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1.
BMC Bioinformatics ; 21(Suppl 14): 364, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32998700

RESUMO

BACKGROUND: Machine learning has been utilized to predict cancer drug response from multi-omics data generated from sensitivities of cancer cell lines to different therapeutic compounds. Here, we build machine learning models using gene expression data from patients' primary tumor tissues to predict whether a patient will respond positively or negatively to two chemotherapeutics: 5-Fluorouracil and Gemcitabine. RESULTS: We focused on 5-Fluorouracil and Gemcitabine because based on our exclusion criteria, they provide the largest numbers of patients within TCGA. Normalized gene expression data were clustered and used as the input features for the study. We used matching clinical trial data to ascertain the response of these patients via multiple classification methods. Multiple clustering and classification methods were compared for prediction accuracy of drug response. Clara and random forest were found to be the best clustering and classification methods, respectively. The results show our models predict with up to 86% accuracy; despite the study's limitation of sample size. We also found the genes most informative for predicting drug response were enriched in well-known cancer signaling pathways and highlighted their potential significance in chemotherapy prognosis. CONCLUSIONS: Primary tumor gene expression is a good predictor of cancer drug response. Investment in larger datasets containing both patient gene expression and drug response is needed to support future work of machine learning models. Ultimately, such predictive models may aid oncologists with making critical treatment decisions.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Aprendizado de Máquina , Antineoplásicos/uso terapêutico , Área Sob a Curva , Análise por Conglomerados , Bases de Dados Genéticas , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Fluoruracila/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Curva ROC
2.
Nat Commun ; 11(1): 4951, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009382

RESUMO

Immunogenic cell death (ICD) and tumour-infiltrating T lymphocytes are severely weakened by elevated reactive oxygen species (ROS) in the tumour microenvironment. It is therefore of critical importance to modulate the level of extracellular ROS for the reversal of immunosuppressive environment. Here, we present a tumour extracellular matrix (ECM) targeting ROS nanoscavenger masked by pH sensitive covalently crosslinked polyethylene glycol. The nanoscavenger anchors on the ECM to sweep away the ROS from tumour microenvironment to relieve the immunosuppressive ICD elicited by specific chemotherapy and prolong the survival of T cells for personalized cancer immunotherapy. In a breast cancer model, elimination of the ROS in tumour microenvironment elicited antitumour immunity and increased infiltration of T lymphocytes, resulting in highly potent antitumour effect. The study highlights a strategy to enhance the efficacy of cancer immunotherapy by scavenging extracellular ROS using advanced nanomaterials.


Assuntos
Antineoplásicos/farmacologia , Espaço Extracelular/metabolismo , Depuradores de Radicais Livres/metabolismo , Morte Celular Imunogênica , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Proteína HMGB1/metabolismo , Morte Celular Imunogênica/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Polietilenoglicóis/química , Microambiente Tumoral/efeitos dos fármacos
3.
Medicine (Baltimore) ; 99(40): e22642, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019490

RESUMO

RATIONALE: Reactivation of hepatitis B virus (HBV) after treatment with bortezomib-based regimens in HBV-positive patients with multiple myeloma (MM) has been reported in the past few years. Nevertheless, there is evidence of inhibition of HBV replication by bortezomib in transgenic mice. However, there is still no clinical evidence that bortezomib inhibits HBV. PATIENT CONCERNS: A 55-year-old MM patient with a family history of MM, who was also a chronic HBV carrier, achieved HBV clearance after treatment with a bortezomib-based regimen in combination with anti-HBV drugs. DIAGNOSES: The diagnosis was MM with chronic carrier of HBV. INTERVENTIONS: He received bortezomib-based regimen for MM as well as entecavir as a prophylaxis to prevent HBV reactivation. OUTCOMES: This patient achieved HBsAg and HBV-DNA clearance after 2 months and the remission was maintained during the next 2 years. He also achieved complete remission of MM and underwent consolidation therapy with autologous hematopoietic stem cell transplantation. LESSONS: This is the first case of MM with HBV clearance after receiving a bortezomib-based regimen combined with anti-HBV drug. Research on related mechanisms might provide new suggestions and hope for better management of HBV positive patients with MM and for the treatment of HBV patients.


