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Esophageal squamous cell carcinoma (ESCC) is a malignant epithelial tumor, characterized by squamous cell differentiation, it is the sixth leading cause of cancer-related deaths globally. The increased mortality rate of ESCC patients is predominantly due to the advanced stage of the disease when discovered, coupled with higher risk of metastasis, which is an exceedingly malignant characteristic of cancer, frequently leading to a high mortality rate. Unfortunately, there is currently no specific and effective marker to predict and treat metastasis in ESCC. MicroRNAs (miRNAs) are a class of small non-coding RNA molecules, approximately 22 nucleotides in length. miRNAs are vital in modulating gene expression and serve pivotal regulatory roles in the occurrence, progression, and prognosis of cancer. Here, we have examined the literature to highlight the intimate correlations between miRNAs and ESCC metastasis, and show that ESCC metastasis is predominantly regulated or regulated by genetic and epigenetic factors. This review proposes a potential role for miRNAs as diagnostic and therapeutic biomarkers for metastasis in ESCC metastasis, with the ultimate aim of reducing the mortality rate among patients with ESCC.
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Carcinoma , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , MicroRNAs , Humanos , MicroRNAs/genética , Carcinoma de Células Escamosas do Esôfago/genética , Neoplasias Esofágicas/genética , EpigenômicaRESUMO
PURPOSE: This study aimed to investigate the relationship between spinal-pelvic parameters and recurrence of lumbar disc herniation (rLDH) after percutaneous endoscopic lumbar discectomy (PELD) through a retrospective case-control study. METHODS: Patients who underwent PELD for single-segment LDH at our hospital were included in this study. The relationship between sagittal balance parameters of the spine and recurrence was analysed through correlation analysis, and ROC curves were plotted. The baseline characteristics, sagittal balance parameters of the spine and radiological parameters of the case and control groups were compared, and the relationship between sagittal balance parameters of the spine and recurrence of rLDH after PELD was determined through univariate and multivariate logistic regression analysis. RESULTS: Correlation analysis showed that PI and ∆PI-LL were negatively correlated with grouping (r = -0.090 and -0.120, respectively, P = 0.001 and 0.038). ROC curve analysis showed that the area under the curve (ROC-AUC) for predicting rLDH based on PI was 0.65 (CI95% = 0.598, 0.720), with a cut-off of 50.26°. The ROC-AUC for predicting rLDH based on ∆PI-LL was 0.56 (CI95% = 0.503, 0.634), with a cut-off of 28.21°. Multivariate logistic regression analysis showed that smoking status (OR = 2.667, P = 0.008), PI ≤ 50.26 (OR = 2.161, P = 0.009), ∆PI-LL ≤ 28.21 (OR = 3.185, P = 0.001) and presence of Modic changes (OR = 4.218, P = 0.001) were independent risk factors, while high DH (OR = 0.788, P = 0.001) was a protective factor. CONCLUSION: PI < 50.26 and ∆PI-LL < 28.21 were risk factors for recurrence of lumbar disc herniation after spinal endoscopic surgery and had some predictive value for post-operative recurrence.
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Discotomia Percutânea , Deslocamento do Disco Intervertebral , Humanos , Estudos de Casos e Controles , Estudos Retrospectivos , Deslocamento do Disco Intervertebral/cirurgia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgiaRESUMO
BACKGROUND: Knee osteoarthritis (KOA) is the most common chronic degenerative joint disease and places a substantial burden on the public health resources in China. The purpose of this study is to preliminarily evaluate whether infrared laser moxibustion (ILM) is non-inferior to traditional moxibustion (TM) in the treatment of KOA. MATERIALS AND METHODS: In the designed Zelen-design randomized controlled non-inferiority clinical trial, a total of 74 patients with KOA will be randomly allocated to one of two interventions: ILM treatment or TM treatment. All participants will receive a 6-week treatment and a follow-up 4 weeks after treatment. The primary outcomes will be the mean change in pain scores on the numeric rating scale (NRS) measured at baseline and the end of last treatment at week 6. The secondary outcomes will be the pain scores on the NRS from weeks 1 to 5 after the start of treatment and the changes from baseline to endpoints (weeks 6 and 10) in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), SF-36, knee circumference, and 6-min walking test. In addition, safety assessment will be performed throughout the trial. CONCLUSION: The results of our study will help determine whether a 6-week treatment with ILM is non-inferior to TM in patients with KOA, therefore providing evidence to verify if ILM can become a safer alternative for TM in clinical applications in the future. TRIAL REGISTRATION: Clinical Trial Registration Platform (ChiCTR2200065264); Pre-results. Registered on 1 November 2022.
