLT) has emerged as a feasible alternative to overcome the paucity of donors. METHODS: In 2001 we started a protocol for LDLT in Child A-B patients with HCC fulfilling a set of criteria - the BCLC expanded criteria- that expanded the conventional indications of transplantation: 1 tumor ≤ 7cm, 5 tumors ≤ 3cm, 3 tumors ≤ 5cm without macrovascular invasion or down-staging to Milan after loco-regional therapies. RESULTS: We present a prospective cohort of 22 patients with BCLC extended indications based on size/number (17) or down-staging (5) treated with LDLT between 2001 and 2014. Characteristics of the patients were as follows: median age: 57yr old; males/female: 20/2, Child-Pugh A/B: 16/6, AFP <100ng/mL: 21. Twelve patients received neo-adjuvant loco-regional therapies. At the time of transplantation, 12 patients had HCC staging beyond Milan criteria and 10 within. Pathological reports showed that 50% exceeded BCLC expanded criteria. Perioperative mortality was 0%. After a median follow up of 81 months, the 1-, 3-, 5- and 10-year survival was 95.5%, 86.4%, 80.2% and 66.8%, respectively. Overall, seven patients recurred (range 9-108 mo), and the 5-y and 10-yr actuarial recurrence rate was of 23.8% and 44,4%, respectively. CONCLUSION: A proper selection of candidates for extended indications of living donor liver transplantation for HCC patients provide survival outcomes comparable

Genomic Analyses across Six Cancer Types Identify Basal-like Breast Cancer as a Unique Molecular Entity

To improve our understanding of the biological relationships among different types of cancer, we have characterized variation in gene expression patterns in a set of 1,707 samples representing 6 human cancer types (breast, ovarian, brain, colorectal, lung adenocarcinoma and squamous cell lung cancer). In the unified dataset, breast tumors of the Basal-like subtype were found to represent a unique molecular entity as any other cancer type, including the rest of breast tumors, while showing striking similarities with squamous cell lung cancers. Moreover, gene signatures tracking various cancer- and stromal-related biological processes such as proliferation, hypoxia and immune activation were found expressed similarly in different proportions of tumors across the various cancer types. These data suggest that clinical trials focusing on tumors with common profiles and/or biomarker expression rather than their tissue of origin are warranted with a special focus on Basal-like breast cancer and squamous cell lung carcinoma

High-resolution hepatitis C virus subtyping using NS5B deep sequencing and phylogeny, an alternative to current methods

HepatitisCvirus(HCV)is classified into seven major genotypesand67 subtypes. Recent studies haveshownthat inHCVgenotype 1-infected patients, response rates to regimens containingdirect-acting antivirals(DAAs)are subtype dependent. Currently available genotypingmethods have limited subtyping accuracy.Wehave evaluated theperformanceof adeep-sequencing-basedHCVsubtyping assay, developed for the 454/GS-Junior platform, in comparisonwith thoseof two commercial assays (VersantHCVgenotype 2.0andAbbott Real-timeHCVGenotype II)andusingdirectNS5Bsequencing as a gold standard (direct sequencing), in 114 clinical specimenspreviously tested by first-generation hybridization assay (82 genotype 1and32 with uninterpretable results). Phylogenetic analysis of deep-sequencing reads matched subtype 1 callingbypopulation Sanger sequencing(69%1b,31%1a) in 81 specimensandidentified amixed-subtype infection (1b/3a/1a) in one sample. Similarly,amongthe 32previously indeterminate specimens, identical genotypeandsubtype results were obtained by directanddeep sequencing in all but four samples with dual infection. In contrast, both VersantHCVGenotype 2.0andAbbott Real-timeHCVGenotype II failed subtype 1 calling in 13 (16%) samples eachandwere unable to identify theHCVgenotype and/or subtype inmore than half of the nongenotype 1 samples.Weconcluded that deep sequencing ismore efficient forHCVsubtyping than currently available methodsandallows qualitative identificationofmixed infectionsandmay bemorehelpfulwith respect to informing treatment strategies withnewDAA-containing regimens across allHCVsubtypesThis study has been supported by CDTI (Centro para el Desarrollo Tecnológico Industrial), Spanish Ministry of Economics and Competitiveness (MINECO), IDI-20110115; MINECO projects SAF 2009-10403; and also by the Spanish Ministry of Health, Instituto de Salud Carlos III (FIS) projects PI10/01505, PI12/01893, and PI13/00456. CIBERehd is funded by the Instituto de Salud Carlos III, Madrid, Spain. Work at CBMSO was supported by grant MINECO-BFU2011-23604, FIPSE, and Fundación Ramón Areces. X. Forns received unrestricted grant support from Roche and has acted as advisor for MSD, Gilead, and Abbvie. M. Alvarez-Tejado, J. Gregori, and J. M. Muñoz work in Roche Diagnostic

