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1.
Cell Death Dis ; 10(10): 764, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601781

RESUMO

Radiotherapy is essential to treat breast cancer and microRNA (miRNA) miR-200c is considered as a radiosensitizer of breast cancer. However, the molecular mechanisms by which miR-200c regulates radiosensitivity remain largely unknown. In the present study, we showed that induction of miR-200c led to widespread alteration in long noncoding RNA (lncRNA) expression in breast cancer cells. We identified lncRNA LINC02582 as a target of miR-200c. Inhibition of LINC02582 expression increased radiosensitvity, while overexpression of LINC02582 promoted radioresistance. Mechanistically, LINC02582 interacts with deubiquitinating enzyme ubiquitin specific peptidase 7 (USP7) to deubiquitinate and stabilize checkpoint kinase 1 (CHK1), a critical effector kinase in DNA damage response, thus promoting radioresistance. Furthermore, we detected an inverse correlation between the expression of miR-200c vs. LINC02582 and CHK1 in breast cancer samples. These findings identified LINC02582 as a downstream target of miR-200c linking miR-200c to CHK1, in which miR-200c increases radiosensitivity by downregulation of CHK1.

2.
Cell Death Dis ; 10(10): 719, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31558697

RESUMO

The ubiquitin-proteasome system (UPS) is a tight homeostatic control mechanism of intracellular protein degradation and turnover involved in many human diseases. Proteasome inhibitors were initially developed as anticancer agents with potential benefits in the suppression of tumor growth. However, clinical trials of patients with solid tumors fail to demonstrate the same efficacy of these proteasome inhibitors. Here, we show that Parkin, an E3 ubiquitin ligase, is implicated in tumorigenesis and therapy resistance of hepatocellular carcinoma (HCC), the most common type of primary liver cancer in adults. Lower Parkin expression correlates with poor survival in patients with HCC. Ectopic Parkin expression enhances proteasome inhibitor-induced apoptosis and tumor suppression in HCC cells in vitro and in vivo. In contrast, knockdown of Parkin expression promotes apoptosis resistance and tumor growth. Mechanistically, Parkin promotes TNF receptor-associated factor (TRAF) 2 and TRAF6 degradation and thus facilitates nuclear factor-kappa-B (NF-κB) inhibition, which finally results in apoptosis. These findings reveal a direct molecular link between Parkin and protein degradation in the control of the NF-κB pathway and may provide a novel UPS-dependent strategy for the treatment of HCC by induction of apoptosis.

3.
J Exp Clin Cancer Res ; 38(1): 354, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412908

RESUMO

BACKGROUND: Estrogen receptor ß (ERß) has been reported to play an anti-cancer role in breast cancer, but the regulatory mechanism by which ERß exerts this effect is not clear. Claudin-6 (CLDN6), a tight junction protein, acts as a tumor suppressor gene in breast cancer. Our previous studies have found that 17ß-estradiol (E2) induces CLDN6 expression and inhibits MCF-7 cell migration and invasion, but the underlying molecular mechanisms are still unclear. In this study, we aimed to investigate the role of ERß in this process and the regulatory mechanisms involved. METHODS: Polymerase chain reaction (PCR) and western blot were used to characterize the effect of E2 on the expression of CLDN6 in breast cancer cells. Chromatin immunoprecipitation (ChIP) assays were carried out to confirm the interaction between ERß and CLDN6. Dual luciferase reporter assays were used to detect the regulatory role of ERß on the promoter activity of CLDN6. Wound healing and Transwell assays were used to examine the migration and invasion of breast cancer cells. Western blot, immunofluorescence and transmission electron microscopy (TEM) were performed to detect autophagy. Xenograft mouse models were used to explore the regulatory effect of the CLDN6-beclin1 axis on breast cancer metastasis. Immunohistochemistry (IHC) was used to detect ERß/CLDN6/beclin1 expression in breast cancer patient samples. RESULTS: Here, E2 upregulated the expression of CLDN6, which was mediated by ERß. ERß regulated CLDN6 expression at the transcriptional level. ERß inhibited the migration and invasion of breast cancer cells through CLDN6. Interestingly, this effect was associated with CLDN6-induced autophagy. CLDN6 positively regulated the expression of beclin1, which is a key regulator of autophagy. Beclin1 knockdown reversed CLDN6-induced autophagy and the inhibitory effect of CLDN6 on breast cancer metastasis. Moreover, ERß and CLDN6 were positively correlated, and the expression of CLDN6 was positively correlated with beclin1 in breast cancer tissues. CONCLUSION: Overall, this is the first study to demonstrate that the inhibitory effect of ERß on the migration and invasion of breast cancer cells was mediated by CLDN6, which induced the beclin1-dependent autophagic cascade.

