👤 Lívia Furquim de Castro

Major Depressive Disorder (MDD) is a multifactorial psychiatric disease influenced by a combination of genetic and environmental factors. Among the genes linked to MDD, the Melanocortin 1 Receptor (MC1R), Catechol-O-Methyltransferase (COMT), Brain-Derived Neurotrophic Factor (BDNF), and the serotonin transporter (5-HTT) are of particular interest due to their critical roles in stress regulation and neural function. Despite their biological significance, the contribution of specific polymorphisms within these genes to MDD risk remains understudied. This retrospective observational case-control study included 87 Colombian patients diagnosed with MDD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). The control group comprised Latino/admixed individuals without, sourced from the gnomAD v2.1.1 database. The complete coding region of the MC1R gene and three polymorphisms: 5-HTTLPR Insertion/Deletion 44 bp, BDNF-c.196G>A, and COMT-c.472G>A were genotyped using PCR and Sanger sequencing. The polymorphisms rs885479 and rs4680 were identified as protective factors against MDD, while the polymorphisms rs796296176, rs779504604, rs1805005 were associated with an increased risk of developing MDD (OR:22.87, OR:51.26, OR: 1.97, respectively). Several of the analyzed polymorphisms (rs796296176, rs779504604, rs1805005) increase the risk for MDD. Notably, we provide novel evidence of these polymorphisms in MC1R as a risk to MDD. Show less

Precision nutrition, guided by genetic testing, has emerged as a promising approach for managing obesity. However, robust clinical trials testing its effectiveness in real-world dietary interventions remain scarce. The GenOn Programme aims to evaluate whether tailoring nutritional care based on genetic risk for obesity enhances weight loss, satiety control, and metabolic outcomes in adults with overweight and obesity. The GenOn Programme is an 18-week, 2 × 2 factorial, randomised controlled trial including 120 adults classified as high or low genetic risk for obesity (variants: FTO rs9939609 and rs1121980; MC4R rs1782313; LEP rs7799039). Participants are randomised to standard or satiety-focused dietary counselling. Both groups receive five calorie-restricted (-500 kcal/day), nutritionally balanced meal plans. The satiety arm additionally includes a high-protein breakfast, daily granola supplementation and behavioural strategies. Assessments at baseline, Week 12, and Week 18 include weight loss, body composition, satiety perception, quality of life, cardiometabolic markers, (epi)genetics, inflammation, neuroendocrine regulation, and metagenomics. The GenOn Programme is a randomised controlled trial to test a precision nutrition approach for overweight and obesity, integrating genetics, dietary strategies, and behavioural support. Findings may inform dietitians and healthcare systems on the clinical value of genetically guided nutritional care to improve outcomes in the treatment of overweight and obesity. Show less

Hispanic/Latino (H/L) adults are more likely than non-Hispanic White individuals to have Alzheimer's disease (AD), yet fewer than one in five H/L adults has apolipoprotein E ( Community-residing, Spanish-preferring Mexican/Mexican American adults ( Participants recognized AD as a memory disorder influenced by aging and genes but were largely unfamiliar with AD genetic testing. Testing was viewed as useful for diagnosis rather than future risk prediction, with limited perceived value for cognitively normal individuals without a family history. Despite this limited familiarity, participants expressed interest in AD research involving genetic testing. Findings suggested a perceived responsibility to use AD genetic testing despite limited awareness of its purposes, applications, and clinical implications. Participants' responses reflected a present-oriented health disposition: Genetic testing was viewed as appropriate once symptoms emerge rather than as a proactive tool for anticipating future decline, consistent with current clinical practice outside autosomal dominant AD. Educational materials co-created by community members and researchers may address these gaps by explaining both limitations of genetic testing in isolation and its potential future applications, including how genetic and multimodal biomarker data may inform risk estimation and prevention-focused decision-making. This approach may foster a future-oriented health disposition while remaining responsive to social and structural contexts. Future work is needed among other H/L heritage groups with differing social and structural experiences, migration histories, and language primacy. Show less

The G protein-coupled receptor (GPCR) melanocortin receptor 4 (MC4R) is an essential regulator of body weight homeostasis. MC4R is unusual among GPCRs in that its activity is regulated by 2 opposing physiological ligands, the agonist ⍺-MSH and the antagonist/inverse agonist AgRP. Paradoxically, while MC4R localizes and functions at the cilium of hypothalamic neurons, the ciliary levels of MC4R are very low under unrestricted feeding conditions. Here, we find that the constitutive activity of MC4R is responsible for the continuous depletion of MC4R from cilia and that inhibition of MC4R's activity via AgRP leads to a robust accumulation of MC4R in cilia. Ciliary targeting of MC4R is mediated by its partner MRAP2 and the constitutive exit of MC4R from cilia relies on the sensor of activation β-arrestin, on ubiquitination, and on the BBSome ciliary trafficking complex. Thus, while MC4R exits cilia via conventional mechanisms, it only accumulates in cilia when its activity is suppressed by AgRP. Show less

