Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 778
Filtrar
1.
BMC Pediatr ; 25(1): 80, 2025 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-39885448

RESUMO

BACKGROUND: Children with non-syndromic cleft lip with or without palate (CL ± P) may present alterations in dental development. The purpose of this cross-sectional study was to compare the dental age (DA) between children with and without CL ± P, and whether single nucleotide polymorphisms (SNPs) in genes encoding growth factors are associated with DA variations. METHODS: Children aged between 5 and 14 years with and without CL ± P were recruited to participate in this study. DA was evaluated by calibrated examiners (kappa > 0.80) using the method proposed by Demirjian et al. (1973). Genomic DNA was extracted from buccal cells, and SNPs in Epidermal Growth Factor (EGF) - rs4444903 and rs2237051, Epidermal Growth Factor Receptor (EGFR) - rs2227983 -, Transforming Growth Factor Beta 1 (TGFB1) - rs1800470 and rs4803455 -, and Transforming Growth Factor Beta Receptor 2 (TGFBR2) - rs3087465 - were genotyped by real-time polymerase chain reactions using the TaqMan assay. The Student T-test was used to compare the variations in DA between the phenotypes "with CL ± P" and "without CL ± P", and the ANOVA two-way test was performed to compare the variations in DA among the genotypes (α = 0.05). A post-hoc analysis was performed using Bonferroni correction. RESULTS: Two hundred and nine (n = 209) children (100 with CL ± P and 109 without CL ± P) with a mean chronological age of 8.66 years - standard deviation (SD) = 1.92 - were included. The group with CL ± P demonstrated a significantly delayed DA (mean=-0.23; SD = 0.71) compared to the group without CL ± P (mean=-0.01; SD = 0.88) (p = 0.049). Genotype distributions were in Hardy-Weinberg equilibrium. The SNP rs4803455 in TGFB1 was significantly associated with DA variations in children without CL ± P (p < 0.01). In the group with CL ± P, no significant differences in DA were observed among the genotypes. CONCLUSION: Children with CL ± P presented delayed DA compared with children without CL ± P. The SNP rs4803455 in TGFB1 is associated with variations in DA in children without CL ± P.


Assuntos
Fenda Labial , Fissura Palatina , Polimorfismo de Nucleotídeo Único , Humanos , Fenda Labial/genética , Estudos Transversais , Criança , Fissura Palatina/genética , Feminino , Masculino , Pré-Escolar , Adolescente , Fator de Crescimento Transformador beta1/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Genótipo , Receptores ErbB/genética
2.
J Gastrointest Cancer ; 56(1): 28, 2024 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-39623250

RESUMO

BACKGROUND: Metastatic colorectal cancer (mCRC) remains a significant clinical challenge. While anti-EGFR inhibitors have improved survival rates, their long-term efficacy is limited by disease progression, which is often associated with the development of acquired resistance mutations. However, some patients may regain sensitivity to anti-EGFR agents after alternative therapies, suggesting a potential benefit for rechallenge strategies. Our study aims to conduct a systematic review and meta-analysis to comprehensively evaluate the efficacy and safety of EGFR rechallenge in patients with mCRC. METHODS: A systematic search of the MEDLINE, EMBASE, and Cochrane databases was conducted between October 28 and December 24, 2023, to identify clinical trials investigating treatment regimens incorporating panitumumab or cetuximab as a rechallenge strategy. Pooled proportions or hazard ratios (HR) were calculated using a random effects model. Inter-study heterogeneity was assessed using the I2. RESULTS: Among the 2105 articles identified through the search, 13 met the predetermined inclusion criteria. Of these, 12 were phase II studies, encompassing 92.3% of the patient population. Cetuximab was administered to 302 patients (75.1%), whereas panitumumab was utilized in 100 patients (24.9%).A pooled analysis of eight studies demonstrated an objective response rate of 20.50% (95% CI 7.94 to 33.07) and a disease control rate of 67.35% (95% CI 58.60 to 76.09). The median progression-free survival was estimated at 3.5 months (95% CI 2.68-6.69), with a median OS of 9.8 months (95% CI 6.71-12.89). Patients exhibiting RAS wild-type status in circulating tumor DNA (ctDNA) analysis derived enhanced benefits from anti-EGFR rechallenge (HR: 0.41; 95% CI 0.28-0.60, I2 = 60%). Common grade 3 or higher treatment-related adverse events included neutropenia (22.8%) and rash (14.9%). CONCLUSION: This meta-analysis underscores the efficacy and safety of anti-EGFR rechallenge as a promising therapeutic approach for a subset of patients afflicted with mCRC. The observed correlation between wild-type RAS status, as determined through ctDNA analysis, and improved OS signals the prospect of precision oncology in guiding treatment decisions.


Assuntos
Cetuximab , DNA Tumoral Circulante , Neoplasias Colorretais , Receptores ErbB , Panitumumabe , Humanos , Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/uso terapêutico , Cetuximab/administração & dosagem , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Metástase Neoplásica , Panitumumabe/uso terapêutico , Panitumumabe/administração & dosagem
3.
JCO Precis Oncol ; 8: e2400331, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39576954

