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Radiation resistance poses a major clinical challenge in breast cancer (BC) treatment, but little is known about how long noncoding RNA (lncRNA) may regulate this phenomenon. Here, we reported that DUXAP8 was highly expressed in radioresistant BC tissues, and high expression of DUXAP8 was associated with poor prognosis. We found that the overexpression of DUXAP8 promoted radioresistance, while the knockdown of DUXAP8 expression increased radiosensitivity. Further studies revealed that DUXAP8 enhanced the radioresistance of BC cells by activating the PI3K/AKT/mTOR pathway and by repressing the expression of E-cadherin and RHOB through interaction with EZH2. Together, our work demonstrates that the overexpression of DUXAP8 promotes the resistance of BC cells toward radiation through modulating PI3K/AKT/mTOR pathway and EZH2-E-cadherin/RHOB axis. Targeting DUXAP8 may serve as a potential strategy to overcome radioresistance in BC treatment.
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Neoplasias de la Mama , ARN Largo no Codificante , Humanos , Femenino , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/radioterapia , Transducción de Señal , Línea Celular Tumoral , Apoptosis , Serina-Treonina Quinasas TOR/metabolismo , Cadherinas/genética , Proliferación Celular , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismoRESUMEN
PURPOSE: At present, whether bariatric surgery before total knee arthroplasty (TKA) affects the prognosis of subsequent TKA has been a topic of debate in the academic community. The primary purpose of this systematic review and meta-analysis was to investigate the effect of previous bariatric surgery on prosthetic revisions and postoperative complications after TKA. METHODS: We included prospective and observational studies published in English involving patients who had undergone bariatric surgery prior to TKA and compared them with morbidly obese patients with no history of bariatric surgery. The Newcastle-Ottawa Scale was used to assess the methodological quality of non-randomized case-control studies. The outcomes included revisions, infections, venous thromboembolism (VTE), blood transfusion, mortality, stiffness or manipulation under anesthesia (MUA), and medical complications. RESULTS: Of the 9 included studies with 166047 patients, 4 were matched cohort studies, 2 were unmatched cohort, and 3 were database studies. Methodological quality was high in ten studies and moderate in thirteen studies. Our analysis demonstrated that patients with TKA who had undergone prior bariatric surgery were associated with increased risks of long-term revision, long-term infection, long-term stiffness or MUA and blood transfusions, whereas prior bariatric surgery did not increase the risk of short-term complications and short-term revision. CONCLUSION: This meta-analysis highlights the risks of bariatric surgery prior to TKA and suggests that prior bariatric surgery may increase the risk of perioperative blood transfusion and also the risk of revision and infection in long-term follow-up. Surgeons can use this information to help counsel patients undergoing bariatric surgery before primary TKA.
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Artroplastia de Reemplazo de Rodilla , Cirugía Bariátrica , Obesidad Mórbida , Humanos , Complicaciones Posoperatorias , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Previous studies investigated the prognostic role of programmed death-ligand 1 (PD-L1) expression in patients with biliary tract cancer (BTC); however, the results remained controversial. Therefore, we conducted the current meta-analysis with the aim of clarifying the association between PD-L1 expression and prognosis as well as with several important clinicopathological features of BTC. We searched PubMed, Embase, and Web of Science for relevant studies. Studies that detected PD-L1 expression in tumor cells by using immunohistochemistry (IHC) were selected. Pooled hazard ratios (HRs) and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the correlations. In total, 15 independent studies with 1,776 patients were included in this meta-analysis. The pooled data demonstrated that high PD-L1 expression was associated with poor overall survival (n=15, HR=1.79, 95% CI=1.55-2.07, p<0.001). The correlation between PD-L1 expression and disease-free survival was not significant (n=6, HR=1.38, 95% CI=1.00-1.91, p=0.051). In addition, no significant correlation was observed between PD-L1 expression and clinical features in patients with BTC. Our study results showed that PD-L1 expression could play a pivotal role as an effective factor of poor prognosis in patients with BTC.
