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1.
Biosens Bioelectron ; 171: 112748, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33113381

RESUMO

Protein phosphorylation, a post-translational modification of proteins, is of vital importance in biological regulation. Highly sensitive and site-specific identification of phosphorylated proteins is a key requirement for unraveling crucial signal transduction pathways relevant to cancers and neurodegenerative disorders. Traditional detection methods, however, suffer from relying on antibodies, labels or fragmentation prior to analysis. Here, an antibody- and label-free in situ approach to fingerprint protein phosphorylation was developed based on intrinsic Raman vibrational information of phosphorylated tyrosine, serine, threonine, or histidine residues. Combining surface-enhanced Raman scattering (SERS) spectroscopy and an immobilized-metal affinity strategy, this method is ultrasensitive to discriminate a single-site phosphorylated S396 in a Tau410 protein, an important biomarker in Alzheimer's disease. The binding feasibility of phosphorylated proteins to the modified SERS-active materials is further evidenced by molecular dynamics simulations. This proof-of-concept study paves a new way for the evaluation of site-specific and intact protein phosphorylation in both fundamental mechanical investigation and clinical applications.

2.
FEBS Open Bio ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33206457

RESUMO

Human umbilical cord mesenchymal stem cells (HUCMSCs) can be obtained from different parts of the umbilical cord, including Wharton's jelly. Transplantation of Wharton's jelly umbilical cord stem cells (WJCMSCs) is a promising strategy for the treatment of various diseases. However, the molecular mechanisms underlying the proliferation of WJCMSCs are incompletely understood. Here, we report that overexpression of miR-196b-5p in WJCMSCs suppresses proliferation and arrests the cell cycle in G0/G1 phase, whereas knock-down of miR-196b-5p promotes WJCMSC proliferation and cell cycle progression. Moreover, miR-196b-5p overexpression resulted in decreased levels of Cyclin A, Cyclin D, Cyclin E, and CDK2 and increased levels of p15INK4b , whereas miR-196b-5p knock-down had the opposite effects. In conclusion, our data suggests that miR-196b-5p inhibits WJCMSC proliferation by enhancing G0/G1-phase arrest.

3.
Asian J Androl ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33208562

RESUMO

We performed this study to investigate the diagnostic performance of prostate-specific antigen density (PSAD) in a multicenter cohort of the Chinese Prostate Cancer Consortium. Outpatients with prostate-specific antigen (PSA) levels ≥4.0 ng ml-1 regardless of digital rectal examination (DRE) results or PSA levels <4.0 ng ml-1 and abnormal DRE results were included from 18 large referral hospitals in China. The diagnostic performance of PSAD and the sensitivity and specificity for the diagnosis of prostate cancer (PCa) and high-grade prostate cancer (HGPCa) at different cutoff values were evaluated. A total of 5220 patients were included in the study, and 2014 (38.6%) of them were diagnosed with PCa. In patients with PSA levels ranging from 4.0 to 10.0 ng ml-1, PSAD was associated with PCa and HGPCa in both univariate (odds ratio [OR] = 45.15, P < 0.0001 and OR = 25.38, P < 0.0001, respectively) and multivariate analyses (OR = 52.55, P < 0.0001 and OR = 26.05, P < 0.0001, respectively). The areas under the receiver operating characteristic curves (AUCs) of PSAD in predicting PCa and HGPCa were 0.627 and 0.630, respectively. With the PSAD cutoff of 0.10 ng ml-2, we obtained a sensitivity of 88.7% for PCa, and nearly all (89.9%) HGPCa cases could be detected and biopsies could be avoided in 20.2% of the patients (359/1776 cases). Among these patients who avoided biopsies, only 30 cases had HGPCa. We recommend 0.10 ng ml-2 as the proper cutoff value of PSAD, which will obtain a sensitivity of nearly 90% for both PCa and HGPCa. The results of this study should be validated in prospective, population-based multicenter studies.

