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1.
World J Gastroenterol ; 27(28): 4667-4686, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34366628

RESUMO

BACKGROUND: Sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Y-box binding protein 1 (YB-1) is closely correlated with tumors and drug resistance. However, the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown. AIM: To explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC. METHODS: The protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues. Next, we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib. Then, we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling, flow cytometry and Western blotting assays. We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo. Moreover, we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing (DGE-seq). RESULTS: YB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues. YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis. Consistently, the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down. Furthermore, KEGG pathway enrichment analysis of DGE-seq demonstrated that the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was essential for the sorafenib resistance induced by YB-1. Subsequently, YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway (Akt1 and PIK3R1) as shown by searching the BioGRID and HitPredict websites. Finally, YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib, and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance. CONCLUSION: Overall, we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene, which is of great significance for the application of sorafenib in advanced-stage HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Proteínas de Transporte , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Sorafenibe/farmacologia , Proteína 1 de Ligação a Y-Box
2.
World J Surg Oncol ; 19(1): 257, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34461923

RESUMO

OBJECTIVE: To establish a risk prediction model for pancreatic fistula according to the pancreatic fistula standards of the 2016 edition. METHODS: Clinical data from 223 patients with PD admitted to Tianjin Third Central Hospital from January 2016 to December 2020 were retrospectively analyzed. Patients were divided into modeling (January 2016 to December 2018) and validation (January 2019 to December 2020) sets according to the time of admission. The risk factors for postoperative pancreatic fistula (POPF) were screened by univariate and multivariate logistic regression analyses, and a risk prediction model for POPF was established in the modeling set. This score was tested in the validation set. RESULTS: Logistic regression analysis showed that the main pancreatic duct index and CT value were independent risk factors according to the 2016 pancreatic fistula grading standard, based on which a risk prediction model for POPF was established. Receiver operating characteristic curve analysis showed that the area under the curve was 0.775 in the modeling set and 0.848 in the validation set. CONCLUSION: The main pancreatic duct index and CT value of the pancreas are closely related to the occurrence of pancreatic fistula after PD, and the established risk prediction model for pancreatic fistula has good prediction accuracy.


Assuntos
Fístula Pancreática , Pancreaticoduodenectomia , Humanos , Pâncreas/cirurgia , Fístula Pancreática/epidemiologia , Fístula Pancreática/etiologia , Pancreaticoduodenectomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(3): 715-719, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34105462

RESUMO

OBJECTIVE: To investigate the value of CD44+ mononuclear cells (MNC) and spleen stiffness measurement (SSM) in minimal residual disease (MRD) in acute myeloid leukemia (AML) and its prognosis. METHODS: Flow cytometry was used to detected the proportion of CD44+ and CD24+ MNC in 44 AML patients after induction chemotherapy. The SSM was tested by FS. The value of MNC and SSM in MRD and its prognosis was explored. RESULTS: The percentage of CD44+ MNC and SSM in MRD positive group were significantly higher than those in MRD negative group (P<0.05). In MRD positive group, there were positive correlation between CD44+ MNC, SSM and MRD level (r=0.998, r=0.939, P<0.05). The median EFS and OS in HCD44+ MNC and HSSM groups were significantly shorter than those in LCD44+ MNC and LSSM (P<0.05). CD24+ MNC showed no association with MRD and its prognosis. CONCLUSION: HCD44+ MNC and HSSM may be used to predict high level MRD and poor prognosis.


Assuntos
Leucemia Mieloide Aguda , Baço , Citometria de Fluxo , Humanos , Receptores de Hialuronatos , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Neoplasia Residual , Prognóstico
5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 348-325, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33812398

