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1.
Mol Cell ; 81(16): 3339-3355.e8, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34352206

RESUMO

Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N7-methylguanosine (m7G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo. Mechanistically, m7G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m7G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m7G tRNA modification in promoting ICC tumorigenesis and progression in vivo. Our study uncovers the important physiological function and mechanism of METTL1-mediated m7G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression.


Assuntos
Colangiocarcinoma/genética , Proteínas de Ligação ao GTP/genética , Metiltransferases/genética , Biossíntese de Proteínas , Animais , Carcinogênese/genética , Colangiocarcinoma/patologia , Progressão da Doença , Receptores ErbB/genética , Guanosina/análogos & derivados , Guanosina/genética , Humanos , Camundongos , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , RNA de Transferência/genética
2.
BMC Med Educ ; 21(1): 378, 2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34246265

RESUMO

BACKGROUND: Among Chinese medical students, there is a high prevalence of mental health-related issues and low empathy. Effective strategies to improve this situation are lacking. This study aims to investigate the efficacy of the intervention courses designed to enhance the mental health and empathy of senior Chinese medical students. METHODS: A total of 146 3rd - and 4th -year medical students were randomized to an intervention group (n = 74) and a control group (n = 72). A pilot study including 5 pre-clinical students and 5 interns was first carried out to determine the themes and content of the intervention courses. The designed courses were delivered in the intervention group once a month three times, while the control group had no specific intervention. Five self-assessment questionnaires, including the General Self-Efficacy (GSE) scale, Medical Outcomes Study Short Form 8 (SF-8), Patient Health Questionnaire-9 (PHQ-9), Maslach Burnout Inventory (MBI), and Jefferson Scale of Empathy-Health Care Provider Student version (JSE-HPS), were completed by the students before and one month after the courses to evaluate their levels of self-efficacy (SE), quality of life (QoL), depression, burnout, and empathy, respectively. Qualitative data were collected via e-mail two years after the intervention. RESULTS: Compared to the control group, the intervention group showed significantly higher scores for empathy (111.0 [IQR 102.0, 118.0] vs. 106.0 [IQR 93.0, 111.5]; P = .01) and QoL (32.0 [IQR 28.0, 35.0] vs. 29.5 [IQR 26.0, 34.0]; P = .04). The rate of depression was significantly lower in the intervention group than in the control group (13.5 % vs. 29.2 %; chi-square test, P = .02). However, no significant differences in self-efficacy (25.6 ± 4.8 vs. 24.3 ± 6.3; P = .16) or burnout (27.0 % vs. 34.7 %; Chi-square test, P = .31) were observed between the two groups. CONCLUSIONS: The intervention courses had a positive impact on mental well-being and empathy in senior Chinese medical students, which might help provide novel information for their incorporation into the medical school curriculum. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02645643; Date of registration: 05/01/2016.


Assuntos
Qualidade de Vida , Estudantes de Medicina , China , Empatia , Humanos , Saúde Mental , Projetos Piloto
3.
ACS Nano ; 15(3): 5355-5365, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33631928

RESUMO

Cellulose fiber (CF) paper is a low-cost, sustainable, and flexible substrate, which has gained increasing interest recently. Before practical usage, the functionalization of the pristine CF paper is indispensable to meet requirements of specific applications. Different from conventional surface modification or physical mixing methods, we report in situ growth of ultralong hydroxyapatite nanowires (HAPNWs) with lengths larger than 10 µm on the CF paper. HAPNWs are radially aligned on the surface of CFs, creating a micro/nanoscale hierarchical structure. By means of the excellent ion exchange ability of HAP and the hierarchical structure, the functions of the CF paper can be easily customized. As a proof-of-concept, we demonstrate two kinds of functional CF paper: (1) the photoluminescent CF paper by doping Eu3+ and Tb3+ ions into the crystal lattice of HAPNWs and (2) the superhydrophobic CF paper by coating poly(dimethylsiloxane) on the HAPNW hierarchical structure, which can be applied for self-cleaning and oil/water separation. It is expected that an in situ growth of ultralong HAPNWs will provide an instructive guideline for designing a CF paper with specific functions.

