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Despite the clinical benefits of androgen deprivation therapy, most patients with advanced androgen-dependent prostate cancer (ADPC) eventually relapse and progress to lethal androgen-independent prostate cancer (AIPC), also termed castration-resistant prostate cancer (CRPC). MiRNAs can be packaged into exosomes (Exos) and shuttled between cells. However, the roles and mechanisms of exosomal miRNAs involved in CRPC progression have not yet been fully elucidated. Here, we find that miR-222-3p is elevated in AIPC cells, which results in remarkable enhancement of cell proliferation, migration, and invasion ability. Furthermore, Exos released by AIPC cells can be uptaken by ADPC cells, thus acclimating ADPC cells to progressing to more aggressive cell types in vitro and in vivo through exosomal transfer of miR-222-3p. Mechanistically, Exos-miR-222-3p promoted ADPC cells transformed to AIPC-like cells, at least in part, by activating mTOR signaling through targeting MIDN. Our results show that AIPC cells secrete Exos containing miRNA cargo. These cargos can be transferred to ADPC cells through paracrine mechanisms that have a strong impact on cellular functional remodeling. The current work underscores the great therapeutic potential of targeting Exo miRNAs, either as a single agent or combined with androgen receptor pathway inhibitors for CRPC treatment.
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Exossomos , MicroRNAs , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Androgênios/metabolismo , Antagonistas de Androgênios , Recidiva Local de Neoplasia , MicroRNAs/genética , MicroRNAs/metabolismo , Proliferação de Células/genética , Serina-Treonina Quinases TOR/genética , Exossomos/genética , Exossomos/metabolismo , Linhagem Celular TumoralRESUMO
Despite achieving optimal initial responses to androgen deprivation therapy, most patients with prostate cancer eventually progress to a poor prognosis state known as castrationresistant prostate cancer (CRPC). Currently, there is a notable absence of reliable early warning biomarkers and effective treatment strategies for these patients. Although androgen receptor (AR)independent pathways have been discovered and acknowledged in recent years, the AR signaling pathway continues to play a pivotal role in the progression of CRPC. The present review focuses on newly identified proteins within human CRPC tissues. These proteins encompass both those involved in ARdependent and ARindependent pathways. Specifically, the present review provides an indepth summary and analysis of the emerging proteins within AR bypass pathways. Furthermore, the significance of these proteins as potential biomarkers and therapeutic targets for treating CRPC is discussed. Therefore, the present review offers valuable theoretical insights and clinical perspectives to comprehensively enhance the understanding of CRPC.
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Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Masculino , Humanos , Antagonistas de Androgênios , Neoplasias de Próstata Resistentes à Castração/genéticaRESUMO
Prostate cancer (PCa) is the most common malignant tumor of the male urological system and poses a severe threat to the survival of middleaged and elderly males worldwide. The development and progression of PCa are affected by a variety of biological processes, including proliferation, apoptosis, migration, invasion and the maintenance of membrane homeostasis of PCa cells. The present review summarizes recent research advances in lipid (fatty acid, cholesterol and phospholipid) metabolic pathways in PCa. In the first section, the metabolism of fatty acids is highlighted, from formation to catabolism and associated proteins. Subsequently, the role of cholesterol in the pathogenesis and evolution of PCa is described in detail. Finally, the different types of phospholipids and their association with PCa progression is also discussed. In addition to the impact of key proteins of lipid metabolism on PCa growth, metastasis and drug resistance, the present review also summarizes the clinical value of fatty acids, cholesterol and phospholipids, as diagnostic and prognostic indicators and therapeutic targets in PCa.
