RESUMO
We previously identified that the expression of chitinase-3-like protein 1 (CHI3L1) was upregulated during thyroid cancer progression. Here, we investigated the prognostic significance of CHI3L1 expression in thyroid neoplasms and examined the potential oncogenic roles. CHI3L1 immunochemical staining was performed on tissue microarrays of benign and malignant thyroid tumours. Compared with normal thyroid tissue and benign thyroid lesions that had low or no detectable CHI3L1 expression, CHI3L1 was overexpressed in both differentiated and undifferentiated thyroid cancer. High CHI3L1 expression was associated with extrathyroidal extension, lymph node metastasis, and shorter recurrence-free survival in differentiated thyroid cancer. The biological roles of CHI3L1 were further investigated by gain- and loss-of-function assays. CHI3L1 silencing suppressed clonogenicity, migration, invasion, anoikis resistance, and angiogenesis in thyroid cancer cells, although exogenous CHI3L1 treatment promoted these malignant phenotypes. Cysteine-rich angiogenic inducer 61 (CYR61) was identified as a downstream target of CHI3L1 by RNA-seq analysis. CYR61 silencing or treatment reversed the alterations induced by CHI3L1 modulation. Our results demonstrate that CHI3L1 is overexpressed in thyroid cancer and is associated with an increased risk of disease recurrence. Additionally, CYR61 may participate in CHI3L1-mediated tumour progression. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteína 1 Semelhante à Quitinase-3/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias da Glândula Tireoide/patologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Neoplasias da Glândula Tireoide/metabolismoRESUMO
BACKGROUND: Hungry bone syndrome is characterized by prolonged and severe hypocalcemia following parathyroidectomy. Previously, we reported that preoperative alkaline phosphatase is a major factor predicting prolonged hospital stay. Nonetheless, some patients with low alkaline phosphatase levels presented with hungry bone syndrome, suggesting that additional factors may play a role. METHODS: From September 2010 to December 2017, consecutive dialysis patients who underwent parathyroidectomy for secondary hyperparathyroidism were analyzed. Length of hospital stay was used as a surrogate marker for postoperative bone hunger. RESULTS: A total of 260 patients were included in the study. The median postoperative hospital stay was 3 days, and 69 (27%) patients had a stay longer than 3 days. Multivariate logistic regression analysis revealed that alkaline phosphatase (odds ratio [OR] = 1.005), osteocalcin (OR = 1.001), and subtotal parathyroidectomy (OR = 0.061) were associated with prolonged hospital stay. Multivariate linear regression analysis indicated that age (ß = - 0.170), alkaline phosphatase (ß = 0.430), and osteocalcin (ß = 0.166) were correlated with the length of stay. After surgery, the median osteocalcin level increased from 264 to 478 ng/mL (P < 0.001). CONCLUSIONS: Alkaline phosphatase is the main predictor of hungry bone syndrome after parathyroidectomy, and preoperative osteocalcin is an additional independent predictor. Patients with a high osteocalcin level may prone to have a higher demand for calcium supplementation.
Assuntos
Hiperparatireoidismo Secundário/cirurgia , Hipocalcemia/etiologia , Osteocalcina/sangue , Paratireoidectomia/efeitos adversos , Adulto , Fosfatase Alcalina/sangue , Feminino , Humanos , Hiperparatireoidismo Secundário/sangue , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Diálise RenalRESUMO
We aimed to ascertain whether therapeutic hypothermia (TH) acts as cardioprotective management for heat stroke (HS). Adult male rats under general anesthesia were exposed to whole-body heating (43°C for 70 min) to induce HS. Rats with HS displayed hyperthermia (core body temperature 42°C vs. 36°C); hypotension (30 mmHg vs. 90 mmHg mean arterial blood pressure); suppressed left ventricular (LV) performance (stroke volume 52 µl/min vs. 125 µl/min), ejection fraction (0.29% vs. 0.69%), relaxation factor (72 ms vs. 12 ms), and arterial elastance (0.31 mmHg/ µl vs. 10 mmHg/ µl); increased myocardial injury markers (e.g., creatine kinase-MB: 86 U/L vs. 24 U/L, cardiac troponin I: 3.08 ng/ml vs. 0.57 ng/ml); increased myocardial oxidative stress markers (e.g., malondialdehyde: 6.52 nmol/mg vs. 1.06 nmol/mg, thiobarbituric acid-reactive substances: 29 nmol/g vs. 2 nmol/g); decreased myocardial antioxidants (e.g., superoxide dismutase: 6 unit/mg vs. 17 unit/mg, reduced glutathione: 0.64 nmol/mg vs. 2.53 nmol/mg); increased myocardial proinflammatory cytokines (e.g., tumor necrosis factor-α 3200 pg/ml vs. 