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1.
BMC Gastroenterol ; 21(1): 360, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34600484

RESUMO

BACKGROUND: Synchronous colorectal cancer (SCRC) is featured by the presence of multiple primary tumor lesions in a single patient at initial diagnosis. It is less common with the prevalence of approximately 3.5% among colorectal cancer (CRC). Some studies of SCRC have been performed in patients with two tumor lesions. However, SCRC cases with three or more tumor lesions were rare and remained to be investigated. CASE PRESENTATION: In this case report, we presented a 56-year-old male SCRC case with quadruple tumor lesions which is rarely seen in clinical practice. After laparoscopic radical resection of sigmoid carcinoma and partial rectum resection, the four tumor samples were subjected to pathological evaluation and next-generation sequencing (NGS) based genetic profiling. The four tumor lesions included two adenocarcinomas with moderate differentiation at sigmoid colon and rectum respectively, a grade 1 neuroendocrine tumor (NET) at rectum and a high-grade intraepithelial neoplasia at ascending colon. Each tumor exhibited distinct histology types and mutation profiles. After surgical resection, the patient remained disease-free after four cycles of chemotherapy with oxaliplatin and capecitabine (XELOX). CONCLUSIONS: The tumor lesions in this case showed different pathological and genetic features which indicats the heterogeneity of SCRC. The genomic profilling might provide novel insights to understand SCRC at molecular level.


Assuntos
Adenocarcinoma , Neoplasias Colorretais , Neoplasias Primárias Múltiplas , Adenocarcinoma/genética , Adenocarcinoma/cirurgia , Neoplasias Colorretais/genética , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/genética , Estudos Retrospectivos
2.
Front Mol Biosci ; 8: 720020, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34540896

RESUMO

Background: The histone deacetylase (HDAC) family limited accessibility to chromatin containing tumor suppressor genes by removing acetyl groups, which was deemed a path for tumorigenesis. Considering glioma remained one of the most common brain cancers with a dichotomy prognosis and limited therapy responses, HDAC inhibitors were an area of intensive research. However, the expression profiles and prognostic value of the HDACs required more elucidation. Methods: Multiple biomedical databases were incorporated, including ONCOMINE, GEPIA, TCGA, CGGA, GEO, TIMER, cBioPortal, and Metascape, to study expression profiles, prognostic value, immune infiltration, mutation status, and enrichment of HDACs in glioma. STRING and GeneMANIA databases were used to identify HDAC1-related molecules. LASSO regression, Cox regression, Kaplan-Meier plot, and receiver operating characteristic (ROC) analyses were performed for HDAC1-related signature construction and validation. Results: HDAC1 was significantly overexpressed in glioma, while HDAC11 was downregulated in glioblastoma. Except for HDAC 6/9/10, the HDAC family expression was significantly associated with glioma grade. Most of the HDAC family also correlated with glioma genetic mutations. Higher HDAC1 expression level predicted more dismal overall survival (OS) (p < 0.0001) and disease-free survival (DFS) (p < 0.0001), but a higher level of HDAC11 held more favorable OS (p = 2.1e-14) and DFS (p = 4.8e-08). HDAC4 displayed the highest mutation ratio, at 2.6% of the family. The prognostic value of HDAC1 was validated with ROC achieving 0.70, 0.77, 0.75, and 0.80 as separability for 1-, 3-, 5-, and 10-years OS predictions in glioma, respectively. Moreover, HDAC1 expression positively correlated with neutrophil (r = 0.60, p = 2.88e-47) and CD4+ T cell infiltration (r = 0.52, p = 3.96e-35) in lower-grade glioma. The final HDAC1-related signature comprised of FKBP3, HDAC1 (Hazard Ratio:1.49, 95%Confidence Interval:1.20-1.86), PHF21A, RUNX1T1, and RBL1, and was verified by survival analysis (p < 0.0001) and ROC with 0.80, 0.84, 0.83, and 0.88 as separability for 1-, 3-, 5-, and 10-years OS predictions, respectively. The signature was enriched in chromatin binding. Conclusion: HDAC family was of clinical significance for glioma. Most of the HDAC family significantly correlated with the glioma grade, IDH1 mutation, and 1p/19q codeletion. HDAC1 was both a prognostic and immune infiltration indicator and a central component of the HDAC1-related signature for precise prognosis prediction in glioma.