4.
Cancer Lett ; 503: 1-10, 2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33444692

RESUMO

Ablative treatment evokes antitumor immunity, but knowledge on the emerging irreversible electroporation (IRE)-induced immunity in hepatocellular carcinoma (HCC) is limited. To investigate the immune effects induced by IRE and its role in preventing post-ablation HCC progression, a C57BL/6J mouse model bearing subcutaneous H22 hepatoma was employed. IRE treatment significantly suppresses HCC growth, and treated mice are tumor-free after secondary tumor injection and show increased splenic interferon-gamma (IFN-γ)+CD8+ T cells. Additionally, more CD8+ T and dendritic cells, but not CD4+ T, B or NK cells, infiltrate into peri-ablation zones after IRE at day 7. Depletion of CD8+ T cells induces local tumor regrowth and distant metastasis after IRE. Vaccination using IRE-processed H22 lysates prevents tumorigenesis in mice, suggesting a protective immune response. IRE also alleviates immunosuppression by reducing local and splenic Treg and PD-1+ T cells. Regarding mechanism, IRE induces cell necrosis and significant release of danger-associated molecular patterns including ATP, high mobility group box 1 and calreticulin that are pivotal to CD8+ T cell immunity. Together, IRE is a promising approach to evoke CD8+ T cell immunity, which help prevent post-ablation HCC progression.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular/terapia , Interferon gama/metabolismo , Neoplasias Hepáticas/terapia , Ablação por Radiofrequência/métodos , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Progressão da Doença , Eletroporação , Células Hep G2 , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Baço/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
EBioMedicine ; 60: 102979, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32980692

RESUMO

BACKGROUND: Log odds of positive lymph nodes (LODDS) classification showed superiority over 8th edition N staging in predicting survival of small bowel adenocarcinoma (SBA) patients. The aim of this study was to develop and validate the Tumor, LODDS, and Metastasis (TLM) staging of SBA. METHODS: Totally 1789 SBA patients from the Surveillance, Epidemiology, and End Results (SEER) database between 1988-2010, 437 patients from SEER database between 2011-2013 and 166 patients from multicenters were categorized into development, validation and test cohort, respectively. The TLM staging was developed in the development cohort using Ensemble Algorithm for Clustering Cancer Data (EACCD) method. C-index was used to assess the performance of the TLM staging in predicting cancer-specific survival (CSS) and was compared with the traditional 8th edition TNM staging. FINDINGS: Four-category TLM staging designed for the development cohort showed higher discriminatory power than TNM staging in predicting CSS in the development cohort (0.682 vs. 0.650, P < 0.001), validation cohort (0.682 vs. 0.654, P = 0.022), and test cohort (0.659 vs. 0.611, P = 0.023), respectively. TLM staging continued to show its higher predictive efficacy than the 8th TNM in TNM stage II/III patients or in patients with lymph node yield less than 8. INTERPRETATION: TLM staging showed a better prognostic performance than the 8th TNM staging especially TNM stage II/III or patients with lymph node yield less than 8 and therefore, could serve to complement the TNM staging in patients with SBA. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

6.
Qual Life Res ; 29(3): 629-638, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31782019

RESUMO

PURPOSE: Adenoid hypertrophy (AH) is common among young children. Adenoid-based surgery and drug therapy could be applied for symptomatic AH patients, yet the treatment decision is difficult to make due to the diverse cost and efficacy between these two treatments. METHODS: A Markov simulation model was designed to estimate the cost-effectiveness (CE) of the adenoid-based surgery and the drug therapy for symptomatic AH patients. Transition probabilities, costs and utilities were extracted from early researches and expert opinions. Simulations using two set of parameter inputs for China and the USA were performed. Primary outcome was cost per QALY gained over a 6-year period. Deterministic and probabilistic sensitivity analyses were also conducted. RESULTS: The utility for the surgery group and the drug group were 4.10 quality-adjusted life years (QALYs) and 3.58 QALYs, respectively. The cost of the surgery group was more than that of the drug group using model parameters specific to China ($1069.0 vs. $753.7) but was less for the USA ($1994.4 vs. $3977.7). Surgery was dominant over drug therapy when US specific parameters were used. Surgery group had an ICER of $604.0 per QALY when parameters specific to China was used. CONCLUSION: Surgery is cost-effective in the simulations for both China and the USA at WTP thresholds of $9633.1 and $62,517.5, respectively.


Assuntos
Tonsila Faríngea/fisiopatologia , Hipertrofia/tratamento farmacológico , Hipertrofia/cirurgia , Análise Custo-Benefício , Humanos , Cadeias de Markov
7.
Cancer Med ; 8(4): 1530-1539, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30864247