1000 pg/ml, interleukin-6: 668 pg/ml vs. 102 pg/ml); and increased cardiac damage scores (2.2 vs. 0.3). TH therapy significantly reversed the following conditions: HS-induced hyperthermia (37.5°C core body temperature), hypotension (71 mmHg), suppressed LV performance (stroke volume: 97 µl/min, ejection fraction: 0.65%, relaxation factor: 39 ms, and arterial elastance: 0.99 mmHg/µl), increased myocardial injury markers (e.g., creatine kinase-MB: 37 U/L, cardiac troponin I: 1.06 ng/ml), increased myocardial oxidative stress markers (e.g., malondialdehyde: 2.68 nmol/mg, thiobarbituric acid-reactive substances: 12.3 nmol/g), decreased myocardial antioxidants (e.g., superoxide dismutase: 13.3 unit/mg, reduced glutathione: 2.71 mmol/mg), increased myocardial proinflammatory cytokines (e.g., tumor necrosis factor-α 1500 pg/ml, interleukin-6: 108 ng/ml); and increased cardiac damage scores (0.9). We thus conclude that TH protects against HS-induced arterial hypotension by promoting LV performance in rats. These results add to the literature regarding the use of TH as cardioprotective management for HS.
Assuntos
Artérias/fisiopatologia , Golpe de Calor/terapia , Hipotensão/prevenção & controle , Hipotermia Induzida , Estresse Oxidativo , Função Ventricular , Anestesia Geral , Animais , Antioxidantes/metabolismo , Elasticidade , Traumatismos Cardíacos/fisiopatologia , Ventrículos do Coração/fisiopatologia , Hemodinâmica , Temperatura Alta , Inflamação , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Estimativa de Kaplan-Meier , Masculino , Miocárdio , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo , Função Ventricular EsquerdaRESUMO
BACKGROUND: Papillary thyroid microcarcinoma exhibits an indolent clinical course and could be a candidate for active surveillance in the appropriate setting. It remains unknown whether papillary microcarcinoma is biologically different from larger papillary carcinoma >1 cm. METHODS: We analyzed clinicopathological information and transcriptome data of papillary thyroid cancer samples from The Cancer Genome Atlas. Propensity-score matching was used to construct a matched cohort consisting of 29 microcarcinomas and 58 carcinomas. Principal component analysis and unsupervised hierarchical cluster analysis were carried out to investigate the similarity of gene expression profiles. RESULTS: After adjustment for differences in baseline clinicopathological and genetic factors, transcriptome could be grouped mainly on the basis of tumor class (BRAF-like vs RAS-like) and tumor size (microcarcinoma vs carcinoma). The gene set enrichment analysis showed that extracellular matrix-associated pathways were enriched in the MSigDB database. CONCLUSION: Papillary thyroid microcarcinomas display a distinct gene expression pattern different from the corresponding carcinomas. We hypothesize that tumor microenvironment may play a role in the microcarcinoma/carcinoma phenotypic divergence.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Papilar/patologia , Pontuação de Propensão , Neoplasias da Glândula Tireoide/patologia , Transcriptoma , Adulto , Carcinoma Papilar/classificação , Carcinoma Papilar/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/classificação , Neoplasias da Glândula Tireoide/genéticaRESUMO
Background: Previously we have shown that an elevated baseline neutrophil-to-lymphocyte ratio (NLR) was associated with a high risk of recurrence in patients with differentiated thyroid cancer. The clinical significance of the longitudinal changes in NLR following treatment remained unestablished. Methods: Adults patients with differentiated thyroid cancer were included in the study if the follow-up NLR data at 6 to 18 months after initial treatment were available. The response to treatment was categorized as excellent, indeterminate, biochemical incomplete, and structural incomplete as per guidelines of the American Thyroid Association. Results: Among 151 patients with thyroid cancer, a significant decrease in NLR following treatment was observed in those with stage I disease, those with low risk of recurrence, and those with an excellent response to therapy. Patients with a structural incomplete response had a significant increase in NLR at follow-up (p = 0.012). On multivariate analysis, incomplete response to therapy was associated with male sex (odds ratio [OR] = 3.35), tumor size (OR = 1.63), lymph node metastasis (OR = 4.80), distant metastasis (OR = 12.95), and increased NLR (OR = 13.68). Conclusions: An increase in systemic inflammation following treatment as measured by NLR is independently associated with an incomplete response to therapy in differentiated thyroid cancer.
