Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Oncol Res Treat ; : 1-7, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32187596

RESUMO

BACKGROUND: The aim of the current study was to estimate two protocols for HER2-negative locally recurrent or metastatic breast cancer patients, bevacizumab combined with paclitaxel versus bevacizumab combined with capecitabine, from the economic view. METHODS: The process of HER2-negative locally recurrent or metastatic breast cancer treated with bevacizumab combined with paclitaxel or bevaciz-umab combined with capecitabine made up the decision model in our analysis. The primary objective was to show the incremental cost-effectiveness ratio (ICER). The critical parameters and the robustness of the model on the results of the analysis were assessed by univariate sensitivity analysis and probabilistic sensitivity analysis. RESULTS: In the analysis, quality-adjusted life year (QALY) increased by 0.4 with bevacizumab plus paclitaxel compared with bevacizumab plus capecitabine, and incremental cost of USD 4,340.46. Therefore, the ICER was USD 27,252.875. The ICER exceeded the commonly accepted willingness to pay on the recommendation of the World Health Organization, which is defined as 3 times of the gross domestic product per capita of China in the model (USD 25,840.88 per QALY). On univariate analysis, it is found that the most significant affecting factor is the cost of progression-free survival state in the bevacizumab plus paclitaxel group. Besides, bevacizumab plus paclitaxel had a 47.8% probability of being cost-effective versus bevacizu-mab plus capecitabine according to probabilistic sensitivity analysis. CONCLUSIONS: Based on the results of the analysis, bevacizumab plus paclitaxel is unlikely to be a cost-effective option for patients with HER2-negative locally recurrent or metastatic breast cancer compared with bevacizumab plus capecitabine.

2.
Pharmacol Ther ; : 107526, 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32173559

RESUMO

The proteasome is a well-identified therapeutic target for cancer treatment. It acts as the main protein degradation system in the cell and degrades key mediators of cell growth, survival and function. The term "proteasome" embraces a whole family of distinct complexes, which share a common proteolytic core, the 20S proteasome, but differ by their attached proteasome activators. Each of these proteasome complexes plays specific roles in the control of cellular function. In addition, distinct proteasome interacting proteins regulate proteasome activity in subcellular compartments and in response to cellular signals. Proteasome activators and regulators may thus serve as building blocks to fine-tune proteasome function in the cell according to cellular needs. Inhibitors of the proteasome, e.g. the FDA approved drugs Velcade™, Kyprolis™, Ninlaro™, inactivate the catalytic 20S core and effectively block protein degradation of all proteasome complexes in the cell resulting in inhibition of cell growth and induction of apoptosis. Efficacy of these inhibitors, however, is hampered by their pronounced cytotoxic side-effects as well as by the emerging development of resistance to catalytic proteasome inhibitors. Targeted inhibition of distinct buiding blocks of the proteasome system, i.e. proteasome activators or regulators, represents an alternative strategy to overcome these limitations. In this review, we stress the importance of the diversity of the proteasome complexes constituting an entire proteasome system. Our building block concept provides a rationale for the defined targeting of distinct proteasome super-complexes in disease. We thereby aim to stimulate the development of innovative therapeutic approaches beyond broad catalytic proteasome inhibition.

3.
J Cell Physiol ; 235(3): 2310-2324, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31489649

RESUMO

Radiation-induced pulmonary fibrosis (RIPF) is a life-threatening complication of thoracic radiotherapy, which contributes to continued deterioration in pulmonary function. Sphingosine-1 phosphate receptor 3 (S1PR3) has been identified as a crucial molecule in fibrosis. Accumulating evidence indicated that the inhibition of the S1PRs ameliorates fibrogenesis. Thus, this study aims to explore whether S1PR3 participates in RIPF and elucidates the molecular mechanisms underlying S1PR3-modulated epithelial-mesenchymal transition (EMT) in transforming growth factor-ß1-induced pulmonary epithelia. A recombinant adeno-associated viral-mediated S1PR3 (AAV-S1PR3) gene therapy analyzed the effect of S1PR3 gene deficiency on the altered histology structure and molecular mechanisms in the lung of mice with whole-lung irradiation. Compared with the AAV-negative control mice, AAV-mediated S1PR3 knockdown in the lung of mice attenuated pulmonary fibrosis induced by the radiation, as indicated by the alleviation of collagen accumulation, lessened histopathological alterations, and the suppression of inflammatory cells infiltration. S1PR3 deficiency reversed the RIPF concomitantly with abrogated EMT-related protein (α-smooth muscle actin). Consistently, S1PR3-deficient pulmonary epithelia inhibited the EMT process changes and fibrosis formation. Furthermore, S1PR3 was designated as one of the target genes for microRNA-495-3p (miR-495-3p). The inhibition of miR-495-3p promoted the expression of S1PR3 in pulmonary epithelia, whereas the overexpression of miR-495-3p inhibited the S1PR3/SMAD2/3 pathway and suppressed the EMT process. Collectively, miR-495-3p might be a negative regulator of the EMT process in fibrosis formation by inhibiting the targeted S1PR3 gene. These results established a link between the S1PR3 gene, the EMT process, and the fibrosis, suggesting the pharmacological blockage of S1PR3 as a potential therapeutic strategy for RIPF.