RESUMO

OBJECTIVE: To detect the relationship between leukocytes derived microparticle (CD45+ MP) and minimal residual disease (MRD) and prognosis of acute myeloid leukemia (AML). METHODS: The expression of CD45+ MP, CD44+ MP and CD24+ MP in peripheral blood of 47 AML patients at the time after induction chemotherapy were detected by using flow cytometry, and the relationship between MP, MRD and prognosis were analyzed. RESULTS: The percentages of CD45+ MP, CD44+ MP and CD24+ MP in MRD positive group were significantly higher than those in MRD negative group. In MRD positive group, there were positive correlation between CD45+ MP, CD44+ MP, CD24+ MP and MRD level. The AUC of CD45+ MP, CD44+ MP, CD24+ MP in predicting positive MRD was 0.949, 0.782, and 0.817, respectively. The EFS and OS in HCD45+ MP, HCD44+ MP and HCD24+ MP groups were significantly shorter than low level group. CONCLUSION: High level of CD45+ MP, CD44+ MP, CD24+ MP can be used to predict high level MRD and poor prognosis.


Assuntos
Leucemia Mieloide Aguda , Citometria de Fluxo , Humanos , Leucócitos , Neoplasia Residual , Prognóstico
6.
Sci Rep ; 11(1): 8054, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33850164

RESUMO

Cromolyn is a known mast cell stabilizer and is approved for treatment of asthma and for other allergic indications. Cromolyn, in a new redesigned dry powder formulation, is being tested in a pivotal clinical trial in combination with low dose ibuprofen to treat early Alzheimer's Disease (AD) subjects. To better understand the mechanistic effect cromolyn has in slowing down or halting the neuroinflammatory response associated with AD progression, we tested the effect of cromolyn to dampen the inflammatory response in the human HMC3 microglia cell line. The direct effect of cromolyn on HMC3 microglia is on cytokines and chemokines production following their activation by the inflammatory cytokine TNF-α. Cromolyn and a new fluorinated analog dramatically reduced the secretion of a wide spectrum of inflammatory mediators, which included cytokines such as IL-1ß, IL-6, IL-8 and IFN-γ, and chemokines such as CXCL10, CCL2, CCL3 and CCL4. These results bolster our understanding of how our cromolyn platform modulates toxic microglia behavior as a dynamic future treatment option for neurodegenerative disorders.

7.
Oncogene ; 40(11): 2035-2050, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33603166

RESUMO

Use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of colorectal cancer (CRC). However, the mechanism by which NSAIDs suppress colorectal tumorigenesis remains unclear. We previously showed that NSAIDs selectively kill emerging tumor cells via death receptor (DR) signaling and a synthetic lethal interaction mediated by the proapoptotic Bcl-2 family protein BID. In this study, we found NSAIDs induce endoplasmic reticulum (ER) stress to activate DR signaling and BID in tumor suppression. Importantly, our results unveiled an ER stress- and BID-dependent immunogenic effect of NSAIDs, which may be critical for tumor suppression. NSAID treatment induced hallmarks of immunogenic cell death (ICD) in CRC cells and colonic epithelial cells upon loss of APC tumor suppressor, and elevated tumor-infiltrating lymphocytes (TILs) in the polyps of APCMin/+ mice. ER stress inhibition or BID deletion abrogated the antitumor and immunogenic effects of NSAIDs. Furthermore, increased ER stress and TILs were detected in human advanced adenomas from NSAID-treated patients. Together, our results suggest that NSAIDs induce ER stress- and BID-mediated ICD to restore immunosurveillance and suppress colorectal tumor formation.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Anti-Inflamatórios não Esteroides/farmacologia , Carcinogênese/genética , Neoplasias Colorretais/tratamento farmacológico , Animais , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Morte Celular Imunogênica/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/patologia , Camundongos , Transdução de Sinais/efeitos dos fármacos
8.
Cell ; 183(5): 1219-1233.e18, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33242418

RESUMO

Cancer therapies kill tumors either directly or indirectly by evoking immune responses and have been combined with varying levels of success. Here, we describe a paradigm to control cancer growth that is based on both direct tumor killing and the triggering of protective immunity. Genetic ablation of serine protease inhibitor SerpinB9 (Sb9) results in the death of tumor cells in a granzyme B (GrB)-dependent manner. Sb9-deficient mice exhibited protective T cell-based host immunity to tumors in association with a decline in GrB-expressing immunosuppressive cells within the tumor microenvironment (TME). Maximal protection against tumor development was observed when the tumor and host were deficient in Sb9. The therapeutic utility of Sb9 inhibition was demonstrated by the control of tumor growth, resulting in increased survival times in mice. Our studies describe a molecular target that permits a combination of tumor ablation, interference within the TME, and immunotherapy in one potential modality.