In recent years we have been experiencing an advance in lipid-lowering therapies, with the appearance of new drugs that act on the different metabolic pathways, reducing both the levels of cholesterol associated with low-density lipoproteins (LDL-C) containing apoproteinB (ApoB), and vascular risk. However, the results in achieving goals are still scarce, as well as the use of the different therapies that help us to achieve them. Among the reasons that justify this situation are: the inadequate identification of vascular risk, the underuse of therapies, poor adherence to the recommended treatment, the lack of organization in terms of the assignment of roles and algorithms of action in the follow-up of patients and the need for improved education and psychosocial interventions that influence both adherence and consolidation of Healthy lifestyle habits. This consensus document aims to improve the approach and follow-up of dyslipidemia in a comprehensive way, defining the planning of lipid-lowering therapies as a control strategy (SEC/SEA/SEEN/SEMFYC/SEMERGEN/SEMG/SEN/SEACV/S.E.N.). Show less

Lacticaseibacillus paracasei cell wall presents two capsular polysaccharides, CPS-1 and CPS-2, and a teichoic acid. CPS-1 is novel and it presents a branched heptasaccharide repeating unit, with the sequence →6)-α-d-Gal-(1→3)-β-l-Rha-(1→4)-β-d-Glc-(1→3)-α-d-GlcNAc-(1→2)-β-d-Glc-(1→6)-β-d-Glc-(1→ in the linear part to which a β-l-Rha is attached to O-4 of GlcNAc. Regarding CPS-2, its structure was previously reported for L.casei, and it presents the tetrasaccharide repeat 2)-α-l-Rha-(1→2)-α-l-Rha-(1→3)-α-l-Rha-(1→3)-α-d-GalNAc-(1→ as backbone, where the first Rha is substituted with a trisaccharide made of Rha, GlcNAc and Glc, and the third Rha has a Glc as a non-stoichiometric substituent. Preliminary in-vitro immunological analyses disclosed that the two glycans exert different activities. CPS-1 is superior to CPS-2 for the elicitation of IL-33, an interleukin that alerts the immune system to tissue damage or danger. CPS-2 instead is more efficient than CPS-1 in the elicitation of the antimicrobial peptides LL-37 and HBD-2, and it is a strong elicitor of occludin, a protein of the tight junctions relevant for the epithelium integrity. These findings suggest that L.paracasei CPSs play a synergistic and beneficial role in the gut, thus paving the way to studies aimed to examine their mode of action or their exploitation in the prevention and treatment of human gastrointestinal diseases. Show less

Osteoglophonic Dysplasia (OGD) is an autosomal dominant skeletal dysplasia characterized by impaired bone growth resulting in short stature, severe craniofacial abnormalities, and in some patients FGF23-mediated hypophosphatemia. It is caused by gain-of-function variants in FGFR1, particularly in or near the transmembrane domain of the receptor. We used CRISPR in mice to knock-in the FGFR1 p.N330I variant, chosen based on its association with FGF23 excess. Skeletal phenotyping of this Show less

Disorders of pubertal onset and progression are a common cause for referral to paediatric endocrinologists, with delayed puberty in males being particularly frequent. Pubertal development depends on the hypothalamic-pituitary-testicular (HPT) axis, which is established during fetal life and undergoes distinct phases: fetal androgen production, postnatal "minipuberty", and reactivation during adolescence. Key regulators include GnRH neurons, Sertoli and Leydig cells, and biomarkers such as AMH, inhibin B, testosterone and INSL3. Puberty is marked clinically by testicular enlargement beyond 4 mL, usually at a median age of 11.5 years. Delayed puberty is defined as absence of testicular enlargement by age 14. The most common cause is self-limited delayed puberty (SLDP), often familial and benign. Functional hypogonadotropic hypogonadism due to chronic illness, and permanent central hypogonadism (congenital or acquired), account for additional cases. Congenital hypogonadotropic hypogonadism (CHH), including Kallmann syndrome, is frequently genetic, with variants in genes such as FGFR1, ANOS1 and GNRHR. Clinical assessment includes family history, growth patterns, and red flags such as micropenis, cryptorchidism or anosmia. Show less

In a phase II study, letrozole/abemaciclib demonstrated an objective response rate of 30% and a median progression-free survival (PFS) of 9.1 months in recurrent estrogen receptor-positive endometrial cancer (EC). While tissue-based tumor profiling revealed several mechanistically relevant candidate baseline genomic predictors of response, circulating tumor DNA (ctDNA) is a less invasive alternative to monitor therapeutic efficacy and define acquired resistance. Serial plasma specimens were obtained at baseline, C2D1, C3D1, C8D1, the time of objective response, and the time of progression. Samples were analyzed using the Guardant Reveal assay to assess methylation-based tumor fraction (TF), with the Guardant360 assay providing genotyping of >700 genes in samples with detectable ctDNA. Treatment response was assessed using a measure of the relative change in TF pre- versus on-treatment. A total of 99 of 102 (97%) samples from 28 patients were successfully analyzed. Patients with above median baseline TF exhibited worse median PFS (2.0 months Baseline and on-treatment ctDNA dynamics may provide an early indication of benefit from letrozole/abemaciclib in EC. ctDNA at the time of progression may identify resistance alterations that may inform subsequent therapy. Show less

