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1.
Artigo em Inglês | MEDLINE | ID: mdl-34510345

RESUMO

Humans who are exposed to metals in road dust may have potential health risks through touching, ingesting, and inhaling the suspended road dust. There were limited studies to link seasonal emission sources to health risks from metals in road dust. In this study, metals in road dust from different functional areas were seasonally monitored. The contributions of the pollutant sources in study areas varied with seasons. By combining the source apportionment model (PMF), road dust emission model, and health risk models (HI: hazard index and ILCR: incremental lifetime carcinogenic risk), industrial and construction activity was identified as the crucial source of both the pollutants in road dust (29-47%), and the HI for adults (27-45%) and children (41-50%) in different seasons. The traffic non-exhaust emission dominated in the carcinogenic risks for children in spring (45%) and summer (36%). Factors such as seasons, particle size, metal bioavailability, human exposure time, and exposure area were all taken into consideration to avoid overestimating or underestimating health risks. The carcinogenic risks for children (1.6 E-06) and adults (2.8 E-06) exposed to Cr both exceed the minimum threshold (10-6). It means that the potential risks were acceptable but could not be completely neglected. Measured metals mainly posed hazard to human health through ingestion route. Pb and Mn, Fe and Mn were the main harmful elements that induced non-carcinogenic risks for adults and children, respectively. Effectively identifying the source-specific health risks in different seasons will help in the formulation of adaptive strategies to diminish the potential risks.

2.
Environ Res ; 204(Pt A): 111903, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34454932

RESUMO

The bacteria (including pathogenic bacteria) attached to road deposited sediments (RDS) may interrelate with the microbe in the atmosphere, soil and water through resuspension and wash-off, and is of great significance to human and ecological health. However, the characteristics of bacterial communities with different time scale on RDS were unknown to dates. Climate change prolonged the dry days between rain events in many areas, making the varied trend of bacterial communities might be more significant in short term. This study revealed the characteristics of bacterial communities on RDS in urban and suburban areas through seasonal and daily scale. The correlations between other factors (land use, particle size, and chemical components) and the bacterial communities were also analyzed. It was found that the season showed a higher association with the bacterial community diversity than land use and particle size in urban areas. The bacterial community diversity increased substantially throughout the short-term study period (41 days) and the variation of dominant bacteria could be fitted by quadratic function in suburbs. In addition, urbanization notably increased the bacterial community diversity, while the potential pathogenic bacteria were more abundant in the suburban areas, coarse RDS (>75 µm), and in spring. The chemical components on RDS showed special correlations with the relative abundance of dominant bacteria. The research findings would fill the knowledge gap on RDS bacterial communities and be helpful for the future research on the assembly process of bacterial communities.

3.
Waste Manag ; 133: 19-27, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34343864

RESUMO

The aim of this study is to examine the effect of bamboo sphere on the organic matter decomposition and humification of food waste composting. Food waste composting were carried out on four treatments, namely control (CK), 3% (T1), 6% (T2) and 9% (T3) (w/w) bamboo sphere treatments. Results showed that adding bamboo sphere facilitated the organic matter decomposition and increased the seed germination index. The number of cells in T2 treatment was always the highest during the composting process. Furthermore, the final humic substances and humic acid contents increased by 41.08% and 68.3%, respectively, in 6% bamboo sphere treatment. Fourier transform infrared and excitation-emission matrix fluorescence spectroscopy analysis revealed that adding bamboo sphere accelerated the humification of composting with more aromatic structures and humic acid-like substances. GC-MS studies revealed that the compost products of 6% bamboo sphere treatment had more ring structures, and thus enhanced the humification.


