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1.
Hemoglobin ; : 1-4, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690131

RESUMO

Although mutations causing α-thalassemia (α-thal) are mainly larger deletions involving one or both of the duplicated α-globin genes, point mutations are not rare. We have identified a novel mutation of the translation initiation codon of the α2-globin gene with DNA sequencing and allele-specific multiplex ligation-dependent probe amplification (MLPA) in a Chinese family. RNA analysis was performed with reverse transcription-MLPA (RT-MLPA). A novel mutation at the translation initiation codon of the α2-globin gene (HBA2: c.3G>C) was identified. The proband and his father, who were both carriers of this mutation, had a hematological phenotype of mild α+-thalassemia (α+-thal) trait with low-normal limit of mean corpuscular volume (MCV) and normal Hb A2. RNA analysis showed markedly decreased levels of α-globin mRNA and the presence of a small amount of mutant mRNA. The HBA2: c.3G>C mutation most likely caused α-thal by lowering levels of wild α-globin chain. Our study increases the mutation spectrum of α-thal.

2.
Psychol Health Med ; : 1-7, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31514506

RESUMO

Posttraumatic growth has become a focus of concern in cancer caregivers, but a few studies have explored relationships among resilience, social support, coping style, and posttraumatic growth, especially in hematopoietic stem cell transplantation caregivers. A descriptive cross-sectional survey was conducted. Three hundred and fourteen participants completed questionnaires consisting of demographics, Posttraumatic Growth Inventory, Perceived Social Support Scale, Connor-Davidson Resilience Scale 10 and Coping Style Questionnaire. Pearson correlation analyses revealed that posttraumatic growth was positively associated with resilience, social support, and positive coping style, while, passive coping style was negatively associated with posttraumatic growth. At the same time, structural equation modeling analyses showed that resilience mediated the relationship between positive coping style and posttraumatic growth. Positive coping style and resilience played completely intermediary role between social support and posttraumatic growth.

3.
Mol Med Rep ; 20(2): 1593-1604, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257512

RESUMO

The present study was designed to investigate the expression and function of transmembrane protein 16 (TMEM16A), a calcium­activated chloride channel (CaCC), in the stria vascularis (SV) of the cochlea of guinea pigs at different ages, and to understand the role of CaCCs in the pathogenesis of presbycusis (age­related hearing loss), the most common type of sensorineural hearing loss that occurs with natural aging. Guinea pigs were divided into the following groups: 2 weeks (young group), 3 months (youth group), 1 year (adult group), D­galactose intervention (D­gal group; aging model induced by subcutaneous injection of D­galactose) and T16Ainh­A01 (intraperitoneal injection of 50 µg/kg/day TMEM16A inhibitor T16Ainh­A01 for 2 weeks). Differences in the hearing of guinea pigs between the various age groups were analyzed using auditory brainstem response (ABR), and immunofluorescence staining was performed to detect TMEM16A expression in the SV and determine the distribution. Reverse transcription­quantitative PCR and western blot analyses were conducted to detect the mRNA and protein levels of TMEM16A in SV in the different age groups. Morris water maze behavior analysis demonstrated that spatial learning ability and memory were damaged in the D­gal group. Superoxide dismutase activity and malondialdehyde content assays indicated that there was oxidative stress damage in the D­gal group. The ABR thresholds gradually increased with age, and the increase in the T16Ainh­A01 group was pronounced. Immunofluorescence analysis in the cochlear SV of guinea pigs in different groups revealed that expression of TMEM16A increased with increasing age (2 weeks to 1 year); fluorescence intensity was reduced in the D­gal model of aging. As the guinea pigs continued to mature, the protein and mRNA contents of TMEM16A in the cochlea SV increased gradually, but were decreased in the D­gal group. The findings indicated that CaCCs in the cochlear SV of guinea pigs were associated with the development of hearing in guinea pigs, and that downregulation of TMEM16A may be associated with age­associated hearing loss.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31209169