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Antígeno B7-H1/metabolismo , Neoplasias del Sistema Biliar/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Antígeno B7-H1/genética , Neoplasias del Sistema Biliar/genética , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Humanos , PronósticoRESUMEN
BACKGROUND: Colon cancer is one of the most common malignancies worldwide. Because of the side effects and defects in tolerance of chemotherapy, it is necessary to discover new drugs for colon cancer treatment. Columbamine has been identified as an effective anti-osteosarcoma compound with only minor side effects. In this study, we analyzed the anticancer effect of columbamine on colon cancer. METHODS: Human colon cancer cell lines were treatment with columbamine. MTT assay, colony formation assay, apoptosis detection and tumorigenicity assay were performed to detect the protective effect of columbamine on colon cancer development. Western blot assay and luciferase reporter assay were conducted to investigate the potential mechanism of the columbamine treatment. RESULTS: Columbamine significantly inhibited the proliferation, migration, invasion process of colon cancer cells, and dramatically promoted the apoptosis rate of colon cancer cells to further suppress the development of colon cancer to tumor. Both the signaling transducing and key factors expression of Wnt/ß-catenin signaling pathway were obviously repressed by columbamine treatment in a dose-dependent manner. CONCLUSION: The present study indicated that columbamine exerts its anti-tumor effect in colon cancer cells through abolishing Wnt/ß-catenin signaling pathway. Columbamine may be a new therapy compound for colon cancer.
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Stem cell-like tumor-repopulating cells (TRCs) have a critical role in establishing a tumor immunosuppressive microenvironment. However, means to enhance antitumor immunity by disrupting TRCs are absent. Our previous studies have shown that tumor cell-derived microparticles (T-MPs) preferentially abrogate TRCs by delivering antitumor drugs into nuclei of TRCs. Here, we show that low dose irradiation (LDI) enhances the effect of cisplatin-packaging T-MPs (Cis-MPs) on TRCs, leading to inhibiting tumor growth in different tumor models. This antitumor effect is not due to the direct killing of tumor cells but is T cell-dependent and relies on macrophages for their efficacy. The underlying mechanism is involved in therapeutic reprograming macrophages from tumor-promotion to tumor-inhibition by disrupting TRCs and curtailing their vicious education on macrophages. These findings provide a novel strategy to reset macrophage polarization and confer their function more like M1 than M2 types with highly promising potential clinical applications.
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Long non-coding RNAs have previously been demonstrated to play important roles in regulating human diseases, especially cancer. However, the biological functions and molecular mechanisms of long non-coding RNAs in hepatocellular carcinoma have not been extensively studied. The long non-coding RNA CASC2 (cancer susceptibility candidate 2) has been characterised as a tumour suppressor in endometrial cancer and gliomas. However, the role and function of CASC2 in hepatocellular carcinoma remain unknown. In this study, using quantitative real-time polymerase chain reaction, we confirmed that CASC2 expression was downregulated in 50 hepatocellular carcinoma cases (62%) and in hepatocellular carcinoma cell lines compared with the paired adjacent tissues and normal liver cells. In vitro experiments further demonstrated that overexpressed CASC2 decreased hepatocellular carcinoma cell proliferation, migration and invasion as well as promoted apoptosis via inactivating the mitogen-activated protein kinase signalling pathway. Our findings demonstrate that CASC2 could be a useful tumour suppressor factor and a promising therapeutic target for hepatocellular carcinoma.
