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PURPOSE: The minimally invasive Chevron-Akin (MICA) is considered the third generation of minimally invasive hallux valgus (HV) surgery, and its original description included fixation of the Akin osteotomy with a screw. The aim of this study is to evaluate a series of patients undergoing HV correction using the MICA technique without screw fixation of the Akin osteotomy. METHODS: We retrospectively evaluated 58 consecutive patients who underwent surgical correction for HV between August 2018 and March 2020. A total of 69 feet were evaluated with a minimum follow-up of 2 years. Clinical outcomes such as pain (VAS), function (AOFAS), range of movement, criteria personal satisfaction and complications were evaluated. RESULTS: The AOFAS score (mean ± standard deviation) significantly improved from 57.0 ± 8.6 preoperatively to 93.9 ± 8.7 postoperatively (p < .001) with a minimum follow-up of 2 years. The VAS score improved from 6.0 ± 1.8 preoperatively to 0.6 ± 1.4 at 2-year follow-up (p < .001), and the hallux valgus angle reduced from 39.7 ± 6.9 to 8.9 ± 9.0 (p < .001). The majority of patients (95.6%) reported the result as excellent or good, and the most common complication was the need to remove the screw (7.2%). CONCLUSIONS: The use of MICA without Akin osteotomy fixation resulted in successful correction of hallux valgus with improvements in clinical and radiographic parameters. LEVEL OF EVIDENCE: IV, case series.
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Hallux Valgus , Procedimentos Cirúrgicos Minimamente Invasivos , Osteotomia , Humanos , Hallux Valgus/cirurgia , Hallux Valgus/diagnóstico por imagem , Osteotomia/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Seguimentos , Adulto , Amplitude de Movimento Articular , Idoso , Resultado do Tratamento , Satisfação do Paciente , Parafusos ÓsseosRESUMO
PROBLEM: Endometriosis exhibits several immune dysfunctions, including deficient natural killer (NK) cell cytotoxicity. MICA (MHC class I chain-related molecule A) is induced by biological stress and soluble MICA (sMICA) negatively modulates the expression of the activating receptor, NKG2D, reducing NK cells activities. We investigated the involvement of soluble MICA in NK cell-deficient activity in endometriosis. METHODS OF STUDY: sMICA levels (serum and peritoneal fluid-PF) were evaluated by ELISA. Circulating NK cell subsets quantification and its NKG2D receptor expression, NK cell cytotoxicity and CD107a, IFN-γ and IL-10 expressions by NK cells stimulated with K562 cells were determined by flow cytometry. RESULTS: We found higher sMICA levels (serum and PF) in endometriosis, especially in advanced and deep endometriosis. Endometriosis presented lower percentages of CD56dim CD16+ cytotoxic cells and impaired NK cell responses upon stimulation, resulting in lower CD107a and IFN-γ expressions, and deficient NK cell cytotoxicity. NK cell stimulation in the MICA-blocked condition (mimicking the effect of sMICA) showed decreased cytotoxicity in initial endometriosis stages and the emergence of a negative correlation between CD107a expression and sMICA levels. CONCLUSIONS: We suggest that soluble MICA is a potential player in endometriosis pathophysiology with involvement in disease progression and severity, contributing to NK cell impaired IFN-γ response and degranulation. NK cell compartment exhibits multiple perturbations, including quantitative deficiency and impaired cytotoxicity, contributing to inadequate elimination of ectopic endometrial tissue.
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Endometriose , Feminino , Humanos , Degranulação Celular , Células Matadoras Naturais , Expressão Gênica , Progressão da Doença , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismoRESUMO
Background: Recognizing preoperative first-ray hypermobility is important to planning hallux valgus (HV) surgery. A recent study showed the minimally invasive chevron Akin (MICA) osteotomy increased varus displacement of the proximal fragment of the first metatarsal osteotomy. The present study aims to evaluate the ability of the radiographic first-ray squeeze test to predict the varus displacement of the proximal fragment of the first metatarsal osteotomy when performing the MICA procedure. Methods: A prospective case series of patients with moderate to severe HV who underwent MICA was performed. The HV deformity correction was analyzed by comparing the preoperative and 12-week postoperative hallux valgus angle (HVA) and the intermetatarsal angle between the first and second rays (1-2 IMA). The ability of the radiographic first-ray squeeze test to predict the varus displacement of the first metatarsal was done by comparing the preoperative 1-2 IMA measured in the AP radiographic first-ray squeeze test (IMA-ST) with the intermetatarsal angle between the second metatarsal and the axis of the first metatarsal osteotomy proximal fragment (IAPF) taken 12 weeks postoperatively. Results: Between July 2022 and May 2023, a total of 39 feet in 28 patients underwent MICA. The mean IMA improved from 13.8 (SD = 2.2) to 3.8 degrees (SD = 1.5) (P < .001), and the mean HVA improved from 27.8 (SD = 6.1) to 4.9 degrees (SD = 2.5) (P < .001). A linear regression analysis revealed that IMA-ST is highly associated with the 12 week assessed IAPF (P < .001). Conclusion: The preoperative radiographic first-ray squeeze test appears to predict with high fidelity the varus displacement of the proximal fragment of the first metatarsal that can occur after the MICA procedure.Level of Evidence: Level III, prospective cohort study.