4.
Anal Chem ; 91(24): 15818-15825, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31743002

RESUMO

Activity-based chemical proteomics approaches used for identifying cellular targets of drugs are mainly dependent on the availability of probes derived from drugs. However, all chemical probes are structurally different from the drugs themselves and cannot fully mimic the real actions of drugs in cells. Here we present a concise and unbiased immunoaffinity-based strategy for identifying covalent drug targets in vivo. By using the specific antibody, we not only confirm the well-known ibrutinib-binding target BTK, but also identify some previously undescribed strongly binding proteins, such as CKAP4 in human cell lines and TAP1 in mouse organs. The observed target profiles between species may partially explain why certain drug candidates are very effective in mice but not in humans. This approach avoids the chemical modification of drugs, eliminates the nonspecific bindings of chemical probes, and allows to unbiasedly decode the underlying mechanisms of action of covalent drugs.

5.
J Cell Mol Med ; 23(12): 7985-7998, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31596045

RESUMO

Non-tuberculous mycobacteria (NTM), also known as an environmental and atypical mycobacteria, can cause the chronic pulmonary infectious diseases. Macrophages have been suggested as the main host cell to initiate the innate immune responses to NTM infection. However, the molecular mechanism to regulate the antimicrobial immune responses to NTM is still largely unknown. Current study showed that the NTM clinical groups, Mycobacterium abscessus and Mycobacterium smegmatis, significantly induced the M1 macrophage polarization with the characteristic production of nitric oxide (NO) and marker gene expression of iNOS, IFNγ, TNF-α, IL1-ß and IL-6. Interestingly, a non-histone nuclear protein, HMGN2 (high-mobility group N2), was found to be spontaneously induced during NTM-activated M1 macrophage polarization. Functional studies revealed that HMGN2 deficiency in NTM-infected macrophage promotes the expression of M1 markers and the production of NO via the enhanced activation of NF-κB and MAPK signalling. Further studies exhibited that HMGN2 knock-down also enhanced IFNγ-induced M1 macrophage polarization. Finally, we observed that silencing HMGN2 affected the survival of NTM in macrophage, which might largely relevant to enhanced macrophage polarization into M1 phenotype under the NTM infection. Collectively, current studies thus suggested a novel function of HMGN2 in regulating the anti-non-tuberculous mycobacteria innate immunity of macrophage.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31597496

RESUMO

Purpose: This study aimed to investigate the cost-effectiveness of adjuvant treatments in resected pancreatic cancer. Methods: A Markov model was developed to mimic the disease process of postoperative pancreatic cancer, encompassing three health states (relapse-free survival, recurrent disease, and death). Health outcomes and utility scores were derived from the phase III trial and available literature. Cost data were calculated using standard fee data from the West China Hospital for 2017. One-way sensitivity analyses and probabilistic sensitivity analyses were developed to explore model uncertainty. Results: Treatment with S-1 was estimated to yield 1.61 quality-adjusted life-years (QALYs) at a cost of $25,696, whereas treatment with gemcitabine yielded 1.27 QALYs at a cost of $28,930. The incremental cost-effectiveness ratio of S-1 versus gemcitabine was $-9,490 per QALY. Based on the willingness-to-pay threshold of $25,841 per QALY, the net monetary benefit (NMB) was $15,786 for S-1 and $3,727 for gemcitabine, generating the incremental NMB of $12,059. A probabilistic sensitivity analysis revealed that the probabilities of S-1 and gemcitabine being cost-effective were 92% and 8%, respectively. Results were robust to changes in parameters. Conclusion: Adjuvant therapy using S-1 is a cost-effective alternative compared to gemcitabine in patients with postoperative pancreatic cancer from the Chinese societal perspective.