Assuntos
Antineoplásicos/uso terapêutico , Antivirais/uso terapêutico , Bortezomib/uso terapêutico , Guanina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Protocolos Clínicos , Quimioterapia Combinada , Guanina/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Antígenos de Superfície da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Hepatite B Crônica/prevenção & controle , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Autólogo/métodos , Resultado do Tratamento
4.
Tumour Biol ; 42(10): 1010428320965284, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33028168

RESUMO

Glucose, as the main consuming nutrient of the body, faces different destinies in cancer cells. Glycolysis, oxidative phosphorylation, and pentose phosphate pathways produce different glucose-derived metabolites and thus affect cells' bioenergetics differently. Tumor cells' dependency to aerobic glycolysis and other cancer-specific metabolism changes are known as the cancer hallmarks, distinct cancer cells from normal cells. Therefore, these tumor-specific characteristics receive the limelight as targets for cancer therapy. Glutamine, serine, and fatty acid oxidation together with 5-lipoxygenase are main pathways that have attracted lots of attention for cancer therapy. In this review, we not only discuss different tumor metabolism aspects but also discuss the metabolism roles in the promotion of cancer cells at different stages and their difference with normal cells. Besides, we dissect the inhibitors potential in blocking the main metabolic pathways to introduce the effective and non-effective inhibitors in the field.


Assuntos
Antineoplásicos/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Medicina de Precisão , Antineoplásicos/farmacologia , Ciclo do Ácido Cítrico/efeitos dos fármacos , Metabolismo Energético/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias/etiologia , Neoplasias/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Via de Pentose Fosfato/efeitos dos fármacos , Medicina de Precisão/métodos
5.
Medicine (Baltimore) ; 99(41): e22402, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031275

RESUMO

BACKGROUND: Sulindac has been used for treating colorectal polyps widely. However, the efficacy and safety of sulindac for colorectal polyps are unclear. This study aims to evaluate the efficacy and safety of sulindac for colorectal polyps. METHODS: Randomized controlled trials of sulindac in the treatment of colorectal polyps will be searched in PubMed, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang, the Chongqing VIP Chinese Science, and Technology Periodical Database, and China biomedical literature database (CBM) from inception to August, 2020. And Baidu Scholar, Google Scholar, International Clinical Trials Registry Platform, and Chinese Clinical Trials Registry will be searched to obtain more relevant studies comprehensively. Two researchers will perform data extraction and risk of bias assessment independently. Statistical analysis will be conducted in RevMan 5.3. RESULTS: This study will summarize the present evidence by exploring the efficacy and safety of sulindac in the treatment of colorectal polyps. CONCLUSION: The findings of the study will provide helpful evidence for the efficacy and safety of sulindac in the treatment of colorectal polyps, facilitating clinical practice and further scientific studies. ETHICS AND DISSEMINATION: The private information from individuals will not publish. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/N5GDH.


Assuntos
Antineoplásicos/uso terapêutico , Pólipos do Colo/tratamento farmacológico , Sulindaco/uso terapêutico , Antineoplásicos/efeitos adversos , Humanos , Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Reto , Projetos de Pesquisa , Sulindaco/efeitos adversos , Revisões Sistemáticas como Assunto
6.
Medicine (Baltimore) ; 99(41): e22516, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031291

RESUMO

BACKGROUND: Xihuang pill, a famous traditional Chinese medicine formulation, is a broad-spectrum anti-tumor drug and has been widely used for the treatment of lung cancer in China. The aim of this study is to systematically investigate the efficacy and safety of Xihuang pill for the treatment of lung cancer. METHODS: We will perform the comprehensive literature search in the following databases from their inceptions to August 2020 for data extraction: PubMed, the Cochrane Library, Embase, the China National Knowledge Infrastructure, Wanfang Database, Chinese Science and Technology Periodical Database, and Chinese Biomedical Literature Database. Cochrane Risk of Bias tool will be used to assess the risk of bias of included studies. The RevMan 5.4 and Stata 16.0 software will be applied for statistical analyses. Statistical heterogeneity will be computed by I tests. Sensitivity analysis will be conducted to evaluate the stability of the results. The publication bias will be evaluated by funnel plots and Egger test. The quality of evidence will be assessed by the Grading of Recommendations Assessment, Development and Evaluate system (GRADE) system. RESULTS: The results of our research will be published in a peer-reviewed journal. CONCLUSION: The conclusion of this study will provide evidence to show whether Xihuang pill is an effective intervention for patient with lung cancer. OSF REGISTRATION NUMBER: 10.17605/OSF.IO/W2GHN.


