Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

STATIS multivariate three-way method for evaluating quality of life after corneal surgery: Methodology and case study in Costa Rica.

Vision-related quality of life (QoL) analyzes the visual function concerning individual well-being based on activity and social participation. Because QoL is a multivariate construct, a multivariate statistical method must be used to analyze this construct. In this paper, we present a methodology based on STATIS multivariate three-way methods to assess the real change in vision-related QoL for myopic patients by comparing their conditions before and after corneal surgery. We conduct a case study in Costa Rica to detect the outcomes of patients referred for myopia that underwent refractive surgery. We consider a descriptive, observational and prospective study. We utilize the NEI VFQ-25 instrument to measure the vision-related QoL in five different stages over three months. After applying this instrument/questionnaire, a statistically significant difference was detected between the perceived QoL levels. In addition, strong correlations were identified with highly similar structures ranging from 0.857 to 0.940. The application of the dual STATIS method found the non-existence of reconceptualization in myopic patients, but a statistically significant recalibration was identified. Furthermore, a real change was observed in all patients after surgery. This finding has not been stated previously due to the limitations of the existing statistical tools. We demonstrated that dual STATIS is a multivariate method capable of evaluating vision-related QoL data and detecting changes in recalibration and reconceptualization.

Intermediate molecular phenotypes to identify genetic markers of anthracycline-induced cardiotoxicity risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex disease whose polygenic component is mainly unidentified. We propose that levels of intermediate molecular phenotypes in the myocardium associated with histopathological damage could explain CDA susceptibility; so that variants of genes encoding these intermediate molecular phenotypes could identify patients susceptible to this complication. A genetically heterogeneous cohort of mice generated by backcrossing (N = 165) was treated with doxorubicin and docetaxel. Cardiac histopathological damage was measured by fibrosis and cardiomyocyte size by an Ariol slide scanner. We determine intramyocardial levels of intermediate molecular phenotypes of CDA associated with histopathological damage and quantitative trait loci (ipQTLs) linked to them. These ipQTLs seem to contribute to the missing heritability of CDA because they improve the heritability explained by QTL directly linked to CDA (cda-QTLs) through genetic models. Genes encoding these molecular subphenotypes were evaluated as genetic markers of CDA in three cancer patient cohorts (N = 517) whose cardiac damage was quantified by echocardiography or Cardiac Magnetic Resonance. Many SNPs associated with CDA were found using genetic models. LASSO multivariate regression identified two risk score models, one for pediatric cancer patients and the other for women with breast cancer. Molecular intermediate phenotypes associated with heart damage can identify genetic markers of CDA risk, thereby allowing a more personalized patient management. A similar strategy could be applied to identify genetic markers of other complex trait diseases.

The effect of mindfulness on the inflammatory, psychological and biomechanical domains of adult patients with low back pain: A randomized controlled clinical trial.

OBJECTIVE: This study aims to study the effect of mindfulness-based program on the psychological, biomechanical and inflammatory domains of patients with chronic low back pain. METHODS: A multicentre randomized and controlled clinical trial of parallel groups in patients with chronic low back pain between March 2019 to March 2020. Participants with no experience in mindfulness based intervention, were randomized to receive (36 patients) or not (34 patients) mindfulness-based stress reduction program for chronic back pain (MBSR-CBP). The program was performed in 9 sessions. Patients with chronic low back pain due to symptomatic discopathy (degenerative disc disease or herniated disc) were included. The principal outcome was changes in the blood level of cortisol and cytokines (tumor necrosis factor- α (TNF- α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and interleukin-17 (IL-17)). Secondary outcomes (psychological factors, pain, and quality of life) were measured by validated questionnaires. RESULTS: Of the 96 randomized patients, 70 who completed the study were included in the analysis (mean [range] age: 53 [33-73] years; 66% females). MBSR-CBP stopped the increase in cortisol, and reduced pro-inflammatory cytokine IL-1ß (p = 0.05). It reduced depression (p = 0.046) and stress (p = 0.0438), perceived pain (p < 0.0001), and limitations related to health (p < 0.0001). It also increased the physical function (p = 0.002) and sleep quality (p = 0.05). Furthermore, it significantly increased life satisfaction (0.006), well-being (p = 0.001) and vitality (p < 0.0001). It also increased self-compassion (p < 0.0001) and significantly reduced the overidentification (p<0.0001) and catastrophization (p = 0.002). CONCLUSIONS: MBSR-CBP could be part of a multidisciplinary approach in the management of patients suffering from chronic low back pain.