4.
Methods Inf Med ; 58(1): 42-49, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31163452

RESUMO

OBJECTIVES: To investigate the performance of texture analysis in characterizing P53 mutations of hepatocellular carcinomas (HCCs) based on computed tomography (CT). METHODS: A total of 63 HCC patients underwent CT scans and were tested for P53 mutations. Patients were divided into two groups of P53(-) and P53(+) according to the P53 scores. First- and second-order texture features were computed from the CT images and compared between groups using independent Student's t-test. A Spearman's correlation coefficient was used for correlations to assess the relationship between the different P53 sores and CT data. The performance of texture features in differentiating the P53 mutations of HCC was assessed using receiver operating characteristic analysis. RESULTS: The mean values of angular second moment (ASM; mean = 0.001) and contrast (mean = 194.727) for P53(-) were higher than those of P53(+). Meanwhile the mean values of correlation (mean = 0.735), sum variance (mean = 1,111.052), inverse difference moment (IDM; mean = 0.090), and entropy (mean = 3.016) for P53(-) were lower than those of P53(+). Significant correlations were found between P53 scores and ASM (r = - 0.439), contrast (r = - 0.263), correlation (r = 0.551), sum of squares (r = 0.282), sum variance (r = 0.417), IDM (r = 0.308), and entropy (r = 0.569). Five texture parameters (ASM, contrast, correlation, IDM, and entropy) were predictive of P53 mutation status, with areas under the curve ranging from 0.621 to 0.792. CONCLUSIONS: There was a direct relationship between P53 mutations and gray-level co-occurrence matrix, but not with histograms for HCC patients. Correlation and entropy seemed to be the most promising in differentiating P53 (-) from P53(+).

5.
EBioMedicine ; 43: 188-200, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30979686

RESUMO

BACKGROUND: It is well-established that activation of nuclear factor-kappa B (NF-κB) signaling plays important roles in cancer development and progression. However, the underlying mechanism by which the NF-κB pathway is constitutively activated in cancer remains largely unclear. The present study aimed to investigate the effect of PICALM interacting mitotic regulator (PIMREG) on sustaining NF-κB activation in breast cancer. METHODS: The underlying mechanisms in which PIMREG-mediated NF-κB constitutive activation were determined via immunoprecipitation, EMSA and luciferase reporter assays. The expression of PIMREG was examined by quantitative PCR and western blotting analyses and immunohistochemical assay. The effect of PIMREG on aggressiveness of breast cancer cell was measured using MTT, soft agar clonogenic assay, wound healing and transwell matrix penetration assays in vitro and a Xenografted tumor model in vivo. FINDINGS: PIMREG competitively interacted with the REL homology domain (RHD) of NF-κB with IκBα, and sustained NF-κB activation by promotion of nuclear accumulation and transcriptional activity of NF-κB via disrupting the NF-κB/IκBα negative feedback loop. PIMREG overexpression significantly enhanced NF-κB transactivity and promoted the breast cancer aggressiveness. The expression of PIMREG was markedly upregulated in breast cancer and positively correlated with clinical characteristics of patients with breast cancer, including the clinical stage, tumor-node-metastasis classification and poorer survival. INTERPRETATION: PIMREG promotes breast cancer aggressiveness via disrupting the NF-κB/IκBα negative feedback loop, which suggests that PIMREG might be a valuable prognostic factor and potential target for diagnosis and therapy of metastatic breast cancer. FUND: The science foundation of China, Guangdong Province, Guangzhou Education System, and the Science and Technology Program of Guangzhou.