Assuntos
Compostagem , Eliminação de Resíduos , Alimentos , Substâncias Húmicas/análise , Esterco , Solo
4.
Nat Commun ; 12(1): 4230, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244494

RESUMO

Extracellular matrix protein-1 (ECM1) promotes tumorigenesis in multiple organs but the mechanisms associated to ECM1 isoform subtypes have yet to be clarified. We report in this study that the secretory ECM1a isoform induces tumorigenesis through the GPR motif binding to integrin αXß2 and the activation of AKT/FAK/Rho/cytoskeleton signaling. The ATP binding cassette subfamily G member 1 (ABCG1) transduces the ECM1a-integrin αXß2 interactive signaling to facilitate the phosphorylation of AKT/FAK/Rho/cytoskeletal molecules and to confer cancer cell cisplatin resistance through up-regulation of the CD326-mediated cell stemness. On the contrary, the non-secretory ECM1b isoform binds myosin and blocks its phosphorylation, impairing cytoskeleton-mediated signaling and tumorigenesis. Moreover, ECM1a induces the expression of the heterogeneous nuclear ribonucleoprotein L like (hnRNPLL) protein to favor the alternative mRNA splicing generating ECM1a. ECM1a, αXß2, ABCG1 and hnRNPLL higher expression associates with poor survival, while ECM1b higher expression associates with good survival. These results highlight ECM1a, integrin αXß2, hnRNPLL and ABCG1 as potential targets for treating cancers associated with ECM1-activated signaling.


Assuntos
Processamento Alternativo , Carcinoma Epitelial do Ovário/genética , Proteínas da Matriz Extracelular/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Ovarianas/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/terapia , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas da Matriz Extracelular/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Integrina alfaXbeta2/genética , Integrina alfaXbeta2/metabolismo , Estimativa de Kaplan-Meier , Camundongos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Ovário/patologia , Ovário/cirurgia , Fosforilação/genética , Prognóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA-Seq , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Chem Commun (Camb) ; 57(59): 7284-7287, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34212953

RESUMO

Natural DNA was employed for the first time as a phosphorization agent and carbon source to controllably synthesize a RuP2/N,P-codoped carbon composite by a simple "mix-and-pyrolyze" strategy, which displays higher activity for alkaline and acidic HER and neutral activity compared to Pt/C together with outstanding durability.


Assuntos
DNA de Cadeia Simples/química , Grafite/química , Hidrogênio/química , Rutênio/química , Animais , Catálise , Concentração de Íons de Hidrogênio , Nitrogênio/química , Fósforo/química , Espectroscopia Fotoeletrônica , Salmão/genética
6.
PLoS Genet ; 17(6): e1009575, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34157017

RESUMO

Over a decade of genome-wide association studies (GWAS) have led to the finding of extreme polygenicity of complex traits. The phenomenon that "all genes affect every complex trait" complicates Mendelian Randomization (MR) studies, where natural genetic variations are used as instruments to infer the causal effect of heritable risk factors. We reexamine the assumptions of existing MR methods and show how they need to be clarified to allow for pervasive horizontal pleiotropy and heterogeneous effect sizes. We propose a comprehensive framework GRAPPLE to analyze the causal effect of target risk factors with heterogeneous genetic instruments and identify possible pleiotropic patterns from data. By using GWAS summary statistics, GRAPPLE can efficiently use both strong and weak genetic instruments, detect the existence of multiple pleiotropic pathways, determine the causal direction and perform multivariable MR to adjust for confounding risk factors. With GRAPPLE, we analyze the effect of blood lipids, body mass index, and systolic blood pressure on 25 disease outcomes, gaining new information on their causal relationships and potential pleiotropic pathways involved.

7.
Front Microbiol ; 12: 663757, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34040597

RESUMO

Low-temperature biohydrometallurgy is implicated in metal recovery in alpine mining areas, but bioleaching using microbial consortia at temperatures <10°C was scarcely discussed. To this end, a mixed culture was used for chalcopyrite bioleaching at 6°C. The mixed culture resulted in a higher copper leaching rate than the pure culture of Acidithiobacillus ferrivorans strain YL15. High-throughput sequencing technology showed that Acidithiobacillus spp. and Sulfobacillus spp. were the mixed culture's major lineages. Cyclic voltammograms, potentiodynamic polarization and electrochemical impedance spectroscopy unveiled that the mixed culture enhanced the dissolution reactions, decreased the corrosion potential and increased the corrosion current, and lowered the charge transfer resistance and passivation layer impedance of the chalcopyrite electrode compared with the pure culture. This study revealed the mechanisms via which the mixed culture promoted the chalcopyrite bioleaching.