Assuntos
Citotoxicidade Imunológica , Imunoterapia , Proteínas de Membrana/metabolismo , Neoplasias/imunologia , Neoplasias/terapia , Serpinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citotoxicidade Imunológica/efeitos dos fármacos , Progressão da Doença , Feminino , Deleção de Genes , Granzimas/metabolismo , Imunidade/efeitos dos fármacos , Melanoma/patologia , Camundongos Endogâmicos C57BL , Neoplasias/prevenção & controle , Bibliotecas de Moléculas Pequenas/farmacologia , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Microambiente Tumoral/efeitos dos fármacos
9.
Biochem Pharmacol ; 175: 113848, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32044354

RESUMO

The enhancement of drug efflux caused by ATP-binding cassette (ABC) transporters (including ABCG2 and ABCB1) overexpression is an important factor for multidrug resistance (MDR) in cancers. After testing the reversal activities of 19 chalcone and bis-chalcone derivatives on MDR cancer cell lines, we found that non-basic chalcone CYB-2 exhibited the most potent reversal activities against both ABCG2- and ABCB1-mediated MDR. The mechanistic studies show that this compound can increase the accumulation of anticancer drugs in both ABCG2- and ABCB1-overexpressing cancer cell lines, resulting from the blocked efflux function of the MDR cancer cell lines. This inhibition is due to the barred ABCG2 and ABCB1 ATPase activities rather than altering the expression or localization of ABCG2 or ABCB1 transporters. The previous studies showed that non-basic chalcones were ABCG2-specific inhibitors; however, we found that non-basic chalcone CYB-2 can be developed as an ABCG2/ABCB1 dual inhibitor to overcome MDR in cancers that co-express both ABCG2 and ABCB1. Moreover, non-basic chalcone CYB-2 has synthetic tractability compared to other chalcone-based derivatives.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Chalconas/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/química , Linhagem Celular Tumoral , Chalconas/química , Humanos , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/genética
10.
Eur J Med Chem ; 179: 849-862, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302589

RESUMO

Ko143, a potent ABCG2 inhibitor that reverses multidrug resistance in cancer, cannot be used clinically due to its unsuitable metabolic stability. We identified benzoyl indoles as reversal agents that reversed ABCG2-mediated multidrug resistance (MDR), with synthetic tractability and enhanced metabolic stability compared to Ko143. Bisbenzoyl indole 2 and monobenzoyl indole 8 significantly increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing NCI-H460/MX20 cells, and sensitized NCI-H460/MX20 cells to mitoxantrone. Mechanistic studies were conducted by [3H]-MX accumulation assay, Western blot analysis, immunofluorescence analysis and ABCG2 ATPase assay. The results revealed that the reversal efficacies of compounds 2 and 8 were not due to an alteration in the expression level or localization of ABCG2 in ABCG2-overexpressing cell lines. Instead, compounds 2 and 8 significantly stimulated the ATP hydrolysis of ABCG2 transporter, suggesting that these compounds could be competitive substrates of ABCG2 transporter. Overall, the results of our study indicated that compounds 2 and 8 significantly reversed ABCG2-mediated MDR by blocking the efflux of anticancer drugs.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Dicetopiperazinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Dicetopiperazinas/química , Dicetopiperazinas/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Humanos , Estrutura Molecular , Proteínas de Neoplasias/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
11.
Biomed Res Int ; 2019: 9379602, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31073532

