Dysexecutive symptomatology in everyday functioning and academic achievement in adolescents.

Background: During the educational stage, academic achievement depends on various social, family, and personal factors. Among the latter, executive skills in everyday life play a significant role in dealing with the academic demands of adolescents. Therefore, the aim of this study is to ascertain the effects of executive symptomatology in everyday functioning on academic achievement in adolescents. Method: The study involved 910 students aged between 13 and 15 years (M = 14.09, SD = 0.68) from both public and private schools in the Community of Madrid. The DEX, BDEFS-CA, and BRIEF-SR questionnaires were utilised to assess executive difficulties, while grades in language, mathematics, and natural sciences were used as a measure of academic achievement. Results: The data revealed statistically significant differences in working memory, emotional control, materials organisation, and task completion. In relation to language and natural sciences subjects. In the case of mathematics, emotional control and task completion were significant variables. Conclusion: Our results indicate that certain executive skills that are manifested in everyday life activities can contribute, albeit in a variable way, to academic achievement in the subjects studied. This aspect is relevant insofar as it allows us to develop preventive interventions based on the executive training of these everyday skills.

Electrophysiological resting-state hyperconnectivity and poorer behavioural regulation as predisposing profiles of adolescent binge drinking.

Adolescent Binge Drinking (BD) has become an increasing health and social concern, with detrimental consequences for brain development and functional integrity. However, research on neurophysiological and neuropsychological traits predisposing to BD are limited at this time. In this work, we conducted a 2-year longitudinal magnetoencephalography (MEG) study over a cohort of initially alcohol-naïve adolescents with the purpose of exploring anomalies in resting-state electrophysiological networks, impulsivity, sensation-seeking, and dysexecutive behaviour able to predict future BD patterns. In a sample of 67 alcohol-naïve adolescents (age = 14.5 ± 0.9), we measured resting-state activity using MEG. Additionally, we evaluated their neuropsychological traits using self-report ecological scales (BIS-11, SSS-V, BDEFS, BRIEF-SR and DEX). In a second evaluation, 2 years later, we measured participant's alcohol consumption, sub-dividing the original sample in two groups: future binge drinkers (22 individuals, age 14.6 ± 0.8; eight females) and future light/no drinkers (17 individuals, age 14.5 ± 0.8; eight females). Then, we searched for differences predating alcohol BD intake. We found abnormalities in MEG resting state, in a form of gamma band hyperconnectivity, in those adolescents who transitioned into BD years later. Furthermore, they showed higher impulsivity, dysexecutive behaviours and sensation seeking, positively correlated with functional connectivity (FC). Sensation seeking and impulsivity mainly predicted BD severity in the future, while the relationship between dysexecutive trait and FC with future BD was mediated by sensation seeking. These findings shed light to electrophysiological and neuropsychological traits of vulnerability towards alcohol consumption. We hypothesise that these differences may rely on divergent neurobiological development of inhibitory neurotransmission pathways and executive prefrontal circuits.

Treatment Landscape of Nonmetastatic Castration-Resistant Prostate Cancer: A Window of Opportunity.

The treatment for nonmetastatic castration-resistant prostate cancer (nmCRPC) is a highly unmet medical need. The classic treatment approach for these patients-androgen deprivation therapy (ADT) alone-until metastatic progression is now considered suboptimal. Several randomized phase III clinical trials have demonstrated significant clinical benefits-including significantly better overall survival (OS)-for treatments that combine ADT with apalutamide, enzalutamide, and darolutamide. As a result, these approaches are now included in treatment guidelines and are considered a standard of care. In the present article, we discuss the changing landscape of the management of patients with nmCRPC.

Metabolic adaptations in spontaneously immortalized PGC-1α knock-out mouse embryonic fibroblasts increase their oncogenic potential.