Assuntos
Biomarcadores Tumorais/sangue , Linfócitos , Recidiva Local de Neoplasia/diagnóstico , Neutrófilos , Neoplasias da Glândula Tireoide/cirurgia , Adulto , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Metástase Linfática/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Fatores Sexuais , Glândula Tireoide/patologia , Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , TireoidectomiaRESUMO
Heme oxygenase-1 (HO-1) is induced by a variety of stimuli and plays a multifaceted role in cellular protection. We have shown that HO-1 is overexpressed in thyroid cancer and is associated with tumor aggressiveness. Therefore, we set out to assess the effects of HO-1 inhibitors on the biology of thyroid cancer cells. Two different classes of HO-1 inhibitors were used, including a metalloporphyrin, zinc protoporphyrin-IX (ZnPP), and an azole antifungal agent, ketoconazole. The viability and colony formation of thyroid cancer cells decreased in a concentration- and time-dependent fashion following treatment with HO-1 inhibitors. Cancer cells exhibited a higher sensitivity to HO-1 inhibitors than non-malignant cells. HO-1 inhibitors induced a G0/G1 arrest accompanied by decreased cyclin D1 and CDK4 expressions and an increase in levels of p21 and p27. HO-1 inhibitors significantly increased intracellular ROS levels and suppressed cell migration and invasion. Oxygen consumption rate and mitochondrial mass were increased with ZnPP treatment. Mice treated with ZnPP had a reduced xenograft growth and diminished cyclin D1 and Ki-67 staining in tumor sections. Taken together, HO-1 inhibitors might have therapeutic potential for inducing cell cycle arrest and promoting growth suppression of thyroid cancer cells in vitro and in vivo.
Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Heme Oxigenase-1/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Xenoenxertos , Humanos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Células-Tronco Neoplásicas , Consumo de Oxigênio/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismoRESUMO
BACKGROUND AND OBJECTIVES: The induction of tumor-associated carbohydrate antigen results from altered glycosylation in transformed cells. Globo H is a hexasaccharide glycosphingolipid overexpressed on malignancies of epithelial origin and has become an attractive vaccine target. We aimed to investigate the expression patterns and prognostic value of Globo H in thyroid neoplasms. METHODS: Globo H expression was examined by immunohistochemical analysis using commercial and in-house tissue microarrays. The expression was correlated with clinicopathologic characteristics in papillary thyroid cancer. RESULTS: Normal or benign thyroid lesions were negative for Globo H expression. Globo H was positive in 33% medullary, 24% papillary, 11% undifferentiated, and 8% follicular thyroid cancer. Globo H expression in papillary thyroid cancer was associated with extrathyroidal invasion (P = 0.017), BRAF mutation (P = 0.010), AMES high risk (P = 0.045), and increased ATA risk of recurrence (P = 0.022). CONCLUSIONS: Globo H is specifically expressed in a subset of thyroid malignancies. In papillary thyroid cancer, Globo H expression is associated with invasiveness and BRAF mutation. Immunotherapy targeting Globo H may have potential applications in thyroid cancer. J. Surg. Oncol. 2016;114:853-858. © 2016 2016 Wiley Periodicals, Inc.
Assuntos
Antígenos Glicosídicos Associados a Tumores/metabolismo , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/metabolismo , Adenocarcinoma Folicular/diagnóstico , Adenocarcinoma Folicular/metabolismo , Adenocarcinoma Folicular/patologia , Adenoma/diagnóstico , Adenoma/metabolismo , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/diagnóstico , Carcinoma/metabolismo , Carcinoma/patologia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Carcinoma Papilar , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/patologia , Análise Serial de TecidosRESUMO
BACKGROUND: Age is an important prognostic factor for papillary thyroid cancer (PTC). However, little is known about why advanced age is associated with poor prognosis. The study investigated the changes in transcriptional profiling related to age. METHODS: RNA sequencing data of PTC samples were retrieved from The Cancer Genome Atlas data portal. Spearman's correlation was used to test the association between age and gene expression. Correlation in the same direction to disease severity was considered functionally relevant. Functional enrichment analysis and pathway annotations were performed. RESULTS: There was no correlation between age and thyroid-specific genes, except for a weak, negative association between age and TSHR expression. Among 272 genes with a positive association between gene expression and age, the most prominent alteration was metabolic pathways, particularly glycolysis. Among 482 genes with a negative association between gene expression and age, the most enriched biological process was immune-related functions, particularly natural killer cell-mediated cytotoxicity. CONCLUSIONS: Our analysis characterized the age-associated molecular landscape in PTC. Metabolic alterations and immune dysregulation are probable mechanisms involving in worse prognosis in older patients with PTC.