4.
Chin Med J (Engl) ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33156008

RESUMO

BACKGROUND: Human immunodeficiency virus (HIV) prevalence among student men who have sex with men (MSM) in college is more than 5.0% and keeps on increasing in China. This study aims to clarify the proportion of HIV recent infection, its propeller and the source among college student MSM. METHODS: We conducted a multicenter cross-sectional study in seven major Chinese cities during 2012-2013. HIV recent infections (≤168 days) and incidence was measured and estimated by BED HIV-1 capture enzyme immunoassay (BED-CEIA) testing strategy. HIV-related behaviors and transmitted drug resistance (TDR) were investigated and compared between the college student MSM, < 25-year-old non-student youth MSM (NSYM), and ≥25-year-old non-student non-youth MSM (NSNYM), using structured survey, and analyses of drug resistance. RESULTS: Overall, 4496 (4496/4526, 99.3%) were eligible for enrollment, comprising 565 college student MSM, 1094 NSYM, and 2837 NSNYM. The proportion of HIV recent infection were 70.3% (26/37), 50.8% (65/128) and 35.1% (95/271), the HIV incidence rate were 10.0 (95% CI: 6.2-13.9)/100 person-year (PY), 12.9 (95% CI: 9.8-16.1)/100PY, 6.8 (95% CI: 5.4-8.2)/100 PY, and TDR prevalences were 7.4% (2/27), 2.0%, (2/98) and 4.9% (11/226), among student MSM, NSYM, and NSNYM, respectively. Among HIV positive student MSM with age <21 years, the proportion of HIV recent infection is 90.9% (10/11). Factors independently associated with HIV recent infection in student MSM was usage of recreational drug in the past 6 months (adjusted [aOR]: 2.5; 95% CI: 1.0-5.8). CONCLUSIONS: College student MSM had higher proportion of HIV recent infection and TDR than the youth and older MSM in China during 2012-2013. The HIV infections were more likely to happen during the early year of college life among student MSM.

5.
Med Sci Monit ; 26: e926323, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33206632

RESUMO

BACKGROUND Previous studies have implicated reduced brain-derived neurotrophic factor (BDNF) expression and BDNF-TrkB receptor signaling as well as microglial activation and neuroinflammation in poststroke depression (PSD). However, the contributions of microglial BDNF-TrkB signaling to PSD pathogenesis are unclear. MATERIAL AND METHODS We compared depression-like behaviors as well as neuronal and microglial BDNF and TrkB expression levels in the amygdala, a critical mood-relating limbic structure, in rat models of stroke, depression, and PSD. Depression-like behaviors were assessed using the sucrose preference test, open-field test, and weight measurements, while immunofluorescence double staining was employed to estimate BDNF and TrkB expression by CD11b-positive amygdala microglia and NeuN-positive amygdala neuron. Another group of PSD model rats were examined following daily intracerebroventricular injection of proBDNF, tissue plasminogen activator (t-PA), or normal saline (NS) for 7 days starting 4 weeks after chronic unpredictable mild stress (CUMS). RESULTS The numbers of BDNF/CD11b- and TrkB/CD11b-immunofluorescence-positive cells were lowest in the PSD group at 4 and 8 weeks after CUMS (P0.05). Injection of t-PA increased BDNF/CD11b- and TrkB/CD11b-positive cells in the amygdala of PSD rats and normalized behavior compared with NS or proBDNF injection (P<0.05). In contrast, proBDNF injection reduced BDNF and TrkB expression compared with NS (P<0.05). CONCLUSIONS These results suggest that decreased BDNF and TrkB expression by amygdala microglia may contribute to PSD pathogenesis and depression-like behaviors.