A 29-gene signature associated with NOX2 discriminates acute myeloid leukemia prognosis and survival.

The molecular complexity displayed in acute myeloid leukemia (AML) hinders patient stratification and treatment decisions. Previous studies support the utility of using specific gene panels for this purpose. Focusing on two salient features of AML, the production of reactive oxygen species (ROS) by NADPH oxidases (NOX) and metabolism, we aimed to identify a gene panel that could improve patient stratification. A pairwise comparison of AML versus healthy gene expression revealed the downregulation of four members of the NOX2 complex including CYBB (coding for NOX2) in AML patients. We analyzed the expression of 941 genes related to metabolism and found 28 genes with expression correlated to CYBB. This panel of 29 genes (29G) effectively divides AML samples according to their prognostic group. The robustness of 29G was confirmed by 6 AML cohort datasets with a total of 1821 patients (overall accuracies of 85%, 78%, 80%, 75%, 59% and 83%). An expression index (EI) was developed according to the expression of the selected discriminatory genes. Overall Survival (OS) was higher for low 29G expression index patients than for the high 29G expression index group, which was confirmed in three different datasets with a total of 1069 patients. Moreover, 29G can dissect intermediate-prognosis patients in four clusters with different OS, which could improve the current AML stratification scheme. In summary, we have found a gene signature (29G) that can be used for AML classification and for OS prediction. Our results confirm NOX and metabolism as suitable therapeutic targets in AML.

Olfactory Groove Meningiomas: Comprehensive assessment between the different microsurgical transcranial approaches and the Endoscopic Endonasal Approaches, systematic review and metanalysis on behalf of the EANS skull base section.

•OGM surgery is much more complex than a simple debate of "from above or from below" (transcranial vs endoscopic).•Lateral Sub-frontal and Superior Interhemispheric seem the most effective, superior and versatile approaches for OGM.•Minimally Invasive Transcranial approaches showed no inferiority in OGM sized <4 â€‹cm.•Endoscopic Endonasal Approaches showed inferior results in surgical and in functional outcomes for OGM.

Multivariate analysis reveals differentially expressed genes among distinct subtypes of diffuse astrocytic gliomas: diagnostic implications.

Diagnosis and classification of gliomas mostly relies on histopathology and a few genetic markers. Here we interrogated microarray gene expression profiles (GEP) of 268 diffuse astrocytic gliomas-33 diffuse astrocytomas (DA), 52 anaplastic astrocytomas (AA) and 183 primary glioblastoma (GBM)-based on multivariate analysis, to identify discriminatory GEP that might support precise histopathological tumor stratification, particularly among inconclusive cases with II-III grade diagnosed, which have different prognosis and treatment strategies. Microarrays based GEP was analyzed on 155 diffuse astrocytic gliomas (discovery cohort) and validated in another 113 tumors (validation set) via sequential univariate analysis (pairwise comparison) for discriminatory gene selection, followed by nonnegative matrix factorization and canonical biplot for identification of discriminatory GEP among the distinct histological tumor subtypes. GEP data analysis identified a set of 27 genes capable of differentiating among distinct subtypes of gliomas that might support current histological classification. DA + AA showed similar molecular profiles with only a few discriminatory genes overexpressed (FSTL5 and SFRP2) and underexpressed (XIST, TOP2A and SHOX2) in DA vs AA and GBM. Compared to DA + AA, GBM displayed underexpression of ETNPPL, SH3GL2, GABRG2, SPX, DPP10, GABRB2 and CNTN3 and overexpression of CHI3L1, IGFBP3, COL1A1 and VEGFA, among other differentially expressed genes.

Heterogeneous EGFR, CDK4, MDM4, and PDGFRA Gene Expression Profiles in Primary GBM: No Association with Patient Survival.

