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BACKGROUND: During the last decade, arthroscopic procedures have been replacing open techniques in Haglund disease treatment because of their considerable advantages. Endoscopic calcaneoplasty is a technique that allows resection of posterosuperior calcaneal exostosis and retrocalcaneal bursitis. The objective of this article was to describe this technique and report its clinical and subjective outcome. METHODS: A retrospective study was performed of consecutive patients undergoing endoscopic Haglund resection surgery between July 2014 and March 2020 at a single academic institution. All patients were surveyed in person about the level of pain (visual analog scale), its location (central, lateral, medial or diffuse), its relation with rest, or physical activity. Clinical evaluation was assessed using the hindfoot scale designed by the American Orthopedics Foot & Ankle Society AOFAS. RESULTS: In this study, 14 endoscopic calcaneoplasties were performed in 14 patients, with an average follow-up of 40 months. The visual analog scale score improved from a preoperative average value of 9.07 to 1.8 after surgery (P > .0001). The AOFAS scale rose from 38.7 before surgery to 94.6 postoperative (P > .0001). Good subjective results were observed in 12 patients (85.7%), and all of them would have surgery again. There were no wound complications or infections. No patient required reoperation. CONCLUSION: In this relatively small cohort, we found that endoscopic calcaneoplasty was associated with good clinical and subjective results with few complications.
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OBJECTIVE: We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts. BACKGROUND AND AIMS: Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results. METHODS: An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA ( CEACAM5 ) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data. RESULTS: Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41-59%) and lower specificities (56-96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity. CONCLUSIONS: PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.
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Cisto Pancreático , Neoplasias Pancreáticas , Humanos , RNA , Detecção Precoce de Câncer , Cisto Pancreático/diagnóstico , Cisto Pancreático/genética , Cisto Pancreático/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , DNA , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias PancreáticasRESUMO
Background and objectives: We aim to verify the use of ML algorithms to predict patient outcome using a relatively small dataset and to create a nomogram to assess in-hospital mortality of patients with COVID-19. Methods: A database of 200 COVID-19 patients admitted to the Clinical Hospital of State University of Campinas (UNICAMP) was used in this analysis. Patient features were divided into three categories: clinical, chest abnormalities, and body composition characteristics acquired by computerized tomography. These features were evaluated independently and combined to predict patient outcomes. To minimize performance fluctuations due to low sample number, reduce possible bias related to outliers, and evaluate the uncertainties generated by the small dataset, we developed a shuffling technique, a modified version of the Monte Carlo Cross Validation, creating several subgroups for training the algorithm and complementary testing subgroups. The following ML algorithms were tested: random forest, boosted decision trees, logistic regression, support vector machines, and neural networks. Performance was evaluated by analyzing Receiver operating characteristic (ROC) curves. The importance of each feature in the determination of the outcome predictability was also studied and a nomogram was created based on the most important features selected by the exclusion test. Results: Among the different sets of features, clinical variables age, lymphocyte number and weight were the most valuable features for prognosis prediction. However, we observed that skeletal muscle radiodensity and presence of pleural effusion were also important for outcome determination. Integrating these independent predictors was successfully developed to accurately predict mortality in COVID-19 in hospital patients. A nomogram based on these five features was created to predict COVID-19 mortality in hospitalized patients. The area under the ROC curve was 0.86 ± 0.04. Conclusion: ML algorithms can be reliable for the prediction of COVID-19-related in-hospital mortality, even when using a relatively small dataset. The success of ML techniques in smaller datasets broadens the applicability of these methods in several problems in the medical area. In addition, feature importance analysis allowed us to determine the most important variables for the prediction tasks resulting in a nomogram with good accuracy and clinical utility in predicting COVID-19 in-hospital mortality.
