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2.
J Cancer Surviv ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31820215

RESUMO

PURPOSE: Cancer survivors should have adequate e-health literacy to help them better use online health information. Online health communities (OHCs) can offer cancer survivors different types of social support that can represent another resource to improve health outcomes. However, there is little knowledge of how these OHC are directly related to a cancer survivors' e-health literacy. This study explores how different types of social support in OHCs are associated with cancer survivors' e-health literacy. METHODS: A questionnaire was developed to collect data from two Chinese OHCs used by cancer survivors. The questionnaire is composed of two parts: six sociodemographic variables (i.e., gender, age, city, education, tenure, and prior Internet experience), two scales for informational support behaviors (i.e., health knowledge seeking and provision of health knowledge), a measure of emotional support within such a setting, and a measure of e-health literacy. Based on 162 complete samples, we determined the measurement properties of the scales used, provided descriptive statistics on major sociodemographic variables and conducted bivariate and multivariable hierarchical regression. RESULTS: For cancer survivors, females demonstrate higher levels of e-health literacy. Higher education level was related to higher e-health literacy. Health knowledge seeking, contributing to health knowledge, and emotional support were all positively associated with e-health literacy. The interaction effect between health knowledge and emotional support is positively associated with e-health literacy. CONCLUSIONS: Informational support and emotional support, as two major subtypes of social support within resources available in OHCs, are positively associated with e-health literacy among cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Cancer survivors might benefit from an active strategy for improving personal e-health literacy that includes more active informational involvement and emotional support rather than a passive lurking through e-health information and seeking and reading postings in OHCs.

3.
BMC Cancer ; 19(1): 1061, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31703584

RESUMO

BACKGROUND: To reveal roles of reactive oxygen species (ROS) status in chemotherapy resistance and to develop a ROS scoring system for prognosis prediction in ovarian cancer. METHODS: We tested the sensitizing effects of ROS elevating drugs to cisplatin (cDDP) in ovarian cancer both in vitro and in vivo. A ROS scoring system was developed using The Cancer Genome Atlas (TCGA) database of ovarian cancer. The associations between ROS scores and overall survival (OS) were analyzed in TCGA, Tothill dataset, and our in-house dataset (TJ dataset). RESULTS: ROS-inducing drugs increased cisplatin-induced ovarian cancer cell injury in vitro and in vivo. ROS scoring system was established using 25 ROS-related genes. Patients were divided into low (scores 0-12) and high (scores 13-25) score groups. Improved patient survival was associated with higher scores (TCGA dataset hazard ratio (HR) = 0.43, P < 0.001; Tothill dataset HR = 0.65, P = 0.022; TJ dataset HR = 0.40, P = 0.003). The score was also significantly associated with OS in multiple datasets (TCGA dataset r2 = 0.574, P = 0.032; Thothill dataset r2 = 0.266, P = 0.049; TJ dataset r2 = 0.632, P = 0.001) and with cisplatin sensitivity in ovarian cancer cell lines (r2 = 0.799, P = 0.016) when used as a continuous variable. The scoring system showed better prognostic performance than other clinical factors by receiver operating characteristic (ROC) curves (TCGA dataset area under the curve (AUC) = 0.71 v.s. 0.65, Tothill dataset AUC = 0.73 v.s. 0.67, TJ dataset AUC = 0.74 v.s. 0.66). CONCLUSIONS: ROS status is associated with chemotherapy resistance. ROS score system might be a prognostic biomarker in predicting the survival benefit from ovarian cancer patients.