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Moxibustão , Osteoartrite do Joelho , Humanos , Osteoartrite do Joelho/terapia , Osteoartrite do Joelho/complicações , Moxibustão/efeitos adversos , Moxibustão/métodos , Articulação do Joelho , Dor , Lasers , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
MicroRNAs (miRNAs) are a class of small noncoding RNAs that are approximately 22 nt in length and regulate gene expression post-transcriptionally. miRNAs play a vital role in both physiological and pathological processes and are regarded as promising biomarkers for cancer, cardiovascular diseases, neurodegenerative diseases, and so on. Accurate detection of miRNA expression level in clinical samples is important for miRNA-guided diagnostics. However, the common miRNA detection approaches like RNA sequencing, qRT-PCR, and miRNA microarray are performed in a professional laboratory with complex intermediate steps and are time-consuming and costly, challenging the miRNA-guided diagnostics. Hence, sensitive, highly specific, rapid, and easy-to-use detection of miRNAs is crucial for clinical diagnosis based on miRNAs. With the advantages of being specific, sensitive, efficient, cost-saving, and easy to operate, point-of-care testing (POCT) has been widely used in the detection of miRNAs. For the first time, we mainly focus on summarizing the research progress in POCT of miRNAs based on portable instruments and visual readout methods. As widely available pocket-size portable instruments and visual detection play important roles in POCT, we provide an all-sided discussion of the principles of these methods and their main limitations and challenges, in order to provide a guide for the development of more accurate, specific, and sensitive POCT methods for miRNA detection.
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MicroRNAs , Neoplasias , Humanos , MicroRNAs/análise , Testes Imediatos , Técnicas de Amplificação de Ácido Nucleico , Reação em Cadeia da PolimeraseRESUMO
Central nervous system (CNS) disease is a general term for a series of complex and diverse diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), CNS tumors, stroke, epilepsy, and amyotrophic lateral sclerosis (ALS). Interneuron and neuron-glia cells communicate with each other through their homeostatic microenvironment. Exosomes in the microenvironment have crucial impacts on interneuron and neuron-glia cells by transferring their contents, such as proteins, lipids, and ncRNAs, constituting a novel form of cell-to-cell interaction and communication. Exosomal noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and PIWI-interacting RNAs (piRNAs), regulate physiological functions and maintain CNS homeostasis. Exosomes are regarded as extracellular messengers that transfer ncRNAs between neurons and body fluids due to their ability to cross the blood-brain barrier. This review aims to summarize the current understanding of exosomal ncRNAs in CNS diseases, including prospective diagnostic biomarkers, pathological regulators, therapeutic strategies and clinical applications. We also provide an all-sided discussion of the comparison with some similar CNS diseases and the main limitations and challenges for exosomal ncRNAs in clinical applications.