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Carcinogénesis/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Carcinoma Hepatocelular/patología , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Células Hep G2 , Humanos , Neoplasias Hepáticas/patología , Sistema de Señalización de MAP Quinasas/genética , Masculino , Persona de Mediana Edad , ARN Largo no Codificante/genéticaRESUMEN
OBJECTIVE: To investigate the effects of co-transfection of miR-520c-3p and miR-132 on proliferation and apoptosis of hepatocellular carcinoma Huh7. METHODS: Hepatocellular carcinoma Huh7 was cultured in vitro and lipidosome was used to transfect miR-520c-3p and miR-132, respectively or together. The effects of transfection of miR-520c-3p and miR-132 on proliferation and apoptosis of Huh7 were detected by CCK8 and Annexin V staining and flow cytometry, and the expression level of the targeted gene of over-expressed miR-520c-3p and miR-132 was determined by Western blot and realtime PCR. RESULTS: Compared with the control group, the proliferation ability of Huh7 of the single transfected and co-transfected miR-520c-3p and miR-132 decreased significantly, and the apoptosis ratio increased distinctly (P < 0.05). Besides, the effect of the co-transfection group was better than that of the single transfection group. The protein levels of GPC3 (Glypican-3) and YAP (Yes-associated protein), the target genes transfected only by miR-520c-3p and miR-132, respectively, reduced obviously (P < 0.05), which was similar with the co-infected cells, but cells transfected by miR-132 only showed a decrease of YAP. CONCLUSIONS: The co-transfection of miR-520c-3p and miR-132 can target-regulate the expression of GPC3 and YAP, enhance the exhibition effect on proliferation of hepatocellular carcinoma Huh7 and induce cell apoptosis synergistically.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/terapia , Radioterapia Adyuvante , Úlcera Cutánea/patología , Adulto , Biopsia , Neoplasias de la Mama/patología , Femenino , Humanos , Úlcera Cutánea/terapia , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
OBJECTIVE: To study the change of the peripheral blood immune pattern and its correlation with prognosis in patients with liver cancer after treated by sorafenib. METHODS: Patients with advanced liver cancer admitted in our hospital were enrolled and treated with sorafenib. After two months of the treatment, their peripheral blood was collected. The immune cell subset and cytokines level were determined by flow cytometry and luminex technology. According to the reaction expressed by patients towards sorafenib, patients were divided into the response group and the no response group. The changes of the peripheral blood immune pattern and its correlation with prognosis of patients in the two groups were compared. RESULTS: Before and after treatment of sorafenib, there was no significant difference in the ratios of T cells, NK cells and their subtypes in peripheral blood of patients between the two groups; while after treatment the ratio of B cells and regulatory B cells (Breg) of patients in the response group was significant higher than that of the no response group (P < 0.05), and the prognosis conditions of patients with decreased ratio of Breg cells were better than other patients after undergoing chemotherapy. The levels of plasma cytokines IL-6, IL-10, IL-12, IL17, FIL-3L, IFN-γ, TNF-α, MCP-1 and VEGF showed no significant differences. CONCLUSIONS: After treatment of sorafenib, the prognosis conditions of patients of advanced liver cancer with a reduced Breg ratio are better than patients with an unaltered or increased Breg ratio. The ratio of Breg in peripheral blood may be considered as early biological indicator for the prediction of the curative effects of sorafenib.
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Developing novel approaches to reverse the drug resistance of tumor-repopulating cells (TRCs) or stem cell-like cancer cells is an urgent clinical need to improve outcomes of cancer patients. Here we show an innovative approach that reverses drug resistance of TRCs using tumor cell-derived microparticles (T-MPs) containing anti-tumor drugs. TRCs, by virtue of being more deformable than differentiated cancer cells, preferentially take up T-MPs that release anti-tumor drugs after entering cells, which in turn lead to death of TRCs. The underlying mechanisms include interfering with drug efflux and promoting nuclear entry of the drugs. Our findings demonstrate the importance of tumor cell softness in uptake of T-MPs and effectiveness of a novel approach in reversing drug resistance of TRCs with promising clinical applications.