4.
Surg Oncol ; 31: 8-13, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446304

RESUMO

BACKGROUND: The standard prognostic system for malignant ovarian germ cell tumors (MOGCT) has not yet been established and the scope of surgery was also controversial. Mixed ovarian malignant germ cell tumor (mGCT) is a rare histological type of MOGCT with higher malignant degree than other types. The aim of the present study was to investigate the clinical features and prognosis of mGCT, and prognostic factors for MOGCT to provide guidance for future treatment. METHODS: Retrospective analysis was carried out on 137 patients, who were admitted from 1991 to 2014. Survival curves were constructed using Kaplan-Meier method and were compared with the log-rank test across various pathological types and different stages. Multivariate survival analysis was performed using Cox's proportional hazards model. RESULTS: There were 29 dysgerminomas (DG), 3 embryonal carcinomas (EC), 43 immature teratomas (IT), 48 yolk sac tumors (YST) and 14 mixed germ cell tumors (mGCT). The most common type of mGCT is YST (85.7%), followed by IT (64.3%), EC (28.6%), and DG (21.4%). The respective 5-year OS rates were 100% in DG, 100% in EC, 92.5% in IT, 54.5% in YST and 66.7% in mGCT, while the corresponding 5-year PFS rate were 89.7% in DG, 100% in EC, 85.1% in IT, 55.9% in YST and 60% in mGCT. FIGO stage Ⅲ-Ⅳ, certain pathological types (Yolk sac tumors and mGCT) and the number of postoperative chemotherapy courses were independently unfavorable prognostic in a multivariate model that included age, Admission decade, fertility-sparing surgery, and comprehensive staging surgery. CONCLUSIONS: Fertility-sparing surgery and incomplete surgical staging did not affect the prognosis. It might be safe to preserve fertility and shrink the scope of the surgical procedures in MOGCT patients regardless of stage or pathology. However, prospective randomized controlled trials were needed for further evaluation.

5.
Mol Genet Genomic Med ; 7(8): e835, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31270966

RESUMO

BACKGROUND: Atrial fibrillation (AF) is one of the common arrhythmia in clinics. Its incidence is high among the elderly. This study aimed to identify a possible connection between ion channel-related gene polymorphisms and the risk of AF. METHODS: A total of 381 patients with coronary heart disease were recruited. Based on complete cardiac examination, the patients were divided into two subgroups: 185 patients with AF and 196 patients without AF. An association analysis was performed using 13 genotyped SNPs. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by conditional logistic regression. RESULTS: In our research, we found that KCNE2 rs8134775 was associated with a decreased AF risk in the allele model (OR = 0.70; 95% CI: 0.50-0.97; p = 0.034). Genetic model analysis shown that the minor allele T of GJA5 rs35594137 was associated with a decreased AF risk under the recessive model (OR = 0.40; 95% CI: 0.19-0.86; p = 0.018) and the minor allele G of KCNJ2 rs8079702 was associated with an increased AF risk in the recessive model (OR = 2.31; 95% CI: 1.20-4.42; p = 0.012). CONCLUSIONS: Our results suggest that KCNE2, KCNJ2, and GJA5 influence the development of AF.

6.
Oncol Lett ; 15(3): 3646-3652, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29467885

RESUMO

The multi-center, randomized, open-label, phase III trial discussed in the present study was performed to compare the clinical outcomes of nedaplatin (NDP) plus paclitaxel, and carboplatin (CBP) plus paclitaxel for the treatment of epithelial ovarian cancer (EOC). In the current study, 182 patients with International Federation of Gynecology and Obstetrics (FIGO) stage II-IV EOC were randomly assigned to receive NDP plus paclitaxel or CBP plus paclitaxel at 3-week intervals for a total of six courses. The primary endpoints were progression-free survival rate (PFS) and overall survival rate (OS). The secondary endpoints were toxicity profiles. The median follow-up was 44.63 months [95% confidence interval (CI) 33.67-46.47 months] for the NDP group and 47.63 months (95% CI 45.13-49.07 months) for the CBP group. Overall, there was no significant difference in PFS or OS between the two groups (P=0.09 for PFS, and P=0.65 for OS). For the patients with FIGO stage III-IV EOC, the NDP plus paclitaxel regimen significantly prolonged PFS (P=0.02) but did not result in improved OS (P=0.53) when compared with the CBP group. The patients in the NDP plus paclitaxel group also exhibited a lower incidence rate of grade 3 or 4 leucopenia (P=0.03). Other hematological and non-hematological toxicity profiles were similar between the two groups. Compared with CBP plus paclitaxel regimens, NDP plus paclitaxel regimens achieved comparable survival outcomes and similar toxicity profiles. However, patients of FIGO stage III-IV EOC may experience more clinical benefits from NDP plus paclitaxel treatment, including a prolonged PFS and a lower incidence rate of leucopenia. Therefore, an NDP-based regimen may be an alternative choice when using platinum-based agents to treat EOC.