3.
Int J Gen Med ; 14: 4545-4554, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34429639

RESUMO

Background: To explore the expression level of has_circ_0000615 in peripheral blood samples and evaluate its diagnostic value for breast cancer patients. Methods: The peripheral blood samples of 95 breast cancer patients who underwent curative surgical resection and 95 age-matched healthy volunteers in our institutions from September 2019 to November 2020 were systematically collected. The expression level of has_circ_0000615 in the plasma was amplified and detected by qRT-PCR, and its correlation to clinicopathological characteristics of breast cancer patients were analyzed. Results: Breast cancer patients had a significantly higher expression level of has_circ_0000615 in the plasma than healthy controls (P < 0.01), and its high expression was closely associated with advanced tumor stage (P=0.010), lymph node metastasis (P = 0.001) and high grade of recurrence risk (P=0.012). The receiver operator characteristic (ROC) curves showed that the area under curve (AUC) value, sensitivity and specificity of has_circ_0000615 for the diagnosis of non-metastatic breast cancer was 0.904 (95% CI: 0.863-0.944), 76.8% and 88.4%, respectively. Serum has_circ_0000615 expression had a better diagnostic efficiency than routine tumor biomarkers such as CA153, CA125 and CEA for distinguishing breast cancer patients from healthy individuals. TEM revealed that isolated exosomes from the culture medium of breast cancer cells had a disk-like appearance with a diameter of 80-200 nm vesicles, and the expression of exosome markers CD9 and CD81 was markedly increased. More importantly, the expression of has_circ_0000615 was detected in the exosomes and its expression level was markedly upregulated in breast cancer cell lines compared with normal ductal epithelial cells. The stability assay showed that there was no difference between RNA extraction at 0 hour and 24 hours in terms of the expression of has_circ_0000615 (P =0.327). Has_circ_0000615 might as exosomes be secreted into the circulating blood of breast cancer patients, resulting in a high expression level in plasma samples. Conclusion: The detection of has_circ_0000615 might be a promising diagnostic method for breast cancer.

4.
BMC Cancer ; 21(1): 639, 2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34051750

RESUMO

BACKGROUND: Although the National Comprehensive Cancer Network (NCCN) Guidelines recommend CCRT+AC and IC + CCRT as level 2A evidence for treatment of the locoregionally advanced NPC (II-IVa), IC + CCRT+AC could also be an alternative but it is seldom used because of the low completion rates. This article aimed to compare the effectiveness of the three radiotherapy regimens using a large-scale retrospective study. METHODS: This retrospective single center analysis enrolled 1812 diagnosed NPC patients at Nanfang Hospital from January 2005 to December 2015 and only 729 patients met the inclusion criteria and were analyzed. Patients without distant metastasis, age of 18-70 years, Karnofsky scores of at least 70,stage III-IVb, and adequate adequate bone marrow, liver and renal function. Were enrolled. Adverse events and other categorical variables were compared by Pearson chi-square test or Fishier exact test. Time-to-event data were described with the Kaplan-Meier curves, time-to-event intervals compared with the log-rank test. We did multivariable analyses with the Cox proportional hazards model to test the independent signifi cance of diff erent factors. Cox proportional hazards model was used to estimate the ß regression coeffi cient, p value, and hazard ratio and its 95% CI for each of the selected risk predictors. RESULTS: The median follow-up time was 47 months. Kaplan-Meier analyses revealed no significant differences among three groups in 3-year failure-free survival (FFS, P = 0.225), 3-year overall survival (OS, P = 0.992), 3-year locoregional failure-free survival (LFFS, P = 0.549), and 3-year distant failure-free survival (DFFS, P = 0.174). Stratified survival analysis based on the risk scoring model revealed no differences in FFS, OS, LFFS, and DFFS between IC + CCRT and CCRT+AC groups for low-risk patients, however, the 3-year OS (88.3% vs. 77.6%, P = 0.049) and 3-year DFFS (84.0% vs.66.8%, P = 0.032) were respectively significantly better in IC + CCRT group compared with CCRT+AC group for high-risk patients. CONCLUSIONS: Compared with CCRT+AC, IC + CCRT lowers distant metastasis rate and improves OS among patients with locally advanced NPC in high risk group.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapia , Terapia Neoadjuvante/estatística & dados numéricos , Recidiva Local de Neoplasia/epidemiologia , Adolescente , Adulto , Idoso , Quimiorradioterapia/métodos , Quimiorradioterapia/estatística & dados numéricos , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/estatística & dados numéricos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/prevenção & controle , Radioterapia de Intensidade Modulada , Estudos Retrospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Adulto Jovem
5.
Artigo em Inglês | MEDLINE | ID: mdl-34029196