RESUMO

PURPOSE: The activity of osimertinib is not fully characterized in non-small-cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations. Therefore, we conducted a systematic review and meta-analysis to assess the safety and efficacy of osimertinib in patients with NSCLC harboring uncommon somatic EGFR mutations. METHODS: PubMed, Embase, and the Cochrane Library were searched for eligible studies reporting the efficacy and safety of osimertinib in NSCLC with uncommon EGFR mutations defined as any mutations other than exon 19 deletion, L858R and T790M mutations, and exon 20 insertion, except when in compound. Then, we performed a meta-analysis to pool survival outcomes and antitumoral activity, including intracranial (ic) response and adverse events. RESULTS: Fifteen studies comprising 594 patients were included. The most frequently observed uncommon solitary mutations were G719X in 25% (81/327) of patients and L861Q in 21% (69/327). The most common compound mutations were G719X with T790M in 12% (23/192) of patients and G719X with S768I in 11% (22/192). Pooled analysis showed an objective response rate (ORR) of 51.30% (95% CI, 45.80 to 56.81), a disease control rate (DCR) of 90.11% (95% CI, 86.27 to 92.96), a median progression-free survival of 9.71 months (95% CI, 7.96 to 11.86), and a median overall survival of 16.79 months (95% CI, 9.93 to 28.39). icORR was 45.96% (95% CI, 30.18 to 62.17), and icDCR was 95.76% (95% CI, 69.84 to 100). Osimertinib was well tolerated with a frequency of grade 3 or more adverse events of 21.77% (95% CI, 6.24 to 43.33). CONCLUSION: Osimertinib demonstrated robust response in NSCLC harboring uncommon EGFR mutations, without unanticipated safety concerns.


Assuntos
Acrilamidas , Compostos de Anilina , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Mutação , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Acrilamidas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Compostos de Anilina/uso terapêutico , Receptores ErbB/genética , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Indóis , Pirimidinas
4.
JCO Glob Oncol ; 10: e2400354, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39571128

RESUMO

PURPOSE: Tissue inadequacy and operational challenges may limit lung cancer comprehensive biomarker testing. Here, we describe the initial implementation of a tailored tissue molecular journey at Oncoclínicas Precision Medicine Laboratory in Brazil, which includes fast-track (FT) non-next-generation sequencing (NGS) assays combined with a broad NGS panel. METHODS: From 2021 to 2023, all nonsquamous lung cancer samples eligible for the patient support program "Lung Mapping Consortium" at Oncoclínicas & Co were evaluated using the FT panel (immunohistochemistry for PD-L1 and anaplastic lymphoma kinase [ALK], polymerase chain reaction for EGFR and BRAF, and fluorescence in situ hybridization for ROS1) plus a broad DNA and RNA sequencing panel of 180 genes (custom ARCHER panel). RESULTS: From 1,272 samples received by the laboratory, 3% had no tissue for any molecular testing, 20% was not eligible for broad NGS panel as per pathologist assessment (tumor purity and quantity), additional 12% did not reach presequencing analytical thresholds (nucleic acid quantity and/or quality), and 3% had postsequencing failure. Most frequent alterations were KRAS mutations (28.4%, KRASG12C 9.7%), EGFR mutations (23.6%, exon20 insertions 2.9%), ALK fusions (6.4%), MET exon 14 skipping (4.4%), ERBB2 mutations (3.4%), ROS1 fusions (3.1%), and BRAFV600E (1.9%). In 35% of the samples, FT non-NGS tests were the only molecular diagnostics: EGFR mutations (14%), ALK fusions (4.4%), ROS1 fusions (1.8%), and BRAFV600E (0.7%). Overall, high PD-L1 expression (≥50%) was found in 12.3%. CONCLUSION: This study provides data on the molecular epidemiology of lung adenocarcinoma in Brazil, confirming high prevalence of EGFR mutations, ALK fusions, and MET exon 14 skipping alteration. Biomarker detection is largely affected by biospecimen collection and processing, with one third of the patients eligible for non-NGS testing only, which presents reduced coverage and sensitivity for actionable drivers.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Brasil , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Quinase do Linfoma Anaplásico/genética , Sequenciamento de Nucleotídeos em Larga Escala , Adulto , Biomarcadores Tumorais/genética , Mutação , Genômica/métodos , Receptores ErbB/genética , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Medicina de Precisão/métodos
5.
Clinics (Sao Paulo) ; 78: 100302, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39491279

RESUMO

OBJECTIVE: MicroRNAs play crucial roles in the pathogenesis of cancers. MiRNA-218-5p may act as either an oncogene or a tumor suppressor, but its role in the pathogenesis of Breast Cancer (BC) remains unclear. METHODS: Infiltrative breast ductal carcinoma as well as corresponding adjacent normal samples were collected from 30 patients. Mimics and inhibitors of miRNA-218-5p or corresponding negative controls were transfected into BC cells. miRNA-218-5p expression was detected by quantitative PCR. The effects of miRNA-218-5p on the malignant behaviors of BC were assessed. Dual-luciferase reporter assay was employed to evaluate the binding of miRNA-218-5p to LRIG1. RESULTS: BC tissues showed higher miRNA-218-5p expression as compared to the adjacent normal tissues. Ectopic miRNA-218-5p expression accelerated the cell cycle, cell growth and migration of BC, while repressed cell apoptosis. Interestingly, ectopic miRNA-218-5p expression down-regulated LRIG1 expression, and miRNA-218-5p could bind to LRIG1. Also, our study indicated that miRNA-218-5p up-regulated ErbB2 and EGFR expression by targeting LRIG1, suggesting that the LRIG1-mediated signaling pathway contributed to the pro-tumor effects of miRNA-218-5p on BC. CONCLUSION: MiRNA-218-5p up-regulates ErbB2 and EGFR expression by suppressing LRIG1 expression, thus promoting the malignant behaviors of BC. miRNA-218-5p may exert a pro-tumor effect on BC and serve as a therapeutic target for BC treatment.