7.
Cell Res ; 28(4): 416-432, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29472691

RESUMO

It is assumed that anti-CTLA-4 antibodies cause tumor rejection by blocking negative signaling from B7-CTLA-4 interactions. Surprisingly, at concentrations considerably higher than plasma levels achieved by clinically effective dosing, the anti-CTLA-4 antibody Ipilimumab blocks neither B7 trans-endocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Consequently, Ipilimumab does not increase B7 on dendritic cells (DCs) from either CTLA4 gene humanized (Ctla4 h/h ) or human CD34+ stem cell-reconstituted NSG™ mice. In Ctla4 h/m mice expressing both human and mouse CTLA4 genes, anti-CTLA-4 antibodies that bind to human but not mouse CTLA-4 efficiently induce Treg depletion and Fc receptor-dependent tumor rejection. The blocking antibody L3D10 is comparable to the non-blocking Ipilimumab in causing tumor rejection. Remarkably, L3D10 progenies that lose blocking activity during humanization remain fully competent in inducing Treg depletion and tumor rejection. Anti-B7 antibodies that effectively block CD4 T cell activation and de novo CD8 T cell priming in lymphoid organs do not negatively affect the immunotherapeutic effect of Ipilimumab. Thus, clinically effective anti-CTLA-4 mAb causes tumor rejection by mechanisms that are independent of checkpoint blockade but dependent on the host Fc receptor. Our data call for a reappraisal of the CTLA-4 checkpoint blockade hypothesis and provide new insights for the next generation of safe and effective anti-CTLA-4 mAbs.


Assuntos
Anticorpos Bloqueadores/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno CTLA-4/imunologia , Ipilimumab/uso terapêutico , Neoplasias/terapia , Animais , Anticorpos Bloqueadores/imunologia , Antineoplásicos Imunológicos/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Antígeno CTLA-4/antagonistas & inibidores , Feminino , Humanos , Imunoterapia/métodos , Ipilimumab/imunologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
8.
Foodborne Pathog Dis ; 14(11): 656-666, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28731389

RESUMO

In this study, novel antimicrobial peptides had been derived by enzymatic hydrolysis of filefish (Thamnaconus modestus) byproduct (HFBP). Different proteases, (papain [P], trypsin [T], neutrase [N], pepsin [PE], and the mixture I [PN] and mixture II [PT]) and different hydrolysis time (60, 120, 180, and 240 min), have been used to generate peptides with different lengths and amino acid sequences. The antimicrobial properties of HFBPs were tested, against Gram-positive and Gram-negative strains, using disc diffusion method. HFBP prepared after 120 min of the enzymatic hydrolysis by trypsin (HFBP-T) exhibited greatest antibacterial activities. Bacillus cereus 10451 (BC) and Salmonella enteritidis 10982 (SE) strains were most sensitive to HFBP-T with an inhibitory zone of 24.68 and 29.67 mm diameter and minimum inhibitory concentration of 1.25 and 2.5 mg/mL, respectively. Moreover, the antimicrobial activities of tested HFBPs increased significantly at low pH and temperature. The amino acid analysis showed that HFBP-T protein hydrolysate is high in an amino acid of proline, which probably contributes to the antimicrobial activity. The results obtained from scanning electron microscopy suggested that HFBPs might kill bacteria by acting on the cell wall of bacteria. Conclusively, the HFBP derived from filefish byproduct with biological activates is an interesting alternative to the use of waste from the fishing industry as natural antimicrobials in food stuff.


Assuntos
Antibacterianos/farmacologia , Peixes , Peptídeo Hidrolases/farmacologia , Salmonella enteritidis/efeitos dos fármacos , Animais , Doenças Transmitidas por Alimentos/prevenção & controle , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/ultraestrutura , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/ultraestrutura , Testes de Sensibilidade Microbiana , Salmonella enteritidis/ultraestrutura
9.
Oncotarget ; 8(26): 42983-42996, 2017 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-28562334

RESUMO

Serous ovarian cancer (SOC) is the most lethal gynecological cancer. Clinical studies have revealed an association between tumor stage and grade and clinical prognosis. Identification of meaningful clusters of co-expressed genes or representative biomarkers related to stage or grade may help to reveal mechanisms of tumorigenesis and cancer development, and aid in predicting SOC patient prognosis. We therefore performed a weighted gene co-expression network analysis (WGCNA) and calculated module-trait correlations based on three public microarray datasets (GSE26193, GSE9891, and TCGA), which included 788 samples and 10402 genes. We detected four modules related to one or more clinical features significantly shared across all modeling datasets, and identified one stage-associated module and one grade-associated module. Our analysis showed that MMP2, COL3A1, COL1A2, FBN1, COL5A1, COL5A2, and AEBP1 are top hub genes related to stage, while CDK1, BUB1, BUB1B, BIRC5, AURKB, CENPA, and CDC20 are top hub genes related to grade. Gene and pathway enrichment analyses of the regulatory networks involving hub genes suggest that extracellular matrix interactions and mitotic signaling pathways are crucial determinants of tumor stage and grade. The relationships between gene expression modules and tumor stage or grade were validated in five independent datasets. These results could potentially be developed into a more objective scoring system to improve prediction of SOC outcomes.


Assuntos
Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Expressão Gênica , Redes Reguladoras de Genes , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Biologia Computacional , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Estudos de Associação Genética , Humanos , Gradação de Tumores , Estadiamento de Neoplasias , Característica Quantitativa Herdável , Reprodutibilidade dos Testes
10.
Oncol Lett ; 13(3): 1553-1562, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28454290

RESUMO

RNA interference (RNAi) is a powerful technology for suppressing gene function. In most studies, small interfering RNAs (siRNAs) consist of one short hairpin RNA (shRNA) and, therefore, are often unable to achieve loss-of-function of their target genes. In the current study, an RNAi vector containing three shRNAs under the control of three RNA polymerase III U6 promoters was constructed. RNAi vectors containing one or two shRNAs were generated for comparisons. A pilot study targeting exogenously expressed DsRed in the HEK293 cell line revealed promising effects and a high selectivity for the multi-shRNA RNAi vector. Akt2 is constitutively expressed in cultured SKOV3 human ovarian cancer cells, and the multi-shRNA RNAi vector showed a strong efficiency for downregulating the expression of Akt2 in these cells, with no apparent interferon response. In addition, the Akt2-3shRNA vector, containing three shRNAs targeting Akt2, showed the best effect of all the shRNA vectors in reversing paclitaxel-induced resistance in SKOV3 cells. This study developed a widely applicable resource for enhancing the efficiency of gene silencing and a novel technique for performing complex loss-of-function screens in mammalian cells.

11.
Gynecol Oncol ; 145(2): 277-283, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28274568

RESUMO

PURPOSE: To evaluate the differences in the treatment outcomes and complications between elderly patients and younger patients with uterine cervical cancer (CxCa). METHODS AND MATERIALS: From April 1993 to December 2007, 138 CxCa patients aged ≥75years (Elderly group) and 334 CxCa patients aged <60years (Young group) who underwent definitive radiotherapy/chemoradiotherapy at our institution were reviewed. Two propensity score-matched cohorts of patients were selected from both age groups to evaluate the differences in the outcomes and complications. The overall survival (OS), cancer-specific survival (CSS), local failure (LF), distant failure (DF), late proctitis, and cystitis were compared between the age groups. RESULTS: The median follow-up time for survivors was 60.6months. A cohort of 99 pairs of patients was selected for the outcome comparison; there was a significant difference in the 5-year OS between the Elderly and Young groups (49.2% and 71.5%, respectively; p<0.001) but no differences in CSS, LF, and DF. Another cohort of 79 pairs of patients was selected for complication analysis. Significant differences between the Elderly and Young groups were observed in the 5-year cumulative grade 2 proctitis (39.7% and 17.2%, respectively; p=0.015) and grade 3 proctitis (18.1% and 6.2%, respectively; p=0.040). CONCLUSIONS: Although OS was worse in the elderly patients, no differences were observed in CSS, LF, and DF. Meanwhile, elderly patients tended to have higher radiation-related proctitis than younger patients. A more conservative treatment strategy for elderly CxCa patients is reasonable in our future practice.


Assuntos
Neoplasias do Colo do Útero/radioterapia , Fatores Etários , Idoso , Braquiterapia/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pontuação de Propensão , Radioterapia/efeitos adversos , Resultado do Tratamento , Neoplasias do Colo do Útero/patologia
13.
PLoS One ; 11(9): e0161779, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27610613