6.
Eur J Radiol ; 114: 25-31, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31005172

RESUMO

PURPOSE: To investigate whether whole-tumor apparent diffusion coefficient (ADC) histogram analysis could be helpful to evaluate breast phyllode tumor (PT) grades. MATERIALS AND METHODS: This institutional review board-approved retrospective study included 56 PTs (23 benign lesions, 22 borderline lesions, and 11 malignant lesions) from August 2011 to November 2017. MRI was performed using a 1.5 T MR system equipped with a 4-channel SENSE breast coil. All cases were divided into two groups, benign PT (BPT) and borderline or malignant PT (BMPT). The conventional MR parameters included age, longest diameter, shape, margin, internal enhancement characteristics, cystic component of the tumor, wall of the cystic component, peritumoral edema on T2-weighted imaging (T2WI), T1-weighted imaging (T1WI) and T2WI signal intensity, time-signal intensity curve (TIC) patterns and early-stage enhancement ratio (EER). The ADC values were determined in three different types of regions of interest (ROIs), including a circular ROI (ROI-c), single-slice ROI (ROI-s), and whole-tumor ROI (ROI-w). All ADC values were measured twice by Observer A and B (with a 2-week interval). The Ki-67 index was determined, and cases were classified into a "negative group" (Ki-67<14%) and a "positive group" (Ki-67≥14%). SPSS Statistics V21.0 was used for the statistical analyses. RESULTS: Our study included 23 cases of BPT and 33 cases of BMPT (including 22 borderline PTs and 11 malignant PTs). Only 23 patients in BMPT group had Ki-67 results, and 17 of these were positive. Regarding conventional MR features, significant differences were observed in the margin (P = 0.011), cystic component (P<0.001), peritumoral edema on T2WI (P<0.001), and cystic wall (P = 0.011) of the PT between the BPT and BMPT groups. Regarding the ADC value, good intraobserver agreement for ROI-c, ROI-s and ROI-w measurements was obtained. For the three different ROIs, the intraclass correlation coefficient (ICC) values were 0.905 for ROI-c (P > 0.05), 0.965 (P > 0.05) for ROI-s and 0.994 (P > 0.05) for ROI-w. ADC parameter indicated that the figure of ROI-s tended to be higher than the ROI-c and ROI-w, while the ROI-c and ROI-w values were similar. However, no significant difference was found in ADC values between the BPT and BMPT groups for ROI-c, ROI-s and mean ROI-w values and the 10th, 25th, 50th and 75th ROI-w. The areas under the ROC curves for the mean ROI-w and the 10th, 25th, 50th and 75th ROI-w were 0.568, 0.613, 0.567, 0.544, and 0.540, respectively. CONCLUSION: Based on the results obtained in our study, the whole-tumor ADC histogram could not improve differentiation of the breast PT grade, while conventional MR images could provide more meaningful information, so morphological characteristics may be valuable than ADC value, and ADC could be used as a supplemental method to differentiate PT grades.


Assuntos
Neoplasias da Mama/patologia , Tumor Filoide/patologia , Adulto , Mama/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Margens de Excisão , Gradação de Tumores , Curva ROC , Estudos Retrospectivos
7.
Int J Oncol ; 54(5): 1843-1852, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864702

RESUMO

Mesenchymal stem cells (MSCs) have been demonstrated to be involved in tumor progression and the modulation of the tumor microenvironment, partly through their secretome. Extracellular vesicles (EVs) are membranous nanovesicles secreted by multiple types of cells and have been demonstrated to mediate intercellular communication in both physiological and pathological conditions. However, numerous questions still remain regarding the underlying mechanisms and functional consequences of these interactions. The purpose of this study was to investigate the effects of human umbilical cord mesenchymal stem cell­derived EVs (hUC­MSC­EVs) on the proliferation, migration and invasion of human breast cancer cells. We successfully generated and identified hUC­MSCs and hUC­MSC­EVs which were used in this study. The results revealed that treatment of the MDA­MB­231 and MCF­7 human breast cancer cells with medium containing hUC­MSC­EVs significantly enhanced the proliferation, migration and invasion of the cells in vitro. Treatment of the cells with medium containing hUC­MSC­EVs also reduced E­cadherin expression and increased N­cadherin expression, thus promoting the epithelial­mesenchymal transition (EMT) of the breast cancer cells. Treatment of the breast cancer cells with extracellular signal­regulated kinase (ERK) inhibitor prior to the interaction with hUC­MSC­EVs significantly reversed the enhanced proliferation, migration and invasion, as well as the EMT of the breast cancer cells induced by the hUC­MSC­EVs. On the whole, these data indicate that hUC­MSC­EVs promote the invasive and migratory potential of breast cancer cells through the induction of EMT via the ERK pathway, leading to malignant tumor progression and metastasis. Taken together, the findings of this study suggest that targeting pathways to reverse EMT may lead to the development of novel therapeutic approaches with which to combat breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Meios de Cultura/farmacologia , Vesículas Extracelulares/patologia , Sistema de Sinalização das MAP Quinases , Células-Tronco Mesenquimais/citologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Meios de Cultura/química , Transição Epitelial-Mesenquimal , Vesículas Extracelulares/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células MCF-7 , Células-Tronco Mesenquimais/metabolismo , Microambiente Tumoral , Cordão Umbilical/citologia , Cordão Umbilical/metabolismo
8.
FASEB J ; 33(5): 6596-6608, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30802149