Exogenous Liposomal ceramide-c6 ammeliorates lipidomic profile, energy homeostasis and anti-oxidant systems in NASH

In non-alcoholic steatohepatitis (NASH), many lines of investigation have reported a dysregulation in lipid homeostasis, leading to intrahepatic lipid accumulation. Recently, the role of dysfunctional sphingolipid metabolism has also been proposed. Human and animal models of NASH have been associated with elevated levels of long chain ceramides and pro-apoptotic sphingolipid metabolites, implicated in regulating fatty acid oxidation and inflammation. Importantly, inhibition of de novo ceramide biosynthesis or knock-down of ceramide synthases reverse some of the pathology of NASH. In contrast, cell permeable, short chain ceramides have shown anti-inflammatory actions in multiple models of inflammatory disease. Here, we investigated non-apoptotic doses of a liposome containing short chain C6-Ceramide (Lip-C6) administered to human hepatic stellate cells (hHSC), a key effector of hepatic fibrogenesis, and an animal model characterized by inflammation and elevated liver fat content. On the basis of the results from unbiased liver transcriptomic studies from non-alcoholic fatty liver disease patients, we chose to focus on adenosine monophosphate activated kinase (AMPK) and nuclear factor-erythroid 2-related factor (Nrf2) signaling pathways, which showed an abnormal profile. Lip-C6 administration inhibited hHSC proliferation while improving anti-oxidant protection and energy homeostasis, as indicated by upregulation of Nrf2, activation of AMPK and an increase in ATP. To confirm these in vitro data, we investigated the effect of a single tail-vein injection of Lip-C6 in the methionine-choline deficient (MCD) diet mouse model. Lip-C6, but not control liposomes, upregulated phospho-AMPK, without inducing liver toxicity, apoptosis, or exacerbating inflammatory signaling pathways. Alluding to mechanism, mass spectrometry lipidomics showed that Lip-C6-treatment reversed the imbalance in hepatic phosphatidylcholines and diacylglycerides species induced by the MCD-fed diet. These results reveal that short-term Lip-C6 administration reverses energy/metabolic depletion and increases protective anti-oxidant signaling pathways, possibly by restoring homeostatic lipid function in a model of liver inflammation with fat accumulation