Assuntos
Fatores Etários , Carcinoma/genética , Neoplasias da Glândula Tireoide/genética , Transcriptoma , Adulto , Carcinoma/diagnóstico , Carcinoma/imunologia , Carcinoma/metabolismo , Carcinoma Papilar , Citotoxicidade Imunológica/genética , Feminino , Perfilação da Expressão Gênica , Glicólise/genética , Humanos , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/imunologia , Neoplasias da Glândula Tireoide/metabolismoRESUMO
AIMS: Haem oxygenase-1 (HO-1) is an inducible enzyme that participates in haem degradation. Recent studies have indicated that HO-1 activation may play a role in tumour development and progression. The aim of this study was to evaluate the expression of HO-1 in thyroid cancer and its clinicopathological significance. METHODS AND RESULTS: We observed up-regulation of HO-1 in papillary thyroid tumours in comparison with normal thyroid tissue. Immunohistochemical analysis revealed that 48% of papillary cancers and 36% of follicular cancers, but none of normal thyroid tissues, were positive for HO-1 expression. Among 129 differentiated thyroid cancers, HO-1 expression was associated with patient age (P = 0.001), TNM stage (P = 0.001), and Mayo Clinic metastasis, patient age, completeness of resection, local invasion and tumour size score (P = 0.001). BRAF V600E expression was evaluated immunohistochemically and validated by Sanger sequencing. There was a strong association between HO-1 and BRAF V600E expression in papillary cancers (P = 0.002). CONCLUSIONS: Overexpression of HO-1 in a subset of thyroid cancers is associated with tumour aggressiveness and BRAF V600E expression. HO-1 might have a potential role in prognosis and targeted treatment in patients with thyroid cancer.
Assuntos
Biomarcadores Tumorais/análise , Heme Oxigenase-1/biossíntese , Proteínas Proto-Oncogênicas B-raf/biossíntese , Neoplasias da Glândula Tireoide/patologia , Adulto , Western Blotting , Feminino , Heme Oxigenase-1/análise , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/análise , Proteínas Proto-Oncogênicas B-raf/genética , Análise Serial de Tecidos , Regulação para CimaRESUMO
BACKGROUND: We sough to elucidate whether purinergic P2X7 receptor is actively involved in the effects of levobupivacaine on inhibiting microglia activation. MATERIALS AND METHODS: Microglia were treated with lipopolysaccharide (LPS, 50 ng/mL), LPS plus levobupivacaine (50 µM), or LPS plus levobupivacaine plus the P2X7 receptor agonist Bz-ATP (100 µM) and denoted as the LPS, LPS + Levo, and LPS + Levo + Bz-ATP group, respectively. Microglia activation was measured by assaying inflammatory molecules expression. Microglia activation was also measured by assaying neuronal cell viability using coculture of microglia and neurons, as activated microglia may cause neuron injury. We also measured the levels of P2X7 receptor activation in microglia using ethidium uptake assay. RESULTS: Our data confirmed the effects of levobupivacaine on inhibiting inflammatory molecules upregulation in activated microglia, as the concentrations of interleukin (IL)-1ß, tumor necrosis factor α, IL-6, and macrophage inflammatory protein 2, of the LPS + Levo group were significantly lower than those of the LPS group (all P < 0.05). Moreover, Bz-ATP significantly abrogated the inhibitory effects of levobupivacaine, as concentrations of IL-1ß, tumor necrosis factor α, IL-6, and macrophage inflammatory protein 2 of the LPS + Levo + Bz-ATP group were significantly higher than those of the LPS + Levo group (all P < 0.05). In contrast, neuronal cell viability of the LPS + Levo group was significantly higher than those of the LPS and LPS + Levo + Bz-ATP groups (P = 0.012 and 0.002). Moreover, levels of P2X7 receptor activation of the LPS and LPS + Levo + Bz-ATP groups were significantly higher than that of the LPS + Levo group (P = 0.003 and 0.006). CONCLUSIONS: P2X7 receptor is involved in the effects of levobupivacaine on inhibiting microglial activation.