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Antineoplásicos/uso terapéutico , Micropartículas Derivadas de Células/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/patología , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Doxorrubicina/farmacología , Humanos , Ratones Endogámicos BALB C , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Derrame Pleural/patología , Análisis de SupervivenciaRESUMEN
To investigate the expression level of NEK2 in 40 tissue specimens of primary liver cancer and to search for clues whether the effect of NEK2 depletion plays a role on biological behaviors of HepG2 cells and the relevant molecular mechanism are the objectives of this study. Real-time PCR and immunohistochemistry assessed expression level of NEK2 in specimens of cancerous tissues and carcinoma-adjacent tissues. The NEK2 expression level in HepG2, Huh7, SMMC, and 7402 cells was detected by real-time PCR and western blot to screen experimental cell line. To assess the expression levels of NEK2 mRNA and protein, an effective siRNA transfected into the HepG2 cells was designed. CCK8 and colony-forming assays were performed to verify short-term and long-term proliferative activities, respectively. Capacity of apoptosis and cell cycle changes were assessed by flow cytometry. Ability of transference and invasion was measured by Transwell Chambers. Western blot approach was used to determine the protein expression levels. There was significantly high expression level of NEK2 in cancerous tissues compared to adjacent tissues. The expression of NEK2 was higher in HepG2 cells than other cell lines. Real-time PCR and western blot shown there were obviously down-regulated NEK2 expression in the NEK2-siRNA group compared to control groups. The capacity of amplification and invasion was inhibited distinctly, and FCM revealed the apoptosis rate was increased and G1 phase was arrested in NEK2-siRNA group. Western blot indicated that low expression of NEK2 in HepG2 cells could increase the expression levels of Bax, caspase-3, P21, and TIMP-1, but significantly suppressed the c-myc, c-jun, Bcl-2, cyclinD1, CDK4, MMP2, and MMP9 expression levels and the phosphorylation levels of ERK, JNK, and P38 compared with the control groups. Our findings demonstrated that NEK2 could be a valuable carcinogenic factor and a promising therapeutic target for primary liver cancer; NEK2 may regulate proliferation, apoptosis, and other biological behaviors of HepG2 cells via MAPK signal pathway.
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Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Sistema de Señalización de MAP Quinasas/fisiología , Quinasas Relacionadas con NIMA/metabolismo , Adulto , Anciano , Apoptosis/fisiología , Western Blotting , Carcinoma Hepatocelular/metabolismo , Proliferación Celular/fisiología , Femenino , Citometría de Flujo , Técnicas de Silenciamiento del Gen , Células Hep G2 , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , TransfecciónRESUMEN
The delivery of high tumoricidal doses of radiation with low rates of toxicity is of particular significance for massive hepatocellular carcinoma (HCC) radiotherapy. In order to observe the efficacy and adverse reactions of alternating hyperfraction radiotherapy treatment of massive HCC, seventy-two cases of massive HCC were randomly divided into two groups, group A and group B. The liver lesions of group A were divided into sublesions and treated with alternating hyperfraction radiotherapy [intensity modulated radiotherapy (IMRT)]. The interval between radiotherapy to the sublesions was a minimum of six hours. The average radiotherapy dose to the sublesions was 2 Gy/fraction, once a day, five times per week, treating the gross tumor volume with a total dose of 40-50 Gy, and the clinical target volume with a total dose of 30-40 Gy. By contrast, the lesions of group B were not divided into sublesions for the IMRT treatment, but were treated with an otherwise identical protocol, by 2 Gy/fraction, once a day, five times per week, and with the same total dose. Patients were followed up with regular blood tests, liver function tests, measurements of serum α-fetoprotein levels and contrast-enhanced magnetic resonance imaging (MRI) of the liver. Treatment responses were assessed every 3 months by MRI. The results revealed that the overall response rates of the two groups were 82.9 and 81.3%, respectively (P=0.864). The alternating hyperfraction radiotherapy protocol resulted in enhanced survival (P=0.002). The median survival time of the two groups was 9.7 and 6.5 months, respectively. The overall 6-month, 1-year, 2-year and 3-year survival rates of the two groups were 62.9 and 59.4% (P=0.770), 48.6 and 21.9% (P=0.040), 17.1 and 0.0% (P=0.025) and 2.9 and 0.0% (P=1.000), respectively. The I-II degree of abnormal liver function and radiation-induced liver disease of group B was higher than that of group A (P=0.021 and 0.046, respectively). In addition, the incidence rate of radiation-induced liver injury of group A was lower than that of group B. Therefore, treatment of massive HCC with alternating hyperfraction radiotherapy improved the quality of life and prolonged the overall survival time, compared with conventional IMRT, suggesting that it was an effective radiation pattern.