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BACKGROUND: Molecular testing improves the diagnostic accuracy of thyroid cancer. Whether specific molecular testing results are associated with tumor phenotype or provide prognostic information needs further delineation. METHODS: Consecutive thyroid cancer patients after index thyroidectomy with ThyroSeq version 3 (Rye Brook, NY) molecular testing obtained on preoperative fine-needle aspiration or thyroidectomy specimens from patients with thyroid cancer were categorized into 3 molecular risk groups based on detected mutations, fusions, copy number alterations, and/or gene expression alterations and correlated with histopathology and recurrence, defined as biochemical or structural. RESULTS: Of 578 patients, 49.9%, 37.5%, and 12.6% had molecular risk group-low, molecular risk group-intermediate, and molecular risk group-high cancers, respectively. With a median 19-month follow-up, 9.1% patients recurred. Compared with molecular risk group-low, molecular risk group-intermediate cancers were diagnosed in younger patients and more often had microscopic extrathyroidal extension, involved margins, and nodal disease. Compared with molecular risk group-intermediate, molecular risk group-high cancers were diagnosed in older patients and more often had gross extrathyroidal extension and vascular invasion. In multivariable analysis, recurrence was more likely in molecular risk group-high cancers than in molecular risk group-intermediate (hazard ratio = 4.0; 95% confidence interval, 1.9-8.6; P < .001) and more likely in molecular risk group-intermediate than in molecular risk group-low (hazard ratio = 5.0; 95% confidence interval, 2.0-12.5; P < .001). CONCLUSION: Using modern comprehensive genotyping, the genetic profile of thyroid cancers can be categorized into 3 novel molecular risk groups that were associated with histopathologic phenotype and recurrence in short-term follow-up.
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Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/diagnóstico , Tireoidectomia/métodos , Biópsia por Agulha Fina , Prognóstico , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
Inflammatory states and body composition changes are associated with a poor prognosis in many diseases, but their role in coronavirus disease 2019 (COVID-19) is not fully understood. To assess the impact of low skeletal muscle radiodensity (SMD), high neutrophil-to-lymphocyte ratio (NLR) and a composite score based on both variables, on complications, use of ventilatory support, and survival in patients with COVID-19. Medical records of patients hospitalized between May 1, 2020, and July 31, 2020, with a laboratory diagnosis of COVID-19 who underwent computed tomography (CT) were retrospectively reviewed. CT-derived body composition measurements assessed at the first lumbar vertebra level, and laboratory tests performed at diagnosis, were used to calculate SMD and NLR. Prognostic values were estimated via univariate and multivariate logistic regression analyses and the Kaplan-Meier curve. The study was approved by the local Institutional Review Board (CAAE 36276620.2.0000.5404). A total of 200 patients were included. Among the patients assessed, median age was 59 years, 58% were men and 45% required ICU care. A total of 45 (22.5%) patients died. Multivariate logistic analysis demonstrated that a low SMD (OR 2.94; 95% CI 1.13-7.66, P = 0.027), high NLR (OR 3.96; 95% CI 1.24-12.69, P = 0.021) and both low SMD and high NLR (OR 25.58; 95% CI 2.37-276.71, P = 0.008) combined, were associated with an increased risk of death. Patients who had both low SMD and high NLR required more mechanical ventilation (P < 0.001) and were hospitalized for a longer period (P < 0.001). Low SMD, high NLR and the composite score can predict poor prognosis in patients with COVID-19, and can be used as a tool for early identification of patients at risk. Systemic inflammation and low muscle radiodensity are useful predictors of poor prognosis, and the assessment of these factors in clinical practice should be considered.
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COVID-19 , Músculo Esquelético , Neutrófilos , Feminino , Humanos , Linfócitos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
PURPOSE: Exposure to ionizing radiation, especially during childhood, is a well-established risk factor for thyroid cancer. The vast majority of radiation-induced cancers are papillary carcinomas (PTCs). These tumors typically have gene fusions in contrast to point mutations prevalent in sporadic PTCs. The aim of this study was to investigate the molecular profiles of PTC patients with workplace exposure to ionizing radiation. METHODS: A retrospective review of 543 patients who underwent surgery with diagnosis of PTC was performed. A cohort of nine healthcare specialists previously exposed to radiation sources during their professional practice was selected and analyzed using the ThyroSeq mutation panel for point mutations and gene fusions associated with thyroid cancer. RESULTS: The molecular analysis of surgical samples of PTCs was informative and revealed genetic alterations in five patients. BRAF V600E was found in four (67%) cases whereas RET/PTC1 fusion in one (17%) and one sample (17%) was wild type for point mutations and fusions. One sample completely failed molecular analysis while two others were negative for genes fusions but failed DNA analysis; these three samples were excluded. CONCLUSIONS: In this limited cohort of healthcare workers exposed to low dose of ionizing radiation at the workplace and developed PTC, the molecular profiling determined BRAF V600E point mutation as the most common event, arguing against the role of workplace radiation exposure in the etiology of these tumors.