Assuntos
Antineoplásicos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Metanálise como Assunto , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Comprimidos
7.
Praxis (Bern 1994) ; 109(13): 1070-1073, 2020.
Artigo em Alemão | MEDLINE | ID: mdl-33050809

RESUMO

Unusual Cause of Acute Kidney Failure in a Patient with Metastatic Bladder Carcinoma Undergoing Palliative Chemotherapy Abstract. Tumour lysis syndrome is a potentially life-threatening complication of cancer and its treatment. It mostly occurs in highly proliferative haematological neoplasms under cytotoxic therapy but can also be seen spontaneously and in solid neoplasms, particularly with high tumour burden and/or high chemosensitivity. The present case report describes a tumour lysis syndrome in a patient with metastatic bladder cancer with an elevated lactate dehydrogenase as only potential correlate of a high tumour burden.


Assuntos
Lesão Renal Aguda , Síndrome de Lise Tumoral , Neoplasias da Bexiga Urinária , Lesão Renal Aguda/etnologia , Antineoplásicos/uso terapêutico , Humanos , Cuidados Paliativos , Neoplasias da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/tratamento farmacológico
8.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(8): 886-891, 2020 Aug 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33053528

RESUMO

OBJECTIVES: To explore the relationship between long non-coding RNA (lncRNA) long stress-induced noncoding transcript 5 (LSINCT5) and erotinib resistance to lung cancer cells and the potential mechanisms. METHODS: Human lung cancer cell line A549, H520, H358, H1299, SPCA1, and PC9 were collected and cultured. Epidermal growth factor receptor (EGFR) mutant lung cancer cell line PC9 was divided into a control group, a resistance group, a interference group I and II. The control group was treated with dimethylsulfoxide (DMSO) for 10 weeks and then was transfected with control target sequence expression vector. The resistant group was treated with erlotinib at gradient concentration (0.1, 0.2, 0.4, 0.8, and 1.6 µmol/L, respectively) for 2 weeks and then transfected with control target sequence expression vector. Interference group I and II were treated with erlotinib at gradient concentration (0.1, 0.2, 0.4, 0.8, and 1.6 µmol/L, respectively) for 2 weeks and then transfected with the shRNA targeting expression vectors 1 and 2. 50% inhibitory concentration (IC50) of erlotinib was detected by cell counting kit-8 (CCK-8) assay. The mRNA expressions of LSINCT5, phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) were measured by real-time PCR. The protein levels of PI3K, Akt, and phospho-Akt (p-Akt) were detected by Western blotting. The divergences of Akt and IgG binding to LSINCT5 were detected by RNA immunoprecipitation (RNA-IP) experiment. RESULTS: The expression of LSINCT5 in PC9 cells was significantly higher than that in other lung cancer cell lines (all P<0.05). Compared with the control group, the IC50 of erotinib and the expression of LSINCT5, PI3K, and Akt mRNA and protein in the resistance group were significantly higher (all P<0.05), and the IC50 of erotinib and the expression of LSINCT5, Akt, and p-Akt in the interference group I and II were significantly lower (all P<0.05). Compared with IgG, LSINCT5 binding to Akt was increased significantly (P<0.05). CONCLUSIONS: The expression of LSINCT5 is high in the erlotinib-resistant cells. Interference with LSINCT5 may inhibit the expression and activity of Akt and promote the cell sensitivity to erlotinib.


Assuntos
Antineoplásicos , Resistencia a Medicamentos Antineoplásicos , Cloridrato de Erlotinib , Neoplasias Pulmonares , RNA Longo não Codificante , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Cloridrato de Erlotinib/farmacologia , Humanos , Neoplasias Pulmonares/genética , Fosfatidilinositol 3-Quinases/genética , RNA Longo não Codificante/genética
9.
Medicine (Baltimore) ; 99(41): e22647, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031325