RESUMO

The application of advanced methodologies such as next-generation sequencing (NGS) and mass spectrometry (MS) to the characterization of cell lines and recombinant proteins has enabled the highly sensitive detection of sequence variants (SVs). However, while these approaches can be leveraged to provide deep insight into product micro-heterogeneity caused by SVs, they are not used in a standardized manner across the industry. Currently, there is little clarity and consensus on the utilization, timing, and significance of SV findings. This white paper addresses the current practices, logistics, and strategies for the analysis of SVs using a bench-marking survey coordinated by the International Consortium for Innovation & Quality in Pharmaceutical Development (IQ) as well as a series of deliberations amongst a panel of experts assembled from across the biopharmaceutical industry. Discussion includes current industry experiences including approaches for detection and quantitation of SVs during cell-line and process development, risk assessments and regulatory feedback. While SVs are a potential issue for all recombinant protein therapeutics, the scope of this discussion will be limited to SVs produced in mammalian cells. Ultimately, it is our hope that the findings from the survey and deliberations of the committee are useful to decision makers in industry and positions them to respond to findings of SVs in recombinant proteins that are destined for clinical or commercial use in a strategic manner.

5.
Clin Neurol Neurosurg ; 182: 1-4, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31048144

RESUMO

OBJECTIVE: This study was designed to evaluate whether preoperative hematological inflammatory markers would be useful in predicting the pathological grade of meningiomas. PATIENTS AND METHODS: A retrospective study of 944 patients with newly diagnosed meningioma was conducted. Preoperative blood results were obtained, including platelet, leukocyte, neutrophil, lymphocyte, and monocyte counts, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), albumin level, globulin level, and albumin-to-globulin ratio (AGR). Logistic regression analysis was performed to identify the independent predictive factors for high-grade meningiomas. RESULTS: Univariate logistic regression analysis indicated that the hematological inflammatory markers associated with tumor grade were leukocyte, neutrophil, and monocyte counts and the LMR (P < 0.05 for all). Multivariate logistic regression analysis showed that high leukocyte count (P = 0.007) and low LMR (P = 0.041) were independent predictive factors for high-grade meningiomas. CONCLUSIONS: Preoperative high leukocyte count and low LMR were independent predictive factors of high-grade meningiomas, suggesting that leukocyte count and LMR could be useful in the assessment of the grade of meningiomas.

6.
J Infect ; 79(1): 43-48, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31100365

RESUMO

OBJECTIVES: Avian influenza viruses (AIVs) poise significant risk to human health and the poultry industry. We evaluated the transmission risk along the poultry supply chain. METHODS: During October 2015 and July 2016, four rounds of cross-sectional surveys were performed to characterize AIV spread in farms, transport vehicles, slaughterhouses, wholesale and retail live poultry markets (LPMs). Poultry cloacal and oral swabs, environmental swabs, bioaerosol samples and human sera were collected. Poultry and environmental samples were tested for AIVs by rRT-PCR, further subtyped by next generation sequencing. Previous human H9N2 infections were identified by hemagglutination inhibition and microneutralization tests. Logistic regression was fitted to compare AIV transmission risk in different settings. RESULTS: AIVs was detected in 23.9% (424/1771) of the poultry and environmental samples. AIV detection rates in farms, transport vehicles, wholesale and retail LPMs were 4.5%, 11.1%, 30.3% and 51.2%, respectively. 5.2%, 8.3% and 12.8% of the poultry workers were seropositive in farms, wholesale and retail LPMs, respectively. The regression analysis showed that virus detection and transmission risk to human increased progressively along the poultry supply chain. CONCLUSIONS: Strengthening control measures at every level along the poultry supply chain, using a one health approach, is crucial to control AIV circulation.