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MIC-A and MIC-B are the natural ligands for NKG2D, an activator receptor expressed in NK cells. Soluble isoforms of MIC-A and MIC-B (sMICA, sMICB) have been identified in different malignancies, affecting NK cells' cytotoxicity. The study was performed to determine the levels of sMICA, sMICB, the expression of MIC-A, and MIC-B on tumor tissues, and lymphocyte subpopulations (CD4 + , CD8 + , NK, NKT, Tγδ cells, B cells, monocytes) in 94 patients with non-Hodgkin's lymphoma (NHL) and 72 healthy donors.The most frequent lymphoma was diffuse large B cell lymphoma (48%). Patients with NHL had decreased numbers of CD4 T cells, CD8 T cells, B cells, monocytes, NK cells, type 1 dendritic cells, γδ T cells, and increased iNKT cells. Patients showed higher levels of sMIC-A and similar serum levels of sMIC-B.Survival was poorer in patients having higher LDH values and lower numbers of CD4 T cells, type 1 dendritic cells, gamma-delta T cells, and high levels of sMIC-A.In conclusion, high levels of sMIC and decreased numbers in circulating lymphocyte subsets are related to poor outcomes in NHL.
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Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Humanos , Prognóstico , Linfoma não Hodgkin/patologia , Subpopulações de Linfócitos , Células Matadoras Naturais/patologia , Linfoma Difuso de Grandes Células B/patologiaRESUMO
Ankylosing spondylitis (AS) is an autoinflammatory disease that affects the sacroiliac joints, causing stiffness and pain in the back. MICA is a ligand of the NKG2D receptor, and an increase in its expression affects the immune response in various diseases. NLRP3 is a multiprotein complex that promotes the release of IL-1ß, but its role in AS has been minimally explored. The objective of this study was to analyze the association and interaction of polymorphic variants of the MICA and NLRP3 genes in patients with AS. In this case-control study, patients with AS were included and compared with healthy controls of Mexican origin. The polymorphisms rs4349859 and rs116488202 of MICA and rs3806268 and rs10754558 of NLRP3 were genotyped using TaqMan probes. Associations were determined using logistic regression models, while interactions were analyzed by the multifactorial dimensionality reduction (MDR) method. A P value < 0.05 was considered statistically significant. The minor allele of rs4349859 (A) and rs116488202 (T) of MICA polymorphisms showed risk associations with AS (OR = 9.22, 95% CI = 4.26-20.0, P < 0.001; OR = 9.36, 95% CI = 4.17-21.0, P < 0.001), while the minor allele of the rs3806268 (A) polymorphism of NLRP3 was associated with protection (OR = 0.55, 95% CI = 0.33-0.91, P = 0.019). MDR analysis revealed synergistic interactions between the MICA and NLRP3 polymorphisms (P = 0.012). In addition, high- and low-risk genotypes were identified among these variants. The study findings suggest that the MICA rs4349859 A allele and rs116488202 T allele are associated with AS risk. An interaction between MICA and NLRP3 was observed which could increase the genetic risk in AS.
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Espondilite Anquilosante , Humanos , Espondilite Anquilosante/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , GenótipoRESUMO
MicroRNAs (miRNAs) are small non-coding RNAs that participate as powerful genetic regulators. MiRNAs can interfere with cellular processes by interacting with a broad spectrum of target genes under physiological and pathological states, including cancer development and progression. Major histocompatibility complex major histocompatibility complex class I-related chain A (MICA) belongs to a family of proteins that bind the natural-killer group 2, member D (NKG2D) receptor on Natural Killer cells and other cytotoxic lymphocytes. MICA plays a crucial role in the host's innate immune response to several disease settings, including cancer. MICA harbors various single nucleotide polymorphisms (SNPs) located in its 3'-untranslated region (3'UTR), a characteristic that increases the complexity of MICA regulation, favoring its post-transcriptional modulation by miRNAs under physiological and pathological conditions. Here, we conducted an in-depth analysis of MICA 3'UTR sequences according to each MICA allele described to date using NCBI database. We also systematically evaluated interactions between miRNAs and their putative targets on MICA 3'UTR containing SNPs using in silico analysis. Our in silico results showed that MICA SNPs rs9266829, rs 1880, and rs9266825, located in the target sequence of miRNAs hsa-miR-106a-5p, hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-20b-5p, hsa-miR-93, hsa-miR-1207.5p, and hsa-miR-711 could modify the binding free energy between -8.62 and -18.14 kcal/mol, which may affect the regulation of MICA expression. We believe that our results may provide a starting point for further exploration of miRNA regulatory effects depending on MICA allelic variability; they may also be a guide to conduct miRNA in silico analysis for other highly polymorphic genes.
