Assuntos
Anticonvulsivantes , Antineoplásicos Alquilantes , Ifosfamida , Levetiracetam , Humanos , Levetiracetam/uso terapêutico , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Antineoplásicos Alquilantes/efeitos adversos , Ifosfamida/efeitos adversos , Piracetam/análogos & derivados , Piracetam/uso terapêutico , Piracetam/efeitos adversos , Eletroencefalografia , Masculino , Encefalopatias/induzido quimicamente , Encefalopatias/diagnóstico por imagem , Encefalopatias/tratamento farmacológico , FemininoRESUMO
Psoriasis is a chronic and recurring condition characterized by scaly red plaques. The most common variant, plaque-type psoriasis, presents distinct clinical features. It profoundly impacts psychological and mental well-being, resulting in depression, anxiety, and suicidal thoughts. Psoriasis occurs due to disruptions in the skin's innate and adaptive immune response triggered by trauma, infection, or medications. Treatment options include topical therapies such as corticosteroids and vitamin D analogs, phototherapy, conventional systemic agents such as methotrexate (MTX), and biologics that target pro-inflammatory cytokines. There has been growing interest in platelet-rich plasma (PRP) as a potential treatment option for plaque psoriasis, given its lower toxicity compared to existing approaches. However, its use is not yet widespread in clinical practice due to the limited awareness of its effectiveness. This review aims to investigate the efficacy of PRP therapy for plaque psoriasis. To conduct a comprehensive analysis, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, thoroughly searching PubMed, Elton Bryson Stephens Company (EBSCO), and ClinicalTrials.gov between February and July 2023. Our focus was on patients diagnosed with plaque psoriasis, and we found multiple studies that demonstrated promising results of PRP either as monotherapy or in combination with current treatments such as MTX. The clinical evidence strongly supports the effectiveness of PRP in treating plaque psoriasis. PRP significantly improves dermatological symptoms and enhances patient and physician satisfaction. Research suggests that PRP reduces the expression of interleukin (IL) 17, a pro-inflammatory mediator, explaining its mechanism of action in treating plaque psoriasis. However, additional clinical trials with larger sample sizes, including PRP as a separate treatment group and comparisons with positive and control groups, are necessary to reinforce its efficacy in plaque psoriasis patients and elucidate other potential mechanisms underlying its beneficial effects.
RESUMO
Dowling Degos disease (DDD) is a rare autosomal dominant genodermatosis characterized by acquired, slowly progressive reticulated pigmented lesions primarily involving flexural skin areas. Mutations in KRT5, POGLUT-1 and POFUT-1 genes have been associated with DDD, and loss-of-function mutations in PSENEN, a subunit of the gamma-secretase complex, were found in patients presenting with DDD or DDD comorbid with hidradenitis suppurativa (HS). A nonsense mutation in NCSTN, another subunit of the gamma-secretase, was already described in a patient suffering from HS and DDD but whether NCSTN could be considered a novel gene for DDD is still debated. Here, we enrolled a four-generation family with HS and DDD. Through Whole Exome Sequencing (WES) we identified a novel nonsense mutation in the NCSTN gene in all the affected family members. To study the impact of this variant, we isolated outer root sheath cells from patients' hair follicles. We showed that this variant leads to a premature stop codon, activates a nonsense-mediated mRNA decay, and causes NCSTN haploinsufficiency in affected individuals. In fact, cells treated with gentamicin, a readthrough agent, had the NCSTN levels corrected. Moreover, we observed that this haploinsufficiency also affects other subunits of the gamma-secretase complex, possibly causing DDD. Our findings clearly support NCSTN as a novel DDD gene and suggest carefully investigating this co-occurrence in HS patients carrying a mutation in the NCSTN gene.