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Metabolismo dos Lipídeos , Neoplasias da Próstata , Idoso , Pessoa de Meia-Idade , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas/metabolismo , Colesterol , Ácidos Graxos , FosfolipídeosRESUMO
Background: Adrenocortical carcinoma (ACC) is an uncommon endocrine malignancy associated with poor clinical outcome. As a novel form of cell death, ferroptosis is reliant on the accumulation of iron and reactive oxygen species and is involved in the pathogenesis of various tumors, including ACC. Our study aimed to identify and characterize the prognostic ferroptosis-related lncRNA signature (FerRLSig) in ACC. Methods: A regulatory network of ferroptosis-related lncRNAs (FerRLs) and mRNAs was constructed based on The Cancer Genome Atlas (TCGA). Univariate and multivariate Cox regression assays were performed to construct the FerRLSig. Results: Twenty-four FerRLs were identified in the prognostic model, and the high-risk FerRLSig was related to the worse overall survival (OS) in ACC [hazard ratio (HR): 1.936 (1.484-2.526), p < 0.001]. The area under the curve (AUC) value of the FerRLSig was 0.936 according to the receiver operating characteristic (ROC) analyses, superior to other traditional clinicopathological features, further supported the utility in prognosis prediction of ACC. We further established a prognostic nomogram combining clinical factors with the FerRLSig, which showed favorable efficacy for survival prediction. Next, gene set enrichment analysis (GSEA) revealed that gene sets were involved in many immune regulatory biological processes related to malignancies. T-cell function of type II INF response and the immune checkpoints, including CD40, CD276, IDO2, NRP1, and CD80, were expressed with a significant difference between the low- and high-risk groups. Conclusion: This study offered new insights into the pathogenesis of ACC. The novel FerRLSig could be useful in predicting survival and may provide information of immunological research and treatment for ACC patients.
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Overexposure to transforming growth factor b1 (TGF-ß1) induces myofibroblastic differentiation of mesenchymal stem cells (MSCs), which could be attenuated by myeloid-derived suppressor cell (MDSC) supernatant. However, the promyofibroblastic effects of TGF-ß1 and the antimyofibroblastic effects of MDSC supernatant in MSCs have not been fully elucidated. To further clarify the latent mechanism and identify underlying therapeutic targets, we used an integrative strategy combining transcriptomics and metabolomics. Bone marrow MSCs were collected 24 h following TGF-ß1 and MDSC supernatant treatment for RNA sequencing and untargeted metabolomic analysis. The integrated data were then analyzed to identify significant gene-metabolite correlations. Differentially expressed genes (DEGs) and differentially expressed metabolites (DEMs) were assessed by Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses for exploring the mechanisms of myofibroblastic differentiation of MSCs. The integration of transcriptomic and metabolomic data highlighted significantly coordinated changes in glycolysis/gluconeogenesis and purine metabolism following TGF-ß1 and MDSC supernatant treatment. By combining transcriptomic and metabolomic analyses, this study showed that glycolysis/gluconeogenesis and purine metabolism were essential for the myofibroblastic differentiation of MSCs and may serve as promising targets for mechanistic research and clinical practice in the treatment of fibrosis by MDSC supernatant.
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Células-Tronco Mesenquimais , Células Supressoras Mieloides , Miofibroblastos , Diferenciação Celular , Células Supressoras Mieloides/metabolismo , Purinas/metabolismo , Purinas/farmacologia , Transcriptoma/genética , Fator de Crescimento Transformador beta1/metabolismo , Fatores de Crescimento Transformadores/genética , Fatores de Crescimento Transformadores/metabolismo , Fatores de Crescimento Transformadores/farmacologia , Miofibroblastos/citologiaRESUMO
Objective: Primary pulmonary synovial sarcoma (PPSS) is extremely rare. This study aims to identify the clinicopathologic and therapeutic factors determining survival in PPSS. Methods: We performed a retrospective analysis of 121 patients from the Surveillance, Epidemiology, and End Results Database as well as 12 patients from our own institution diagnosed with PPSS. Patient survival was evaluated using the Kaplan-Meier method. Results: The median survival time for 12 PPSS patients in our institution was 78 months. Postoperative chemotherapy (P = .027 for overall survival and P = .035 for disease-specific survival) was associated with superior survival, whereas pneumonectomy (P = .011 for overall survival and P = .006 for disease-specific survival) was associated with worse survival. Single lobe involvement (P = .022) and the absence of lymph node involvement (P = .045) were associated with improved disease-specific survival and overall survival, respectively. In the Surveillance, Epidemiology, and End Results Database, the median survival time was 23 months. Significantly superior survival was observed in patients with earlier American Joint Committee on Cancer stage (â -â ¡) (P < .001 for both overall survival and disease-specific survival). Patients who were diagnosed within the recent decade did not achieve a better survival (P = .599 for overall survival and P = .596 for disease-specific survival). Conclusions: PPSS was aggressive with a very poor prognosis. The seventh American Joint Committee on Cancer stage might aid in predicting survival. Pneumonectomy and lymph node involvement might be associated with worse survival, whereas single lobe involvement and postoperative chemotherapy might be associated with improved survival.