Assuntos
Apoptose , Neoplasias da Mama , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glicoproteínas de Membrana , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/genética , Apoptose/genética , Movimento Celular/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação para Cima , Linhagem Celular Tumoral , Regulação para Baixo , Ciclo Celular/genética , Pessoa de Meia-Idade
6.
Biol Res ; 57(1): 72, 2024 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-39420441

RESUMO

BACKGROUND: ABO blood group antigens (ABH antigens) are carbohydrate chains glycosylated on epithelial and red blood cells. Recent findings suggest reduced ABH expression in psoriasis and atopic dermatitis, a chronic inflammatory skin disease with retained scale. H antigen, a precursor for A and B antigens, is synthesized by fucosyltransferase 1 (FUT1). Desmosomes, critical for skin integrity, are known to require N-glycosylation for stability. We investigate the impact of H antigens, a specific type of glycosylation, on desmosomes in keratinocytes. METHOD: Primary human keratinocytes were transfected with FUT1 siRNA or recombinant adenovirus for FUT1 overexpression. Cell adhesion and desmosome characteristics and their underlying mechanisms were analyzed. RESULT: The knockdown of FUT1, responsible for H2 antigen expression in the skin, increased cell-cell adhesive strength and desmosome size in primary cultured keratinocytes without altering the overall desmosome structure. Desmosomal proteins, including desmogleins or plakophilin, were upregulated, suggesting enhanced desmosome assembly. Reduced H2 antigen expression via FUT1 knockdown led to increased keratinocyte differentiation, evidenced by elevated expression of differentiation markers. Epidermal growth factor receptor (EGFR) has been described to be associated with FUT1 and promotes cell migration and differentiation. The effects of FUT1 knockdown were recapitulated by an EGFR inhibitor concerning desmosomal proteins and cellular differentiation. Further investigation demonstrated that the FUT1 knockdown reduced EGFR signaling by lowering the levels of EGF ligands rather than directly regulating EGFR activity. Moreover, FUT1 overexpression reversed the effects observed in FUT1 knockdown, resulting in the downregulation of desmosomal proteins and differentiation markers while increasing both mRNA and protein levels of EGFR ligands. CONCLUSION: The expression level of FUT1 in the epidermis appears to influence cell-cell adhesion and keratinocyte differentiation status, at least partly through regulation of H2 antigen and EGFR ligand expression. These observations imply that the fucosylation of the H2 antigen by FUT1 could play a significant role in maintaining the molecular composition and regulation of desmosomes and suggest a possible involvement of the altered H2 antigen expression in skin diseases, such as psoriasis and atopic dermatitis.


Assuntos
Diferenciação Celular , Fucosiltransferases , Queratinócitos , Humanos , Queratinócitos/metabolismo , Diferenciação Celular/fisiologia , Fucosiltransferases/genética , Fucosiltransferases/metabolismo , Desmossomos/metabolismo , Células Cultivadas , Adesão Celular/fisiologia , Receptores ErbB/metabolismo , Sistema ABO de Grupos Sanguíneos/genética , Galactosídeo 2-alfa-L-Fucosiltransferase , RNA Interferente Pequeno/genética
7.
J Gastrointest Cancer ; 56(1): 9, 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39436445

RESUMO

BACKGROUND: Colorectal cancer (CRC) represents the second leading cause of cancer-related mortality worldwide, with a significant portion of patients presenting with metastatic disease at diagnosis. Resistance to initial anti-EGFR therapy, a key treatment for RAS wild-type metastatic CRC, remains a major challenge. This study aimed to assess the efficacy and safety of rechallenge with anti-EGFR therapy in patients with metastatic CRC who have progressed after prior treatments. METHODS: A systematic search was conducted across PubMed, Web of Science, Cochrane, and Scopus. Studies were included if they were randomized controlled trials (RCTs) or observational studies involving patients with EGFR-mutated metastatic CRC who received anti-EGFR therapy as a rechallenge. Endpoints included objective response rate (ORR), disease control rate (DCR), and the incidence of adverse events. Statistical analyses were performed using the DerSimonian/Laird random effect model, with heterogeneity assessed via I2 statistics. R, version 4.2.3, was used for statistical analyses. RESULTS: Fourteen studies were included with 520 patients; 50.3% were male, and the median age was 63 years old. The median progression-free survival (mPFS) ranged between 2.4 and 4.9 months, while the median overall survival (mOS) ranged from 5 to 17.8 months. Our pooled analysis demonstrated an objective response rate (ORR) of 17.70% (95% CI, 8.58-26.82%) and a disease control rate (DCR) of 61.72% (95% CI, 53.32-70.11%), both with significant heterogeneity (I2, 84% and 80%, respectively; p < 0.01). In the subgroup analysis, cetuximab showed an ORR of 18.31% (95% CI, 4.67-31.94%), and panitumumab an ORR of 10.9% (95% CI, 0.00-26.82%), while the combination of both resulted in an ORR of 29.24% (95% CI, 0.00-65.84%). For DCR, cetuximab resulted in 62.1% (95% CI, 49.32-74.87%), panitumumab in 63.05% (95% CI, 52.13-73.97%), and the combination in 60.34% (95% CI, 31.92-88.77%), all with significant heterogeneity. Adverse events included anemia (15.39%), diarrhea (4.20%), hypomagnesemia (6.40%), neutropenia (22.57%), and skin rash (13.22%). CONCLUSIONS: Rechallenge with anti-EGFR therapy in metastatic CRC patients shows moderate efficacy with manageable safety profiles. These findings highlight the need for careful patient selection and monitoring to optimize outcomes. Further studies are warranted to refine strategies for maximizing the therapeutic benefits of anti-EGFR rechallenge.