RESUMO

Background: Prostate cancer (PCa) is the ninth most common cause of cancer death globally. Many studies have investigated aspirin exposure and mortality risk among PCa patients, returning inconsistent results. We conducted a comprehensive meta-analysis to explore the association between aspirin exposure and mortality risk among PCa patients and to investigate potential dose/duration/frequency-response relationships. Methods and Results: Studies published from 1980 to 2018 of PubMed and EMBASE databases were searched. We included 14 studies with 110,000 participants. Multivariate-adjusted odds ratios (ORs) were pooled using random-effect models. Potential dose/duration/frequency-response relationships were evaluated for aspirin exposure and prostate cancer-specific mortality (PCSM) risk. We did not detect an association between the highest aspirin exposure and mortality risk (PCSM of prediagnostic aspirin exposure, OR: 0.96, 95% confidence interval [CI]: 0.87-1. 07, I2= 0%; PCSM of postdiagnostic aspirin exposure, OR:0.92, 95% CI: 0.77-1.10, I2 = 56.9%; all-cause mortality [ACM] of prediagnostic aspirin exposure, OR: 0.96, 95% CI: 0.88-1.04, I2 = 9.4%; ACM of postdiagnostic aspirin exposure, OR: 0.95, 95% CI: 0.73-1.23, I2 = 88.9%). There was no significant dose/frequency-response association observed for aspirin exposure and PCSM risk. On duration-response analysis, we found that short-term postdiagnostic aspirin exposure (shorter than 2.5 years) increased the risk of PCSM. Conclusions: Our meta-analysis suggests that there is no association between aspirin exposure and PCSM risk. Nor is there an association between the highest aspirin exposure and ACM risk among PCa patients. More studies are needed for a further dose/duration/frequency-response meta-analysis.


Assuntos
Aspirina/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/mortalidade , Aspirina/efeitos adversos , Estudos de Coortes , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Próstata/efeitos dos fármacos , Próstata/patologia , Neoplasias da Próstata/patologia , Fatores de Risco
12.
Cancer Res ; 79(6): 1191-1203, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30674532

RESUMO

Bromodomain and extraterminal domain (BET) family proteins such as BRD4 are epigenetic readers that control expression of a number of oncogenic proteins. Targeting this family of proteins has recently emerged as a promising anticancer approach. BET inhibitors (BETi), either alone or in combination with other anticancer agents, have exhibited efficacy in a variety of tumors. However, the molecular mechanisms underlying differential response to BETi are not well understood. In this study, we report that death receptor 5 (DR5), a key component of the extrinsic apoptotic pathway, is markedly induced in response to BRD4 depletion and BETi treatment in colorectal cancer cells. Induction of DR5, following BET inhibition, was mediated by endoplasmic reticulum stress and CHOP-dependent transcriptional activation. Enhanced DR5 induction was necessary for the chemosensitization and apoptotic effects of BETi and was responsible for increased BETi sensitivity in colorectal cancer cells containing a mutation in speckle-type POZ protein (SPOP), a subunit of BRD4 E3 ubiquitin ligase. In a colorectal cancer xenograft model, BETi combined with chemotherapy suppressed the tumor growth in a DR5-dependent manner and potently inhibited patient-derived xenograft tumor growth with enhanced DR5 induction and apoptosis. These findings suggest that BETi alone or in combination with chemotherapy is effective against colorectal cancer due to enhanced DR5 induction and apoptosis. DR5 induction may also serve as a useful marker for designing personalized treatment and improved colorectal cancer combination therapies.Significance: These findings reveal how BET inhibition sensitizes chemotherapy and kills a subset of colon cancer cells with specific genetic alterations and may provide a new molecular marker for improving colon cancer therapies.


Assuntos
Azepinas/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias do Colo/tratamento farmacológico , Sinergismo Farmacológico , Fluoruracila/farmacologia , Mutação , Proteínas Nucleares/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteínas Repressoras/genética , Fatores de Transcrição/antagonistas & inibidores , Triazóis/farmacologia , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Cancer Lett ; 442: 104-112, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30392788