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Carcinoma Papilar , Neoplasias da Glândula Tireoide , Carcinoma Papilar/patologia , Pessoal de Saúde , Humanos , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/etiologia , Neoplasias da Glândula Tireoide/genética , Local de TrabalhoRESUMO
Entamoeba histolytica is an intestinal parasite that causes dysentery and amebic liver abscess. E. histolytica has the capability to invade host tissue by union of virulence factor Gal/GalNAc lectin; this molecule induces an adherence-inhibitory antibody response as well as to protect against amebic liver abscess (ALA). The present work showed the effect of the immunization with PEΔIII-LC3-KDEL3 recombinant protein. In vitro, this candidate vaccine inhibited adherence of E. histolytica trophozoites to HepG2 cell monolayer, avoiding the cytolysis, and in a hamster model, we observed a vaccine-induced protection against the damage to tissue liver and the inhibition of uncontrolled inflammation. PEΔIII-LC3-KDEL3 reduced the expression of TNF-α, IL-1ß, and NF-κB in all immunized groups at 4- and 7-day postinfection. The levels of IL-10, FOXP3, and IFN-γ were elevated at 7 days. The immunohistochemistry assay confirmed this result, revealing an elevated quantity of +IFN-γ cells in the liver tissue. ALA formation in hamsters immunized was minimal, and few trophozoites were identified. Hence, immunization with PEΔIII-LC3-KDEL3 herein prevented invasive amebiasis, avoided an acute proinflammatory response, and activated a protective response within a short time. Finally, this recombinant protein induced an increase of serum IgG.
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Entamoeba histolytica/imunologia , Abscesso Hepático Amebiano/prevenção & controle , Proteínas de Protozoários/administração & dosagem , Vacinas Protozoárias/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Animais , Anticorpos Antiprotozoários/sangue , Modelos Animais de Doenças , Entamoeba histolytica/genética , Humanos , Imunogenicidade da Vacina , Lectinas/genética , Lectinas/imunologia , Fígado/imunologia , Fígado/parasitologia , Fígado/patologia , Abscesso Hepático Amebiano/sangue , Abscesso Hepático Amebiano/parasitologia , Abscesso Hepático Amebiano/patologia , Masculino , Mesocricetus , Proteínas de Protozoários/genética , Proteínas de Protozoários/imunologia , Vacinas Protozoárias/genética , Vacinas Protozoárias/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologiaRESUMO
[This corrects the article DOI: 10.3389/fphys.2020.00697.].
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This study aimed to explore different substances (or cold sea water) as potential anesthetic agents to facilitate short-term handling in Octopus maya juveniles. We investigated oxygen consumption before (baseline), during (first 600 s of exposure) and after anesthesia (recovery) of octopuses (n = 98; 1.67 ± 0.5 g) exposed to cold sea water (SW; 11 and 13°C), ethanol (EtOH; 0.5; 1.5 and 3.0%), magnesium chloride (MgCl2; 0.75; 1.5 and 3.75%), ethanol combined with magnesium chloride (Mix; 1.5:0.75%; 0.75:1.13%; and 2.25:0.37%) and clove oil (0.15 mL L-1). After exposure, the animals were handled for 180 s (exposed to air) and weighted. Two experimental groups not exposed to anesthetics (with or without handling) were also evaluated. The criteria for general anesthesia were analysed. Times of induction and recovery, incidence of attack response after recovery and possible longer-term effects of repeated general anesthesia on growth and mortality of the octopuses were evaluated. During anesthesia, O. maya juveniles exposed to SW (11 and 13°C), EtOH (0.5; 1.5 and 3.0%), Mix (0.75:1.13%), and clove oil, presented a significant decrease on oxygen consumption. In animals exposed to different concentrations of EtOH and Mix 0.75:1.13%, this decrease was registered after an increase on oxygen consumption. Animals exposed to MgCl2 did not show significant changes on oxygen consumption, except for animals exposed MgCl2 3.75%, which showed a significant increase on oxygen consumption. At the end of recovery, except for octopuses exposed to clove oil and MgCl2 0.75%, the values of oxygen consumption observed were comparable to the ones registered during baseline. Animals exposed to SW 11°C, EtOH 3.0%, Mix 1.5:0.75% and MgCl2 3.75% fulfilled the criteria defined for general anesthesia. Exposure to MgCl2 (all concentrations), SW 13°C and clove oil reduced or inhibited the incidence of attack response after recovery. Except for animals exposed to clove oil, growth of the juveniles was not affected by the exposure to the different substances. Short-term handling (180 s) of O. maya juveniles can eventually be carried out without anesthesia. However, to facilitated handling, we suggest the use of EtOH 3.0% or cold sea water 11°C.