Assuntos
Hidradenite Supurativa , Papulose Atrófica Maligna , Humanos , Secretases da Proteína Precursora do Amiloide/genética , Códon sem Sentido , Hidradenite Supurativa/complicações , Hidradenite Supurativa/genética , Proteínas de Membrana/genética , Mutação , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: The pathophysiological picture underlying hidradenitis suppurativa (HS) and its syndromic forms is still patchy, thus presenting a great challenge for dermatologists and researchers since just by better understanding the pathogenesis of disease we could identify novel therapeutic targets. METHODS: We propose a practical framework to improve subcategorization of HS patients and support the genotype-phenotype correlation, useful for endotype-directed therapies development. RESULTS: This framework includes (i) clinical work-up that involves the collection of demographic, lifestyle, and clinical data as well as the collection of different biological samples; (ii) genetic-molecular work-up, based on multi-omics analysis in combination with bioinformatics pipelines to unravel the complex etiology of HS and its syndromic forms; (iii) functional studies, - represented by skin fibroblast cell cultures, reconstructed epidermal models (both 2D and 3D) and organoids -, of candidate biomarkers and genetic findings necessary to validate novel potential molecular mechanisms possibly involved and druggable in HS; (iv) genotype-phenotype correlation and clinical translation in tailored targeted therapies. CONCLUSION: Omic findings should be merged and integrated with clinical data; moreover, the skin-omic profiles from each HS patient should be matched and integrated with the ones already reported in public repositories, supporting the efforts of the researchers and clinicians to discover novel biomarkers and molecular pathways with the ultimate goal of providing faster development of novel patient-tailored therapeutic approaches.
Assuntos
Hidradenite Supurativa , Humanos , Hidradenite Supurativa/tratamento farmacológico , Hidradenite Supurativa/genética , Pele/patologia , Estudos de Associação Genética , Epiderme/patologia , BiomarcadoresRESUMO
Pyoderma gangrenosum (PG) is a rare inflammatory skin disease classified within the spectrum of neutrophilic dermatoses. The pathophysiology of PG is yet incompletely understood but a prominent role of genetics facilitating immune dysregulation has been proposed. This study investigated the potential contribution of disrupted molecular pathways in determining the susceptibility and clinical severity of PG. Variant Enrichment Analysis, a bioinformatic pipeline applicable for Whole Exome Sequencing data was performed in unrelated PG patients. Eleven patients were enrolled, including 5 with unilesional and 6 with multilesional PG. Fourteen pathways were exclusively enriched in the "multilesional" group, mainly related to immune system (i.e., type I interferon signaling pathway), cell metabolism and structural functions. In the "unilesional" group, nine pathways were found to be exclusively enriched, mostly related to cell signaling and cell metabolism. Genetically altered pathways involved in immune system biology and wound repair appear to be nodal pathogenic drivers in PG pathogenesis.
Assuntos
Pioderma Gangrenoso , Humanos , Pioderma Gangrenoso/genética , Pioderma Gangrenoso/patologiaRESUMO
The variant enrichment analysis (VEA), a recently developed bioinformatic workflow, has been shown to be a valuable tool for whole-exome sequencing data analysis, allowing finding differences between the number of genetic variants in a given pathway compared to a reference dataset. In a previous study, using VEA, we identified different pathway signatures associated with the development of pulmonary toxicities in mesothelioma patients treated with radical hemithoracic radiation therapy. Here, we used VEA to discover novel pathways altered in individuals exposed to asbestos who developed or not asbestos-related diseases (lung cancer or mesothelioma). A population-based autopsy study was designed in which asbestos exposure was evaluated and quantitated by investigating objective signs of exposure. We selected patients with similar exposure to asbestos. Formalin-fixed paraffin-embedded (FFPE) tissues were used as a source of DNA and whole-exome sequencing analysis was performed, running VEA to identify potentially disrupted pathways in individuals who developed thoracic cancers induced by asbestos exposure. By using VEA analysis, we confirmed the involvement of pathways considered as the main culprits for asbestos-induced carcinogenesis: oxidative stress and chromosome instability. Furthermore, we identified protective genetic assets preserving genome stability and susceptibility assets predisposing to a worst outcome.