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Non-Hodkin's lymphoma (NHL) is the most frequent hematologic malignancy in humans and dogs. NKG2D is one of the most critical receptors on NK cells, recognizing their natural ligands on malignant cells such as A and B major histocompatibility complex-related proteins (MIC-A and MIC-B). Soluble molecules (sMIC-A and sMIC-B) can interfere with immune synapsis between NK cells and tumor cells, impeding NK cytotoxicity. The main objectives of this study were to analyze, in dogs with diffuse large B cell lymphoma, NK cell lymphoma, and reactive lymphadenopathies, the role of NK cells, their activating receptors NKG2D and NKp46, and their ligands MIC-A and MIC-B, as well as soluble molecules sMIC-A and sMIC-B. Thirty-six dogs with a possible diagnosis of NHL and eight healthy dogs were studied. NHL was diagnosed in 28 (78 %) dogs; in the other 8 (22 %), reactive lymphadenopathies were present. Most of the lymphomas corresponded to B cell NHL (82 %). The most predominant subtype was diffuse large B cell lymphoma (21, 71.5 %), followed by five cases (18 %) that were Non-B Non-T lymphomas (presumably NK cell lymphomas) and other B cell lymphomas (3, 10.5%). There were no cases of T cell NHL. MIC-A was positive in 7 of 27 (26 %) cases of NHL, and MIC-B in 20 of 27 (74 %) NHL. In non-malignant lymphadenopathies, three (37.5 %) dogs were positive for MIC-A, and five (62.5 %) expressed MIC-B. Dogs with lymphoma had higher numbers of NK cells than eight healthy dogs. In 15 dogs (12 cases with NHL and three cases with reactive adenopathies) and eight controls, there were no differences in the number of NK cells expressing NKP46 and NKG2D. NHL dogs had higher values of sMIC-A and sMIC-B. B-cell and NK cell lymphomas correspond to 86 % and 14 % of all canine lymphomas. MIC-A, MIC-B, and sMIC-A and sMIC-B were increased in canine lymphomas.
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Doenças do Cão , Linfadenopatia , Linfoma Difuso de Grandes Células B , Animais , Cães , Doenças do Cão/metabolismo , Células Matadoras Naturais , Linfadenopatia/metabolismo , Linfadenopatia/veterinária , Linfoma Difuso de Grandes Células B/veterinária , Linfoma Difuso de Grandes Células B/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismoRESUMO
NKG2D is a major natural killer (NK) cell-activating receptor that recognizes eight ligands (NKG2DLs), including MICA, and whose engagement triggers NK cell effector functions. As NKG2DLs are upregulated on tumor cells but tumors can subvert the NKG2D-NKG2DL axis, NKG2DLs constitute attractive targets for antibody (Ab)-based immuno-oncology therapies. However, such approaches require a deep characterization of NKG2DLs and NKG2D cell surface expression on primary tumor and immune cells. Here, using a bioinformatic analysis, we observed that MICA is overexpressed in renal cell carcinoma (RCC), and we also detected an association between the NKG2D-MICA axis and a diminished overall survival of RCC patients. Also, by flow cytometry (FC), we observed that MICA was the only NKG2DL over-expressed on clear cell renal cell carcinoma (ccRCC) tumor cells, including cancer stem cells (CSC) that also coexpressed NKG2D. Moreover, tumor-infiltrating leukocytes (TIL), but not peripheral blood lymphoid cells (PBL) from ccRCC patients, over-expressed MICA, ULBP3 and ULBP4. In addition, NKG2D was downregulated on peripheral blood NK cells (PBNK) from ccRCC patients but upregulated on tumor-infiltrating NK cells (TINK). These TINK exhibited impaired degranulation that negatively correlated with NKG2D expression, diminished IFN-γ production, upregulation of TIM-3, and an impaired glucose intake upon stimulation with cytokines, indicating that they are dysfunctional, display features of exhaustion and an altered metabolic fitness. We conclude that ccRCC patients exhibit a distorted MICA-NKG2D axis, and MICA emerges as the forefront NKG2DL for the development of targeted therapies in ccRCC.
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Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/terapia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Neoplasias Renais/terapia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptores de Células Matadoras NaturaisRESUMO
INTRODUCTION: Minimally Invasive Chevron Akin (MICA) can be used to treat hallux valgus (HV) associated with a hypermobility of the first metatarsal-cuneiform joint (1MTCJ). The aim of this study was to perform a radiographic analysis of the MICA, focused on evaluating the 1MTCJ. METHODS: Forty patients (50 feet) with moderate to severe HV underwent a MICA procedure. Radiographic analysis included hallux valgus angle (HVA), intermetatarsal angles between the first and second rays (IMA), the intermetatarsal angle between the proximal fragment of the osteotomy and the second ray (IAPF) and the distance between a point 3 cm distal from the base of the second metatarsal and a point located at the same height for the first metatarsal base (Dist 1-2). The IAPF was compared with the preoperative IMA, and the other parameters were compared preoperatively and postoperatively. The radiographic complications were also recorded. RESULTS: Most patients were female (92%). The mean age was 50.4 years (SD = 16.1) and the mean follow-up was 16.1 months (SD = 3.5). The average HVA improved from 32.5° to 7.3°, and the average IMA from 14.2° to 4.2°. The IAPF and Dist1-2 values showed an increase of 4.8° and 4.0 mm respectively. There were no radiographic complications. Conclusion. Minimally invasive Chevron Akin promotes a great correction of the moderate to severe HV conventional parameters and increase the transversal stability of the 1MTCJ fixing this joint as medial as possible. LEVEL OF EVIDENCE: Level IV, case series.