RESUMO

Overexpression of breast cancer resistance protein (BCRP) has been shown to produce multidrug resistance (MDR) in colon cancer, leading to major obstacles for chemotherapy. In this study, we evaluated the effect of regorafenib, an oral multi-kinase inhibitor, in inhibiting BCRP-mediated MDR in silico, in vitro and in vivo. We found that regorafenib significantly sensitized MDR colon cancer cells to BCRP substrates by increasing their intracellular accumulation. There are no significant changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Investigation of the mechanism revealed that regorafenib stimulated BCRP ATPase activity. Our induced-fit docking and molecular dynamics simulations suggested the existence of a strong and stable interaction between regorafenib and the transmembrane domain of human crystalized BCRP. In vivo tumor xenograft study revealed that the combination of regorafenib and topotecan exhibited synergistic effects on mitoxantrone-resistant S1-M1-80 xenograft tumors. In conclusion, our studies indicate that regorafenib would be beneficial in combating MDR in colon cancer.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/agonistas , Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Neoplasias/agonistas , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Humanos , Masculino , Camundongos Nus , Mitoxantrona/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Compostos de Fenilureia/química , Ligação Proteica , Conformação Proteica , Piridinas/química , Topotecan/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Clin Chim Acta ; 490: 207-213, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30201368

RESUMO

BACKGROUND: Inflammation plays a critical role in the development of acute kidney injury (AKI). Neutrophil-lymphocyte ratio (NLR) is a biomarker of systemic inflammation used to predict the prognostic outcome of several diseases. We conducted a retrospective cohort study to investigate if NLR can be used as a biomarker to predict the mortality of AKI. METHODS AND RESULTS: Records of critically ill patients with AKI were extracted from the Medical Information Mart for Intensive Care Database III version 1.3 (MIMIC-III v1.3). The primary outcome was 30-day mortality and the two secondary outcomes were in hospital and 90-day mortality. We used the Cox proportional hazards models to assess the association between different categories of NLR and outcomes. This analysis included data for 13,678 eligible subjects, with a total of 2,588 30-day, 2,224 in-hospital and 3,545 90-day deaths during the follow-up period. For 30-day mortality, an increased risk of mortality was associated with a higher level of NLR. The HR (95% confidence interval [CI]) of upper tertile (NLR > 12.14) was 1.37 (1.17-1.60) in a multivariate model when compared with that of the lower tertile (NLR < 5.55). In the quintile analysis, we confirmed the upward trend with HR (95% CI) of the fifth quintile (NLR > 17.4) of 1.35 (1.08, 1.69) in a multivariate model compared to the first quintile (NLR < 3.82). A similar tendency was observed for 90-day mortality. In the analysis of in-hospital mortality, the HR of fifth quintile (NLR > 17.4) showed a slight decrease. CONCLUSIONS: Our analysis indicates that a higher level of NLR is associated with increased risk of 30-day and 90-day mortality in AKI patients. The similar upward trend is not detected in analysis of in-hospital mortality.


Assuntos
Injúria Renal Aguda/imunologia , Injúria Renal Aguda/mortalidade , Linfócitos/citologia , Neutrófilos/citologia , Injúria Renal Aguda/diagnóstico , Idoso , Estado Terminal , Feminino , Humanos , Contagem de Linfócitos , Masculino , Prognóstico , Estudos Retrospectivos
15.
Ying Yong Sheng Tai Xue Bao ; 29(12): 4199-4207, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30584749

RESUMO

Nitric oxide (NO) is a well-known signaling molecular that plays a significant role in stress tolerance of plants to heavy metals. However, the detoxification mechanism of NO has not been well studied. Here, we examined the absorbing and transporting characteristics of copper (Cu) and cadmium (Cd) in tomato seedlings through nutrient solution culture and its response to exogenous NO under Cu and/or Cd stress. Results showed that Cu and Cd with the concentration of 50 &Mgr;mol·L-1 greatly inhibited plant growth, with Cd having a higher inhibiting effect than Cu. Under single or dual stresses of Cu and Cd, their contents in both tomato roots and leaves were significantly increased. However, tomato roots showed preference to essential element Cu with a luxury uptake and strictly against Cd through cell plasma membrane in which the content of Cd was only one tenth of Cu in plants. These metal stresses, especially Cd stress, could be alleviated by application of exogenous NO. Tomato plants detoxify these passively-absorbed elements through similar mechanisms, including chelation with glutathione, phytochelatin or metallothionein, as well as vascular compartmentalization. Exogenous NO could alleviate these stresses through regulating the oxidation-reduction condition of GSH-GSSH, controlling the metabolism of GSH-PCs, as well as promoting the vascular compartmentalization of excessive Cu and Cd. In addition, NO could induce higher expression of chelators, such as MTs, GSH and PCs, in both roots and shoots, which showed additive effects to other responses and might be another important detoxification pathway mediated through NO for the responses of tomato plants to Cu and Cd stresses.