Assuntos
Cetuximab , Neoplasias Colorretais , Receptores ErbB , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cetuximab/administração & dosagem , Cetuximab/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Receptores ErbB/antagonistas & inibidores , Metástase Neoplásica , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
J Transl Med ; 22(1): 841, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39267111

RESUMO

BACKGROUND: CD155 is a transmembrane protein that inhibits antitumor immune response and represents a predictor of worse prognosis in non-small-cell lung cancer (NSCLC). However, it remains unexplored its association with clinical characteristics and genomic status of Latin American patients. This study characterizes the CD155 expression and its clinical implications in this population. METHODS: Tissue biopsies from 86 patients with locally-advanced or metastatic NSCLC were assessed for CD155 protein expression, ALK rearrangements and EGFR mutations. Cutoff values for high CD155 expression (CD155high) were determined from receiver operating characteristic (ROC) curves according to 2-year survival. It was evaluated its association with clinicopathological features, median progression-free survival (mPFS) and overall survival (mOS). RESULTS: the cutoff score for CD155high was 155 in the entire cohort and in patients without oncogenic alterations, and it was 110 in patients with oncogenic alterations. Eighty-four patients (97.7%) were CD155 positive, of which fifty-six (65.0%) had CD155high. EGFR L858R mutation related to lower CD155 IHC score than exon 19 deletion. Individuals with CD155high showed a shorter mOS (13.0 vs. 30.8 months; HR: 1.96 [95% CI, 1.15-3.35]; p = 0.014). Patients without oncogenic alterations having a CD155high displayed shorter mPFS (1.6 vs. 6.4 months, HR: 2.09 [95% CI, 1.06-4.20]; p = 0.034) and mOS (2.9 vs. 23.1 months; HR: 1.27 [95% CI, 1.07- 4.42]; p = 0.032). Patients with oncogenic alterations having CD155high only showed a trend to shorter mOS (26.3 vs. 52.0 months; HR: 2.39 [95% CI, 0.98-5.83]; p = 0.058). CONCLUSION: CD155high is a predictor of worse outcomes in patients with advanced NSCLC, predominantly among those without oncogenic alterations. CD155 could be a potential biomarker and a molecular target in patients with poor responses to current therapies.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Receptores Virais , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Masculino , Feminino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Pessoa de Meia-Idade , Prognóstico , Idoso , Receptores Virais/genética , Receptores Virais/metabolismo , Mutação/genética , Adulto , Receptores ErbB/metabolismo , Receptores ErbB/genética , Idoso de 80 Anos ou mais , Curva ROC
9.
Oncol Res Treat ; 47(12): 616-623, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39293418

RESUMO

INTRODUCTION: Oncogenic-addicted non-small cell lung cancer (NSCLC) has emerged as the most prevalent form of lung cancer, presenting a dynamic landscape in treatment modalities. Among these, epidermal growth factor receptor (EGFR)-mutant NSCLC remains the predominant oncogenic mutation, particularly prevalent in regions such as Asia and Latin America. CASE PRESENTATION: This case study highlights the experience of a woman diagnosed with EGFR-sensitive (del exon 19) mutant NSCLC who demonstrated an extended duration of response to third-generation EGFR-tyrosine kinase inhibitor (TKI) therapy. Upon disease progression, detection of MET gene amplification prompted the addition of a selective MET inhibitor to the existing EGFR-TKI regimen, resulting in a complete response for the patient. DISCUSSION: The molecular heterogeneity of this condition has significantly increased in complexity over recent years, marked by the identification of baseline co-alterations and development of a broad spectrum of resistance mechanisms post-EGFR-TKI therapy. This complexity poses a substantial challenge to clinicians. Despite the rapid advancement of targeted therapies and the implementation of treatment escalation through combination strategies, there remains an ongoing debate regarding which patients would benefit most from combination therapies, both in the initial treatment phase and in the setting of disease progression, particularly when off-target resistance mechanisms or co-alterations are identified.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-met , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Proteínas Quinases/uso terapêutico , Terapia de Alvo Molecular/métodos , Mutação , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pessoa de Meia-Idade
10.
Arq. bras. cardiol ; Arq. bras. cardiol;121(9 supl.1): 279-279, set.2024. tab
Artigo em Inglês | CONASS, Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1568600

RESUMO

Breast Cancer (BC) is one of the most common cancers diagnosed in population femmale and it has several subtypes, one of them being theexpressing human epidermal growth factor receptor 2 positive (HER2 +), one of the treatments for HER2+ breast cancer consists of chemotherapy plus trastuzumab deruxtecan. Several clinical trials have shown the effectiveness and safety of trastuzumabe deruxtecano in cancer patients, however, several Adverse Events (AEs) have been described and the decrease in left ventricular ejection has been singled out for more prominent analysis. Objective: We conducted a systematic review and meta-analysis to investigate the cardiovascular effects of Trastuzumab Deruxtecano and whether it can influence the appearance of reduced left ventricular ejection fraction.. METHODS: We performed a systematic search in Embase, PubMed and Cochrane databases for randomized controlled trials (RCTs) showed a decrease in left ventricular ejection fraction in patients using trastuzumab deruxtecan against Her-2-positive breast cancer compared to patients to used another's treatments against this disease. Mean difference (MD) with 95% confidence intervals (CI) were calculated using a random effects model. The heterogeneity was examined in the I2 statistic. P-values > 0.05 were considered statistically significant. The statistical analysis was carried out using R software version 4.2.3. RESULTS: A total of 3 RCTs were included, with a total of 1656 patients evaluated, 928 patients randomized to the use of Trastuzumab Deruxtecan and 728 patients to the use of other treatments according to medical choice, follow-up ranged from 10 to 38 months. There was a visible in the decrease in left ventricular ejection fraction, with a higher incidence in the group that used trastuzumab compared to the placebo group (RR: 5.73%; 95% CI 1.51 - 21.78; I2 33% ; P= 0.010466). Another important point is the discontinuation of treatment due to grade 2 adverse events, classified as reduced LVEF, where a higher incidence is seen in the group that used Trastuzumab Deruxtecan compared to the placebo group (RR 2.11%; 95% CI 1.54 - 2.89; P = 0.000003),7. CONCLUSION: In this meta-analysis, Trastuzumab Deruxtecan showed a relationship with a decrease in left ventricular ejection fraction, displaying the need for more studies to evaluate the cardiotoxicity of trastuzumab and its effects as a whole on the cardiovascular system.