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Despite the high number of individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) symptoms worldwide, many exposed individuals remain asymptomatic and/or uninfected and seronegative. This could be explained by a combination of environmental (exposure), immunological (previous infection), epigenetic, and genetic factors. Aiming to identify genetic factors involved in immune response in symptomatic COVID-19 as compared to asymptomatic exposed individuals, we analyzed 83 Brazilian couples where one individual was infected and symptomatic while the partner remained asymptomatic and serum-negative for at least 6 months despite sharing the same bedroom during the infection. We refer to these as "discordant couples". We performed whole-exome sequencing followed by a state-of-the-art method to call genotypes and haplotypes across the highly polymorphic major histocompatibility complex (MHC) region. The discordant partners had comparable ages and genetic ancestry, but women were overrepresented (65%) in the asymptomatic group. In the antigen-presentation pathway, we observed an association between HLA-DRB1 alleles encoding Lys at residue 71 (mostly DRB1*03:01 and DRB1*04:01) and DOB*01:02 with symptomatic infections and HLA-A alleles encoding 144Q/151R with asymptomatic seronegative women. Among the genes related to immune modulation, we detected variants in MICA and MICB associated with symptomatic infections. These variants are related to higher expression of soluble MICA and low expression of MICB. Thus, quantitative differences in these molecules that modulate natural killer (NK) activity could contribute to susceptibility to COVID-19 by downregulating NK cell cytotoxic activity in infected individuals but not in the asymptomatic partners.
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Infecções Assintomáticas , COVID-19 , Antígenos de Histocompatibilidade , Complexo Principal de Histocompatibilidade , SARS-CoV-2 , Adulto , Idoso , Brasil , COVID-19/genética , COVID-19/imunologia , Feminino , Predisposição Genética para Doença , Genótipo , Antígenos de Histocompatibilidade/genética , Antígenos de Histocompatibilidade/imunologia , Humanos , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Masculino , Pessoa de Meia-Idade , Sequenciamento do ExomaRESUMO
Immune checkpoint inhibitors (ICI) revolutionized the field of immuno-oncology and opened new avenues towards the development of novel assets to achieve durable immune control of cancer. Yet, the presence of tumor immune evasion mechanisms represents a challenge for the development of efficient treatment options. Therefore, combination therapies are taking the center of the stage in immuno-oncology. Such combination therapies should boost anti-tumor immune responses and/or target tumor immune escape mechanisms, especially those created by major players in the tumor microenvironment (TME) such as tumor-associated macrophages (TAM). Natural killer (NK) cells were recently positioned at the forefront of many immunotherapy strategies, and several new approaches are being designed to fully exploit NK cell antitumor potential. One of the most relevant NK cell-activating receptors is NKG2D, a receptor that recognizes 8 different NKG2D ligands (NKG2DL), including MICA and MICB. MICA and MICB are poorly expressed on normal cells but become upregulated on the surface of damaged, transformed or infected cells as a result of post-transcriptional or post-translational mechanisms and intracellular pathways. Their engagement of NKG2D triggers NK cell effector functions. Also, MICA/B are polymorphic and such polymorphism affects functional responses through regulation of their cell-surface expression, intracellular trafficking, shedding of soluble immunosuppressive isoforms, or the affinity of NKG2D interaction. Although immunotherapeutic approaches that target the NKG2D-NKG2DL axis are under investigation, several tumor immune escape mechanisms account for reduced cell surface expression of NKG2DL and contribute to tumor immune escape. Also, NKG2DL polymorphism determines functional NKG2D-dependent responses, thus representing an additional challenge for leveraging NKG2DL in immuno-oncology. In this review, we discuss strategies to boost MICA/B expression and/or inhibit their shedding and propose that combination strategies that target MICA/B with antibodies and strategies aimed at promoting their upregulation on tumor cells or at reprograming TAM into pro-inflammatory macrophages and remodeling of the TME, emerge as frontrunners in immuno-oncology because they may unleash the antitumor effector functions of NK cells and cytotoxic CD8 T cells (CTL). Pursuing several of these pipelines might lead to innovative modalities of immunotherapy for the treatment of a wide range of cancer patients.
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Proteínas Ligadas por GPI/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Animais , Terapia Combinada , Gerenciamento Clínico , Suscetibilidade a Doenças , Proteínas Ligadas por GPI/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ligantes , Terapia de Alvo Molecular , Neoplasias/patologia , Neoplasias/terapia , Receptores de Células Matadoras Naturais/genética , Receptores de Células Matadoras Naturais/metabolismo , Transdução de Sinais , Evasão Tumoral , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Gastric cancer (GC) is the fifth most prevalent type of cancer worldwide. Gastric tumor cells express MICA protein, a ligand to NKG2D receptor that triggers natural killer (NK) cells effector functions for early tumor elimination. MICA gene is highly polymorphic, thus originating alleles that encode protein variants with a controversial role in cancer. The main goal of this work was to study MICA gene polymorphisms and their relationship with the susceptibility and prognosis of GC. Fifty patients with GC and 50 healthy volunteers were included in this study. MICA alleles were identified using Sanger sequencing methods. The analysis of MICA gene sequence revealed 13 MICA sequences and 5 MICA-short tandem repeats (STR) alleles in the studied cohorts We identified MICA*002 (*A9) as the most frequent allele in both, patients and controls, followed by MICA*008 allele (*A5.1). MICA*009/049 allele was significantly associated with increased risk of GC (OR: 5.11 [95% CI: 1.39-18.74], p = 0.014). The analysis of MICA-STR alleles revealed a higher frequency of MICA*A5 in healthy individuals than GC patients (OR = 0.34 [95% CI: 0.12-0.98], p = 0.046). Survival analysis after gastrectomy showed that patients with MICA*002/002 or MICA*002/004 alleles had significantly higher survival rates than those patients bearing MICA*002/008 (p = 0.014) or MICA*002/009 (MICA*002/049) alleles (p = 0.040). The presence of threonine in the position MICA-181 (MICA*009/049 allele) was more frequent in GC patients than controls (p = 0.023). Molecular analysis of MICA-181 showed that the presence of threonine provides greater mobility to the protein than arginine in the same position (MICA*004), which could explain, at least in part, some immune evasion mechanisms developed by the tumor. In conclusion, our findings suggest that the study of MICA alleles is crucial to search for new therapeutic approaches and may be useful for the evaluation of risk and prognosis of GC and personalized therapy.