RESUMO

BACKGROUND: The role of transarterial chemoembolization (TACE) as the standard treatment for intermediate-stage hepatocellular carcinoma (HCC) is being challenged by increasing studies supporting liver resection (LR); but evidence of survival benefits of LR is lacking. We aimed to compare the overall survival (OS) of LR with that of TACE for the treatment of intermediate-stage HCC in cirrhotic patients. METHODS: A Markov model, comparing LR with TACE over 15 years, was developed based on the data from 31 literatures. Additionally, external validation of the model was performed using a data set (n = 1735; LR: 701; TACE: 1034) from a tertiary center with propensity score matching method. We conducted one-way and two-way sensitivity analyses, in addition to a Monte Carlo analysis with 10 000 patients allocated into each arm. RESULTS: The mean expected survival times and survival rates at 5 years were 77.8 months and 47.1% in LR group, and 48.6 months and 25.7% in TACE group, respectively. Sensitivity analyses found that initial LR was the most favorable treatment. The 95% CI for the difference in OS was 2.42-2.46 years between the two groups (P < 0.001). In the validation set, the 5-year survival rates after LR were significantly better than those after TACE before (40.2% vs. 25.9%, P < 0.001) and after matching (43.2% vs 30.9%, P < 0.001), which was comparable to the model results. CONCLUSIONS: For cirrhotic patients with resectable intermediate-stage HCC, LR may provide survival benefit over TACE, but large-scale studies are required to further stratify patients at this stage for different optimal treatments.


Assuntos
Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Hepatectomia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Carcinoma Hepatocelular/mortalidade , Quimioembolização Terapêutica/efeitos adversos , Quimioembolização Terapêutica/métodos , Hepatectomia/efeitos adversos , Hepatectomia/métodos , Humanos , Neoplasias Hepáticas/mortalidade , Cadeias de Markov , Estadiamento de Neoplasias , Prognóstico , Pontuação de Propensão , Taxa de Sobrevida , Resultado do Tratamento
8.
PLoS One ; 13(12): e0208783, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30586373

RESUMO

OBJECTIVES: The objective of this study was to assess the reliability of online information, as provided by three major search engines in China, about the usage of antiepileptic drugs (AEDs) during pregnancy. METHOD: Over eight weeks, six physicians conducted a literature search on six computers and six smartphones at a frequency of once per week. During each web search on each computer and smartphone, three major search engines in China were used, namely, Baidu, Sogou and 360. The search terms used were a combination of words, including one AED name (valproate/oxcarbazepine/levetiracetam/lamotrigine) and one Chinese word ("huaiyun" or "renshen", which means pregnancy in Chinese). The top ten websites retrieved from each search were recorded. After the content of each website was evaluated, the sites were categorized into 9 types. Meanwhile, commercial advertisements on each web page were also registered. RESULTS: A total of 16,411 search results were assessed. After excluding the redundant web pages, 4840 search results were included in the data analysis. Only 12.05% of the search results were reliable, 47.75% were partly reliable, and 40.21% were unreliable. A total of 4139 (85.52%) webpages contained commercial advertisements. The results from a multivariate analysis suggested that websites with no advertisements and professional websites have an independent positive impact on reliability. CONCLUSION: Overall, little information on AED usage during pregnancy provided by major search engines in China was reliable. PRACTICE IMPLICATIONS: Accurate and professional online information for female patients with epilepsy should be provided through major efforts by the government, search engine companies, professional websites and epilepsy physicians.


Assuntos
Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Educação em Saúde , Internet , Complicações na Gravidez/tratamento farmacológico , Ferramenta de Busca , China , Feminino , Humanos , Gravidez , Reprodutibilidade dos Testes
9.
BMC Cancer ; 18(1): 392, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29621988

RESUMO

BACKGROUND: Sorafenib and transarterial chemoembolization (TACE) might both provide survival benefit for advanced hepatocellular carcinoma (HCC). Adopting either as a first-line therapy carries major cost and resource implications. We aimed to estimate the cost-effectiveness of sorafenib and TACE in advanced HCC. METHODS: A Markov model was constructed in a hypothetical cohort of patients aged 60 years with advanced HCC and Child-Pugh A/B cirrhosis over a 2-year time frame. Three strategies (full or dose-adjusted sorafenib and TACE) were compared in two cost settings: China and the USA. Transition probabilities, utility and costs were extracted from systematic review of 27 articles. Sensitivity analysis and Monte Carlo analysis were conducted. RESULTS: Full and dose-adjusted sorafenib respectively produced 0.435 and 0.482 quality-adjusted life years (QALYs) while TACE produced 0.375 QALYs. The incremental cost-effectiveness ratio (ICER) of full-dose sorafenib versus TACE was $101,028.83/QALY in China whereas full-dose sorafenib is a dominant strategy (ICER of -$1,014,507.20/ QALY) compared with TACE in the USA. Compared to full-dose sorafenib, dose-adjusted sorafenib was the dominant strategy with the negative ICERs in both China (-$132,238.94/QALY) and the USA (-$230,058.09/QALY). However, dose-adjusted sorafenib is not available currently, so full-dose sorafenib should be compared with TACE. As the acceptability curves shown, full-dose sorafenib was the optimal strategy at the accepted thresholds of WTP in these two countries. Specifically, full-dose sorafenib was the cost-effective treatment compared with TACE if a WTP was set above $21,670 in the USA, whereas in China, TACE could be more favorable than full-dose sorafenib if a WTP was set below $10,473. CONCLUSIONS: Dose-adjusted sorafenib may be cost-effective compared to full-dose sorafenib or TACE for advanced HCC patients. However, when confining the comparisons between full-dose sorafenib and TACE, full-dose sorafenib was cost-effective for these patients, under the accepted thresholds of WTP.