Assuntos
Terapêutica , Neoplasias da Mama , Doenças Cardiovasculares , Tratamento Farmacológico , Cardiotoxicidade , Trastuzumab , Interpretação Estatística de Dados , Receptores ErbB
11.
Int J Mol Sci ; 25(15)2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39126006

RESUMO

The use of tyrosine kinase inhibitors (TKI) has been growing in veterinary oncology and in the past few years several TKI have been tested in dogs. However, different from human medicine, we lack strategies to select patients to be treated with each TKI. Therefore, this study aimed to screen different tumor subtypes regarding TKI target immunoexpression as a predictor strategy to personalize the canine cancer treatment. It included 18 prostatic carcinomas, 36 soft tissue sarcomas, 20 mammary gland tumors, 6 urothelial bladder carcinomas, and 7 tumors from the endocrine system. A total of 87 patients with paraffin blocks were used to perform immunohistochemistry (IHC) of human epidermal growth factor receptor 2 (HER-2), epidermal growth factor receptors 1 (EGFR1), vascular endothelial growth factor receptor 2 (VEGFR-2), platelet derived growth factor receptor beta (PDGFR-ß), c-KIT, and extracellular signal-regulated kinase 1/2 (ERK1/ERK2). The immunohistochemical screening revealed a heterogeneous protein expression among histological types with mesenchymal tumors showing the lowest expression level and carcinomas the highest expression. We have demonstrated by IHC screening that HER2, EGFR1, VEGFR-2, PDGFR-ß and ERK1/ERK2 are commonly overexpressed in dogs with different carcinomas, and KIT expression is considered relatively low in the analyzed samples.


Assuntos
Doenças do Cão , Imuno-Histoquímica , Cães , Animais , Doenças do Cão/metabolismo , Doenças do Cão/tratamento farmacológico , Doenças do Cão/patologia , Masculino , Feminino , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/veterinária , Neoplasias/patologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Biomarcadores Tumorais/metabolismo , Receptor ErbB-2/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores ErbB/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Humanos
12.
Int J Pharm ; 661: 124439, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38972520

RESUMO

Liposomes functionalized with monoclonal antibodies offer targeted therapy for cancer, boasting advantages like sustained drug release, enhanced stability, passive accumulation in tumors, and interaction with overexpressed receptors on cancer cells. This study aimed to develop and characterize anti-EGFR immunoliposomes loaded with cabazitaxel and assess their properties against prostate cancer in vitro and in vivo. Using a Box-Behnken design, a formulation with soy phosphatidylcholine, 10% cholesterol, and a 1:20 drug-lipid ratio yielded nanometric particle size, low polydispersity and high drug encapsulation. Immunoliposomes were conjugated with cetuximab through DSPE-PEG-Maleimide lipid anchor. Characterization confirmed intact antibody structure and interaction with EGFR receptor following conjugation. Cabazitaxel was dispersed within the liposomes in the amorphous state, confirmed by solid-state analyses. In vitro release studies showed slower cabazitaxel release from immunoliposomes. Immunoliposomes had enhanced cabazitaxel cytotoxicity in EGFR-overexpressing DU145 cells without affecting non-tumor L929 cells. Cetuximab played an important role to improve cellular uptake in a time-dependent fashion in EGFR-overexpressing prostate cancer cells. In vivo, immunoliposomes led to significant tumor regression, improved survival, and reduced weight loss in xenograft mice. While cabazitaxel induced leukopenia, consistent with clinical findings, histological analysis revealed no evident toxicity. In conclusion, the immunoliposomes displayed suitable physicochemical properties for cabazitaxel delivery, exhibited cytotoxicity against EGFR-expressing prostate cancer cells, with high cell uptake, and induced significant tumor regression in vivo, with manageable systemic toxicity.


Assuntos
Cetuximab , Liberação Controlada de Fármacos , Receptores ErbB , Lipossomos , Neoplasias da Próstata , Taxoides , Ensaios Antitumorais Modelo de Xenoenxerto , Masculino , Animais , Receptores ErbB/imunologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Humanos , Linhagem Celular Tumoral , Taxoides/administração & dosagem , Taxoides/farmacocinética , Taxoides/farmacologia , Taxoides/química , Cetuximab/administração & dosagem , Camundongos , Camundongos Nus , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/química , Polietilenoglicóis/química , Polietilenoglicóis/administração & dosagem , Tamanho da Partícula , Sistemas de Liberação de Medicamentos
13.
PLoS One ; 19(7): e0306429, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38980867

RESUMO

Brucella abortus (Ba) is a pathogen that survives inside macrophages. Despite being its preferential niche, Ba infects other cells, as shown by the multiple signs and symptoms humans present. This pathogen can evade our immune system. Ba displays a mechanism of down-modulating MHC-I on monocytes/macrophages in the presence of IFN-γ (when Th1 response is triggered) without altering the total expression of MHC-I. The retained MHC-I proteins are located within the Golgi Apparatus (GA). The RNA of Ba is one of the PAMPs that trigger this phenomenon. However, we acknowledged whether this event could be triggered in other cells relevant during Ba infection. Here, we demonstrate that Ba RNA reduced the surface expression of MHC-I induced by IFN-γ in the human bronchial epithelium (Calu-6), the human alveolar epithelium (A-549) and the endothelial microvasculature (HMEC) cell lines. In Calu-6 and HMEC cells, Ba RNA induces the retention of MHC-I in the GA. This phenomenon was not observed in A-549 cells. We then evaluated the effect of Ba RNA on the secretion of IL-8, IL-6 and MCP-1, key cytokines in Ba infection. Contrary to our expectations, HMEC, Calu-6 and A-549 cells treated with Ba RNA had higher IL-8 and IL-6 levels compared to untreated cells. In addition, we showed that Ba RNA down-modulates the MHC-I surface expression induced by IFN-γ on human monocytes/macrophages via the pathway of the Epidermal Growth Factor Receptor (EGFR). So, cells were stimulated with an EGFR ligand-blocking antibody (Cetuximab) and Ba RNA. Neutralization of the EGFR to some extent reversed the down-modulation of MHC-I mediated by Ba RNA in HMEC and A-549 cells. In conclusion, this is the first study exploring a central immune evasion strategy, such as the downregulation of MHC-I surface expression, beyond monocytes and could shed light on how it persists effectively within the host, enduring unseen and escaping CD8+ T cell surveillance.


