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OBJECTIVE: To describe in as much detail as possible the method for ablating the ventromedial shell of the nucleus accumbens (NAc) and investigate the efficacy and safety of the ablation treatment. METHODS: Sixty-five patients with drug addictions received operations within the time frame from 2004 to 2009. The ablation targets were located in the bilateral medial posterior inferior shell of the NAc. Intraoperative electrophysiological monitoring was performed. RESULTS: Tissue impedance in the shell of the NAc varied from 185 to 355 Ω. When stimulated with a low frequency (2 Hz) and a voltage above 3 V, 57 out of 65 (87.7%) patients experienced slight throbbing sensations. During the lesion procedure, fever was detected on the head and face of 59 patients (90.8%), the heart rate decreased in 19 cases (29.2%), and restlessness, irritability and hyperalgia were noted for all patients. Among the 65 patients, 52 (80%) no longer experienced a psychological craving for the drug. CONCLUSIONS: The shell of the NAc may be a promising surgical target for psychosurgery. Electrophysiological recordings revealed that the shell is indeed an appropriate structure.
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Técnicas de Ablação/métodos , Fenômenos Eletrofisiológicos/fisiologia , Procedimentos Neurocirúrgicos/métodos , Núcleo Accumbens/fisiopatologia , Núcleo Accumbens/cirurgia , Técnicas Estereotáxicas , Técnicas de Ablação/efeitos adversos , Adolescente , Adulto , Feminino , Febre/epidemiologia , Febre/etiologia , Humanos , Hiperalgesia/epidemiologia , Hiperalgesia/etiologia , Incidência , Masculino , Monitorização Fisiológica/métodos , Procedimentos Neurocirúrgicos/efeitos adversos , Transtorno Obsessivo-Compulsivo/fisiopatologia , Transtorno Obsessivo-Compulsivo/cirurgia , Psicocirurgia/efeitos adversos , Psicocirurgia/métodos , Estudos Retrospectivos , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/cirurgia , Tabagismo/fisiopatologia , Tabagismo/cirurgia , Resultado do Tratamento , Adulto JovemRESUMO
This study aimed to examine expression and microstructural distribution of prestin in outer hair cells, and the effect of dose and time of radiation on prestin expression in the BALB/c mouse. We also investigated the molecular biological characteristics of prestin and possible mechanisms of sensorineural hearing loss caused by radiation. Seventy 4-week-old mice were randomly divided into four groups, including one control group and three experimental groups. Each experimental group was randomly divided into two groups, which were killed to collect specimens of the cochlea on the 3rd and 7th days after exposure to different doses of 8, 12, and 16 Gy radiation. These cochleas were embedded in paraffin, and then cut into sections. The sections were immunostained with anti-prestin antibodies. The distribution of prestin was observed under optical microscopy and the density of prestin-positive expression was quantitatively calculated by Image-Pro Plus. Prestin had high expression in the lateral membrane and low expression in the cytoplasm of outer hair cells above the nucleus. The density of prestin protein expression of the basal turn was not significantly different after exposure to the different doses of radiation compared with the control group, but up-regulation occurred after radiation in the apex turn. We conclude that prestin protein is mainly expressed in the lateral membrane above the nucleus. Prestin protein may be responsible for the mechanism of injury to the inner ear caused by radiation.