RESUMO

Deep learning has become the most powerful machine learning tool in the last decade. However, how to efficiently train deep neural networks remains to be thoroughly solved. The widely used minibatch stochastic gradient descent (SGD) still needs to be accelerated. As a promising tool to better understand the learning dynamic of minibatch SGD, the information bottleneck (IB) theory claims that the optimization process consists of an initial fitting phase and the following compression phase. Based on this principle, we further study typicality sampling, an efficient data selection method, and propose a new explanation of how it helps accelerate the training process of the deep networks. We show that the fitting phase depicted in the IB theory will be boosted with a high signal-to-noise ratio of gradient approximation if the typicality sampling is appropriately adopted. Furthermore, this finding also implies that the prior information of the training set is critical to the optimization process, and the better use of the most important data can help the information flow through the bottleneck faster. Both theoretical analysis and experimental results on synthetic and real-world datasets demonstrate our conclusions.

6.
Cancer Med ; 10(3): 883-894, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33378109

RESUMO

BACKGROUND: This study was performed to investigate whether long-term monitoring of dynamic changes in plasma Epstein-Barr virus (EBV) DNA could improve prognosis prediction of nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: About 1077 nonmetastatic NPC patients were recruited to retrospectively analyze the prognostic value of plasma EBV DNA load pretreatment and 3, 12, 24, and 36 months posttreatment. We also examined the prognostic value of dynamic changes in plasma EBV DNA at various time points. RESULTS: Patients with plasma EBV DNA load above optimal pre- and posttreatment cut-offs had significantly worse five-year progression-free survival, distant metastasis-free survival, locoregional relapse-free survival, and overall survival (OS) at all-time points, excluding only OS at 36 months posttreatment due to limited mortalities. Patients with persistently undetectable plasma EBV DNA at the first four time points had the best prognosis, followed by those with positive detection pretreatment and consistently negative detection posttreatment, those with negative detection pretreatment and positive detection at one time point posttreatment, and those with positive detection pretreatment and at one time point posttreatment, whereas patients with positive detection at ≥2 time points posttreatment had the worst prognosis. Cox proportional hazard models identified the dynamic change pattern as an independent prognostic factor, and receiver operating characteristic curve analysis demonstrated that the dynamic change at four time point was more valuable than any single time point for predicting disease progression, distant metastasis, locoregional relapse, and mortality. CONCLUSIONS: Dynamic changes in plasma EBV DNA pre- and posttreatment could predict the long-term survival outcome and provide accurate risk stratification in NPC.