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Developing erythroblasts acquire massive amounts of iron through the transferrin (Tf) cycle, which involves endocytosis, sorting, and recycling of the Tf-Tf receptor (Tfrc) complex. Previous studies on the hemoglobin-deficit (hbd) mouse have shown that the exocyst complex is indispensable for the Tfrc recycling; however, the precise mechanism underlying the efficient exocytosis and recycling of Tfrc in erythroblasts remains unclear. Here, we identify the guanine nucleotide exchange factor Grab as a critical regulator of the Tf cycle and iron metabolism during erythropoiesis. Grab is highly expressed in differentiating erythroblasts. Loss of Grab diminishes the Tfrc recycling and iron uptake, leading to hemoglobinization defects in mouse primary erythroblasts, mammalian erythroleukemia cells, and zebrafish embryos. These defects can be alleviated by supplementing iron together with hinokitiol, a small-molecule natural compound that can mediate iron transport independent of the Tf cycle. Mechanistically, Grab regulates the exocytosis of Tfrc-associated vesicles by activating the GTPase Rab8, which subsequently promotes the recruitment of the exocyst complex and vesicle exocytosis. Our results reveal a critical role for Grab in regulating the Tf cycle and provide new insights into iron homeostasis and erythropoiesis.
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Eritroblastos , Fatores de Troca do Nucleotídeo Guanina , Ferro , Receptores da Transferrina , Animais , Eritroblastos/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Ferro/metabolismo , Mamíferos/metabolismo , Camundongos , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo , Transferrina/metabolismo , Peixe-Zebra/metabolismoRESUMO
BACKGROUND: Adrenocortical carcinoma (ACC) is extremely rare in elderly patients. Thus, this study aimed to identify the incidence rate and develop nomogram models for predicting survival in elderly ACC patients. METHODS: Data of ACC patients aged >60 years from 1975 to 2016 were obtained from the Surveillance, Epidemiology, and End Results dataset. The national incidence rate was estimated, and survival was subjected to Kaplan-Meier analysis. A multivariate Cox regression model was used to identify predictors of survival. Nomograms were generated to predict survival, calibrated and internally validated. RESULTS: We identified 583 cases. Univariate analysis showed that patients with younger age (≤67 years), female sex, lower tumor grade, surgical treatment performed, and earlier European Network for the Study of Adrenal Tumors (ENSAT) stage had a better survival (P < 0.05). In the Cox regression analysis, no surgery performed (hazard ratio [HR]: 3.544, 95% CI: 1.142-10.995, P = 0.029 for overall survival [OS]; HR: 3.230, 95% CI: 1.040-10.034, P = 0.043 for disease-specific survival [DSS]) and advanced ENSAT stage (HR: 3.328, 95% CI: 1.628-6.801, P = 0.001 for OS; HR: 3.701, 95% CI: 1.682-8.141, P = 0.001 for DSS) were associated with worse outcomes. Age, sex, histologic grade, surgical resection, radiotherapy, and ENSAT stage were included in the nomograms, with a C-index of 0.692 for OS and 0.694 for DSS, demonstrating a good accuracy in predicting survival. CONCLUSIONS: This study is the largest review of ACC in elderly patients. We present nomograms to predict survival in elderly ACC patients using clinicopathologic data, which could aid in accurate clinical decision-making.
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Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/cirurgia , Idoso , Feminino , Humanos , Nomogramas , Prognóstico , Taxa de SobrevidaRESUMO
Patients with Huntington's disease (HD) have an increased incidence of diabetes. However, the molecular mechanisms of pancreatic ß-cell dysfunction have not been entirely clarified. Revealing the pathogenesis of diabetes can provide a novel understanding of the onset and progression of HD, as well as potential clues for the development of new therapeutics. Here, we demonstrated that the mouse pancreatic insulinoma cell line NIT-1 expressing N-terminal mutant huntingtin (mHTT) containing 160 polyglutamine (160Q cells) displayed lower cell proliferative ability than the cells expressing N-terminal wild-type HTT containing 20 polyglutamine (20Q cells). In addition, 160Q cells were more prone to apoptosis and exhibited deficient glucose-stimulated insulin expression and secretion. Furthermore, insulin signaling molecule insulin receptor substrate 2 (IRS-2) expression decreased and was recruited into mHTT aggregates. Consequently, glucose stimulation failed to activate the downstream molecule phosphatidylinositol-3 kinase (PI3K) in 160Q cells, leading to reduced phosphorylation levels of serine-threonine protein kinase AKT and forkhead box protein O1 (FoxO1). These data indicate that activation of the glucose-stimulated PI3K/AKT/FoxO1 signaling pathway is significantly blocked in pancreatic ß-cells in HD. Importantly, insulin treatment inhibited the aggregation of mHTT and significantly improved the activation of PI3K/AKT/FoxO1 signaling in 160Q cells. These results suggest that the inhibition of the PI3K/AKT/FoxO1 pathway might be due to the recruitment of IRS-2 into mHTT aggregates in HD ß-cells, ultimately contributing to the impairment of pancreatic ß-cells. In conclusion, our work provides new insight into the underlying mechanisms of the high incidence of diabetes and abnormal glucose homeostasis in HD.