RESUMO

The monoclonal antibodies ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have shown remarkable antitumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have demonstrated superior activity in patients with metastatic melanoma (CHECKMATE-067). Here we describe the preclinical development strategy that predicted these clinical results. Synergistic antitumor activity in mouse MC38 and CT26 colorectal tumor models was observed with concurrent, but not sequential CTLA-4 and PD-1 blockade. Significant antitumor activity was maintained using a fixed dose of anti-CTLA-4 antibody with decreasing doses of anti-PD-1 antibody in the MC38 model. Immunohistochemical and flow cytometric analyses confirmed that CD3+ T cells accumulated at the tumor margin and infiltrated the tumor mass in response to the combination therapy, resulting in favorable effector and regulatory T-cell ratios, increased pro-inflammatory cytokine secretion, and activation of tumor-specific T cells. Similarly, in vitro studies with combined ipilimumab and nivolumab showed enhanced cytokine secretion in superantigen stimulation of human peripheral blood lymphocytes and in mixed lymphocyte response assays. In a cynomolgus macaque toxicology study, dose-dependent immune-related gastrointestinal inflammation was observed with the combination therapy; this response had not been observed in previous single agent cynomolgus studies. Together, these in vitro assays and in vivo models comprise a preclinical strategy for the identification and development of highly effective antitumor combination immunotherapies.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia , Melanoma/tratamento farmacológico , Animais , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/terapia , Terapia Combinada , Modelos Animais de Doenças , Feminino , Humanos , Ipilimumab , Linfócitos/imunologia , Linfócitos/metabolismo , Macaca fascicularis , Melanoma/metabolismo , Melanoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Nivolumabe , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T Reguladores/metabolismo
14.
Oncotarget ; 7(28): 43924-43938, 2016 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-27270322

RESUMO

Approximately 50-75% of patients with serous ovarian carcinoma (SOC) experience recurrence within 18 months after first-line treatment. Current clinical indicators are inadequate for predicting the risk of recurrence. In this study, we used 7 publicly available microarray datasets to identify gene signatures related to recurrence in optimally debulked SOC patients, and validated their expressions in an independent clinic cohort of 127 patients using immunohistochemistry (IHC). We identified a two-gene signature including KCNN4 and S100A14 which was related to recurrence in optimally debulked SOC patients. Their mRNA expression levels were positively correlated and regulated by DNA copy number alterations (CNA) (KCNN4: p=1.918e-05) and DNA promotermethylation (KCNN4: p=0.0179; S100A14: p=2.787e-13). Recurrence prediction models built in the TCGA dataset based on KCNN4 and S100A14 individually and in combination showed good prediction performance in the other 6 datasets (AUC:0.5442-0.9524). The independent cohort supported the expression difference between SOC recurrences. Also, a KCNN4 and S100A14-centered protein interaction subnetwork was built from the STRING database, and the shortest regulation path between them, called the KCNN4-UBA52-KLF4-S100A14 axis, was identified. This discovery might facilitate individualized treatment of SOC.


Assuntos
Biomarcadores Tumorais/análise , Cistadenocarcinoma Seroso/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação ao Cálcio/análise , Proteínas de Ligação ao Cálcio/biossíntese , Carcinoma Epitelial do Ovário , Cistadenocarcinoma Seroso/mortalidade , Feminino , Perfilação da Expressão Gênica , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/análise , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/biossíntese , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/mortalidade , Prognóstico , Transcriptoma
15.
Oncotarget ; 7(15): 21054-63, 2016 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-27014971

RESUMO

BACKGROUND: Most cervical cancer patients worldwide receive surgical treatments, and yet the current International Federation of Gynecology and Obstetrics (FIGO) staging system do not consider surgical-pathologic data. We propose a more comprehensive and prognostically valuable surgical-pathologic staging and scoring system (SPSs). METHODS: Records from 4,220 eligible cervical cancer cases (Cohort 1) were screened for surgical-pathologic risk factors. We constructed a surgical-pathologic staging and SPSs, which was subsequently validated in a prospective study of 1,104 cervical cancer patients (Cohort 2). RESULTS: In Cohort 1, seven independent risk factors were associated with patient outcome: lymph node metastasis (LNM), parametrial involvement, histological type, grade, tumor size, stromal invasion, and lymph-vascular space invasion (LVSI). The FIGO staging system was revised and expanded into a surgical-pathologic staging system by including additional criteria of LNM, stromal invasion, and LVSI. LNM was subdivided into three categories based on number and location of metastases. Inclusion of all seven prognostic risk factors improves practical applicability. Patients were stratified into three SPSs risk categories: zero-, low-, and high-score with scores of 0, 1 to 3, and ≥4 (P=1.08E-45; P=6.15E-55). In Cohort 2, 5-year overall survival (OS) and disease-free survival (DFS) outcomes decreased with increased SPSs scores (P=9.04E-15; P=3.23E-16), validating the approach. Surgical-pathologic staging and SPSs show greater homogeneity and discriminatory utility than FIGO staging. CONCLUSIONS: Surgical-pathologic staging and SPSs improve characterization of tumor severity and disease invasion, which may more accurately predict outcome and guide postoperative therapy.