Assuntos
Bupivacaína/análogos & derivados , Inflamação/tratamento farmacológico , Inflamação/imunologia , Microglia/efeitos dos fármacos , Receptores Purinérgicos P2X7/imunologia , Anestésicos Locais/farmacologia , Animais , Bupivacaína/farmacologia , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/imunologia , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Técnicas de Cocultura , Levobupivacaína , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/citologia , Microglia/imunologia , NF-kappa B/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/imunologiaRESUMO
BACKGROUND: Somatic BRAF mutation is frequently observed in papillary thyroid carcinoma (PTC). Recent evidence suggests that PTCs are heterogeneous tumors containing a subclonal or oligoclonal occurrence of BRAF mutation. Conflicting results have been reported concerning the prognostic significance of the mutant allele frequency. Our present aim was to investigate the association between the percentage of BRAF c.1799T > A (p.Val600Glu) alleles and clinicopathological parameters in PTC. METHODS: Genomic DNA was extracted from fresh-frozen specimens obtained from 50 PTC patients undergoing total thyroidectomy. The BRAF mutation status was determined by Sanger sequencing. The percentage of mutant BRAF alleles was quantified by mass spectrometric genotyping, pyrosequencing, and competitive allele-specific TaqMan PCR (castPCR). RESULTS: Positive rate of BRAF mutation was 72 % by Sanger sequencing, 82 % by mass spectrometric genotying, and 84 % by pyrosequencing or castPCR. The average percentage of mutant BRAF alleles was 22.5, 31, and 30.7 %, respectively. There was a good correlation among three quantification methods (Spearman's rho = 0.87-0.97; p < 0.0001). The mutant allele frequency was significantly correlated with tumor size (rho = 0.47-0.52; p < 0.01) and extrathyroidal invasion. The frequency showed no difference in pathological lymph node metastasis. CONCLUSIONS: The percentage of mutant BRAF alleles is positively associated with tumor burden and extrathyroidal invasion in PTC. Relatively good correlations exist among mass spectrometric genotyping, pyrosequencing, and castPCR in quantification of mutant BRAF allele frequency.
Assuntos
Carcinoma/genética , Carcinoma/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adulto , Alelos , Carcinoma Papilar , Feminino , Frequência do Gene , Genótipo , Técnicas de Genotipagem , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Mutação , Invasividade Neoplásica/genética , Reação em Cadeia da Polimerase , Análise de Sequência de DNA/métodos , Câncer Papilífero da Tireoide , Carga Tumoral/genéticaRESUMO
BACKGROUND: Aluminum overload and accumulation in tissues may lead to skeletal, hematological, and neurological toxicity. The aim of this study was to assess the effects of serum aluminum levels on presentations, postoperative recovery, and symptom improvement in patients undergoing parathyroidectomy for secondary hyperparathyroidism. METHODS: From 2008 to 2013, all patients with end-stage renal disease undergoing initial parathyroidectomy were included in the study. Serum aluminum level was measured preoperatively and/or within 1 week after surgery. Preoperative and postoperative biochemical profile and symptoms were compared between the low and high aluminum groups. RESULTS: A total of 176 patients were included in the study. Of these, 38 (22 %) patients had serum aluminum levels higher than 20 µg/L. A higher percentage of patients in the high aluminum group were on peritoneal dialysis than in the low aluminum group (24 vs. 4 %, p = 0.001). Both groups had similar bone mineral density and changes in biochemical profiles. The preoperative parathyroidectomy assessment of symptoms (PAS) score was not associated with serum aluminum levels (p = 0.349), whereas the postoperative PAS score showed positive association (p = 0.005). There was a negative association between serum aluminum levels and the improvement of total PAS scores (p = 0.001). The high aluminum group had more residual symptoms in three aspects: bone pain (p = 0.038), difficulty getting out of a chair or car (p = 0.045), and pruritus (p = 0.041). CONCLUSIONS: A high serum aluminum level was associated with reduced symptom improvement in patients undergoing parathyroidectomy for secondary hyperparathyroidism.