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There are several unmet needs in modern immunology. Among them, vaccines against parasitic diseases and chronic infections lead. Trypanosoma cruzi, the causative agent of Chagas disease, is an excellent example of a silent parasitic invasion that affects millions of people worldwide due to its progression into the symptomatic chronic phase of infection. In search for novel vaccine candidates, we have previously introduced Traspain, an engineered trivalent immunogen that was designed to address some of the known mechanisms of T. cruzi immune evasion. Here, we analyzed its performance in different DNA prime/protein boost protocols and characterized the systemic immune response associated with diverse levels of protection. Formulations that include a STING agonist, like c-di-AMP in the boost doses, were able to prime a Th1/Th17 immune response. Moreover, comparison between them showed that vaccines that were able to prime polyfunctional cell-mediated immunity at the CD4 and CD8 compartment enhanced protection levels in the murine model. These findings contribute to a better knowledge of the desired vaccine-elicited immunity against T. cruzi and promote the definition of a vaccine correlate of protection against the infection.
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Imunidade/imunologia , Vacinas Protozoárias/imunologia , Trypanosoma cruzi/imunologia , Vacinação/métodos , Animais , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos/imunologia , Citocinas/metabolismo , Feminino , Imunização Secundária , Masculino , Camundongos , Modelos Animais , Resultado do TratamentoRESUMO
Carbapenem-resistant Enterobacterales (CREs) have been recognized as an important threat to global health. CRE cause the majority of the difficult-to-treat infections in health-care settings and are associated with high mortality. Klebsiella pneumoniae carbapenemase (KPC)-producing CREs, in particular Klebsiella pneumoniae, are globally disseminated and responsible for a large number of outbreaks. Development of rapid methods for KPC detection can provide great clinical and epidemiological benefits to prevent KPC dissemination. The aim of this study was to standardize and validate a LC-MS/MS method to detect KPC. This method was also tested against a broad variety of species, including CRE with other carbapenemase genes and the recently reported mcr-1. For validation, 111 isolates with reduced susceptibility to carbapenems were selected (49 KPC-positive and 62 KPC-negative). The presence of four tryptic peptides related to the KPC enzyme was evaluated, and the identification of at least two of them classified the isolate as "KPC-positive." The LTLGSALAAPQR and LALEGLGVNGQ peptides were both detected in 47 of 49 isolates with the blaKPC gene. The other two peptides, GFLAAAVLAR and APIVLAVYTR, were detected in 46 and 19 isolates with the blaKPC gene, respectively. The method correctly classified 47 of 49 KPC-positive and all KPC-negative isolates yielding 96.07% of sensitivity and 100% of specificity. In conclusion, our results demonstrate that the KPC peptide markers were robustly detected by the method which presented high sensitivity and full specificity and therefore can be used as a reliable method to identify this resistance mechanism.