Assuntos
Brucella abortus , Células Endoteliais , Células Epiteliais , Antígenos de Histocompatibilidade Classe I , Interferon gama , Humanos , Interferon gama/metabolismo , Interferon gama/farmacologia , Células Endoteliais/metabolismo , Células Endoteliais/microbiologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Células Epiteliais/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , RNA Bacteriano/genética , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Receptores ErbB/metabolismo , Brucelose/imunologia , Brucelose/metabolismo , Brucelose/microbiologia , Brucelose/genética , Complexo de Golgi/metabolismo , Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos/microbiologia , Monócitos/metabolismo , Monócitos/imunologia , Monócitos/efeitos dos fármacos
14.
Sci Rep ; 14(1): 16721, 2024 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-39030304

RESUMO

Antigen-specific cytotoxic CD8 T cells are extremely effective in controlling tumor growth and have been the focus of immunotherapy approaches. We leverage in silico tools to investigate whether the occurrence of mutations in proteins previously described as immunogenic and highly expressed by glioblastoma multiforme (GBM), such as Epidermal Growth Factor Receptor (EGFR), Isocitrate Dehydrogenase 1 (IDH1), Phosphatase and Tensin homolog (PTEN) and Tumor Protein 53 (TP53), may be contributing to the differential presentation of immunogenic epitopes. We recovered Class I MHC binding information from wild-type and mutated proteins using the Immune Epitope Database (IEDB). After that, we built peptide-MHC (pMHC-I) models in HLA-arena, followed by hierarchical clustering analysis based on electrostatic surface features from each complex. We identified point mutations that are determinants for the presentation of a set of peptides from TP53 protein. We point to structural features in the pMHC-I complexes of wild-type and mutated peptides, which may play a role in the recognition of CD8 T cells. To further explore these features, we performed 100 ns molecular dynamics simulations for the peptide pairs (wt/mut) selected. In pursuit of novel therapeutic targets for GBM treatment, we selected peptides where our predictive results indicated that mutations would not disrupt epitope presentation, thereby maintaining a specific CD8 T cell immune response. These peptides hold potential for future GBM interventions, including peptide-based or mRNA vaccine development applications.


Assuntos
Apresentação de Antígeno , Linfócitos T CD8-Positivos , Glioblastoma , Isocitrato Desidrogenase , Proteína Supressora de Tumor p53 , Glioblastoma/imunologia , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Linfócitos T CD8-Positivos/imunologia , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/imunologia , Isocitrato Desidrogenase/química , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia , Apresentação de Antígeno/imunologia , Mutação , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/imunologia , PTEN Fosfo-Hidrolase/química , Receptores ErbB/imunologia , Receptores ErbB/genética , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia
15.
Res Vet Sci ; 177: 105363, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39053093

RESUMO

Cutaneous squamous cell carcinoma (cSCC) is a neoplasm type often diagnosed in dogs. However, studies focused on further investigating its molecular biology, mainly biomarkers to help implementing new therapies, remain scare in the literature. Thus, immunostaining and the gene expression of epidermal growth factor receptors (HER1 and HER2) in canine cSCC presenting different cell differentiation degrees were herein assessed. Thirty-two (32) canine cSCC were selected, classified based on to their cell differentiation degree and subjected to immunohistochemical study to assess HER1 and HER2 immunostaining intensity and distribution. In addition, HER1 and HER2 gene expression was investigated through real-time PCR. Membranous and cytoplasmic immunostaining were observed in both markers. HER2 prevailed in poorly differentiated cSCC; there was positive protein expression correlation between both markers. Mean HER1 gene expression was higher in moderately differentiated, whereas mean HER2 gene expression was higher in poorly differentiated cSCC. Moreover, there was gene expression correlation between markers, regardless of cell differentiation degree. Thus, HER2 protein immunostaining and gene expression were higher in poorly differentiated canine cSCC and it enabled understanding that increase observed in this epidermal growth factor receptor is proportional to this neoplasm's cell differentiation degree in canine species. Results in the current study helped better understanding canine cSCC's molecular biology; however, it is relevant studying other markers aiming to investigate signaling pathways.