Which phenotypes can be confidently linked to a genetic etiology in males with congenital hypogonadotropic hypogonadism (CHH) resulting in absent or arrested puberty? In this systematic review and reclassification of the disease-causing potential of gene variants using the recommendations of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), we found that absent or arrested puberty in males with CHH was linked to 93 genes, of which 29 were unequivocally disease-causing. The number of genes and phenotype characterizations associated with CHH in males has rapidly increased since the advent of next-generation sequencing technologies; however, the quality of the evidence for the interpretation of the causal relationship of gene variants is limited due to the lack of systematic criteria applied to the assessment of the pathogenic potential of the variants. We performed a systematic review of original articles indexed in PubMed until 5 October 2022 and using the search terms '(('hypogonadotropic hypogonadism' OR Kallmann) AND (sequencing OR mutation OR variant))' limited to 'Humans' and 'English'. After two investigators undertook the literature search independently, titles and abstracts of all records were reviewed by four of the authors to identify those articles to be included in the full-text review. Clinical data and the association with gene variants were extracted from males with delayed or arrested puberty due to CHH according to the article authors' criteria. Raw sequence variant information was used to reevaluate their pathogenic potential applying the ACMG/AMP guidelines for variant classification with InterVar. Subsequently, we considered the phenotype specificity criteria for sequence variant pathogenicity classification, based on curated genes associated with CHH, and classified patients into three categories: with monogenic disease-causing variants in genes associated with CHH, with variants in genes whose causality is unclear, and with variants that are not disease-causing. From a total of 1083 records, we included 245 publications with 775 male patients with CHH resulting in absent or arrested puberty, carrying 1001 variants in 93 genes. Gene variants were detected by Sanger sequencing in 61.8% of the cases and by next-generation sequencing (NGS) technologies in the rest. After variant reclassification of causality, 278 individuals were not considered to have a bona fide disease-causing gene variant, and 497 patients were reclassified as carrying at least one disease-causing variant associated with CHH. They carried 503 different disease-causing variants in 29 genes. Spontaneous puberty was absent in 85.5% and arrested in 14.5% of the 497 individuals with CHH carrying bona fide disease-causing variants. In males with absent puberty (complete hypogonadotrophic hypogonadism), FGFR1 and ANOS1 were the most frequently affected genes, accounting for 53.5% of the disease-causing variants. In males with incomplete spontaneous puberty (partial hypogonadotrophic hypogonadism), variants in FGFR1, NR0B1, and GNRHR were found in 70.3% of the cases. Micropenis, cryptorchidism and/or low testicular volume, considered 'red flags' for the diagnosis of CHH, were found in less than 30% of males, with cryptorchidism being more frequently observed in association with variants in FGFR1, ANOS1, KISS1R, SOX10, and GNRH1, and micropenis being more prevalent in patients with variants in TACR3, KISS1R, or GNRH1. Clinical manifestations in non-reproductive organs were found in 39.8% of the patients with bona fide disease-causing variants. Because we included studies going back to the initial genetic reports of patients with CHH, results obtained by Sanger sequencing represent a significant proportion of the whole sample, which may be biased by the use of a candidate gene strategy. A subanalysis of cases studied by NGS modified the results only slightly. This comprehensive synthesis will help clinicians in the guidance of reverse phenotyping once the precise genetic diagnosis is established, and researchers in the design of functional studies to clarify the role of specific sequence variants in the etiology of male CHH. A genetic etiology of CHH in males with absent or arrested puberty should be considered even in the absence of micropenis, cryptorchidism, and/or low testicular volume. This work was partially funded by grants PICT I-A-2018-02972 of Fondo de Promoción Científica y Técnica (FONCYT), PICT A-CAT III2021-73 of Fondo Argentino Sectorial (FONARSEC) and Proyectos de Redes Federales de Alto Impacto 2023 #3 of Ministerio de Ciencia, Tecnología e Innovación, Argentina. Competing interests: None declared. None declared. Show less