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BACKGROUND: This multicenter prospective, randomized controlled clinical trial compared the clinical performance of supraglottic airway device (SAD) BlockBusterTM and laryngeal mask airway (LMA) Supreme for airway maintenance in anesthetized, paralyzed adult patients. METHODS: A total of 651 adult patients scheduled for elective surgery in 13 hospitals were randomly allocated into BlockBuster group (n = 351) or Supreme group (n = 300). The primary outcome was oropharyngeal leak pressure (OLP). Duration and ease of insertion, fiberscopic view of positioning, airway manipulations, and complications were also assessed. RESULTS: The OLP was significantly higher in BlockBuster group compared with Supreme group (29.9 ± 4.2 cmH2O vs 27.4 ± 4.3 cmH2O, p < 0.001). Success rate of insertion at the first attempt (90.2% vs 85.1%, p = 0.027), rate of optimal fiberscopic view (p = 0.002) and satisfactory positioning of SAD (p < 0.001) were significantly increased in BlockBuster group. CONCLUSIONS: Both SAD BlockBusterTM and LMA Supreme are safe, effective, and easy-to-use devices for airway maintenance in anesthetized, paralyzed adult patients, but the SAD BlockBusterTM is superior to LMA Supreme in terms of OLP, success rate at the first attempt, and fiber-optic view of positioning. TRIAL REGISTRATION: The trial is registered at www.chictr.org.cn (ChiCTR-ONC-16009105).
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Máscaras Laríngeas , Adulto , Humanos , Estudos Prospectivos , Tecnologia de Fibra Óptica , OrofaringeRESUMO
INTRODUCTION: Predicting survival time for patients with spinal metastases is important in treatment choice. Generally speaking, six months is a landmark cutoff point. Revised Tokuhashi score (RTS), the most widely used scoring system, lost its accuracy in predicting 6-month survival, gradually. Therefore, a more precise scoring system is urgently needed. OBJECTIVE: The aim of this study is to create a new scoring system with a higher accuracy in predicting 6-month survival based on the previously used RTS. METHODS: Data of 171 patients were examined to determine factors that affect prognosis (reference group), and the remaining (validation group) were examined to validate the reliability of a new score, adjusted Tokuhashi score (ATS). We compared their discriminatory abilities of the prediction models using area under receiver operating characteristic curve (AUC). RESULTS: Target therapy and the Z score of BMI (Z-BMI), which adjusted to the patients' sex and age, were additional independent prognostic factors. Patients with target therapy use are awarded 4 points. The Z score of BMI could be added directly to yield ATS. The AUCs were 0.760 for ATS and 0.636 for RTS in the validation group. CONCLUSION: Appropriate target therapy use can prolong patients' survival. Z-BMI which might reflect nutritional status is another important influencing factor. With the optimization, surgeons could choose a more individualized treatment for patients.
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INTRODUCTION: The overall outcome of patients with refractory AML (rAML) remains poor. Though allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered as the only curative therapy, it is routinely recommended only for patients after remission with salvage chemotherapy. OBJECTIVE: In this study, we evaluated the impact of salvage chemotherapy or allo-HSCT on the overall outcome in rAML. METHODS: We collected the clinical data of 220 patients from 4 medical centers and performed retrospective analysis of prognosis factors, including salvage chemotherapy, intensity of chemotherapy, and allo-HSCT. RESULTS: A total of 29 patients received allo-HSCT directly without salvage chemotherapy, 26 patients achieved complete remission (CR) or complete remission with incomplete hematological recovery (CRi) after transplantation and 4-year leukemia-free survival (LFS) and overall survival (OS) were 45.0 ± 10.7 and 51.0 ± 10.6%, respectively. Another 191 patients received salvage chemotherapy and 81 (42.2%) achieved CR or CRi. Thirty-four patients among them underwent subsequent allo-HSCT with 4-year LFS and OS of 46.0 ± 8.8 and 46.2 ± 9.0%. The 4-year LFS and OS in 26 patients who failed to obtain CR or CRi but received allo-HSCT with active disease were 32.9 ± 10.0 and 36.9 ± 10.8%, respectively. For patients who received salvage chemotherapy but not allo-HSCT, few of them became long-term survivors. In multivariate analysis, salvage chemotherapy and the intensity of chemotherapy failed to have significant impact on both OS and LFS. Allo-HSCT was the only prognostic factor for improved OS and LFS in multivariate analysis. CONCLUSIONS: These results indicate the benefit of allo-HSCT in patients with rAML and direct allo-HSCT without salvage chemotherapy could be treatment option.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia Mieloide Aguda/terapia , Indução de Remissão , Estudos Retrospectivos , Terapia de Salvação/métodosRESUMO