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Proteínas de Bactérias/metabolismo , Técnicas Bacteriológicas/métodos , Enterobacteriáceas Resistentes a Carbapenêmicos/enzimologia , Klebsiella pneumoniae/enzimologia , beta-Lactamases/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Cromatografia Líquida , Infecções por Enterobacteriaceae/microbiologia , Humanos , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/isolamento & purificação , Espectrometria de Massas em Tandem , beta-Lactamases/química , beta-Lactamases/genéticaRESUMO
BACKGROUND: Chagas disease, also known as American Trypanosomiasis, is a chronic parasitic disease caused by the flagellated protozoan Trypanosoma cruzi that affects about 8 million people around the world where more than 25 million are at risk of contracting the infection. Despite of being endemic on 21 Latin-American countries, Chagas disease has become a global concern due to migratory movements. Unfortunately, available drugs for the treatment have several limitations and they are generally administered during the chronic phase of the infection, when its efficacy is considered controversial. Thus, prophylactic and/or therapeutic vaccines are emerging as interesting control alternatives. In this work, we proposed Trypanosoma cruzi 80 kDa prolyl oligopeptidase (Tc80) as a new antigen for vaccine development against Chagas disease. METHODOLOGY/PRINCIPAL FINDINGS: In a murine model, we analyzed the immune response triggered by different immunization protocols based on Tc80 and evaluated their ability to confer protection against a challenge with the parasite. Immunized mice developed Tc80-specific antibodies which were able to carry out different functions such as: enzymatic inhibition, neutralization of parasite infection and complement-mediated lysis of trypomastigotes. Furthermore, vaccinated mice elicited strong cell-mediated immunity. Spleen cells from immunized mice proliferated and secreted Th1 cytokines (IL-2, IFN-γ and TNF-α) upon re-stimulation with rTc80. Moreover, we found Tc80-specific polyfunctional CD4 T cells, and cytotoxic T lymphocyte activity against one Tc80 MHC-I peptide. Immunization protocols conferred protection against a T. cruzi lethal challenge. Immunized groups showed a decreased parasitemia and higher survival rate compared with non-immunized control mice. Moreover, during the chronic phase of the infection, immunized mice presented: lower levels of myopathy-linked enzymes, parasite burden, electrocardiographic disorders and inflammatory cells. CONCLUSIONS/SIGNIFICANCE: Considering that an early control of parasite burden and tissue damage might contribute to avoid the progression towards symptomatic forms of chronic Chagas disease, the efficacy of Tc80-based vaccines make this molecule a promising immunogen for a mono or multicomponent vaccine against T. cruzi infection.
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Doença de Chagas/prevenção & controle , Vacinas Protozoárias/imunologia , Serina Endopeptidases/imunologia , Trypanosoma cruzi/enzimologia , Trypanosoma cruzi/imunologia , Animais , Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/imunologia , Linfócitos T CD4-Positivos/imunologia , Doença de Chagas/imunologia , Doença de Chagas/parasitologia , Citocinas/imunologia , Imunidade Celular , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Prolil Oligopeptidases , Proteínas de Protozoários , Vacinas Protozoárias/administração & dosagem , Vacinas Protozoárias/genética , Serina Endopeptidases/genética , Baço/citologia , Baço/imunologia , Linfócitos T Citotóxicos/imunologia , VacinaçãoRESUMO
Mycosporine-like amino acids (MAA) are ultraviolet screen substances synthesized by marine algae. The physiological function of these substances is related to cellular protection against UV radiation and as a protective mechanism against oxidative stress. These substances can be found mainly in the ocean, among red seaweeds. Its concentration in organisms has been related to ultraviolet radiation and availability of inorganic nitrogen in the environment. We start our study of MAA content in different species to understand if environmental conditions influence the concentration of MAAs in red seaweeds. The Brazilian coast presents abiotic factors that interact to create different physical-chemical features in the environment. We collected 441 samples from 39 species of red seaweed easily found in the intertidal zone, in low tide, during the summer of 2015. The sampling encompassed a latitudinal gradient (3° S to 28°5' S) at 23 points along the coast. We quantified and identified the content of MAAs in species through the method of high performance liquid chromatography. We detected for the first time the occurrence of MAAs in certain species of red algae that have not been reported to contain MAAs before. We confirmed that some environmental factors influenced the content of MAAs. Enhanced MAA contents, for example, were found in environments with a basic pH, a high ultraviolet index, and high concentrations of phosphate and nitrate. Salinity, dissolved oxygen and variations of sea surface temperature also influenced, in a secondary way, MAA content in algae in their natural environments.