7.
Nature ; 569(7754): 99-103, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043727

RESUMO

Since their discovery in 19601, metallic glasses based on a wide range of elements have been developed2. However, the theoretical prediction of glass-forming compositions is challenging and the discovery of alloys with specific properties has so far largely been the result of trial and error3-8. Bulk metallic glasses can exhibit strength and elasticity surpassing those of conventional structural alloys9-11, but the mechanical properties of these glasses are critically dependent on the glass transition temperature. At temperatures approaching the glass transition, bulk metallic glasses undergo plastic flow, resulting in a substantial decrease in quasi-static strength. Bulk metallic glasses with glass transition temperatures greater than 1,000 kelvin have been developed, but the supercooled liquid region (between the glass transition and the crystallization temperature) is narrow, resulting in very little thermoplastic formability, which limits their practical applicability. Here we report the design of iridium/nickel/tantalum metallic glasses (and others also containing boron) with a glass transition temperature of up to 1,162 kelvin and a supercooled liquid region of 136 kelvin that is wider than that of most existing metallic glasses12. Our Ir-Ni-Ta-(B) glasses exhibit high strength at high temperatures compared to existing alloys: 3.7 gigapascals at 1,000 kelvin9,13. Their glass-forming ability is characterized by a critical casting thickness of three millimetres, suggesting that small-scale components for applications at high temperatures or in harsh environments can readily be obtained by thermoplastic forming14. To identify alloys of interest, we used a simplified combinatorial approach6-8 harnessing a previously reported correlation between glass-forming ability and electrical resistivity15-17. This method is non-destructive, allowing subsequent testing of a range of physical properties on the same library of samples. The practicality of our design and discovery approach, exemplified by the identification of high-strength, high-temperature bulk metallic glasses, bodes well for enabling the discovery of other glassy alloys with exciting properties.

8.
Leukemia ; 33(10): 2454-2465, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30953029

RESUMO

New prognostic factors are needed to establish indications for haematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) for T-cell lymphoblastic lymphoma (T-LBL) patients. We used microarray to compare T-LBL tissue samples (n = 75) and fetal thymus tissues (n = 20), and identified 35 differentially expressed miRNAs. Using 107 subjects as the training group, we developed a five-miRNA-based classifier to predict patient survival with LASSO Cox regression: lower risk was associated with better prognosis (disease-free survival (DFS): hazard ratio (HR) 4.548, 95% CI 2.433-8.499, p < 0.001; overall survival (OS): HR 5.030, 95% CI 2.407-10.513, p < 0.001). This classifier displayed good performance in the internal testing set (n = 106) and the independent external set (n = 304). High risk was associated with more favorable response to HSCT (DFS: HR 1.675, 95% CI 1.127-2.488, p = 0.011; OS: HR 1.602, 95% CI 1.055-2.433, p = 0.027). When combined with ECOG-PS and/or NOTCH1/FBXW7 status, this classifier had even better prognostic performance in patients receiving HSCT (DFS: HR 2.088, 95% CI 1.290-3.379, p = 0.003; OS: HR 1.996, 95% CI 1.203-3.311, p = 0.007). The five-miRNA classifier may be a useful prognostic biomarker for T-LBL adults, and could identify subjects who could benefit from HSCT.

9.
Artigo em Inglês | MEDLINE | ID: mdl-30887590

RESUMO

Rare autosomal trisomies (RATs) refer to chromosomal trisomies that are uncommonly seen at birth. Genome-wide sequencing of maternal plasma cell-free DNA (cfDNA) enables noninvasive prenatal testing (NIPT) of all 24 chromosomes. An expanded NIPT approach can identify RATs. However, this is not without interpretative challenge. More evidence is needed to determine the pregnancy outcome of RATs detected by NIPT. This article is protected by copyright. All rights reserved.