8.
Elife ; 102021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33899735

RESUMO

Recent genetic data can offer important insights into the roles of lipoprotein subfractions and particle sizes in preventing coronary artery disease (CAD), as previous observational studies have often reported conflicting results. We used the LD score regression to estimate the genetic correlation of 77 subfraction traits with traditional lipid profile and identified 27 traits that may represent distinct genetic mechanisms. We then used Mendelian randomization (MR) to estimate the causal effect of these traits on the risk of CAD. In univariable MR, the concentration and content of medium high-density lipoprotein (HDL) particles showed a protective effect against CAD. The effect was not attenuated in multivariable analyses. Multivariable MR analyses also found that small HDL particles and smaller mean HDL particle diameter may have a protective effect. We identified four genetic markers for HDL particle size and CAD. Further investigations are needed to fully understand the role of HDL particle size.

9.
Front Pharmacol ; 12: 629264, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33927617

RESUMO

Cisplatin-based regimens are commonly used for the treatment of nasopharyngeal carcinoma (NPC) in patients who receive concurrent chemoradiotherapy. The sensitivity of NPC cells to cisplatin is closely associated with the efficacy of radiation therapy. In this study, we established two radioresistant NPC cell lines, HONE1-IR and CNE2-IR, and found that both cell lines showed reduced sensitivity to cisplatin. RNA-sequence analysis showed that SLC1A6 was upregulated in both HONE1-IR and CNE2-IR cell lines. Downregulation of SLC1A6 enhanced cisplatin sensitivity in these two radioresistant NPC cell lines. It was also found that the expression of SLC1A6 was induced during radiation treatment and correlated with poor prognosis of NPC patients. Notably, we observed that upregulation of SLC1A6 led to elevating level of glutamate and the expression of drug-resistant genes, resulted in reduced cisplatin sensitivity. Our findings provide a rationale for developing a novel therapeutic target for NPC patients with cisplatin resistance.

10.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33649223

RESUMO

In the mammalian neocortex, projection neuron types are sequentially generated by the same pool of neural progenitors. How neuron type specification is related to developmental timing remains unclear. To determine whether temporal gene expression in neural progenitors correlates with neuron type specification, we performed single-cell RNA sequencing (scRNA-Seq) analysis of the developing mouse neocortex. We uncovered neuroepithelial cell enriched genes such as Hmga2 and Ccnd1 when compared to radial glial cells (RGCs). RGCs display dynamic gene expression over time; for instance, early RGCs express higher levels of Hes5, and late RGCs show higher expression of Pou3f2 Interestingly, intermediate progenitor cell marker gene Eomes coexpresses temporally with known neuronal identity genes at different developmental stages, though mostly in postmitotic cells. Our results delineate neural progenitor cell diversity in the developing mouse neocortex and support that neuronal identity genes are transcriptionally evident in Eomes-positive cells.


Assuntos
Diferenciação Celular , Neocórtex/embriologia , Células-Tronco Neurais/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteína HMGA2/metabolismo , Camundongos , Neocórtex/citologia , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/citologia , Neuroglia/citologia , Neuroglia/metabolismo , Fatores do Domínio POU/metabolismo , Proteínas Repressoras/metabolismo , Proteínas com Domínio T/metabolismo
11.
J Oral Biosci ; 63(1): 58-65, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33484883

RESUMO

OBJECTIVES: Tooth bleaching has become one of the most frequently requested esthetic procedures in dental practice. A side effect of bleaching is gingival irritation. This study examined the efficacy of propolis to treat gingival irritation caused by bleaching in vivo and in vitro. METHODS: Gingival irritation was mimicked by a mild burn injury to oral mucosa in young (10 week old) and aged (18 month old) mice. Propolis ointment was immediately applied to the burn area. After 24 h, gingiva was collected to determine the efficacy of propolis by hematoxylin and eosin staining and real-time polymerase chain reaction (PCR). RESULTS: Topical application of propolis ointment reduced the infiltration of inflammatory cells at irritated sites and promoted the repair of the mucosal epithelium in young and aged mice. It also suppressed the expression of IL-1ß and TNF-α and increased keratin 1 and 5 expression in the irritated gingiva. Propolis suppressed an increase in IL-1ß and TNF-α upon stimulation with H2O2 in young and SA-ß-gal-expressing senescent human gingival fibroblasts (HGFs) cultures. CONCLUSIONS: Propolis may be effective for mucosal repair in gingival irritation as it suppresses the expression of proinflammatory cytokines and promotes keratin expression.


Assuntos
Própole , Clareamento Dental , Animais , Gengiva , Peróxido de Hidrogênio , Camundongos , Extratos Vegetais , Própole/farmacologia
12.
PeerJ ; 8: e10255, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33282553

RESUMO

Background: Ovarian cancer is one of the leading causes of cancer-related death in women. The incidence of ovarian cancer is insidious, and the recurrence rate is high. The survival rate of ovarian cancer has not significantly improved over the past decade. Recently, immune checkpoint inhibitors such as those targeting CTLA-4, PD-1, or PD-L1 have been used to treat ovarian cancer. Therefore, a full analysis of the immune biomarkers associated with this malignancy is necessary. Methods: In this study, we used data from The Cancer Genome Atlas (TCGA) database to analyze the infiltration patterns of specific immune cell types in tumor samples. Data from the Gene Expression Omnibus (GEO) database was used for external validation. According to the invasion patterns of immune cells, we divided the ovarian cancer microenvironment into two clusters: A and B. These tumor microenvironment (TME) subtypes were associated with genomic and clinicopathological characteristics. Subsequently, a random forest classification model was established. Differential genomic features, functional enrichment, and DNA methylation were analyzed between the two clusters. The characteristics of immune cell infiltration and the expression of immune-related cytokines or markers were analyzed. Somatic mutation analysis was also performed between clusters A and B. Finally, multivariate Cox analysis was used to analyze independent prognostic factors. Results: The ovarian cancer TME cluster A was characterized by less infiltration of immune cells and sparse distribution and low expression of immunomodulators. In contrast, cytotoxic T cells and immunosuppressive cells were significantly increased in the ovarian cancer TME cluster B. Additionally, immune-related cytokines or markers, including IFN-γ and TNF-ß, were also expressed in large quantities. In total, 35 differentially methylated and expressed genes (DMEGs) were identified. Functional enrichment analyses revealed that the DMEGs in cluster B participated in important biological processes and immune-related pathways. The mutation load in cluster B was insignificantly higher than that of cluster A (p = 0.076). Multivariate Cox analysis showed that TME was an independent prognostic factor for ovarian cancer (hazard ratio: 1.33, 95% confidence interval: 1.01-1.75, p = 0.041). Conclusion: This study described and classified basic information about the immune invasion pattern of ovarian cancer and integrated biomarkers related to different immunophenotypes to reveal interactions between ovarian cancer and the immune system.

