Apoptosis regulation in adrenocortical carcinoma

Apoptosis evading is a hallmark of cancer. Tumor cells are characterized by having an impaired apoptosis signaling, a fact that deregulates the balance between cell death and survival, leading to tumor development, invasion and resistance to treatment. In general, patients with adrenocortical carcinomas (ACC) have an extremely bad prognosis, which is related to disease progression and significant resistance to treatments. In this report, we performed an integrative review about the disruption of apoptosis in ACC that may underlie the characteristic poor prognosis in these patients. Although the apoptosis has been scarcely studied in ACC, the majority of the deregulation phenomena already described are anti-apoptotic. Most importantly, in a near future, targeting apoptosis modulation in ACC patients may become a promising therapeutic.The work was supported by the Foundation for Science and Technology (FCT) (PTDC/MEC-ONC/31384/2017). Unit for Multidisciplinary Research in Biomedicine (UMIB) is funded by grants from FCT (UID/Multi/00215/2013)

Angiogenesis in the Normal Adrenal Fetal Cortex and Adrenocortical Tumors

Simple Summary Pharmacological angiogenesis modulation was robustly demonstrated to be a powerful clinical resource in oncotherapy. Adrenocortical carcinomas (ACC) often have a poor prognosis for which therapeutic options are limited. Understanding the mechanisms that regulate adrenocortical angiogenesis both under physiological conditions and in ACC could provide important clues on how these processes could be modulated for clinical purposes. This report summarizes the current knowledge on adrenal cortex angiogenesis regulation in physiological conditions and ACC. Embryonic adrenal angiogenesis is regulated by VEGF and Ang-Tie signaling pathways. VEGF angiogenic pathway was initially considered a promising therapeutic target for improving ACC prognosis. However, every single VEGF pathway-targeting clinical trial in ACC so far conducted yielded disappointing results. In contrast, the potential of Ang-Tie pathway-targeting in ACC is yet to be explored. Therefore, further investigation on the role and efficacy of modulating both Ang-Tie and VEGF pathways in ACC is still an unmet need. Angiogenesis plays an important role in several physiological and pathological processes. Pharmacological angiogenesis modulation has been robustly demonstrated to achieve clinical benefits in several cancers. Adrenocortical carcinomas (ACC) are rare tumors that often have a poor prognosis. In addition, therapeutic options for ACC are limited. Understanding the mechanisms that regulate adrenocortical angiogenesis along the embryonic development and in ACC could provide important clues on how these processes could be pharmacologically modulated for ACC treatment. In this report, we performed an integrative review on adrenal cortex angiogenesis regulation in physiological conditions and ACC. During embryonic development, adrenal angiogenesis is regulated by both VEGF and Ang-Tie signaling pathways. In ACC, early research efforts were focused on VEGF signaling and this pathway was identified as a good prognostic factor and thus a promising therapeutic target. However, every clinical trial so far conducted in ACC using VEGF pathway- targeting drugs, alone or in combination, yielded disappointing results. In contrast, although the Ang-Tie pathway has been pointed out as an important regulator of fetal adrenocortical angiogenesis, its role is yet to be explored in ACC. In the future, further research on the role and efficacy of modulating both Ang-Tie and VEGF pathways in ACC is needed

The WINGS Survey: a progress report

A two-band (B and V) wide-field imaging survey of a complete, all-sky X-ray selected sample of 78 clusters in the redshift range z=0.04-0.07 is presented. The aim of this survey is to provide the astronomical community with a complete set of homogeneous, CCD-based surface photometry and morphological data of nearby cluster galaxies located within 1.5 Mpc from the cluster center. The data collection has been completed in seven observing runs at the INT and ESO-2.2m telescopes. For each cluster, photometric data of about 2500 galaxies (down to V~23) and detailed morphological information of about 600 galaxies (down to V~21) are obtained by using specially designed automatic tools. As a natural follow up of the photometric survey, we also illustrate a long term spectroscopic program we are carrying out with the WHT-WYFFOS and AAT-2dF multifiber spectrographs. Star formation rates and histories, as well as metallicity estimates will be derived for about 350 galaxies per cluster from the line indices and equivalent widths measurements, allowing us to explore the link between the spectral properties and the morphological evolution in high- to low-density environments, and across a wide range in cluster X-ray luminosities and optical properties.Comment: 12 pages, 10 eps figures, Proceedings of the SAIt Conference 200

Metabolic Perspectives for Non-classical Congenital Adrenal Hyperplasia With Relation to the Classical Form of the Disease

Non-classical congenital adrenal hyperplasia (NC-CAH) represents mild form of CAH with the prevalence of 0. 6 to 9% in women with androgen excess. Clinical and hormonal findings in females with NC-CAH are overlapping with other hyperandrogenic entities such as polycystic ovary syndrome hence causing difficulties in diagnostic approach. Metabolic consequences in subjects with NC-CAH are relatively unknown. We are lacking longitudinal follow of these patients regarding natural course of the disease or the therapeutic effects of the different drug regiments. Patients with NC-CAH similarly to those with classical form are characterized with deteriorated cardiovascular risk factors that are probably translated into cardiometabolic diseases and events. An increased preponderance of obesity and insulin resistance in patients with NC-CAH begin at young age could result in increased rates of metabolic sequelae and cardiovascular disease later during adulthood in both sexes. On the other hand, growth disorder was not proven in patients with NC-CAH in comparison to CAH patients of both gender characterized with reduced final adult height. Similarly, decreased bone mineral density and osteoporosis are not constant findings in patients with NC-CAH and could depend on the sex, and type or dose of corticosteroids applied. It could be concluded that NC-CAH represent a particular form of CAH that is characterized with specificities in clinical presentation, diagnosis, therapeutic approach and metabolic outcomes.This study was funded by the Serbian Ministry of Education, Science and Technological Development (grant numbers 175032 and 41009)