7.
Mol Psychiatry ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444471

RESUMO

Psychiatric disorders are a collection of heterogeneous mental disorders arising from a contribution of genetic and environmental insults, many of which molecularly converge on transcriptional dysregulation, resulting in altered synaptic functions. The underlying mechanisms linking the genetic lesion and functional phenotypes remain largely unknown. Patient iPSC-derived neurons with a rare frameshift DISC1 (Disrupted-in-schizophrenia 1) mutation have previously been shown to exhibit aberrant gene expression and deficits in synaptic functions. How DISC1 regulates gene expression is largely unknown. Here we show that Activating Transcription Factor 4 (ATF4), a DISC1 binding partner, is more abundant in the nucleus of DISC1 mutant human neurons and exhibits enhanced binding to a collection of dysregulated genes. Functionally, overexpressing ATF4 in control neurons recapitulates deficits seen in DISC1 mutant neurons, whereas transcriptional and synaptic deficits are rescued in DISC1 mutant neurons with CRISPR-mediated heterozygous ATF4 knockout. By solving the high-resolution atomic structure of the DISC1-ATF4 complex, we show that mechanistically, the mutation of DISC1 disrupts normal DISC1-ATF4 interaction, and results in excessive ATF4 binding to DNA targets and deregulated gene expression. Together, our study identifies the molecular and structural basis of an DISC1-ATF4 interaction underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders.

8.
Biosci Rep ; 39(8)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366566

RESUMO

In the present study, we aim to examine the relationship between genetic polymorphism and transcriptional expression of cyclic AMP response element binding protein (CREBBP) and the risk of diffuse large B-cell lymphoma (DLBCL). Two hundred and fifty healthy individuals and 248 DLBCL patients participated in the present study. The CREBBP rs3025684 polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The mRNA expression of CREBBP was tested by the real-time quantitative PCR (RT-qPCR). The allele A frequency of CREBBP rs3025684 in DLBCL patients was obviously higher than that of controls (P=0.01). No significant difference was detected between CREBBP rs3025684 polymorphism and clinical characteristics of DLBCL patients when subgrouped according to different parameters. The results demonstrated that the allele A of CREBBP rs3025684 increased the susceptibility to DLBCL (P=0.004), with a worse overall survival (OS) rate (P=0.002), a worse progression-free survival (PFS) rate (P=0.033) and poor prognosis (P=0.003) in DLCBL patients. Furthermore, the expression of CREBBP mRNA was considerably decreased in DLBCL patients as compared with controls (P<0.001), and the expression in patients with GG genotype was up-regulated in comparison with patients with GA and AA genotype (P=0.016 and P=0.001, respectively). However, no statistical differences were found in OS (P=0.201) and PFS (P=0.353) between the lower CREBBP mRNA level subgroup and higher CREBBP mRNA level subgroup. These data suggested that the CREBBP gene may be an important prognostic factor in DLBCL patients and perform an essential function in the development of DLBCL.

9.
J Orthop Res ; 37(11): 2348-2357, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31254413

RESUMO

Early diagnosis and prevention of glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) continues to be a challenging problem for clinicians and researchers. However, the role of circulating biomarkers for GC-induced ONFH, which may reveal individual susceptibility and facilitate earlier diagnosis, remains to be determined. The aim of this study was to identify potential biomarkers that may predict early GC-induced ONFH. A total of 123 patients scheduled for initial systemic GC therapy were enrolled in this prospective nested case-control study. The serum concentrations of 13 potential biomarkers were measured in seven patients with GC-induced ONFH, diagnosed instantly after short-term use of GCs and in 20 controls who did not develop osteonecrosis despite similar GC therapy. Biomarkers were measured both before and after taking GCs to identify any differences in marker levels and the changes during GC therapy between two groups. Type I collagen cross-linked C-telopeptide (ß-CTX; p = 0.000) was significantly lower, high-density lipoprotein cholesterol (p = 0.092) and apolipoprotein (apo)-B/apo-A1 (p = 0.085) tended to be lower and higher, respectively, before GC treatment in osteonecrosis group. After GC therapy, ß-CTX (p = 0.014) was significantly lower and amino terminal telopeptide of procollagen type I (PINP; p = 0.068) tended to be lower in the osteonecrosis group. As secondary outcomes, we observed remarkable changes in nine potential biomarkers following short-term GC therapy in both groups. In conclusion, we found that ß-CTX, could potentially be used to predict GC-induced ONFH before GC therapy. Lower ß-CTX and PINP are promising biomarkers for the early diagnosis of GC-induced ONFH. These findings need to be confirmed in large-scale prospective studies. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2348-2357, 2019.