Assuntos
Histerectomia , Excisão de Linfonodo , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgia , Idoso , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida
16.
Tumour Biol ; 37(8): 11007-15, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26894601

RESUMO

The PI3K/Akt/mTOR axis in ovarian cancer is frequently activated and implicated in tumorigenesis. Specific targeting of this pathway is therefore an attractive therapeutic approach for ovarian cancer. However, ovarian cancer cells are resistant to PP242, a dual inhibitor of mTORC1 and mTORC2. Interestingly, blockage of GLS1 with a selective inhibitor, CB839, or siRNA dramatically sensitized the PP242-induced cell death, as evident from increased PARP cleavage. The anti-cancer activity of CB-839 and PP242 was abrogated by the addition of the TCA cycle product α-ketoglutarate, indicating the critical function of GLS1 in ovarian cancer cell survival. Finally, glutaminolysis inhibition activated apoptosis and synergistically sensitized ovarian cancer cells to priming with the mTOR inhibitor PP242. GLS1 inhibition significantly reduced phosphorylated STAT3 expression in ovarian cancer cells. These findings show that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy to overcome resistance to PI3K/Akt/mTOR inhibition.


Assuntos
Resistencia a Medicamentos Antineoplásicos/fisiologia , Glutaminase/metabolismo , Neoplasias Ovarianas/metabolismo , Fator de Transcrição STAT3/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzenoacetamidas/farmacologia , Western Blotting , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Glutamina/metabolismo , Humanos , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tiadiazóis/farmacologia
17.
J Huazhong Univ Sci Technolog Med Sci ; 35(4): 469-476, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26223912

RESUMO

SWI1 is a member of a new class of tumor DNA-binding proteins named as the AT-rich interaction domain family (ARID), and considered to bind with AT base pairs specifically. Genomic and functional data support ARID1A as a tumor suppressor because ARID1A/BAF250a (SWI1) subunit of the SWI/SNF chromatin-remodeling complex has emerged as recurrently mutated in a broad array of tumor types. But the crystal structure of SWI1 has not been solved as yet. Using docking and molecular dynamics, we predicted the DNA interaction pattern of human SWI1 ARID and made comparisons with the other two representative ARID family members, human Mrf-2 ARID and Drosophila Dri ARID. Dynamic results revealed that the N-terminal and loop L1 of SWI1 ARID bound with the DNA major groove, while the loop L2 and helix H6 bound with the minor groove. Moreover, it was found that SWI1 ARID bound with DNA apparently in a sequence-nonspecific manner. It was concluded that SWI1 ARID can form stable complex with sequence-nonspecific DNA segment comparing to Mrf-2 ARID/DNA and Dri ARID/DNA sequence-specific complexes.


Assuntos
Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Sítios de Ligação , DNA/química , Proteínas de Drosophila/química , Proteínas de Homeodomínio/química , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas Nucleares/química , Estrutura Terciária de Proteína
18.
BMC Med Genet ; 16: 25, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25928231

RESUMO

BACKGROUND: A large number of single nucleotide polymorphisms (SNPs) associated with cervical cancer have been identified through candidate gene association studies and genome-wide association studies (GWAs). However, some studies have yielded different results for the same SNP. To obtain a more comprehensive understanding, we performed a meta-analysis on previously published case-control studies involving the SNPs associated with cervical cancer. METHODS: Electronic searches of PubMed and Embase were conducted for all publications about the association between gene polymorphisms and cervical cancer. One-hundred and sixty-seven association studies were included in our research. For each SNP, three models (the allele, dominant and recessive effect models) were adopted in the meta-analysis. For each model, the effect summary odds ratio (OR) and 95% CI were calculated. Heterogeneity between studies was evaluated by Cochran's Q test. If the p value of Q test was less than 0.01, a random effect model was used; otherwise, a fixed effect model was used. RESULTS: The results of our meta-analysis showed that: (1) There were 8, 2 and 8 SNPs that were significantly associated with cervical cancer (P < 0.01) in the allele, dominant and recessive effect models, respectively. (2) rs1048943 (CYP1A1 A4889G) showed the strongest association with cervical cancer in the allele effect model (1.83[1.57, 2.13]); in addition, rs1048943 (CYP1A1 A4889G) had a very strong association in the dominant and recessive effect model. (3) 15, 11 and 10 SNPs had high heterogeneity (P < 0.01) in the three models, respectively. (4) There was no published bias for most of the SNPs according to Egger's test (P < 0.01) and Funnel plot analysis. For some SNPs, their association with cervical cancer was only tested in a few studies and, therefore, might have been subjected to published bias. More studies on these loci are required. CONCLUSION: Our meta-analysis provides a comprehensive evaluation of cervical cancer association studies.