Requisits higienicosanitaris en l’elaboració de formatges a partir de llet crua

Control oficial; Formatges; Llet crua; APPCCControl oficial; Quesos; Leche cruda; APPCCOfficial control; Cheeses; Raw milk; HACCPL’objectiu d’aquesta Comunitat de Pràctica (CoP ) és recollir uns criteris i elaborar un document de requisits sanitaris que cal seguir en la gestió del risc de l’elaboració dels formatges fets amb llet crua amb un període de maduració inferior a 60 dies. Els operadors econòmics han de garantir la seguretat dels seus productes i han d’aplicar programes d’autocontrol en matèria de seguretat alimentària, basats en l’anàlisi de perills i punts de control crític (APPCC), per garantir la innocuïtat dels seus productes. Les autoritats sanitàries són responsables de vetllar, mitjançant la vigilància i el control oficials, perquè aquests productes respectin les normes de seguretat alimentària. En el cas dels formatges elaborats amb llet crua, se’ns plantegen diversos problemes respecte a la seguretat alimentària, i comprovem que, cada cop més, els petits productors elaboren formatges amb llet crua amb períodes de maduració inferiors als 60 dies, que després són venuts en fires, mercats locals o altres establiments alimentaris i fins i tot exportats. El marc normatiu (Reglament (CE) 853/2004)1 recull l’elaboració d’aquests tipus de formatges sempre que es reuneixin uns requisits sanitaris específics, cosa que fins que no va entrar en vigor havia estat prohibida per la normativa espanyola (Reial decret 1679/1994). Atesa la complexitat i el risc que aquests productes poden suposar, tant els inspectors de l’ASPCAT com els inspectors de l’àmbit local es preocupen pels criteris tecnològics i d’autocontrols microbiològics que s’han de complir en aquests establiments per garantir la seguretat alimentària.El objetivo de esta Comunidad de Práctica (CoP) es recoger unos criterios y elaborar un documento de requisitos sanitarios a seguir en la gestión del riesgo de la elaboración de los quesos hechos con leche cruda con un período de maduración inferior a 60 días . Los operadores económicos deben garantizar la seguridad de sus productos y deben aplicar programas de autocontrol en materia de seguridad alimentaria, basados en el análisis de peligros y puntos de control crítico (APPCC), para garantizar la inocuidad de sus productos. Las autoridades sanitarias son responsables de velar, mediante la vigilancia y control oficiales, para que estos productos respeten las normas de seguridad alimentaria. En el caso de los quesos elaborados con leche cruda, se nos plantean varios problemas respecto a la seguridad alimentaria, y comprobamos que, cada vez más, los pequeños productores elaboran quesos con leche cruda con períodos de maduración inferiores a los 60 días, que después son vendidos en ferias, mercados locales u otros establecimientos alimenticios e incluso exportados. El marco normativo (Reglamento (CE) 853/2004)1 recoge la elaboración de este tipo de quesos siempre que se reúnan unos requisitos sanitarios específicos, algo que hasta que no entró en vigor había sido prohibido por la normativa española (Real decreto 1679/1994). Dada la complejidad y el riesgo que estos productos pueden suponer, tanto los inspectores de la ASPCAT como los inspectores del ámbito local se preocupan por los criterios tecnológicos y de autocontroles microbiológicos que deben cumplirse en estos establecimientos para garantizar la seguridad alimentaria.The objective of this Community of Practice (CoP) is to collect criteria and prepare a document of health requirements to be followed in the management of the risk of the production of cheeses made with raw milk with a maturation period of less than 60 days. Economic operators must guarantee the safety of their products and must apply self-control programs regarding food safety, based on hazard analysis and critical control points (HACCP), to guarantee the safety of their products. Health authorities are responsible for ensuring, through official surveillance and control, that these products respect food safety standards. In the case of cheeses made with raw milk, we face several problems regarding food safety, and we see that, increasingly, small producers make cheeses with raw milk with maturation periods of less than 60 days, which then They are sold at fairs, local markets or other food establishments and even exported. The regulatory framework (Regulation (EC) 853/2004)1 includes the production of this type of cheese as long as specific health requirements are met, something that until it came into force had been prohibited by Spanish regulations (RD 1679/1994). Given the complexity and risk that these products can pose, both ASPCAT inspectors and local inspectors are concerned about the technological and microbiological self-control criteria that must be met in these establishments to guarantee food safety

Analizando la cinética de las remagnetizaciones por enterramiento. El caso de la Cuenca turbidítica de Jaca (Pirineos occidentales).