Assuntos
Amianto , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Exposição Ocupacional , Humanos , Autopsia , Amianto/toxicidade , Mesotelioma/induzido quimicamente , Mesotelioma/genética , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Exposição Ocupacional/efeitos adversosRESUMO
Hidradenitis suppurativa (HS) is an inflammatory skin condition clinically characterized by recurrent painful deep-seated nodules, abscesses, and sinus tracks in areas bearing apocrine glands, such as axillae, breasts, groins, and buttocks. Despite many recent advances, the pathophysiological landscape of HS still demands further clarification. To elucidate HS pathogenesis, we performed a meta-analysis, set analysis, and a variant calling on selected RNA-Sequencing (RNA-Seq) studies on HS skin. Our findings corroborate the HS triad composed of upregulated inflammation, altered epithelial differentiation, and dysregulated metabolism signaling. Upregulation of specific genes, such as KRT6, KRT16, serpin-family genes, and SPRR3 confirms the early involvement of hair follicles and the impairment of barrier function in HS lesioned skin. In addition, our results suggest that adipokines could be regarded as biomarkers of HS and metabolic-related disorders. Finally, the RNA-Seq variant calling identified several mutations in HS patients, suggesting potential new HS-related genes associated with the sporadic form of this disease. Overall, this study provides insights into the molecular pathways involved in HS and identifies potential HS-related biomarkers.
Assuntos
Hidradenite Supurativa , Serpinas , Humanos , Hidradenite Supurativa/genética , Hidradenite Supurativa/metabolismo , Transcriptoma , Inflamação/genética , Inflamação/complicações , Adipocinas , RNARESUMO
OBJECTIVES: The purpose of this case-control study was to verify the association between single nucleotide polymorphisms (SNPs) in genes encoding drug transporters related to tenofovir disoproxil fumarate (TDF) and proximal renal tubular dysfunction (PRTD), and the association between PRTD and clinical characteristics. METHODS: The 'cases' met the diagnostic criteria for PRTD, determined by the presence of two or more of the following abnormalities: non-diabetic glycosuria, metabolic acidosis, increased uric acid and phosphorus excretion, decreased tubular phosphorus reabsorption and ß2-microglobulinuria. We analyzed eight SNPs in ABCC2, ABCC4, ABCC10 and SLC28A2 genes. Genotyping was performed using real-time PCR. RESULTS: Of the 204 people living with HIV, 38 (18.6%) met the criteria for diagnosis of PRTD and 131 were male (64.2%), with a mean age of 49 years and a history of previous antiretroviral therapy for an average of 5 years. In the multivariate analysis, older individuals, TDF use, protease inhibitor, antihypertensives and anticonvulsants were associated with a risk of developing PRTD. Increased excretion of ß2microglobulin was associated with the A/G genotype of rsCC8187710 from ABCC2 ( P = 0.003) and the following genotypes of ABCC4 SNPs: A/G from rs1059751 ( P = 0.023), G/G from rs1059751 ( P = 0.030) and C/C of rs3742106 ( P = 0.041). The increase in the fraction of excreted phosphorus was associated with the C/T genotype of SNCC rsP40037 from ABCC2 ( P = 0.0041). CONCLUSIONS: The results indicate an important relationship between SNPs associated with these markers and changes in proximal renal tubule function, and thus support their use as biomarkers for the early detection of PRTD risk.
Assuntos
Síndrome da Imunodeficiência Adquirida , Fármacos Anti-HIV , Infecções por HIV , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Tenofovir/efeitos adversos , Fármacos Anti-HIV/efeitos adversos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Testes Farmacogenômicos , Estudos de Casos e Controles , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Proteína 2 Associada à Farmacorresistência Múltipla , Fósforo/uso terapêuticoRESUMO
Zika virus (ZIKV) is an enveloped, single-stranded RNA arbovirus belonging to the genus Flavivirus. It was first isolated from a sentinel monkey in Uganda in 1947. More recently, ZIKV has undergone rapid geographic expansion and has been responsible for outbreaks in Southeast Asia, the Pacific Islands, and America. In this review, we have highlighted the influence of viral genetic variants on ZIKV pathogenesis. Two major ZIKV genotypes (African and Asian) have been identified. The Asian genotype is subdivided into Southwest Asia, Pacific Island, and American strains, and is responsible for most outbreaks. Non-synonymous mutations in ZIKV proteins C, prM, E, NS1, NS2A, NS2B, NS3, and NS4B were found to have a higher prevalence and association with virulent strains of the Asian genotype. Consequently, the Asian genotype appears to have acquired higher cellular permissiveness, tissue persistence, and viral tropism in human neural cells. Therefore, mutations in specific coding regions of the Asian genotype may enhance ZIKV infectivity. Considering that mutations in the genomes of emerging viruses may lead to new virulent variants in humans, there is a potential for the re-emergence of new ZIKV cases in the future.