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Aminoácidos/análise , Meio Ambiente , Rodófitas/química , Brasil , Alga Marinha/químicaRESUMO
Background: Exposure to ionizing radiation during childhood is a well-established risk factor for thyroid cancer. However, the genetic mechanisms of radiation-associated carcinogenesis remain not fully understood. Methods: In this study, we used targeted next-generation sequencing and RNA-Seq to study 65 papillary thyroid cancers (PTCs) from patients in the Ukrainian-American cohort with measurement-based iodine-131 (I-131) thyroid doses received as a result of the Chernobyl accident. We fitted linear regression models to evaluate differences in distribution of risk factors for PTC according to type of genetic alteration and logistic regression models to evaluate the I-131 dose response. All statistical tests were two-sided. Results: Driver mutations were identified in 96.9% of these thyroid cancers, including point mutations in 26.2% and gene fusions in 70.8% of cases. Novel driver fusions such as POR-BRAF, as well as STRN-ALK fusions that have not been implicated in radiation-associated cancer before, were found. The mean I-131 dose in cases with point mutations was 0.2 Gy (range = 0.013-1.05 Gy), statistically significantly lower than 1.4 Gy (range = 0.009-6.15 Gy) for cases with fusions (P < .001). No driver point mutations were found in tumors from individuals who received more than 1.1 Gy of radiation. Relative to tumors with point mutations, the proportion of tumors with gene fusions increased with radiation dose, reaching 87.8% among individuals exposed to 0.3 Gy or higher. With a limited study sample size, the estimated odds ratio at 1 Gy was 20.01 (95% confidence interval = 2.57 to 653.02, P < .001). In addition, after controlling for I-131 dose, we found higher odds ratios for gene fusion-positive PTCs associated with several specific demographic and geographic features. Conclusions: Our data provide support for a link between I-131 thyroid dose and generation of carcinogenic gene fusions, the predominant mechanism of thyroid cancer associated with radiation exposure from the Chernobyl accident.
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Acidente Nuclear de Chernobyl , Fusão Gênica , Radioisótopos do Iodo/efeitos adversos , Mutação , Neoplasias Induzidas por Radiação/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/genética , Proteínas de Ligação a Calmodulina/genética , Carcinoma Papilar/etiologia , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Criança , Pré-Escolar , Estudos de Coortes , Sistema Enzimático do Citocromo P-450/genética , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Proteínas de Membrana/genética , Neoplasias Induzidas por Radiação/etiologia , Neoplasias Induzidas por Radiação/patologia , Proteínas do Tecido Nervoso/genética , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Doses de Radiação , Neoplasias da Glândula Tireoide/etiologia , Neoplasias da Glândula Tireoide/patologia , Adulto JovemAssuntos
Proteínas de Bactérias/genética , Enterobacteriaceae/genética , Enterobacteriaceae/isolamento & purificação , beta-Lactamases/genética , Antibacterianos/farmacologia , Enterobacteriaceae/enzimologia , Infecções por Enterobacteriaceae/tratamento farmacológico , Humanos , Testes de Sensibilidade MicrobianaRESUMO
The aim of the present study was to investigate the relationship of four TNF-α SNP with inflammatory biomarkers and plasma fatty acids (FA), and the interaction among them in a population-based, cross-sectional study in São Paulo, Brazil. A total of 281 subjects, aged >19 and <60 years, participated in a cross-sectional, population-based study performed in Brazil. The following SNP spanning the TNF-α gene were genotyped: -238G/A (rs361525), -308G/A (rs1800629), -857C/T (rs1799724) and -1031T/C (rs1799964). In all, eleven plasma inflammatory biomarkers and plasma FA profile were determined. To analyse the interaction between TNF-α SNP and plasma FA, a cluster analysis was performed to stratify individuals based on eleven inflammatory biomarkers into two groups used as outcome: inflammatory (INF) and non-inflammatory clusters. The -238A allele carriers had higher TNF-α (P=0·033), IL-6 (P=0·013), IL-1ß (P=0·037), IL-12 (0·048) and IL-10 (P=0·010) than the GG genotype. The -308A allele carriers also had lower levels of plasma palmitoleic acid (P=0·009), oleic acid (P=0·039), total MUFA (P=0·014), stearoyl-CoA desaturase (SCD) activity index-16 (P=0·007), SCD-18 (P=0·020) and higher levels of PUFA (P=0·046) and DHA (P=0·044). Significant interactions modifying the risk of belonging to the INF cluster were observed with inflammatory cluster as outcome between -857C/T and plasma α-linolenic acid (P=0·026), and also between -308G/A and plasma stearic acid (P=0·044) and total SFA (P=0·040). Our study contributes to knowledge on TNF-α SNP and their association with inflammatory biomarker levels, plasma FA and the interaction among them, of particular interest for the Brazilian population.