Nontyphoidal Salmonella Gastroenteritis in Children: a 10 Year Review

Introdução: A Salmonella não tifoide é o agente mais frequente das toxinfeções alimentares nos países desenvolvidos. Em Portugal, são notificados em média 450 casos por ano, 80% dos quais em crianças. Métodos: Revisão casuística dos casos confirmados por coprocultura, internados num hospital do grupo I, na região de Lisboa e Vale do Tejo, entre 1999 e 2008. Análise estatística no programa SPSS® v16.0, com aplicação do teste de Spearman e significância estatística para p< 0,05. Resultados: Identificaram-se 213 internamentos. A mediana anual foi de 21 internamentos, 39% ocorrendo no verão. A mediana das idades foi de 4,2 anos, com doze casos em lactentes até aos três meses. Houve um predomínio no sexo masculino (57%). A mediana do total de leucócitos foi de 9300/mL e da proteína C reativa de 8,8 mg/dL, não se relacionando com a ocorrência de bacteriemia. A duração média do internamento foi de 5,2 dias. As principais complicações foram desidratação (117/213), bacteriemia (8/213), convulsão febril (6/213), síndrome de Mallory-Weiss (5/213) e apendicite aguda (3/213). Os serotipos mais isolados foram: S. Enteritidis (76%), S. Typhimurium (19%), outros (S. O4,5:i-, S. Derby, S. Hayfa, S. Menden, S. Rissen) (5%). Encontraram-se 27% de resistências à ampicilina e 15% ao trimetoprim-sulfametoxazol, sem resistências ao ceftriaxone. Conclusões: Nos 10 anos estudados, o número de casos manteve-se elevado, com morbilidade relevante e resistências significativas aos antibióticos de primeira linha

The complexities in genotyping of congenital adrenal hyperplasia: 21-hydroxylase deficiency

The deficiency of 21-hydroxylase due to CYP21A2 pathogenic variants is a rather frequent disease with serious consequences, going from a real mortality risk to infertility and to milder symptoms, nevertheless important for affecting the patients’ self-esteem. In the most severe cases life-threatening adrenal salt wasting crises may occur. Significant morbidity including the possibility of mistaken gender determination, precocious puberty, infertility and growth arrest with consequent short stature may also affect these patients. In the less severe cases milder symptoms like hirsutism will likely affect the image of the self with strong psychological consequences. Its diagnosis is confirmed by 17OH-progesterone dosages exceeding the cut-off value of 10/15 ng/ml but genotyping is progressively assuming an essential role in the study of these patients particularly in confirming difficult cases, determining some aspects of the prognosis and allowing a correct genetic counseling. Genotyping is a difficult process due to the occurrence of both a gene and a highly homologous pseudo gene. However, new tools are opening new possibilities to this analysis and improving the chances of a correct diagnosis and better understanding of the underlying mechanisms of the disease. Beyond the 10 classic pathogenic variants usually searched for in most laboratories, a correct analysis of 21OH-deficiency cases implies completely sequencing of the entire gene and the determination of gene duplications. These are now recognized to occur frequently and can be responsible for some false positive cases. And finally, because gene conversions can include several pathogenic variants one cannot be certain of identifying that both alleles are affected without studying parental DNA samples. A complete genotype characterization should be considered essential in the preparation for pregnancy, even in the case of parents with milder forms of the disease, or even just carriers, since it has been reported that giving birth to progeny with the severe classic forms occurs with a much higher frequency than expected.The work was supported by the Foundation for Science and Technology (FCT) (PTDC/MEC-ONC/31384/2017). SG was funded through FCT grant SFRH/BPD/1117441/2015

Spontaneous creation of discrete breathers in Josephson arrays

We report on the experimental generation of discrete breather states (intrinsic localized modes) in frustrated Josephson arrays. Our experiments indicate the formation of discrete breathers during the transition from the static to the dynamic (whirling) system state, induced by a uniform external current. Moreover, spatially extended resonant states, driven by a uniform current, are observed to evolve into localized breather states. Experiments were performed on single Josephson plaquettes as well as open-ended Josephson ladders with 10 and 20 cells. We interpret the breather formation as the result of the penetration of vortices into the system.Comment: 5 pages, 5 figure

gp91phox-dependent expression of platelet CD40 ligand

Background-CD40 ligand (CD40L) expression on platelets is mediated by agonists, but the underlying mechanism is still unclear. Methods and Results-CD40L expression was measured in platelets from healthy subjects both with and without the addition of antioxidants or a phospholipase A2 (PLA2) inhibitor and in platelets from 2 patients with an inherited deficiency of gp91phox. Immunoprecipitation analysis was also performed to determine whether normal platelets showed gp91phox expression. Unlike catalase and mannitol, superoxide dismutase inhibited agonist-induced platelet CD40L expression in healthy subjects. Immunoprecipitation analysis also showed that platelets from healthy subjects expressed gp91phox. In 2 male patients with inherited gp91phox deficiency, collagen-, thrombin-, and arachidonic acid-stimulated platelets showed an almost complete absence of superoxide anion (O2-) and CD40L expression. Incubation of platelets from healthy subjects with a PLA2 inhibitor almost completely prevented agonist-induced O2- and CD40L expression. Conclusions-These data provide the first evidence that platelet CD40L expression occurs via arachidonic acid-mediated gp91phox activation