RESUMO

RATIONALE: Signet ring cell carcinoma of the stomach is prone to relapse and metastasis after traditional surgical treatment, and the prognosis is also poor. We improved the concept of treatment and conducted cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) combined with intraperitoneal (IP) and intravenous (IV) chemotherapy for a gastric signet-cell carcinoma patient. PATIENT CONCERNS: A 65-year-old male patient with complaint of intermittent hematemesis for over 10 days was referred to our hospital for treatment. The patient developed hematemesis of 800 mL without obvious causes on May 27, 2015, accompanied by dizziness and amaurosis fugax. After the bleeding was stopped with medicinal treatment, diagnostic gastroscopy revealed an ulcer at the less curvature of the stomach, with biopsy pathology diagnosis as severe atypical hyperplasia, which was confirmed to be poorly differentiated adenocarcinoma by a second biopsy. In past medical history, the patient had 5 coronary stents implanted because of coronary atherosclerotic heart disease 3 years ago. DIAGNOSIS: Gastric cancer (cT4NxMx) according to the patient's history and biopsy pathology. INTERVENTIONS: the patient was treated surgery-based multidisciplinary treatments integrating CRS + HIPEC and IP + IV adjuvant chemotherapy. The CRS was curative distal gastrectomy with D2 lymphadenectomy, and HIPEC was cisplatin 120 mg plus mitomycin C 30 mg at 43 °C, for 60 minutes. Final pathological diagnosis of after surgery was: poorly differentiate adenocarcinoma with signet-ring cells, with invasion beyond the serosal layer and into the duodenum, 10/23 lymph nodes positive, nerve invasion, vascular tumor thrombi, Borrmann type IV, Lauren type diffuse. TNM stage was pT4aN3M0, IIIC. After operation, the patient received 6 courses of IV chemotherapy with oxaliplatin and 5-fluorouracil/Tegafur Gimeracil Oteracil Potassium capsules, and IP chemotherapy with docetaxel and carboplatin. OUTCOMES: Regular follow-up till July 20, 2020, revealed that the patient has a disease-free survival of over 61+ months. LESSONS: CRS + HIPEC combined with IP + IV chemotherapy achieved long-term disease-free survival for this patient with gastric signet-ring cell carcinoma and deserve further study. This new treatment modality deserves appropriate consideration in routine clinical practice for patients with advanced gastric cancer.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma de Células em Anel de Sinete/cirurgia , Procedimentos Cirúrgicos de Citorredução , Hipertermia Induzida , Neoplasias Gástricas/cirurgia , Idoso , Carcinoma de Células em Anel de Sinete/tratamento farmacológico , Terapia Combinada , Humanos , Masculino , Neoplasias Gástricas/tratamento farmacológico
10.
Ann Palliat Med ; 9(5): 3373-3378, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33065788

RESUMO

BACKGROUND: The coronavirus disease (COVID-19) poses an unprecedented challenge to health and epidemic prevention system, especially the healthcare of patients with cancer. We sought to study the impact of COVID-19 on lung cancer patients in our center. METHODS: We initiated a retrospectively study to analyze the impact of COVID-19 on lung cancer patients in our center, who were accepted for routine anticancer treatment before the epidemic and planned to return to hospital in January and February of 2020. RESULTS: A total of 161 cases of lung cancer were included in the final analysis. As of April 15, 95 patients had delayed their return visit, and 47 cases were finally designated as having delayed admission during the epidemic and having to discontinue or delay their regular anticancer treatments. Of these 47 delayed patients, 33 were evaluated for tumor status using a computed tomography scan, 6 of these 33 cases (18.18%) were diagnosed as progressive disease (PD), and 5 cases did not return for visit. CONCLUSIONS: This is the first study investigating impact of COVID-19 on non-COVID-19 lung cancer patients during the pandemic. The study demonstrates the significant impact of the COVID-19 crisis on oncological care, indicating the need for appropriate change of treatment decisions and continued follow-up and psycho-oncological support during this pandemic.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Infecções por Coronavirus , Imunoterapia , Neoplasias Pulmonares/terapia , Pandemias , Pneumonia Viral , Radioterapia , Carcinoma de Pequenas Células do Pulmão/terapia , Tempo para o Tratamento/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Quimiorradioterapia , China , Assistência à Saúde , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem
11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1451-1458, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067936