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Proteína Huntingtina/genética , Doença de Huntington/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Proteína Forkhead Box O1/metabolismo , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Natural extracellular vesicles (EVs) are ideal drug carriers due to their remarkable biocompatibility. Their delivery specificity can be achieved by the conjugation of targeting ligands. However, existing methods to engineer target-specific EVs are tedious or inefficient, having to compromise between harsh chemical treatments and transient interactions. Here, we describe a novel method for the covalent conjugation of EVs with high copy numbers of targeting moieties using protein ligases. Conjugation of EVs with either an epidermal growth factor receptor (EGFR)-targeting peptide or anti-EGFR nanobody facilitates their accumulation in EGFR-positive cancer cells, both in vitro and in vivo. Systemic delivery of paclitaxel by EGFR-targeting EVs at a low dose significantly increases drug efficacy in a xenografted mouse model of EGFR-positive lung cancer. The method is also applicable to the conjugation of EVs with peptides and nanobodies targeting other receptors, such as HER2 and SIRP alpha, and the conjugated EVs can deliver RNA in addition to small molecules, supporting the versatile application of EVs in cancer therapies. This simple, yet efficient and versatile method for the stable surface modification of EVs bypasses the need for genetic and chemical modifications, thus facilitating safe and specific delivery of therapeutic payloads to target cells.
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Sistemas de Liberação de Medicamentos/métodos , Vesículas Extracelulares , Peptídeos/uso terapêutico , Anticorpos de Domínio Único/uso terapêutico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêutico , Receptores ErbB/química , Receptores ErbB/uso terapêutico , Eritrócitos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Paclitaxel/uso terapêutico , Peptídeos/química , Anticorpos de Domínio Único/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The appropriate surgical modality for early-stage non-small cell lung cancer (NSCLC) among the elderly remains controversial; identifying appropriate modalities will be helpful in clinical practice. METHODS: It's a cohort study and we explored the Surveillance, Epidemiology, and End Results (SEER) database for identifying patients aged ≥70 years with pathologic stage IA NSCLC. Three types of surgeries were compared (lobectomy, segmentectomy, and wedge resection) via survival and stratification analyses. RESULTS: Overall, 6,197 patients were enrolled. Among patients aged ≥76 years with tumor diameters ≤1 cm, significant differences in survival were noted for segmentectomy vs. lobectomy [hazard ratio (HR) =0.294, P=0.007] and wedge resection vs. lobectomy (HR =0.548, P=0.017) but not in those with tumors diameters >1 cm. Among patients aged 70-75 years with tumor diameters >1-2 cm, significant differences in survival were observed for segmentectomy vs. lobectomy (HR =0.671, P=0.037) and segmentectomy vs. wedge resection (HR =0.556, P=0.003) and for wedge resection vs. lobectomy (HR =1.283, P=0.003) among those with tumor diameters >2-3 cm but not in those with tumor diameters ≤1 cm. CONCLUSIONS: Both age and tumor size should be considered when selecting the surgical modality. Lobectomy is not recommended for lesions ≤1 cm among patients aged ≥76 years. Segmentectomy was associated with superior prognosis for tumor diameters >1-2 cm and survival favored lobectomy rather than wedge resection for NSCLCs >2-3 cm among patients aged 70-75 years. Surgeons could rely on personal experience to determine the appropriate surgical modality for NSCLCs >1 cm among patients aged ≥76 years and NSCLCs ≤1 cm among patients aged 70-75 years.