PGC-1α controls, to a large extent, the capacity of cells to respond to changing nutritional requirements and energetic demands. The key role of metabolic reprogramming in tumor development has highlighted the potential role of PGC-1α in cancer. To investigate how loss of PGC-1α activity in primary cells impacts the oncogenic characteristics of spontaneously immortalized cells, and the mechanisms involved, we used the classic 3T3 protocol to generate spontaneously immortalized mouse embryonic fibroblasts (iMEFs) from wild-type (WT) and PGC-1α knockout (KO) mice and analyzed their oncogenic potential in vivo and in vitro. We found that PGC-1α KO iMEFs formed larger and more proliferative primary tumors than WT counterparts, and fostered the formation of lung metastasis by B16 melanoma cells. These characteristics were associated with the reduced capacity of KO iMEFs to respond to cell contact inhibition, in addition to an increased ability to form colonies in soft agar, an enhanced migratory capacity, and a reduced growth factor dependence. The mechanistic basis of this phenotype is likely associated with the observed higher levels of nuclear ß-catenin and c-myc in KO iMEFs. Evaluation of the metabolic adaptations of the immortalized cell lines identified a decrease in oxidative metabolism and an increase in glycolytic flux in KO iMEFs, which were also more dependent on glutamine for their survival. Furthermore, glucose oxidation and tricarboxylic acid cycle forward flux were reduced in KO iMEF, resulting in the induction of compensatory anaplerotic pathways. Indeed, analysis of amino acid and lipid patterns supported the efficient use of tricarboxylic acid cycle intermediates to synthesize lipids and proteins to support elevated cell growth rates. All these characteristics have been observed in aggressive tumors and support a tumor suppressor role for PGC-1α, restraining metabolic adaptations in cancer.

Melatonin Effects on Non-Alcoholic Fatty Liver Disease Are Related to MicroRNA-34a-5p/Sirt1 Axis and Autophagy.

Melatonin, an indole produced by pineal and extrapineal tissues, but also taken with a vegetarian diet, has strong anti-oxidant, anti-inflammatory and anti-obesogenic potentials. Non-alcoholic fatty liver disease (NAFLD) is the hepatic side of the metabolic syndrome. NAFLD is a still reversible phase but may evolve into steatohepatitis (NASH), cirrhosis and carcinoma. Currently, an effective therapy for blocking NAFLD staging is lacking. Silent information regulator 1 (SIRT1), a NAD+ dependent histone deacetylase, modulates the energetic metabolism in the liver. Micro-RNA-34a-5p, a direct inhibitor of SIRT1, is an emerging indicator of NAFLD grading. Thus, here we analyzed the effects of oral melatonin against NAFLD and underlying molecular mechanisms, focusing on steatosis, ER stress, mitochondrial shape and autophagy. Male C57BL/6J (WT) and SIRT1 heterozygous (HET) mice were placed either on a high-fat diet (58.4% energy from lard) (HFD) or on a standard maintenance diet (8.4% energy from lipids) for 16 weeks, drinking melatonin (10 mg/kg) or not. Indirect calorimetry, glucose tolerance, steatosis, inflammation, ER stress, mitochondrial changes, autophagy and microRNA-34a-5p expression were estimated. Melatonin improved hepatic metabolism and steatosis, influenced ER stress and mitochondrial shape, and promoted autophagy in WT HFD mice. Conversely, melatonin was ineffective in HET HFD mice, maintaining NASH changes. Indeed, autophagy was inconsistent in HET HFD or starved mice, as indicated by LC3II/LC3I ratio, p62/SQSTM1 and autophagosomes estimation. The beneficial role of melatonin in dietary induced NAFLD/NASH in mice was related to reduced expression of microRNA-34a-5p and sterol regulatory element-binding protein (SREBP1) but only in the presence of full SIRT1 availability.

Perspective: Mitochondria-ER Contacts in Metabolic Cellular Stress Assessed by Microscopy.

The interplay of mitochondria with the endoplasmic reticulum and their connections, called mitochondria-ER contacts (MERCs) or mitochondria-associated ER membranes (MAMs), are crucial hubs in cellular stress. These sites are essential for the passage of calcium ions, reactive oxygen species delivery, the sorting of lipids in whole-body metabolism. In this perspective article, we focus on microscopic evidences of the pivotal role of MERCs/MAMs and their changes in metabolic diseases, like obesity, diabetes, and neurodegeneration.

Alcohol Binge Drinking and Executive Functioning during Adolescent Brain Development.