X Congreso Geológico de España, 5-7 Julio 2021, Vitoria - GasteizLas remagnetizaciones químicas regionales relacionadas con procesos de enterramiento y diagénesis son un proceso ampliamente extendido en cuñas orogénicas y cuencas sedimentarias. Este proceso conlleva la neoformación autigénica de minerales ferromagnéticos s.l. en relación con el aumento de temperatura asociado al enterramiento. Sin embargo, todavía no se conoce bien la cinética de estos procesos, debido en parte a que la mayoría de las remagnetizaciones de este tipo descritas en la literatura científica se produjeron durante supercrones magnéticos. Los materiales turbidíticos eocenos de la Cuenca de Jaca (Pirineos Occidentales) muestran una remagnetización química de doble polaridad, registrando varios crones a lo largo de la secuencia sedimentaria remagnetizada. Dentro del proyecto UKRIA4D (PID2019-104693GB-I00/CTA), se va a realizar un estudio multidisciplinar para relacionar temperatura de enterramiento, mineralogía magnética y edad de la remagnetización con la que evaluar de manera empírica las relaciones cinéticas entre los distintos factores

Development of a novel anti-CD19 chimeric antigen receptor: A paradigm for an affordable CAR T cell production at academic institutions

Genetically modifying autologous T cells to express an anti-CD19 chimeric antigen receptor (CAR) has shown impressive response rates for the treatment of CD19+ B cell malignancies in several clinical trials (CTs). Making this treatment available to our patients prompted us to develop a novel CART19 based on our own anti-CD19 antibody (A3B1), followed by CD8 hinge and transmembrane region, 4-1BB- and CD3z-signaling domains. We show that A3B1 CAR T cells are highly cytotoxic and specific against CD19+ cells in vitro, inducing secretion of pro-inflammatory cytokines and CAR T cell proliferation. In vivo, A3B1 CAR T cells are able to fully control disease progression in an NOD.Cg-Prkdcscid Il2rdtm1Wjl/SzJ (NSG) xenograph B-ALL mouse model. Based on the pre-clinical data, we conclude that our CART19 is clearly functional against CD19+ cells, to a level similar to other CAR19s currently being used in the clinic. Concurrently, we describe the implementation of our CAR T cell production system, using lentiviral vector and CliniMACS Prodigy, within a medium-sized academic institution. The results of the validation phase show our system is robust and reproducible, while maintaining a low cost that is affordable for academic institutions. Our model can serve as a paradigm for similar institutions, and it may help to make CAR T cell treatment available to all patients

Microscopía virtual en la enseñanza de la Anatomía Patológica en Medicina

Podeu consultar la Vuitena trobada de professorat de Ciències de la Salut completa a: http://hdl.handle.net/2445/66524Introducción y objetivos: La microscopía virtual (MV) se ha introducido en la educación post-graduada en las Facultades de Medicina. No obstante, la experiencia acumulada con esta tecnología es aún limitada y existen muy escasas evidencias sobre su impacto sobre los estudiantes. Los objetivos del estudio fueron: 1) determinar si el posible impacto sobre las notas en los exámenes prácticos de la asignatura del paso de las preparaciones de cristal y el microscopio convencional (MC) a las preparaciones virtuales y el MV, y 2) evaluar la impresión subjetiva de los estudiantes en relación con el impacto de la MV en su aprendizaje. Métodos: Se evaluaron dos grupos que realizaron la asignatura de Anatomía Patológica en el curso 2013-2014, uno usando MC y el otro MV. Las mismas preparaciones utilizadas en el grupo de MC fueron digitalizadas en un escáner Ventana iScan HT a 20x y presentadas a los estudiantes con el visor Virtuoso (Roche diagnostics). Se evaluó el nivel de conocimientos alcanzado por los estudiantes mediante un examen online. Se realizó una encuesta a los estudiantes del grupo MV para evaluar sus impresiones sobre el recurso docente. Resultados: No existieron diferencias entre los dos grupos en cuanto a las notas obtenidas en el examen online: 9,87 ± 0,34 para el grupo de MC, vs 9,86 ± 0,53 para el grupo de MV; p=0,880). La característica más valorada de la MV fue la posibilidad de acceder a las imágenes en cualquier lugar y a cualquier hora (93.3%). El 86.6% de los estudiantes encontraron que el software era fáci