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Alelos , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe I/genética , Repetições de Microssatélites , Proteínas de Neoplasias/genética , Polimorfismo Genético , Neoplasias Gástricas/genética , Idoso , Feminino , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/imunologia , Neoplasias Gástricas/imunologiaRESUMO
Leprosy is a prevalent disease in Brazil, which ranks as the country with the second highest number of cases in the world. The disease manifests in a spectrum of forms, and genetic differences in the host can help to elucidate the immunopathogenesis. For a better understanding of MICA association with leprosy, we performed a case-control and a family-based study in two endemic populations in Brazil. MICA and HLA-B alleles were evaluated in 409 leprosy patients and in 419 healthy contacts by PCR-SSOP-Luminex-based technology. In the familial study, analysis of 46 families was completed by direct sequencing of all exons and 3'/5'untranslated regions, using the Ilumina MiSeq platform. All data were collected between 2006 and 2009. Statistical analysis was performed using the Chi-square or Fisher's exact test together with a multivariate analysis. Family-based association was assessed by transmission disequilibrium test (TDT) software FBAT 2.0.4. We found associations between the haplotype MICA*002-HLA-B*35 with leprosy in both the per se and the multibacillary (MB) forms when compared to healthy contacts. The MICA allele *008 was associated with the clinical forms of paucibacillary (PB). Additionally, MICA*029 was associated with the clinical forms of MB. The association of MICA*029 allele (MICA-A4 variant) with the susceptibility to the MB form suggests this variant for the transmembrane domain of the MICA molecule may be a risk factor for leprosy. Two MICA and nine HLA-B variants were found associated with leprosy per se in the Colônia do Prata population. Linkage disequilibrium analysis revealed perfect linkage disequilibrium (LD) between HLA-B markers rs2596498 and rs2507992, and high LD (R2 = .92) between these and the marker rs2442718. This familial study demonstrates that MICA association signals are not independent from those observed for HLA-B. Our findings contribute the knowledge pool of the immunogenetics of Hansen's disease and reveals a new association of the MICA*029 allele.
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Antígenos HLA-B/genética , Antígenos de Histocompatibilidade Classe I/genética , Hanseníase/imunologia , Regiões 3' não Traduzidas/genética , Regiões 5' não Traduzidas/genética , Adolescente , Adulto , Alelos , Brasil/epidemiologia , Estudos de Casos e Controles , Criança , Doenças Endêmicas , Etnicidade/genética , Éxons/genética , Saúde da Família , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Haplótipos/genética , Humanos , Hanseníase/epidemiologia , Hanseníase/genética , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Domínios Proteicos , Adulto JovemRESUMO
Leprosy is a prevalent disease in Brazil, which ranks as the country with the second highest number of cases in the world. The disease manifests in a spectrum of forms, and genetic differences in the host can help to elucidate the immunopathogenesis. For a better understanding of MICA association with leprosy, we performed a casecontrol and a familybased study in two endemic populations in Brazil. MICA and HLAB alleles were evaluated in 409 leprosy patients and in 419 healthy contacts by PCRSSOPLuminexbased technology. In the familial study, analysis of 46 families was completed by direct sequencing of all exons and 3'/5'untranslated regions, using the Ilumina MiSeq platform. All data were collected between 2006 and 2009. Statistical analysis was performed using the Chisquare or Fisher's exact test together with a multivariate analysis. Familybased association was assessed by transmission disequilibrium test (TDT) software FBAT 2.0.4. We found associations between the haplotype MICA*002HLAB*35 with leprosy in both the per se and the multibacillary (MB) forms when compared to healthy contacts. The MICA allele *008 was associated with the clinical forms of paucibacillary (PB). Additionally, MICA*029 was associated with the clinical forms of MB. The association of MICA*029 allele (MICAA4 variant) with the susceptibility to the MB form suggests this variant for the transmembrane domain of the MICA molecule may be a risk factor for leprosy. Two MICA and nine HLAB variants were found associated with leprosy per se in the Colônia do Prata population. Linkage disequilibrium analysis revealed perfect linkage disequilibrium (LD) between HLAB markers rs2596498 and rs2507992, and high LD (R2 = .92) between these and the marker rs2442718. This familial study demonstrates that MICA association signals are not independent from those observed for HLAB. Our findings contribute the knowledge pool of the immunogenetics of Hansen's disease and reveals a new association of the MICA*029 allele(AU).