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Células Ciliadas Auditivas Externas/metabolismo , Perda Auditiva Neurossensorial/metabolismo , Proteínas Motores Moleculares/biossíntese , Lesões Experimentais por Radiação/metabolismo , Animais , Seguimentos , Células Ciliadas Auditivas Externas/efeitos da radiação , Perda Auditiva Neurossensorial/etiologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Lesões Experimentais por Radiação/complicações , Fatores de TempoRESUMO
OBJECTIVE: Vascular hyporeactivity increases with the incidence of obstructive jaundice (OJ). Evidence suggests that OJ activates the farnesoid X receptor (FXR) as well as the large-conductance Ca2+-activated K+ (BKCa or MaxiK) channel. This study was designed to explore the role of the FXR in vascular hyporesponsiveness induced by cholestasis. METHODS: The OJ model rats were constructed by bile duct ligation (BDL) and treated with an FXR agonist or antagonist. Vasoconstriction of the mesenteric arteries (MAs) was assessed in vitro. Whole-cell patch clamp recordings were used to investigate BKCa channel function. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to detect mRNA and protein levels. RESULTS: A significant increase in vascular tone and responsiveness to norepinephrine (NE) was observed after the MaxiK channel blocker (IbTX) was administered. This effect was pronounced in BDL animals and can be mimicked by the FXR agonist GW4064 and inhibited by the FXR antagonist Z-guggulsterone (Z-Gu). GW4064 has a similar effect as cholestasis in promoting MaxiK currents in isolated arterial smooth muscle cells (ASMCs), while Z-Gu blunted this effect. The mRNA and protein expression of FXR and MaxiK-ß1, but not MaxiK-α, were significantly increased in the BDL group in comparison to the sham. Furthermore, activation or inhibition of FXR promoted or inhibited the mRNA and protein expression of the MaxiK-ß1 subunit, respectively. CONCLUSION: Activation of FXR enhances the capability of the MaxiK channel to regulate vascular tone and leads to vascular hyporesponsiveness in the MAs of BDL rats, which may be mediated by the nonparallel upregulation of MaxiK-α and MaxiK-ß1 subunit expression.
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BACKGROUND: Cranial radiation therapy has been used for the treatment of primary and metastatic brain tumors. A prominent feature of brain injury induced by the radiation therapy is hippocampal dysfunction, characterized by a decline in memory. Cdk5 plays an important role in memory formation. Abnormal Cdk5 activity is associated with neuronal apoptosis induced by neurotoxic stimuli. However, the roles of Cdk5 in hippocampal apoptosis in response to X-ray irradiation have not been explored. METHODS: The expression of Cdk5 activators, p35 and p25, in hippocampal neurons was tested in both in vivo animal and in vitro couture after X-ray irradiation. RESULTS: After X-ray irradiation at 20 Gy and 30 Gy in rats, the number of hippocampal neuronal pyknosis was increased, but the number of hippocampal neuron was decreased, in the hippocampal CA1 region of rats. In these animals undergone with X-ray irradiation, the expression of p35 was significantly down-regulated, but it was up-regulated in p25. These opposite expressions were also shown in the primary cultured hippocampal neurons with 30 Gy irradiation. The apoptosis induced by X-ray irradiation were significantly prevented by the pretreatment of Cdk5 inhibitor, roscovitine, in both in vivo and in vitro settings. CONCLUSIONS: X-ray irradiation resulted in a hippocampal neuronal apoptosis through up-regulation of p25, the Cdk5 activator. Hyperactivity of Cdk5 was involved in the pathogenesis of X-ray irradiation-induced hippocampal neuronal apoptosis. Blockade of Cdk5 signal pathway effectively protected neurons from the irradiation-induced brain injury.
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AIMS: Anxiety disorders associated with pain are a common health problem. However, the underlying mechanisms remain poorly understood. We aimed to investigate the role of paraventricular nucleus (PVN)-central nucleus of the amygdala (CeA) oxytocinergic projections in anxiety-like behaviors induced by inflammatory pain. METHODS: After inflammatory pain induction by complete Freund's adjuvant (CFA), mice underwent elevated plus maze, light-dark transition test, and marble burying test to examine the anxiety-like behaviors. Chemogenetic, optogenetic, and fiber photometry recordings were used to modulate and record the activity of the oxytocinergic projections of the PVN-CeA. RESULTS: The key results are as follows: inflammatory pain-induced anxiety-like behaviors in mice accompanied by decreased activity of PVN oxytocin neurons. Chemogenetic activation of PVN oxytocin neurons prevented pain-related anxiety-like behaviors, whereas inhibition of PVN oxytocin neurons induced anxiety-like behaviors in naïve mice. PVN oxytocin neurons projected directly to the CeA, and microinjection of oxytocin into the CeA blocked anxiety-like behaviors. Inflammatory pain also decreased the activity of CeA neurons, and optogenetic activation of PVNoxytocin -CeA circuit prevented anxiety-like behavior in response to inflammatory pain. CONCLUSION: The results of our study suggest that oxytocin has anti-anxiety effects and provide novel insights into the role of PVNoxytocin -CeA projections in the regulation of anxiety-like behaviors induced by inflammatory pain.