RESUMO

Blockade of immune-checkpoint programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 can enhance effector T-cell responses. However, the lack of response in many patients to checkpoint-inhibitor therapies emphasizes the need for combination immunotherapies to pursue maximal antitumor efficacy. We have previously demonstrated that antagonism of C-X-C chemokine receptor type 4 (CXCR4) by plerixafor (AMD3100) can decrease regulatory T (Treg)-cell intratumoral infiltration. Therefore, a combination of these 2 therapies might increase antitumor effects. Here, we evaluated the antitumor efficacy of AMD3100 and anti-PD-1 (αPD-1) antibody alone or in combination in an immunocompetent syngeneic mouse model of ovarian cancer. We found that AMD3100, a highly specific CXCR4 antagonist, directly down-regulated the expression of both C-X-C motif chemokine 12 (CXCL12) and CXCR4 in vitro and in vivo in tumor cells. AMD3100 and αPD-1 significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice when given as monotherapy. Combination of these 2 agents significantly enhanced antitumor effects compared with single-agent administration. Benefits of tumor control and animal survival were associated with immunomodulation mediated by these 2 agents, which were characterized by increased effector T-cell infiltration, increased effector T-cell function, and increased memory T cells in tumor microenvironment. Intratumoral Treg cells were decreased, and conversion of Treg cells into T helper cells was increased by AMD3100 treatment. Intratumoral myeloid-derived suppressor cells were decreased by the combined treatment, which was associated with decreased IL-10 and IL-6 in the ascites. Also, the combination therapy decreased suppressive leukocytes and facilitated M2-to-M1 macrophage polarization in the tumor. These results suggest that AMD3100 could be used to target the CXCR4-CXCL12 axis to inhibit tumor growth and prevent multifaceted immunosuppression alone or in combination with αPD-1 in ovarian cancer, which could be clinically relevant to patients with this disease.-Zeng, Y., Li, B., Liang, Y., Reeves, P. M., Qu, X., Ran, C., Liu, Q., Callahan, M. V., Sluder, A. E., Gelfand, J. A., Chen, H., Poznansky, M. C. Dual blockade of CXCL12-CXCR4 and PD-1-PD-L1 pathways prolongs survival of ovarian tumor-bearing mice by prevention of immunosuppression in the tumor microenvironment.

9.
J Exp Clin Cancer Res ; 38(1): 82, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30770775

RESUMO

BACKGROUND: Aberrant EVI1 expression is frequently reported in cancer studies; however, its role in nasopharyngeal carcinoma (NPC) has not been examined in detail. The aim of the present study is to investigate the involvement of EVI1 in progression and prognosis of NPC. METHODS: RT-PCR, immunohistochemistry and western blot assays were used to examine the expression of EVI1 in NPC tissues and cell lines. Fluorescence in situ hybridization assay was used to examine the amplification of EVI1 in NPC tissues. The biological effect of EVI1 was determined by both in vitro and in vivo studies. The dual-luciferase reporter assay was performed to confirm that EVI1 bind at E-cadherin andß-catenin promoters. The ChIP, EMSA, and coimmunoprecipitation combined with mass spectrometry assays were used to analyze the EVI1 regulated proteins. RESULTS: EVI1 expression level was up-regulated in NPC tissues and cell lines. EVI1 was amplificated in NPC tissues. We observed that EVI1 down-regulation decreased the cell proliferation and invasive capacity of NPC cells in vitro and in vivo. EVI1, snail, and HDAC1 formed a co-repressor complex to repress E-cadherin expression and ultimately contributed to epithelial mesenchymal transition (EMT) phenotype in NPC cells. In another way, EVI1 directly bound at ß-catenin promoter and activated its expression. ß-catenin mediated EVI1's function on cancer stem cells (CSCs) properties. EVI1 up-regulation predicted unfavorable prognosis and contributed to chemo/radio-resistance in NPC cells. Finally, we constructed arsenic trioxide-loaded nanoparticles (ALNPs) and revealed that ALNPs exerted anti-tumor effect in NPC cells. CONCLUSIONS: Our data indicated that EVI1 played an oncogenic role in NPC growth and metastasis and that EVI1 might serve as a novel molecular target for the treatment of NPC.