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Esophageal squamous cell carcinoma (ESCC) is an invasive gastrointestinal malignancy and in urgent need of new effective therapies. Gambogic acid (GA) exhibits anti-cancer effects in many cancer cells, but it remains to be determined whether GA has the same effect on ESCC. Here, we reported that GA treatment caused an inhibition in ESCC cell proliferation, migration and invasion. Meanwhile, GA induced dose-dependent apoptosis of ESCC cells, repressed the expression of Bcl2 and up-regulated the levels of Bax protein, cleaved-PARP1 and cleaved-caspase 3/9. Further investigation showed that GA down-regulated the levels of PI3K, p-AKT and p-mTOR, while promoted PTEN expression in ESCC cells. Taken together, we provided the first demonstration that GA exerts anti-tumor effects on ESCC cells presumably through regulating PTEN-PI3K-AKT-mTORpathway, suggestive of a therapeutic potential for ESCC.
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BACKGROUND: Thymic carcinoma is a type of rare and highly malignant tumor. Limited information was available on prognostic factors of late-stage thymic carcinoma. The aim of this study was to identify factors that impact prognosis and to define the relationship between survival and surgical intervention in patients with Masaoka stage IV thymic carcinoma. METHODS: From 1973 to 2015, a total of 311 consecutive patients were enrolled in this study with pathologic confirmed Masaoka stage IV thymic carcinoma from the Surveillance, Epidemiology, and End Results database. Kaplan-Meier analyses, Cox-regression analyses and propensity score matching (PSM) were performed to evaluate prognosis. RESULTS: In the multivariate analysis, larger tumor size, distant metastasis and positive lymph node status were associated with poorer outcome. After PSM, no receipt of surgery was the prognostic factor indicating poorer survival [hazard ratio (HR) 1.985, 95% confidence interval (CI) 1.007-3.913, P=0.048 for overall survival (OS); HR 1.649, 95% CI: 1.009-2.697, P=0.046 for disease-specific survival (DSS)]. Subgroup analysis indicated that significantly improved survival with surgery was observed in patients who were <60 years (HR 0.48, 95% CI: 0.32-0.72), female (HR 0.37, 95% CI: 0.23-0.60), Caucasian (HR 0.56, 95% CI: 0.40-0.77), with larger tumor size (≥7.0 cm, HR 0.42, 95% CI: 0.25-0.69), with (HR 0.60, 95% CI: 0.39-0.90) or without distant metastasis (HR 0.46, 95% CI: 0.26-0.83), and node-positive (HR 0.56, 95% CI: 0.38-0.82). CONCLUSIONS: Surgical treatment could be beneficial in patients with Masaoka stage IV thymic carcinoma. This SEER based analysis revealed the role of surgical resection and the favorable effect of surgery in specific thymic carcinoma subgroups.
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Synovial sarcoma (SS) is an uncommon malignant tumor associated with poor prognosis, and SS arising from the trachea is even rarer, with only 3 cases reported previously. We present the case of a 19-year-old man for whom imaging studies revealed a mass of soft tissue density in the lower trachea. An en bloc trachea segmental resection and postoperative proton beam therapy were performed. Diagnosis was confirmed by the SS18-SSX gene rearrangement. The patient was alive without tumor recurrence for 18 months. This case report presents tracheal SS successfully treated with surgery and postoperative proton therapy.
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Terapia com Prótons , Sarcoma Sinovial/radioterapia , Sarcoma Sinovial/cirurgia , Neoplasias da Traqueia/radioterapia , Neoplasias da Traqueia/cirurgia , Terapia Combinada , Humanos , Masculino , Adulto JovemRESUMO
Objective Up to 40% of multiple endocrine neoplasia type 1 (MEN1) patients may have adrenal cortical tumors. However, adrenocortical carcinoma (ACC) is rare. The clinical manifestations, prevalence, inheritance and prognosis of ACC associated with MEN1 remain unclear. Here we report the clinical manifestations and prevalence of ACC in patients with MEN1. Design and methods A retrospective analysis of ACC associated with MEN1 patients at a single tertiary care center from December 2001 to June 2017. Genetic analysis of MEN1 and other ACC associated genes, loss of heterozygosity (LOH) of MEN1 locus, immunohistochemistry staining of menin, P53 and ß-catenin in ACC tissue were performed. Results Two related patients had ACC associated with MEN1. The father had ENSAT stage IV tumor with excessive production of cortisol; the daughter had nonfunctional ENSAT stage I tumor. Both patients carried novel germline heterozygous mutation (c.400_401insC) of MEN1. The wild-type MEN1 allele was lost in the resected ACC tissue from the daughter with no menin staining. The ACC tissue had nuclear ß-catenin staining, with heterozygous CTNNB1 mutation of 357del24 and P53 staining in only 20% cells. Conclusions ACC associated with MEN1 is rare and may occur in familial aggregates.