Understanding the immunopathogenesis of COVID-19 has yielded valuable insights into predicting adverse outcomes-particularly mortality. However, significant gaps persist in our comprehension of the complex interplay among the proposed pathophysiological mechanisms. Here, we aim to investigate the immunological factors associated with mortality in critically ill, unvaccinated COVID-19 patients admitted to the intensive care unit (ICU). We conducted a single-center, prospective study involving 56 unvaccinated COVID-19 patients admitted to the ICU. Plasma cytokine levels at admission were quantified using enzyme-linked immunosorbent assay (ELISA). Continuous variables were presented as median (IQR), and categorical variables as frequencies and percentages. Non-parametric tests assessed group differences. Logistic regression and receiver operating characteristic (ROC) curve analyses identified predictors of mortality, with bootstrapping (1000 re-samplings; 95 % BCa CI) applied for model validation. Deceased patients exhibited significantly higher levels of interleukin (IL)-1β, IL-2, IL-6, transforming growth factor (TGF)-β, and interferon (IFN)-γ compared to survivors. Conversely, IL-10 and IL-27 were associated with favorable outcomes. Logistic regression modeling identified elevated IL-2 and IFN-γ levels as significant predictors of mortality. Notably, individual ROC curve analyses demonstrated that IL-1β and TGF-β had excellent discriminatory ability for mortality, while IFN-γ, IL-2, and IL-27 showed very good to excellent discriminatory capacity. Our results indicate that distinct cytokine profiles differentiate survivors from non-survivors in critically ill, unvaccinated COVID-19 patients. These findings highlight the importance of cytokine dysregulation in severe COVID-19 cases and suggest potential targets for prognostic approaches. Further research is warranted to validate these results and translate them into effective clinical management strategies. Show less

Models for estimating the risk of sudden cardiac death (SCD) in pediatric hypertrophic cardiomyopathy (HCM) used in our setting do not consider some parameters of routine clinical practice. The objective was to identify non-classical risk factors and evaluate their prognostic value. Retrospective observational study, including patients with isolated HCM 0-18 years old, evaluating clinical, genetic, and imaging variables. The risk of SCD or major arrhythmic cardiac events (MACEs) was estimated according to the three most widely used European models (HCM Risk-SCD, European Society of Cardiology [ESC] algorithm, and HCM Risk-Kids), analyzing their predictive capacity by adding genotyping and advanced cardiac imaging parameters. The sample included 77 patients followed up for 5.25 years. Ten (13%) experienced a MACE. We found that MACE was significantly associated with myocardial deformation and positive genotype status, and associated, although not significantly, to late gadolinium enhancement (LGE) in cardiac MRI (P = .062). Events were more frequent (hazard ratio = 18.5; P = .006) and occurred earlier (P = .022) in association with variants in genes other than MYBPC3. The inclusion of "genotype other than MYBPC3" and "presence of LGE" improved the predictive capacity of the models for the high-risk (C-statistic 0.94 vs 0.84 with HCM Risk-SCD; 0.88 vs 0.74 with ESC algorithm; 0.90 vs 0.80 with HCM Risk-Kids) and intermediate-risk categories (C-statistic 0.88 vs 0.51 with HCM Risk-SCD; 0.85 vs 0.64 with ESC algorithm; 0.84 vs 0.51 with HCM Risk-Kids). The predictive capacity of European risk models improves by incorporating the variables "genotype other than MYBPC3" and "presence of LGE", although larger studies are required to validate their prognostic value. Show less

Although it has been shown that the tumor extracellular matrix (ECM) may sustain the cancer stem cell (CSC) niche, its role in the modulation of CSC properties remains poorly characterized. To elucidate this, paired tumor and adjacent normal mucosa, derived from colon cancer patients' surgical resections, were decellularized and recellularized with two distinct colon cancer cells, HT-29 or HCT-15. Methods: The matrix impact on cancer stem cell marker expression was evaluated by flow cytometry and qRT-PCR, while transforming growth factor-β (TGF-β) secretion and matrix metalloprotease (MMP) activity were quantified by ELISA and zymography. Results: In contrast to their paired normal counterparts, the tumor decellularized matrices enhanced HT-29 expression of the pluripotency and stemness genes Show less

Studies addressing the methylation pattern in adamantinomatous craniopharyngioma (ACP) are lacking. To identify methylation signatures in ACPs regarding clinical presentation and outcome. Clinical and pathology data were collected from 35 patients with ACP (54% male; 18.1 years [2-68]). CTNNB1 mutations and methylation profile (MethylationEPIC/Array-Illumina) were analyzed in tumoral DNA. Unsupervised machine learning analysis of this comprehensive methylome sample was achieved using hierarchical clustering and multidimensional scaling. Statistical associations between clusters and clinical features were achieved using the Fisher test and global biological process interpretations were aided by Gene Ontology enrichment analyses. Two clusters were revealed consistently by all unsupervised methods (ACP-1: n = 18; ACP-2: n = 17) with strong bootstrap statistical support. ACP-2 was enriched by CTNNB1 mutations (100% vs 56%, P = .0006), hypomethylated in CpG island, non-CpG Island sites, and globally (P < .001), and associated with greater tumor size (24.1 vs 9.5 cm3, P = .04). Enrichment analysis highlighted pathways on signaling transduction, transmembrane receptor, development of anatomical structures, cell adhesion, cytoskeleton organization, and cytokine binding, and cell type-specific biological processes as regulation of oligodendrocytes, keratinocyte, and epithelial cells differentiation. Two clusters of patients with ACP were consistently revealed by unsupervised machine learning methods, with one of them significantly hypomethylated, enriched by CTNNB1 mutated ACPs, and associated with increased tumor size. Enrichment analysis reinforced pathways involved in tumor proliferation and in cell-specific tumoral microenvironment. Show less