Assuntos
Resistencia a Medicamentos Antineoplásicos/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Proteína do Locus do Complexo MDS1 e EVI1/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Tolerância a Radiação/fisiologia , Adulto , Idoso , Animais , Biomarcadores Tumorais/análise , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/mortalidade , Neoplasias Nasofaríngeas/mortalidade , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Prognóstico , Intervalo Livre de Progressão
10.
Theranostics ; 9(2): 449-465, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809286

RESUMO

The Wnt/ß-catenin pathway is constitutively active and promotes multiple tumor processes, including breast cancer metastasis. However, the underlying mechanism by which the Wnt/ß-catenin pathway is constitutively activated in breast cancer metastasis remains unclear. Inhibition of Wnt antagonists is important for Wnt/ß-catenin signaling activation, and post-transcriptional regulation of these antagonists by microRNAs (miRNAs) might be a possible mechanism underlying signaling activation. Regulation of nuclear pre-mRNA domain-containing 1A (RPRD1A) is a known inhibitor of cell growth and Wnt/ß-catenin signaling activity, but the function and regulatory mechanism of RPRD1A in breast cancer have not been clarified. The aim of this study was to understand how regulators of the Wnt/ß-catenin pathway may play a role in the metastasis of this cancer. Methods: RPRD1A expression and its association with multiple clinicopathological characteristics was analyzed immunohistochemically in human breast cancer specimens. miR-454-3p expression was analyzed using real-time PCR. RPRD1A or miR-454-3p knockdown and overexpression were used to determine the underlying mechanism of their functions in breast cancer cells. Xenografted tumor model, 3D invasive culture, cell migration and invasion assays and sphere formation assay were used to determine the biofunction of RPRD1A and miR-454-3p in breast cancer. Electrophoretic mobility shift assay (EMSA), luciferase reporter assay, and RNA immunoprecipitation (RIP) were performed to study the regulation and underlying mechanisms of RPRD1A and miR-454-3p expression and their correlation with the Wnt/ß-catenin pathway in breast cancer. Results: The Wnt/ß-catenin signaling antagonist RPRD1A was downregulated and its upstream regulator miR-454-3p was amplified and overexpressed in metastatic breast cancer, and both were correlated with overall and relapse-free survival in breast cancer patients. The suppression by miR-454-3p on RPRD1A was found to activate Wnt/ß-catenin signaling, thereby promoting metastasis. Simultaneously, three other negative regulators of the Wnt/ß-catenin pathway, namely, AXIN2, dickkopf WNT signaling pathway inhibitor (DKK) 3 and secreted frizzled related protein (SFRP) 1, were also found to be targets of miR-454-3p and were involved in the signaling activation. miR-454-3p was found to be involved in early metastatic processes and to promote the stemness of breast cancer cells and early relapse under both in vitro and in vivo conditions. Conclusions: The findings indicate that miR-454-3p-mediated suppression of Wnt/ß-catenin antagonist RPRD1A, as well as AXIN2, DKK3 and SFRP1, sustains the constitutive activation of Wnt/ß-catenin signaling; thus, miR-454-3p and RPRD1A might be potential diagnostic and therapeutic targets for breast cancer metastasis.