6.
World J Gastroenterol ; 26(39): 5983-5996, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33132649

RESUMO

BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease that is difficult to diagnose and treat. To date, the degree of inflammation in patients with UC has mainly been determined by measuring the levels of nonspecific indicators, such as C-reactive protein and the erythrocyte sedimentation rate, but these indicators have an unsatisfactory specificity. In this study, we performed bioinformatics analysis using data from the National Center for Biotechnology Information-Gene Expression Omnibus (NCBI-GEO) databases and verified the selected core genes in a mouse model of dextran sulfate sodium (DSS)-induced colitis. AIM: To identify UC-related differentially expressed genes (DEGs) using a bioinformatics analysis and verify them in vivo and to identify novel biomarkers and the underlying mechanisms of UC. METHODS: Two microarray datasets from the NCBI-GEO database were used, and DEGs between patients with UC and healthy controls were analyzed using GEO2R and Venn diagrams. We annotated these genes based on their functions and signaling pathways, and then protein-protein interactions (PPIs) were identified using the Search Tool for the Retrieval of Interacting Genes. The data were further analyzed with Cytoscape software and the Molecular Complex Detection (MCODE) app. The core genes were selected and a Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed. Finally, colitis model mice were established by administering DSS, and the top three core genes were verified in colitis mice using real-time polymerase chain reaction (PCR). RESULTS: One hundred and seventy-seven DEGs, 118 upregulated and 59 downregulated, were initially identified from the GEO2R analysis and predominantly participated in inflammation-related pathways. Seven clusters with close interactions in UC formed: Seventeen core genes were upregulated [C-X-C motif chemokine ligand 13 (CXCL13), C-X-C motif chemokine receptor 2 (CXCR2), CXCL9, CXCL5, C-C motif chemokine ligand 18, interleukin 1 beta, matrix metallopeptidase 9, CXCL3, formyl peptide receptor 1, complement component 3, CXCL8, CXCL1, CXCL10, CXCL2, CXCL6, CXCL11 and hydroxycarboxylic acid receptor 3] and one was downregulated [neuropeptide Y receptor Y1 (NYP1R)] in the top cluster according to the PPI and MCODE analyses. These genes were substantially enriched in the cytokine-cytokine receptor interaction and chemokine signaling pathways. The top three core genes (CXCL13, NYP1R, and CXCR2) were selected and verified in a mouse model of colitis using real-time PCR Increased expression was observed compared with the control mice, but only CXCR2 expression was significantly different. CONCLUSION: Core DEGs identified in UC are related to inflammation and immunity inflammation, indicating that these reactions are core features of the pathogenesis of UC. CXCR2 may reflect the degree of inflammation in patients with UC.

7.
Front Immunol ; 11: 576903, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33133095

RESUMO

Circular RNAs (circRNAs) constitute a class of covalently circular non-coding RNA molecules formed by 5' and 3' end back-splicing. The rapid development of bioinformatics and large-scale sequencing has led to the identification of functional circRNAs. Despite an overall upward trend, studies focusing on the roles of circRNAs in immune diseases remain relatively scarce. In the present study, we obtained a differential circRNA expression profile based on microarray analysis of peripheral blood mononuclear cells (PBMCs) in children with type 1 diabetes mellitus (T1DM). We characterized one differentially expressed circRNA back-spliced from the MYB Proto-Oncogene Like 2 (MYBL2) gene in patients with T1DM, termed as hsa_circ_0060450. Subsequent assays revealed that hsa_circ_0060450 can serve as the sponge of miR-199a-5p, release its target gene, Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), encoded by the tyrosine-protein phosphatase non-receptor type 11 gene (PTPN11), and further suppress the JAK-STAT signaling pathway triggered by type I interferon (IFN-I) to inhibit macrophage-mediated inflammation, which indicates the important roles of circRNAs in T1DM and represents a promising therapeutic molecule in the treatment of T1DM.

8.
Arch. bronconeumol. (Ed. impr.) ; 56(10): 621-629, oct. 2020. tab, graf
Artigo em Espanhol | IBECS-Express | IBECS | ID: ibc-ET5-2128