The early initiation of binge-drinking and biological sex are critical risk factors for the development of affective disturbances and cognitive decline, as well as neurodegenerative diseases including Alzheimer's disease. Further, a history of excessive alcohol consumption alters normal age-related changes in the pattern of protein expression in the brain, which may relate to an acceleration of cognitive decline. Here, we aimed to disentangle the interrelation between a history of binge-drinking during adolescence, biological sex and normal aging on the manifestation of negative affect, cognitive decline and associated biochemical pathology. To this end, adolescent male and female C57BL/6J mice (PND 28-29) underwent 30 days of alcohol binge-drinking using a modified drinking-in-the-dark (DID) paradigm. Then, mice were assayed for negative affect, sensorimotor gating and cognition at three developmental stages during adulthood-mature adulthood (6 months), pre-middle age (9 months) and middle age (12 months). Behavioural testing was then followed by immunoblotting to index the protein expression of glutamate receptors, neuropathological markers [Tau, p (Thr217)-Tau, p (Ser396)-Tau, BACE, APP, Aβ], as well as ERK activation within the entorhinal cortex, prefrontal cortex and amygdala. Across this age span, we detected only a few age-related changes in our measures of negative affect or spatial learning/memory in the Morris water maze and all of these changes were sex-specific. Prior adolescent binge-drinking impaired behaviour only during reversal learning in 9-month-old females and during radial arm maze testing in 12-month-old females. In contrast to behaviour, we detected a large number of protein changes related to prior binge-drinking history, several of which manifested as early as 6 months of age, with the prefrontal cortex particularly affected at this earlier age. While 6-month-old mice exhibited relatively few alcohol-related protein changes within the entorhinal cortex and amygdala, the number of alcohol-related protein changes within the entorhinal cortex increased with age, while the 12-month-old mice exhibited the largest number of protein changes within the amygdala. Approximately a third of the alcohol-related protein changes were sex-selective. Taken together, the results of our longitudinal study using a murine model of binge-drinking indicate that a prior history of heavy alcohol consumption, beginning in adolescence, is sufficient to induce what we presume to be latent changes in protein indices of cellular activity, glutamate transmission and neuropathology within key brain regions governing cognition, executive function and emotion that appear to precede the onset of robust behavioural signs of dysregulated affect and cognitive impairment. Show less

Tenosynovial giant cell tumor is a benign neoplasm arising from the synovium of joints, including the temporomandibular joint (TMJ). Despite its benign nature, these tumors may exhibit aggressive behavior. A 57-year-old woman with a swollen, hardened area in the left TMJ was referred to the university´s clinic. The diagnosis of tenosynovial giant cell tumor was made based on the presence of hyperplastic synovial lining containing mononuclear and giant cells, hemorrhagic areas, hemosiderin deposits, and calcification foci in the biopsy. A low condylectomy was performed, and histopathologic analysis of the surgical piece upheld the diagnosis. Due to histopathologic resemblance with other giant cell-rich lesions (giant cell granuloma of the jaws, brown tumor of hyperparathyroidism, and non-ossifying fibroma) for which signature mutations are known, mutational analysis of KRAS, FGFR1, and TRPV4 genes was conducted. The results revealed wild-type sequences for all the mutations tested, thereby supporting the diagnosis of tenosynovial giant cell tumor. Show less

Hypertriglyceridemia (HTG) is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. It is well stablished that the severe cases of disease often present with an underlying genetic cause. In this study, we determined the frequency and variation spectrum of genes involved in the triglyceride metabolism in a series of Brazilian patients with severe HTG. A total of 212 patients with very high HTG, defined with fasting triglycerides (TG) ≥ 880 mg/ dL, that underwent a multi-gene panel testing were included in this research. Germline deleterious variants (i.e. Pathogenic/Likely Pathogenic (P/LP) variants) were identified in 28 out of 212 patients, reflecting an overall diagnostic yield of 13% in our cohort. Variants of unknown significance (VUS) were identified in 87 patients, and represent 80% of detected variants in this dataset. We confirm the Show less