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Humanos , Masculino , Feminino , Antígenos de Histocompatibilidade Classe I , Antígenos HLA-B , Hanseníase/genética , Hanseníase/imunologia , Polimorfismo Genético , Desequilíbrio de Ligação , Fatores de Risco , Predisposição Genética para Doença , Alelos , Hanseníase/transmissãoRESUMO
Objective: For a dental material to be machinable for CAD/CAM technology, it must offer convenient machining, under a given set of cutting conditions. Quantitative evaluation of machinability has been assessed in literature through various parameters such as tool wear, penetration rates, surface roughness, cutting force and power. A machinable ceramic will typically demonstrate a higher tool penetration rate with signs of reduced diamond tool wear and edge chipping. The purpose of this in vitro study was to evaluate the feasibility of machining an experimental ceramic, 20 wt.% zirconia reinforced mica glass ceramics (G20Z) for indirect dental restorations and compare the tool penetration rates of G20Z to commercially available dental ceramics, Presintered Zirconia (PSZ) and IPS emax CAD. Material and Methods: Precursors of base glass (SiO2 -Al2O3 -K2O -MgO-B2O3 -F) were melted at 15000C for 2 h in a platinum crucible and quenched in deionised water. The glass frit was ball milled with 20 wt. % YSZ (G20Z) and subject to two stage heat treatment in a muffle furnace. Specimens of G20Z (12 X 2 mm) were evaluated for their feasibility of machining under varying spindle speed, depth of cut, and feed rates. Influence of depth of cut, spindle speed and feed rate (vc=8000-16000 rpm, d=0.4-0.8 mm, f=0.1- 0.3 mm/tooth) on cutting forces, material response, surface roughness and tool wear were investigated. Tool penetration rates, tool wear and margin chipping were also evaluated and compared with Pre-sintered Zirconia (PSZ) and e.max CAD in a custom dental milling surveyor at 30,000 rpm with a load of 0.98 N under water lubrication for 6 min. Tool penetration rates were calculated as the ratio of length of cut and milling time with a measuring microscope and scanning electron microscope was used for tool wear and edge chipping. ANOVA and Tukey Kramer tests were used for statistically comparing the means of each group. Results: Spindle speed and feed rate play a significant role in influencing surface roughness, thrust force, cutting forces and tool wear. Penetration rates of G20Z (0.32 ±0.12 mm/min) was significantly greater than PSZ (0.26 ±0.06 mm/min) and IPS e.max CAD (0.21 ±0.05 mm/min). SEM observations reveal tool abrasion and edge chipping regardless of the ceramic type. Conclusion: High spindle speeds delivers low cutting forces with an average surface roughness of 1.61 µm, with abrasive wear of the tool insert and brittle fracture of zirconia mica glass ceramic composites. G20Z with its machinable nature demonstrates greater tool penetration rates than PSZ and IPS e.max CAD. Tool wear and edge chipping is seen in all the investigated ceramics. (AU)
Objetivo: Para que um material odontológico seja usinável para a tecnologia CAD / CAM, ele deve oferecer uma usinagem conveniente, sob um determinado conjunto de condições de corte. A avaliação quantitativa da usinabilidade tem sido avaliada na literatura por meio de vários parâmetros, como desgaste da ferramenta, taxas de penetração, rugosidade da superfície, força de corte e potência. Uma cerâmica usinável normalmente demonstrará uma maior taxa de penetração da ferramenta com sinais de desgaste reduzido da ferramenta de diamante e lascamento da borda. O objetivo deste estudo in vitro foi avaliar a viabilidade da usinagem de uma cerâmica experimental, 20% em peso de cerâmica de vidro de mica reforçada com zircônia (G20Z) para restaurações dentárias indiretas e comparar as taxas de penetração da ferramenta de G20Z com as cerâmicas dentais comercialmente disponíveis, Zircônia Presinterizada (PSZ) e IPS emax CAD. Material e Métodos: Precursores de vidro base (SiO2-Al2O3-K2O -MgO-B2O3 -F) foram fundidos a 15000C por 2 h em um cadinho de platina e temperados em água deionizada. A frita de vidro foi moída com 20% em peso de YSZ (G20Z) e submetida a tratamento térmico em duas fases em mufla. Amostras de G20Z (12 x 2 mm) foram avaliadas quanto à sua viabilidade de usinagem sob variação de velocidade do fuso, profundidade de corte e taxas de avanço. A influência da profundidade de corte, velocidade do fuso e taxa de avanço (vc = 8000-16000 rpm, d = 0,4-0,8 mm, f = 0,1- 0,3 mm / dente) nas forças de corte, resposta do material, rugosidade da superfície e desgaste da ferramenta foram investigadas. As taxas de penetração da ferramenta, o desgaste da ferramenta e o lascamento da margem também foram avaliados e comparados com Zircônia pré-sinterizada (PSZ) e e.max CAD em um topógrafo de fresamento dentário personalizado a 30.000 rpm com uma carga de 0,98 N de lubrificação subaquática por 6 min. As taxas de penetração da ferramenta foram calculadas como a razão entre o comprimento de corte e o tempo de fresamento com um microscópio de medição e um microscópio eletrônico de varredura foi usado para o desgaste da ferramenta e lascamento da borda. Os testes ANOVA e Tukey Kramer foram usados para comparar estatisticamente as médias de cada grupo. Resultados: a velocidade do fuso e a taxa de avanço desempenham um papel significativo em influenciar a rugosidade da superfície, força de impulso, forças de corte e desgaste da ferramenta. As taxas de penetração de G20Z (0,32 ± 0,12 mm / min) foram significativamente maiores do que PSZ (0,26 ± 0,06 mm / min) e IPS e.max CAD (0,21 ± 0,05 mm / min). As observações do SEM revelam a abrasão da ferramenta e o lascamento da borda, independentemente do tipo de cerâmica. Conclusão: As altas velocidades do fuso proporcionam baixas forças de corte com uma rugosidade superficial média de 1,61 µm, com desgaste abrasivo do inserto da ferramenta e fratura frágil de compósitos de cerâmica de vidro de zircônia. G20Z com sua natureza usinável demonstra maiores taxas de penetração da ferramenta do que PSZ e IPS e.max CAD. O desgaste da ferramenta e o lascamento da borda são vistos em todas as cerâmicas investigadas. (AU)
