👤 João Pedro Ferreira

Peripheral nerve injuries (PNI) often lead to long-term functional impairment. Mesenchymal stem cells (MSCs) and cannabidiol (CBD) have shown anti-inflammatory and neuroprotective effects in vitro, which may be relevant for PNI research. The aim of this study was to evaluate CBD-rich cannabis extract’s potential to induce anti-inflammatory and neurotrophic gene expression in equine adipose tissue-derived MSCs (EqAT-MSCs) in an inflammatory in vitro environment. The morphology and metabolic activity of EqAT-MSCs ( Show less

Auricular vagus nerve stimulation (aVNS) has emerged as a noninvasive neuromodulatory strategy with the potential to modulate central sensitization and inflammatory pathways. However, its role in fibromyalgia (FM) remains insufficiently explored. To investigate whether stimulation laterality (left vs. right auricular branch of the vagus nerve, ABVN) differentially influences clinical and biological outcomes in women with FM. In this randomized, double-blind, sham-controlled trial, 51 women with FM were allocated to sham stimulation, right-sided aVNS (aVNS-R), or left-sided aVNS (aVNS-L). Participants underwent weekly sessions for four weeks and were followed for 12 weeks. Pain intensity was the primary outcome. Secondary outcomes included psychological symptoms, sleep, functional status, quality of life, and circulating biomarkers (pro- and anti-inflammatory cytokines, brain-derived neurotrophic factor [BDNF]). While no significant between-group differences were observed in pain intensity, left-sided stimulation (aVNS-L) was associated with a modest but significant reduction in global symptom severity. Importantly, aVNS-L produced consistent immunomodulatory effects, including decreased IL-1β and TNF-α levels, and increased IL-4, IL-10, and BDNF concentrations. This exploratory trial suggests that stimulation laterality may shape the biological response to aVNS in FM. Although clinical pain relief was not superior to sham, left-sided stimulation promoted an anti-inflammatory profile and enhanced neuroplasticity markers. These findings support further investigation of aVNS laterality as a targeted neuromodulatory approach for FM. Brazilian Clinical Trials Registry RBR-10d3crcf. Show less

Neurodegenerative diseases such as Huntington's Disease (HD) have a significant impact on healthcare accessibility and costs. A fatal genetic condition, characterized by the progressive loss of striatal neurons, HD is hindered by the lack of endogenous repair in the adult brain. Recent efforts toward protecting neural circuits through neurotrophic support using brain-derived neurotrophic factor (BDNF) have been suboptimal due to the protein's short half-life and limited diffusion. Addressing this, adeno-associated viral vectors (AAV) can be employed as a delivery tool to spatially transduce cells, enabling the localised production of BDNF with consequential neuron protection and/or plasticity, yet present their own constraints. To overcome these known challenges of AAV gene delivery, an injectable, physiologically stable hydrogel-mimic of the brain's extracellular matrix was fabricated to encapsulate the AAVs. This smart system both shielded and constrained the AAV; optimising transfection and therefore elevated and sustained BDNF presentation at the target site. Here, we achieved high neuroprotection using AAVDJ-BDNF delivered through a hydrogel formed via self-assembling peptide nanoscaffolds. These findings support the notion that the spatiotemporal release of BDNF to striatal neurons, facilitated by engineered biomaterial delivery systems, demonstrates tremendous promise by enhancing the efficacy of gene therapy targeted at slowing neurodegenerative disease progression. Show less

IntroductionAging and metabolic disease enhance inhaled particulate toxicity. Nanoparticles (NPs) are rapidly coated with biomolecules forming a biocorona (BC), upon entering the body and may contribute to the susceptibility. Aging and metabolic syndrome (MetS) are progressive conditions resulting in biomolecule alterations over time potentially influencing susceptibility. We hypothesize NP-biomolecule interactions are altered during aging and throughout MetS progression.MethodsC57BL/6J mice at 6 weeks of age were fed a healthy diet or a high-fat western diet. BALF was collected after 2, 4, 8, 12, 16, 20 or 24 weeks on diets. NP-biomolecules interactions were compared between healthy and MetS to determine age- and disease progression-related BC variations (proteins and lipids).ResultsUnique BCs were determined to form at each time point indicative of aging for the healthy and aging and disease progression for the MetS. Comparisons between healthy and MetS BCs at each time demonstrated distinct biomolecule interactions attributable to disease. Comparisons determined both unique protein and lipid content as well as quantitative differences. Proteins such as apolipoprotein A-IV, complement C3 and lipids such as PE (37:5), PE (O-38:5), PE (P-38:4), PC(40:7), PC(39:0), and PC(O-40:0) were identified on the MetS BC suggesting disease progression modifications. Proteins such as pulmonary surfactant protein A, fibrinogen alpha-chain and lipids such as CE (19:0)-NH4, DG (36:7), and DG (35:0)_C18:0 were increasingly present in the healthy BC over time, suggesting age-related interactions.DiscussionOverall, unique BCs were identified demonstrating the impact of age and disease progression on BC formation which will aid in understanding initial pulmonary NP-biomolecular interactions potentially contributing to susceptibility. Show less

Brain atrophy subtypes are increasingly recognized in Alzheimer’s disease (AD) dementia. However, their relevance across the real-world memory clinic spectrum, from subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) to AD and non-AD dementias, remains unclear. This cross-sectional study aimed to identify MRI-based atrophy subtypes in a relatively young memory clinic and examine associations with demographic, cerebrospinal fluid (CSF) biomarkers, and cerebrovascular burden to inform precision medicine approaches. We included all consecutive patients (SCI to dementia), evaluated at the Karolinska University-Hospital Memory Clinic (Stockholm, Sweden) between 2018 and 2023 with available clinical and 3T MRI data. Subtypes were defined using FreeSurfer-derived volumetric measures and a validated algorithm combining categorical classification (typical, limbic predominant, cortical predominant, minimal atrophy) with continuous indices of typicality (cortical predominant–limbic predominant) and severity (minimal atrophy–typical). Demographics, cognitive profiles, Among 809 patients (median age 60.0 years [interquartile-range 56.0–63.0], 56.1% female), 38.2% had SCI, 44.4% MCI, and 17.4% dementia. CSF biomarkers were available in 596 (73.7%). Limbic predominant and typical subtypes had more males (59.3% and 50.0%, respectively; group-wise p < 0.001), higher APOE ε4 frequency (47.7% and 41.0%, p = 0.02), greater cerebrovascular burden, and poorer memory. These subtypes were more often Aβ positive (46.1% and 46.5%, p = 0.01). A cortical predominant pattern was frequent in females (66.0%, p < 0.001), while minimal atrophy was associated with milder cognitive impairment (49.0% SCI, 45.5% MCI) and higher depressive symptoms. In Aβ-positive patients (n = 231), typical and limbic subtypes had higher p-tau181 (median: 83.0 and 84.5 pg/mL, respectively; p < 0.001), NFL (1120.0 and 1125.0 pg/mL, p < 0.001), and lower Aβ42/40 ratios (0.051 and 0.049, p = 0.02). Findings remained consistent across continuous atrophy measures and in the 14.9% (n = 89) eligible for anti-Aβ therapy. MRI-based atrophy subtypes exhibit distinct clinical and biomarker profiles, consistently observed in Aβ-positive and anti-Aβ-therapy-eligible patients. These findings support their diagnostic utility in memory clinics and relevance for biologically targeted AD trials. The online version contains supplementary material available at 10.1186/s13195-026-01972-2. Show less

Congenital hypogonadotropic hypogonadism (CHH) arises from defects in the synthesis, secretion, or action of gonadotropin-releasing hormone (GnRH), resulting in incomplete or absent pubertal development and various nonreproductive features. CHH is genetically heterogeneous, with over 50 genes implicated in its pathogenesis. This study aimed to elucidate the genetic variants of CHH in a cohort of patients from a single-center endocrinology unit. We used a targeted next-generation sequencing panel to analyze 52 CHH-related genes in 35 patients. Functional studies validated two of the identified variants. Molecular etiology was identified in 20 of 35 (57%) patients. Among these, 12 (39%) had variants in multiple CHH-related genes, with oligogenic inheritance confirmed in two cases. Novel pathogenic variants (both single nucleotide variants and copy number variants) were identified, including ANOS1 p.Gln238* and c.318+2T>C, CHD7 p.Ser734Ilefs5 and p.Gln592Serfs16, FGFR1 p.Ala36Profs67, c.1663+5G>A, and p.Tyr210*, DMXL2 deletion (83.1 Kb), and SOX2 deletion (1.1 Mb). In total, 21 pathogenic or likely pathogenic variants across 15 CHH-related genes were detected, including ANOS1, CHD7, FGFR1, PROKR2, and others. A functional study confirmed the loss of function in the KISS1R p.Ala203Asp variant. Our findings demonstrate the utility of a next-generation sequencing panel in diagnosing genetically complex conditions like CHH and underscore the role of oligogenic inheritance in its phenotypic diversity. The inclusion of genes previously associated with syndromic CHH forms such as CHARGE in the exome panel may highlight possible shared mechanisms with neurodevelopmental disorders, aiding early diagnosis, genetic counseling, and treatment. Show less

Lipoprotein(a) [Lp(a)] is recognized as an independent risk factor for coronary disease owing to its atherogenic, proinflammatory, and prothrombotic properties. Current guidelines recommend a single measurement in adults to refine cardiovascular (CV) risk assessment. We aimed to characterize Lp(a) levels in patients with acute coronary syndrome (ACS) and explore associations with sex, age, comorbidities, and traditional cardiovascular risk factors. We conducted a cross-sectional study of patients with ACS admitted to our center between January 2022 and December 2023, with Lp(a) measured at admission. Patients were stratified into two groups: Lp(a) >100 nmol/L and ≤100 nmol/L. Demographic and clinical data, including traditional cardiovascular risk factors (dyslipidemia, diabetes mellitus, arterial hypertension, smoking, and obesity), were collected from hospital records. Chi-square and independent t or Mann-Whitney U tests were used to compare categorical and quantitative variables; linear regression analysis assessed associations between continuous Lp(a) values and independent variables. Among 903 patients admitted with ACS during the study period, Lp(a) was measured in 388 (42%). Median Lp(a) level was 62.0 [18.4, 153.8] nmol/L. Of these, 38.7% had Lp(a) >100 nmol/L. Women had higher Lp(a) than men (p-trend=0.014). Lp(a) levels were similar across traditional cardiovascular risk factors categories. Among patients without traditional cardiovascular risk factors, women also had higher Lp(a) than men (p=0.003). Elevated Lp(a) was associated with history of coronary artery disease (p-trend=0.003) and with treatment with high-intensity statins alone (p-trend=0.032) or in combination with ezetimibe (p-trend=0.014). Lp(a) levels showed a heterogeneous distribution and was not associated with traditional cardiovascular risk factors or other lipid parameters. This reinforces Lp(a) as an independent risk factor, supporting active screening in patients with ACS, particularly in women not affected by traditional cardiovascular risk factors. Show less

Association studies have linked many genetic variants to a variety of phenotypes but understanding the biological mechanisms underlying these signals remains a major challenge. Since genes operate within complex networks, statistical interactions between genetic mutations that reflect biological pathways are expected to exist. However, their discovery has been hampered by the vast search space of variant combinations and the multiplicatively small expected effect sizes of interactions. To increase power, we created a test for interaction between single-nucleotide polymorphisms (SNPs) and 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

Osteoglophonic dysplasia (OGD) is a rare skeletal disorder caused by certain variants in FGFR1. The FGFR1 gene encodes a receptor vital for osteogenesis in the axial and craniofacial skeleton. Key OGD features include craniosynostosis, craniofacial dysmorphism, impacted teeth, rhizomelic shortening, and nonossifying fibromas. Patients may have hypophosphatemia due to high FGF23 levels. We report two OGD patients with the c.1141T > C FGFR1 variant [p.(Cys381Arg)], initially diagnosed with Pfeiffer syndrome. Both showed classic symptoms as well as signs not previously reported, including elevated frontal temperature and overlapping toes. This report emphasizes distinguishing OGD from similar disorders and expanding the clinical phenotype. Show less

In this study, we aimed to describe the mutations associated with first-line drug resistance in Mycobacterium tuberculosis complex (MTBC) isolates from São Paulo, Brazil, between 2019 and 2021. Mutations in the coding regions of rpoB and katG genes and in the promoter region of the inhA gene in MTBC clinical isolates were detected using the GenoType MTBDRplus assay (LPA). All mutations inferred by LPA were sequenced. Of the 13,489 MTBC isolates with valid LPA results, 657 (4.9%) harbored mutations. The overall prevalence rates of rifampicin-resistant (RIF-R) tuberculosis (TB), isoniazid-resistant (INH-R) TB, and multidrug-resistant (MDR) TB were 1.5, 2.0, and 1.2%, respectively. A significant proportion of RIF-R isolates presented inferred rpoB mutations (89.1%), most of which were the borderline H445N mutation. The inhA promoter C-15T mutation was predominant among the INH-R isolates (52.8%). Most MDR isolates presented rpoB S450L + katG S315T1 mutations. Gene sequencing identified mutations not included in the catalogue of mutations published by the World Health Organization. Phenotypic drug susceptibility testing on isolates with inferred rpoB mutations revealed that the 0.5 µg/mL critical concentration of RIF failed to detect most borderline mutations when using the BACTEC MGIT 960 system. These findings emphasize the need for continuous surveillance and the integration of molecular and phenotypic methods to ensure an accurate detection and management of drug-resistant TB in high-burden settings. Show less

In this study, we analyzed over 500 ST30 genomes from diverse sources, including Brazilian strains sequenced by our team, using genomic, pangenomic, phylogenetic, and time-calibrated phylogenetic analyses. We traced key evolutionary events, estimating that the specialization of PT80/81 and SWP occurred after a divergence around 1868, forming a group of PT80/81-related strains and another group formed by SWP-related strains. Our findings highlight major events involving gene acquisition and loss, as well as mobile genetic elements (MGE). Notably, PT80/81 lost most Our study revises the evolutionary history of ST30 Show less

Variations in lipid profile have been observed in sickle cell disease (SCD) and understanding their relationship with disease severity is crucial. This study aimed to investigate the association of polymorphisms of the CETP gene and laboratory markers of disease severity with lipid profile in a pediatric population with SCD. Biochemical and anthropometric analyses and CETP and alpha-thalassemia genotyping were performed. The study included 133 children and adolescents with sickle cell anemia (SCA) or hemoglobin SC disease (SCC), in steady-state. The SCA and no hydroxyurea (no HU) groups had higher values of ApoB, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) compared to the SCC and HU groups. However, there were no significant differences in ApoA1 and HDL-C levels between the groups based on genotype. Furthermore, the groups with altered levels of ApoA1, HDL-C, and the triglyceride/HDL ratio exhibited lower hemoglobin (Hb) levels and higher white blood cell counts. Hb level was associated to HDL-C levels. Analysis of CETP gene variants showed that the minor alleles of rs3764261 (C>A), rs247616 (C>T), and rs183130 (C>T), as well as the TTA haplotype, are explanatory variables for HDL-C levels. These findings suggested that dyslipidemia in SCD, specifically related to HDL-C levels, may be influenced by individual genetic background. Additionally, further investigation is needed to determine if clinical manifestations are impacted by CETP gene variants. Show less

Progressive exercise intolerance is a hallmark of pulmonary hypertension (pH), severely impacting patients' independence and quality of life (QoL). Accumulating evidence over the last decade shows that combined abnormalities in peripheral reflexes and target organs contribute to disease progression and exercise intolerance. The aim of this study was to review the literature of the last decade on the contribution of the cardiovascular, respiratory, and musculoskeletal systems to pathophysiology and exercise intolerance in pH. A systematic literature search was conducted using specific terms in PubMed, SciELO, and the Cochrane Library databases for original pre-clinical or clinical studies published between 2013 and 2023. Studies followed randomized controlled/non-randomized controlled and pre-post designs. The systematic review identified 25 articles reporting functional or structural changes in the respiratory, cardiovascular, and musculoskeletal systems in pH. Moreover, altered biomarkers in these systems, lower cardiac baroreflex, and heightened peripheral chemoreflex activity seemed to contribute to functional changes associated with poor prognosis and exercise intolerance in pH. Potential therapeutic strategies acutely explored involved manipulating the baroreflex and peripheral chemoreflex, improving cardiovascular autonomic control via cardiac vagal control, and targeting specific pathways such as GPER1, GDF-15, miR-126, and the JMJD1C gene. Information published in the last 10 years advances the notion that pH pathophysiology involves functional and structural changes in the respiratory, cardiovascular, and musculoskeletal systems and their integration with peripheral reflexes. These findings suggest potential therapeutic targets, yet unexplored in clinical trials, that could assist in improving exercise tolerance and QoL in patients with pH. Show less

Cross-language studies suggest more similarities than differences in how dysarthria affects the speech of people with Parkinson's disease (PwPD) who speak different languages. In this study, we aimed to identify the relative contribution of acoustic variables to distinguish PwPD from controls who spoke varieties of two Romance languages, French and Portuguese. This bi-national, cross-sectional, and case-controlled study included 129 PwPD and 124 healthy controls who spoke French or Portuguese. All participants underwent the same clinical examinations, voice/speech recordings, and self-assessment questionnaires. PwPD were evaluated French-speaking and Portuguese-speaking individuals were distinguished from each other with over 90% accuracy by five acoustic variables (the mean fundamental frequency and the shimmer of the sustained vowel /a/ production, the oral diadochokinesis performance index, the relative sound level pressure and the relative sound pressure level standard deviation of the text reading). A distinct set of parameters discriminated between controls and PwPD: for men, maximum phonation time and the oral diadochokinesis speech proportion were the most significant variables; for women, variables calculated from the oral diadochokinesis were the most discriminative. Acoustic variables related to phonation and voice quality distinguished between speakers of the two languages. Variables related to pneumophonic coordination and articulation rate were the more effective in distinguishing PwPD from controls. Thus, our research findings support that respiration and diadochokinesis tasks appear to be the most appropriate to pinpoint signs of dysarthria, which are largely homogeneous and language-universal. In contrast, identifying language-specific variables with the speech tasks and acoustic variables studied was less conclusive. Show less

This study explored the association of deleterious variants in pharmacodynamics (PD) genes with statin response and adverse effects in patients with familial hypercholesterolemia (FH) and analyzed their potential effects on protein structure and stability. Clinical and laboratory data were obtained from 144 adult FH patients treated with statins. A panel of 32 PD genes was analyzed by exon-targeted gene sequencing. Deleterious variants were identified using prediction algorithms and their structural effects were analyzed by molecular modeling studies. A total of 102 variants were predicted as deleterious (83 missense, 8 stop-gain, 4 frameshift, 1 indel, 6 splicing). The variants ABCA1 rs769705621 (indel), LPA rs41267807 (p.Tyr2023Cys) and KIF6 rs20455 (p.Trp719Arg) were associated with reduced low-density lipoprotein cholesterol (LDLc) response to statins, and the LPL rs1801177 (p.Asp36Asn) with increased LDLc response (P < 0.05). LPA rs3124784 (p.Arg2016Cys) was predicted to increase statin response (P = 0.022), and ABCA1 rs769705621 to increase the risk of statin-related adverse events (SRAE) (P = 0.027). LPA p.Arg2016Cys and LPL p.Asn36Asp maintained interactions with solvent, LPA p.Tyr2023Cys reduced intramolecular interaction with Gln1987, and KIF6 p.Trp719Arg did not affect intramolecular interactions. DDMut analysis showed that LPA p.Arg2016Cys and p.Tyr2023Cys and LPL p.Asp36Asn caused energetically favorable changes, and KIF6 p.Trp719Arg resulted in unfavorable energetic changes, affecting protein stability. Deleterious variants in ABCA1, LPA, LPL and KIF6 are associated with variability in LDLc response to statins, and ABCA1 rs769705621 is associated with SRAE risk in FH patients. Molecular modeling studies suggest that LPA p.Tyr2023Cys and KIF6 p.Trp719Arg disturb protein conformational structure and stability. Show less

Interleukin-27 (IL-27) is able to inhibit HIV-1 replication in peripheral blood mononuclear cells (PBMCs), macrophages, and dendritic cells. Here, we identify that IL-27 can produce opposing effects on HIV-1 replication in PBMCs and that the HIV-1 restriction factor BST-2/Tetherin is involved in both inhibitory and enhancing effects on HIV-1 infection induced by IL-27. IL-27 inhibited HIV-1 replication when added to cells 2 h after infection, promoting the prototypical BST-2/Tetherin-induced virion accumulation at the cell membrane of HIV-1-infected PBMCs. BST-2/Tetherin gene expression was significantly upregulated in the IL-27-treated PBMCs, with a simultaneous increase in the number of BST-2/Tetherin Show less

Long-chain polyunsaturated fatty acids (PUFAs) generate diverse bioactive lipid mediators, which tightly regulate vascular inflammation. The effects of omega-3 PUFA supplementation in cardiovascular prevention however remain controversial. In addition to direct dietary intake, fatty acid desaturases (FADS) determine PUFA levels. Increased arterial stiffness represents an independent predictor of mortality and cardiovascular events. The aim of the present study was to determine the association of PUFA intake, FADS1 genotype, and FADS expression with arterial stiffness. A cross-sectional population-based cohort study of 1464 participants without overt cardiovascular disease was conducted. Dietary intake was assessed using a food frequency questionnaire. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV), and the FADS1 locus variant was determined. Blood cell transcriptomics was performed in a subset of 410 individuals. Pulse wave velocity was significantly associated with the FADS1 locus variant. Differential associations between PWV and omega-3 PUFA intake were observed depending on the FADS1 genotype. High omega-3 PUFA intake attenuated the FADS1 genotype-dependent associations. Carriers of the minor FADS1 locus variant exhibited increased expression of FADS2, which is associated with PWV. Taken together, these findings point to FADS1 genotype-dependent associations of omega-3 PUFA intake on subclinical cardiovascular disease. These findings may have implications for identifying responders and non-responders to omega-3 PUFA supplementation and open up for personalized dietary counselling in cardiovascular prevention. Show less

Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors ( Show less

Neonatal-onset urea cycle disorders (UCDs) may result in hyperammonemic (HA) encephalopathy presenting with several neurologic sequelae including seizures, coma, and death. However, no recommendations are given in how and when neurodiagnostic studies should be used to screen or assess for these neurologic complications. We present a case of carbamoyl phosphate synthetase 1 (CPS1) deficiency in a newborn female in which electroencephalogram monitoring to assess encephalopathy and seizures, and magnetic resonance imaging measurements of brain metabolites were used to guide care during her hyperammonemic crisis. Her neurologic course and response to treatment characterizes the significant neurologic impact of HA encephalopathy. Our group herein proposes a clinical neurodiagnostic pathway for managing acute HA encephalopathy. Show less

CD38, a druggable ectoenzyme, is involved in the generation of adenosine, which is implicated in tumour immune evasion. Its expression and role in prostate tumour-infiltrating immune cells (TIICs) have not been elucidated. To characterise CD38 expression on prostate cancer (PC) epithelial cells and TIICs, and to associate this expression with clinical outcomes. RNAseq from 159 patients with metastatic castration-resistant prostate cancer (mCRPC) in the International Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF) cohort and 171 mCRPC samples taken from 63 patients in the Fred Hutchinson Cancer Research Centre cohort were analysed. CD38 expression was immunohistochemically scored by a validated assay on 51 castration-resistant PC (CRPC) and matching, same-patient castration-sensitive PC (CSPC) biopsies obtained between 2016 and 2018, and was associated with retrospectively collected clinical data. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: mCRPC transcriptomes were analysed for associations between CD38 expression and gene expression signatures. Multiplex immunofluorescence determined CD38 expression in PC biopsies. Differences in CD38 CD38 mRNA expression in mCRPC was most significantly associated with upregulated immune signalling pathways. CD38 mRNA expression was associated with interleukin (IL)-12, IL-23, and IL-27 signalling signatures as well as immunosuppressive adenosine signalling and T cell exhaustion signatures. CD38 protein was frequently expressed on phenotypically diverse TIICs including B cells and myeloid cells, but largely absent from tumour epithelial cells. CD38 CD38 CD38 is expressed on the surface of white blood cells surrounding PC cells. These cells may impact PC growth and treatment resistance. Patients with PC with more CD38-expressing white blood cells are more likely to die earlier. Show less

Currently, there are no biomarkers for Chikungunya fever (CHIK) in clinical practice that can accurately predict the severity or chronification of the disease. The aim of this study is to evaluate the existing literature on biomarkers related to the severity and chronification of CHIK. In this sense, a systematic review was conducted based on the PRISMA Statement guideline. Articles that described the association of biomarkers with the evolution of the disease (severity or chronification), published until August 20th 2019 were considered eligible. The search was carried out in the PubMed, Scopus, Virtual Health Library (VHL) and Science Direct databases. After searching the databases, 17 articles were added to the review, and after analyzing the articles, several biomarkers were associated with severity, such as increased levels of IL-6, IP-10, IL-1b, MIG, MCP-1, and reduced levels of RANTES and IL-8 or chronification, such as increased levels of IL-6, TNF-α, MCP-1, IL-12, INF-α, IL-13, INF-γ, GM-CSF, CRP, IL-1a, IL-15, Factor VII, IP-10, IL-10, IL-4, IL-1RA, IL-8, MIP-1α, MIP-1β, ferritin, MIG, ESR, NO, malondialdehyde, and reduced levels of RANTES, ferritin, eotaxin, HGF, IL-27, IL-17A, IL-29, TGF-β, IL-10, and thiols. IL-6, CRP and TNF-α were included in the meta-analysis to assess the relationship with chronification, although they did not reach statistical significance. It was concluded that several biomarkers showed a relationship with severity and chronification of CHIK; the search for these biomarkers can reveal prognostic factors and important therapeutic targets for the treatment of the disease. 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

This cross-sectional study investigated associations between SNPs in metabolizing lipid genes, alpha-thalassemia and laboratory parameters in two forms of sickle cell disease (SCD), sickle cell anemia (SCA) and hemoglobin SC disease (HbSC) in a pediatric population. Among the groups SCA and HbSC was found a higher proportion of increased triglycerides (TG) in SCA. High levels of TG were significantly associated with lower hemoglobin (p = 0.006) and HDL-C (p = 0.037), higher white blood cell count (p = 0.027), LDH (p = 0.004) and bilirubins (p < 0.05) in SCD. Patients with HDL-C ≤40 mg/dL had higher markers hemolytic levels. Therapy of HU significantly influenced several hematological and biochemical parameters but not lipid fractions. Genotypes of the APOA5 rs662799 were not associated with lipid levels. The G-risk allele rs964184/ZPRI ZNF259/ZPR1 gene (GC + GG genotypes) was associated with increased levels of TG in children ≥10 years old (p = 0.045) and the atherogenic ratio TG/HDL-C (p = 0.032) in SCD. The use of HU improves levels of hemolysis and inflammation markers in SCD with high TG and, while not interfering with lipid levels, seems to overlap the effect of the G-risk allele in on them. This study reported for the first time that rs964184 SNP could be a genetic modifier of TG in SCD. Show less

Sepsis is a dysregulated host response to infection and a major cause of death worldwide. Respiratory tract infections account for most sepsis cases and depending on the place of acquisition, i.e., community or hospital acquired infection, differ in etiology, antimicrobial resistance and outcomes. Accordingly, the host response may be different in septic patients secondary to community-acquired pneumonia and hospital acquired pneumonia (HAP). Proteomic analysis is a useful approach to evaluate broad alterations in biological pathways that take place during sepsis. Here we evaluated plasma proteome changes in sepsis secondary to HAP. Plasma samples were obtained from patients (n = 27) at admission and after 7 days of follow-up, and were analyzed according to the patients' outcomes. The patients' proteome profiles were compared with healthy volunteers (n = 23). Pooled plasma samples were labeled with isobaric tag for relative and absolute quantitationand analyzed by LC-MS/MS. We used bioinformatics tools to find altered functions and pathways. Results were validated using biochemical estimations and ELISA tests. We identified 159 altered proteins in septic patients; most of them were common when comparing patients' outcomes, both at admission and after 7 days. The top altered biological processes were acute inflammatory response, response to wounding, blood coagulation and homeostasis. Lipid metabolism emerged as the main altered function in patients, with HDL as a central node in the network analysis, interacting with downregulated proteins, such as APOA4, APOB, APOC1, APOL1, SAA4 and PON1. Validation tests showed reduced plasma levels of total cholesterol, HDL-C, LDL-C, non-HDL cholesterol, apolipoproteins ApoA1 and ApoB100, and Paraoxonase 1 in HAP patients. Proteomic analysis pointed to impairment of lipid metabolism as a major change in septic patients secondary to HAP, which was further validated by the reduced levels of cholesterol moieties and apolipoproteins in plasma. Our results stress the involvement of lipids in the pathogenesis of sepsis, which is in accordance with previous reports supporting the role of lipid moieties in pathogen toxin clearance and in modulating inflammatory responses. Show less