RESUMO

Contexto: Las exacerbaciones son eventos cruciales durante la progresión de la bronquiectasia. OBJETIVOS: Analizar las asociaciones entre el aislamiento de bacterias, virus y virus y bacterias juntas y las exacerbaciones de las bronquiectasias. MÉTODOS: En este estudio prospectivo se incluyó a 108 pacientes a los que se siguió cada 3-6 meses y al comienzo de las exacerbaciones entre marzo de 2017 y noviembre de 2018. La muestra de esputo espontáneo se dividió para la detección de bacterias (cultivo de rutina) y virus (reacción en cadena de la polimerasa cuantitativa). Se evaluaron los síntomas y la función pulmonar durante las exacerbaciones. RESULTADOS: La mediana de la tasa de exacerbación fue de 2,0 (rango intercuartil: 1,0-2,5) por paciente/año. En cualquier visita, los aislamientos de virus (V+) tuvieron lugar con mayor frecuencia durante el inicio de las exacerbaciones (odds ratio [OR]: 3,28; intervalo de confianza del 95% [IC 95%]: 1,76-6,12), al igual que el aislamiento de nuevas bacterias (NB+) (OR: 2,52; IC 95%: 1,35-4,71) y los aislamientos de bacterias y virus juntos (OR: 2,24; IC 95%: 1,11-4,55). Mientras que la coriza parecía más común en las exacerbaciones con V+ que en las exacerbaciones sin aislamientos de patógenos y en aquellas con NB+, los síntomas de las vías respiratorias inferiores fueron más graves en las exacerbaciones con NB+ (p < 0,05). Los niveles de interleucina-1β en el esputo fueron más altos en las exacerbaciones con NB+ que en las exacerbaciones sin aislamiento de patógenos, y aquellas con V+ (ambos p < 0,05). De manera significativa, más síntomas de coriza se correlacionaron con aislamientos de bacterias y virus juntos durante las exacerbaciones (p = 0,019). Comparados con los V+ en solitario, los aislamientos de bacterias con y sin virus tienden a producir síntomas más graves en las vías respiratorias inferiores, pero no alteran los niveles de citocinas en el esputo durante las exacerbaciones. CONCLUSIONES: Los aislamientos de virus, el aislamiento de nuevas bacterias y el aislamiento de bacterias y virus juntos están asociados a las exacerbaciones de las bronquiectasias. Los síntomas de las exacerbaciones pueden proporcionar información a los médicos sobre los posibles patógenos responsables


BACKGROUND: Exacerbations are crucial events during bronchiectasis progression. OBJECTIVES: To explore the associations between bacterial, viral, and bacterial plus viral isolations and bronchiectasis exacerbations. METHODS: In this prospective study, we enrolled 108 patients who were followed up every 3-6 months and at onset of exacerbations between March 2017 and November 2018. Spontaneous sputum was split for detection of bacteria (routine culture) and viruses (quantitative polymerase chain reaction). Symptoms and lung function were assessed during exacerbations. RESULTS: The median exacerbation rate was 2.0 (interquartile range: 1.0-2.5) per patient-year. At any visit, viral isolations (V+) occurred more frequently during onset of exacerbations [odds ratio (OR): 3.28, 95% confidence interval (95%CI): 1.76-6.12], as did isolation of new bacteria (NB+) (OR: 2.52, 95%CI: 1.35-4.71) and bacterial plus viral isolations (OR: 2.24, 95%CI: 1.11-4.55). Whilst coryza appeared more common in exacerbations with V+ than in exacerbations with no pathogen isolations and those with NB+, lower airway symptoms were more severe in exacerbations with NB+ (P < .05). Sputum interleukin-1β levels were higher in exacerbations with NB+ than in exacerbations with no pathogen isolations and those with V+ (both P < .05). Significantly more coryza symptoms correlated with bacterial plus viral isolations at exacerbations (P = .019). Compared with V+ alone, bacterial with and without viral isolations tended to yield more severe lower airway symptoms, but not sputum cytokine levels at exacerbations. CONCLUSIONS: Viral isolations, isolation of new bacteria and bacterial plus viral isolation are associated with bronchiectasis exacerbations. Symptoms at exacerbations might inform clinicians the possible culprit pathogens