Assuntos
Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Neoplasias do Colo do Útero/genética , Alelos , Feminino , Humanos , Modelos Estatísticos , Fenótipo
19.
Asian Pac J Cancer Prev ; 16(9): 3773-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25987036

RESUMO

BACKGROUND: This study aimed to establish a nomogram by combining clinicopathologic factors with overall survival of stage IA-IIB cervical cancer patients after complete resection with pelvic lymphadenectomy. MATERIALS AND METHODS: This nomogram was based on a retrospective study on 1,563 stage IA-IIB cervical cancer patients who underwent complete resection and lymphadenectomy from 2002 to 2008. The nomogram was constructed based on multivariate analysis using Cox proportional hazard regression. The accuracy and discriminative ability of the nomogram were measured by concordance index (C-index) and calibration curve. RESULTS: Multivariate analysis identified lymph node metastasis (LNM), lymph-vascular space invasion (LVSI), stromal invasion, parametrial invasion, tumor diameter and histology as independent prognostic factors associated with cervical cancer survival. These factors were selected for construction of the nomogram. The C-index of the nomogram was 0.71 (95% CI, 0.65 to 0.77), and calibration of the nomogram showed good agreement between the 5-year predicted survival and the actual observation. CONCLUSIONS: We developed a nomogram predicting 5-year overall survival of surgically treated stage IA-IIB cervical cancer patients. More comprehensive information that is provided by this nomogram could provide further insight into personalized therapy selection.


Assuntos
Carcinoma de Células Escamosas/secundário , Histerectomia/mortalidade , Excisão de Linfonodo/mortalidade , Nomogramas , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/cirurgia , Feminino , Seguimentos , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/cirurgia
20.
Int J Gynecol Cancer ; 25(5): 910-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25867278

RESUMO

OBJECTIVE: To compare the clinical outcomes of patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIB cervical carcinoma receiving neoadjuvant chemotherapy followed by radical hysterectomy (RH) with those of patients receiving chemoradiation therapy (CRT) alone. METHODS: We retrospectively reviewed the medical records of patients with FIGO stage IIB cervical carcinoma. A total of 621 patients were eligible for the study according to the surgery-based or radiotherapy-based treatment; 285 patients received cisplatin-based neoadjuvant chemotherapy (NACT) followed by RH, and 336 patients underwent sequential or concurrent chemoradiation. The disease-free survival, overall survival, recurrence rates, and late complications were compared. Cox regression analysis was used to identify potential prognostic factors. RESULTS: Complete or partial response was seen in 77.6% (221/285) of the NACT-treated patients. Disease-free survival and overall survival rates of the patients who had NACT-sensitive responses were significantly higher than those who did not response (P = 0.021 and P = 0.008). Overall survival rates in the NACT + RH group were comparable with the concurrent chemoradiotherapy or chemoradiation groups (P > 0.05). Neoadjuvant chemotherapy followed by RH significantly decreased the recurrence rate (22.6% vs 35.5%), resulted in fewer treatment-related complications, and ultimately improved survival when compared with concurrent CRT. A survival benefit was observed for 63.9% of the patients in the NACT + RH group without adjuvant radiotherapy or CRT. CONCLUSIONS: Compared with concurrent chemoradiotherapy, NACT followed by RH achieved comparable survival outcomes for patients with FIGO stage IIB cervical cancer. This treatment method was significantly effective at reducing radiotherapy rates and complications, and it is worthy of recommending for younger patients.


Assuntos
Adenocarcinoma/terapia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia/mortalidade , Histerectomia/mortalidade , Terapia Neoadjuvante , Recidiva Local de Neoplasia/terapia , Neoplasias do Colo do Útero/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/secundário , Terapia Combinada , Feminino , Seguimentos , Humanos , Agências Internacionais , Excisão de Linfonodo , Metástase Linfática , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Obstetrícia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia
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