10.
Sci Total Environ ; 663: 227-235, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30711589

RESUMO

OBJECTIVE: To explore the relationship between meteorological factors and scarlet fever incidence from 2006 to 2017 in Guangzhou, the largest subtropical city of Southern China, and assist public health prevention and control measures. METHODS: Data for weekly scarlet fever incidence and meteorological variables from 2006 to 2017 in Guangzhou were collected from the National Notifiable Disease Report System (NNDRS) and the Guangzhou Meteorological Bureau (GZMB). Distributed lag nonlinear models (DLNMs) were conducted to estimate the effect of meteorological factors on weekly scarlet fever incidence in Guangzhou. RESULTS: We observed nonlinear effects of temperature, relative humidity, and wind velocity. The risk was the highest when the weekly mean temperature was 31 °C during lag week 14, yielding a relative risk (RR) of 1.48 (95% CI: 1.01-2.17). When relative humidity was 43.5% during lag week 0, the RR was 1.49 (95% CI: 1.04-2.12); the highest RR (1.55, 95% CI: 1.20-1.99) was reached when relative humidity was 93.5% during lag week 20. When wind velocity was 4.4 m/s during lag week 13, the RR was highest at 3.41 (95% CI: 1.57-7.44). Positive correlations were observed among weekly temperature ranges and atmospheric pressure with scarlet fever incidence, while a negative correlation was detected with aggregate rainfall. The cumulative extreme effect of meteorological variables on scarlet fever incidence was statistically significant, except for the high effect of wind velocity. CONCLUSION: Weekly mean temperature, relative humidity, and wind velocity had double-trough effects on scarlet fever incidence; high weekly temperature range, high atmospheric pressure, and low aggregate rainfall were risk factors for scarlet fever morbidity. Our findings provided preliminary, but fundamental, information that may be useful for a better understanding of epidemic trends of scarlet fever and for developing an early warning system. Laboratory surveillance for scarlet fever should be strengthened in the future.


Assuntos
Umidade , Escarlatina/epidemiologia , Vento , China/epidemiologia , Incidência , Conceitos Meteorológicos , Dinâmica não Linear , Escarlatina/microbiologia , Temperatura Ambiente , População Urbana/estatística & dados numéricos
11.
Chin J Nat Med ; 17(2): 122-130, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30797418

RESUMO

Macrophages show significant heterogeneity in function and phenotype, which could shift into different populations of cells in response to exposure to various micro-environmental signals. These changes, also termed as macrophage polarization, of which play an important role in the pathogenesis of many diseases. Numerous studies have proved that Hesperidin (HDN), a traditional Chinese medicine, extracted from fruit peels of the genus citrus, play key roles in anti-inflammation, anti-tumor, anti-oxidant and so on. However, the role of HDN in macrophage polarization has never been reported. Additional, because of its poor water solubility and bioavailability. Our laboratory had synthesized many hesperidin derivatives. Among them, hesperidin derivatives-12 (HDND-12) has better water solubility and bioavailability. So, we evaluated the role of HDND-12 in macrophage polarization in the present study. The results showed that the expression of Arginase-1 (Arg-1), interleukin-10 (IL-10), transforming growth factor ß (TGF-ß) were up-regulated by HDND-12, whereas the expression of inducible Nitric Oxide Synthase (iNOS) was down-regulated in LPS- and IFN-γ-treated (M1) RAW264.7 cells. Moreover, the expression of p-JAK2 and p-STAT3 were significantly decreased after stimulation with HDND-12 in M1-like macrophages. More importantly, when we taken AG490 (inhibitor of JAK2/STAT3 signaling), the protein levels of iNOS were significantly reduced in AG490 stimulation group compare with control in LPS, IFN-γ and HDND-12 stimulation cells. Taken together, these findings indicated that HDND-12 could prevent polarization toward M1-like macrophages, at least in part, through modulating JAK2/STAT3 pathway.


Assuntos
Hesperidina/farmacologia , Janus Quinase 2/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Citocinas/genética , Citocinas/metabolismo , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hesperidina/química , Inflamação/genética , Inflamação/metabolismo , Janus Quinase 2/antagonistas & inibidores , Macrófagos/metabolismo , Medicina Tradicional Chinesa , Camundongos , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Fator de Transcrição STAT3/antagonistas & inibidores
12.
Breast Cancer Res Treat ; 175(1): 51-57, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30712197