BACKGROUND AND AIMS: Survival estimation for patients with spinal metastasis is crucial to treatment decisions. Psoas muscle area (PMA), a surrogate for total muscle mass, has been proposed as a useful survival prognosticator. However, few studies have validated the predictive value of decreased PMA in an Asian cohort or its predictive value after controlling for existing preoperative scoring systems (PSSs). In this study, we aim to answer: (1) Is PMA associated with survival in Han Chinese patients with spinal metastasis? (2) Is PMA a good prognosticator according to concordance index (c-index) and decision curve analysis (DCA) after controlling for six existing and commonly used PSSs? METHODS: This study included 180 adult (≥18 years old) Taiwanese patients with a mean age of 58.3 years (range: 22-85) undergoing surgical treatment for spinal metastasis. A patient's PMA was classified into decreased, medium, and large if it fell into the lower (0-33%), middle (33-67%), and upper (67-100%) 1/3 in the study cohort, respectively. We used logistic and cox proportional-hazard regressions to assess whether PMA was associated with 90-day, 1-year, and overall survival. The model performance before and after addition of PMA to six commonly used PSSs, including Tomita score, original Tokuhashi score, revised Tokuhashi score, modified Bauer score, New England Spinal Metastasis Score, and Skeletal Oncology Research Group machine learning algorithms (SORG-MLAs), was compared by c-index and DCA to determine if PMA was a useful survival prognosticator. RESULTS: Patients with a larger PMA is associated with better 90-day, but not 1-year, survival. The model performance of 90-day survival prediction improved after PMA was incorporated into all PSSs except SORG-MLAs. PMA barely improved the discriminatory ability (c-index, 0.74; 95% confidence interval [CI], 0.67-0.82 vs. c-index, 0.74; 95% CI, 0.66-0.81) and provided little gain of clinical net benefit on DCA for SORG-MLAs' 90-day survival prediction. CONCLUSIONS: PMA is a prognosticator for 90-day survival and improves the discriminatory ability of earlier-proposed PSSs in our Asian cohort. However, incorporating PMA into more modern PSSs such as SORG-MLAs did not significantly improve its prediction performance.
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Músculos Psoas , Neoplasias da Coluna Vertebral , Adolescente , Adulto , Estudos de Coortes , Humanos , Aprendizado de Máquina , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias da Coluna Vertebral/secundário , Neoplasias da Coluna Vertebral/cirurgiaRESUMO
Internal tandem duplication (ITD) mutations within the FMS-like receptor tyrosine kinase-3 (FLT3) can be found in up to 25% to 30% of acute myeloid leukemia (AML) patients and confer a poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs) have shown clinical responses, they cannot eliminate primitive FLT3-ITD+ AML cells, which are potential sources of relapse. Therefore, elucidating the mechanisms underlying FLT3-ITD+ AML maintenance and drug resistance is essential to develop novel effective treatment strategies. Here, we demonstrate that FLT3 inhibition induces histone deacetylase 8 (HDAC8) upregulation through FOXO1- and FOXO3-mediated transactivation in FLT3-ITD+ AML cells. Upregulated HDAC8 deacetylates and inactivates p53, leading to leukemia maintenance and drug resistance upon TKI treatment. Genetic or pharmacological inhibition of HDAC8 reactivates p53, abrogates leukemia maintenance, and significantly enhances TKI-mediated elimination of FLT3-ITD+ AML cells. Importantly, in FLT3-ITD+ AML patient-derived xenograft models, the combination of FLT3 TKI (AC220) and an HDAC8 inhibitor (22d) significantly inhibits leukemia progression and effectively reduces primitive FLT3-ITD+ AML cells. Moreover, we extend these findings to an AML subtype harboring another tyrosine kinase-activating mutation. In conclusion, our study demonstrates that HDAC8 upregulation is an important mechanism to resist TKIs and promote leukemia maintenance and suggests that combining HDAC8 inhibition with TKI treatment could be a promising strategy to treat FLT3-ITD+ AML and other tyrosine kinase mutation-harboring leukemias.