Assuntos
DNA Viral/genética , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/secundário , Recidiva Local de Neoplasia/patologia , Quimiorradioterapia , DNA Viral/análise , Infecções por Vírus Epstein-Barr/virologia , Feminino , Seguimentos , Herpesvirus Humano 4/isolamento & purificação , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/virologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Recidiva Local de Neoplasia/virologia , Prognóstico , Curva ROC , Estudos Retrospectivos , Taxa de Sobrevida
8.
Int J Mol Sci ; 21(17)2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32887330

RESUMO

Secondary caries often occurs at the tooth-composite margins. This study developed a novel bioactive composite containing DMAHDM (dimethylaminohexadecyl methacrylate) and NACP (nanoparticles of amorphous calcium phosphate), inhibiting caries at the enamel restoration margins in an in vitro saliva-derived biofilm secondary caries model for the first time. Four composites were tested: (1) Heliomolar nanocomposite, (2) 0% DMAHDM + 0% NACP, (3) 3% DMAHDM + 0% NACP, (D) 3% DMAHDM + 30% NACP. Saliva-derived biofilms were tested for antibacterial effects of the composites. Bovine enamel restorations were cultured with biofilms, Ca and P ion release of nanocomposite and enamel hardness at the enamel restoration margins was measured. Incorporation of DMAHDM and NACP into composite did not affect the mechanical properties (p > 0.05). The biofilms' CFU (colony-forming units) were reduced by 2 logs via DMAHDM (p < 0.05). Ca and P ion release of the nanocomposite was increased at cariogenic low pH. Enamel hardness at the margins for DMAHDM group was 25% higher than control (p < 0.05). With DMAHDM + NACP, the enamel hardness was the greatest and about 50% higher than control (p < 0.05). Therefore, the novel composite containing DMAHDM and NACP was strongly antibacterial and inhibited enamel demineralization, resulting in enamel hardness at the margins under biofilms that approached the hardness of healthy enamel.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Fosfatos de Cálcio/farmacologia , Cárie Dentária/prevenção & controle , Esmalte Dentário/efeitos dos fármacos , Nanocompostos/química , Saliva/microbiologia , Animais , Biofilmes/crescimento & desenvolvimento , Bovinos , Cárie Dentária/microbiologia , Cárie Dentária/patologia , Esmalte Dentário/microbiologia , Esmalte Dentário/patologia , Modelos Animais de Doenças , Dureza , Técnicas In Vitro
9.
Biomed Res Int ; 2020: 1872962, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32964017

RESUMO

The current glioma classification could be optimized to cover such a separate and individualized prognosis ranging from a few months to over ten years. Considering its highly conserved role and potential in therapies, autophagy might be a promising element to be incorporated as a refinement for improved survival prognostication. The expression and RNA-seq data of 881 glioma patients from the Gene Expression Omnibus and The Cancer Genome Atlas were included, mapped with autophagy-related genes. Weighted gene coexpression network analysis and Cox regression analysis were used for the autophagy signature establishment, which composed of MUL1, NPC1, and TRIM13. Validations were represented by Kaplan-Meier plots and receiver operating curves (ROC). Cluster analysis suggested the IDH1 mutant involved in the favorable prognosis of the signature clusters. The signature was also immune-related shown by the Gene Ontology analysis and the Gene Set Enrichment Analysis. The high signature risk group held a higher ESTIMATE score (p = 2.6e - 11) and stromal score (p = 1.8e - 10). CD276 significantly correlated with the signature (r = 0.51, p < 0.05). The final nomogram integrated with the autophagy signature, IDH1 mutation, and pathological grade was built with accuracy and discrimination (1-year survival AUC = 0.812, 5-year survival AUC = 0.822, and 10-year survival AUC = 0.834). Its prognostic value and clinical utility were well-defined by the superiority in the comparisons with the current World Health Organization glioma classification in ROC (p < 0.05) and decision curve analysis. The autophagy signature-based IDH1 mutation and grade nomogram refined glioma classification for a more individualized and clinically applicable survival estimation and inspired potential autophagy-related therapies.