Assuntos
Ácidos Graxos/sangue , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Adolescente , Adulto , Alelos , Biomarcadores/sangue , Brasil , Criança , Colesterol/sangue , Estudos Transversais , Exercício Físico , Ácidos Graxos Monoinsaturados/sangue , Feminino , Técnicas de Genotipagem , Humanos , Interleucinas/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Ácido Oleico/sangue , Ácidos Esteáricos/sangue , Estearoil-CoA Dessaturase/sangue , Estearoil-CoA Dessaturase/genética , Inquéritos e Questionários , Triglicerídeos/sangue , Circunferência da Cintura , Adulto Jovem , Ácido alfa-Linolênico/sangueRESUMO
The development of new adjuvants enables fine modulation of the elicited immune responses. Ideally, the use of one or more adjuvants should result in the induction of a protective immune response against the specific pathogen. We have evaluated the immune response and protection against Trypanosoma cruzi infection in mice vaccinated with recombinant Tc52 or its N- and C-terminal domains (NTc52 and CTc52) adjuvanted either with the STING (Stimulator of Interferon Genes) agonist cyclic di-AMP (c-di-AMP), a pegylated derivative of α-galactosylceramide (αGC-PEG), or oligodeoxynucleotides containing unmethylated CpG motifs (ODN-CpG). All groups immunized with the recombinant proteins plus adjuvant: Tc52+c-di-AMP, NTc52+c-di-AMP, CTc52+c-di-AMP, NTc52+c-di-AMP+αGC-PEG, NTc52+CpG, developed significantly higher anti-Tc52 IgG titers than controls. Groups immunized with c-di-AMP and Tc52, NTc52 or CTc52 showed the highest Tc52-specific IgA titers in nasal lavages. All groups immunized with the recombinant proteins plus adjuvant developed a strong specific cellular immune response in splenocytes and lymph node cells with significant differences for groups immunized with c-di-AMP and Tc52, NTc52 or CTc52. These groups also showed high levels of Tc52-specific IL-17 and IFN-γ producing cells, while NTc52+CpG group only showed significant difference with control in IFN-γ producing cells. Groups immunized with c-di-AMP and Tc52, NTc52 or CTc52 developed predominantly a Th17 and Th1immune response, whereas for NTc52+CpG it was a dominant Th1 response. It was previously described that αGC-PEG inhibits Th17 differentiation by activating NKT cells. Thus, in this work we have also included a group immunized with both adjuvants (NTc52+c-di-AMP+αGC-PEG) with the aim to modulate the Th17 response induced by c-di-AMP. This group showed a significant reduction in the number of Tc52-specific IL-17 producing splenocytes, as compared to the group NTc52+c-di-AMP, which has in turn correlated with a reduction in protection against infection. These results suggest that the Th17 immune response developed after immunizing with NTc52+c-di-AMP could have a protective role against T. cruzi infection. Groups NTc52+c-di-AMP, Tc52+c-di-AMP and NTc52PB, were the ones that showed better protection against infection with lower parasitemia and weight loss, and higher survival.