Assuntos
Flavivirus , Infecção por Zika virus , Zika virus , Flavivirus/genética , Genótipo , Humanos , RNA/metabolismo , Zika virus/genética , Infecção por Zika virus/epidemiologiaRESUMO
The challenge of unravelling the molecular basis of multifactorial disorders nowadays cannot rely just on association studies searching for potential causative variants shared by groups of patients and not present in healthy individuals; indeed, association studies have as a main limitation the lack of information on the interactions between the disease-causing variants. Thus, new genomic analysis tools focusing on disrupted pathways rather than associated gene variants are required to better understand the complexity of a disease. Therefore, we developed the Variant Enrichment Analysis (VEA) workflow, a tool applicable for whole exome sequencing data, able to find differences between the numbers of genetic variants in a given pathway in comparison with a reference dataset. In this study, we applied VEA to discover novel pathways altered in patients with complex autoinflammatory skin disorders, namely PASH (n = 9), 3 of whom are overlapping with SAPHO) and PAPASH (n = 3). With this approach we have been able to identify pathways related to neutrophil and endothelial cells homeostasis/activations, as disrupted in our patients. We hypothesized that unregulated neutrophil transendothelial migration could elicit increased neutrophil infiltration and tissue damage. Based on our findings, VEA, in our experimental dataset, allowed us to predict novel pathways impaired in subjects with autoinflammatory skin disorders.
Assuntos
Inflamação/genética , Dermatopatias/genética , Pele/patologia , Movimento Celular/genética , Células Endoteliais/patologia , Homeostase/genética , Humanos , Inflamação/patologia , Neutrófilos/patologia , Transdução de Sinais/genética , Dermatopatias/patologia , Sequenciamento do Exoma/métodosRESUMO
BACKGROUND: The genetics of syndromic hidradenitis suppurativa (HS), an immune-mediated condition associated with systemic comorbidities such as inflammatory bowel diseases and arthritis, has not been completely elucidated. OBJECTIVE: To describe clinical features and genetic signature of patients with the main syndromic HS forms, i.e., PASH, PAPASH, and PASH/SAPHO overlapping. METHODS: Whole-exome sequencing (WES) approach was performed in ten patients with syndromic HS. RESULTS: Three clinical settings have been identified based on presence/absence of gut and joint inflammation. Four PASH patients who had also gut inflammation showed three different variants in NOD2 gene, two variants in OTULIN, and a variant in GJB2, respectively. Three PAPASH and three PASH/SAPHO overlapping patients who had also joint inflammation showed two different variants in NCSTN, one in WDR1 and PSTPIP1, and two variants in NLRC4, one of whom was present in a patient with a mixed phenotype characterized by gut and joint inflammation. LIMITATIONS: Limited number of patients that can be counterbalanced by the rarity of syndromic HS. CONCLUSION: Syndromic HS can be considered as a polygenic autoinflammatory condition; currently WES is a diagnostic tool allowing more accurate genotype-phenotype correlation.
Assuntos
Artrite , Hidradenite Supurativa , Pioderma Gangrenoso , Estudos de Associação Genética , Hidradenite Supurativa/diagnóstico , Humanos , Inflamação , Pioderma Gangrenoso/diagnóstico , Sequenciamento do ExomaRESUMO
ABSTRACT Zika virus (ZIKV) is an enveloped, single-stranded RNA arbovirus belonging to the genus Flavivirus. It was first isolated from a sentinel monkey in Uganda in 1947. More recently, ZIKV has undergone rapid geographic expansion and has been responsible for outbreaks in Southeast Asia, the Pacific Islands, and America. In this review, we have highlighted the influence of viral genetic variants on ZIKV pathogenesis. Two major ZIKV genotypes (African and Asian) have been identified. The Asian genotype is subdivided into Southwest Asia, Pacific Island, and American strains, and is responsible for most outbreaks. Non-synonymous mutations in ZIKV proteins C, prM, E, NS1, NS2A, NS2B, NS3, and NS4B were found to have a higher prevalence and association with virulent strains of the Asian genotype. Consequently, the Asian genotype appears to have acquired higher cellular permissiveness, tissue persistence, and viral tropism in human neural cells. Therefore, mutations in specific coding regions of the Asian genotype may enhance ZIKV infectivity. Considering that mutations in the genomes of emerging viruses may lead to new virulent variants in humans, there is a potential for the re-emergence of new ZIKV cases in the future.