Assuntos
Autofagia/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Glioma/mortalidade , Glioma/patologia , Idoso , Antígenos B7/genética , Neoplasias Encefálicas/genética , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Glioma/genética , Humanos , Isocitrato Desidrogenase/genética , Masculino , Mutação/genética , Nomogramas , Prognóstico , Análise de Regressão
10.
PLoS One ; 15(7): e0236511, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32722717

RESUMO

The severe side effects of chemosynthetic anti-diarrhea drugs have created an interest in low-toxic alternative plant-derived compounds. FengLiao consists of Polygonum hydropiper Linn. and Daphniphyllum calycinum Bench., and is widely used in China to treat diarrhea due to low levels of toxicity. In this study, the effects of FengLiao were analyzed in a castor oil-induced diarrhea model, using the anti-diarrhea drug, loperamide, as the positive control. The effects were evaluated using stool characteristics and the expression levels of various diarrhea-related factors in the jejunum and liver, as well as changes in the microbiota of the jejunum. The symptoms of diarrhea and stool consistency were improved through FengLiao and loperamide treatment. Furthermore, FengLiao down-regulated alpha 1-acid glycoprotein (AGP) and C-reactive protein (CRP) levels, and up-regulated transferrin (TRF) mRNA levels in the liver, and down-regulated Aquaporin 3 (AQP3) and Na+/H+ exchanger isoform 8 (NHE8) expression in the epithelial cells of the jejunum. It also increased the relative abundance of Bifidobacterium, Aerococcus, Corynebacterium_1 and Pseudomonas, and lowered the Firmicutes/Bacteroidetes (F/B) ratio, which maintained the balance between immunity and intestinal health. Taken together, FengLiao alleviated castor oil-induced diarrhea by altering gut microbiota, and levels of jejunum epithelial transport proteins and acute phase proteins.


Assuntos
Proteínas de Fase Aguda/genética , Aquaporinas/genética , Diarreia/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Trocadores de Sódio-Hidrogênio/genética , Animais , Óleo de Rícino/toxicidade , Daphniphyllum/química , Diarreia/genética , Diarreia/microbiologia , Medicamentos de Ervas Chinesas/uso terapêutico , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Jejuno/microbiologia , Camundongos , Polygonum/química
11.
J Mater Chem B ; 8(17): 3939-3948, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32236239

RESUMO

Doxorubicin (DOX) is a widely-used anticancer drug, but its cardiotoxicity severely hampers its potency in chemotherapy. Herein, human serum albumin (HSA) is engaged as a biocompatible nanocarrier to load a pH-sensitive DOX prodrug, DMDOX, generating HSA-DMDOX nanoparticles via self-assembly driven by hydrophobic interactions. HSA-DMDOX disperses well in a physiological environment (∼40 nm) but aggregates in a tumor acidic microenvironment (pH 6.5, ∼140 nm) owing to the hydrophobicity increase of DMDOX by protonation of carboxylic groups. In vitro anticancer study showed that HSA-DMDOX exhibited enhanced cellular uptake by 4T1 cells and superior cytotoxicity in comparison to HSA-DOX nanoparticles. In vivo study suggested that HSA-DMDOX achieved long blood circulation, aggregation enhanced tumor retention, comparable antitumor efficacy and reduced cardiotoxicity relative to free DOX. Our work presents a facile and effective approach to delivering anthracyclines by HSA-based tumor pH-responsive nanoparticles with aggregation-enhanced tumor retention and reduced toxicity.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Nanopartículas/química , Pró-Fármacos/farmacologia , Albumina Sérica Humana/química , Animais , Antibióticos Antineoplásicos/síntese química , Antibióticos Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/síntese química , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Peróxido de Hidrogênio/sangue , Concentração de Íons de Hidrogênio , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Mutantes , Camundongos Nus , Estrutura Molecular , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/química , Propriedades de Superfície , Células Tumorais Cultivadas
12.
PLoS Negl Trop Dis ; 14(3): e0008023, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32163408