Assuntos
Biomarcadores/sangue , Necrose da Cabeça do Fêmur/sangue , Glucocorticoides/efeitos adversos , Adolescente , Adulto , Estudos de Casos e Controles , Necrose da Cabeça do Fêmur/induzido quimicamente , Glucocorticoides/administração & dosagem , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
10.
Oral Oncol ; 93: 15-20, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31109691

RESUMO

BACKGROUND: Nedaplatin-based concurrent chemoradiotherapy became an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy in patients with locoregional, advanced nasopharyngeal carcinoma. MATERIALS AND METHODS: Using a Markov model, we simulated patients with nasopharyngeal carcinoma from disease-free to death. Input data for the model were collected from published literature and the standard fee database of West China Hospital. The outcome was expressed in quality-adjusted-years (QALYs), net monetary benefit at the threshold of $25,841, three times the Gross Domestic Product of China in 2017. The costs and benefits were discounted at 3% annually and a half-cycle correction was considered. The input parameters were varied in one-way sensitivity analysis to confirm the robustness of the model. All of the primary analyses used second-order probabilistic sensitivity analysis to capture the impact of parameter uncertainty based on 10,000 Monte-Carlo simulations. RESULTS: The mean QALYs of treatment in stage II-IVB nasopharyngeal carcinoma were comparable: 2.90 QALYs for nedaplatin and 3.12 QALYs for cisplatin. Nedaplatin cost $34,505 compared with $27,167 for cisplatin, generating an incremental net monetary benefit of nedaplatin versus cisplatin of $-13,357 at the ceiling ratio of $25,841. The results of nedaplatin remained cost-ineffective over the majority of the sensitivity analyses. The cost-effectiveness curve showed that the probability of strategies being cost-effective were 0% for nedaplatin and 100% for cisplatin in stage II-IVB nasopharyngeal carcinoma at any willingness-to-pay threshold. CONCLUSIONS: Nedaplatin is a dominated, cost-ineffective alternative to concurrent chemoradiotherapy in stage II-IVB nasopharyngeal carcinoma compared with cisplatin from the perspective of Chinese society.

11.
World J Gastroenterol ; 25(9): 1067-1079, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30862995

RESUMO

BACKGROUND: Studies show that the antifibrotic mechanism of taurine may involve its inhibition of the activation and proliferation of hepatic stellate cells (HSCs). Since the molecular mechanism of taurine-mediated antifibrotic activity has not been fully unveiled and is little studied, it is imperative to use "omics" methods to systematically investigate the molecular mechanism by which taurine inhibits liver fibrosis. AIM: To establish a network including transcriptomic and protein-protein interaction data to elucidate the molecular mechanism of taurine-induced HSC apoptosis. METHODS: We used microarrays, bioinformatics, protein-protein interaction (PPI) network, and sub-modules to investigate taurine-induced changes in gene expression in human HSCs (LX-2). Subsequently, all of the differentially expressed genes (DEGs) were subjected to gene ontology function and Kyoto encyclopedia of genes and genomes pathway enrichment analysis. Furthermore, the interactions of DEGs were explored in a human PPI network, and sub-modules of the DEGs interaction network were analyzed using Cytoscape software. RESULTS: A total of 635 DEGs were identified in taurine-treated HSCs when compared with the controls. Of these, 304 genes were statistically significantly up-regulated, and 331 down-regulated. Most of these DEGs were mainly located on the membrane and extracellular region, and are involved in the biological processes of signal transduction, cell proliferation, positive regulation of extracellular regulated protein kinases 1 (ERK1) and ERK2 cascade, extrinsic apoptotic signaling pathway and so on. Fifteen significantly enriched pathways with DEGs were identified, including mitogen-activated protein kinase (MAPK) signaling pathway, peroxisome proliferators-activated receptor signaling pathway, estrogen signaling pathway, Th1 and Th2 cell differentiation, cyclic adenosine monophosphate signaling pathway and so on. By integrating the transcriptomics and human PPI data, nine critical genes, including MMP2, MMP9, MMP21, TIMP3, KLF10, CX3CR1, TGFB1, VEGFB, and EGF, were identified in the PPI network analysis. CONCLUSION: Taurine promotes the apoptosis of HSCs via up-regulating TGFB1 and then activating the p38 MAPK-JNK-Caspase9/8/3 pathway. These findings enhance the understanding of the molecular mechanism of taurine-induced HSC apoptosis and provide references for liver disorder therapy.