RESUMO
BACKGROUND: Antiretroviral therapy (ART) is an important hallmark of HIV-1 treatment, enabling viral load suppression to undetectable levels and CD4+ T-cell recovery. However, some individuals do not recover the CD4+ T-cell count to normal levels, despite viral suppression. We hypothesize that variation in genes involved in extrinsic apoptosis pathways may influence interindividual immune recovery during ART. METHODS: We assessed clinical-epidemiological variables and the allelic/genotypic distribution of functional single nucleotide polymorphisms in genes involved in extrinsic apoptosis pathways (TNFRSF1A: rs1800692 and rs767455; TNFAIP3: rs2270926; NFKBIA: rs8904; and TNF-α: rs1800629) and their relationship with immune recovery in ART-treated (1 year) HIV-1-infected individuals. We enrolled 155 HIV-1-infected individuals, with 102 individuals showing immunological success and 53 with immunological failure. RESULTS: Through univariate analysis, we observed that the male sex (60.4%, P = 0.002) showed a higher median of age at treatment onset (34.8 years, P = 0.034) and higher time until virological suppression (6 months, P = 0.035), both risk factors for immune failure. Survival analysis revealed that individuals who started ART treatment with CD4+ T-cell count <200 cells/mm3 took a longer time to immunological recovery (median time = 27 months, P = 0.029). ART containing zidovudine also was associated with immune recovery in univariate e multivariate analysis. Variants in TNFRSF1A (rs767455: T and TT; rs1800692-rs767455: T-T combination) and NFKBIA (rs8904: A) genes were associated with immune failure, whereas NFKBIA (rs8904: GA) and TNF-α (rs1800629: GA) were with CD4+ T-cell recovery. CONCLUSIONS: Clinical-epidemiological variants in genes involved in extrinsic apoptosis pathways might influence the CD4+ T-cell immune recovery.
Assuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Fator de Necrose Tumoral alfa/genética , Adolescente , Adulto , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/metabolismo , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , Soropositividade para HIV , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/uso terapêutico , Carga Viral , Adulto JovemRESUMO
Proinflammatory microenvironmental is crucial for the Human Immunodeficiency Virus Type 1 (HIV-1) pathogenesis. The viral glycoprotein 120 (gp120) must interact with the CD4+ T cell chemokine receptor (CCR5) and a co-receptor C-X-C chemokine receptor type 4 (CXCR4) to let the virus entry into the host cells. However, the interaction of the viral particle with other cell surface receptors is mandatory for its attachment and subsequently entry. Tumor Necrosis Factor receptor type I (TNFR1), type II (TNFR2) and Fas are a superfamily of transmembrane proteins involved in canonical inflammatory pathway and cell death by apoptosis as responses against viral pathogens. In our study, we performed an in silico evaluation of the molecular interactions between viral protein gp120 and TNF receptors (TNFR1, TNFR2 and Fas). Protein structures were retrieved from Protein Databank (PDB), and Molecular Docking and dynamics were performed using ClusPro 2.0 server and GROMACS software, respectively. We observed that gp120 is able to bind TNFR1, TNFR2 and Fas receptors, although only the TNFR2-gp120 complex demonstrated to produce a stable and durable binding. Our findings suggest that gp120 may act as an agonist to TNF-α and also function as an attachment factor in HIV-1 entry process. These molecular interaction by gp120 may be the key to HIV-1 immunopathogenesis. In conclusion, gp120 may stimulate pro-inflammatory and apoptotic signaling transduction pathways mediated by TNFR2 and may act as an attachment factor retaining HIV-1 viral particles on the host cell surface.