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Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteína Forkhead Box O1/metabolismo , Histona Desacetilases/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas Repressoras/metabolismo , Proteína Supressora de Tumor p53/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Proteína Forkhead Box O1/genética , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/genética , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Repressoras/genética , Sequências de Repetição em Tandem , Células Tumorais Cultivadas , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To discuss the clinical effect and safety evaluation of laparoscopic nephron sparing surgery (LNSS) under selective segmental renal artery clamping (SSRAC) and main renal artery clamping (MRAC). METHODS: Eighty-four patients with T1 localized renal tumors who were admitted and treated from October 2017 to October 2018 were retrospectively analyzed, and they were classified into the S group (42 patients) and M group (42 patients). The patients in the S group received LNSS under SSRAC, while the patients in the M group received LNSS under MRAC. The duration of the operation, amount of intraoperative blood loss, intraoperative warm ischemia time, duration of postoperative hospital stay and positive rate of incisal edge; the serum creatinine and blood urea nitrogen values before and after the operation; and the occurrence rates of intraoperative and postoperative complications were compared. RESULTS: All operations were completed smoothly. No patients had a positive incisal edge, and no patients were converted to MRAC during the operation. The duration of the operation and the amount of intraoperative blood loss increased in the S group compared with the M group. The differences were statistically significant (P <0.05). The differences in the intraoperative warm ischemia time, postoperative drainage and duration of postoperative hospital stay in both groups had no statistical significance (P >0.05). The differences in serum creatinine (SCr) and blood urea nitrogen (BUN) in both groups before the operation had no statistical significance (P >0.05). The SCr and BUN levels significantly increased 1 d and 1 m after the operation. The SCr and BUN levels 1 d and 1 m after the operation were significantly lower in the S group than in the M group, and the differences were statistically significant (P <0.05). The differences in the occurrence rates of intraoperative and postoperative complications in both groups had no statistical significance (P >0.05). CONCLUSION: SSRAC is a new renal artery clamping technology, and its curative effect on LNSS patients is significant. In addition, SSRAC has high safety and little influence on renal functions.
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To investigate if andrographolide impairs cholestatic liver injury. All rats were randomly divided into six groups-(1) control (n = 6), (2) control + 200 mg/kg andrographolide (n = 6), (3) alpha-naphthylisothiocyanate (ANIT)-control (n = 6), (4) ANIT + 50 mg/kg andrographolide (n = 6), (5) ANIT + 100 mg/kg andrographolide (n = 6), and (6) ANIT + 200 mg/kg andrographolide (n = 6). We gavaged 50 mg/kg ANIT to mimic cholestatic liver injury in rats. Seven days after treatment, all the rats were killed. Serum biochemistry and hepatic histopathological assays were performed to evaluate liver injury. We observed that 200 mg/kg andrographolide significantly decreased the level of alanine transaminase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyltranspeptidase, total bilirubin, and total bile acid in the blood. It also markedly decreased hepatic interleukin-6 and tumor necrosis factor α. Furthermore, 200 mg/kg andrographolide significantly decreased malondialdehyde but increased superoxide dismutase, glutathione, and erythrocyte glutathione peroxidase. Moreover, 200 mg/kg andrographolide effectively increased the accumulation of sirtuin 1 and nuclear erythroid 2-related factor-2. It also attenuated the level of nuclear factor kappa-light-chain-enhancer of activated B and cyclooxygenase-2. These data suggest that andrographolide may impair cholestatic liver injury via anti-inflammatory and anti-oxidative stress.