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Alumínio/sangue , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/cirurgia , Adulto , Idoso , Densidade Óssea , Feminino , Humanos , Hiperparatireoidismo Secundário/etiologia , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Dor Musculoesquelética/sangue , Dor Musculoesquelética/etiologia , Paratireoidectomia , Diálise Peritoneal , Período Pós-Operatório , Prurido/sangue , Prurido/etiologia , Índice de Gravidade de DoençaRESUMO
BACKGROUND AND AIMS: High levels of parathyroid hormone (PTH) appear to be associated with an increased mortality. Previous studies concerning the relationship of inflammatory markers with hyperparathyroidism have yielded inconsistent results. This study investigated whether serum PTH concentrations were independently associated with several inflammatory markers among the US adults. MATERIALS AND METHODS: Using data from the National Health and Nutrition Examination Survey, we examined the relation between serum PTH and C-reactive protein (CRP), red cell distribution width (RDW), and platelet-to-lymphocyte ratio (PLR) levels with weighted linear regression. Additionally, we examined the relation with increased modified Glasgow Prognostic Score (mGPS) by using weighted logistic regression. RESULTS: CRP, RDW, and PLR values increased with increasing serum PTH concentration. After extensively adjusting for covariates, CRP and RDW increased linearly and across PTH categories (all P < 0.001), while PLR marginally increased (P = 0.190 and P = 0.095 using PTH as a categorical and continuous variable, resp.). The odds ratio of increased mGPS was 1.11 and 1.31 across PTH categories and with increasing PTH levels continuously. CONCLUSION: These nationally representative data indicate that serum PTH levels are independently associated with several inflammatory markers in the US population. The casual relationship between PTH levels and inflammation remains to be elucidated.
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Inflamação/sangue , Hormônio Paratireóideo/sangue , Adulto , Idoso , Proteína C-Reativa/metabolismo , Estudos Transversais , Eritrócitos/citologia , Feminino , Taxa de Filtração Glomerular , Humanos , Inflamação/epidemiologia , Leucócitos/citologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Razão de Chances , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Human cytomegalovirus (CMV) has been detected in the thyroid gland and thyroid tumors. CMV infection may activate the mitogen-activated protein kinase pathway, of which aberrant activation is frequently associated with BRAF mutation in papillary thyroid cancer. METHODS: A total of 45 paired tumorous and adjacent non-neoplastic tissue samples, including 5 follicular adenoma and 40 papillary thyroid cancer, were obtained during thyroidectomy. BRAF mutational status was determined using direct sequencing. The presence of CMV DNA was determined using conventional PCR and quantitative real-time PCR. CMV protein in the tissue samples were evaluated with Western blot analysis. RESULTS: BRAF mutation was identified in the cancerous part of 31 (78%) papillary thyroid cancers. Papillary cancer with BRAF mutation was significantly associated with a larger tumor size (P = 0.045), extrathyroidal invasion (P = 0.012), lymph node metastasis (P = 0.008), and a higher TNM stage (P = 0.044). CMV DNA and protein were not detected in any studied samples. CONCLUSIONS: Our results suggest no association between CMV infection and papillary thyroid cancer.
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Adenoma/virologia , Carcinoma Papilar/virologia , Infecções por Citomegalovirus/virologia , Neoplasias da Glândula Tireoide/virologia , Adenoma/genética , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Papilar/genética , Carcinoma Papilar/secundário , Citomegalovirus , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/patologia , DNA de Neoplasias/genética , DNA Viral/genética , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Mutação/genética , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Reação em Cadeia da Polimerase em Tempo Real , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia , Adulto JovemRESUMO
In this study, the neuroprotective effect of an extract of Antrodia camphorata (A. camphorata), a fungus commonly used in Chinese folk medicine for treatment of viral hepatitis and cancer, alone or in combination with aspirin was investigated in a rat embolic stroke model. An ischemic stroke was induced in rats by a selective occlusion of the middle cerebral artery (MCA) with whole blood clots and then orally treated with A. camphorata (0.25 and 0.75 g/kg/day) alone and combined with aspirin (5 mg/kg/day). Sixty days later, the brains were removed, sectioned, and stained with triphenyltetrazolium chloride and analysed by a commercial image processing software program. Brain infarct volume, neurobehavioral score, cerebral blood perfusion, and subarachnoid and intracerebral hemorrhage incidence were perceived. In addition, potential bleeding side effect of the combinative therapy was assessed by measuring hemoglobin (Hb) content during intracerebral hemorrhage and gastric bleeding, prothrombin time (PT), and occlusion time (OT) after oral administration. Posttreatment with high dose A. camphorata significantly reduced infarct volume and improved neurobehavioral score (P < 0.05). Since A. camphorata alone or with aspirin did not alter the Hb level, this treatment is safe and does not cause hemorrhagic incident. Remarkably, the combination of A. camphorata and aspirin did not show a significant effect on the bleeding time, PT and OT increase suggesting that A. camphorata may have the neuroprotective effect without the prolongation of bleeding time or coagulation time. From these observations, we suggest that combinative therapy of A. camphorata and aspirin might offer enhanced neuroprotective efficacies without increasing side effects.