RESUMO

OBJECTIVES: Human epidermal growth factor receptor 2 (HER2, ERBB2) is a valuable prognostic and predictive biomarker in breast cancer. Accurate assessment of HER2 status is essential in selecting the patients with invasive breast cancer who will likely response to HER2-targeted therapies. Some major modifications in the diagnostic recommendation for fluorescence in situ hybridization (FISH) have been made in the updated 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologist (CAP) guideline. According to the revised guideline, concomitant IHC assays are required to arrive at the most accurate HER2 status designation after HER2 FISH equivocal results; however, little is known about its influence on the clinical practice of pathologist. The purpose of this study was to evaluate the impact of the revised 2018 ASCO/CAP guidelines on the HER2 status designation. METHODS: We retrospectively reviewed the HER2 FISH testing results from 2233 cases of invasive breast cancer between January 2014 and December 2017. Concomitant immunohistochemistry (IHC) were performed on the same tissue blocks that were used for the FISH testing. RESULTS: Compared to the 2013 guidelines, the HER2 status in 183 (8.2%) cases were re-defined when reassessed by the 2018 guidelines. Among these 183 cases, 175 equivocal cases according to the 2013 guideline were re-defined as HER2 negative (n = 173) or HER2 positive (n = 2). Eight previously classified as HER2 positive cases were converted to negative in the 2018 scheme, all of which were with HER2 IHC scores of 1+ or 2+. The number of cases in the negative category was 1705 according to the 2018 guidelines as opposed to 1524 by the 2013 guidelines. CONCLUSIONS: The updated 2018 ASCO/CAP guidelines eliminated the FISH equivocal category, which can be attributed to reflex HER2 IHC, and partly ease the dilemma for clinical practice. Reflex IHC for FISH equivocal cases is of prime importance; furthermore, HER2 FISH results were converted from positivity to negativity based on the concomitant IHC results in a small percentage of cases. In all, implementation of the 2018 ASCO/CAP guidelines provides much clearer instructions and recommendations for the HER2 status designation, and thus reduces the risk of misdiagnosis.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Hibridização in Situ Fluorescente , Receptor ErbB-2/genética , Neoplasias da Mama/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Invasividade Neoplásica , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Receptor ErbB-2/metabolismo , Estudos Retrospectivos
13.
Pharmacogenomics ; 20(3): 167-177, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30777785

RESUMO

AIM: To evaluate the accuracy and predictive performance of Bayesian dosing for warfarin in Chinese patients. MATERIALS & METHODS: Six multiple linear regression algorithms (Wei, Lou, Miao, Huang, Gage and IWPC) and a Bayesian method implemented in Warfarin Dose Calculator were compared with each other. RESULTS: Six multiple linear regression warfarin dosing algorithms had similar predictive ability, except Miao and Lou. The mean prediction error of Bayesian priori and posteriori method were 0.01 mg/day (95% CI: -0.18 to 0.19) and 0.17 mg/day (95% CI: -0.05 to 0.29), respectively, and Bayesian posteriori method demonstrated better performance in all dose ranges. CONCLUSION: The Bayesian method showed a good potential for warfarin maintenance dose prediction in Chinese patients requiring less than 6 mg/day.

14.
Anal Chem ; 91(3): 2192-2200, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30608647

RESUMO

Oxidation of tryptophan not only generates heterogeneity of a therapeutic monoclonal antibody (mAb) but also can be a potential critical quality attribute (CQA) of the product. In this study, mAbs A-C of IgG1 and IgG4 (immunoglobulin G, IgG) isotypes with oxidized tryptophan (Trp) residues were selectively generated by incubating the mAbs with 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) in formulations containing l-methionine. The site-specific oxidation of tryptophan residues were confirmed by liquid chromatography coupled with mass spectrometry (LC-MS) studies. The site of oxidation was identified to be a conserved tryptophan residue in the heavy chain complementarity determining region 3 (CDR3) of mAbs A and B with no significant oxidation found on other tryptophan residues including those in close proximity to CDR3. For mAb C, all tryptophan residues including one in the heavy chain CDR1 and a tryptophan in close proximity to heavy chain CDR3 were not susceptible to oxidation. For all three mAbs, the structure and tryptophan oxidation relationship was further studied by computational modeling of the variable domain of the antibodies (variable fragment, Fv). The computational modeling provided a structural understanding at the molecular level to the tryptophan oxidation, where high solvent accessibility is a prerequisite for heavy chain CDR3 tryptophan oxidation. However, higher oxidation susceptibility of tryptophan in heavy chain CDR3 did not linearly correlate to higher solvent accessibility, suggesting that other factors including side-chain orientation and/or surrounding structure elements around the heavy chain CDR3 may also be involved. Through this study, we demonstrate that a selective oxidation system, together with computational modeling, can be an important tool to identify potential CQAs of a therapeutic mAb such as tryptophan oxidation liabilities during the mAb's development.