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Colestase/tratamento farmacológico , Diterpenos/uso terapêutico , Fígado/efeitos dos fármacos , 1-Naftilisotiocianato , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Colestase/sangue , Colestase/induzido quimicamente , Diterpenos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Medicamentos de Ervas Chinesas , Inflamação/prevenção & controle , Fígado/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Sirtuína 1/metabolismoRESUMO
Epithelial-to-mesenchymal transition (EMT) is essential for the progression of non-invasive tumor cells into malignancy and metastasis. We found that miR-214 was increased in lung adenocarcinoma (LAD) and positively associated with metastasis, which was mediated by EMT. However, the mechanism whereby the overexpression of microRNAs (miRNAs), such as miR-214, promote EMT in LAD remains unclear. In this study, we found that TWIST1, an independent prognostic factor for overall survival, was increased in LAD and correlated positively with LAD recurrence and progression. We also found that TWIST1 contributes to the EMT process and metastasis of LAD cells. Most importantly, a positive correlation was found between the expression of miR-214 and TWIST1 in clinical LAD tissue. Additionally, miR-214 expression was decreased and its target gene suppressor of fused homolog (SUFU) was increased in LAD cells in response to the impairment of TWIST1 expression by shRNA. Overall, this study provides the first evidence to show that the high expression of TWIST1 increases the expression of miR-214 to promote the EMT process and metastasis in LAD. These findings contribute to clarify the mechanisms whereby miRNAs regulate the EMT process and implicate a new TWIST1-miR-214 pathway in the control of migration and invasion of LAD.
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Adenocarcinoma/genética , Adenocarcinoma/patologia , Transição Epitelial-Mesenquimal/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Proteínas Nucleares/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Regulação para Cima/genética , Adenocarcinoma de Pulmão , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Metástase Neoplásica , Proteínas Nucleares/genética , Prognóstico , RNA Interferente Pequeno/metabolismo , Proteína 1 Relacionada a Twist/genéticaRESUMO
The prognosis of patients suffering from glioblastoma [also referred to as glioblastoma multiforme (GBM)] is dismal despite multimodal therapy. Chemotherapy with temozolomide may suppress tumor growth for a certain period of time (a few months); however, invariable tumor recurrence suggests that glioblastoma initiating cells (GICs) render these tumors persistant. Thus, the understanding of the molecular mechanisms of action of GICs as regards their role in the progression of GBM is important as such knowledge will be helpful in the discovery of novel drug targets, as well as in the design of novel therapeutic strategies for more effective treatment of the disease. In this study, we found that tumor suppressor candidate 3 (TUSC3) was downregulated in temozolomide-resistant U87MG cells (U87MG-res cells) and its restoration sensitized U87MG-res cells to temozolomide. TUSC3 was able to inhibit the formation of GIC phenotypes in the U87MG-res cells. The overexpression of microRNA (miR)132 inhibited TUSC3 protein expression in the U87MG cells. However, its overexpression did not degrade TUSC3 mRNA expression in the cells. miR132 was upregulated in the U87MG-res cells and its overexpression induced temozolomide resistance and the formation of cancer stem cell phenotypes in the U87MG cells. Thus, our data indicate that miR-132 induces temozolomide resistance and promotes the formation of cancer stem cell phenotypes by targeting TUSC3 in glioblastoma.
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Neoplasias Encefálicas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/genética , Proteínas de Membrana/genética , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo , Proteínas Supressoras de Tumor/genética , Regiões 3' não Traduzidas , Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Fenótipo , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , TemozolomidaRESUMO
Hepatocellular carcinoma (HCC) accounts for approximately 90% of all cases of primary liver cancer, and the majority of patients with HCC are deprived of effective curative methods. Osthole is a Chinese herbal medicine which has been reported to possess various pharmacological functions, including hepatocellular protection. In the present study, we investigated the anticancer activity of osthole using HCC cell lines. We found that osthole inhibited HCC cell proliferation, induced cell cycle arrest, triggered DNA damage and suppressed migration in HCC cell lines. Furthermore, we demonstrated that osthole not only contributed to cell cycle G2/M phase arrest via downregulation of Cdc2 and cyclin B1 levels, but also induced DNA damage via an increase in ERCC1 expression. In addition, osthole inhibited the migration of HCC cell lines by significantly downregulating MMP-2 and MMP-9 levels. Finally, we demonstrated that osthole inhibited epithelial-mesenchymal transition (EMT) via increasing the expression of epithelial biomarkers E-cadherin and ß-catenin, and significantly decreasing mesenchymal N-cadherin and vimentin protein expression. These results suggest that osthole may have potential chemotherapeutic activity against HCC.