Assuntos
Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Substâncias Protetoras/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Taurina/farmacologia , Linhagem Celular , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Cirrose Hepática/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Substâncias Protetoras/uso terapêutico , Taurina/uso terapêutico , Transcriptoma/efeitos dos fármacos
12.
Mol Microbiol ; 112(1): 29-46, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30927282

RESUMO

In Streptomyces, GlnR is an activator protein that activates nitrogen-assimilation genes under nitrogen-limiting conditions. However, less is known regarding the regulation of these genes under nitrogen-rich conditions. We determined that the developmental regulator MtrA represses nitrogen-assimilation genes in nitrogen-rich media and that it competes with GlnR for binding to GlnR boxes. The GlnR boxes upstream of multiple nitrogen genes, such as amtB, were confirmed as MtrA binding sites in vitro by electrophoretic mobility shift assays and in vivo by ChIP-qPCR analysis. Transcriptional analysis indicated that, on nutrient-rich medium, MtrA profoundly repressed expression of nitrogen-associated genes, indicating opposing roles for MtrA and GlnR in the control of nitrogen metabolism. Using in vitro and in vivo analysis, we also showed that glnR is itself a direct target of MtrA and that MtrA represses glnR transcription. We further demonstrated functional conservation of MtrA homologues in the recognition of GlnR boxes upstream of nitrogen genes from different actinobacterial species. As mtrA and glnR are widespread among actinomycetes, this mechanism of potential competitive control over nitrogen metabolism genes may be common in this group, adding a major new layer of complexity to the known regulatory network for nitrogen metabolism in Streptomyces and related species.

13.
J Tradit Chin Med ; 39(3): 393-401, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32186011

RESUMO

OBJECTIVE: To investigate the protective effect and molecular mechanisms of Weining granule on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric cancer in rats. METHODS: A total of sixty healthy male wistar rats were randomly divided into five groups, including control group (CG), gastric cancer model group (MG), low-dose Weining granule treated group (LWT), medium-dose Weining granule treated group (MWT), and high-dose Weining granule treated group (HWT). Except the control group, the other groups were treated with MNNG to establish a rat model of gastric cancer. Low-dose Weining granule treated group, medium-dose Weining granule treated group, and high-dose Weining granule treated group were fed 9.0, 18.0 and 36.0 g/kg Weining granule, respectively. Histopathologic and molecular biologic technology were adopted to determine the protective effect of Weining granule on MNNG-induced gastric cancer in rats. The pathological changes of gastrointestinal tissue were observed. Meanwhile, the differential expression of proliferation, apoptosis and angiogenesis markers were determined, including proliferating cell nuclear antigen (PCNA), pokemon, cyclin D1, B-cell lymphoma-2 (Bcl-2), caspase-3, phosphatase and tensin homolog (PTEN) and vascular endothelial growth factor (VEGF). RESULTS: After the MNNG treated, the pathological changes of stomach tissue were improved noticeably, including the intestinal metaplasia and atypic hyperplasia. The experiment was completed in 58 rats (96.67%). As compared with gastric cancer model group, the general states of rats were improved significantly after treated with different dose Weining granule. Moreover, treatment with different doses of Weining granule could inhibit the protein and mRNA expression of PCNA, pokemon, cyclin D1, Bcl-2, and VEGF, while increase caspase-3 and PTEN (P < 0.01). CONCLUSION: Weining granule could improve gastric cancer by suppressing cell proliferation, promoting tumor cell apoptosis, and inhibiting angiogenesis.