16.
Artigo em Inglês | MEDLINE | ID: mdl-30478816

RESUMO

Direct characterization of disulfide linkages in proteins by mass spectrometry has been challenging. Here, we report analysis of disulfide linkages in insulin variant, endothelin 3, and relaxin 2 by in-source dissociation (ISD) during LC-MS. A duplet insulin peptide from Glu-C digestion that contains peptides p1 and p2 (from chains A and B, respectively) was selected as a model peptide. This duplet peptide has an inter-chain disulfide bond between p1 and p2, and an intra-chain disulfide bond in p1. To compare the gas-phase fragmentation, it was subjected to ISD MS and MS/MS methods, including collision-induced dissociation (CID) and electron transfer dissociation (ETD). The pattern and efficiency of peptide backbone and disulfide cleavage varied with these dissociation methods. ETD, CID, and ISD were able to generate single backbone, double backbone, and triple (double backbone and single disulfide bond) cleavages in this model peptide, respectively. Specifically, CID did not cleave disulfide bonds and ETD was able to only cleave the inter-chain disulfide bond at low efficiency, limiting their usage in this disulfide analysis. In contrast, ISD was able to cleave the intra-chain disulfide bond in addition to peptide backbone, creating multiple fragment ions that allow accurate assignment of both intra- and inter-chain disulfide linkages. ISD was also successfully applied to determine double disulfide linkages in endothelin 3 and relaxin 2 peptides. This study contributes to the fundamental understanding of disulfide bond cleavages in different gas-phase fragmentations and provides an efficient cleavage strategy for identification of disulfide bonds in proteins by ISD ESI-MS. Graphical Abstract ᅟ.

17.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 49(3): 388-393, 2018 May.
Artigo em Chinês | MEDLINE | ID: mdl-30014640

RESUMO

OBJECTIVE: To study the effect of cinobufagin (CB) on the proliferation inhibition and induction of apoptosis in glioblastoma cell lines U87 and its molecular mechanism. METHODS: A gradient concentration (0-20 µmol/L) of CB was used to treat the U87 glioma cells for 6 h,12 h,24 h and 48 h,respectively. Cell viabilities were determined by CCK-8 assay to discover the effects of different concentrations of CB on the proliferation of glioma cells. Different concentrations (1-20 µmol/L) of CB were used to treat the U87 glioma cells for 12 h and 24 h,hochest33342 staining assay was used to assess the apoptosis levels. Immunofluorescence staining was used to determine the expression of growth related proteins phospho-protein kinase B(T308)[ p-AKT(T308)] in U87 glioma cells after being treated with CB for 24 h. Western blot was used to determine the apoptotic related proteins (BAX,cleaved-caspase 3,cleaved-caspase 9) and growth related proteins [phospho-inositide 3-kinase (p-PI3K),p-AKT(T308),p-AKT(S473),phospho-ribosomal protein S6 kinase (PS6),phospho-4E-binding protein 1 (p-4EBP1)]. RESULTS: A significant effect of CB on the proliferation inhibition and induction of apoptosis in U87 glioma cells in a time- and dose-dependent manner was observed. Treatment with CB induced the expression levels of apoptosis-related protein,cleaved-caspase 3 and BAX,and the PI3K-AKT-4EBP1 signaling pathway related proteins p-AKT(T308) and p-4EBP1 were decreased. CONCLUSION: CB can inhibit U87 glioma cells growth and induce apoptosis,which may involve the PI3K-AKT-4EBP1 and BAX-caspase signaling pathways.

