AIP and MEN1 mutations and AIP immunohistochemistry in pituitary adenomas in a tertiary referral center.

Background: Pituitary adenomas have a high disease burden due to tumor growth/ invasion and disordered hormonal secretion. Germline mutations in genes such as MEN1 and AIP are associated with early onset of aggressive pituitary adenomas that can be resistant to medical therapy. Aims: We performed a retrospective screening study using published risk criteria to assess the frequency of AIP and MEN1 mutations in pituitary adenoma patients in a tertiary referral center. Methods: Pituitary adenoma patients with pediatric/adolescent onset, macroadenomas occurring ≤30 years of age, familial isolated pituitary adenoma (FIPA) kindreds and acromegaly or prolactinoma cases that were uncontrolled by medical therapy were studied genetically. We also assessed whether immunohistochemical staining for AIP (AIP-IHC) in somatotropinomas was associated with somatostatin analogs (SSA) response. Results: Fifty-five patients met the study criteria and underwent genetic screening for AIP/MEN1 mutations. No mutations were identified and large deletions/duplications were ruled out using MLPA. In a cohort of sporadic somatotropinomas, low AIP-IHC tumors were significantly larger (P = 0.002) and were more frequently sparsely granulated (P = 0.046) than high AIP-IHC tumors. No significant relationship between AIP-IHC and SSA responses was seen. Conclusions: Germline mutations in AIP/MEN1 in pituitary adenoma patients are rare and the use of general risk criteria did not identify cases in a large tertiary-referral setting. In acromegaly, low AIP-IHC was related to larger tumor size and more frequent sparsely granulated subtype but no relationship with SSA responsiveness was seen. The genetics of pituitary adenomas remains largely unexplained and AIP screening criteria could be significantly refined to focus on large, aggressive tumors in young patients

Identificación de posibles biomarcadores de la enfermedad inflamatoria intestinal

La enfermedad inflamatoria intestinal (EII) es caracterizada por una inflamación crónica del tracto gastrointestinal. Clásicamente, el estado de los pacientes con EII ha sido valorado mediante parámetros clínicos como el peso corporal, la diarrea y el sangrado rectal. Sin embargo, éstos no tienen una buena correlación con la actividad de la enfermedad. Hoy en día, se disponen de numerosos marcadores biológicos, no obstante distan de ser ideales. A pesar de ello, la aportación de marcadores biológicos permitiría valorar la enfermedad de manera más objetiva. Por esta razón, la presente Tesis doctoral tiene como objetivo la búsqueda de nuevos biomarcadores de la EII que permitan la estandarización de ensayos clínicos y un mejor seguimiento de la enfermedad. Para llevar a cabo dicho objetivo, se utilizaron métodos clásicos de bioquímica y biología molecular tanto in vitro como in vivo. In vitro, se emplearon células mononucleares aisladas de sangre periférica y la línea celular en cultivo HepG2. Por otro lado, in vivo se utilizó un modelo experimental de colitis en rata inducido mediante dextrán sulfato sódico (DSS) al 5% en el agua de bebida.Durante la fase de inducción de la colitis experimental se produce una alteración del moco intestinal y un aumento de las células inmunes infiltradas en la lámina propria del colon de las ratas enfermas, la mayoría de estas células son positivas para AIF-1 (factor inflamatorio de injerto alogénico-1). El tratamiento con infliximab (IFX) produjo cambios en el colon a nivel histológico en la mucina, el AIF-1 y la pp38 (proteína p38 fosforilada). Estos cambios durante la fase de inducción de la enfermedad conllevaron una mejoría del animal durante la fase de recuperación, no presentando dichos animales diarrea. Además, hemos observado que durante la colitis experimental se produce la oxidación de la albúmina del suero y que el tratamiento con IFX protege de dicho evento.Por otro lado, los estudios in vitro demostraron que el AIF-1 se comporta como una proteína de secreción que potencia la diferenciación del linfocito T a un fenotipo Th 1 y que promueve la supervivencia de los linfocitos T efectores. Además, determinamos que el AIF-1 está aumentado en el suero de pacientes con EII activa. En relación a esto, en pacientes con enfermedad de Crohn tratados con medicamentos anti-TNF-α (IFX y adalimumab) presentaron niveles más bajos de AIF-1 sérico que los pacientes con tratamientos clásicos, encontrándose una correlación positiva entre índice de Harvey-Bradshaw y los niveles séricos de AIF-1.Por todo ello consideramos que la albúmina sérica oxidada y el AIF-1 sérico pueden ser buenos candidatos a biomarcadores de la enfermedad inflamatoria intestinal