Alcohol consumption in adolescents causes negative effects on familiar, social, academic life, as well as neurocognitive alterations. The binge drinking (BD) pattern of alcohol is characterized by the alternation of episodes of heavy drinking in a short interval of time, and periods of abstinence, a practice that can result in important brain alterations; even more than regular alcohol consumption. The prefrontal cortex, which acts as neural support for the executive processes, is particularly affected by alcohol; however, not all studies are in agreement about how BD alcohol consumption affects executive functioning. Some research has found that alcohol consumption in adolescence does not significantly affect executive functioning while others found it does. It is possible that these discrepancies could be due to the history of alcohol consumption, that is, at what age the subjects started drinking. The aim of our study is to assess the performance on executive functioning tasks of 13-19-year-old adolescents according to their pattern of alcohol consumption. We hypothesize that BD adolescents will perform worse than non-BD subjects in tasks that evaluate executive functions, and these differences will increase depending on how long they have been consuming alcohol. Three hundred and twenty-two students (48.14% females; age range 13-22 years; mean aged 16.7 ± 2.59) participated in the study; all of them had begun drinking at the age of 13 years. Participant were divided into three groups, according to their age range (13-15, 16-18, and 19-22 years) and divided according to their pattern of alcohol consumption (BD and control groups). Then, the subjects were evaluated with neuropsychological tasks that assess executive functions like working memory, inhibition, cognitive flexibility, or self-control among others. The entire sample showed a normal improvement in their executive performance, but this improvement was more stable and robust in the control group. Regarding the executive performance among age groups, control subjects only obtained better results than BDs in the 19-22-year-old range, whereas the performance was quite similar at younger ages. Considering that all the BD subjects started drinking at the same age (13 years old), it is possible that a kind of compensation mechanism exists in the adolescent brain which allows them to reach a normal performance in executive tasks. This theoretical mechanism would depend upon neuronal labor, which could lose efficacy over time with further alcohol ingestion. This process would account for the differences in neuropsychological performance, which were only observed in older students with a longer history of alcohol consumption.

Fractionated stereotactic radiotherapy plus bevacizumab after response to bevacizumab plus irinotecan as a rescue treatment for high-grade gliomas.

AIM: To evaluate the possibility of implementing a new scheme of rescue treatment after relapse or progression of high-grade glioma (HGG) treated at the first-line with bevacizumab and irinotecan (BVZ+CPT11), evaluating the response and toxicity of associating BVZ and fractionated stereotactic radiotherapy (BVZ+FSRT). MATERIALS AND METHODS: We retrospectively analysed data from 59 patients with relapse of HGG. Nine patients with HGG relapse after treatment using the Stupp protocol that were treated with BVZ+CPT11 for progression between July 2007 and August 2012, after which the response was assessed according to the Revised Assessment in Neuro-Oncology (RANO) criteria. BVZ was administered at a dose of 10 mg/kg and FSRT up to a prescribed dose of 30 Gy, 500 cGy per fraction, three days a week. The median follow-up was 38 months. RESULTS: The treatment was well-tolerated by all patients. The response after nuclear magnetic resonance imaging (MRI) at 3-6 months was progression in two patients, stable disease in four, and three patients had a partial response. The median overall survival (OS) from diagnosis until death or the last control was 36.8 months. The median progression-free survival (PFS) was 10.8 months. The results from tumour sub-group analysis indicated that the PFS was not statistically significant although it seemed that it was higher in grade-III. The OS was higher in grade-III gliomas. CONCLUSIONS: The combination of BVZ+FSRT as a second-line HGG relapse rescue treatment is well-tolerated and seems to offer promising results. We believe that multi-centre prospective studies are needed to determine the long-term efficacy and toxicity of this therapeutic approach.

Oligometastases in prostate cancer: restaging stage IV cancers and new radiotherapy options.

There are various subgroups of patients with metastatic prostate cancer: polymetastatic, oligometastatic, or oligo-recurrent cancers whose progression follows different courses and for whom there are different treatment options. Knowledge of tumor dissemination pathways and different genetic and epigenetic tumor profiles, as well as their evolution during disease progression, along with new diagnostic and therapeutic advances has allowed us to address these situations with local ablative treatments such as stereotactic body radiation therapy or stereotactic radiosurgery. These treatments provide high rates of local control with low toxicity in metastatic spread for primary cancers including those of pulmonary, digestive, and renal origin, while these types of treatments are still emerging for cancers of prostatic origin. There are several retrospective studies showing the effectiveness of such treatments in prostate cancer metastases, which has led to the emergence of prospective studies on the issue and even some phase II studies intended to prevent or delay systemic treatments such as chemotherapy. Here we collect together and review these past experiences and the studies currently underway. These types of radiotherapy treatments redefine how we approach extracranial metastatic disease and open up new possibilities for combination therapy with new systemic treatment agents.