9.
J Mass Spectrom ; : e4650, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-33043550

RESUMO

A fully automated method for identification and quantification of five polar pesticides in groundwater by isotope dilution-online solid-phase extraction (SPE) coupled with high-performance liquid chromatography-quadrupole Orbitrap high-resolution mass spectrometry was developed. After one step of filtration, an aliquot of a 7.5-ml water sample was automatedly preconcentrated and purified on a turbulent Cyclone SPE column. The analytes were eluted in backflush mode, then separated on an analytical column and acquired by full MS/dd-MS2 scan in negative and positive ions mode. The major parameters for sample loading, cleanup, and elution were optimized in detail. Preconcentration and ionization efficiency were highly improved by using 0.1% acid solution in the mobile phase. The method provided good linearity of calibration coefficients (R2 > 0.995), sensitive method limits of detection (0.5-10.0 ng/L), accurate mass spectra (within 5 ppm error), satisfactory matrix spiking recoveries (98.4% to 109%), and high precision (intraday/interday relative standard deviations 1.57-8.90%). The method was successfully applied to analyze large batch groundwater of National Groundwater Monitoring Project and suspect screening of potential pesticides in groundwater. The study provided a practical alternative for a simple, robust, sensitive, and accurate identification and qualification of five polar pesticides in groundwater.

10.
Anticancer Drugs ; 31(10): 1018-1025, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33009035

RESUMO

X-inactive-specific transcript (XIST) is a 19 kb noncoding RNA which is oncogenic in many cancers including gastric cancer. It is reported that XIST contributes to gastric cancer cells resistant to cisplatin, but specific mechanisms governing this resistance remain unclear. We firstly examined the XIST level in gastric cancer cells and tumor specimens. We confirmed that XIST is overexpressed in gastric cancer cells and tumors, which further contributed to the poor prognosis of patients with gastric cancer. We also confirmed that high XIST level contributes to the cisplatin resistance in gastric cancer cells. Subsequently, we predicted microRNAs that have the potential to interact with XIST and found that Let-7b-5p may directly interact with XIST. We confirmed the direct interaction between XIST and Let-7b-5p and identified a negative correlation between the level of Let-7b-5p and XIST in gastric cancer tumors. Meanwhile, Let-7b-5p inhibitor treatment can partially rescued the effect of XIST-specific small interfering RNA on cell proliferation and apoptosis by regulating Aurora kinase B expression. XIST functions as an oncogene in gastric cancer which contributes to the cisplatin resistance by interacting with Let-7b-5p.

11.
Zootaxa ; 4786(1): zootaxa.4786.1.4, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-33056496

RESUMO

Ostrinia furnacalis (Guenée) (Lepidoptera: Crambidae), often called the Asian corn borer, is a complicated pest because of its complex biological features, such as its adult dynamics, host choice, and life span. This complexity has been causing difficulties in both pest forecasting and control for more than 60 years. One likely explanation for this complexity is that O. furnacalis has several varieties that vary based on some specific features. During 2015-2017, postmedial line-based varieties of male O. furnacalis were identified as distinct clades (I, II, and III), which were then compared based on COI gene sequences, male sacculus construction, life span, male dynamics, and host preference. The results showed that: (1) clades II and III were more closely related to each other than Clade I, because they both completed two generations per year, more were captured in 2016 or fewer were captured in 2015, and they were more closely related according to phylogenetic inference; (2) all three clades shared some features, such as life spans under various rearing conditions, similar dynamic trends, and three teeth on the male sacculus; and (3) all three clades were significantly different from O. nubilalis based on genetic sequences, postmedial line pattern of the forewing, and sacculus construction. Overall, if O. furnacalis is categorized into clades, the species' features are likely to be a combination or mixture of the features of each individual clade. Our findings help explain the biological complexity of O. furnacalis. Future investigations on each individual clade are essential for improving forecasting and control of this pest.