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Núcleo Central da Amígdala , Ratos , Camundongos , Animais , Núcleo Hipotalâmico Paraventricular , Ocitocina , Ratos Wistar , Ansiedade/etiologia , Transtornos de Ansiedade , DorRESUMO
BACKGROUND: To analysis the clinical outcomes of concurrent chemoradiotherapy (CCRT) alone based on 10-year results for loco-regionally advanced nasopharyngeal carcinoma (LANPC), so as to provide evidence for individualized treatment strategy and designing appropriate clinical trial for different risk LANPC patients. METHODS: Consecutive patients with stage III-IVa (AJCC/UICC 8th) were enrolled in this study. All patients received radical intensity-modulated radiotherapy (IMRT) and concurrent cisplatin chemotherapy (CDDP). The hazard ratios (HRs) of death risk in patients with T3N0 was used as baseline, relative HRs were calculated by a Cox proportional hazard model to classify different death risk patients. Survival curves for the time-to-event endpoints were analyzed by the Kaplan-Meier method and compared using the log-rank test. All statistical tests were conducted at a two-sided level of significance of 0.05. RESULTS: A total of 456 eligible patients were included. With 12-year median follow-up, 10-year overall survival (OS) was 76%. 10-year loco-regionally failure-free survival (LR-FFS), distant failure-free survival (D-FFS) and failure-free survival (FFS) were 72%, 73% and 70%, respectively. Based on the relative hazard ratios (HRs) of death risk, LANPC patients were classified into 3 subgroups, low-risk group (T1-2N2 and T3N0-1) contained 244 patients with HR < 2; medium-risk group (T3N2 and T4N0-1) contained 140 patients with HR of 2 - 5; high-risk group (T4N2 and T1-4N3) contained 72 patients with HR > 5. The 10-year OS for patients in low-, medium-, and high-risk group were 86%, 71% and 52%, respectively. Significantly differences of OS rates were found between each of the two groups (low-risk group vs. medium-risk group, P < 0.001; low-risk group vs. high-risk group, P < 0.001; and medium-risk group vs. high-risk group, P = 0.002, respectively). Grade 3-4 late toxicities included deafness/otitis (9%), xerostomia (4%), temporal lobe injury (5%), cranial neuropathy (4%), peripheral neuropathy (2%), soft tissue damage (2%) and trismus (1%). CONCLUSIONS: Our classification criteria demonstrated that significant heterogeneity in death risk among TN substages for LANPC patients. IMRT plus CDDP alone maybe suitable for low-risk LANPC (T1-2N2 or T3N0-1), but not for medium- and high-risk patients. These prognostic groupings provide a practicable anatomic foundation to guide individualized treatment and select optimal targeting in the future clinical trials.
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Neoplasias Nasofaríngeas , Radioterapia de Intensidade Modulada , Humanos , Carcinoma Nasofaríngeo/radioterapia , Seguimentos , Neoplasias Nasofaríngeas/radioterapia , Prognóstico , Cisplatino , Quimiorradioterapia/métodos , Radioterapia de Intensidade Modulada/métodos , Estudos RetrospectivosRESUMO
Although radiotherapy results of nasopharyngeal carcinoma (NPC) at an early stage are better than other tumors, there is still a portion of patients with NPC who die before 5 years after the treatment; the underlying mechanism remains to be further understood. This study aims to investigate the mechanism by which NPC cells escape from irradiation. Patients with NPC at stage I was included in this study. All the patients were treated with irradiation. NPC biopsies were obtained from each patient before and 1 week after the start of radiotherapy. Expression of AKT in NPC tissue was assessed by Western blotting. NPC cell line, SUNE-1 cells, was treated with irradiation. The levels of AKT in SUNE-1 cells were also assessed. The frequency of apoptotic SUNE-1 cells was evaluated by flow cytometry. The levels of AKT were markedly increased in NPC tissue after treatment with irradiation, which was significantly correlated with NPC metastasis and mortality. After irradiation, NPC cell line, SUNE-1 cells, expressed higher levels of AKT than control cells. The knockdown of AKT in SUNE-1 cells markedly increased apoptotic cell rate. Radiotherapy can increase the levels of AKT in NPC cells that are associated with NPC metastasis and increase in mortality.