11.
Lab Invest ; 99(5): 602-611, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30664712

RESUMO

Recurrence or metastasis resulting from radioresistance are the main challenges for the treatment of nasopharyngeal carcinoma (NPC). A great deal of evidence supports the role of abnormal expression of miRNAs in radioresistance and malignancy. In some cancers, miR-483-5p is associated with inferior disease-specific survival. Therefore, we investigated the role of miR-483-5p in NPC radiosensitivity and the mechanism by which the miR-483-5p affects the radiosensitivity of NPC cells. In this study, we show that the overexpression of miR-483-5p decreases the radiosensitivity of NPC cells in vitro and in vivo. Mechanistically, miR-483-5p exerts these functions by decreasing radiation-induced apoptosis and DNA damage, and by increasing NPC cell colony formation, via targeting death-associated protein kinase 1 (DAPK1). Finally, our results confirm that the upregulation of miR-483-5p is correlated with advanced clinical stage and inferior overall survival of patients with NPC. These findings provide novel insights into our understanding of the molecular mechanisms underlying therapy failure in NPC. Modulation of miR-483-5p and DAPK1 levels may provide a new approach for increasing the radiosensitivity of these tumors.

12.
Zhongguo Zhong Yao Za Zhi ; 43(21): 4264-4266, 2018 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-30583627

RESUMO

To investigate the chemical compounds from the ripe fruit of Cornus officinalis, a new phenylpropanoid glycoside 1-O-(6'-O-p-hydroxybenzoyl-ß-D-glucopyranosyl)-p-phenylpropanol, named cornuphenylpropanoid A (1), were separated and purified by D101 macroporous resin, silica gel and ODS column chromatography. Its structure was extensively determined on basis of ¹H-NMR, ¹³C-NMR, DEPT, HSQC, HMBC and HR-ESI-MS spectroscopic data.


Assuntos
Cornus/química , Frutas/química , Glicosídeos/química , Glicosídeos/isolamento & purificação , Estrutura Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação
13.
J Am Chem Soc ; 140(45): 15153-15156, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30207157

RESUMO

Highly crystalline films of a silver-based coordination polymer, [Ag5(C6S6)] n (Ag-BHT, BHT = benzenehexathiol), have been prepared. The structure of Ag-BHT, solved by combining rotation electron diffraction and powder X-ray diffraction techniques, indicates that it has a lamellar structure with alternatively stacked two-dimensional Ag-S networks and layers composed of one-dimensional metal-dithiolene polymers. In addition, the polycrystalline Ag-BHT film shows high electrical conductivity of up to 250 S·cm-1 at 300 K. The ultraviolet-photoelectron spectroscopy and electronic band structure calculations reveal that this can be attributed to the partially filled valence band and the unique two-dimensional Ag-S networks.

14.
Technol Cancer Res Treat ; 17: 1533033818798792, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30213236

RESUMO

Stereotactic radiosurgery provides effective local control, but high recurrence rate are observed while ipilimumab have shown promising improvements in survival in the treatment of melanoma brain metastases. This meta-analysis was done to review the clinical evidence regarding the combination of stereotactic radiosurgery and ipilimumab in the treatment of brain metastases from melanoma. Comprehensive research of the electronic databases (PubMed and Cochrane Library) was carried out in April 2017. Different combination of MESH headings and words were used. Review Manager was used to analyze the outcome data of interest. According to heterogeneity, fixed effects model or random effects model was adapted. Six retrospective studies comparing stereotactic radiosurgery plus ipilimumab with stereotactic radiosurgery alone were found. Total of 411 participants were included in this meta-analysis. Of that, 128 patients had received stereotactic radiosurgery + ipilimumab, while 283 patients had received stereotactic radiosurgery only. Stereotactic radiosurgery plus ipilimumab significantly improved survival when compared to stereotactic radiosurgery alone (hazard ratio: 0.74 [95% confidence interval: 0.56-0.99, P = .04]), with no significant increase in the incidence of adverse events (odds ratio 0.57 [95% confidence interval: 0.28-1.17, P = .12]). Stereotactic radiosurgery with ipilimumab is safe and effective treatment option and can be recommended for the treatment of brain metastases in patients with melanoma.