14.
Clin Drug Investig ; 40(7): 629-643, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32418051

RESUMO

BACKGROUND AND OBJECTIVE: Over the past 5 years, adjuvant treatment options for surgically resected stage III melanoma have expanded with the introduction of several novel immune checkpoint inhibitors and targeted therapies. Pembrolizumab, a programmed cell death protein 1 inhibitor, received US Food and Drug Administration approval in 2019 for resected high-risk stage III melanoma based on significantly longer recurrence-free survival versus placebo. This study evaluated the cost-effectiveness of pembrolizumab versus other adjuvant treatment strategies for resected high-risk stage III melanoma from a US health system perspective. METHODS: A Markov cohort-level model with four states (recurrence-free, locoregional recurrence, distant metastases, death) estimated costs and quality-adjusted life-years (QALYs) for pembrolizumab versus routine observation and other adjuvant comparators: ipilimumab in the overall population; and dabrafenib + trametinib in the BRAF-mutation positive (BRAF+) subgroup. Transition probabilities starting from recurrence-free were estimated through parametric multi-state modeling based on phase 3 KEYNOTE-054 (NCT02362594) trial data for pembrolizumab and observation, and network meta-analyses for other comparators. Post-recurrence transitions were modeled based on electronic medical records data and trials in advanced/metastatic melanoma. Utilities were derived using quality-of-life data from KEYNOTE-054 and literature. Costs of treatment, adverse events, disease management, and terminal care were included. RESULTS: Over a lifetime, pembrolizumab, ipilimumab, and observation were associated with QALYs of 9.24, 7.09, and 5.95 and total costs of $511,290, $992,721, and $461,422, respectively (2019 US dollars). Pembrolizumab was thus dominant (less costly, more effective) versus ipilimumab, with an incremental cost-effectiveness ratio of $15,155/QALY versus observation. In the BRAF+ subgroup, pembrolizumab dominated dabrafenib + trametinib and observation, decreasing costs by $62,776 and $11,250 and increasing QALYs by 0.93 and 3.10 versus these comparators, respectively. Results were robust in deterministic and probabilistic sensitivity analyses. CONCLUSIONS: As adjuvant treatment for resected stage III melanoma, pembrolizumab was found to be dominant and therefore cost-effective compared with the active comparators ipilimumab and dabrafenib + trametinib. Pembrolizumab increased costs relative to observation in the overall population, with sufficient incremental benefit to be considered cost-effective based on typical willingness-to-pay thresholds.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Melanoma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/economia , Análise Custo-Benefício , Feminino , Custos de Cuidados de Saúde , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Anos de Vida Ajustados por Qualidade de Vida
16.
Sci Total Environ ; 718: 137282, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32086087

RESUMO

Trace metals and nutrients attached on road deposited sediments (RDS) are the main source of non-point pollution to urban waterbodies causing ecological degradation and eutrophication problems. Mathematical models of the pollutant build-up process on road surfaces can be used to develop remediation measures. However, there was lack of research on the pollutant build-up process of various sized particles during a long dry period. This research investigated the build-up behaviors of specific pollutants in size-fractioned particles during 41 antecedent dry-weather days (ADDs), which was the longest build-up period ever studied. This research revealed that the pollution concentration exhibited a mono-growth behavior, while the pollutant mass followed a cyclic behavior during the study period. The time to peak and the build-up cycle of various pollutant mass were all highly associated with the particle characteristics, and the mass and concentration levels of pollutants in various sized particles were different. Furthermore, two important phenomena were found in this study: the bioavailability of phosphorus as well as the enrichment factors of metals all increased along with time during the build-up process. These findings provide new insights in non-point source pollution build-up and improve the water quality modelling.

17.
Nat Commun ; 11(1): 651, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005835

RESUMO

While single cell RNA sequencing (scRNA-seq) is invaluable for studying cell populations, cell-surface proteins are often integral markers of cellular function and serve as primary targets for therapeutic intervention. Here we propose a transfer learning framework, single cell Transcriptome to Protein prediction with deep neural network (cTP-net), to impute surface protein abundances from scRNA-seq data by learning from existing single-cell multi-omic resources.


Assuntos
Células/metabolismo , Perfilação da Expressão Gênica/métodos , Proteínas de Membrana/genética , Análise de Célula Única/métodos , Transcriptoma , Células/citologia , Humanos , Proteínas de Membrana/metabolismo , Redes Neurais de Computação , Análise de Sequência de RNA
18.
Nanomaterials (Basel) ; 10(1)2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31963179

RESUMO

The charge carrier behavior and dielectric properties of BaF2:Tb3+ nanocrystals have been studied by alternating current (AC) impedance spectroscopy. The electron and ion coexist in the transport process. The F- ion's contribution to the total conduction increases with the doping concentration up to 4% and then decreases. Tb doping leads to the increase of defect quantities and a variation of charge carrier transport paths, which causes the increase of the ion diffusion coefficient and the decreases of bulk and grain boundary resistance. When the Tb-doped concentration is higher than 4%, the effect of deformation potential scattering variation on the transport property is dominant, which results in the decrease of the ion diffusion coefficient and increases of bulk and grain boundary resistance. The conduction properties of our BaF2:Tb3+ nanocrystals are compared with previous results that were found for the single crystals of rare earth-doped BaF2. Tb doping causes increases of both the quantity and the probability of carrier hopping, and it finally leads to increases of BaF2 nanocrystals' permittivity in the low frequency region.