Loss of pancreas upon activated Wnt signaling is concomitant with emergence of gastrointestinal identity

Organ formation is achieved through the complex interplay between signaling pathways and transcriptional cascades. The canonical Wnt signaling pathway plays multiple roles during embryonic development including patterning, proliferation and differentiation in distinct tissues. Previous studies have established the importance of this pathway at multiple stages of pancreas formation as well as in postnatal organ function and homeostasis. In mice, gain-of-function experiments have demonstrated that activation of the canonical Wnt pathway results in pancreatic hypoplasia, a phenomenon whose underlying mechanisms remains to be elucidated. Here, we show that ectopic activation of epithelial canonical Wnt signaling causes aberrant induction of gastric and intestinal markers both in the pancreatic epithelium and mesenchyme, leading to the development of gut-like features. Furthermore, we provide evidence that β -catenin-induced impairment of pancreas formation depends on Hedgehog signaling. Together, our data emphasize the developmental plasticity of pancreatic progenitors and further underscore the key role of precise regulation of signaling pathways to maintain appropriate organ boundaries

“Producción y exportación de cubiertos de plata 925 con diseños tradicionales a New York : “Silqic Perú”

El presente plan se basa en comprobar la sostenibilidad de poner en ejercicio un negocio dedicado a la exportación de cubiertos finos hechos en plata labrados con motivos alusivos a las culturas pre-hispánicas del Perú en el mango del cubierto al mercado de New York – Estados Unidos. Para lograr el objetivo se sustentan las razones de lanzar al mercado el producto ya descrito, y que está relacionado al apogeo que vive el Perú con su turismo y gastronomía. Seguidamente, se proponen el uso de herramientas metodológicas como el análisis PESTA que incluye el análisis de los 5 factores externos, el cual describe un entorno favorable que permitirá poner en marcha el proyecto; luego se realiza un análisis de las Fuerzas de Porter para ver el estado actual del mercado; así como también se realizará una matriz de Ansoff para tener en cuenta la estrategia de posicionamiento a utilizar; por último realizamos una matriz FODA de nuestra empresa. Asimismo, notaremos que el mercado al cual apuntamos tiene un déficit comercial en cuanto a orfebrería y joyas de plata, por lo que entraremos a ese mercado para satisfacer a personas con gustos también sofisticados, lo que nos resulta favorable pues, el Perú es uno de los primeros exportadores de plata en el mundo, sin embargo solo como materia prima, más no como plata transformada en valiosos objetos o joyas. Luego de comprobar que existe capacidad de oferta y que el entorno es beneficioso, se comprueba la capacidad de demanda, por lo que se recurre a la metodología de carácter cualitativa como entrevistas para demostrar que existen potenciales compradores. Del mismo modo, seguiremos el método profesional de las exportaciones que consiste en la prospección del mercado, promoción, y posicionamiento del producto. Como resultado de la etapa de prospección de mercados e inteligencia comercial, se describe a detalle el desarrollo del plan de negocios, el cual incluirán marketing, comercialización, producción, logística, calidad, seguridad, organización y recursos humanos. Finalmente, se detalla el plan Financiero y Evaluación Económica en el que describiremos los costos fijos y variables, así como también la proyección de ventas y los estados financieros respectivos.Trabajo de suficiencia profesiona

Production of HlyA and ClyA haemolysins among quinolone-resistant Escherichia coli isolated from clinical samples

Most Escherichia coli resistant to quinolones are not haemolytic. The objective of this study was to determine the phylogroup, clonal relationship, mechanism of quinolone resistance and virulence factors in 70 haemolytic E. coli resistant to nalidixic acid. Sixty-six isolates contained the hlyA gene, belonged to phylogroup B2, and 61 of them presented low-level resistance to fluoroquinolones. Four isolates presented high-level resistance to fluoroquinolones, contained the clyA gene and were included in phylogroup D. One single isolate (phylogroup D, with low level resistance to fluoroquinolones) contained both cytotoxins.Supported by Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, Madrid, Spain, co-financed by European Development Regional Fund “A way to achieve Europe” ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015). Alicia Márquez-López was supported by the REIPI and has been supported by a grant from the Instituto de Formación e Investigación Marqués de Valdecilla (IFIMAV), Santander, Spain. We want to thank Eduardo López for his review of English version of the manuscript.S

Biased receptor functionality versus biased agonism in G-protein-coupled receptors