Assuntos
Antrodia/química , Aspirina/uso terapêutico , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Encéfalo/patologia , Quimioterapia Combinada , Hemoglobinas/metabolismo , Hemorragia/induzido quimicamente , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/isolamento & purificação , Tempo de Protrombina , Ratos Wistar , Acidente Vascular Cerebral/complicaçõesRESUMO
Hyperglycaemia, a characteristic feature of diabetes mellitus, induces endothelial dysfunction and vascular complications by limiting the proliferative potential of these cells. Here we aimed to investigate the effect of an ethanolic extract of Sanguis draconis (SD), a kind of dragon's blood resin that is obtained from Daemonorops draco (Palmae), on human umbilical vein endothelial cells (HUVEC) under high-glucose (HG) stimulation and its underlying mechanism. Concentration-dependent (0-50 µg/mL) assessment of cell viability showed that SD does not affect cell viability with a similar trend up to 48 h. Remarkably, SD (10-50 µg/mL) significantly attenuated the high-glucose (25 and 50 mM) induced cell toxicity in a concentration-dependent manner. SD inhibited high glucose-induced nitrite (NO) and lipid peroxidation (MDA) production and reactive oxygen species (ROS) formation in HUVEC. Western blot analysis revealed that SD treatments abolished HG-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2), nuclear transcription factor, κB (NF-κB), VCAM-1, and E-selectin, and it also blocked the breakdown of PARP-116 kDa protein in a dose-dependent manner. Furthermore, we found that SD increased the expression of Bcl-2 and decreased Bax protein expression in HG-stimulated HUVEC. Thus, these results of this study demonstrate for the first time that SD inhibits glucose induced oxidative stress and vascular inflammation in HUVEC by inhibiting the ERK/NF-κB/PARP-1/Bax signaling cascade followed by suppressing the activation of VCAM-1 and E-selectin. These data suggest that SD may have a therapeutic potential in vascular inflammation due to the decreased levels of oxidative stress, apoptosis, and PARP-1 activation.
Assuntos
Glucose/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Moléculas de Adesão Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glucose/farmacologia , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , NF-kappa B/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/metabolismo , Nitrilas/metabolismo , Fosforilação , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
In primary hyperparathyroidism, postoperative hypocalcemia can be exacerbated by magnesium deficiency. However, the significance of magnesium homeostasis in surgery for secondary hyperparathyroidism is unknown. In this study, 268 consecutive adult patients on renal replacement therapy who underwent parathyroidectomy for secondary hyperparathyroidism were included for analysis. We found that about one fifth presented with hypomagnesemia (5.6%) or hypermagnesemia (14.6%). Hypomagnesemia was associated with lower calcium levels and longer postoperative hospital stays. Hypermagnesemia was associated with higher calcium-phosphorus products and lower parathyroid hormone levels. In multivariate analysis, patient age, alkaline phosphatase, and osteocalcin were independent predictors of prolonged stay after parathyroidectomy. There was a positive correlation between serum magnesium levels and severity of itching in these patients. Calcium-phosphorus products and serum magnesium levels were independently associated with pruritus. In conclusion, magnesium abnormalities play a minor role in hungry bone syndrome after parathyroidectomy for secondary hyperparathyroidism. Patients with higher serum magnesium levels had greater severity of pruritus.
Assuntos
Hiperparatireoidismo Secundário , Magnésio , Paratireoidectomia , Diálise Renal , Humanos , Magnésio/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Hiperparatireoidismo Secundário/cirurgia , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/etiologia , Idoso , Adulto , Prurido/etiologia , Prurido/sangue , Cálcio/sangue , Hipocalcemia/etiologia , Hipocalcemia/sangue , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Tempo de Internação , Estudos RetrospectivosRESUMO
Objective: In addition to the well-established advantage that strengthened pelvic musculature increases urethral resistance in stress urinary incontinence (SUI) patients, intra-vaginal electrical stimulation (iVES) has been shown in preclinical studies to improve bladder capacity via the pudendal-hypogastric mechanism. This study investigated whether iVES also benefits bladder storage in SUI patients by focusing on compliance, a viscoelastic parameter critically defining the bladder's storage function, in a clinical study. Moreover, the potential involvement of stimulation-induced neuromodulation in iVES-modified compliance was investigated by comparing the therapeutic outcomes of SUI patients treated with iVES to those who underwent a trans-obturator tape (TOT) implantation surgery, where a mid-urethral sling was implanted without electric stimulation. Patients and methods: Urodynamic and viscoelastic data were collected from 21 SUI patients treated with a regimen combining iVES and biofeedback-assisted pelvic floor muscle training (iVES-bPFMT; 20-min iVES and 20-min bPFMT sessions, twice per week, for 3 months). This regimen complied with ethical standards. Data from 21 SUI patients who received TOT implantation were retrospectively analyzed. Mean compliance (Cm), infused volume (Vinf), and threshold pressure (Pthr) from the pressure-flow/volume investigations were assessed. Results: Compared with the pretreatment control, iVES-bPFMT consistently and significantly increased Cm (18/21; 85%, p = 0.017, N = 21) and Vinf (16/21; 76%, p = 0.046; N = 21) but decreased Pthr (16/21; 76%, p = 0.026, N = 21). In contrast, TOT implantation did not result in consistent or significant changes in Cm, Vinf, or Pthr (p = 0.744, p = 0.295, p = 0.651, respectively; all N = 21). Conclusion: Our results provide viscoelastic and thermodynamic evidence supporting an additional benefit of iVES-bPFMT to bladder storage in SUI patients by modifying bladder compliance, possibly due to the potentiated hypogastric tone, which did not occur in TOT-treated SUI patients.Clinical trial registration: ClinicalTrials.gov, NCT02185235 and NCT05977231.
