BRAF and TERT mutations in papillary thyroid cancer patients of Latino ancestry.

Papillary thyroid cancer (PTC) is the second most commonly diagnosed malignancy in U.S. Latinas and in Colombian women. Studies in non-Latinos indicate that BRAF and TERT mutations are PTC prognostic markers. This study aimed to determine the prevalence and clinical associations of BRAF and TERT mutations in PTC Latino patients from Colombia. We analyzed mutations of BRAF (V600E) and TERT promoter (C228T, C250T) in tumor DNA from 141 patients (75 with classical variant PTC, CVPTC; 66 with follicular variant PTC, FVPTC) recruited through a multi-center study. Associations between mutations and clinical variables were evaluated with Fisher exact tests. Survival was evaluated with Kaplan-Meier plots. Double-mutant tumors (BRAF+/TERT+, n = 14 patients) were more common in CVPTC (P = 0.02). Relative to patients without mutations (n = 48), double mutations were more common in patients with large tumors (P = 0.03), lymph node metastasis (P = 0.01), extra-thyroid extension (P = 0.03), and advanced stage (P = 6.0 × 10-5). In older patients, TERT mutations were more frequent (mean age 51 years vs 45 years for wild type TERT, P = 0.04) and survival was lower (HR = 1.20; P = 0.017); however, given the small sample size, the decrease in survival was not statically significant between genotypes. Comparisons with published data in US whites revealed that Colombian patients had a higher prevalence of severe pathological features and of double-mutant tumors (10 vs 6%, P = 0.001). Mutations in both oncogenes show prognostic associations in Latinos from Colombia. Our study is important to advance Latino PTC precision medicine and replicates previous prognostic associations between BRAF and TERT in this population

Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy

Spinal and bulbar muscular atrophy (SBMA) is characterized by loss of motoneurons and sensory neurons, accompanied by atrophy of muscle cells. SBMA is due to an androgen receptor containing a polyglutamine tract (ARpolyQ) that misfolds and aggregates, thereby perturbing the protein quality control (PQC) system. Using SBMA AR113Q mice we analyzed proteotoxic stress-induced alterations of HSPB8-mediated PQC machinery promoting clearance of misfolded proteins by autophagy. In muscle of symptomatic AR113Q male mice, we found expression upregulation of Pax-7, myogenin, E2-ubiquitin ligase UBE2Q1 and acetylcholine receptor (AchR), but not of MyoD, and of two E3-ligases (MuRF-1 and Cullin3). TGF beta 1 and PGC-1 alpha were also robustly upregulated. We also found a dramatic perturbation of the autophagic response, with upregulation of most autophagic markers (Beclin-1, ATG10, p62/SQSTM1, LC3) and of the HSPB8-mediated PQC response. Both HSPB8 and its co-chaperone BAG3 were robustly upregulated together with other specific HSPB8 interactors (HSPB2 and HSPB3). Notably, the BAG3: BAG1 ratio increased in muscle suggesting preferential misfolded proteins routing to autophagy rather than to proteasome. Thus, mutant ARpolyQ induces a potent autophagic response in muscle cells. Alteration in HSPB8-based PQC machinery may represent muscle-specific biomarkers useful to assess SBMA progression in mice and patients in response to pharmacological treatments

Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion

PMCID: PMC3544714This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Understanding prime ministerial leadership in the United Kingdom and Japan in the twenty-first century: introduction to a special issue

The introduction to this special issue begins by presenting a recent puzzle – the increasingly strong position of the Japanese prime minister, who has traditionally been regarded as weak, in contrast to the increasingly fragile position of the United Kingdom prime minister, who has traditionally been regarded as strong. To make sense of these developments, the introduction reviews existing academic perspectives related to prime ministerial leadership with a specific focus on the literature on the UK and Japanese prime ministers. It subdivides our understanding of prime ministerial leadership into three distinct but inter-related levels of analysis. First, the institutional setting, which concentrates attention upon prime ministers’ relations with the machinery of government and a range of institutions including the executive, legislature and judiciary, and relates to prime ministerial versus cabinet government debates, and the core-executive model. Second, the party context, which focuses on prime ministers as leaders of their political parties and debates surrounding party centralisation, internal party cohesion and leadership selection and ejection. Third, the role of agency within these above two settings and in relation to the broader public, which includes the personal skills and performative styles of individual prime ministers

Tasa metabólica basal ¿una medición sin fundamento adecuado?

La energía necesaria para la regulación de las funciones fisiológicas depende del equilibrio entre el aporte y el gasto energético. Un disbalance entre estas condiciones, donde se vea favorecido el consumo sobre el gasto, lleva a un incremento de la reserva, el cual, a su vez, favorece la hipertrofia e hiperplasia del tejido adiposo; en condiciones crónicas, este reservorio energético lleva a la obesidad. A través del uso de fórmulas, se ha tratado calcular la tasa metabólica basal para considerar el aporte óptimo energético y, por ende, la individualización en la prescripción de estrategias nutricionales en el paciente sano y con enfermedades crónicas no transmisibles (ECNT). Sin embargo, estas fórmulas no han sido evaluadas ni validadas para todas las poblaciones y menos en obesidad, que es, de forma coincidente, la población donde más se usan en la práctica clínica, además del poco conocimiento en medicina y la mayor aplicación por nutrición. El propósito de este artículo es revisar los elementos que constituyen las fórmulas de cálculo de la tasa metabólica basal (TMB) y la población de estudio para evidenciar la usabilidad de estas fórmulas en la práctica clínica en pacientes sanos y con ECNT, como la obesidad y diabetes mellitus, dada la importancia que esto representa en el contexto del balance energético

Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease characterized by the loss of lower motor neurons. SBMA is caused by expansions of a polyglutamine tract in the gene coding for androgen receptor (AR). Expression of polyglutamine-expanded AR causes damage to motor neurons and skeletal muscle cells. Here we investigated the effect of β-agonist stimulation in SBMA myotube cells derived from mice and patients, and in knock-in mice. We show that treatment of myotubes expressing polyglutamine-expanded AR with the β-agonist clenbuterol increases their size. Clenbuterol activated the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway and decreased the accumulation of polyglutamine-expanded AR. Treatment of SBMA knock-in mice with clenbuterol, which was started at disease onset, ameliorated motor function and extended survival. Clenbuterol improved muscle pathology, attenuated the glycolytic-to-oxidative metabolic alterations occurring in SBMA muscles and induced hypertrophy of both glycolytic and oxidative fibers. These results indicate that β-agonist stimulation is a novel therapeutic strategy for SBMA

Hydrothermal multivariable approach. Full-scale feasibility study

A process configuration combining thermal hydrolysis (TH) and anaerobic digestion (AD) of sludge has been studied with the objective of analysing the feasibility of the technology for full scale installations. The study has been performed through pilot scale experiments and energy integration considerations, and a scheme of the most profitable option is presented: thermal hydrolysis unit fed with 7% total solids (TS) secondary sludge, anaerobic digestion of the hydrolysed sludge together with fresh primary sludge, and a cogeneration unit to produce green electricity and provide hot steam for the thermal hydrolysis process. From a technical and practical point of view, the process scheme proposed is considered to be feasible. Based on the results of the pilot plant performance and the laboratory studies, the process has proven to operate successfully at a concentration of 7-8% TS. After the thermal hydrolysis, sludge viscosity becomes radically smaller, and this favours the digesters mixing and performance (40% more biogas can be obtained in nearly half the residence time compared to the conventional digestion). From an economic point of view, the key factors in the energy balance are: the recovery of heat from hot streams, and the concentration of sludge. The article presents the main energy integration schemes and defines the most profitable one: an energetically self-sufficient process, with a cogeneration unit. The scheme proposed has proven to need no additional energy input for the sludge hydrolysis, generates more that 1 MW green electricity (246 kW surplus with respect to the conventional process), and produces 58% less volume of Class A biowaste. The study and balances here presented set the basis for the scale-up to a demonstration plant (hydrolysis + anaerobic digestion + cogeneration unit)

Transfusión intrauterina en hidrops fetal por Parvovirus B19: a propósito de un caso clínico

Hidrops fetal no inmunológico diagnosticado a las 22 semanas de gestación, secundario a infección por Parvovirus B19, tratado exitosamente con cinco transfusiones intrauterinas. Parto vaginal con recién nacido de término sin estigmas de enfermedad. Enfatizamos la importancia de sospechar el diagnóstico, el manejo basado en Vmax de ACM y la capacidad actual de tratamiento exitoso a través de transfusiones intrauterinas

Microgotas: Método de inoculación con Rhizoctonia solani Kühn para evaluar genotipos de habichuela (Phaseolus vulgaris L.)

Three methods, namely, bulk, microdrops, and 0.5-cm discs of potato dextrose agar (PDA) with fungal mycelium, were evaluated in order to identify a suitable methodology to inoculate bean with Rhizoctonia solani. In the microdrop method, the combination of dilution and volume of inoculum was examined.The effect of age of inoculum and of the leaf on symptom expression was also tested. All inoculations were done on the upper side of the leaf. The best method for symptom expression was the combination of 10 µl with dilutions of 100 ml of sterilized distilled water per Petri dish (60-mm diam).The bulk and disc methods induced severe symptoms causing defoliation 72 h after the inoculation. Four-day-old colonies as source of inoculum were best for symptom expression. With older colonies, lesion size was smaller and the induction of symptoms less successful. Age of trifoliate did not influence the success of the inoculations. Validation tests showed the potential of microdrops as a useful technique for the evaluation of bean genotypes.Con el propósito de desarrollar una metodología para inocular habichuela con Rhizoctonia solani se evaluaron los siguientes métodos: masivo, microgotas y discos de 0.5 cm de agar de papa y dextrosa con micelio del hongo. En el método de inoculación con microgotas se examinó la combinación de dilución y volumen de inóculo. El efecto de la edad del inóculo y de la hoja en la expresión de los síntomas también se evaluó. Todas las inoculaciones se realizaron en el haz de la hoja. El método de inoculación más efectivo para la expresión de síntomas fue el de microgotas utilizando la combinación de 10 µl a una dilución de 100 ml de agua destilada esterilizada por plato de Petri (60 mm diam). Los métodos masivo y de discos indujeron síntomas severos con defoliación 72 hrs después de la inoculación. La edad más adecuada de la colonia es de cuatro días. A medida que aumenta la edad del inóculo se reduce el tamaño de la lesión y el éxito de las inoculaciones. La edad de las hojas trifoliadas no influye en la respuesta a la infección. El ensayo de validación demostró el potencial del método para evaluaciones de genotipos de habichuela