19.
Artigo em Inglês | MEDLINE | ID: mdl-31969794

RESUMO

Background: Pembrolizumab has been shown to improve overall survival (OS) and progression free survival (PFS) compared to ipilimumab in patients with ipilimumab-naïve advanced melanoma; however, there are no published data on the cost-effectiveness for pembrolizumab compared to standard-of-care treatments currently used in Hong Kong for advanced melanoma. Methods: A partitioned-survival model based on data from a recent randomized phase 3 study (KEYNOTE-006) and meta-analysis was used to derive time in PFS, OS, and post-progression survival for pembrolizumab and chemotherapy, such as dacarbazine (DTIC), temozolomide (TMZ), and the paclitaxel-carboplatin combination (PC). A combination of clinical trial data, published data, results of meta-analysis, and melanoma registry data was used to extrapolate PFS and OS curves. The base-case time horizon for the model was 30 years with costs and health outcomes discounted at a rate of 5% per year. Individual patient level data on utilities and frequencies of adverse events were obtained from the final analysis of KEYNOTE-006 (cut-off date: 3-Dec-15) for pembrolizumab. Cost data included drug acquisition, treatment administration, adverse event management, and clinical management of advanced melanoma. The distribution of patient weight from the Hong Kong population was applied to calculate the drug costs. Analyses were performed from a payer's perspective. The incremental cost effectiveness ratio (ICER) expressed as cost in US Dollars (USD) per quality-adjusted life years (QALYs) was the main outcome. Results: In base-case scenario, the ICER for pembrolizumab as a first-line treatment for advanced melanoma was USD49,232 compared to DTIC, with the ICER values lower than cost-effectiveness threshold in Hong Kong. Results comparing pembrolizumab to TMZ and to PC were similar to that when compared to DTIC. Probability sensitivity analyses showed that 99% of the simulated ICERs were below three times the Gross Domestic Product (GDP) per capita for Hong Kong (currently at $119,274//QALY threshold). In a scenario analysis comparing pembrolizumab with ipilimumab, the estimated ICER was USD8,904. Conclusions: Pembrolizumab is cost-effective relative to chemotherapy (DTIC, TMZ and PC), and highly-cost-effective compared to ipilimumab, for the first-line treatment of advanced melanoma in Hong Kong.

20.
Oncogenesis ; 8(10): 59, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597912

RESUMO

Chemoresistance has been the biggest obstacle in ovarian cancer treatment, and STAT3 may play an important role in chemoresistance of multiple cancers, but the underlying mechanism of STAT3 in ovarian cancer chemoresistance has long been truly illusive, particularly in association with p53 and RAS signaling. In this study, by using wild type, constitutive active, and dominant negative STAT3 constructs, wild-type p53, and RAS-mutant V12, we performed a series of in vitro and in vivo experiments by gene overexpression, drug treatment, and animal assays. We found that phosphorylation of STAT3 Y705 but not S727 promoted cancer cell EMT and metastasis through the Slug-mediated regulation of E-cadherin and Vimentin. The phosphorylation of STAT3 at Y705 also activated the MAPK and PI3K/AKT signaling to inhibit the ERS-mediated autophagy through down-regulation of pPERK, pelf2α, ATF6α, and IRE1α, which led to increased cisplatin resistance. Induction of wild type p53 in STAT3-DN-transfected cells further diminished the chemoresistance and tumor growth through the upregulation of the MAPK- and PI3K/AKT-mediated ERS and autophagy. Introduction of STAT3-DN deprived the RASV12-induced ERS, autophagy, oncogenicity, and cisplatin resistance, whereas introduction of p53 in STAT3-DN/RASV12 expressing cells induced additional tumor retardation and cisplatin sensitivity. Thus, our data provide strong evidence that the crosstalk between STAT3 and p53/RAS signaling controls ovarian cancer cell metastasis and cisplatin resistance via the Slug/MAPK/PI3K/AKT-mediated regulation of EMT and autophagy.

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