Assuntos
Ligas Metalo-Cerâmicas , Reparação de Restauração DentáriaRESUMO
Cervical carcinoma and cervical intraepithelial neoplasia (CIN) are associated with persistent infection by oncogenic subtypes of HPV (Human Papillomavirus). Factors linked to immunity, genetics and others like oral contraceptive use, sexual behavior, coinfections with other microorganisms and smoking seem to influence the mechanisms that determine regression or progression to CIN and cervical cancer. We investigated the effect of the MHC class I chain-related gene A (MICA) and Killer Cell Lectin Like receptor K1 (KLRK1) genes on cervical cancer and CIN lesions susceptibility in a group of 195 patients from southern Brazil. There were found a significantly higher number of ex-smokers in the control group (p = 0.005). There were more oral contraceptives (OC) users in the patient group. MICA*008:01/04 allele showed a significant difference between patient and control groups (p = 0.03; OR = 0.63, 95% CI 0.41-0.96), as well as MICA*018:01(p = 0.004, OR = 0.15, 95% CI 0.03-0.64) and MICA*002:01/020 (p = 0.01; OR = 0.60, 95% CI 0.40-0.88). We also analyzed cases and controls according to the MICA-129 genotypes (Met/Val). There was found a difference (p = 0.02) with the Met/Val genotype in a higher frequency in controls and Val/Val and Val/MICA del at a higher frequency in the patient group. For the KLRK1 gene there was no significant difference between groups.
Assuntos
Antígenos de Histocompatibilidade Classe I/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Papillomaviridae , Infecções por Papillomavirus/complicações , Displasia do Colo do Útero/etiologia , Displasia do Colo do Útero/imunologia , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/imunologia , Adulto , Alelos , Brasil/epidemiologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Células Matadoras Naturais/imunologia , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Subpopulações de Linfócitos T/imunologia , Neoplasias do Colo do Útero/epidemiologia , Adulto Jovem , Displasia do Colo do Útero/epidemiologiaRESUMO
In this study we investigated the impact of rs2596542A/G single nucleotide polymorphism (SNP) in the major histocompatibility complex class I chain-related sequence A (MICA) gene on HCV-induced hepatocellular carcinoma (HCC) susceptibility in a Brazilian population. In total, 252 HCV-infected patients (98 with HCV-induced HCC and 154 non-malignant HCV-induced liver cirrhosis) were enrolled and 98 healthy control subjects (negative anti-HCV). The MICA rs2596542 SNP genotypes were determined by real-time PCR assay. No differences in MICA genotype frequencies between HCV-induced cirrhosis patients and controls were observed. However, genotype frequencies of rs2596542A/G SNP were statistically different between HCV-induced HCC patients and controls (p = 0.048), and also between HCC and HCV-induced cirrhosis patients (p = 0.039). The highest frequency of the rs2596542AA genotype was observed in HCC patients (31.6%) when compared with HCV-induced cirrhosis patients (18.8%) and healthy controls (19.4%). Also, rs2596542AA genotype carriers have an increased risk for HCC when compared to HCV-induced cirrhosis status [odds ratio (OR) = 1.99; 95% confidence interval (CI) = 1.06-3.74, p = 0.020)] and healthy individuals (OR = 1.92, 95% CI = 1.00-3.70, p = 0.049). Taken together our study suggest that MICA rs2596542 SNP impacts HCV-induced HCC susceptibility suggesting that genetic variants in MICA are of clinical relevance to hepatocarcinogenesis by impacting host immune response in chronic HCV infection.
Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Hepatite C Crônica/complicações , Antígenos de Histocompatibilidade Classe I/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Idoso , Brasil , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Despite the lack of a complete understanding of the disparities involved, prostate cancer (PCa) has both higher incidence and death rates in African American Men (AAM) relative to those of Caucasian American Men (CAM). MHC class I polypeptide related sequence A (MICA) is an innate immunity protein involved in tumor immunoevasion. Due to a lack of reports of race-specific expression of MICA in PCa, we evaluated MICA expression in patients' tumors and in cell lines from a racially diverse origin. Immunohistochemistry was done on a tissue microarray (TMA) with antibodies against MICA. Tumor MICA mRNA was assessed by data mining using Oncomine and PROGeneV2. Surface MICA and release rate of soluble (s) MICA was evaluated in PCa cell lines originally derived from African American (MDA-PCa-2b) or Caucasian (LNCaP and DU-145) PCa patients. Prostate tumor tissue had a 1.7-fold higher MICA expression relative to normal tissue (pâ¯<â¯.0001). MICA immunoreactivity in PCa tissue from AAM was 24% lower (pâ¯=â¯.002) compared to CAM. Survival analysis revealed a marginal association of low MICA with poor overall survival (OS) (pâ¯=â¯.058). By data mining analysis, a 2.9-fold higher level of MICA mRNA was evidenced in tumor compared to normal tissue (pâ¯<â¯.0001). Tumors from AAM had 24% lower levels of MICA mRNA compared to tumors from CAM (pâ¯=â¯.038), and poor prognosis was found for patients with lower MICA mRNA (pâ¯=â¯.028). By flow cytometry analysis, cell fraction positive for surface MICA was of 3% in MDA-PCa-2b cells, 54% in DU-145 cells, and 67% in LNCaP cells (pâ¯<â¯.0001). sMICA was detected in DU-145 and LNCaP cells, but was not detected in MDA-PCa-2b cells. Both LNCaP and DU-145 cells were sensitive to cytolysis mediated by Natural killer (NK) cells. MDA-PCa-2b cells, however were between 1.3-fold at 10:1 Effector:Target (E:T) ratio (pâ¯<â¯.0001) and 2-fold at 50:1 E:T ratio (pâ¯<â¯.0001) more resistant to NK-mediated cytolysis relative to cells from Caucasian origin. These results suggest that MICA expression may be related to the aggressive nature of PCa. Our findings also demonstrate for the first time that there are variations in MICA expression in the context of racial differences. This study establishes a rationale for further investigation of MICA as a potential race-specific prognostic marker in PCa.