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Bloqueadores dos Canais de Cálcio/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Transformação Celular Neoplásica/efeitos dos fármacos , Cumarínicos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Western Blotting , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , CicatrizaçãoRESUMO
Ubiquitinspecific protease 22 (USP22) is a component of the transcription regulatory histone acetylation complex SAGA, which broadly regulates gene transcription and correlates with cancer progression, metastasis and prognosis. Autophagy is a cell pathway with dual functions that promotes cell survival or death. However, it is not known whether USP22 can regulate autophagy in pancreatic cancer. In the present study, we first identified that USP22 was overexpressed in a large number of pancreatic cancer patient samples, concomitant with the increased expression of LC3, a marker of autophagy. Statistical analysis revealed that the increase in USP22 and autophagy was positively correlated with poor prognosis of pancreatic cancer patients. Further investigation using a human pancreatic cancer cell (Panc1) identified that the overexpression of USP22 increased the processing of LC3 into the active form LC3II and the number of autophagosomes, thus leading to enhanced autophagy. Activation of ERK1/2 kinase rather than AKT1 by USP22 was found to be one of the mechanisms promoting LC3 processing. USP22induced autophagy was also found to enhance cell proliferation and resistance to starvation and chemotherapeutic drugs in Panc1 cells, therefore expressing an overall effect that promotes cell survival. Collectively, the present study demonstrated a new function of USP22 that induces autophagy, thus leading to the poor prognosis of pancreatic cancer.
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Autofagia/genética , Neoplasias Pancreáticas/genética , Prognóstico , Tioléster Hidrolases/biossíntese , Idoso , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Espécies Reativas de Oxigênio/metabolismo , Tioléster Hidrolases/genética , Ubiquitina TiolesteraseRESUMO
Resistance to chemotherapy is a major obstacle for the effective treatment of breast cancer and is partially due to the presence of drug resistant stem cell-like side population (SP). Previous studies have shown elevated miR-125b is associated with chemoresistance and metastasis; however, the relationship between miR-125b and SP cells remains unknown. In this study, we isolated and characterized SP cells in a panel of breast cancer cell lines and primary cancer cells from breast cancer patients. SP cells showed cancer stem cells (CSCs) properties, including self-renewal, resistance to chemotherapy and high expression of stem cell markers. The percentage of SP cells was higher in chemotherapy resistant patients compared to that in chemotherapy responsive patients (5.8 ± 2.4% in non-responsive patients vs. 1.2 ± 0.5% in responsive patients, P = 0.012). Importantly, SP cells had higher level of miR-125b than NSP cells and the elevated miR-125b expression in chemoresistant cancer cells were due to high percentage of SP cells. Overexpression of miR-125b correlated with an increase in tumor SP and CSC property, whereas knockdown of miR-125b correlated with decreased incidence of SP. In addition, miR-125b overexpression in breast cancer cells induced epithelial-mesenchymal transition (EMT)-like cellular marker alteration, suggesting a potential mechanism of miR-125b in the regulation of cancer stem-like SP cells. Taken together, these results suggest an important role for miR-125b in breast cancer chemoresistance by maintaining cancer stem-like SP fraction, and raise the possibility that miR-125b may be a significant prognostic response marker for cancer therapy.