BACKGROUND: The prognostic impact of the expression profile of genes recurrently amplified in glioblastoma multiforme (GBM) remains controversial. METHODS: We investigated the RNA gene expression profile of epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 (CDK4), murine doble minute 4 (MDM4), and platelet derived growth factor receptor alpha (PDGFRA) in 83 primary GBM tumors vs. 42 normal brain tissue samples. Interphase FISH (iFISH) analysis for the four genes, together with analysis of intragenic deletions in EGFR and PDGFRA, were evaluated in parallel at the DNA level. As validation cohort, publicly available RNA gene expression data on 293 samples from 10 different GBM patient series were also studied. RESULTS: At the RNA level, CDK4 was the most frequently overexpressed gene (90%) followed by EGFR (58%) and PDGFRA (58%). Chromosome 7 copy number alterations, i.e., trisomy (49%) and polysomy (44%), showed no clear association with EGFR gene expression levels. In turn, intragenic EGFR deletions were found in 39 patients (47%), including EGFRvIII (46%) in association with EGFRvIVa (4%), EGFRvII (2%) or other EGFR deletions (3%) and PDGFRA deletion of exons 8-9 was found in only two tumors (2%). CONCLUSIONS: Overall, none of the gene expression profiles and/or intragenic EGFR deletions showed a significant impact on overall survival of GBM supporting the notion that other still unraveled features of the disease might play a more relevant prognostic role in GBM.

Toddler Screening for Autism Spectrum Disorder: A Meta-Analysis of Diagnostic Accuracy.

Great efforts focus on early detection of autism spectrum disorder, although some scientists and policy-makers have questioned early universal screening. The aim of this meta-analysis was to evaluate the diagnostic accuracy of the different screening tools. Several electronic databases were used to identify published studies. A Bayesian model was used to estimate the screening accuracy. The pooled sensitivity was 0.72 (95% CI 0.61-0.81), and the specificity was 0.98 (95% CI 0.97-0.99). Subgroup analyses to remove heterogeneity indicated sensitivity was 0.77 (95% CI 0.69-0.84), and specificity was 0.99 (95% CI 0.97-0.99; SD ≤ 0.01). Level 1 screening tools for ASD showed consistent statistically significant results and therefore are adequate to detect autism at 14-36 months.

Supplementary data for the biological age linked to oxidative stress modifies breast cancer aggressiveness.

The data presented in this article are related to the research paper entitled "The biological age linked to oxidative stress modifies breast cancer aggressiveness" (M.M. Sáez-Freire, A. Blanco-Gómez, S. Castillo-Lluva, A. Gómez-Vecino, J.M. Galvis-Jiménez, C. Martín-Seisdedos, M. Isidoro-García, L. Hontecillas-Prieto, M.B. García-Cenador, F.J. García-Criado, M.C. Patino-Alonso, P. Galindo-Villardón, J.H. Mao, C. Prieto, A. Castellanos-Martín, L. Kaderali, J. Pérez-Losada). The data shown were obtained from a population of transgenic mice, MMTV-Erbb2/Neu, with different susceptibility to breast cancer and a mixed genetic background generated by backcrossing. It was observed that the aggressiveness of breast cancer negatively correlates with age, being lower in chronologically old mice, similar to what occurs in humans. Given that oxidative stress is associated with tumour susceptibility and the degree of aging, the association between the aggressiveness of breast cancer and multiple intermediate phenotypes directly or indirectly related to oxidative stress was studied. Using a mathematical model, we defined biological age and the degree of aging as the difference between biological and chronological ages. As a result, we observed that biologically old mice predominated among those that developed the disease early on, that is, those that were chronologically young. We then identified the specific and common genetic components of Quantitative Trait loci or QTL associated with different evolution of breast cancer, the intermediate phenotypes related to oxidative stress studied, the biological age and the degree of aging. Lastly, we showed that the expression pattern in the livers of biologically old mice were enriched in signalling pathways related to inflammation and response to infections; whereas the biologically young mice exhibited enriched pathways related to mitochondrial activity. For the explanation and discussion of these data refer to the research article cited above.

The biological age linked to oxidative stress modifies breast cancer aggressiveness.