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BACKGROUND: Iron accumulation in basal ganglia accompanies neuronal loss in Huntington's disease (HD) patients and mouse disease models. Disruption of HD brain iron homeostasis occurs before the onset of clinical signs. Therefore, investigating the mechanism of iron accumulation is essential to understanding its role in disease pathogenesis. METHODS: N171-82Q HD transgenic mice brain iron was detected by using Diaminobenzidine-enhanced Perls' stain. Iron homeostatic proteins including iron response protein 1 (IRP1), transferrin (Tf), ferritin and transferrin receptor (TfR) were determined by using western blotting and immunohistochemistry, and their relative expression levels of RNA were measured by RT-PCR in both N171-82Q HD transgenic mice and HEK293 cells expressing N-terminal of huntingtin. RESULTS: Iron was increased in striatum and cortex of N171-82Q HD transgenic mice. Analysis of iron homeostatic proteins revealed increased expression of IRP1, Tf, ferritin and TfR in N171-82Q mice striatum and cortex. The same results were obtained in HEK293 cells expressing N-terminal of mutant huntingtin containing 160 CAG repeats. CONCLUSION: We conclude that mutant huntingtin may cause abnormal iron homeostatic pathways by increasing IRP1 expression in Huntington's disease, suggesting potential therapeutic target.
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OBJECTIVE: Thymic neuroendocrine tumour (TH-NET) accounts for almost 20% of multiple endocrine neoplasia type 1 (MEN1)-associated mortality. Identifying risk factors for the development of these rare tumours and prognostic factors for clinical outcomes will be helpful in clinical practice. DESIGN AND PATIENTS: We performed a retrospective analysis of patients treated for TH-NET associated with MEN1 in a single institution and meta-analysis of literature reports. We used a fixed effect model to pool results across studies to evaluate the prevalence, clinical features and prognosis. RESULTS: TH-NET was detected in 9 (7.4%) of 121 patients with MEN1 seen in our institution, and 5 (55.6%) were women. Seven additional studies were identified through a systematic review of the literature. The pool estimate of TH-NET prevalence was 3.7% (n = 99) in MEN1 (n = 2710), sex ratio was 79:20 (male vs female), and the median age at diagnosis was 43.0 years (range, 16.0-72.0 years). Forty-three patients died with a median survival time of 8.4 years. Older age at diagnosis (HR = 1.4, 95% CI = 1.0-1.8, P = .03), maximum tumour diameter (HR = 1.5, 95% CI = 1.0-2.3, P = .04) and presence of metastasis (HR = 1.6, 95% CI = 1.0-2.5, P = .04) were associated with worse outcome. A male predominance (91.9% vs 59.5%, P < .001) and history of smoking (59.0% vs 23.5%, P = .015) were more common in American/European series compared to Asian reports. CONCLUSION: TH-NET is a rare but fatal component of MEN1. Earlier detection of TH-NET in patients with MEN1 may be recommended which should theoretically result in better outcomes. Different genetic backgrounds (race) appear to result in clinical difference.
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Neoplasia Endócrina Múltipla Tipo 1/patologia , Tumores Neuroendócrinos/patologia , Neoplasias do Timo/patologia , Feminino , Humanos , Masculino , PrognósticoRESUMO
The genomic alterations for benign thyroid nodule, especially adenomatoid nodule, one of the most common types of hyperplasia lesion, are ill-studied. Here, we show whole-exome sequencing and/or transcriptome sequencing data on adenomatoid nodules with or without coincidental papillary thyroid carcinoma (PTC). Somatic mutation of BRAF (22/32) is only detected in PTC, while mutations in SPOP (4/38), ZNF148 (6/38) and EZH1 (3/38) are found enriched in adenomatoid nodule. In an expanded cohort of adenomatoid nodule (n=259) mutually exclusive SPOPP94R, EZH1Q571R and ZNF148 mutations are identified in 24.3% of them. Adenomatoid nodules show very few overlapped mutations and distinct gene expression patterns with their coincidental PTC. Phylogenetic tree analysis uncovers that PTCs evolved independently from their matched benign nodules. Our findings reveal that benign nodules possess a unique molecular signature that differs from PTC and provide genomic evidence for the conventional belief that PTC and benign nodules have independent origin.