RESUMO

BACKGROUND: Human cystic echinococcosis (CE) is one of the commonest zoonoses, and it is endemic in many parts of the world including China. Complications and recurrences after the surgical treatment of hepatic CE (HCE) incur a large personal, healthcare, and societal burden. There has been some progress in HCE prevention, diagnosis, and treatment, but there is no "one size fits all" approach, and surgery still remains the cornerstone of treatment for some cyst stages and locations or in areas with little knowledge or access to other treatment modalities. In 2009 we designed and implemented a program to improve surgical outcomes from HCE in Xinjiang province, China. METHODOLOGY/PRINCIPAL FINDINGS: A multimodal HCE training program was implemented in eleven primary hospitals in Xinjiang province, China, which provided education and training on HCE clinical knowledge and practice, the application of diagnostic and treatment options, and optimal surgery. The management of HCE cases was analyzed before and after program implementation. Contrast enhanced CT use, application of scoloicidal agents, removal of necrotic cyst wall remnants, appropriate perioperative drug use, and the use of optimal surgical approach increased after program implementation. Further, postoperative recurrences and residual cavity complications creased from 7.4% to 1.3% and 15.2% to 9.0% after program implementation, respectively. CONCLUSIONS/SIGNIFICANCE: Tis integrated surgical training program is useful for improving outcomes of patients with HCE and can be used in institutions in other endemic areas.


Assuntos
Equinococose Hepática/cirurgia , Educação/organização & administração , Procedimentos Cirúrgicos Operatórios/educação , Adulto , Anti-Helmínticos/uso terapêutico , China , Gerenciamento Clínico , Equinococose Hepática/diagnóstico , Equinococose Hepática/tratamento farmacológico , Feminino , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Operatórios/métodos , Tomografia Computadorizada por Raios X/métodos
13.
J Mater Chem B ; 8(8): 1728-1738, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32022097

RESUMO

Polymer microspheres are attracting wide attention in localized cancer therapy owing to the excellent biocompatibility and drug loading capacity, controllable biodegradation speeds, and minimized systemic toxicity. Herein, we presented poly(ester-thioether) microspheres, porous and nonporous, as drug depots for localized therapy of non-small cell lung cancer (NSCLC). Specifically, erlotinib and α-tocopheryl succinate (α-TOS), which are respectively an epidermal growth factor receptor (EGFR) inhibitor and mitochondria destabilizer, were efficiently loaded into porous and nonporous poly(ester-thioether) microspheres for the treatment of EGFR-overexpressing NSCLC (A549 cells). The poly(ester-thioether) microspheres significantly improved the bioavailability of both erlotinib and α-TOS in comparison to the free drug combination, realizing synergistic inhibition of A549 cells both in vitro and in vivo. The porous microspheres displayed faster degradation and drug release than the nonporous counterpart, thereby showing better anticancer efficacy. Overall, our study reported a new anticancer strategy of erlotinib and α-TOS combination for therapy of NSCLC, and established that poly(ester-thioether) microspheres could be a robust and biodegradable reservoir for drug delivery and localized cancer therapy.


Assuntos
Cloridrato de Erlotinib/química , Microesferas , Polímeros/química , Inibidores de Proteínas Quinases/química , alfa-Tocoferol/química , Células A549 , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Portadores de Fármacos/química , Quimioterapia Combinada , Cloridrato de Erlotinib/metabolismo , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Nus , Porosidade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , alfa-Tocoferol/farmacologia , alfa-Tocoferol/uso terapêutico
14.
IEEE Trans Neural Netw Learn Syst ; 31(11): 4649-4659, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-31899442

RESUMO

Machine learning, especially deep neural networks, has developed rapidly in fields, including computer vision, speech recognition, and reinforcement learning. Although minibatch stochastic gradient descent (SGD) is one of the most popular stochastic optimization methods for training deep networks, it shows a slow convergence rate due to the large noise in the gradient approximation. In this article, we attempt to remedy this problem by building a more efficient batch selection method based on typicality sampling, which reduces the error of gradient estimation in conventional minibatch SGD. We analyze the convergence rate of the resulting typical batch SGD algorithm and compare the convergence properties between the minibatch SGD and the algorithm. Experimental results demonstrate that our batch selection scheme works well and more complex minibatch SGD variants can benefit from the proposed batch selection strategy.