RESUMO
Hepatocellular carcinoma (HCC), the primary form of liver cancer, is the third leading cause of cancer-related death globally. Hernandonine is a natural alkaloid derived from Hernandia nymphaeifolia that has been shown to exert various biological functions. In a previous study, hernandonine was shown to suppress the proliferation of several solid tumor cell lines without affecting normal human cell lines. However, little is known about the effect of hernandonine on HCC. Therefore, this study aimed to investigate the effect and mechanism of hernandonine on HCC in relation to autophagy. We found that hernandonine inhibited HCC cell growth in vitro and in vivo. In addition, hernandonine elicited autophagic cell death and DNA damage in HCC cells. RNA-seq analysis revealed that hernandonine upregulated p53 and Hippo signaling pathway-related genes in HCC cells. Small RNA interference of p53 resulted in hernandonine-induced autophagic cell death attenuation. However, inhibition of YAP sensitized HCC cells to hernandonine by increasing the autophagy induction. This is the first study to illustrate the complex involvement of p53 and YAP in the hernandonine-induced autophagic cell death in human HCC cells. Our findings provide novel evidence for the potential of hernandonine as a therapeutic agent for HCC treatment.
Assuntos
Morte Celular Autofágica , Carcinoma Hepatocelular , Proliferação de Células , Neoplasias Hepáticas , Transdução de Sinais , Proteína Supressora de Tumor p53 , Proteínas de Sinalização YAP , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Morte Celular Autofágica/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Sinalização YAP/metabolismo , Quinolinas/farmacologiaRESUMO
Thrombin activates platelets mainly through protease-activated receptor (PAR)1 and PAR4. However, downstream platelet signaling between PAR1 and PAR4 is not yet well understood. This study investigated the relationship between nSMase/ceramide and the NF-κB signaling pathway in PARs-mediated human platelet activation. The LC-MS/MS, aggregometry, flow cytometry, immunoprecipitation, and mesenteric microvessels of mice were used in this study. Human platelets stimulated by thrombin, 3-OMS (a neutral sphingomyelinase [nSMase] inhibitor) and Bay11-7082 (an NF-κB inhibitor) significantly inhibited platelet activation such as P-selectin expression. Thrombin also activated IκB kinase (IKK)ß and IκBα phosphorylation; such phosphorylation was inhibited by 3-OMS and SB203580 (a p38 MAPK inhibitor). Moreover, 3-OMS abolished platelet aggregation, IKKß, and p38 MAPK phosphorylation stimulated by PAR4-AP (a PAR4 agonist) but not by PAR1-AP (a PAR1 agonist). Immunoprecipitation revealed that nSMase was directly associated with PAR4 but not PAR1 in resting platelets. In human platelets, C24:0-ceramide is the predominant form of ceramides in the LC/MS-MS assay; C24:0-ceramide increases after stimulation by thrombin or PAR4-AP, but not after stimulation by PAR1-AP. We also found that C2-ceramide (a cell-permeable ceramide analog) activated p38 MAPK and IKKß phosphorylation in platelets and markedly shortened the occlusion time of platelet plug formation in vivo. This study demonstrated that thrombin activated nSMase by binding to PAR4, but not to PAR1, to increase the C24:0-ceramide level, followed by the activation of p38 MAPK-NF-κB signaling. Our results showed a novel physiological significance of PAR4-nSMase/ceramide-p38 MAPK-NF-κB cascade in platelet activation.