Assuntos
Mariposas , Animais , China , Masculino , Filogenia
12.
Behav Brain Res ; : 112971, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33075396

RESUMO

Methamphetamine addiction causes serious public health problems worldwide. However, there is no effective medication licensed for methamphetamine addiction. The endogenous opioid system is considered to be a common substrate in drug addiction due to its regulation of dopamine release. In recent clinical trials, (-)-naltrexone, an opioid receptors and Toll-like receptor 4 antagonist, has exhibited encouraging findings for treating methamphetamine addiction; however, the understanding of its pharmacological mechanisms remains insufficient. By using mice models of behavioral sensitization and conditioned place preference (CPP), the present study was performed to investigate the effects of naltrexone on the methamphetamine-associated properties of incentive salience and reward-related memory, the two crucial factors for the development of addictive process and relapse. We found that naltrexone reduced single methamphetamine-induced hyperlocomotion in mice. In the paradigm of methamphetamine-induced behavioral sensitization paired with contextual cues in mice, naltrexone suppressed the development and expression of locomotor sensitization, suggesting the decrease in incentive salience to methamphetamine and context. In the methamphetamine-induced CPP paradigm in mice, naltrexone attenuated both the expression and methamphetamine-priming reinstatement of CPP response, suggesting the impairment of either contextual cue- or drug-induced retrieval of methamphetamine-associated memory. After the establishment of methamphetamine-induced CPP in mice, naltrexone treatment during the extinction training produced conditioned place adverse response, suggesting that naltrexone facilitated negative affection-associated extinction learning. Taken together, these findings demonstrate that naltrexone could intervene in the properties of incentive salience and reward-related memory in methamphetamine addiction, which may contribute to its therapeutic effects on methamphetamine addicts in clinical studies.

13.
J Cancer Res Ther ; 16(5): 1134-1139, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33004760

RESUMO

Objective: The hemoglobin, albumin, lymphocyte, and platelet (HALP) score, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are the important prognostic markers in some tumor types. This study aimed to evaluate the prognostic impact of pretreatment using HALP, NLR, and PLR for patients with small-cell lung cancer (SCLC), who were undergoing chemotherapy. Materials and Methods: In this retrospective study, 335 patients with SCLC were included between 2016 and 2018. The cutoff values for HALP, NLR, and PLR were defined using X-tile software. Survival was analyzed by the Kaplan-Meier method, with differences analyzed through the log-rank test. The multivariate Cox proportional hazard model was used to evaluate the prognostic significance of HALP, NLR, and PLR for SCLC. Results: The median follow-up period was 27.1 months (range: 0.5-46.2 months). Based on the Kaplan-Meier curve analysis, it was noticed that the low pretreatment HALP (≤18.6), high pretreatment NLR (>2.4), and high PLR (>191.6) were significantly associated with worse overall survival (OS) (P = 0.009, 0.001, and 0.033, respectively). Cox multivariate analysis demonstrated that low pretreatment HALP and high pretreatment NLR were the independent prognostic factors for worse OS (hazard ratio [HR] = 1.468, 95% confidence interval [CI]: 1.004-2.146, P = 0.047; HR = 0.722, 95% CI: 0.542-0.960, P = 0.025, respectively). Conclusion: HALP and NLR were the independent prognostic factors of OS for SCLC patients undergoing chemotherapy.

14.
Carbohydr Polym ; 250: 117010, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33049871

RESUMO

The development of biomass-based hydrogel conductive devices is a promising but challenging subject. Here, cellulose was used to develop a strong, tough, and self-adhesive conductive hydrogel by constructing a synergistic covalent cross-link network and multiple physical interactions. Tannic acid-coated cellulose nanofibrils (TA@CNFs), poly(acrylamide), and ferric ions (Fe3+) were introduced in a composite network by coordination and hydrogen bonds. The strategy of interpenetrating network endowed this hydrogel with high mechanical strength (storage modulus over 14 K Pa), and strong toughness and tensile strength (fracture stress up to 108 K Pa). Chelated Fe3+ by metal coordination as inorganic conductive phase leads to good electrical conductivity (conductivity up to 3.12 S m-1). The obtained hydrogel also exhibited fine flexibility, extensive self-adhesion, and adjustable strain responsiveness for monitoring human joint movements. This work provided a new approach to design conductive hydrogels, and also can expand the application of cellulose-reinforced materials in the sensor field.