Assuntos
Carcinoma de Células Escamosas , Doenças do Cão , Receptores ErbB , Imuno-Histoquímica , Receptor ErbB-2 , Neoplasias Cutâneas , Animais , Cães , Doenças do Cão/genética , Doenças do Cão/metabolismo , Carcinoma de Células Escamosas/veterinária , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Neoplasias Cutâneas/veterinária , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Imuno-Histoquímica/veterinária , Feminino , Regulação Neoplásica da Expressão Gênica , Masculino , Reação em Cadeia da Polimerase em Tempo Real/veterinária
16.
Int J Mol Sci ; 25(13)2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38999930

RESUMO

Although SARS-CoV-2 induces mucin hypersecretion in the respiratory tract, hyposalivation/xerostomia has been reported by COVID-19 patients. We evaluate the submandibular gland (SMGs) pathogenesis in SARS-CoV-2-infected K18-hACE2 mice, focusing on the impact of infection on the mucin production and structural integrity of acini, ductal system, myoepithelial cells (MECs) and telocytes. The spike protein, the nucleocapsid protein, hACE2, actin, EGF, TNF-α and IL-1ß were detected by immunofluorescence, and the Egfr and Muc5b expression was evaluated. In the infected animals, significant acinar hypertrophy was observed in contrast to ductal atrophy. Nucleocapsid proteins and/or viral particles were detected in the SMG cells, mainly in the nuclear membrane-derived vesicles, confirming the nuclear role in the viral formation. The acinar cells showed intense TNF-α and IL-1ß immunoexpression, and the EGF-EGFR signaling increased, together with Muc5b upregulation. This finding explains mucin hypersecretion and acinar hypertrophy, which compress the ducts. Dying MECs and actin reduction were also observed, indicating failure of contraction and acinar support, favoring acinar hypertrophy. Viral assembly was found in the dying telocytes, pointing to these intercommunicating cells as viral transmitters in SMGs. Therefore, EGF-EGFR-induced mucin hypersecretion was triggered by SARS-CoV-2 in acinar cells, likely mediated by cytokines. The damage to telocytes and MECs may have favored the acinar hypertrophy, leading to ductal obstruction, explaining xerostomia in COVID-19 patients. Thus, acinar cells, telocytes and MECs may be viral targets, which favor replication and cell-to-cell viral transmission in the SMG, corroborating the high viral load in saliva of infected individuals.


Assuntos
COVID-19 , Receptores ErbB , SARS-CoV-2 , Glândula Submandibular , Xerostomia , COVID-19/patologia , COVID-19/virologia , COVID-19/metabolismo , Animais , Glândula Submandibular/virologia , Glândula Submandibular/patologia , Glândula Submandibular/metabolismo , SARS-CoV-2/fisiologia , Camundongos , Xerostomia/etiologia , Xerostomia/patologia , Xerostomia/virologia , Xerostomia/metabolismo , Receptores ErbB/metabolismo , Humanos , Enzima de Conversão de Angiotensina 2/metabolismo , Mucina-5B/metabolismo , Células Acinares/patologia , Células Acinares/metabolismo , Células Acinares/virologia , Interleucina-1beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Modelos Animais de Doenças
17.
Clin Transl Oncol ; 26(12): 3236-3245, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38872053

RESUMO

BACKGROUND: TP53 is a frequently mutated oncogene within non-small cell lung cancer (NSCLC). However, the clinical and prognostic significance of co-mutations in TP53 in patients with advanced NSCLC has not been fully elucidated. METHODS: A total of 174 patients with advanced NSCLC were enrolled in this study. All patients were subjected to sequencing analysis of tumor-related genes and information such as PD-L1 expression, TMB, and co-mutation changes were collected. Patients were categorized into TP53 mutant and TP53 wild-type groups according to their TP53 mutation status and then statistically analyzed. RESULTS: TP53 mutations were the most common among all patients, accounting for 56.32%, followed by epidermal growth factor receptor mutations at 48.27%. The most common mutation sites in the TP53 mutation group were exons 5-8.TP53 mutations were significantly associated with PD-L1 and TMB levels. Univariate Cox analysis showed that gender and EGFR mutation affected the prognosis of TP53-mutated NSCLC patients, and multivariate Cox regression analysis identified EGFR mutation as an independent risk factor. The OS of NSCLC patients in the TP53 mutation group was significantly shorter than that of the TP53wt group. Survival curves in the TP53/EGFR combined mutation group showed that patients with combined EGFR mutation had a lower survival rate. DISCUSSION: TP53 mutations are associated with different clinical indicators and have important implications in clinical treatment. TP53 is a poor prognostic factor for NSCLC patients, and TP53/EGFR co-mutation will affect the survival time of patients. TP53/EGFR co-mutation may be a new prognostic marker for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Mutação , Proteína Supressora de Tumor p53 , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Masculino , Feminino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Prognóstico , Pessoa de Meia-Idade , Proteína Supressora de Tumor p53/genética , Idoso , Receptores ErbB/genética , Adulto , Antígeno B7-H1/genética , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Taxa de Sobrevida
18.
Clin Transl Oncol ; 26(12): 3218-3225, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38862862

RESUMO

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for the vast majority of all diagnosed lung cancers. According to their histology, most NSCLCs are considered non-squamous cell carcinoma (NSCC), and up to 85% of the latter may lack either one of the two main actionable oncogenic drivers (i.e., EGFR mutations and ALK rearrangements). OBJECTIVE: Our analysis aimed to describe the clinical and epidemiological characteristics of Spanish patients suffering from NSCC with no actionable oncogenic driver in daily clinical practice. DESIGN: A retrospective, cross-sectional, descriptive analysis. METHODS: We analyzed the records of all Spanish patients with advanced NSCC diagnosed between January 2011 and January 2020 and included in the Spanish Thoracic Tumor Registry database. We evaluated the presence of metastasis and molecular profiling at the time of diagnosis and treatments received. We also assessed overall survival (OS) and progression-free survival (PFS) according to first-line treatment. RESULTS: One thousand seven hundred ninety-seven Spanish patients with NSCC were included. They were mainly men (73.2%), smokers (current [44.4%] and former [44.4%]) and presented adenocarcinoma histology (97.6%). Most patients had at least one comorbidity (80.4%) and one metastatic site (96.8%), and a non-negligible number of those tested were PD-L1 positive (35.2%). Notably, the presence of liver metastasis indicated a shorter median OS and PFS than metastasis in other locations (p < 0.001). Chemotherapy was more often prescribed than immunotherapy as first-, second-, and third-line treatment in that period. In first-line, the OS rates were similar in patients receiving either regimen, but PFS rates significantly better in patients treated with immunotherapy (p = 0.026). Also, a high number of patients did not reach second- and third-line treatment, suggesting the failure of current early diagnostic measures and therapies. CONCLUSIONS: This analysis of the most lethal tumor in Spain could highlight the strengths and the weaknesses of its clinical management and set the ground for further advances and research.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Sistema de Registros , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Espanha/epidemiologia , Masculino , Feminino , Estudos Transversais , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Adulto , Receptores ErbB/genética , Idoso de 80 Anos ou mais , Mutação , Quinase do Linfoma Anaplásico/genética , Intervalo Livre de Progressão , Antígeno B7-H1/genética
19.
J Hypertens ; 42(6): 984-999, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38690903