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Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/radioterapia , Proteínas Proto-Oncogênicas c-akt/biossíntese , Adulto , Idoso , Apoptose/genética , Apoptose/efeitos da radiação , Carcinoma , Linhagem Celular Tumoral , Ativação Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/enzimologia , Metástase Neoplásica , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas c-akt/genética , Interferência de RNARESUMO
PURPOSE: To investigate whether the addition of fluorouracil to docetaxel and cisplatin induction chemotherapy (IC) can truly improve the prognosis of patients with locoregionally advanced nasopharyngeal carcinoma (NPC). METHODS: A total of 801 patients newly diagnosed with non-metastatic locoregionally advanced NPC were included as the subjects. In this study, propensity score matching (PSM) was used for analysis of overall survival (OS), distant metastasis-free survival (DMFS), progression-free survival (PFS) and locoregional relapse-free survival (LRRFS), and the chi-squared test or Fisher's exact test was used to investigate toxic reactions. RESULTS: Patients received treatment with docetaxel and cisplatin (TP) or docetaxel, cisplatin and fluorouracil (TPF). With a median follow-up time of 60 months (range: 5-124 months), the TPF group had better 5-year OS (84.7% vs 79.0%; P = 0.037), PFS (84.6% vs 76.8%; P = 0.008) and DMFS (89.5% vs 82.3%; P = 0.004) than the TP group. After PSM, 258 patients were matched in each cohort. The Kaplan-Meier analysis showed that the 5-year OS, PFS and DMFS were 85.5%, 84.2% and 89.2%, respectively, in the TPF group, higher than the 80.8%, 75.0% and 81.4%, respectively, in the TP group (P = 0.048, 0.009 and 0.006, respectively). Moreover, the multivariate analysis revealed that different IC regimens were independent prognostic factors for PFS and DMFS (P = 0.014 and 0.010, respectively). CONCLUSION: This study found that compared with the TP regimen, TPF induction chemotherapy is associated with improved survival in patients with locoregionally advanced NPC. TPF can produce more mucosal and nausea/vomiting adverse reactions than TP.
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Quimioterapia de Indução , Neoplasias Nasofaríngeas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia , Cisplatino , Docetaxel , Fluoruracila/efeitos adversos , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Pontuação de Propensão , Estudos RetrospectivosRESUMO
OBJECTIVE: This study aimed to explore the clinical value of adjuvant chemotherapy (ACT) following concurrent chemo-radiotherapy (CCRT) and induction chemotherapy (ICT) in loco-regionally advanced nasopharyngeal carcinoma (LANC). METHODS: We included 839 newly diagnosed LANC patients in this study. ICT plus CCRT (ICT + CCRT group) was administered to 443 patients, and 396 patients received ACT after ICT plus CCRT (ICT + CCRT + ACT group). Univariate and multivariate Cox regression analyses were carried out. Furthermore, propensity score matching (PSM) was applied to balance the study and control groups. RESULTS: A total of 373 pairs of LANC patients were obtained after PSM analysis. We found that ACT following ICT + CCRT has no significant effect on improving the survival of LANC patients. By further exploring the ICT + CCRT + ACT treatment protocol, we excluded N0-1-positive patients and re-performed PSM in the ICT + CCRT and ICT + CCRT + ACT groups. Each group consisted of 237 patients. Kaplan-Meier analysis revealed that there were differences between the ICT + CCRT and ICT + CCRT + ACT groups in terms of the 5-year overall survival (OS) (78.9% vs. 85.0%, P = 0.034), disease-free survival (DFS) (73.4% vs. 81.7%, P = 0.029), and distant metastasis-free survival (DMFS) (84.9% vs. 76.0%, P = 0.019). In addition, the ICT + CCRT + ACT group had a higher incidence of grade 3/4 acute leukocytopenia/neutropenia. CONCLUSION: Compared with ICT + CCRT, ACT following ICT plus CCRT can reduce distant metastasis of N2-3-positive LANC and improve the OS and DFS. The results demonstrated the feasibility and clinical utility of ACT following ICT plus CCRT.