Assuntos
Glicoproteínas/metabolismo , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/patogenicidade , Receptores do Fator de Necrose Tumoral/metabolismo , Apoptose/fisiologia , Humanos , Inflamação/metabolismo , Inflamação/virologia , Simulação de Acoplamento Molecular/métodos , Transdução de Sinais/fisiologia , Internalização do VírusRESUMO
HIV-1 infection elicits a complex dynamic of the expression various host genes. High throughput sequencing added an expressive amount of information regarding HIV-1 infections and pathogenesis. RNA sequencing (RNA-Seq) is currently the tool of choice to investigate gene expression in a several range of experimental setting. This study aims at performing a meta-analysis of RNA-Seq expression profiles in samples of HIV-1 infected CD4+ T cells compared to uninfected cells to assess consistently differentially expressed genes in the context of HIV-1 infection. We selected two studies (22 samples: 15 experimentally infected and 7 mock-infected). We found 208 differentially expressed genes in infected cells when compared to uninfected/mock-infected cells. This result had moderate overlap when compared to previous studies of HIV-1 infection transcriptomics, but we identified 64 genes already known to interact with HIV-1 according to the HIV-1 Human Interaction Database. A gene ontology (GO) analysis revealed enrichment of several pathways involved in immune response, cell adhesion, cell migration, inflammation, apoptosis, Wnt, Notch and ERK/MAPK signaling.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Transcriptoma , Linfócitos T CD4-Positivos/virologia , Perfilação da Expressão Gênica , Ontologia Genética , Infecções por HIV/genética , Infecções por HIV/metabolismo , Interações Hospedeiro-Patógeno , HumanosRESUMO
The high volume of information produced in the age of omics was and still is an important step to understanding several pathological processes, providing the enlightenment of complex molecular networks and the identification of molecular targets associated with many diseases. Despite these remarkable scientific advances, the majority of the results are disconnected and divergent, making their use limited. Skin diseases with alterations in the Notch signaling pathway were extensively studied during the omics era. In the GWAS Catalog, considering only studies on genomics association (GWAS), several works were deposited, some of which with divergent results. In addition, there are thousands of scientific articles available about these skin diseases. In our study, we focused our attention on skin diseases characterized by the impairment of Notch signaling, this pathway being of pivotal importance in the context of epithelial disorders. We considered the pathologies of five human skin diseases, Hidradenitis Suppurativa, Dowling Degos Disease, Adams-Oliver Syndrome, Psoriasis, and Atopic Dermatitis, in which the molecular alterations in the Notch signaling pathway have been reported. To this end, we started developing a new multiomics platform, PlatOMICs, to integrate and re-analyze omics information, searching for the molecular interactions involved in the pathogenesis of skin diseases with alterations in the Notch signaling pathway.
Assuntos
Suscetibilidade a Doenças , Genômica , Mutação , Receptores Notch/genética , Transdução de Sinais , Dermatopatias/etiologia , Dermatopatias/metabolismo , Animais , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Genômica/métodos , Humanos , Proteoma , Proteômica/métodos , Dermatopatias/patologia , TranscriptomaRESUMO
Radical hemithoracic radiotherapy (RHR), after lung-sparing surgery, has recently become a concrete therapeutic option for malignant pleural mesothelioma (MPM), an asbestos-related, highly aggressive tumor with increasing incidence and poor prognosis. Although the toxicity associated to this treatment has been reduced, it is still not negligible and must be considered when treating patients. Genetic factors appear to play a role determining radiotherapy toxicity. The aim of this study is the identification of biological pathways, retrieved through whole exome sequencing (WES), possibly associated to the development of lung adverse effects in MPM patients treated with RHR. The study included individuals with MPM, treated with lung-sparing surgery and chemotherapy, followed by RHR with curative intent, and followed up prospectively for development of pulmonary toxicity. Due to the strong impact of grade 3 pulmonary toxicities on the quality of life, compared with less serious adverse events, for genetic analyses, patients were divided into a none or tolerable pulmonary toxicity (NoSTox) group (grade ≤2) and a severe pulmonary toxicity (STox) group (grade = 3). Variant enrichment analysis allowed us to identify different pathway signatures characterizing NoSTox and Stox patients, allowing to formulate hypotheses on the protection from side effects derived from radiotherapy as well as factors predisposing to a worst response to the treatment. Our findings, being aware of the small number of patients analyzed, could be considered a starting point for the definition of a panel of pathways, possibly helpful in the management of MPM patients.