15.
Medicine (Baltimore) ; 97(33): e11936, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30113497

RESUMO

BACKGROUND: Recently, immune checkpoint inhibitors have shown survival advantage over chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC). This meta-analysis was conducted to gather and analyze the available evidence (Evidence level I; Randomized Controlled Trials) comparing efficacy and safety of anti-programmed cell death-1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies and chemotherapy in the treatment of advanced NSCLC. METHODS: A search strategy was devised to identify the randomized controlled trials (RCTs) using electronic databases of PubMed, Cochrane Library, and Web of Science. Hazard ratios or odds ratios obtained for overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment related adverse events (TRAEs) were analyzed using fixed effect model or random effects model. Additionally, subgroup analysis was also performed. RESULTS: A total of seven RCTs (n = 3867) were identified and selected for inclusion in this meta-analysis. Anti-PD1/PD-L1 therapies (nivolumab, pembrolizumab, atezolizumab) resulted in better OS (HR 0.72 [95% confidence interval [CI] 0.63, 0.82; P < .00001]), PFS (HR 0.84 [95% CI 0.72, 0.97; P < .02]), and ORR (odds ratio [OR] 1.52 [95% CI 1.08, 2.14; P < .02]) in comparison to chemotherapy in advanced NSCLC. Improved safety was observed with anti-PD1/PD-L1 therapies (OR 0.31 [95%CI 0.26, 0.38; P < .00001]). Subgroups analysis revealed Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1 (HR 0.76 [95%CI 0.62, 0.93; P = .007]), squamous cell type (HR 0.76 [95% CI 0.63, 0.92; P = .005]), current/former smoker (HR 0.76 [95% CI 0.63, 0.92; P = .005]), epidermal growth factor receptor (EGFR) wild type (HR 0.67 [95% CI 0.60, 0.76; P < .00001]), Kirsten rat sarcoma oncogene mutation (KRAS) mutant (HR 0.60 [95% CI 0.39, 0.93; P < .02]), and absence of central nervous system (CNS) metastases (HR 0.71 [95% CI 0.63, 0.80; P < .00001]) were associated with better overall survival. CONCLUSIONS: Anti-PD1/PD-L1 therapies are safe and effective treatment option in advanced non-small cell lung cancer and can be recommended selectively.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Nivolumabe , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
16.
Medicine (Baltimore) ; 97(34): e12071, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30142864

RESUMO

INTRODUCTION: Accurate detection and characterization of focal liver lesions, including differentiation between malignant and benign lesions, are particularly important. The objective of this meta-analysis was to evaluate the parameters of intravoxel incoherent motion (IVIM), including apparent diffusion coefficient (ADC), pure molecular diffusion coefficient (D), perfusion-related diffusion coefficient (D*), and perfusion fraction (f) in differentiating focal liver lesions. METHODS: IVIM method employed for focal liver lesion and the quality assessment of diagnostic studies were evaluated. Standardized mean differences and 95% confidence intervals were calculated. The heterogeneity was quantified with the I statistic. RESULTS: The difference between groups was analyzed according to the I values from 6 different studies using fixed effects or random effects models. Significant differences in ADC (P < .001) and D (P < .001) were observed between benign and malignant lesions. Moreover, significant differences in ADC (P < .001), D (P < .001), and f (P = .01) were found between hemangioma and hepatocellular carcinoma (HCC). In addition, no significant difference was observed between the metastases and HCC. CONCLUSIONS: D and ADC values were useful for the differentiation between benignity and malignancy; higher values of ADC, D, and f were observed in hemangioma compared to HCC. Nevertheless, IVIM did not result as the optimal approach for differentiation between the metastases and HCC.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Hemangioma/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Fígado/diagnóstico por imagem , Masculino , Movimento (Física) , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
17.
Cancer Lett ; 432: 75-83, 2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-29864454

RESUMO

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.

18.
Clin Imaging ; 52: 36-43, 2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29908348

RESUMO

OBJECTIVE: To assess the added benefit of combining different MRI techniques for preoperative diagnosis of parotid tumors when compared to conventional MRI and advanced MRI techniques alone with meta-analysis. METHODS: A comprehensive PubMed electronic database search was performed for original diagnostic studies up to July 2017. The methodologic quality of each study was evaluated by two independent reviewers who used the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Statistical analysis included pooling of sensitivity and specificity with 95% confidence intervals (CI). All analyses were conducted using STATA (version 12.0), RevMan (version 5.2), and Meta-Disc 1.4 software programs. RESULTS: Pooled sensitivity and specificity of conventional MRI, diffusion weighted imaging (DWI), dynamic contrast enhanced (DCE) and the above combination were 76% (95%CI)/91% (95%CI)/80% (95%CI)/86% (95%CI) and 83% (95%CI)/56% (95%CI)/90% (95%CI)/90% (95%CI). CONCLUSION: Conventional MRI combined with DWI and DCE showed higher diagnostic accuracy than conventional or advanced MRI alone, supporting their use in parotid tumors diagnosis.