Assuntos
Cádmio/toxicidade , Cobre/toxicidade , Lycopersicon esculentum/fisiologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poluentes do Solo/toxicidade , Glutationa , Raízes de Plantas , Plântula
16.
Genes Dis ; 5(3): 194-203, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30320184

RESUMO

Emerging evidence suggests that the clinical success of conventional chemotherapy is not solely attributed to tumor cell toxicity, but also results from the restoration of immunosurveillance, which has been largely neglected in the past preclinical and clinical research. Antitumor immune response can be primed by immunogenic cell death (ICD), a type of cell death characterized by cell-surface translocation of calreticulin (CRT), extracellular release of ATP and high mobility group box 1 (HMGB1), and stimulation of type I interferon (IFN) responses. Here we summarize recent studies showing conventional chemotherapeutics as ICD inducers, which are capable of modulating tumor infiltrating lymphocytes (TILs) and reactivating antitumor immunity within an immuno-suppressive microenvironment. Such immunological effects of conventional chemotherapy are likely critical for better prognosis of cancer patients. Furthermore, combination of ICD-inducing chemotherapeutics with immunotherapy is a promising approach for improving the clinical outcomes of cancer patients.

17.
Gut ; 67(11): 2006-2016, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29802174

RESUMO

OBJECTIVE: There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need. DESIGN AND RESULTS: A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI -12.59 to -2.50; p=0.0018), respectively. CONCLUSIONS: This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group. TRIAL REGISTRATION: NCT01770431; Post-results.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Misturas Complexas/uso terapêutico , Hepatectomia/efeitos adversos , Neoplasias Hepáticas/tratamento farmacológico , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Quimioterapia Adjuvante , Misturas Complexas/efeitos adversos , Feminino , Humanos , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Análise de Sobrevida , Trametes , Resultado do Tratamento
18.
Oncogene ; 37(33): 4599-4610, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29755130

RESUMO

Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by a mutant or amplified KRAS oncogene, is a significant challenge in the treatment of colorectal cancer (CRC). However, the mechanism of KRAS-mediated therapeutic resistance is not well understood. In this study, we demonstrate that clinically used anti-EGFR antibodies, including cetuximab and panitumumab, induce killing of sensitive CRC cells through p73-dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein PUMA. PUMA induction and p73 activation are abrogated in CRC cells with acquired resistance to anti-EGFR antibodies due to KRAS alterations. Inhibition of aurora kinases preferentially kills mutant KRAS CRC cells and overcomes KRAS-mediated resistance to anti-EGFR antibodies in vitro and in vivo by restoring PUMA induction. Our results suggest that PUMA plays a critical role in meditating the sensitivity of CRC cells to anti-EGFR antibodies, and that restoration of PUMA-mediated apoptosis is a promising approach to improve the efficacy of EGFR-targeted therapy.


Assuntos
Anticorpos Monoclonais/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cetuximab/farmacologia , Receptores ErbB/metabolismo , Feminino , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Panitumumabe/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
19.
J Laparoendosc Adv Surg Tech A ; 28(9): 1053-1060, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29641365

RESUMO

BACKGROUND: Hilar cholangiocarcinoma (HCCA) is a rare tumor, usually associated with obstructive jaundice and unfavorable prognosis. Obstructive jaundice can affect the liver, kidney, heart, and the immune system of the patients. Currently, controversy exists in whether preoperative biliary drainage (PBD) is of any benefit to the patients, and the best way for PBD in patients with resectable HCCA of malignant biliary obstruction remains to be determined. OBJECTIVES: To compare the clinical outcomes and effectiveness of endoscopic biliary drainage (EBD) treatment with those of percutaneous transhepatic biliary drainage (PTBD) treatment in patients with malignant biliary obstruction caused by resectable HCCA. MATERIALS AND METHODS: The databases including MEDLINE, EMBASE, PubMed, CBM (China Biological Medicine Database), and CNKI were employed to identify the clinic trials on EBD versus PTBD for malignant biliary obstruction associated with resectable HCCA from January 2008 to October 2017. A systematic review and meta-analysis were carried out. RESULTS: Six trials were identified and included in this study. Overall, the differences in technical success rate, R0 resection, incidence of total complication after resection, postoperative hospitalization time, resection time, and recurrence were not statistically significant between the EBD group and PTBD group (all P > .05). However, the incidence of total complications after EBD treatment is higher than that after PTBD treatment (P < .05). CONCLUSION: For patients with obstructive jaundice associated with HCCA, current evidence indicate no superiority of PTBD over EBD regarding clinical feasibility and success rate, but data suggest a better clinical safety of PTBD compared with EBD in short-term postoperation. In long-term evaluation, the differences in clinical outcomes are not statistically significant between PTBD and EBD.


Assuntos
Neoplasias dos Ductos Biliares/cirurgia , Drenagem/métodos , Endoscopia do Sistema Digestório , Icterícia Obstrutiva/cirurgia , Tumor de Klatskin/cirurgia , Recidiva Local de Neoplasia , Neoplasias dos Ductos Biliares/complicações , Ductos Biliares Intra-Hepáticos/patologia , Drenagem/efeitos adversos , Endoscopia do Sistema Digestório/efeitos adversos , Humanos , Icterícia Obstrutiva/etiologia , Tumor de Klatskin/complicações , Tempo de Internação , Recidiva Local de Neoplasia/diagnóstico , Neoplasia Residual , Duração da Cirurgia , Complicações Pós-Operatórias/etiologia , Cuidados Pré-Operatórios , Prognóstico , Resultado do Tratamento
20.
J Transl Med ; 16(1): 46, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29490660

RESUMO

BACKGROUND: The role of transforming growth factorß (TGF-ß)-induced tumor progression in advanced malignancy is well established, but the involvement of long non-coding RNAs (lncRNAs) in TGF-ß signaling remains unclear. This study aimed to identify TGF-ß-associated lncRNAs in head and neck squamous cell carcinoma (HNSCC). METHODS: Expression profiling of lncRNAs was obtained using Gene Expression Omnibus and The Cancer Genome Atlas. Real-time quantitative PCR was used to analyze the expression of EPB41L4A-AS2 in HNSCC cell line. We used bioinformatics resources (DAvID) to conduct Gene Ontology biological processes and KEGG pathways at the significant level. Wound healing assay, cell migration and invasion assays, were used to examine the effects of EPB41L4A-AS2 on tumor cell metastasis in vivo. Protein levels of EPB41L4A-AS2 targets were determined by western blot. RESULTS: A novel TGF-ß-associated lncRNA, EPB41L4A-AS2, was found downregulated by TGF-ß and associated with invasion and metastasis. The relationship of EPB41L4A-AS2 with the clinicopathological features and prognosis of HNSCC patients was evaluated. Bioinformatic analyses revealed that EPB41L4A-AS2 may be involved in processes associated with the tumor-associated signaling pathway, especially the TGF-ß signaling pathway. Furthermore, a TGF-ß-induced epithelial-to-mesenchymal transition (EMT) model was established. Low EPB41L4A-AS2 expression was determined, and overexpression of this gene inhibited cell migration and invasion in the EMT model. Moreover, EPB41L4A-AS2 suppressed TGFBR1 expression. CONCLUSIONS: EPB41L4A-AS2 might serve as a negative regulator of TGF-ß signaling and as an effective prognostic biomarker and important target in anti-metastasis therapies of HNSCC patients.


Assuntos
Biologia Computacional/métodos , RNA Longo não Codificante/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Genéticos , Invasividade Neoplásica , Metástase Neoplásica , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Análise de Sobrevida , Regulação para Cima/genética
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