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Nasopharyngeal carcinoma (NPC) is a relatively radiosensitive disease. However, the therapeutic effects of radiotherapy are not always satisfactory due to radioresistance. The hypofractionated schema is currently widely used in clinical practice. In the present study, we investigated the effects of hypofractionated radiotherapy on NPC cells and explored the mechanisms involved. In addition, we aimed to determine the role of miR-34a in the effects of hypofractionated radiotherapy and whether these effects occur in a p53-dependent manner. For this purpose, we used CNE1 and CNE2 NPC cells which were subjected to hyperfractionated and hypofractionated radiotherapy. The viability of the cells was measured by MTT assay and acridine orange (AO) and ethidium bromide (EB) staining was used to observe morphological changes. In addition, Annexin V-propidium iodide (PI) staining and flow cytometry were used to determine the number of apoptotic cells and mRNA and protein expression was measured by qPCR and western blot analysis, respectively. The results revealed that hypofractionated radiotherapy enhanced apoptosis and increased the expression of miR-34a and p53 in the NPC cells. In addition, it stimulated p53 promoter activity and downregulated the protein expression of c-Myc in the human NPC cells. Furthermore, the knockdown of miR-34a suppressed the growth inhibitory effects induced by hypofractionated radiotherapy. Thus, our results suggest that the enhanced apoptosis of NPC cells may be associated with the miR-34a-mediated suppression of c-Myc in a p53-dependent manner.
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Apoptosis/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , MicroARNs/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Carcinoma , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , Regulación hacia Abajo , Humanos , MicroARNs/genética , Carcinoma Nasofaríngeo , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Tolerancia a Radiación , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Radiation leads to a rapid burst of reactive oxygen species (ROS), which is considered to be one of the major causes of radiation-induced injury. ROS have previously been shown to induce changes in cytosolic Ca²âº ([Ca²âº]i) including [Ca²âº]i oscillation. However, the role of radiation in [Ca²âº]i oscillation is poorly understood. The purpose of this study was to identify the effect of ROS and X ray on [Ca²âº]i oscillation, as well as their role in radiation-induced lung injury. Alveolar macrophages were cultured in the absence and presence of different doses of hydrogen peroxide (H2O2) or exposed to X-ray irradiation with or without pretreatment of diphenyleneiodonium chloride (DPI, an inhibitor of NADPH oxidases) or tetrandrine (TET, a calcium entry blocker) and cytosolic Ca²âº concentration was detected by fluorescent Ca²âº indicator Fura-2. Rat radiation lung injury was induced in vivo by using 40 Gy X ray and DPI or TET was used to prevent radiation-induced lung injury. The results showed that there was spontaneous [Ca²âº]i oscillation in alveolar macrophages under normal conditions, and treatment of H2O2 (100-500 µM) or 2 Gy X ray inhibited the spontaneous [Ca²âº]i oscillation and induced [Ca²âº]i rise. TET abolished H2O2 or X ray induced [Ca²âº]i rise in alveolar macrophages, and attenuated X ray- induced rat alveolitis in vivo. DPI prevented X-ray-induced inhibition of [Ca²âº]i oscillation in alveolar macrophages and prevented X-ray-induced rat alveolitis. Taken together, the data suggest that the disruption of [Ca²âº]i oscillation and induction of [Ca²âº]i rise through ROS is involved in the mechanism of radiation-induced lung injury.