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Exoma , Mutação , Nódulo da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/fisiopatologia , Transcriptoma , Adulto , Idoso , Proliferação de Células , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas Nucleares/genética , Filogenia , Complexo Repressor Polycomb 2/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Repressoras/genética , Análise de Sequência de RNA , Câncer Papilífero da Tireoide/genética , Glândula Tireoide/metabolismo , Fatores de Transcrição/genéticaRESUMO
Huntington's disease (HD) is an inherited neurodegenerative disease that is caused by the abnormal expansion of CAG repeats in the gene encoding huntingtin (Htt). Reduced AKT phosphorylation and inhibited AKT activity have been shown to be involved in mutant Htt (mHtt)-induced cell death. Lycium barbarum polysaccharide (LBP), the main bioactive component of Lycium barbarum, reportedly has neuroprotective roles in neural injuries, including neurodegenerative diseases. Here, we report that treatment with LBP can increased the viability of HEK293 cells that stably expressed mHtt containing 160 glutamine repeats and significantly improved motor behavior and life span in HD-transgenic mice. Furthermore, we found that in LBP-treated HEK293 cells expressing mHtt, mHtt levels were reduced and the phosphorylation of AKT at Ser473 (p-AKT-Ser473) was significantly increased. We also found that treatment with LBP increased p-AKT-Ser473 and decreased mHtt in the cortex, hippocampus and striatum in HD-transgenic mice. The level of phosphorylation of p-GSK3ß-Ser9 remained unchanged in both cultured cells and HD-transgenic mice. Our findings suggest that LBP alleviates the cytotoxicity of mHtt by activating AKT and reducing mHtt levels, indicating that LBP may be potentially useful for treating HD.
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Medicamentos de Ervas Chinesas/uso terapêutico , Proteína Huntingtina/genética , Doença de Huntington/tratamento farmacológico , Mutação/genética , Proteína Oncogênica v-akt/metabolismo , Análise de Variância , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cromonas/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Doença de Huntington/genética , Doença de Huntington/mortalidade , Doença de Huntington/fisiopatologia , Camundongos , Camundongos Transgênicos , Morfolinas/farmacologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Análise de Sobrevida , TransfecçãoRESUMO
BACKGROUND: The aim of the present study was to investigate whether the expression of Brain-Derived Neurotrophic Factor (BDNF) and its receptor Tropomyosin-related kinase B (TrkB) is correlated with the clinical progression of salivary adenoid cystic carcinoma (SACC) and whether the BDNF/TrkB axis is associated with the induction of epithelial-mesenchymal transition (EMT) in SACC cells. METHOD: The expression of BDNF, TrkB, and E-cadherin (an EMT biomarker) in 76 primary SACC specimens and 20 normal salivary gland tissues was analyzed by immunohistochemistry. Additionally, the expression of BDNF, TrkB, and E-cadherin in SACC cell lines (SACC-83 and SACC-LM) was analyzed by RT-PCR and Western blotting. The biological role of the BDNF/TrkB axis in the EMT progression of SACC was evaluated after treatment with increased levels of BDNF and by inhibiting TrkB activity in SACC-83 cell line. The progression of SACC cells through EMT was assessed by RT-PCR, Western blotting, photography, migration and invasion assays. RESULTS: Elevated expression of TrkB (92.1%) and BDNF (89.5%), and downregulated expression of E-cadherin (47.4%) was found in SACC specimens, which was significantly correlated with the invasion and metastasis in SACC (P<0.05). The high expression of TrkB and the low expression of E-cadherin was significantly correlated with the poor prognosis of SACC patients (P<0.05). The expression of TrkB was inversely correlated with the expression of E-cadherin in both SACC cases and cell lines (P<0.05). Increasing BDNF levels after treatment with exogenous recombinant human BDNF (rhBDNF) at 100 ng/ml significantly promoted the activation of TrKB and the progression of EMT in SACC cells. While obstruction of TrkB by its inhibitor, k252a (100 nM), significantly inhibited the EMT progression of SACC cells. CONCLUSIONS: These results suggest that BDNF-mediated TrkB activation contributes to the EMT progression and the poor prognosis in SACC. The present study demonstrated that the BDNF/TrkB axis promotes the migration and invasion of SACC cells via EMT in vitro. Targeting the inactivation of the BDNF/TrkB axis may be a potential strategy for the treatment of SACC.