Assuntos
Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Quimioembolização Terapêutica/métodos , Análise Custo-Benefício , Humanos , Neoplasias Hepáticas/epidemiologia , Cadeias de Markov , Método de Monte Carlo , Metástase Neoplásica , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Anos de Vida Ajustados por Qualidade de Vida , Sorafenibe/administração & dosagem , Sorafenibe/efeitos adversos , Resultado do Tratamento
10.
Oncogene ; 37(26): 3514-3527, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29559743

RESUMO

Recent studies indicated that insufficient radiofrequency ablation (RFA) could endow hepatocellular carcinoma (HCC) with higher aggressive potential. Stress-induced phosphoprotein 1 (STIP1), which was found highly expressed in HCC, is a chaperone molecule mediating cell homeostasis under thermal stress. We aimed to explore the role of STIP1 on the metastasis of residual HCC after RFA. Mice model with orthotopic HCC implants or caudal vein injection were employed to assess potential of lung metastasis and/or intrahepatic metastasis (IHM) of HCC cells. Cell culture model was used to determine cell invasion, mesenchymal marker genes expression, and underlying molecular mechanisms. Clinical specimens were collected to analyze the relationship between STIP1 and clinical outcome. We found that insufficient RFA elicited more IHM of HCCLM3 tumors, which could be reduced by silencing STIP1. Knockdown of STIP1 also significantly decreased lung metastatic potential of HCCLM3 cells. In vitro, HCCLM3 and HepG2 displayed a spindle-shaped morphology with upregulation of STIP1 and mesenchymal markers after sublethal heat exposure. Mechanistically, heat exposure induced the formation of STIP1-heat shock protein 90 (HSP90) complex, which could shuttle epithelial transcription repressor Snail1 into nucleus and regulate mesenchymal gene transcription. Blocking the HSP90-STIP1 complex reduced the invasive potential of HCC cells after heat exposure. Using clinical specimen, we found that STIP1 was expressed significantly higher in metastatic tumor tissues and in sera from metastatic HCC patients (p < 0.05). The high expression of STIP1 was significantly linked to shorter recurrence-free survival (p < 0.05). To sum up, our study found that STIP1 is positively associated with the sublethal heat-induced cancer cell metastasis through mediating the mesenchymal gene transcription. Blocking STIP1 activity may suppress HCC cell metastatic potential after RFA.


Assuntos
Carcinoma Hepatocelular/patologia , Ablação por Cateter/métodos , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico/metabolismo , Neoplasias Hepáticas/patologia , Ablação por Radiofrequência/métodos , Fatores de Transcrição da Família Snail/metabolismo , Animais , Carcinoma Hepatocelular/mortalidade , Linhagem Celular Tumoral , Movimento Celular/genética , Modelos Animais de Doenças , Proteínas de Choque Térmico/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Interferência de RNA , RNA Interferente Pequeno/genética
11.
Mater Sci Eng C Mater Biol Appl ; 71: 51-59, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27987738

RESUMO

The rare earth ion doped upconversion nanoparticles (UCNPs) synthesized by hydrophobic organic ligands possess poor solubility and low fluorescence quantum yield in aqueous media. To conquer this issue, NaYF4:Yb3+/Tm3+ UCNPs, synthesized by a hydrothermal method, were coated with F127 and then assembled with chitosan to fabricate the chitosan/NaYF4:Yb3+/Tm3+ composite beads (CS/NaYF4:Yb3+/Tm3+ CBs) by Pickering emulsion system. The characterization results revealed that the as-synthesized NaYF4:Yb3+/Tm3+ UCNPs with an average size of 20nm exhibited spherical morphology, high crystallinity and characteristic emission upconversion fluorescence with an overall blue color output. The NaYF4:Yb3+/Tm3+ UCNPs were successfully conjugated on the surface of chitosan beads by the gelling of emulsion droplets. The resultant CS/NaYF4:Yb3+/Tm3+ CBs showed good upconversion luminescent property, drug-loading capacity, release performance and excellent biocompatibility, exhibiting great potentials in targeted drug delivery and tissue engineering with potential tracking capability and lasting release performance.


Assuntos
Quitosana/química , Fluoretos/química , Nanopartículas/química , Túlio/química , Itérbio/química , Ítrio/química , Avaliação Pré-Clínica de Medicamentos , Emulsões , Nanopartículas/ultraestrutura
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