15.
J Med Chem ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33058680

RESUMO

We report compounds 5 (CG416) and 6 (CG428) as two first-in-class tropomyosin receptor kinase (TRK) degraders that target the intracellular kinase domain of TRK. Degraders 5 and 6 reduced levels of the tropomyosin 3 (TPM3)-TRKA fusion protein in KM12 colorectal carcinoma cells and inhibited downstream PLCγ1 signaling at sub-nanomolar concentrations. Both degraders also degraded human wild-type TRKA with similar potency. Interestingly, both degraders, especially 6, showed selectivity for the degradation of endogenous TPM3-TRKA over ectopically expressed ATP/GTP binding protein-like 4 (AGBL4)-TRKB or ETS variant transcription factor 6 (ETV6)-TRKC fusion proteins in KM12 cells. Global proteomic profiling assays demonstrated that 5 is highly selective for the intended target. TPM3-TRKA protein degradation induced by 5 and 6 was further confirmed to be mediated through cereblon and the ubiquitin-proteasome system. Compared with the parental TRK kinase inhibitor, both degraders exhibited higher potency for inhibiting growth of KM12 cells. Moreover, both 5 and 6 showed good plasma exposure levels in mice. Therefore, 5 and 6 are valuable chemical tool compounds for investigating the in vivo function of TRK fusion during tumorigenesis. Our study also paves the way for pharmacological degradation of TRK.

16.
Oncologist ; 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33000474

RESUMO

Patients with non-small cell lung cancer (NSCLC) containing ROS1 fusions can have a marked response to the ROS1-targeted tyrosine kinase inhibitors (TKIs), such as crizotinib. Common resistance mechanisms of ROS1-fusion targeted therapy are acquired mutations in ROS1. Along with the use of next-generation sequencing in the clinical management of patients with NSCLC during sequential targeted therapy, many mechanisms of acquired resistance have been discovered in patients with activated tyrosine kinase receptors. Besides acquired resistance mutations, bypass mechanisms of resistance to epidermal growth factor receptor (EGFR)-TKI treatment are common in patients with EGFR mutations. Here we describe a patient with metastatic lung adenocarcinoma with CD74-ROS1 fusion who initially responded to crizotinib and then developed resistance by the acquired mutation of D1228N in the MET kinase domain, which showed short-term disease control for cabozantinib. KEY POINTS: The D1228N point mutation of MET is an acquired mutation for crizotinib resistance. The patient obtained short-term clinical benefit from cabozantinib therapy after resistance to crizotinib. The clinical use of next-generation sequencing could maximize the benefits of precision medicine in patients with cancer.

17.
Shanghai Kou Qiang Yi Xue ; 29(4): 405-409, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-33089291

RESUMO

PORPOSE: To establish a prospective cohort of kindergarten children and longitudinally study the causes of early childhood caries. METHODS: Cluster random sampling was used to select a kindergarten in the urban and suburban areas of Pudong New District of Shanghai, a total of 240 small-class children joined the study. Chi-square test, analysis of variance, binomial logistic regression model and general linear regression model was used to analyze caries of the cohort children at baseline and 1 year after follow-up with SPSS 21.0 software package. RESULTS: In the first two years of this cohort study, the follow-up rate was 88.3%, the caries rate in the first year of baseline and follow-up were 58.3% and 69.8%, and the mean dmft values were 3.1±4.2 and 4.5±4.9, respectively. 56.1% of children had new caries. Logistic regression results showed that children who lived in the suburbs (P=0.010) and ate candy more frequently (P=0.036) had higher rates of new caries. The results of general linear regression equation showed that children in the suburbs (P<0.001), those who did not use fluoridated toothpaste (P=0.003) and those who ate candy more frequently (P=0.002) had higher new mean dmft values. CONCLUSIONS: Living in the suburbs, not using fluoride toothpaste and eating candy more frequently are important risk factors for new caries in preschool children in Pudong New District of Shanghai.