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Leucopenia , Neoplasias Nasofaríngeas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/métodos , Quimioterapia Adjuvante/métodos , Cisplatino/efeitos adversos , Humanos , Quimioterapia de Indução/métodos , Leucopenia/induzido quimicamente , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Estudos RetrospectivosRESUMO
Worldwide, nasopharyngeal carcinoma (NPC) is a rare head and neck cancer; however, it is a common malignancy in southern China. Radiotherapy is the most important treatment strategy for NPC. However, although radiotherapy is a strong tool to kill cancer cells, paradoxically it also promotes aggressive phenotypes. Therefore, we mimicked the treatment process in NPC cells in vitro. Upon exposure to radiation, a subpopulation of NPC cells gradually developed resistance to radiation and displayed cancer stem-cell characteristics. Radiation-induced stemness largely depends on the accumulation of the antiapoptotic myeloid cell leukemia 1 (MCL-1) protein. Upregulated MCL-1 levels were caused by increased stability and more importantly, enhanced protein synthesis. We showed that repeated ionizing radiation resulted in persistently enhanced reactive oxygen species (ROS) production at a higher basal level, further promoting protein kinase B (AKT) signaling activation. Intracellular ROS and AKT activation form a positive feedback loop in the process of MCL-1 protein synthesis, which in turn induces stemness and radioresistance. AKT/MCL-1 axis inhibition attenuated radiation-induced resistance, providing a potential target to reverse radiation therapy-induced radioresistance.
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Proteína de Sequência 1 de Leucemia de Células Mieloides , Neoplasias Nasofaríngeas , Proteínas Proto-Oncogênicas c-akt , Linhagem Celular Tumoral , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/radioterapia , Tolerância a Radiação/genética , Espécies Reativas de OxigênioRESUMO
Objective: To investigate the clinical value of induction chemotherapy (IC) with docetaxel plus cisplatin (TP) followed by concurrent chemoradiotherapy (CCRT) with TP in locoregionally advanced nasopharyngeal carcinoma (NPC). Methods: A total of 544 patients with locoregionally advanced NPC that was newly diagnosed from January 2009 to December 2015 were included in this study. Among these patients, 251 were treated with TP induction chemotherapy followed by CCRT with cisplatin (DDP) alone (TP + DDP group), 167 were treated with TP followed by CCRT with TP (TP + TP group), and 126 were treated with docetaxel, DDP and fluorouracil (TPF) followed by CCRT with DDP alone (TPF + DDP group). Overall survival (OS), distant metastasis-free survival (DMFS), progression-free survival (PFS) and locoregional relapse-free survival (LRRFS) were analyzed using the Kaplan-Meier method and a Cox proportional hazards model. Results: Survival analysis showed that the 5-year OS, PFS and DMFS rates in the TP + DDP group were significantly lower than those in the TP + TP group after propensity score matching (PSM). Multivariate analysis revealed that CCRT with TP was an independent prognostic factor for OS, PFS and DMFS. During CCRT, the incidence rates of grade 3/4 nausea/vomiting, oral mucositis, leukocytopenia and neutropenia were significantly increased in the TP + TP group compared with the TP + DDP group (all P < 0.05). To further explore the value of TP + TP, we performed PSM again with the TPF + DDP group. After PSM, there were 100 patients in each group. Survival analysis showed no significant differences in the 5-year OS, PFS, DMFS and LRRFS rates between the two groups. During IC and CCRT, the rate of grade 3/4 nausea/vomiting in the TPF + DDP group was higher than that in the TP+TP group (9.0% vs. 2.0%, P = 0.030; 18.0% vs. 8.0%, P = 0.036, respectively). No significant difference in the incidence of grade 3/4 hematologic toxicity was found between the two groups (all P > 0.05). Conclusion: TP + TP can reduce the distant metastasis of locoregionally advanced NPC and improve OS compared with TP + DDP; TP + TP has the same effect as TPF + DDP and is clinically feasible.