Tocilizumab (TCZ) treatment is associated with dyslipidaemia, including a rise in triglycerides through a mechanism poorly understood. Three molecules play key roles in the regulation of triglyceride metabolism: apolipoprotein C-III (ApoC-III), angiopoietin-like protein 4(ANGPLT4) and lipoprotein lipase (LPL). The aim of this work was to analyse whether the changes in triglycerides shown by TCZ-treated RA patients could stem from the dysregulation that can occur in these regulatory molecules. Twenty-seven RA patients included in the TOCRIVAR study who received TCZ (8 mg/kg IV/q4w) were evaluated at baseline and at Weeks 12, 24 and 52 of treatment. ANGPTL4, ApoC-III and LPL, a complete lipid profile and RA disease activity, were analysed at baseline and at each visit. Multivariable linear mixed models were performed to study changes over time in lipids and regulatory molecules. After 24 weeks of TCZ treatment, HDL cholesterol, apolipoprotein A1 and triglycerides increased, whereas lipoprotein (a) decreased significantly from baseline values. However, 1 year after TCZ, no significant differences in lipid pattern were observed with respect to baseline. Serum ANGPTL4 and Apo-CIII levels decreased gradually over time, both being significantly lower than baseline values at Week 52. LPL concentration did not change significantly during TCZ treatment. Remarkably, the elevation of triglycerides at Week 24 maintained its statistical significance after adjusting for the changes in ApoC-III, ANGPTL4 and LPL. In TCZ-treated RA patients basal serum levels of ANGPLT4 and ApoC-III, but not LPL, decreased significantly. However, the elevation of triglycerides after TCZ was not related to changes in these regulatory molecules. Show less

Mutations or triplication of the alpha synuclein (ASYN) gene contribute to synucleinopathies including Parkinson's disease (PD), Dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Recent evidence suggests that ASYN also plays an important role in amyloid-induced neurotoxicity, although the mechanism(s) remains unknown. One hypothesis is that accumulation of ASYN alters endolysosomal pathways to impact axonal trafficking and processing of the amyloid precursor protein (APP). To define an axonal function for ASYN, we used a transgenic mouse model of synucleinopathy that expresses a GFP-human ASYN (GFP-hASYN) transgene and an ASYN knockout (ASYN Show less

Obesity and overweight are worldwide public health problems with an evident genetic predisposition that is still poorly understood. In addition, great variability has been described across populations. In this work, we analyzed the association of variants in four genes: PPARG (rs1801282), PPARGC1A (rs8192678), FTO (rs9939609) and MC4R (rs17782313) with overweight and obesity in a large sample of the Brazilian population. The case-control study involved 4084 individuals (1844 with overweight or obesity; and 2240 with normal BMI). Genotyping was performed by quantitative PCR. MC4R rs17782313-C was associated with obesity (OR = 1.27, p = 0.038) and when stratifying by sex associated only in women (OR = 1.36, p = 0.030). FTO rs9939609-A allele was associated with overweight however for women it represented a risk factor (OR = 1.24, p = 0.034) and for men, a protective factor (OR = 0.68, p = 0.033). PPARG was the strongest associated gene, with both overweight and obesity, and this association was also restricted to women (rs1801282-GG OR = 1.46, p = 0.027). The combined effect of the three risk alleles on overweight and obesity had an OR of 1.65 (p = 0.008) and when stratifying by sex again it was significant only in females (OR = 1.95, p = 0.0028). Our findings indicate that the three genes play a significant role in predisposing to overweight and/or obesity in the Brazilian population, reaching together a relatively high impact on these traits. Interestingly our results also suggest a strong sex-specific genetic effect of these variants. Show less

Schistosomiasis and Leishmaniasis are chronic parasitic diseases with high prevalence in some tropical regions and, due to their wide distribution, a risk of co-infections is present in some areas. Nevertheless, the impact of this interaction on human populations is still poorly understood. Thus, the current study evaluated the effect of previous American Tegumentary Leishmaniasis (ATL) on the susceptibility and immune response to Show less

Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy (LVH) and is one of the major causes of sudden cardiac death (SCD). An exon-targeted gene sequencing strategy was used to investigate the association of functional variants in sarcomeric genes (MYBPC3, MYH7 and TNNT2) with severe LVH and other SCD-related risk factors in Brazilian HCM patients. Clinical data of 55 HCM patients attending a Cardiology Hospital (Sao Paulo city, Brazil) were recorded. Severe LVH, aborted SCD, family history of SCD, syncope, non-sustained ventricular tachycardia and abnormal blood pressure in response to exercise were evaluated as SCD risk factors. Blood samples were obtained for genomic DNA extraction and the exons and untranslated regions of the MYH7, MYBPC3 and TNNT2 were sequenced using Nextera® and MiSEq® reagents. Variants were identified and annotated using in silico tools, and further classified as pathogenic or benign according to the American College of Medical Genetics and Genomics guidelines. Variants with functional effects were identified in MYBPC3 (n = 9), MYH7 (n = 6) and TNNT2 (n = 4). The benign variants MYBPC3 p.Val158Met and TNNT2 p.Lys263Arg were associated with severe LVH (p < 0.05), and the MYH7 p.Val320Met (pathogenic) was associated with family history of SCD (p = 0.037). Increased risk for severe LVH was found in carriers of MYBPC3 Met158 (c.472 A allele, OR = 13.5, 95% CI = 1.80-101.12, p = 0.011) or combined variants (MYBPC3, MYH7 and TNNT2: OR = 12.39, 95% CI = 2.14-60.39, p = 0.004). Carriers of TNNT2 p.Lys263Arg and combined variants had higher values of septum thickness than non-carriers (p < 0.05). Molecular modeling analysis showed that MYBPC3 158Met reduces the interaction of cardiac myosin-binding protein C (cMyBP-C) RASK domain (amino acids Arg215-Ala216-Ser217-Lys218) with tropomyosin. In conclusion, the variants MYBPC3 p.Val158Met, TNNT2 p.Lys263Arg and MYH7 p.Val320Met individually or combined contribute to the risk of sudden cardiac death and other outcomes of hypertrophic cardiomyopathy. Show less