RESUMO

OBJECTIVE: To investigate the proliferation inhibition and pro-apoptotic effect of Huaier aqueous extract combined with routine chemotherapeutic drugs including Vincristine (VCR), Daunorubicin (DNR), L-aspartase (L-Asp) on human acute lymphoblastic leukemia cell lines Nalm-6 and Sup-B15. METHODS: Nalm-6 and Sup-B15 cell lines were treated with different concentrations of Huaier aqueous extract and chemotherapeutics including VCR, DNR, L-Asp alone or in combination for 48 h, and the growth inhibitory effect and IC50 values (the half maximal inhibitory concentration) were detected by CCK-8. Jin's formula was used to estimated the synergistic effect of these combinations. Apoptosis rates of Nalm-6 and Sup-B15 cells and expression of apoptosis-related proteins BAX, BCL-2, cleaved Caspase-3 were determined by flow cytometry and Western blot respectivcly. RESULTS: Huaier aqueous extract, VCR, DNR and L-Asp had inhibition effect on Nalm-6 and Sup-B15 cell lines. The inhibition rate of Huaier aqueous extract combined with VCR, DNR and L-Asp were all higher than those of each dug alone (P<0.05) and the combination index (q) was between 0.85 and 1.15 or greater than 1.15. The two kinds of drugs showed had additive or synergistic effects. The results of flow cytometry showed that the cell apoptosis rates in combined treatment group were higher than those of each drug alone (P<0.05). The results of Western blot revealed that Huaier aqueous extract and VCR all decreased protein expression of BCL-2 (P<0.05) and increase protein expression of BAX (P<0.05) and cleaved Caspase-3 (P<0.05) in Nalm-6 and Sup-B15 cells. Compared with Huaier aqueous extract or VCR alone, the effect of two drug combination were more significant. DNR down-regulated protein expression of BCL-2 (P<0.05) and up-regulated cleaved Caspase-3 (P<0.05). However, it had no effect on the expression of BAX in Nalm-6 and Sup-B15 cells. When it was combined with Huaier aqueous extract, the expression of cleaved Caspase-3 and BCL-2 showed more significant changes. The expression of BAX in combined treated group did not show significant difference, compared with group treated with Huaier aqueous extract in Nalm-6 and Sup-B15 cells. L-Asp did not show significant effect on the three apoptosis-related proteins and there was no significant difference between the combination group and the Huaier aqueous extract group. CONCLUSION: the combination of Huaier aqueous extract and VCR, DNR, L-Asp shows additive or synergistic effects on human acute lymphoblastic leukemia cell lines Nalm-6 and Sup-B15.


Assuntos
Antineoplásicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Misturas Complexas/uso terapêutico , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Trametes
12.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1762-1768, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067987

RESUMO

OBJECTIVE: To investigate the effect of dasatinib on the expansion of NK cells in vitro, as well as the subsets, receptor expression and cytotoxic function of NK cells. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy adult volunteers and cultured with SCGM added IL-2 and IL-15 for expansion of NK cells. In this culture system, dasatinib of different concentrations were added. Cell counting and phenotyping by flow cytometry were used to evaluate the amplification efficiency of NK cells. FCM was used to detect the expression of receptors on the surface of NK cells and the distribution of subsets. Subsequently, degranulation assay and CFSE/7AAD based cytotoxicity assay were used to detect the effects of dasatinib on NK cytotoxicity against leukemia cell line K562 cells. RESULTS: The expansion efficiency of NK cells in vitro could be increased by dasatinib at the concentration range of 5-50 nmol/L, and the expansion efficiency of NK cells reached the peak at 20 nmol/L of dasatinib. The NK cytotoxicity against K562 cells in dasatinib cultured group at the concentration of 20 nmol/L was significantly higher than that in control group. For the cells cultured by disatinib in vitro, the MFI of CD226, NKP46 and NKG2D was up-regulated; the ratio of NKG2A+CD57- subset was down-regulated, while the ratio of NKG2A-CD57+ subset was up-regulated.The degranulation response of NKG2A-CD57+ NK cells to K562 cells was stronger than that of NKG2A+CD57- NK cells. CONCLUSION: The results shows that appropriate dose of dasatinib(20 nmol/L) can increases the amplification efficiency of NK cells, simultaneously up-regulates the expression of NK activating receptors and increases the NKG2A-CD57+ subset, which lead to the enhancement of NK cytotoxicty against leukemia cell lines.