Assuntos
Negro ou Afro-Americano/genética , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/genética , Neoplasias da Próstata/genética , População Branca/genética , Idoso , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Perfilação da Expressão Gênica/métodos , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/metabolismo , Análise de Sobrevida , Estados UnidosRESUMO
Los septos del seno maxilar son variantes anatómicas que se forman como resultado de los residuos de la hipoplasia en diferentes áreas del proceso alveolar siendo de forma, tamaño y número variable. Su hallazgo se puede realizar mediante radiografÃas panorámicas de rutina. La importancia de un septo en el seno maxilar es que puede generar modificaciones para las cirugÃas, pudiendo ser necesario abrir dos o más ventanas quirúrgicas para su remoción. Objetivo: La finalidad de este estudio fue analizar los rasgos tomográficos de los septos del seno maxilar en pacientes que asistieron entre los años 2014 - 2016 a la clÃnica dental docente de la Universidad Peruana Cayetano Heredia. Materiales y métodos: Esta investigación fue de tipo transversal y descriptivo, para ello se examinaron 813 tomografÃas computarizadas volumétricas. La prueba de chi cuadrado y la estadÃstica descriptiva se usaron para el análisis, con un intervalo de confianza al 95%, con un valor p < 0,05. Resultados: 298 pacientes presentaron septos, presentando mayor porcentaje los septos congénitos (69.2%) y fueron más comunes en pacientes de sexo femenino con un 36%.Conclusiones: prevalecieron los septos de tipo congénito, lo que indica que se formaron a partir del desarrollo radicular.
The septa of the maxillary sinus are anatomical variants that are formed as a result of the residues of hypoplasia in different areas of the alveolar process, being of variable shape, size and number.Your finding can be made using routine panoramic radiographs. The importance of a septum in the maxillary sinus is that it can generate modifications for maxillary sinus surgeries, and it may be necessary to open two or more surgical windows for its removal. Objective: The purpose of this study was to analyze the tomographic features of the maxillary sinus septa in patients who attended the teaching dental clinic of the Universidad Peruana Cayetano Heredia between 2014- 2016. Materials and methods: This research was cross-sectional and descriptive, for which 813 cone beam CT scans were examined. Chi square test and descriptive statistics were used for the analysis, with a 95% confidence interval, with a value p < 0.05. Results: 298 patients presented septa, with a higher percentage of congenital septa (69.2%) and were more common in female patients with 36%. Conclusions: the congenital type septa prevailed, which indicates that they were formed from root development.
RESUMO
O objetivo do texto é apresentar dados que constituíram a arqueologia da Psicodinâmica do Trabalho no Brasil. Metodologia: foram realizadas 16 entrevistas individuais com Dejours e outros pesquisadores brasileiros que contribuíram para a introdução e disseminação dela no país e que adotam a abordagem em suas pesquisas. Para as entrevistas, considerou-se como critério o levantamento dos pesquisadores que estiveram no CNAM e os componentes do GT (Grupo de Trabalho em Psicodinâmica do Trabalho) da ANPEPP (Associação Nacional de Pós-graduação e Pesquisa no Brasil). Os resultados são apresentados considerando quatro aspectos: as raízes da Psicodinâmica do Trabalho no Brasil; a expansão da Psicodinâmica no Brasil; divergências e convergências entre contexto francês e brasileiro; e críticas e limitações em relação à Psicodinâmica do Trabalho. Seguem as considerações finais.
The purpose of the text is to present data that constituted the archeology of work psychodynamics in Brazil. Methodology: individual interviews were conducted with Dejours and 16 Brazilian researchers who contributed to the introduction and dissemination of it in the country and researchers that currently use this regard in their researches. For the interviews, the survey had considered as a criteria the researchers that had been in the CNAM and the components of the GT (working group) on Psychodynamics of the work of Anpepp (National Association of Postgraduate and Research in Brazil). Results are presented considering four aspects: the roots of the Psychodynamics in Brazil; the expansion of the Psychodynamic in Brazil; divergences and convergences between the French and Brazilian context; and critics and limits concerning the Psychodynamics. Afterwards conclusions are presented.