RESUMO
AIMS: Brazil is nowadays one of the epicentres of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and new therapies are needed to face it. In the context of specific immune response against the virus, a correlation between Major Histocompatibility Complex Class I (MHC-I) and the severity of the disease in patients with COVID-19 has been suggested. Aiming at better understanding the biology of the infection and the immune response against the virus in the Brazilian population, we analysed SARS-CoV-2 protein S peptides in order to identify epitopes able to elicit an immune response mediated by the most frequent MHC-I alleles using in silico methods. METHODS: Our analyses consisted in searching for the most frequent Human Leukocyte Antigen (HLA)-A, HLA-B and HLA-C alleles in the Brazilian population, excluding the genetic isolates; then, we performed: molecular modelling for unsolved structures, MHC-I binding affinity and antigenicity prediction, peptide docking and molecular dynamics of the best fitted MHC-I/protein S complexes. RESULTS: We identified 24 immunogenic epitopes in the SARS-CoV-2 protein S that could interact with 17 different MHC-I alleles (namely, HLA-A*01:01; HLA-A*02:01; HLA-A*11:01; HLA-A*24:02; HLA-A*68:01; HLA-A*23:01; HLA-A*26:01; HLA-A*30:02; HLA-A*31:01; HLA-B*07:02; HLA-B*51:01; HLA-B*35:01; HLA-B*44:02; HLA-B*35:03; HLA-C*05:01; HLA-C*07:01 and HLA-C*15:02) in the Brazilian population. CONCLUSIONS: Being aware of the intrinsic limitations of in silico analysis (mainly the differences between the real and the Protein Data Bank (PDB) structure; and accuracy of the methods for simulate proteasome cleavage), we identified 24 epitopes able to interact with 17 MHC-I more frequent alleles in the Brazilian population that could be useful for the development of strategic methods for vaccines against SARS-CoV-2.
Assuntos
Mapeamento de Epitopos , Epitopos , Antígenos HLA/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Brasil , Frequência do Gene , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe I/genética , Interações Hospedeiro-Patógeno , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , SARS-CoV-2/patogenicidadeRESUMO
Notch pathway is a highly conserved intracellular signaling route that modulates a vast variety of cellular processes including proliferation, differentiation, migration, cell fate and death. Recently, the presence of a strict crosstalk between Notch signaling and inflammation has been described, although the precise molecular mechanisms underlying this interplay have not yet been fully unravelled. Disruptions in Notch cascade, due both to direct mutations and/or to an altered regulation in the core components of Notch signaling, might lead to hypo- or hyperactivation of Notch target genes and signaling molecules, ultimately contributing to the onset of autoinflammatory diseases. To date, alterations in Notch signaling have been reported as associated with three autoinflammatory disorders, therefore, suggesting a possible role of Notch in the pathogenesis of the following diseases: hidradenitis suppurativa (HS), Behçet disease (BD), and giant cell arteritis (GCA). In this review, we aim at better characterizing the interplay between Notch and autoinflammatory diseases, trying to identify the role of this signaling route in the context of these disorders.
Assuntos
Doenças Hereditárias Autoinflamatórias/genética , Inflamação/genética , Receptores Notch/genética , Animais , Síndrome de Behçet/genética , Síndrome de Behçet/patologia , Diferenciação Celular/genética , Arterite de Células Gigantes/genética , Arterite de Células Gigantes/patologia , Doenças Hereditárias Autoinflamatórias/classificação , Doenças Hereditárias Autoinflamatórias/patologia , Hidradenite Supurativa/genética , Hidradenite Supurativa/patologia , Humanos , Inflamação/patologia , Mutação/genética , Transdução de Sinais/genéticaRESUMO
Loss of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) causes increased mRNA translation and aberrant synaptic development. We find neurons of the Fmr1-/y mouse have a mitochondrial inner membrane leak contributing to a "leak metabolism." In human Fragile X syndrome (FXS) fibroblasts and in Fmr1-/y mouse neurons, closure of the ATP synthase leak channel by mild depletion of its c-subunit or pharmacological inhibition normalizes stimulus-induced and constitutive mRNA translation rate, decreases lactate and key glycolytic and tricarboxylic acid (TCA) cycle enzyme levels, and triggers synapse maturation. FMRP regulates leak closure in wild-type (WT), but not FX synapses, by stimulus-dependent ATP synthase ß subunit translation; this increases the ratio of ATP synthase enzyme to its c-subunit, enhancing ATP production efficiency and synaptic growth. In contrast, in FXS, inability to close developmental c-subunit leak prevents stimulus-dependent synaptic maturation. Therefore, ATP synthase c-subunit leak closure encourages development and attenuates autistic behaviors.