Functional selectivity is a property of G-protein-coupled receptors (GPCRs) by which activation by different agonists leads to different signal transduction mechanisms. This phenomenon is also known as biased agonism and has attracted the interest of drug discovery programs in both academy and industry. This relatively recent concept has raised concerns as to the validity and real translational value of the results showing bias; firstly biased agonism may vary significantly depending on the cell type and the experimental constraints, secondly the conformational landscape that leads to biased agonism has not been defined. Remarkably, GPCRs may lead to differential signaling even when a single agonist is used. Here we present a concept that constitutes a biochemical property of GPCRs that may be underscored just using one agonist, preferably the endogenous agonist. 'Biased receptor functionality' is proposed to describe this effect with examples based on receptor heteromerization and alternative splicing. Examples of regulation of final agonist-induced outputs based on interaction with β-arrestins or calcium sensors are also provided. Each of the functional GPCR units (which are finite in number) has a specific conformation. Binding of agonist to a specific conformation, i.e. GPCR activation, is sensitive to the kinetics of the agonist-receptor interactions. All these players are involved in the contrasting outputs obtained when different agonists are assayed

Seasonal variation of biogas upgrading coupled with digestate treatment in an outdoors pilot scale algal-bacterial photobioreactor

Producción CientíficaThe yearly variations of the quality of the upgraded biogas and the efficiency of digestate treatment were evaluated in an outdoors pilot scale high rate algal pond (HRAP) interconnected to an external absorption column (AC) via a conical settler. CO2 concentrations in the upgraded biogas ranged from 0.7% in August to 11.9% in December, while a complete H2S removal was achieved regardless of the operational month. CH4 concentrations ranged from 85.2% in December to 97.9% in June, with a limited O2 and N2 stripping in the upgraded biogas mediated by the low recycling liquid/biogas ratio in the AC. Biomass productivity ranged from 0.0 g m−2 d−1 in winter to 22.5 g m−2 d−1 in summer. Finally, microalgae diversity was severely reduced throughout the year likely due to the increasing salinity in the cultivation broth of the HRAP induced by process operation in the absence of effluent.INCOVER - Innovative Eco-Technologies for Resource Recovery from Wastewater (689242

Characterising an abandoned phosphogypsum deposit by combining radiological, geophysical, geochemical, and statistical techniques

Phosphoric fertiliser has enormously contributed to agriculture; however, it generates five tonnes of phosphogypsum per ton of phosphoric acid synthesised. Phosphogypsum houses heavy metals and long-lived radioactive elements that represents an environmental issue requiring remediation. This paper presents a methodology for characterising phosphogypsum deposits using geophysical, geochemical, and statistical tools. Gamma-ray probes determined the abnormal radioactive zones within the phosphogypsum deposits while electrical resistivity tomography provided the geometry and distribution of the phosphogypsum deposits. Chemical results confirmed the high presence of heavy metals in the waste determining chromium as the most concentrated metal. Radiological measures indicate that the effective ambient dose equivalent average in the study area surface is approximately 8.5 times higher than the average for Europe. While at 1.0 m depth, in the phosphogypsum layer, the ambient dose equivalent average surpasses approximately 27 times the European average. Statistical correlation analysis supports that the radiation increases due to the uranium presence. This methodology might reduce time and cost avoiding the use of expensive traditional methods, and it is exportable to any deposit.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

E-cadherin expression is associated with somatostatin analogue response in acromegaly

Acromegaly is a rare disease resulting from hypersecretion of growth hormone (GH) and insulin‐like growth factor 1 (IGF1) typically caused by pituitary adenomas, which is associated with increased mortality and morbidity. Somatostatin analogues (SSAs) represent the primary medical therapy for acromegaly and are currently used as first‐line treatment or as second‐line therapy after unsuccessful pituitary surgery. However, a considerable proportion of patients do not adequately respond to SSAs treatment, and therefore, there is an urgent need to identify biomarkers predictors of response to SSAs. The aim of this study was to examine E‐cadherin expression by immunohistochemistry in fifty‐five GH‐producing pituitary tumours and determine the potential association with response to SSAs as well as other clinical and histopathological features. Acromegaly patients with tumours expressing low E‐cadherin levels exhibit a worse response to SSAs. E‐cadherin levels are associated with GH‐producing tumour histological subtypes. Our results indicate that the immunohistochemical detection of E‐cadherin might be useful in categorizing acromegaly patients based on the response to SSAs.ISCIII‐Subdirección General de Evaluación y Fomento de la Investigación PI13/02043 PI16/00175FEDER PI13/02043 PI16/00175Junta de Andalucía A‐0023‐2015 A‐0003‐2016 CTS‐1406 BIO‐0139Andalusian Ministry of Health C‐0015‐2014CIBERobn PI13/ 02043 PI16/0017