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Background: The optimal second-line systemic treatment model for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains controversial. A Bayesian network meta-analysis (NMA) was performed to address this issue with regard to efficacy and toxicity. Methods: By searching MEDLINE (via PubMed), Embase, the Cochrane Central Register of Controlled Trials and Web of Science, we extracted eligible studies. Efficacy, represented as overall survival (OS) and progression-free survival (PFS), and overall toxicity, represented as ≥ grade 3 severe acute events (sAE), were assessed to compare the following 7 treatment models through an NMA: standard-of-care therapy (SoC), single targeted therapy different from SoC (ST), double targeted therapy (DT), targeted therapy combined with chemotherapy (T+C), single immune checkpoint inhibitor therapy (SI), double immune checkpoint inhibitor therapy (DI) and single chemotherapy different from SoC (SC). Rank probabilities according to the values of the surface under the cumulative ranking curve (SUCRA) were separately determined for efficacy and toxicity. Results: In total, 5285 patients from 24 eligible studies were ultimately screened, with 5184, 4532 and 4026 involved in the NMA of OS, PFS and sAE, respectively. All qualifying studies were absent from first-line immune checkpoint inhibitor therapy. In terms of OS, SI was superior to the other treatments, followed by DI, ST, T+C, SoC, DT and SC. Other than SI and SC, all treatments tended to be consistent, with hazard ratios (HRs) close to 1 between groups. For PFS, ST ranked first, while DT ranked last. For the toxicity profiles, compared with the other models, SI resulted in the lowest incidences of sAE, with statistical significance over SoC (odds ratio [OR] 0.31, 95% credible interval [CrI] 0.11 to 0.90), ST (OR 0.23, 95% CrI 0.06 to 0.86) and DT (OR 0.11, 95% CrI 0.02 to 0.53), while DT was the worst. When the SUCRA values of OS and sAE were combined, a cluster plot illustrated the superiority of SI, which demonstrated the best OS and tolerability toward sAE. Conclusion: For R/M HNSCC patients without immune checkpoint inhibitors in the first-line setting, SI may serve as the optimal second-line systemic treatment model, demonstrating the best OS and least sAE.
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Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Teorema de Bayes , Tomada de Decisão Clínica , Terapia Combinada , Gerenciamento Clínico , Resistencia a Medicamentos Antineoplásicos , Humanos , Metástase Neoplásica , Estadiamento de Neoplasias , Metanálise em Rede , Prognóstico , Recidiva , Retratamento , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Resultado do TratamentoRESUMO
Nasopharyngeal carcinoma (NPC) is a highly aggressive tumor characterized by distant metastasis. Deletion or down-regulation of the tumor suppressor protein ras-association domain family protein1 isoform A (RASSF1A) has been confirmed to be a key event in NPC progression; however, little is known about the effects or underlying mechanism of RASSF1A on the malignant phenotype. In the present study, we observed that RASSF1A expression inhibited the malignant phenotypes of NPC cells. Stable silencing of RASSF1A in NPC cell lines induced self-renewal properties and tumorigenicity in vivo/in vitro and the acquisition of an invasive phenotype in vitro. Mechanistically, RASSF1A inactivated Yes-associated Protein 1 (YAP1), a transcriptional coactivator, through actin remodeling, which further contributed to Platelet Derived Growth Factor Subunit B (PDGFB) transcription inhibition. Treatment with ectopic PDGFB partially increased the malignancy of NPC cells with transient knockdown of YAP1. Collectively, these findings suggest that RASSF1A inhibits malignant phenotypes by repressing PDGFB expression in a YAP1-dependent manner. PDGFB may serve as a potential interest of therapeutic regulators in patients with metastatic NPC.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Citoesqueleto de Actina/metabolismo , Animais , Biomarcadores Tumorais/biossíntese , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Genes Supressores de Tumor , Xenoenxertos , Humanos , Camundongos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Fenótipo , Proteínas Proto-Oncogênicas c-sis/antagonistas & inibidores , Transdução de Sinais , Transfecção , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/genética , Proteínas de Sinalização YAPRESUMO
Aims: This study aimed to investigate the clinical value of induction chemotherapy (IC) with docetaxel, 5-fluorouracil plus nedaplatin followed by concurrent chemoradiotherapy (CCRT) with nedaplatin for locoregional advanced nasopharyngeal carcinoma (NPC). Materials and Methods: In total, 269 patients diagnosed with locoregional advanced NPC between June 2012 and June 2017 were retrospectively included and divided into two groups: IC (docetaxel plus nedaplatin and 5-fluorouracil) followed by nedaplatin-based CCRT (TNF + N group, n = 146) and IC (docetaxel plus cisplatin and 5-fluorouracil) followed by cisplatin-based CCRT (TPF + P group, n = 123). The Kaplan-Meier method and Cox proportional hazards model were applied to analyse survival and prognosis. After propensity score-matched (PSM), 113 patients remained in each group. Toxicities were compared between the two groups using the Chi-square test or Fisher's exact test. Results: The overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) rates of the TNF + N and TPF + P groups were 90.7% vs. 92.3% (P = 0.315), 78.9% vs. 79.4% (P = 0.715), 82.4% vs. 85.1% (P = 0.441) and 96.1% vs. 93.3% (P = 0.414), respectively, with no significant difference in 3-year survival outcome between the two groups, and this outcome was confirmed after using PSM analyses. In the PSM cohort, a significant higher frequency of grade 3/4 vomiting was observed in the TPF + P group compared to the TNF + N group (22.1% vs. 0%, P = 0.000). However, 15.9% of patients in the TNF + N group had grade 3/4 thrombocytopenia in comparison with 6.2% in the TPF + P group (P = 0.020). Conclusions: The TNF regimen followed by CCRT with nedaplatin is an alternative treatment strategy to the standard TPF regimen followed by CCRT with cisplatin for patients with locoregional advanced NPC.
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Cisplatin (DDP)-based concurrent chemo-radiotherapy is a standard approach to treat locoregionally advanced nasopharyngeal carcinoma (NPC). However, many patients eventually develop recurrence and/or distant metastasis due to chemoresistance. In this study, we aimed to elucidate the effects of melatonin on DDP chemoresistance in NPC cell lines in vitro and vivo, and we explored potential chemoresistance mechanisms. We found that DDP chemoresistance in NPC cells is mediated through the Wnt/ß-catenin signaling pathway. Melatonin not only reversed DDP chemoresistance, but also enhanced DDP antitumor activity by suppressing the nuclear translocation of ß-catenin, and reducing expression of Wnt/ß-catenin response genes in NPC cells. In vivo, combined treatment with DDP and melatonin reduced tumor burden to a greater extent than single drug-treatments in an orthotopic xenograft mouse model. Our findings provide novel evidence that melatonin inhibits the Wnt/ß-catenin pathway in NPC, and suggest that melatonin could be applied in combination with DDP to treat NPC.
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Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Melatonina/farmacologia , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Via de Sinalização Wnt , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Recidiva Local de Neoplasia , beta Catenina/metabolismoRESUMO
DNA methylation is an important epigenetic change in carcinogenesis. However, the function and mechanism of DNA methylation dysregulation in nasopharyngeal carcinoma (NPC) is still largely unclear. Our previous genome-wide microarray data showed that NFAT1 is one of the most hypermethylated transcription factor genes in NPC tissues. Here, we found that NFAT1 hypermethylation contributes to its down-regulation in NPC. NFAT1 overexpression inhibited cell migration, invasion, and epithelial-mesenchymal transition in vitro and tumor metastasis in vivo. We further established that the tumor suppressor effect of NFAT1 is mediated by its inactivation of ITGA6 transcription. Our findings suggest the significance of activating NFAT1/ITGA6 signaling in aggressive NPC, defining a novel critical signaling mechanism that drives NPC invasion and metastasis and providing a novel target for future personalized therapy.
Assuntos
Metilação de DNA , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Integrina alfa6/genética , Fatores de Transcrição NFATC/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Ativação Transcricional , Linhagem Celular Tumoral , Epigênese Genética , Perfilação da Expressão Gênica , Humanos , Metástase Linfática , Estadiamento de Neoplasias , Interferência de RNA , TranscriptomaRESUMO
Ras association domain family member 6 (RASSF6) has been shown to act as a tumor suppressor and predictor of poor prognosis in renal cell carcinoma (RCC). However, little is known about the effects of RASSF6 on sorafenib resistance or the underlying mechanism. Here, we show that RASSF6 expression positively correlates with sorafenib sensitivity in RCC cells and human samples. Stable ectopic overexpression of RASSF6 in RCC cell lines reduces resistance to sorafenib in vitro and in vivo. At a molecular level, RASSF6 activates the JNK signaling pathway, which further contributes to Mcl-1 inhibition. Suppression of the JNK pathway can partially restore Mcl-1 expression and sorafenib resistance. Together, these findings suggest that RASSF6 inhibits sorafenib resistance by repressing Mcl-1 through the JNK-dependent pathway. RASSF6 may serve as a novel regulator for sorafenib therapy in RCC.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MAP Quinase Quinase 4/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Sorafenibe/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose , Proteínas Reguladoras de Apoptose , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Proliferação de Células , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , MAP Quinase Quinase 4/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Monoméricas de Ligação ao GTP/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Prognóstico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To silence annexin II gene expression by using small interference RNA (siRNA) in prostate cancer cell line PC3. METHODS: For in vitro transcription, four sequences of 29-nucleotide DNA template oligonucleotides were designed, and one pair of the sequences were complementary to annexin II gene. The other pair was negative control. The 8 nucleotides at the 3' end of each oligonucleotide were complementary to the T7 Promoter Primer. The sense and antisense siRNA templates were transcribed by T7 RNA polymerase and the resulting RNA transcripts were hybridized to create dsRNA. The siRNA was transfected into prostate cancer cell PC3. For assaying the efficiency of siRNA, confocal microscopy, Northern blotting, and Western blotting were employed to examine the expression of annexin II protein and its mRNA. 3H thymidine was used to measure DNA synthesis. RESULTS: The siRNA sequence specific to annexin II gene was capable of inhibiting the expression of annexin II protein and its mRNA. And cellular DNA synthesis was significantly reduced in siRNA transfected cells. CONCLUSIONS: The protocol for the synthesis of siRNA by T7 RNA polymerase is feasible. Annexin II might be involved in DNA synthesis.
Assuntos
Anexina A2/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Linhagem Celular Tumoral , Replicação do DNA , DNA de Neoplasias/genética , Humanos , Masculino , Regiões Promotoras Genéticas/genética , Neoplasias da Próstata/genética , RNA Neoplásico/genética , Transcrição GênicaRESUMO
Marked up-regulation of aldose reductase (AR) is reportedly associated with the development of hepatocellular carcinoma (HCC). We investigated how aberrantly overexpressed AR might promote oncogenic transformation in liver cells and tissues. We found that overexpressed AR interacted with the kinase domain of AKT1 to increase AKT/mTOR signaling. In both cultured liver cancer cells and liver tissues in DEN-induced transgenic HCC model mice, we observed that AR overexpression-induced AKT/mTOR signaling tended to enhance lactate formation and hepatic inflammation to enhance hepatocarcinogenesis. Conversely, AR knockdown suppressed lactate formation and inflammation. Using cultured liver cancer cells, we also demonstrated that AKT1 was essential for AR-induced dysregulation of AKT/mTOR signaling, metabolic reprogramming, antioxidant defense, and inflammatory responses. These findings suggest that aberrantly overexpressed/over-activated hepatic AR promotes HCC development at least in part by interacting with oncogenic AKT1 to augment AKT/mTOR signaling. Inhibition of AR and/or AKT1 might serve as an effective strategy for the prevention and therapy of liver cancer.
RESUMO
Substantial evidence has shown that obstructive jaundice can induce vascular hyporesponsiveness. The present study was designed to investigate mechanisms of MaxiK channel and KATP underlying cholestasis-induced vascular dysfunction. The isolated thoracic aorta was used to explore norepinephrine (NE)-induced contraction. The function of MaxiK and KATP channels were investigated using whole-cell patch clamp recording. Compared with Sham group, NE-induced vascular contraction was blunted after bile duct ligation (BDL), which could not be ameliorated significantly after endothelial denudation. Charybdotoxin and glibenclamide induced a more pronounced recovery from vascular hyporesponsiveness to NE in BDL group compared with Sham group. BDL significantly promoted the charybdotoxin sensitive MaxiK current and KATP current in isolated aortic smooth muscle cells. In addition, the expression of auxiliary subunits (MaxiK-ß1 and SUR2B) rather pore-forming subunits (MaxiK-α and Kir6.1) was significantly up-regulated after BDL. These findings suggest that MaxiK and KATP channels play an important role in regulating vascular hyporesponsiveness in BDL rats.