Assuntos
Antineoplásicos , Leucócitos Mononucleares , Adulto , Antineoplásicos/farmacologia , Dasatinibe/farmacologia , Humanos , Células K562 , Células Matadoras Naturais
13.
Nat Commun ; 11(1): 4931, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004795

RESUMO

Testis-restricted melanoma antigen (MAGE) proteins are frequently hijacked in cancer and play a critical role in tumorigenesis. MAGEs assemble with E3 ubiquitin ligases and function as substrate adaptors that direct the ubiquitination of novel targets, including key tumor suppressors. However, how MAGEs recognize their targets is unknown and has impeded the development of MAGE-directed therapeutics. Here, we report the structural basis for substrate recognition by MAGE ubiquitin ligases. Biochemical analysis of the degron motif recognized by MAGE-A11 and the crystal structure of MAGE-A11 bound to the PCF11 substrate uncovered a conserved substrate binding cleft (SBC) in MAGEs. Mutation of the SBC disrupted substrate recognition by MAGEs and blocked MAGE-A11 oncogenic activity. A chemical screen for inhibitors of MAGE-A11:substrate interaction identified 4-Aminoquinolines as potent inhibitors of MAGE-A11 that show selective cytotoxicity. These findings provide important insights into the large family of MAGE ubiquitin ligases and identify approaches for developing cancer-specific therapeutics.


Assuntos
Antígenos de Neoplasias/ultraestrutura , Proteínas de Neoplasias/ultraestrutura , Neoplasias/tratamento farmacológico , Ubiquitina-Proteína Ligases/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Motivos de Aminoácidos , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Células HeLa , Ensaios de Triagem em Larga Escala , Humanos , Mutagênese , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patologia , Estudo de Prova de Conceito , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Domínios Proteicos/genética , Mapeamento de Interação de Proteínas , Relação Estrutura-Atividade , Especificidade por Substrato/efeitos dos fármacos , Especificidade por Substrato/genética , Ubiquitinação/efeitos dos fármacos , Ubiquitinação/genética
14.
Nat Commun ; 11(1): 4965, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009371

RESUMO

Next-generation sequencing (NGS) can identify novel cancer targets. However, interpreting the molecular findings and accessing drugs/clinical trials is challenging. Furthermore, many tumors show resistance to monotherapies. To implement a precision strategy, we initiated a multidisciplinary (basic/translational/clinical investigators, bioinformaticians, geneticists, and physicians from multiple specialties) molecular tumor board (MTB), which included a project manager to facilitate obtaining clinical-grade biomarkers (blood/tissue NGS, specific immunohistochemistry/RNA expression including for immune-biomarkers, per physician discretion) and medication-acquisition specialists/clinical trial coordinators/navigators to assist with medication access. The MTB comprehensively reviewed patient characteristics to develop N-of-One treatments implemented by the treating physician's direction under the auspices of a master protocol. Overall, 265/429 therapy-evaluable patients (62%) were matched to ≥1 recommended drug. Eighty-six patients (20%) matched to all drugs recommended by MTB, including combinatorial approaches, while 38% received physician's choice regimen, generally with unmatched approach/low degree of matching. Our results show that patients who receive MTB-recommended regimens (versus physician choice) have significantly longer progression-free (PFS) and overall survival (OS), and are better matched to therapy. High (≥50%) versus low (<50%) Matching Score therapy (roughly reflecting therapy matched to ≥50% versus <50% of alterations) independently correlates with longer PFS (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.50-0.80; P < 0.001) and OS (HR, 0.67; 95% CI, 0.50-0.90; P = 0.007) and higher stable disease ≥6 months/partial/complete remission rate (52.1% versus 30.4% P < 0.001) (all multivariate). In conclusion, patients who receive MTB-based therapy are better matched to their genomic alterations, and the degree of matching is an independent predictor of improved oncologic outcomes including survival.


Assuntos
Neoplasias/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , DNA Tumoral Circulante/genética , Intervalo Livre de Doença , Feminino , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Medicina de Precisão , Resultado do Tratamento , Adulto Jovem
16.
Yakugaku Zasshi ; 140(10): 1243-1249, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999203

RESUMO

Here the author describes the tumor-selective delivery of a fluorescence photosensitizing agent and an antitumor agent, based on the polymer effect of an N-(2-hydroxypropyl)methacrylamide (HPMA) based copolymer, by utilizing the enhanced permeability and retention (EPR) effect seen in solid tumors. Firstly, the tumor distribution of the photosensitizer, zinc-protoporphyrin IX (ZnPP), was significantly increased by conjugation with the HPMA polymer (P-ZnPP). The P-ZnPP suppressed tumor growth by local generation of cytotoxic singlet oxygen, and the tumor tissue was visualized by fluorescence upon light irradiation. Subsequently, a two-step mechanism for tumor selectivity was observed for the cytotoxic anthracycline, pirarubicin (THP), which conjugated the HPMA-based copolymer via a hydrazone bond (P-THP). The EPR-dependent accumulation of P-THP and the tumor-selective release of THP in the tumor tissues led to highly tumor-selective toxicity. Rapid cell uptake of THP compared to other anthracyclines, and deeper P-THP penetration of the tumor cell spheroid were attributed to the superior antitumor activity of P-THP. The molecular weight of P-THP affected its antitumor activity; oligomeric P-THP derivatives with higher molecular weights, DP-THP and SP-THP, showed even higher antitumor activity. P-THP was effective for both implanted tumor and autochthonous tumor models. These results indicate that nano-sized anticancer drugs based on polymer effect are promising clinical therapeutics.


Assuntos
Antineoplásicos , Sistemas de Liberação de Medicamentos , Desenvolvimento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fármacos Fotossensibilizantes , Polímeros , Protoporfirinas , Animais , Antraciclinas/química , Antraciclinas/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Doxorrubicina/análogos & derivados , Doxorrubicina/química , Doxorrubicina/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Metacrilatos/química , Terapia de Alvo Molecular , Peso Molecular , Neoplasias/patologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/metabolismo , Protoporfirinas/química , Protoporfirinas/metabolismo
17.
Phys Rev Lett ; 125(12): 128103, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-33016731

RESUMO

While many cellular mechanisms leading to chemotherapeutic resistance have been identified, there is an increasing realization that tumor-stroma interactions also play an important role. In particular, mechanical alterations are inherent to solid cancer progression and profoundly impact cell physiology. Here, we explore the influence of compressive stress on the efficacy of chemotherapeutics in pancreatic cancer spheroids. We find that increased compressive stress leads to decreased drug efficacy. Theoretical modeling and experiments suggest that mechanical stress decreases cell proliferation which in turn reduces the efficacy of chemotherapeutics that target proliferating cells. Our work highlights a mechanical form of drug resistance and suggests new strategies for therapy.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Modelos Biológicos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Estresse Mecânico
18.
Beijing Da Xue Xue Bao Yi Xue Ban ; 52(5): 902-906, 2020 Oct 18.
Artigo em Chinês | MEDLINE | ID: mdl-33047727

RESUMO

OBJECTIVE: To investigate the effects of salinomycin on the proliferation and apoptosis of oral squamous carcinoma cells and to further understand the mechanisms of these effects. METHODS: The human oral squamous carcinoma cell line CAL-27 was cultured in different concentrations of salinomycin and cisplatin. After co-culture with 0, 1, 2, 4, 8, 16 and 32 µmol/L salinomycin or 0, 1.25, 2.5, 5, 10, 20, 40 and 80 µmol/L cisplatin for 24 hours and 48 hours, the proliferation of oral squamous carcinoma cells were detected by cell counting kit-8(CCK-8) assay. After being exposed to 0, 2, 4, 8 µmol/L salinomycin and 0, 5, 10, 20 µmol/L cisplatin for 48 hours, the cell cycle of oral squamous carcinoma cells was detected by flow cytometry assay, and Western blot analysis was performed to analyze the expressions of cysteine-containing aspartate-specific proteases-3(Caspase-3), cysteine-containing aspartate-specific proteases-9(Caspase-9), poly ADP-ribose polymerase (PARP), protein kinase B (Akt) and phosphorylated protein kinase B (p-Akt) protein in oral squamous carcinoma cells. RESULTS: Both salinomycin and cisplatin significantly inhibited the proliferation of oral squamous cell carcinoma CAL-27 cells in a time- and dose-dependent manner. However, compared with the first-line chemotherapeutic drug cisplatin, salinomycin showed stronger anti-proliferation activity in oral squamous carcinoma cells than cisp-latin (P < 0.001). After being exposed to 8 µmol/L salinomycin, CAL-27 cells exhibited markedly higher proportion in quiescent/ first gap phases (40.40%±1.99% vs. 64.46%±0.90%, P < 0.05), and had a significantly lower proportion in synthesis phases and second gap / mitosis phases (24.32%±2.30% vs. 18.73%±0.61%, P < 0.05; 35.01%±1.24% vs. 16.54%±1.31%, P < 0.05) compared with the dimethyl sulfoxide control group; moreover cisplatin didn't show cell-cycle specific effect on CAL-27. Western blot proved that salinomycin could up-regulate the expressions of Caspase-3 and Caspase-9 protein in oral squamous cell carcinoma CAL-27 cells (P < 0.05). At the same time, the levels of PARP, Akt and p-Akt protein were down-regulated (P < 0.05). CONCLUSION: Compared with cisplatin, salinomycin has a better inhibitory effect on the proliferation of oral squamous carcinoma cells and blocks the cell cycle process at the quiescent / first gap phase. At the same time, salinomycin could trigger apoptosis of oral squamous carcinoma cells and the mechanism is associated with the Akt/p-Akt signaling pathway.


Assuntos
Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias Bucais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Bucais/tratamento farmacológico , Piranos
19.
Medicine (Baltimore) ; 99(40): e22493, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019445

RESUMO

RATIONALE: Gastrointestinal stromal tumors that present outside the gastrointestinal tract are known for extra-gastrointestinal stromal tumors (EGISTs) and they share the same morphological and immunohistochemical characteristics with gastrointestinal stromal tumors. Here we report a rare case of diffuse primary EGIST arising at peritoneum. PATIENT CONCERNS: A 57-year-old male presented to the hospital with abdominal pain and right lower abdominal tenderness. DIAGNOSIS: The core needle puncture biopsy showed epithelial-like cells and the nuclei were ovoid and focally elongated. Immunohistochemical examination was consistent with a primary EGIST of the peritoneum. INTERVENTIONS: The patient was treated with Imatinib mesylate. OUTCOMES: Five months later, there is no complication resulting from treatment. The follow-up abdominal contrast-enhanced CT showed the lesion was significantly decreased in size, and was evaluated as partial response. The patient continued the treatment with Imatinib as prescribed by the oncologist. LESSONS: EGISTs are rare and should be considered in the differential diagnosis of the peritoneal tumors and immunohistochemistry helps to confirm the diagnosis. Further study with longer follow-up is desired to characterize these uncommon tumors.


Assuntos
Tumores do Estroma Gastrointestinal/patologia , Neoplasias Peritoneais/patologia , Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Mesilato de Imatinib/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias Peritoneais/diagnóstico , Neoplasias Peritoneais/tratamento farmacológico
20.
Rev Lat Am Enfermagem ; 28: e3363, 2020.
Artigo em Inglês, Português, Espanhol | MEDLINE | ID: mdl-33084773

RESUMO

OBJECTIVE: to evaluate the effect of oral cryotherapy compared to physiological serum on the development of oral mucositis in outpatient cancer patients using the 5-fluorouracil antineoplastic agent. METHOD: this is a controlled, randomized, double-blind, and multi-center clinical trial, conducted with 60 patients undergoing chemotherapy. The experimental group (n=30) used oral cryotherapy during the infusion of the 5-FU antineoplastic agent, while the control group (n=30) performed mouthwash with physiological serum at their homes. The oral cavity of the participants was assessed at three times: before randomization, and on the 7th and 14th days after using 5-FU. For data analysis, descriptive analyses and the ANOVA, paired t, and McNemar tests were used. RESULTS: there was no statistically significant difference between the experimental and control groups in the assessments regarding the grade of mucositis. However, cryotherapy presented the chance to reduce the presence of intragroup mucositis, between the first and second assessments (p=0.000126). CONCLUSION: cryotherapy did not obtain statistical significance in relation to oral hygiene with serum, but it proved to be effective intragroup. Record number: RBR-4k7zh3.


Assuntos
Antineoplásicos , Mucosite , Estomatite , Crioterapia , Fluoruracila/efeitos adversos , Humanos , Estomatite/induzido quimicamente , Estomatite/prevenção & controle
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