18.
Blood ; 132(11): 1146-1158, 2018 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-30054295

RESUMO

Mature T-cell lymphomas, including peripheral T-cell lymphoma (PTCL) and extranodal NK/T-cell lymphoma (NKTL), represent a heterogeneous group of non-Hodgkin lymphomas with dismal outcomes and limited treatment options. To determine the extent of involvement of the JAK/STAT pathway in this malignancy, we performed targeted capture sequencing of 188 genes in this pathway in 171 PTCL and NKTL cases. A total of 272 nonsynonymous somatic mutations in 101 genes were identified in 73% of the samples, including 258 single-nucleotide variants and 14 insertions or deletions. Recurrent mutations were most frequently located in STAT3 and TP53 (15%), followed by JAK3 and JAK1 (6%) and SOCS1 (4%). A high prevalence of STAT3 mutation (21%) was observed specifically in NKTL. Novel STAT3 mutations (p.D427H, E616G, p.E616K, and p.E696K) were shown to increase STAT3 phosphorylation and transcriptional activity of STAT3 in the absence of cytokine, in which p.E616K induced programmed cell death-ligand 1 (PD-L1) expression by robust binding of activated STAT3 to the PD-L1 gene promoter. Consistent with these findings, PD-L1 was overexpressed in NKTL cell lines harboring hotspot STAT3 mutations, and similar findings were observed by the overexpression of p.E616K and p.E616G in the STAT3 wild-type NKTL cell line. Conversely, STAT3 silencing and inhibition decreased PD-L1 expression in STAT3 mutant NKTL cell lines. In NKTL tumors, STAT3 activation correlated significantly with PD-L1 expression. We demonstrated that STAT3 activation confers high PD-L1 expression, which may promote tumor immune evasion. The combination of PD-1/PD-L1 antibodies and STAT3 inhibitors might be a promising therapeutic approach for NKTL, and possibly PTCL.

20.
Physiol Mol Biol Plants ; 24(3): 349-358, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29692543

RESUMO

The phytohomorne methyl jasmonate (MeJA) is known to trigger extensive reprogramming of gene expression leading to transcriptional activation of many secondary metabolic pathways. However, natural rubber is a commercially important secondary metabolite and little is known about the genetic and genomic basis of jasmonate-elicited rubber biosynthesis in rubber tree (Hevea brasiliensis). RNA sequencing (RNA-seq) of H. brasiliensis bark treated with 1 g lanolin paste containing 0.02% w/w MeJA for 24 h (M2) and 0.04% w/w MeJA for 24 h (M4) was performed. A total of 2950 and 2850 differentially expressed genes in M2 and M4 compared with control (C) were respectively detected. Key genes involved in 2-C-methyl-D-erythritol 4-phosphate, rubber biosynthesis, glycolysis and carbon fixation (Calvin cycle) pathway were found to be up-regulated by MeJA treatment. Particularly, the expression of 3-hydroxy-3-metylglutaryl coenzyme A reductase in MVA pathway was down-regulated by MeJA treatment, but the expression of farnesyl diphosphate synthase (FPS) and cis-prenyltransferase (CPT, or rubber transferase) in rubber biosynthesis pathway were up-regulated by MeJA treatment. Up-regulation of critical genes in JA biosynthesis in response to MeJA treatment exhibited the self-activation of JA biosynthesis. In addition, up-regulated genes of great regulatory importance in cross-talk between JA and other hormone signaling, and of transcriptional regulation were identified. The increased expression levels of FPS and CPT in rubber biosynthesis pathway possibly resulted in an increased latex production in rubber tree treated with MeJA. The present results provide insights into the mechanism by which MeJA activates the rubber biosynthesis and the transcriptome data can also serve as the foundation for future research into the molecular basis for MeJA regulation of other cellular processes.

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