Assuntos
Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND AND OBJECTIVE: Fentanyl is metabolised by cytochrome P450 (CYP) 3A4 and CYP3A5. Our previous work demonstrated that the CYP3A4*1G polymorphism significantly affects the post-operative fentanyl analgesic effect in Chinese women undergoing gynaecological surgery. However, whether CYP3A5*3, a frequent single nucleotide polymorphism of CYP3A5 in Chinese people, affects the post-operative analgesic effect of fentanyl is unclear. In this study, we assessed the influence of the CYP3A5*3 polymorphism and the interaction of the CYP3A5*3 and CYP3A4*1G polymorphisms on post-operative fentanyl analgesia in Chinese women undergoing gynaecological surgery. METHODS: We enrolled 203 women scheduled for abdominal total hysterectomy or myomectomy under general anaesthesia. Intravenous fentanyl patient-controlled analgesia was provided post-operatively for adequate analgesia. Pain scores and fentanyl consumption were recorded 24 h post-operatively. Midazolam was used as a probe drug, and CYP3A activity was measured by plasma ratio of 1'-hydroxymidazolam to midazolam 1 h after intravenous administration of 0.1 mg kg-1 midazolam. Blood samples were genotyped for the CYP3A5*3 polymorphism. RESULTS: The frequency of the CYP3A5*3 allele was 72.4% in 203 patients. CYP3A activity did not differ among CYP3A5*3 genotypes. Fentanyl consumption 24 h post-operatively was lower with CYP3A5*1/*3 and CYP3A5*3/*3 polymorphisms than with CYP3A5*1/*1, but the differences were not statistically significant. However, combined with CYP3A4*1G polymorphism, post-operative fentanyl consumption at 24 h was significantly lower for the CYP3A5*1/*3 or CYP3A5*3/*3 group than the CYP3A5*1/*1 group. CONCLUSION: CYP3A5*3 is not the main genetic factor contributing to interindividual variation in the post-operative analgesic effect of fentanyl in Chinese women undergoing gynaecological surgery; an interaction between CYP3A5*3 and CYP3A4*1G polymorphisms can significantly influence the post-operative effect.
Assuntos
Analgésicos Opioides/administração & dosagem , Povo Asiático/genética , Citocromo P-450 CYP3A/genética , Fentanila/administração & dosagem , Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Dor Pós-Operatória/tratamento farmacológico , Polimorfismo Genético , Adulto , Analgesia Controlada pelo Paciente , Analgésicos Opioides/metabolismo , Análise de Variância , Distribuição de Qui-Quadrado , China , Citocromo P-450 CYP3A/metabolismo , Feminino , Fentanila/metabolismo , Frequência do Gene , Genótipo , Humanos , Histerectomia/efeitos adversos , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etnologia , Dor Pós-Operatória/genética , Farmacogenética , Fenótipo , Fatores de Tempo , Miomectomia Uterina/efeitos adversos , Adulto JovemRESUMO
PURPOSE: To investigate whether the CYP3A4*1G genetic polymorphism contributes to the variability in CYP3A activity and response to fentanyl. METHODS: One hundred and forty-three gynecologic patients who were scheduled to undergo abdominal total hysterectomy or myomectomy with general anesthesia were enrolled in this study. Intravenous fentanyl patient-controlled analgesia was provided postoperatively for satisfactory analgesia. The degrees of pain at rest during PCA treatment were assessed with visual analog scale. The fentanyl consumption and occurrence of any adverse effects were recorded in the first 24 h postoperatively. CYP3A activity was measured by plasma 1'-hydroxymidazolam-to-midazolam ratio 1 h after intravenous administration of 0.1 mg/kg midazolam. CYP3A4*1G variant allele was genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The frequency of the CYP3A4*1G variant allele was 0.269 in 143 Chinese gynecologic patients. The activity of CYP3A4 in patients homozygous for the *1G/*1G variant (0.34 +/- 0.15) was significantly lower than that in patients bearing the wild-type allele (*1/*1) (0.46 +/- 0.14) or in patients heterozygous for the *1/*1G variant (0.46 +/- 0.12) (P < 0.05). The patients with the CYP3A4*1G/*1G genotype needed less fentanyl (227.8 +/- 55.2 microg) to achieve pain control than patients carrying the CYP3A4*1/*1 (381.6 +/- 163.6 microg) and CYP3A4*1/*1G (371.9 +/- 180.1 microg) genotypes (P < 0.05) during the first 24 h postoperatively. There was no significant difference in incidence of adverse events among the different genotype groups (P > 0.05). CONCLUSIONS: CYP3A4*1G genetic polymorphism decreases CYP3A activity and fentanyl consumption for postoperative pain control.