Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegaly

Most of acromegaly is caused by a sporadic somatotropinoma and a couple of novel gene mutations responsible for somatotropinoma have recently been reported. To determine the cause of sporadic somatotropinoma in Japanese patients, we analyzed 61 consecutive Japanese patients with somatotropinoma without apparent family history. Comprehensive genetic analysis revealed that 31 patients harbored guanine nucleotide-binding protein, alpha stimulating (GNAS) mutations (50.8%) and three patients harbored aryl hydrocarbon receptor interacting protein (AIP) mutations (4.9%). No patients had G protein-coupled receptor 101 (GPR101) mutations. The patients in this cohort study were categorized into three groups of AIP, GNAS, and others and compared the clinical characteristics. The AIP group exhibited significantly younger age at diagnosis, larger tumor, and higher nadir GH during oral glucose tolerance test. In all patients with AIP mutation, macro- and invasive tumor was detected and repetitive surgery or postoperative medical therapy was needed. One case showed a refractory response to postoperative somatostatin analogue (SSA) but after the addition of cabergoline as combined therapy, serum IGF-I levels were controlled. The other case showed a modest response to SSA and the switching to cabergoline monotherapy was also effective. These data suggest that although resistance to SSA has been reported in patients with AIP mutations, the response to dopamine agonist (DA) may be retained. In conclusion, the cause of sporadic somatotropinoma in Japanese patients was comparable with the previous reports in Caucasians, patients with AIP mutations showed unique clinical characteristics, and DA may be a therapeutic option for patients with AIP mutations

Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.</p

Politics in Spain: A Case of Monitory Democracy

Analysing the current political context in Spain is a major challenge to political theory. Spain is experiencing the accumulation of trends that in recent years have focused the attention of most theorists and political scientists: discrediting of the major parties, falling numbers of party members, disaffection, etc. In parallel, this trend has been accompanied by citizen mobilisations that, since 15 May 2011, are manifest in numerous channels and strategies. The aim of this paper was to analyse the complex Spanish context from the monitory democracy proposal. The results show how in recent years processes of public scrutiny have been consolidated through a range of citizen initiatives. The study offers an in-depth analysis of the main characteristics of the most notable cases and monitoring initiatives, and also reflects on their democratising potential.El análisis del contexto político actual en España es un reto importante para la teoría política. España está experimentando la acumulación de tendencias que en años recientes han centrado la atención de la mayor parte de teóricos y científicos políticos: desacreditación de los principales partidos, caída del número de miembros de los partidos, desafección, etc. Paralelamente, esta tendencia se ha visto acompañada por movilizaciones ciudadanas que, desde el 15 de mayo de 2011, son manifiestas en numerosos canales y estrategias. El objetivo de este documento es analizar el complejo contexto español desde la propuesta de democracia monitorizada. Los resultados muestran que en años recientes se han consolidado los procesos de escrutinio público mediante una serie de iniciativas ciudadanas. El estudio ofrece un análisis en profundidad de las principales características de los casos e iniciativas de monitorización más notables, y reflexiona también sobre su potencial democratizador

The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury

Acetaminophen (APAP) is the active component of many medications used to treat pain and fever worldwide. Its overuse provokes liver injury and it is the second most common cause of liver failure. Mitochondrial dysfunction contributes to APAP-induced liver injury but the mechanism by which APAP causes hepatocyte toxicity is not completely understood. Therefore, we lack efficient therapeutic strategies to treat this pathology. Here we show that APAP interferes with the formation of mitochondrial respiratory supercomplexes via the mitochondrial negative regulator MCJ, and leads to decreased production of ATP and increased generation of ROS. In vivo treatment with an inhibitor of MCJ expression protects liver from acetaminophen-induced liver injury at a time when N-acetylcysteine, the standard therapy, has no efficacy. We also show elevated levels of MCJ in the liver of patients with acetaminophen overdose. We suggest that MCJ may represent a therapeutic target to prevent and rescue liver injury caused by acetaminophen

Criteria for the definition of Pituitary Tumor Centers of Excellence (PTCOE): A Pituitary Society Statement

Introduction With the goal of generate uniform criteria among centers dealing with pituitary tumors and to enhance patient care, the Pituitary Society decided to generate criteria for developing Pituitary Tumors Centers of Excellence (PTCOE). Methods To develop that task, a group of ten experts served as a Task Force and through two years of iterative work an initial draft was elaborated. This draft was discussed, modified and finally approved by the Board of Directors of the Pituitary Society. Such document was presented and debated at a specific session of the Congress of the Pituitary Society, Orlando 2017, and suggestions were incorporated. Finally the document was distributed to a large group of global experts that introduced further modifications with final endorsement. Results After five years of iterative work a document with the ideal criteria for a PTCOE is presented. Conclusions Acknowledging that very few centers in the world, if any, likely fulfill the requirements here presented, the document may be a tool to guide improvements of care delivery to patients with pituitary disorders. All these criteria must be accommodated to the regulations and organization of Health of a given country

Colonic epithelial adaptation to EGFR-independent growth induces chromosomal instability and is accelerated by prior injury

10.1016/j.neo.2021.03.010Neoplasia (United States)235488-50

Enfermedad celíaca del adulto: aspectos endocrinológicos y nutricionales Adult celiac disease: endocrinological and nutritional issues

La enfermedad celíaca es una enteropatía autoinmune que aparece como respuesta a la ingesta de gluten en sujetos genéticamente predispuestos. Aunque históricamente se la ha considerado una patología pediátrica e infrecuente su prevalencia está próxima al 1% de la población general, siendo todavía más elevada en pacientes con determinadas patologías endocrinológicas y déficits nutricionales. El empleo de los anticuerpos antitransglutaminasa y antiendomisio y la endoscopia digestiva con toma de biopsia serán elementos clave para su diagnóstico. La instauración de una dieta sin gluten logrará la recuperación del trofismo intestinal y evitará el riesgo de complicaciones a largo plazo a la vez que mejora la calidad de vida del paciente. El seguimiento médico y nutricional será clave para lograr una buena adherencia terapéutica.Celiac disease is an autoinmune enterophaty induced by the ingestion of gluten in genetically susceptible individuals. Although historically it was thought that it was an infrequent pediatric disease, now it is know that its prevalence is close to 1% in the general population. It is even higher between patients with some endocrine disorders and nutritional deficits. The use of antitransglutaminase and antiendomisium antibodies and the endoscopical duodenal biopsy are the cornerstones for its diagnosis. The introduction of a gluten-free diet will achieve the normalization of the intestinal mucosa. It will avoid the risk of long term complications and an it will achieve an improvement in quality of life. Medical and dietitian long term follow-up will be important to improve the compliance to the treatment