14.
Cancer Cell Int ; 18: 163, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30377410

RESUMO

Background: The aim of the study was to explore the association between the SIRT1 single nucleotide polymorphism (SNP) rs3758391 and diffuse large B cell lymphoma (DLBCL) in a Chinese Han population. Methods: 206 patients diagnosed with DLBCL and 219 healthy individuals were recruited in the present study. The genotyping of SIRT1 rs3758391 polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism. The SIRT1 mRNA expression was detected by the Taqman real-time quantitative PCR. Results: Our study showed that the genotype TT and allele T frequency were significantly higher in DLBCL patients than that of controls (p = 0.02 and 0.01, respectively). No statistical differences were observed between SIRT1 rs3758391 and clinical characteristics of DLBCL patients. Analysis of the polymorphism revealed an increased risk of DLBCL associated with TC and TT genotype when compared with CC genotype [odds ratio = 2.621 and 3.518, respectively; 95% confidence interval (CI) 1.249-5.501 and 1.675-7.390, respectively; p = 0.011 and 0.001, respectively]. The survival analysis indicated that the patients with C allele had higher overall survival rate than those with genotype TT (p = 0.005). Furthermore, multivariate Cox regression analysis showed that the TT genotype of SIRT1 SNP rs3758391 was an independent poor prognostic factor for DLBCL patients (p = 0.006, HR 1.981, 95% CI 1.215-3.231). The SIRT1 mRNA expression was significantly upregulated in DLBCL patients than that of controls (p < 0.001). In addition, the SIRT1 mRNA expression of TT subgroup was upregulated compared with TC/CC subgroup in DLBCL patients (p < 0.001). Conclusion: These results suggest that the SIRT1 rs3758391 polymorphism is associated with the risk and survival rate of DLBCL in Chinese Han population.

15.
Cancer Manag Res ; 10: 4065-4072, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30323662

RESUMO

Background: The effectiveness of gemcitabine plus capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer has been evaluated in the ESPAC-4 trial. We aimed to assess the cost-effectiveness of these adjuvant regimens on resected pancreatic cancer. Methods: A Markov model was established to simulate the disease process of resected pancreatic cancer (relapse-free survival, progressive disease, and death). The efficacy and toxicity profiles were collected from the ESPAC-4 trial. Transition probabilities were calculated based on survival in each group. Cost data were calculated from the perspective of the Chinese health-care payer. The primary endpoint in the analysis was the incremental cost-effectiveness ratio (ICER), and model uncertainties were explored by one-way sensitivity analysis and probabilistic sensitivity analysis. Results: Our results demonstrated that gemcitabine monotherapy cost $36,028.45 and yielded a survival of 1.02 quality-adjusted life year (QALY), while gemcitabine plus capecitabine cost $46,095.05 and yielded a survival of 1.23 QALY. Therefore, the incremental cost-effectiveness ratio of gemcitabine plus capecitabine vs gemcitabine monotherapy was $45,191.23 which surpassed the willingness-to-pay threshold of $29,291.42 per QALY in China. Conclusion: The gemcitabine monotherapy regimen is more cost-effective compared with gemcitabine plus capecitabine regimen for the patients with postoperative pancreatic cancer from the Chinese societal perspective.

16.
Cell Stem Cell ; 23(3): 444-452.e4, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30174295

RESUMO

Adult neurogenesis, arising from quiescent radial-glia-like neural stem cells (RGLs), occurs throughout life in the dentate gyrus. How neural stem cells are maintained throughout development to sustain adult mammalian neurogenesis is not well understood. Here, we show that milk fat globule-epidermal growth factor (EGF) 8 (Mfge8), a known phagocytosis factor, is highly enriched in quiescent RGLs in the dentate gyrus. Mfge8-null mice exhibit decreased adult dentate neurogenesis, and furthermore, adult RGL-specific deletion of Mfge8 leads to RGL overactivation and depletion. Similarly, loss of Mfge8 promotes RGL activation in the early postnatal dentate gyrus, resulting in a decreased number of label-retaining RGLs in adulthood. Mechanistically, loss of Mfge8 elevates mTOR1 signaling in RGLs, inhibition of which by rapamycin returns RGLs to quiescence. Together, our study identifies a neural-stem-cell-enriched niche factor that maintains quiescence and prevents developmental exhaustion of neural stem cells to sustain continuous neurogenesis in the adult mammalian brain.