The incidence of breast cancer increases with age until menopause, and breast cancer is more aggressive in younger women. The existence of epidemiological links between breast cancer and aging indicates that both processes share some common mechanisms of development. Oxidative stress is associated with both cancer susceptibility and aging. Here we observed that ERBB2-positive breast cancer, which developed in genetically heterogeneous ERBB2-positive transgenic mice generated by a backcross, is more aggressive in chronologically younger than in older mice (differentiated by the median survival of the cohort that was 79 weeks), similar to what occurs in humans. In this cohort, we estimated the oxidative biological age using a mathematical model that integrated several subphenotypes directly or indirectly related to oxidative stress. The model selected the serum levels of HDL-cholesterol and magnesium and total AKT1 and glutathione concentrations in the liver. The grade of aging was calculated as the difference between the predicted biological age and the chronological age. This comparison permitted the identification of biologically younger and older mice compared with their chronological age. Interestingly, biologically older mice developed more aggressive breast cancer than the biologically younger mice. Genomic regions on chromosomes 2 and 15 linked to the grade of oxidative aging were identified. The levels of expression of Zbp1 located on chromosome 2, a gene related to necroptosis and inflammation, positively correlated with the grade of aging and tumour aggressiveness. Moreover, the pattern of gene expression of genes linked to the inflammation and the response to infection pathways was enriched in the livers of biologically old mice. This study shows part of the complex interactions between breast cancer and aging.

Advantages of Using HJ-Biplot Analysis in Executive Functions Studies / Vantagens do Uso da Análise HJ-Biplot em Estudos de Funções Executivas

Abstract Executive functions (EFs) are considered a multiple system of processing, associated with different components, such as inhibition, working memory, planning, among others. The study of EFs requires the assessment of all its components, having in mind the socio-demographic and cognitive characteristics of the target population. Nowadays, analysis of variance is used to achieve this goal; nevertheless, HJ-Biplot analysis overcome its limitations by allowing simultaneous examination of multiple data, such as those generated in EFs studies. This study evaluates possible differences in the EFs of 80 8-year-old Colombian children by their sex, socio-economic status and type of school they attend, to exemplify the advantages of using HJ-Biplot analysis in neuropsychological studies.

Resumo As funções executivas (EFs) são consideradas um sistema de vários componentes associados, como inibição, memoria de trabalho, planejamento e outros. O estudo das EFs requer a avaliação da totalidade dos seus componentes, tendo em conta as caraterísticas sociodemográficas e cognitivas da população-alvo. A analise de variância é usada para atingir esse objetivo. No entanto, a análise HJ-Biplot supera suas limitações, permitindo o exame simultâneo de dados múltiplos, como os gerados nos estudos de EFs. Este estudo avalia as possíveis diferenças nas EFs de 80 crianças de 8 anos de idade na Colômbia segundo seu sexo, nível socioeconômico e tipo de escola que frequentam, para exemplificar as vantagens de usar a analise HJ-Biplot nos estudos neuropsicológicos.

Unraveling heterogeneous susceptibility and the evolution of breast cancer using a systems biology approach.

BACKGROUND: An essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels. RESULTS: Here, we present a model in which there are complex interactions at different cellular and systemic levels that account for the heterogeneity of susceptibility to and evolution of ERBB2-positive breast cancers. Our model is based on our analyses of a cohort of mice that are characterized by heterogeneous susceptibility to ERBB2-positive breast cancers. Our analysis reveals that there are similarities between ERBB2 tumors in humans and those of backcross mice at clinical, genomic, expression, and signaling levels. We also show that mice that have tumors with intrinsically high levels of active AKT and ERK are more resistant to tumor metastasis. Our findings suggest for the first time that a site-specific phosphorylation at the serine 473 residue of AKT1 modifies the capacity for tumors to disseminate. Finally, we present two predictive models that can explain the heterogeneous behavior of the disease in the mouse population when we consider simultaneously certain genetic markers, liver cell signaling and serum biomarkers that are identified before the onset of the disease. CONCLUSIONS: Considering simultaneously tumor pathophenotypes and several molecular levels, we show the heterogeneous behavior of ERBB2-positive breast cancer in terms of disease progression. This and similar studies should help to better understand disease variability in patient populations.

[Factors related to polypharmacy in the non-institutionalised elderly. Analysis of the subsample of the national survey of health 2006 for the elderly in Castile-Leon]. / Factores asociados a la polifarmacia en población anciana no institucionalizada. Análisis de la submuestra de la Encuesta Nacional de Salud 2006 para personas mayores de Castilla y León.

BACKGROUND: The increase in chronic and degenerative diseases in the elderly leads to increased and multiple drug usage, which in turn leads to problems associated with adverse reactions and drug interactions. MATERIAL AND METHODS: We analysed the subsample of the National Health Survey 2006, for adults over 65 living in Castile-León (n=458). Using a logistic regression model and correlation analysis the variables having more influence on polypharmacy were evaluated. RESULTS: A total of 86% of those interviewed claimed to be taking drugs and 93.9% had a chronic illness. The most common health problems included arthrosis, arthritis or rheumatism (53.5%) and hypertension (48.3%), and most frequently used drugs were hypotensives (45%), pain medications (37.1%) and those for rheumatism (21.4%). Both the mean number of illnesses suffered and the drugs consumed are significantly higher in those who claimed to have, "or or fair health, used the health services, had impaired eyesight and hearing, dependent for personal care and domestic tasks, and mobility (P<.05). The variables associated with polypharmacy are three or more chronic diseases (OR=18.3), regular-poor self perceived health (OR=3.4) and females (OR=1.9). CONCLUSIONS: Given the magnitude of the problem it would be appropriate to include a review of the medications in health examinations of the elderly, particularly in women older than 75 years, with regular or self-perceived poor health and who have 3 or more diseases.

E-cadherin, laminin and collagen IV expression in the evolution from dysplasia to oral squamous cell carcinoma.

OBJECTIVES: Study the loss or reduction of the cellular adhesion mediated for E-cadherin in oral leukoplakias, oral squamous cell carcinomas and metastatic nodules. Study the loss of continuity of the laminin and collagen IV expression in the epithelial basal membrane from the biological development of the oral leukoplakias and oral carcinomas. MATERIAL AND METHOD: we have studied 124 samples of patient pays leukoplakias and oral carcinomas with diverse diagnosis that embrace from normal epithelium (13 samples), mild dysplasias (2), moderate dysplasias (12), in situ carcinomas (13), microinvasive carcinomas (11) oral squamous cell carcinomas (64 samples) and metastatic nodules (9). 7 blocks of tissue microarrays were built with needle of 2mm and was carried out a study by means of immunohistochemical technique for E-cadherin (clone 36, Biogenex), Laminin (078P, Biogenex) and Collagen IV (PHM12, Biogenex). RESULTS: In Mild and Moderate Dysplasias the results present loss of E-cadherin, Laminin, and Collagen IV (20%) expression. in situ and microinvasive carcinomas, the results presented loss of E-cadherin expression (73%), and loss in Laminin and Collagen IV expression (57%). In the squamous cell carcinomas , we find E-cadherin underexpression (90%) and discontinuity in the Basal Membrane. (70%). All the metastatic nodules presented loss of E-cadherin expression and discontinuity in Laminin and Collagen IV expression. CONCLUSIONS: The loss of E-cadherin expression is increased when increasing the dysplasia grade of lesions. The loss of continuity in the laminin and Collagen IV expression follow a parallel evolution from dysplasias to metastatic nodules. The underexpression of the three markers has been significant in the evolution of the oral lesions.

Determinación de puntos atípicos en estudios longitudinales: mediante el análisis biplot de datos sin transformaciones previas / Determination atypicals points in longitudinal studies: using biplot analysis to non transformed

En este trabajo se propone un procedimiento basado en la aplicación de la técnica Biplot a datos sin transformaciones previas, el cual se complementa con un índice que permite detectar puntos atípicos en un estudio longitudinal, y simultáneamente explicar su comportamiento. El método es aplicado al estudio de los valores de triglicéridos séricos en una submuestra del Estudio Longitudinal de Caracas, formada por varones adolescentes entre 12 y 16 años. Los resultados permitieron distinguir individuos cuyos valores de triglicéridos estaban muy por encima, o por debajo, del valor promedio de su grupo a lo largo de casi todos los períodos. Además, fue posible identificar individuos cuyos perfiles no guardan paralelismo con respecto al patrón promedio de subgrupo, lográndose también una aproximación a la forma de evolución temporal del fenómeno