Assuntos
Cárie Dentária , Criança , Pré-Escolar , China/epidemiologia , Estudos de Coortes , Índice CPO , Cárie Dentária/epidemiologia , Humanos , Prevalência , Estudos Prospectivos , Fatores de Risco
18.
Nucleic Acids Res ; 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33095866

RESUMO

With the study of human diseases and biological processes increasing, a large number of non-coding variants have been identified and facilitated. The rapid accumulation of genetic and epigenomic information has resulted in an urgent need to collect and process data to explore the regulation of non-coding variants. Here, we developed a comprehensive variation annotation database for human (VARAdb, http://www.licpathway.net/VARAdb/), which specifically considers non-coding variants. VARAdb provides annotation information for 577,283,813 variations and novel variants, prioritizes variations based on scores using nine annotation categories, and supports pathway downstream analysis. Importantly, VARAdb integrates a large amount of genetic and epigenomic data into five annotation sections, which include 'Variation information', 'Regulatory information', 'Related genes', 'Chromatin accessibility' and 'Chromatin interaction'. The detailed annotation information consists of motif changes, risk SNPs, LD SNPs, eQTLs, clinical variant-drug-gene pairs, sequence conservation, somatic mutations, enhancers, super enhancers, promoters, transcription factors, chromatin states, histone modifications, chromatin accessibility regions and chromatin interactions. This database is a user-friendly interface to query, browse and visualize variations and related annotation information. VARAdb is a useful resource for selecting potential functional variations and interpreting their effects on human diseases and biological processes.

19.
Aging (Albany NY) ; 12(20): 20308-20331, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33091876

RESUMO

The tumor immune microenvironment (TIME) is an important determinant of cancer prognosis and treatment efficacy. To identify immune-related prognostic biomarkers of lung adenocarcinoma, we used the ESTIMATE algorithm to calculate the immune and stromal scores of 517 lung adenocarcinoma patients from The Cancer Genome Atlas (TCGA). We detected 985 differentially expressed genes (DEGs) between patients with high and low immune and stromal scores, and we analyzed their functions and protein-protein interactions. TRIM28 was upregulated in lung adenocarcinoma patients with low immune and stromal scores, and was associated with a poor prognosis. The TISIDB and TIMER databases indicated that TRIM28 expression correlated negatively with immune infiltration. We then explored genes that were co-expressed with TRIM28 in TCGA, and investigated DEGs based on TRIM28 expression in GSE43580 and GSE7670. The 429 common DEGs from these analyses were functionally analyzed. We also performed a Gene Set Enrichment Analysis using TCGA data, and predicted substrates of TRIM28 using UbiBrowser. The results indicated that TRIM28 may negatively regulate the TIME by increasing the SUMOylation of IRF5 and IRF8. Correlation analyses and validations in two lung adenocarcinoma cell lines (PC9 and H1299) confirmed these findings. Thus, TRIM28 may worsen the TIME and prognosis of lung adenocarcinoma.

20.
Stem Cells Int ; 2020: 8881021, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33082788

RESUMO

Understanding the regulation mechanisms of mesenchymal stem cells (MSCs) can assist in tissue regeneration. The histone demethylase (KDM) family has a crucial role in differentiation and cell proliferation of MSCs, while the function of KDM3B in MSCs is not well understood. In this study, we used the stem cells from the apical papilla (SCAPs) to test whether KDM3B could regulate the function of MSCs. By an alkaline phosphatase (ALP) activity assay, Alizarin red staining, real-time RT-PCR, and western blot analysis, we found that KDM3B enhanced the ALP activity and mineralization of SCAPs and promoted the expression of runt-related transcription factor 2 (RUNX2), osterix (OSX), dentin sialophosphoprotein (DSPP), and osteocalcin (OCN). Additionally, the CFSE, CCK-8, and flow cytometry assays revealed that KDM3B improved cell proliferation by accelerating cell cycle transition from the G1 to S phase. Scratch and transwell migration assays displayed that KDM3B promoted the migration potential of SCAPs. Mechanically, microarray results displayed that 98 genes were upregulated, including STAT1, CCND1, and FGF5, and 48 genes were downregulated after KDM3B overexpression. Besides, we found that the Toll-like receptor and JAK-STAT signaling pathway may be involved in the regulating function of KDM3B in SCAPs. In brief, we discovered that KDM3B promoted the osteo-/odontogenic differentiation, cell proliferation, and migration potential of SCAPs and provided a novel target and theoretical basis for regenerative medicine.

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