15.
Molecules ; 25(3)2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31991678

RESUMO

The oral cavity is a unique complex ecosystem colonized with huge numbers of microorganism species. Oral cavities are closely associated with oral health and sequentially with systemic health. Many factors might cause the shift of composition of oral microbiota, thus leading to the dysbiosis of oral micro-environment and oral infectious diseases. Local therapies and dental hygiene procedures are the main kinds of treatment. Currently, oral drug delivery systems (DDS) have drawn great attention, and are considered as important adjuvant therapy for oral infectious diseases. DDS are devices that could transport and release the therapeutic drugs or bioactive agents to a certain site and a certain rate in vivo. They could significantly increase the therapeutic effect and reduce the side effect compared with traditional medicine. In the review, emerging recent applications of DDS in the treatment for oral infectious diseases have been summarized, including dental caries, periodontitis, peri-implantitis and oral candidiasis. Furthermore, oral stimuli-responsive DDS, also known as "smart" DDS, have been reported recently, which could react to oral environment and provide more accurate drug delivery or release. In this article, oral smart DDS have also been reviewed. The limits have been discussed, and the research potential demonstrates good prospects.


Assuntos
Candidíase Bucal/prevenção & controle , Cárie Dentária/prevenção & controle , Sistemas de Liberação de Medicamentos , Peri-Implantite/prevenção & controle , Periodontite/prevenção & controle , Humanos
16.
J Mater Chem B ; 8(6): 1235-1244, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31957757

RESUMO

Herein, we reported a primary amine containing polycationic polymer to load an oppositely charged anticancer drug (doxorubicin, DOX) and a photosensitizer (chlorin e6, Ce6) for combinational chemo-photodynamic therapy. The electrostatic interactions as well as other multiple interactions between the polymer and payloads endowed the drug-loaded nanoparticles with excellent stability. Moreover, the electrostatic attraction between the cationic polymer and anionic Ce6 dictated that Ce6 had higher loading efficiency than DOX. DOX showed pH-responsive drug release owing to the increased solubility of protonated DOX and reduced interaction with the partially protonated polymer under acidic conditions. In contrast, Ce6 showed pH-insensitive release because of the smaller change in solubility and the intense interactions between Ce6 and the polymer. Synergistic chemo/photodynamic therapy of 4T1 cancer cells was achieved by light-triggered reactive oxygen species (ROS)-mediated enhanced cellular uptake and effective endo/lysosomal escape of drug-loaded nanoparticles. Our study demonstrated that the polycationic polymer could act as a robust carrier for differential loading and release of oppositely charged cargos for combinational therapy.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Polímeros/química , Porfirinas/farmacologia , Animais , Antibióticos Antineoplásicos/química , Cátions/síntese química , Cátions/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Luz , Masculino , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Células NIH 3T3 , Tamanho da Partícula , Fármacos Fotossensibilizantes/química , Polímeros/síntese química , Porfirinas/química , Propriedades de Superfície
17.
Front Microbiol ; 10: 2309, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681193

RESUMO

Necrotic enteritis (NE) causes huge economic losses to the poultry industry. Probiotics are used as potential alternatives to antibiotics to prevent NE. It is known that Clostridium butyricum can act as a probiotic that can prevent infection. However, whether or not it exerts a beneficial effect on NE in chickens remains elusive. Therefore, we investigated the impact of C. butyricum on immune response and intestinal microbiota during the development of NE in chickens, including experimental stages with basal diets, high-fishmeal-supplementation diets, and Clostridium perfringens challenge. Chickens were divided into two groups from day 1 to day 20: one group had its diet supplemented with C. butyricum supplementation and one did not. At day 20, the chickens were divided into four groups: C. perfringens challenged and unchallenged chickens with and without C. butyricum supplementation. All groups were fed a basal diet for 13 days and thereafter a basal diet with 50% fishmeal from day 14 to 24. Chickens were infected with C. perfringens from day 21 to 23. At days 13, 20 and 24, samples were collected for analysis of the relative expression of immune response and intestinal mucosa barrier-related genes and intestinal microbes. The results show that C. butyricum can inhibit the increase in IL-17A gene expression and the reduction in Claudin-1 gene induced-expression caused by C. perfringens challenge. Moreover, C. butyricum was found to increase the expression of anti-inflammatory IL-10 in infected chickens. Although C. butyricum was found to have a significant beneficial effect on the structure of intestinal bacteria in the basal diet groups and decrease the abundance of C. perfringens in the gut, it did not significantly affect the occurrence of intestinal lesions and did not significantly correct the shift in gut bacterial composition post C. perfringens infection. In conclusion, although C. butyricum promotes the expression of anti-inflammatory and tight junction protein genes and inhibits pro-inflammatory genes in C. perfringens-challenged chickens, it is not adequate to improve the structure of intestinal microbiota in NE chickens. Therefore, more effective schemes of C. butyricum supplementation to prevent and treat NE in chickens need to be identified.

19.
J Biomed Nanotechnol ; 15(8): 1673-1687, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31219020

RESUMO

Prodrug self-assembled nanomedicines with cleavable moieties sensitive to intracellular stimuli have attracted great interest to pharmacists. In this paper, a docetaxel-hyaluronic acid (DTX-HA) conjugate with peptide, hydrazone bonds and disulfide in sequence, which were cleavable catalyzed by metalloproteinase (MMP), weak acidity and glutathione (GSH), respectively, were involved in a moiety as the linker to immobilize DTX on HA chains, the prodrugs were self-assembled into nanoparticles and utilized for cancer chemotherapy. The synthesis of conjugate was characterized by 1H NMR, ESI-TOF and GPC. The self-assembly of the conjugates was investigated via DLS and TEM. The release profiles revealed that the nanomedicine was disassociated to trigger the drug release in the simulated intracellular conditions of MMP, pH value and GSH, respectively. The in vitro anticancer activity of the nanomedicine with IC50 test, cytometry and confocal laser scanning microscopy exhibited efficient cellular uptake and apoptosis of cancer cells. The in vivo anticancer study of the nanomedicine in tumor-bearing nude mice showed promising therapeutic efficacy in magnificent inhibition tumor growth, long circulation time in pharmacokinetic and low toxicity to organs.


Assuntos
Nanomedicina , Animais , Linhagem Celular Tumoral , Glutationa , Concentração de Íons de Hidrogênio , Metaloproteases , Camundongos , Camundongos Nus , Pró-Fármacos
20.
Biomacromolecules ; 20(6): 2372-2383, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31117352

RESUMO

Disulfiram (DSF) has excellent in vitro anticancer activity in the presence of Cu(II). The anticancer mechanism studies have demonstrated that copper(II) diethyldithiocarbamate, Cu(DDC)2, is the crucial DSF's metabolite exhibiting anticancer activity. In this paper, highly stable polymeric nanoparticles were fabricated via a coordination strategy between Cu(II) and carboxylic groups in poly(ethylene glycol)- b-poly(ester-carbonate) (PEC) for efficient loading of Cu(DDC)2, which was generated by the in situ reaction of DSF and Cu(II). The properties of nanoparticles such as drug loading contents, sizes, and morphologies could be tuned by varying the feeding ratios of DSF, Cu(II), and PEC. These Cu(II)/DDC-loaded nanoparticles showed excellent stability in both neutral and weak acidic solutions and under dilution. In vitro anticancer study established that Cu(II)/DDC-loaded nanoparticles could enable a combination therapy of Cu(DDC)2-based chemotherapy and chemodynamic therapy mediated by bioavailable Cu(II) that was not in the form of Cu(DDC)2. The in vivo antitumor results demonstrated that the Cu(II)/DDC-loaded nanoparticles showed superior antitumor efficacy to DSF/Cu(II). Our study provided a facile and effective strategy of highly stable coordination-mediated polymeric nanoparticles for combinational therapy of cancer.


Assuntos
Cobre , Ditiocarb , Nanopartículas , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Células A549 , Cobre/química , Cobre/farmacologia , Ditiocarb/química , Ditiocarb/farmacologia , Humanos , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/metabolismo , Neoplasias/patologia
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