Assuntos
Células-Tronco Adultas/metabolismo , Antígenos de Superfície/metabolismo , Proteínas do Leite/metabolismo , Células-Tronco Neurais/metabolismo , Transdução de Sinais , Animais , Células Cultivadas , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Knockout
17.
J Arid Environ ; 157: 116-123, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30174356

RESUMO

Monitoring ecosystem functioning is a significant step towards detecting changes in ecosystem attributes that could be linked to land degradation and desertification in drylands worldwide. Remote sensing-based vegetation indices (VIs) and land surface albedo are two favorite indicators to monitor desertification process due to their close relationship with ecosystem status and to their increasing applicability over multiple spatiotemporal scales. While VIs are routinely used to monitor ecosystem attributes and functions such as vegetation cover and productivity, no previous study has evaluated whether remote sensing-measured albedo is related to the simultaneous provision of multiple ecosystem functions (multifunctionality) in global drylands. In this study, we evaluated the correlation of six albedo metrics (shortwave black-sky albedo, shortwave white-sky albedo, visible black-sky albedo, visible white-sky albedo, near-infrared black-sky albedo and near-infrared white-sky albedo) and two VIs (Normalized Difference Vegetation Index (NDVI) and Enhanced Vegetation Index (EVI)) with multifunctionality indices related to carbon, nitrogen and phosphorus cycling measured in 61 dryland ecosystems from all continents except Antarctica. We found a negative relationship between land surface albedo and multifunctionality. Black-sky albedo had a stronger correlation with multifunctionality than white-sky albedo. Visible black-sky albedo showed the strongest correlation with multifunctionality (MUL, -0.314), as well as with functions related to carbon (CCY, -0.216) and nitrogen cycling (NCY, -0.410), while near-infrared (-0.339) and shortwave black-sky albedo (-0.325) showed stronger correlations with functions related to phosphorus cycling (PCY) than visible black-sky albedo (-0.233) did. VIs showed significant positive correlations with MUL, CCY, and NCY, and the magnitudes were higher than those observed between albedo metrics and the multifunctionality indices. However, VIs were not correlated with PCY, which had significant correlations with both shortwave and near-infrared albedo. Though the magnitudes of the correlations observed were not high, which may result from the wide variability in soil and vegetation types in our dataset, our findings indicate that remotely sensed albedo correlates to multifunctionality, which has been linked to alternative states in global drylands. As such, albedo has the potential to monitor changes in dryland ecosystem functioning, which can inform us about the onset of desertification in these areas.

18.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 32(9): 1167-1171, 2018 09 15.
Artigo em Chinês | MEDLINE | ID: mdl-30129333

RESUMO

Objective: To evaluate the short-term effectiveness of arthroscopic surgery combined with direct anterior approach for hip diseases. Methods: A retrospective study was performed on 23 cases with hip diseases (23 hips), who were treated with the arthroscopic surgery combined with direct anterior approach, between January 2015 and December 2016. There were 9 males and 14 females, aged from 27 to 49 years (mean, 38.6 years). There were 11 cases of posterior dislocation of the hip associated with femoral head fracture (Pipkin typeⅠ) and 7 cases of femoral neck fracture (Garden type Ⅳ). And the interval between injury and operation was 2-8 days (mean, 4.3 days). Five cases were osteonecrosis of femoral head at precollapse stage which were rated as stageⅡA according to Association Research Circulation Osseous (ARCO) classification system. The disease duration was 3-8 months (mean, 5.9 months). The preoperative Harris hip score, Oxford Hip Score (OHS), Postel score, and visual analogue scale (VAS) were 57.3±8.2, 11.2±3.6, 3.2±1.5, and 7.2±1.3, respectively. Results: All the wounds healed primarily. Lateral femoral nerve injury occurred in 3 cases. All patients were followed up 8-19 months (mean, 15.6 months). Bone union achieved in all patients after 14-19 weeks (mean, 15.8 weeks) and no secondary osteoarthritis or heterotopic ossification occurred. At last follow-up, the Harris hip score (92.5±5.3), OHS (36.5±5.9), and Postel score (14.2±2.6) were significantly higher than preoperative scores ( t=45.274, P=0.000; t=36.586, P=0.000; t=32.486, P=0.000), and VAS score (1.8±0.9) was significantly lower than preoperative score ( t=21.314, P=0.000). Conclusion: Arthroscopic surgery combined with direct anterior approach for hip diseases can effectively relieve pain, improve hip function, and obtain the satisfactory short-term effectiveness.