The aim of this pilot study was to analyze the serum proteomic profile of women suffering from menstrual-related migraine (MM group, n = 15) and migraine in post-menopause (PM group, n = 15) in comparison with non-headache control females (C group, n = 15). Serum samples were subjected to two-dimensional gel electrophoresis (2-DE) followed by mass spectrometry (MS) analysis for protein identification. Based on 2D-gel maps and PDQuest 2-D software, 13 differentially expressed spots, corresponding to 12 unique proteins identified by Liquid Chromatography-Electrospray Ionization-Quadrupole-Time of Flight/tandem mass spectrometry (LC-ESI-QToF-MS/MS), were detected in the MM and PM groups vs C group. Five inflammatory and regulatory of vascular integrity proteins (prothrombin, serum amyloid P-component, Ig kappa chain C region, apolipoprotein A-I, serum amyloid A-4 protein) were found deregulated in both MM and PM groups compared to C group; MM group showed the upregulation of other inflammatory protein fragments (inter-alpha-trypsin inhibitor heavy chain H4 and complement C4-A) compared to C group; PM group, in comparison with C group, displayed a noteworthy upregulation of transthyretin and other deregulated proteins (tetranectin, alpha-1-antitrypsin, haptoglobin, apolipoprotein A-IV) playing a role in anti-inflammatory and reparative processes. In conclusion, proteomic analysis was able to reveal differences in protein expression between migraine sufferers and non-headache women; as in other neurological diseases characterized by neuroinflammation, the serum proteome of migraine women presents an abundance of proteins indicative of cellular damage, oxidative stress and inflammation. This relevant inflammatory status, if confirmed in larger series, could represent a target for menstrual-related migraine treatment. Show less

Interleukin-27, a cytokine of the IL-12 family, is secreted by antigen-presenting cells such as macrophages and dendritic cells (DCs). Recent studies suggest an anti-inflammatory role for IL-27 by inducing IL-10 producing Tr1 cells capable of inhibiting Th1 and Th17 type responses. Our study aimed to investigate the involvement of IL-27 and Tr1 cells in the immunomodulation of paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Brazil. The presence of IL-27 was evaluated in serum and biopsies of patients with PCM by ELISA, immunohistochemistry, and immunofluorescence. The presence of Tr1 in peripheral blood was analyzed by flow cytometry. In vitro assays were performed to verify the ability of P. brasiliensis yeast to induce IL-27 production by DCs and macrophages, as well as the polarization of lymphocytes to the Tr1 phenotype. Patients with the acute form and severe chronic form, the most severe and disseminated forms of PCM, presented higher serum concentrations of IL-27 and higher percentage of Tr1 cells compared to patients with mild chronic form. IL-27 was also detected in lesions of patients with PCM and associated with DCs and macrophages. P. brasiliensis Pb18 yeasts were able to induce IL-27 production by both DCs and macrophages. We found that DCs pulsed with Pb18 were able to induce Tr1 lymphocytes in vitro. Our data suggest that IL-27 and Tr1 cells could contribute to the deficient immune response to P. brasiliensis that leads to severe and disseminated forms of the disease. Show less

DUSP6/MKP3 is a dual-specific phosphatase that regulates extracellular regulated kinase ERK1/2 and ERK5 activity, with an increasingly recognized role as tumor suppressor. In silico studies from Gene expression Omnibus (GEO) and Cancer Genome atlas (TCGA) databases reveal poor prognosis in those Non-small cell lung cancer (NSCLC) patients with low expression levels of Show less

Aberrant formation of blood vessels precedes a broad spectrum of vascular complications; however, the cellular and molecular events governing vascular malformations are not yet fully understood. Here, we investigated the role of CDC42 (cell division cycle 42) during vascular morphogenesis and its relative importance for the development of cerebrovascular malformations. To avoid secondary systemic effects often associated with embryonic gene deletion, we generated an endothelial-specific and inducible knockout approach to study postnatal vascularization of the mouse brain. Postnatal endothelial-specific deletion of Cdc42 elicits cerebrovascular malformations reminiscent of cerebral cavernous malformations (CCMs). At the cellular level, loss of CDC42 function in brain endothelial cells (ECs) impairs their sprouting, branching morphogenesis, axial polarity, and normal dispersion within the brain tissue. Disruption of CDC42 does not alter EC proliferation, but malformations occur where EC proliferation is the most pronounced during brain development-the postnatal cerebellum-indicating that a high, naturally occurring EC proliferation provides a permissive state for the appearance of these malformations. Mechanistically, CDC42 depletion in ECs elicited increased MEKK3 (mitogen-activated protein kinase kinase kinase 3)-MEK5 (mitogen-activated protein kinase kinase 5)-ERK5 (extracellular signal-regulated kinase 5) signaling and consequent detrimental overexpression of KLF (Kruppel-like factor) 2 and KLF4, recapitulating the hallmark mechanism for CCM pathogenesis. Through genetic approaches, we demonstrate that the coinactivation of Klf4 reduces the severity of vascular malformations in Cdc42 mutant mice. Moreover, we show that CDC42 interacts with CCMs and that CCM3 promotes CDC42 activity in ECs. We show that endothelial-specific deletion of Cdc42 elicits CCM-like cerebrovascular malformations and that CDC42 is engaged in the CCM signaling network to restrain the MEKK3-MEK5-ERK5-KLF2/4 pathway. Show less

High-fat (HF) and rapid digestive (RD) carbohydrate diets during pregnancy promote excessive adipogenesis in offspring. This effect can be corrected by diets with similar glycemic loads, but low rates of carbohydrate digestion. However, the effects of these diets on metabolic programming in the livers of offspring, and the liver metabolism contributions to adipogenesis, remain to be addressed. In this study, pregnant insulin-resistant rats were fed high-fat diets with similar glycemic loads but different rates of carbohydrate digestion, High Fat-Rapid Digestive (HF-RD) diet or High Fat-Slow Digestive (HF-SD) diet. Offspring were fed a standard diet for 10 weeks, and the impact of these diets on the metabolic and signaling pathways involved in liver fat synthesis and storage of offspring were analyzed, including liver lipidomics, glycogen and carbohydrate and lipid metabolism key enzymes and signaling pathways. Livers from animals whose mothers were fed an HF-RD diet showed higher saturated triacylglycerol deposits with lower carbon numbers and double bond contents compared with the HF-SD group. Moreover, the HF-RD group exhibited enhanced glucose transporter 2, pyruvate kinase (PK), acetyl coenzyme A carboxylase (ACC) and fatty acid (FA) synthase expression, and a decrease in pyruvate carboxylase (PyC) expression leading to an altered liver lipid profile. These parameters were normalized in the HF-SD group. The changes in lipogenic enzyme expression were parallel to changes in AktPKB phosphorylation status and nuclear expression in carbohydrate-response element and sterol regulatory element binding proteins. In conclusion, an HF-RD diet during pregnancy translates to changes in liver signaling and metabolic pathways in offspring, enhancing liver lipid storage and synthesis, and therefore non-alcoholic fatty liver disease (NAFLD) risk. These changes can be corrected by feeding an HF-SD diet during pregnancy. Show less

Nut consumption is associated with reduced risks of cardiovascular disease. Baru almonds have a high protein content and high quantities of mono- and polyunsaturated fatty acids, phenolic compounds, and antioxidants. This study aimed to evaluate the effects of a baru almond-enriched diet on body composition and markers of lipid metabolism in overweight and obese women. A randomized, placebo-controlled, 8-wk clinical trial of 46 overweight and obese women was conducted. Participants were randomly assigned to 1 of 2 normocaloric and isoenergetic diets: baru almond-enriched diet or baru almond-free diet. Both groups received dietary instructions. Body composition was assessed by anthropometry and dual-energy x-ray absorptiometry. Blood pressure, glucose levels, lipid profile, and plasma fatty acids, as well as apolipoproteins, angiopoietin-like-3, and cholesteryl ester transfer protein expression, were determined at the beginning and end of the study. The consumption of baru almonds reduced waist circumference (-2.45 cm; 95% confidence interval [CI], -3.90 to -0.23; P = 0.03), cholesteryl ester transfer protein expression (-0.23 mcg/mL; 95% CI, -1.24 to-0.08; P = 0.03), and increased high-density lipoprotein concentrations (+4.82 mg/dL; 95% CI, 0.03-8.88; P = 0.04) compared with baru almond-free diet. A baru almond-enriched diet for 8-wk reduced abdominal adiposity and improved high-density lipoprotein in overweight and obese women. This trial was registered at clinicaltrials.gov as RBR-2 wpryx. Show less