RESUMO

Nox1 signaling is a causal key element in arterial hypertension. Recently, we identified protein disulfide isomerase A1 (PDI) as a novel regulatory protein that regulates Nox1 signaling in VSMCs. Spontaneously hypertensive rats (SHR) have increased levels of PDI in mesenteric resistance arteries compared with Wistar controls; however, its consequences remain unclear. Herein, we investigated the role of PDI in mediating Nox1 transcriptional upregulation and its effects on vascular dysfunction in hypertension. We demonstrate that PDI contributes to the development of hypertension via enhanced transcriptional upregulation of Nox1 in vascular smooth muscle cells (VSMCs). We show for the first time that PDI sulfenylation by hydrogen peroxide contributes to EGFR activation in hypertension via increased shedding of epidermal growth factor-like ligands. PDI also increases intracellular calcium levels, and contractile responses induced by ANG II. PDI silencing or pharmacological inhibition in VSMCs significantly decreases EGFR activation and Nox1 transcription. Overexpression of PDI in VSMCs enhances ANG II-induced EGFR activation and ATF1 translocation to the nucleus. Mechanistically, PDI increases ATF1-induced Nox1 transcription and enhances the contractile responses to ANG II. Herein we show that ATF1 binding to Nox1 transcription putative regulatory regions is augmented by PDI. Altogether, we provide evidence that HB-EGF in SHR resistance vessels promotes the nuclear translocation of ATF1, under the control of PDI, and thereby induces Nox1 gene expression and increases vascular reactivity. Thus, PDI acts as a thiol redox-dependent enhancer of vascular dysfunction in hypertension and could represent a novel therapeutic target for the treatment of this disease.


Assuntos
Hipertensão , Músculo Liso Vascular , NADPH Oxidase 1 , Isomerases de Dissulfetos de Proteínas , Ratos Endogâmicos SHR , Regulação para Cima , Animais , Isomerases de Dissulfetos de Proteínas/metabolismo , Isomerases de Dissulfetos de Proteínas/genética , NADPH Oxidase 1/metabolismo , NADPH Oxidase 1/genética , Hipertensão/fisiopatologia , Hipertensão/genética , Hipertensão/metabolismo , Ratos , Músculo Liso Vascular/metabolismo , Masculino , Miócitos de Músculo Liso/metabolismo , Receptores ErbB/metabolismo , Receptores ErbB/genética , Ratos Wistar , Transcrição Gênica
20.
Eur J Pharmacol ; 975: 176636, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38729417

RESUMO

Endothelial cells express multiple receptors mediating estrogen responses; including the G protein-coupled estrogen receptor (GPER). Past studies on nitric oxide (NO) production elicited by estrogens raised the question whether 17-ß-estradiol (E2) and natural phytoestrogens activate equivalent mechanisms. We hypothesized that E2 and phytoestrogens elicit NO production via coupling to distinct intracellular pathways signalling. To this aim, perfusion of E2 and phytoestrogens to the precontracted rat mesentery bed examined vasorelaxation, while fluorescence microscopy on primary endothelial cells cultures quantified single cell NO production determined following 4-amino-5-methylamino-2',7'-difluoroescein diacetate (DAF) incubation. Daidzein (DAI) and genistein (GEN) induced rapid vasodilatation associated to NO production. Multiple estrogen receptor activity was inferred based on the reduction of DAF-NO signals; G-36 (GPER antagonist) reduced 75 % of all estrogen responses, while fulvestrant (selective nuclear receptor antagonist) reduced significantly more the phytoestrogens responses than E2. The joint application of both antagonists abolished the E2 response but not the phytoestrogen-induced DAF-NO signals. Wortmannin or LY-294002 (PI3K inhibitors), reduced by 90% the E2-evoked signal while altering significantly less the DAI-induced response. In contrast, H-89 (PKA inhibitor), elicited a 23% reduction of the E2-induced signal while blocking 80% of the DAI-induced response. Desmethylxestospongin-B (IP3 receptor antagonist), decreased to equal extent the E2 or the DAI-induced signal. Epidermal growth factor (EGF) induced NO production, cell treatment with AG-1478, an EGF receptor kinase inhibitor reduced 90% DAI-induced response while only 53% the E2-induced signals; highlighting GPER induced EGF receptor trans-modulation. Receptor functional selectivity may explain distinct signalling pathways mediated by E2 and phytoestrogens.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico , Receptores ErbB , Estradiol , Óxido Nítrico , Fosfatidilinositol 3-Quinases , Fitoestrógenos , Transdução de Sinais , Vasodilatação , Animais , Fitoestrógenos/farmacologia , Estradiol/farmacologia , Óxido Nítrico/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Receptores ErbB/metabolismo , Masculino , Isoflavonas/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Genisteína/farmacologia , Receptores de Estrogênio/metabolismo , Ratos Wistar
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA