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1.
Int J Cancer ; 146(1): 272-280, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31162842

RESUMO

Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) may account for 8-9% of all gastric cancer (GC) patients. All previous reports on EBVaGC were retrospective. Prospective study is warranted to evaluate the exact role of EBV status in predicting the prognosis of GC. It is of special interest to figure out whether dynamic detection of plasma EBV-DNA load could be a feasible biomarker for the monitor of EBVaGC. From October 2014 to September 2017, we consecutively collected GC patients (n = 2,760) from Sun Yat-sen University Cancer Center for EBER examination. We detected EBV-DNA load in plasma and tissue samples of EBVaGC patients at baseline. Subsequently, plasma EBV-DNA load was dynamically monitored in EBVaGC patients. The overall prevalence of EBVaGC is 5.1% (140/2,760). The incidence rate of EBVaGC decreased with advanced AJCC 7th TNM stage (p < 0.001), with the corresponding percentages of 9.3, 9.9, 6.7 and 1.4% for Stage I, II, III and IV patients. EBVaGC patients were predominately young males with better histologic differentiation and earlier TNM stage than EBV-negative GC (EBVnGC) patients. EBVaGC patients were confirmed to had a favorable 3-year survival rate (EBVaGC vs. EBVnGC: 76.8% vs. 58.2%, p = 0.0001). Though only 52.1% (73/140) EBVaGC patients gained detectable EBV-DNA and 43.6% (61/140) reached a positive cutoff of 100 copies/ml, we found the plasma EBV-DNA load in EBVaGC decreased when patients got response, while it increased when disease progressed. Our results suggested that plasma EBV-DNA is a good marker in predicting recurrence and chemotherapy response for EBVaGC patients.

2.
Talanta ; 207: 120261, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31594567

RESUMO

Significant progress on circulating tumor cells (CTCs) has profound impact for noninvasive tumor profiling including early diagnosis, treatment monitoring, and metastasis recognition. Therefore, CTCs based liquid biopsy technology is taking a rapid growth in the field of precision oncology. The label-free approaches relied on microfluidic chip stand out from a crowd of methods that suffer from time consuming, extensive blood samples, lost target cells and labor-intensive operation. In this paper, a label-free separation microfluidic device was developed using multistage channel, which took full advantage of inertial lift force. Our strategy demonstrated CTCs were efficiently isolated from untreated human blood samples including antibody conjugation and erythrocyte lysis. This device was applied for isolating human brain malignant glioma cells that were spiked in human peripheral blood samples. The experimental condition was optimized and exhibited an average separation efficiency of ≥ 90% across cell morphological analysis, up to 84.96% purity of collected CTCs and the viability of all cells is >95%, which was better than other one-step CTCs separation methods. Furthermore, the CTCs were successfully separated from untreated clinical blood sample of cancer patient on the proposed microfluidic device. The entire experimental procedures are extremely low-cost and easy manipulation. It is believed that the proposed multistage microfluidic chip can become a promising tool for CTCs separation and early diagnosis of cancer.

3.
Int J Hyg Environ Health ; 223(1): 171-178, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31548162

RESUMO

AIMS: Evidence concerning the impact of ambient particulate matter (PM) on mental health is just emerging and inconsistent. Air pollution with high PM levels has been frequently reported in China, however, no Chinese study has determined the association between PM exposures and anxiety hospitalizations. We examined the potential association between PM concentrations and anxiety admissions in 26 Chinese cities from January 2014 to December 2015. METHODS: A time-stratified case-crossover design was employed in the study. Anxiety hospitalizations were identified according to ICD-10 from the electronic hospitalization summary reports system in China. Conditional logistic regression was applied to estimate the relation between PM levels and anxiety admissions, stratified by age and sex. RESULTS: Positive associations between PM2.5/PM10 and admitted anxiety cases were observed. PM2.5 had the largest effect estimate at lag 5 days, with a per 10 µg/m3 increase corresponding to a 0.63% (95% CI, 0.26-1.00) increase in anxiety admissions. PM10's largest effect estimate was observed at lag 3 days, increasing 0.37% (95% CI, 0.12-0.62) anxiety admissions per 10 µg/m3. Females were more sensitive to PM2.5/PM10 concentrations than males, however, the effect modification by age was not significant. A marginally significant distinction in anxiety hospitalizations was found in patients with and without CVDs when they were exposed to PM2.5. CONCLUSIONS: Our findings indicate that short-term exposure to increased concentrations of PM2.5/PM10 exacerbates risks of anxiety hospitalizations in 26 Chinese cities. We observed effect modification by sex, with significantly stronger associations in female patients. This study offers the promise that reducing PM air pollution could probably reduce the huge disease burden from anxiety disorders.

4.
J Nanosci Nanotechnol ; 20(4): 2395-2401, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492253

RESUMO

In this paper, ß-Ga2O3 nanowires were synthesized by vapor transport method at different temperatures. The as-prepared samples were analyzed for crystal structure by X-ray diffraction (XRD), transmission electron microscopy (TEM) and selected area electron diffraction (SAED), and for morphology using scanning electron microscopy (SEM). The results show that the Ga2O3 nanowires present a monoclinic structure, the length and diameter of the Ga2O3 nanowires increased with the growth temperature. A majority of the Ga2O3 nanowires present longitudinal twinning structures. A broad photoluminescence emission band was observed from the Ga2O3 nanowires at room temperature, which is caused by different kinds of vacancy defects. Our study shows an unusual twinning structure of ß-Ga2O3 nanowires, which may be helpful to understand the growth mechanism of nanowires.

5.
Front Biosci (Landmark Ed) ; 25: 798-816, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31585918

RESUMO

Previous studies have shown that amentoflavone (AF) elicits anti-inflammatory and neuroprotective effects. To further investigate the effects of AF on the microglia cell line BV-2, proteomic analysis was performed to screen potential key regulators. The top 5 canonical pathways associated with AF treatment were EIF2 signaling, regulation of eIF4 and p70s6k signaling, mTOR signaling, protein ubiquitination pathway and phagosome maturation. The top up-regulated genes were DOCK2, SEC23A, ME1, UGGT1 and STOM, while the most down-regulated molecules were IGF2R, ATP5O, DDX47, WBP11 and IKBIP. AF significantly decreased BV-2 cell proliferation. It induced cell cycle arrest at G2/M, increased CDK2, p27Kip1 and p53/p-p53, and decreased CDK1/CDC2 and cyclin B1. Cell apoptosis was induced, with increased levels of BAX, c-caspase-3 and c-caspase-9, and decreased levels of BCL-XL. Increased level of autophagosome induced by AF was observed, and increased Beclin-1 and decreased phosphorylation of PI3K and Erk1 were found as well. In conclusion, AF induces cell cycle arrest at G2/M, promotes apoptosis and autophagy in BV-2 cells, which may account for the anti-inflammatory effect of AF in epilepsy.

6.
Carbohydr Polym ; 227: 115296, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31590872

RESUMO

Cutaneous chronic wounds are characterized by an impaired wound healing which may lead to infection. To surmount this problem, a novel quaternary ammonium chitosan nanoparticles (TMC NPs)/chitosan (CS)composite sponge with asymmetric wettability surfaces was successfully prepared. The optimum concentrations of TMC NPs and CS were 0.2 mg/mL and 2.0%, respectively. The incorporated TMC NPs could improve the antibacterial activity of the CS sponge. Asymmetric modification enables the CS sponge to have hydrophobic outer surface and hydrophilic inner surface. The hydrophobic surface of the sponge shows waterproof and anti-adhesion contaminant properties, whereas the hydrophilic surface preserves water-absorbing capability and efficiently inhibits the growth of bacteria. More importantly, in vivo chronic wound healing model evaluation reveals that TMC NPs/CS composite sponge promotes the wound healing and accelerates re-epithelialization and angiogenesis. And in vivo anti-infection test shows the TMC NPs/CS composite sponge could effectively prevent wound infection. These findings demonstrate that TMC NPs/CS composite sponge is a promising dressing material for chronic wounds.

7.
Sci Total Environ ; 698: 134239, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31505340

RESUMO

The control of environmental pollutants is a global concern. Recently, heteroatom-doped graphene has drawn increasing attention due to their widespread applications in removing and detecting environmental pollutants. Owing to the introduction of heteroatoms into pristine graphene, the properties of heteroatom-doped graphene have been significantly enhanced in physic, chemistry, and biology. This review focuses on the approaches for synthesis and characterization of boron-, sulfur-, and phosphorus-doped graphene and their applications in the fields of adsorption, catalysis, and detection for environmental pollutants. The mechanisms of environmental applications, including π-π interactions, complexation, hydrophobic interactions, electronic conductivity, and active sites and reactive radicals, are elaborated. Furthermore, the challenges associated with the use of heteroatom-doped graphene materials and their prospective applications are also proposed.

8.
Appl Ergon ; 82: 102952, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31546093

RESUMO

In contrast to the conventional safety philosophy (Safety-I) which focuses on 'what goes wrong', a newborn one (Safety-II) focusing on 'what goes right' endows people with more opportunities to realize productive safety in complex socio-technical systems. Yet, it is challenging to make the best of both the philosophies in a period of knowledge transition when they may have to coexist. This work investigates how Safety-II may resemble, differ from, and correlate to Safety-I. From individual, environmental and organizational aspects, 9 impacting factors are identified and expounded comparatively in the two philosophies. To examine impact of the factors on accidents and resilience respectively, an empirical approach is presented in the context of Beijing taxi service system (BTSS). Multiple means such as questionnaire surveys, semi-structured interviews, and statistical analysis with bi-method (Correlation Analysis, and Data Envelopment Analysis) cross-checking are utilized comprehensively to support the empirical study. The results show that: a) individual factors play a dominant role in system risk/performance management, in respect to views of both Safety-I and II; and b) organizational factors are more influential in creating and maintaining system resilience. Based on the findings, possible patterns of integrating the two philosophies are instantiated through mutually complementary application to BTSS. Despite the context of BTSS, this work provides a feasible way of comparing between Safety-I and Safety-II, for beneficial reference of other socio-technical systems.

9.
Opt Express ; 27(21): 29803-29816, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31684237

RESUMO

Traditional methods for distortion measurement of large-aperture optical systems are time-consuming and ineffective because they require each field of view to be individually measured using a high-precision rotating platform. In this study, a new method that uses a phase diffractive beam splitter (DBS) is proposed to measure the distortion of optical systems, which has great potential application for the large-aperture optical system. The proposed method has a very high degree of accuracy and is extremely economical. A high-precision calibration method is proposed to measure the angular distribution of the DBS. The uncertainty analysis of the factors involved in the measurement process has been performed to highlight the low level of errors in the measurement methodology. Results show that high-precision measurements of the focal length and distortion were successfully achieved with high efficiency. The proposed method can be used for large-aperture wide-angle optical systems such as those used for aerial mapping applications.

10.
Opt Express ; 27(20): 27488-27499, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31684514

RESUMO

In conventional heterodyne phase-sensitive optical time domain reflectometry (Φ-OTDR), the optical path difference (OPD) between sensing and reference arms deteriorates the signal-to-noise ratio (SNR). We counteract this effect by introducing a loop path in reference arm. This facilitates the use of laser source with low coherence length. Compared with an ordinary Φ-OTDR system, SNR increased from ~1 dB to 5 dB. Regardless of OPD compensation features, the probability to getting a better output increases by generation of multiple reference beams (and consequently multiple beat signals), as compared to conventional systems. The method is cost efficient and suitable for practical purposes.

11.
Opt Express ; 27(20): 28337-28349, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31684587

RESUMO

In this paper, the Indices of Polarimetric Purity (IPPs) [1-3] have been proposed to analyze the depolarization performances of mono-dispersion and poly-dispersion scattering systems. Here, we mainly investigate the influences of the particles' density, Refractive Index (RI) of the medium, incident wavelengths, the mixing ratio of bi-dispersion scattering particles and particle-size distributions of poly-dispersion scattering system on the depolarization performances for the backscattering detection. For the mono-dispersion scattering system under same incident wavelength, if the relative RI ratios (m) increase linearly, the depolarization performances of the system will first weaken and then strengthen, and of course, the incident wavelength and density of scattering particles will also influence the depolarization performances of the scattering system. For the bi-dispersion scattering system, the proportion of small particles will be negatively correlated with the depolarization property of the dispersion system, and meanwhile, the particle-size distributions will also affect the depolarization performances greatly in the poly-dispersion scattering system. The results demonstrate that the IPPs can be used to describe the depolarization performances of dispersion systems effectively.

13.
Virchows Arch ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31720832

RESUMO

Although the positivity of human epidermal growth factor receptor 2 (HER2) is low in colorectal cancer (CRC), anti-HER2 is becoming a new target therapy in metastatic colorectal cancer (mCRC). However, assessment of the HER2 scoring system was still not established in CRC. The purpose of our study was to evaluate HER2 status and its correlation with clinicopathological characteristics and survival according to the HER2 diagnostic criteria for gastroesophageal adenocarcinoma (GEA criteria) and the HERACLES diagnostic criteria (HERACLES criteria) in a large cohort of Chinese CRC patients. The HER2 positivity was 2.9% (43/1490) and 2.6% (39/1490) in CRCs based on the GEA criteria and the HERACLES criteria, and 3.7% (9/243) in mCRC according to both criteria. HER2 status was associated with primary tumor location (P = 0.037), regional lymph node metastasis (P = 0.035), and TNM stage (P = 0.022) in CRCs based on the HERACLES criteria. No such association was found based on the GEA criteria. Furthermore, HER2 positive only presented in patients with RAS gene wild type (P = 0.001). Significant difference was only observed between the HER2-positive and HER2-negative groups in terms of disease-free survival for stage II-III CRCs (P = 0.048) according to the HERACLES criteria, but not based on the GEA criteria. Our findings suggest that the frequency of HER2 overexpression or amplification was low in Chinese CRC patients, and provide a rationale for further evaluation of HER2 in CRC based on the HERACLES criteria and the HER2 diagnostic criteria for gastroesophageal adenocarcinoma.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31711313

RESUMO

MiR-203 is known to target estrogen receptor α (ERα) in various cancer cell lines, such as MCF-7. However, whether miR-203 regulates ERα and contributes to the onset and progression of osteoarthritis (OA) is poorly understood. A combined protocol of the bilateral ovariectomy and the intra-articular monosodium iodoacetate (MIA) injection was applied to establish a postmenopausal OA model in rats. Real-time quantitative PCR was used to detect miR-203 and mRNAs and Western blotting was exploited to quantify the expressions on the protein level. ELISA assays were deployed to detect the expression of MMP-1, MMP-3, PGE2 and CTX-II in serum samples. Dual-luciferase reporter assay was utilized to confirm the direct binding of miR-203 on ERα in postmenopausal OA rats. Expression of miR-203 was elevated; while ERα mRNA and protein were down-regulated in postmenopausal OA rats, compared to sham rats. Dual-luciferase reporter assay confirmed miR-203 bound and negatively regulated ERα, resulting in promoted cellular inflammation and cartilage destruction in postmenopausal OA rats. Suppression of miR-203 using a specific inhibitor ameliorated cartilage degradation in postmenopausal OA rats. MiR-203 is pivotal in the onset and progression of OA in the postmenopausal rat model, and holds promise for a therapeutic target of OA treatment.

15.
Ophthalmic Epidemiol ; : 1-10, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722595

RESUMO

Purpose: To describe the rationale, design, methodology and baseline characteristics of Fushun Diabetic Retinopathy Cohort Study (FS-DIRECT), a community-based prospective cohort study in patients with type 2 diabetes mellitus (T2DM) living in northeast China.Methods: Patients with T2DM, aged 30 years and above from communities of Fushun city, Liaoning province, China, were recruited. The presence and severity of the diabetic retinopathy (DR) were determined by a modified Early Treatment Diabetic Retinopathy Study (ETDRS) retinopathy scale of 6 fields fundus photographs. Detailed ocular examinations and questionnaires were collated, in addition to blood and urine sample collection.Results: Of the 2224 subjects eligible for the FS-DIRECT, 2033 (91.4%) participated in the study. The majority of participants were female (58.9%), the average age was 62.1 ± 9.1 years. The overall prevalence rates of DR, non-proliferative DR, proliferative DR, diabetic macular edema, and vision-threatening retinopathy were 44.3%, 40.0%, 4.3%, 15.2%, and 12.3%, respectively. Compared to the patients without DR, patients with DR had lower income, an earlier onset of diabetes, a longer duration of diabetes, higher proportion of insulin use, higher fasting plasma glucose, HbA1c, systolic blood pressure, total cholesterol and high density lipoprotein, as well as a higher level of urine protein (all P < .05).Conclusion: The baseline data of FS-DIRECT showed a high prevalence of DR in a community of northeast China. Further investigation will provide key information about the risk factors, impact, and trends of DR in this region.

16.
Blood ; 134(Supplement_1): 47, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31723997

RESUMO

DISCLOSURES: Oran: AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Champlin:Sanofi-Genzyme: Research Funding; Actinium: Consultancy; Johnson and Johnson: Consultancy. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Jazz Pharma: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Popat:Jazz: Consultancy; Incyte: Research Funding; Bayer: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy.

17.
Blood ; 134(Supplement_1): 17, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31724013

RESUMO

DISCLOSURES: DiNardo: celgene: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; daiichi sankyo: Honoraria; agios: Consultancy, Honoraria; medimmune: Honoraria; jazz: Honoraria. Kadia:Bioline RX: Research Funding; Celgene: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; AbbVie: Consultancy, Research Funding. Ravandi:Selvita: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding. Konopleva:Astra Zeneca: Research Funding; Agios: Research Funding; Ablynx: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Kantarjian:Takeda: Honoraria; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Jazz Pharma: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Champlin:Johnson and Johnson: Consultancy; Sanofi-Genzyme: Research Funding; Actinium: Consultancy. Garcia-Manero:Onconova: Research Funding; H3 Biomedicine: Research Funding; Astex: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Amphivena: Consultancy, Research Funding; Merck: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy.