19.
Brain Behav ; 8(5): e00930, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29761003

RESUMO

Objective: To investigate the cause of the motor asymmetry in Wilson's disease (WD) patients using functional MRI. Methods: Fifty patients with WD and 20 age-matched healthy controls were enrolled. Neurological symptoms were scored using the modified Young Scale. All study subjects underwent diffusion tensor imaging (DTI), susceptibility-weighted imaging (SWI), and resting-state functional MRI (rs-fMRI) of the brain. Six regions of interest (ROI) were chosen. Fiber volumes between ROIs on DTI, corrected phase (CP) values on SWI, amplitude of low-frequency fluctuation (ALFF), and regional homogeneity (REHO) values on rs-fMRI were determined. Asymmetry index (right or left value/left or right value) was evaluated. Results: Asymmetry of rigidity, tremor, choreic movement, and gait abnormality (asymmetry index = 1.33, 1.39, 1.36, 1.40), fiber tracts between the GP and substantia nigra (SN), GP and PU, SN and thalamus (TH), SN and cerebellum, head of the caudate nucleus (CA) and SN, PU and CA, CA and TH, TH and cerebellum (asymmetry index = 1.233, 1.260, 1.269, 1.437, 1.503, 1.138, 1.145, 1.279), CP values in the TH, SN (asymmetry index = 1.327, 1.166), ALFF values, and REHO values of the TH (asymmetry index = 1.192, 1.233) were found. Positive correlation between asymmetry index of rigidity and fiber volumes between the GP and SN, SN and TH (r = .221, .133, p = .043, .036), and tremor and fiber volumes between the CA and TH (r = .045, p = .040) was found. Conclusions: The neurological symptoms of patients with WD were asymmetry. The asymmetry of fiber projections may be the main cause of motor asymmetry in patients with WD.

20.
Cancer Immunol Res ; 6(5): 539-551, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29511032

RESUMO

AMD3100 (plerixafor), a CXCR4 antagonist, has been demonstrated to suppress tumor growth and modulate intratumoral T-cell trafficking. However, the effect of AMD3100 on immunomodulation remains elusive. Here, we explored immunomodulation and antitumor efficacy of AMD3100 in combination with a previously developed mesothelin-targeted, immune-activating fusion protein, VIC-008, in two syngeneic, orthotopic models of malignant mesothelioma in immunocompetent mice. We showed that combination therapy significantly suppressed tumor growth and prolonged animal survival in two mouse models. Tumor control and survival benefit were associated with enhanced antitumor immunity. VIC-008 augmented mesothelin-specific CD8+ T-cell responses in the spleen and lymph nodes and facilitated intratumoral lymphocytic infiltration. However, VIC-008 treatment was associated with increased programmed cell death protein-1 (PD-1) expression on intratumoral CD8+ T cells, likely due to high CXCL12 in the tumor microenvironment. AMD3100 alone and in combination with VIC-008 modulated immunosuppression in tumors and the immune system through suppression of PD-1 expression on CD8+ T cells and conversion of regulatory T cells (Tregs) into CD4+CD25-Foxp3+IL2+CD40L+ helper-like cells. In mechanistic studies, we demonstrated that AMD3100-driven Treg reprogramming required T cell receptor (TCR) activation and was associated with loss of PTEN due to oxidative inactivation. The combination of VIC-008 augmentation of tumor-specific CD8+ T-cell responses with AMD3100 abrogation of immunosuppression conferred significant benefits for tumor control and animal survival. These data provide new mechanistic insight into AMD3100-mediated immunomodulation and highlight the enhanced antitumor effect of AMD3100 in combination with a tumor antigen-targeted therapy in mouse malignant mesothelioma, which could be clinically relevant to patients with this difficult-to-treat disease. Cancer Immunol Res; 6(5); 539-51. ©2018 AACR.

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