Assuntos
Doença de Chagas/prevenção & controle , Proteínas de Protozoários/imunologia , Células Th1/imunologia , Células Th17/imunologia , Trypanosoma cruzi/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/química , Animais , Anticorpos Antiprotozoários/imunologia , Doença de Chagas/imunologia , Doença de Chagas/parasitologia , AMP Cíclico/administração & dosagem , AMP Cíclico/química , Feminino , Humanos , Imunização , Camundongos , Camundongos Endogâmicos C3H , Domínios Proteicos , Proteínas de Protozoários/administração & dosagem , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Trypanosoma cruzi/química , Trypanosoma cruzi/genéticaRESUMO
Women with advanced breast carcinomas have few therapeutic options. Recent advances in genomic profiling represent a new paradigm of cancer classification and treatment, but experience with genomic testing in a clinical setting remains limited. We retrospectively determined the genomic variants and correlate these with histology [histomorphologic subtype, nuclear grade, standard immunohistochemistry (IHC)] and clinical utilization (ordering, turnaround time, report review, and targeted therapy). Among 48 patients, 2 showed no genetic alterations, 11 (23%) showed variants of unclear significance only and 35 (73%) showed variant(s) affecting function (VaF) and/or variants of unclear significance. Overall, 119 variants were observed in 20 of 50 tested genes. Each patient had a unique molecular profile, with numerous (n=58) variants not previously reported in breast cancer. VaF detected in more than 2 patients included: TP53 (n=21), PIK3CA (n=20), and FGFR1 (n=3). VaF comprised 46 single nucleotide variants (79%), 7 amplifications (12%), 3 frameshifts (5%), 1 insertion (2%), and 1 deletion (2%). The tested samples had very high Ki67 index (average 57%±23%) and approximately half were hormone receptor and HER2 negative (25/46, 54%). Metastatic breast carcinomas showed a higher average VaF versus breast-localized tumors (1.3±0.99 vs. 0.18±0.60, P<0.05). Next-generation sequencing reports were promptly reported and reviewed (average 1 to 2 d) and 7 (â¼25%) of potentially eligible patients received targeted therapy. Advanced breast cancers show unique landscapes of genetic variants. Most testing was done in late disease, often in metastatic and receptor-negative carcinomas. Next-generation sequencing results were promptly reported and reviewed, but the utilization of targeted therapies was limited.
Assuntos
Neoplasias da Mama/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Idoso , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Preoperative detection of RAS mutations can contribute to cancer risk assessment in indeterminate thyroid nodules, although RAS is not always associated with malignancy. METHODS: Fine-needle aspiration samples classified in 1 of 3 indeterminate cytology categories were prospectively tested for N-, H-, and K-RAS mutations using next-generation sequencing assay. RESULTS: In the study, 93 patients with 94 nodules had preoperative RAS detected, of whom 86 patients had an operation (69% total thyroidectomy, 29% lobectomy). In total, 76% of RAS-positive nodules were malignant and follicular variant papillary thyroid cancer was the most common cancer type (83%). HRAS mutations had the greatest risk of cancer (92%) followed by NRAS (74%) and KRAS (64%; P = .05). No preoperative variables were associated with malignancy including age (P = .07), sex (P = .49), RAS isoform (P = .05), mutational allelic frequency (P = .49), nodule size (P = .14), cytology category (P = .63), or ultrasound bilaterality (P = .24), multifocality (P = .23), or presence of ≥1 suspicious feature (P = .86). Only 60% of patients with a unifocal nodule on ultrasound had single focus low-risk encapsulated follicular variant papillary thyroid cancer or benign disease. CONCLUSION: Preoperative RAS mutation detection in thyroid nodules carries a substantial risk of cancer with a greater risk associated with HRAS and NRAS. Most RAS malignancies are follicular variant papillary thyroid cancer, which may inform the extent of operation.
Assuntos
Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia/métodos , Adulto , Idoso , Biópsia por Agulha Fina , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios/métodos , Prognóstico , Estudos Prospectivos , Medição de Risco , Análise de Sobrevida , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/cirurgia , Tireoidectomia/mortalidade , Resultado do TratamentoRESUMO
Alginates are abundant polysaccharides in brown algae that constitute an important energy source for marine heterotrophic bacteria. Despite the key role of alginate degradation processes in the marine carbon cycle, little information is available on the bacterial populations involved in these processes. The aim of this work was to gain a better understanding of alginate utilization capabilities in cold coastal environments. Sediment metagenomes from four high-latitude regions of both Hemispheres were interrogated for alginate lyase gene homologue sequences and their genomic context. Sediments contained highly abundant and diverse bacterial assemblages with alginolytic potential, including members of Bacteroidetes and Proteobacteria, as well as several poorly characterized taxa. The microbial communities in Arctic and Antarctic sediments exhibited the most similar alginolytic profiles, whereas brackish sediments showed distinct structures with a higher proportion of novel genes. Examination of the gene neighbourhood of the alginate lyase homologues revealed distinct patterns depending on the potential lineage of the scaffolds, with evidence of evolutionary relationships among alginolytic gene clusters from Bacteroidetes and Proteobacteria. This information is relevant for understanding carbon fluxes in cold coastal environments and provides valuable information for the development of biotechnological applications from brown algae biomass.