18.
Cancer Med ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31724334

RESUMO

BACKGROUND: Monosialotetrahexosylganglioside (GM1) is a neuroprotective glycosphingolipid that repairs nerves. Oxaliplatin-based chemotherapy is neurotoxic. This study assessed the efficacy of GM1 for preventing oxaliplatin-induced peripheral neurotoxicity (OIPN) in colorectal cancer (CRC) patients receiving oxaliplatin-based chemotherapy. METHODS: In total, 196 patients with stage II/III CRC undergoing adjuvant chemotherapy with mFOLFOX6 were randomly assigned to intravenous GM1 or a placebo. The primary endpoint was the rate of grade 2 or worse cumulative neurotoxicity (NCI-CTCAE). The secondary endpoints were chronic cumulative neurotoxicity (EORTC QLQ-CIPN20), time to grade 2 neurotoxicity (NCI-CTCAE or the oxaliplatin-specific neuropathy scale), acute neurotoxicity (analog scale), rates of dose reduction or withdrawal due to OIPN, 3-year disease-free survival (DFS) and adverse events. RESULTS: There were no significant differences between the arms in the rate of NCI-CTCAE grade 2 or worse neurotoxicity (GM1: 33.7% vs placebo: 31.6%; P = .76) or neuropathy measured by the EORTC QLQ-CIPN20 or time to grade 2 neurotoxicity using NCI-CTCAE and the oxaliplatin-specific neuropathy scale. GM1 substantially decreased participant-reported acute neurotoxicity (sensitivity to cold items [P < .01], discomfort swallowing cold liquids [P < .01], throat discomfort [P < .01], muscle cramps [P < .01]). The rates of dose reduction or withdrawal were not significantly different between the arms (P = .08). The 3-year DFS rates were 85% and 83% in the GM1 and placebo arms, respectively (P = .19). There were no differences in toxicity between the arms. CONCLUSION: Patients receiving GM1 were less troubled by the symptoms of acute neuropathy. However, we do not support the use of GM1 to prevent cumulative neurotoxicity. (ClinicalTrials.gov number, NCT02251977).

19.
J Med Chem ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31724864

RESUMO

The treatment of tumors driven by overexpression or amplification of MYC oncogenes remains a significant challenge in drug discovery. Here, we present a new strategy towards the inhibition of MYC via the disruption of the protein-protein-interaction between MYC and its chromatin cofactor WDR5. Blocking the association of these proteins is hypothesized to disrupt the localization of MYC to chromatin, thus disrupting the ability of MYC to sustain tumorigenesis. Utilizing a high-throughput screening campaign and subsequent structure-guided design, we identify small molecule inhibitors of this interaction with potent in vitro binding affinity, and report structurally related negative controls that can be used to study the effect of this disruption. Our work suggests that disruption of this protein-protein interaction may provide a path toward an effective approach for the treatment of multiple tumors, and anticipate that the molecules disclosed can be used as starting points for future efforts toward compounds with improved drug-like properties.

20.
J Cell Mol Med ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31691506

RESUMO

Type 2 diabetes mellitus (T2DM) is the most common diabetes and has numerous complications. Recent studies demonstrated that T2DM compromises bone fracture healing in which miR-222 might be involved. Furthermore, tissue inhibitor of metalloproteinase 3 (TIMP-3) that is the target of miR-222 accelerates fracture healing. Therefore, we assume that miR-222 could inhibit TIMP-3 expression. Eight-week-old rats were operated femoral fracture or sham, following the injection of streptozotocin (STZ) to induce diabetes one week later in fractured rats, and then, new generated tissues were collected for measuring the expression of miR-222 and TIMP-3. Rat mesenchymal stem cells (MSCs) were isolated and treated with miR-222 mimic or inhibitor to analyse osteogenic differentiation. MiR-222 was increased in fractured rats and further induced in diabetic rats. In contrast, TIMP-3 was reduced in fractured and further down-regulated in diabetic rats. Luciferase report assay indicated miR-222 directly binds and mediated TIMP-3. Furthermore, osteogenic differentiation was suppressed by miR-222 mimic and promoted by miR-222 inhibitor. miR-222 is a key regulator that is promoted in STZ-induced diabetic rats, and it binds to TIMP3 to reduce TIMP-3 expression and suppressed MSCs' differentiation.

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