Assuntos
Artroscopia , Adulto , Artroplastia de Quadril , Feminino , Fraturas do Fêmur , Fraturas do Colo Femoral , Cabeça do Fêmur , Quadril , Articulação do Quadril , Humanos , Masculino , Pessoa de Meia-Idade , Ossificação Heterotópica , Osteoartrite , Osteonecrose , Estudos Retrospectivos , Resultado do Tratamento
19.
Food Funct ; 9(5): 2684-2694, 2018 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-29721568

RESUMO

Hepatic fibrosis is a pathological process that eventually leads to the development of cirrhosis and liver cancer by various types of chronic liver disease. To date, there is no standard treatment for the progression of liver fibrosis. This study aims to investigate the hepatoprotection of auraptene (AUR), a simple coumarin contained in the peels of citrus fruits such as grapefruit, against thioacetamide (TAA)-induced hepatic fibrosis in mice. The involvement of farnesoid X receptor (FXR) in the anti-fibrotic effect of AUR was further elucidated using in vivo and in vitro experiments. AUR was found to remarkably protect against liver injury induced by TAA in mice and maintain the homeostasis of bile acids via the regulation of FXR-target genes including Bsep, Mrp2, Ntcp, Cyp7a1 and Cyp8b1. Masson and Sirius red staining indicated a reduction of the collagen content in the liver of AUR treated mice. Furthermore, AUR inhibited the activation of hepatic stellate cells (HSCs) by down-regulating the expression of TGF-ß1 and α-SMA and expressed anti-inflammatory effects by reducing the expression of NF-κB, TNF-α and IL-1ß. However, the changes in these genes and protein as well as ameliorative liver histology induced by AUR were abrogated by FXR antagonist guggulsterone in vivo and FXR siRNA in vitro. Overall, AUR protects against TAA-induced hepatic fibrosis due to the reduction of toxic bile acids and inhibition of hepatic stellate cell (HSC) activation and inflammation, which were all in association with FXR activation. AUR might be efficacious for the prevention and treatment of hepatic fibrosis in mice.


Assuntos
Citrus/química , Cumarínicos/administração & dosagem , Cirrose Hepática/prevenção & controle , Substâncias Protetoras/administração & dosagem , Receptores Citoplasmáticos e Nucleares/metabolismo , Tioacetamida/efeitos adversos , Animais , Ácidos e Sais Biliares/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Simportadores/genética , Simportadores/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
20.
Front Immunol ; 9: 921, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29760709

RESUMO

Interleukin 17 (IL-17) is a key inflammatory cytokine that plays a critical role in tissue inflammation and autoimmune diseases. However, its signaling remains poorly understood. In this study, we identified serine/threonine kinase 24 (Stk24) as a positive modulator of IL-17-mediated signaling and inflammation. Stk24 deficiency or knockdown markedly inhibited IL-17-induced phosphorylation of NF-κB and impaired IL-17-induced chemokines and cytokines expression. Stk24 overexpression greatly enhanced IL-17-induced NF-κB activation and expression of chemokines and cytokines in a kinase activity-independent manner. The IL-17-induced inflammatory response was significantly reduced in Stk24-deficient mice. In addition, the severity of experimental autoimmune encephalomyelitis was markedly reduced in mice with a deficiency of Stk24 in non-hematopoietic cells. We further demonstrated that Stk24 directly interacts with TAK1 and IKKß and promotes the formation of TAK1/IKK complexes, leading to enhanced IKKß/NF-κB activation and downstream cytokines and chemokines induction. Collectively, our findings suggest that Stk24 plays an important role in controlling IL-17-triggered inflammation and autoimmune diseases and provides new insight into the therapeutic targets of IL-17-mediated inflammatory disease.


Assuntos
Quinase I-kappa B/genética , Inflamação/imunologia , Interleucina-17/imunologia , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Animais , Linhagem Celular , Citocinas/imunologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Interleucina-17/genética , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Fosforilação
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA