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1.
Artigo em Inglês | MEDLINE | ID: mdl-32182036

RESUMO

A series of 3,3'-dithioalkyl-2,2'-bithiophene (SBT)-based organic chromophores were designed and developed for the use in dye-sensitized solar cells (DSSCs). By appropriate structural modification of the SBT π-linkers with different alkyl chains and conjugated thiophene units, chromophore aggregation and interfacial charge recombination could be suppressed to a remarkable degree. Single-crystal and optical/electrochemical data clearly show that the SBT core is nearly planar with the torsional angle <1°, likely via S(alkyl)···S(thiophene) intramolecular locks. Therefore, this highly π-conjugated unit should enhance panchromatic light-harvesting and prove to be an excellent core for organic dye. For comparison, the 3,3'-dialkyl-2,2'-bithiophene (BT)-based dye was also prepared. Under 1 sun (100 mW cm-2) illumination, an optimized SBT-6 dye-sensitized cell indicates a short-circuit current density (JSC) of 17.21 mA cm-2, an open-circuit voltage (VOC) of 0.78 V, and a fill factor (FF) of 0.71, corresponding to a power conversion efficiency (η) of 9.47%, which is nearly two times higher than that of alkylated bithiophene (BT)-based chromophores. Finally, the proposed sensitizer SBT-6 exhibited an excellent η of 23.57% under the T5 fluorescent illumination of 6000 lux. To the best of our knowledge, this is the highest power conversion efficiencies (PCE) value reported to date among the studied thiophene or bithiophene-based chromophores.

2.
Clin Transl Sci ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32166908

RESUMO

Drug lag - delayed approval or reimbursement - is a major barrier to accessing cutting-edge drugs. Unlike approval lag, reimbursement lag is under-researched. We investigated the key determinants of reimbursement lag under Taiwan National Health Insurance (NHI), and compared this lag to those in the United Kingdom (UK), Canada, Australia, Japan, and South Korea. Using retrospective data on 190 new NHI-reimbursed drugs from 2007-2014, we studied reimbursement lag in Taiwan versus other countries, and investigated associated factors using generalized linear models (GLM). The median reimbursement lags during before ("first-generation") and after ("second-generation") NHI drug reimbursement scheme was re-organized in Taiwan were 378 and 458 days, respectively. The "first-generation" lag was shorter only than that in South Korea, while the "second-generation" lag only exceeded those of the UK and Japan. In GLM models, higher drug expenditure and the introduction of the "second-generation" NHI were two statistically significant parameters associated with reimbursement lag among antineoplastic and immunomodulating agents. For other drug classes, the reimbursement price proposed by pharmaceutical companies and use of price-volume agreements were two statistically significant parameters associated with longer reimbursement lags. The current reimbursement lag in Taiwan is longer than one year, but only longer than those of the UK and Japan. The determinants differ between drug categories. A specific review process for antineoplastic and immunomodulating drugs may expedite reimbursement. There is a clear need for systematic data collection and analysis to ascertain factors associated with reimbursement lag and thereby inform future policy-making.

3.
Aging Cell ; : e13128, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32196916

RESUMO

Aging impairs the functions of human mesenchymal stem cells (MSCs), thereby severely reducing their beneficial effects on myocardial infarction (MI). MicroRNAs (miRNAs) play crucial roles in regulating the senescence of MSCs; however, the underlying mechanisms remain unclear. Here, we investigated the significance of miR-155-5p in regulating MSC senescence and whether inhibition of miR-155-5p could rejuvenate aged MSCs (AMSCs) to enhance their therapeutic efficacy for MI. Young MSCs (YMSCs) and AMSCs were isolated from young and aged donors, respectively. The cellular senescence of MSCs was evaluated by senescence-associated ß-galactosidase (SA-ß-gal) staining. Compared with YMSCs, AMSCs exhibited increased cellular senescence as evidenced by increased SA-ß-gal activity and decreased proliferative capacity and paracrine effects. The expression of miR-155-5p was much higher in both serum and MSCs from aged donors than young donors. Upregulation of miR-155-5p in YMSCs led to increased cellular senescence, whereas downregulation of miR-155-5p decreased AMSC senescence. Mechanistically, miR-155-5p inhibited mitochondrial fission and increased mitochondrial fusion in MSCs via the AMPK signaling pathway, thereby resulting in cellular senescence by repressing the expression of Cab39. These effects were partially reversed by treatment with AMPK activator or mitofusin2-specific siRNA (Mfn2-siRNA). By enhancing angiogenesis and promoting cell survival, transplantation of anti-miR-155-5p-AMSCs led to improved cardiac function in an aged mouse model of MI compared with transplantation of AMSCs. In summary, our study shows that miR-155-5p mediates MSC senescence by regulating the Cab39/AMPK signaling pathway and miR-155-5p is a novel target to rejuvenate AMSCs and enhance their cardioprotective effects.

4.
J Neurosci Methods ; 337: 108670, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32142909

RESUMO

BACKGROUND: An asynchronous brain-computer interface (BCI) allows subject to freely switch between the working state and the idle state, improving the subject's comfort. However, using only the event-related potential (ERP) to detect these two states is difficult because of the small amplitude of the ERP. METHOD: Our previous study finds that an odd-ball paradigm could evoke transient visual evoked potentials (TSVEPs) simultaneously with ERPs. This study adopts the TSVEP and the ERP to detect the idle state in the design of an asynchronous TSVEP-ERP-based BCI (T-E BCI). The T-E BCI extracts time and frequency features from brain signals and uses a novel probability-based fisher linear discriminant analysis (P-FLDA) to combine the classification results of the ERP and the TSVEP. RESULT: Ten subjects perform visual speller and video watching experiments, and their brain signals are measured under the working and idle states. The main results show that the T-E BCI achieves a higher accuracy than the ERP-based BCI when judging the subject's intentions and the two states. The P-FLDA performs better than the FLDA in combining the classification results. CONCLUSIONS: The study demonstrates that adding the TSVEP can substantially reduce the number of wrongly detected trials. The T-E BCI provides a new way of designing an asynchronous BCI without adding any additional visual stimuli, which makes the BCI more practical.

5.
Int J Neural Syst ; 30(3): 2050009, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32116091

RESUMO

Traditional training methods need to collect a large amount of data for every subject to train a subject-specific classifier, which causes subjects fatigue and training burden. This study proposes a novel training method, TrAdaBoost based on cross-validation and an adaptive threshold (CV-T-TAB), to reduce the amount of data required for training by selecting and combining multiple subjects' classifiers that perform well on a new subject to train a classifier. This method adopts cross-validation to extend the amount of the new subject's training data and sets an adaptive threshold to select the optimal combination of the classifiers. Twenty-five subjects participated in the N200- and P300-based brain-computer interface. The study compares CV-T-TAB to five traditional training methods by testing them on the training of a support vector machine. The accuracy, information transfer rate, area under the curve, recall and precision are used to evaluate the performances under nine conditions with different amounts of data. CV-T-TAB outperforms the other methods and retains a high accuracy even when the amount of data is reduced to one-third of the original amount. The results imply that CV-T-TAB is effective in improving the performance of a subject-specific classifier with a small amount of data by adopting multiple subjects' classifiers, which reduces the training cost.

7.
J Am Chem Soc ; 142(11): 5212-5220, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32091888

RESUMO

In the presence of an alternating magnetic field (AMF), a superparamagnetic iron oxide nanoparticle (SPION) generates heat. Understanding the local heating mechanism of a SPION in suspension and in a mesoporous silica nanoparticle (MSN) will advance the design of hyperthermia-based nanotheranostics and AMF-stimulated drug delivery in biomedical applications. The AMF-induced heating of single-domain SPION can be explained by the Néel relaxation (reorientation of the magnetization) or the Brownian relaxation (motion of the particle). The latter is investigated using fluorescence depolarization based on detecting the mobility-dependent polarization anisotropy (r) of two luminescence emission bands at different wavelengths corresponded to the europium-doped luminescent SPION (EuSPION) core and the silica-based intrinsically emitting shell of the core-shell MSN. The fluorescence depolarization experiments are carried out with both the free and the silica-encapsulated SPION nanoparticles with and without application of the AMF. The r value of a EuSPION core-mesoporous silica shell in the presence of the AMF does not change, indicating that no additional rotational motion of the core-shell nanoparticles is induced by the AMF, disproving the contribution of Brownian heating and thus supporting Néel relaxation as the dominant heating mechanism.

8.
J Formos Med Assoc ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32081563

RESUMO

BACKGROUND: The recommended target low-density lipoprotein cholesterol (LDL-C) level for coronary artery disease (CAD) patients has been lowered from 100 to 70 mg/dL in several clinical guidelines for secondary prevention. We aimed to assess whether initiating statin treatment in CAD patients with baseline LDL-C 70-100 mg/dL in Taiwan could be cost-effective. METHODS: A Markov model was developed to simulate a hypothetical cohort of CAD patients with a baseline LDL-C level of 90 mg/dL. The incidence and recurrence of MI and stroke related to specific LDL-C levels as well as the statin effect, mortality rate, and health state utilities were obtained from the literature. The direct medical costs and rate of fatal events were derived from the national claims database. The incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALYs) was calculated, and sensitivity analyses were performed. RESULTS: Moderate-intensity statin use, a treatment regimen expected to achieve LDL <70 mg/dL in the base case, resulted in a net gain of 562 QALYs but with an additional expenditure of $11.4 million per 10,000 patients over ten years. The ICER was $20,288 per QALY gained. The probabilities of being cost-effective at willingness-to-pay thresholds of one and three gross domestic product per capita ($24,329 in 2017) per QALY were 51.1% and 94.2%, respectively. Annual drug cost was the most influential factor on the ICER. CONCLUSION: Lowering the target LDL-C level from 100 to 70 mg/dL among treatment-naïve CAD patients could be cost-effective given the health benefits of preventing cardiovascular events and deaths.

9.
Chem Commun (Camb) ; 56(10): 1481-1484, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31938795

RESUMO

A series of one-dimensional silver iodide based inorganic-organic hybrid structures with tunable white light emissions have been synthesized by Cu substitution. The white-light-emitting hybrid 1D-Ag2-xCuxI2L2 (x < 2, L = ligand) compounds exhibit extremely strong luminescence with internal quantum yield (IQY) as high as 95%, significantly higher than most of the previously reported direct white-light-emitting hybrid structures and comparable to the IQYs of commercial phosphors.

10.
Crit Rev Oncol Hematol ; 146: 102863, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31935617

RESUMO

Lung cancer is the most frequent cancer for males and third most frequent cancer for females. Targeted therapy drugs based on molecular alterations, such as angiogenesis inhibitors, epidermal growth factor receptor (EGFR) inhibitors, and anaplastic lymphoma kinase (ALK) inhibitors are important part of treatment of NSCLC. However, the quality of the available tumor biopsy and/or cytology material is sometimes not adequate to perform the necessary molecular testing, which has prompted the search for alternatives. This review examines the use of tumor-educated platelet (TEP) as a liquid biopsy in lung cancer patients. The development of sensitive and accurate techniques have made it possible to detect the specific genetic alterations for which targeted therapies are already available. Liquid biopsy offers opportunities to detect resistance mechanisms at an early stage. To conclude, tumor-educated platelet has the potential to be used as liquid biopsy for a variety of clinical and investigational applications.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Ácidos Nucleicos Livres/sangue , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Biópsia Líquida/métodos , Neoplasias Pulmonares/patologia , Biomarcadores Tumorais/genética , Plaquetas/patologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Ácidos Nucleicos Livres/genética , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Masculino , Mutação , Medicina de Precisão , Inibidores de Proteínas Quinases/uso terapêutico
11.
Mol Oncol ; 14(3): 657-668, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31899582

RESUMO

Oncolytic viruses armed with therapeutic transgenes of interest show great potential in cancer immunotherapy. Here, a novel oncolytic adenovirus carrying a signal regulatory protein-α (SIRPα)-IgG1 Fc fusion gene (termed SG635-SF) was constructed, which could block the CD47 'don't eat me' signal of cancer cells. A strong promoter sequence (CCAU) was chosen to control the expression of the SF fusion protein, and a 5/35 chimeric fiber was utilized to enhance the efficiency of infection. As a result, SG635-SF was found to specifically proliferate in hTERT-positive cancer cells and largely increased the abundance of the SF gene. The SF fusion protein was effectively detected, and CD47 was successfully blocked in SK-OV3 and HO8910 ovarian cancer cells expressing high levels of CD47. Although the ability to induce cell cycle arrest and cell death was comparable to that of the control empty SG635 oncolytic adenovirus in vitro, the antitumor effect of SG635-SF was significantly superior to that of SG635 in vivo. Furthermore, CD47 was largely blocked and macrophage infiltration distinctly increased in xenograft tissues of SK-OV3 cells but not in those of CD47-negative HepG2 cells, indicating that the enhanced antitumor effect of SG635-SF was CD47-dependent. Collectively, these findings highlight a potent antitumor effect of SG635-SF in the treatment of CD47-positive cancers.

12.
Mol Cell Biol ; 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964753

RESUMO

Cdk2-dependent TopBP1/Treslin interaction is critical for DNA replication initiation. However, it remains unclear how this association is terminated after replication initiation is finished. Here we demonstrate that phosphorylation of TopBP1 by Akt coincides with Cyclin A activation during S and G2 phases, and switches TopBP1-interacting partner from Treslin to E2F1, which results in the termination of replication initiation. Premature activation of Akt in G1 phase causes early switch and inhibits DNA replication. TopBP1 is often overexpressed in cancer and can bypass the control by Cdk2 to interact with Treslin, leading to the enhanced DNA replication. Consistent with this notion, reducing the levels of TopBP1 in cancer cells restores the sensitivity to a Cdk2 inhibitor. Together, our study links Cdk2 and Akt pathways to the control of DNA replication through the regulation of TopBP1/Treslin interaction. These data also suggest an important role for TopBP1 in driving abnormal DNA replication in cancer.

13.
J Cell Mol Med ; 24(1): 431-440, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31660694

RESUMO

The cardiac protection of mesenchymal stem cell (MSC) transplantation for myocardial infarction (MI) is largely hampered by low cell survival. Haem oxygenase 1 (HO-1) plays a critical role in regulation of cell survival under many stress conditions. This study aimed to investigate whether pre-treatment with haemin, a potent HO-1 inducer, would promote the survival of MSCs under serum deprivation and hypoxia (SD/H) and enhance the cardioprotective effects of MSCs in MI. Bone marrow (BM)-MSCs were pretreated with or without haemin and then exposed to SD/H. The mitochondrial morphology of MSCs was determined by MitoTracker staining. BM-MSCs and haemin-pretreated BM-MSCs were transplanted into the peri-infarct region in MI mice. SD/H induced mitochondrial fragmentation, as shown by increased mitochondrial fission and apoptosis of BM-MSCs. Pre-treatment with haemin greatly inhibited SD/H-induced mitochondrial fragmentation and apoptosis of BM-MSCs. These effects were partially abrogated by knocking down HO-1. At 4 weeks after transplantation, compared with BM-MSCs, haemin-pretreated BM-MSCs had greatly improved the heart function of mice with MI. These cardioprotective effects were associated with increased cell survival, decreased cardiomyocytes apoptosis and enhanced angiogenesis. Collectively, our study identifies haemin as a regulator of MSC survival and suggests a novel strategy for improving MSC-based therapy for MI.

14.
Int J Mol Med ; 45(2): 353-364, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31789413

RESUMO

Persistent ventricular remodeling following myocardial ischemia/reperfusion (MI/R) injury results in functional decompensation and eventual progression to heart failure. VCP979, a novel small­molecule compound developed in­house, possesses anti­inflammatory and anti­fibrotic activities. In the present study, no significant pathological effect was observed following the administration of VCP979 on multiple organs in mice and no difference of aspartate transaminase/alanine aminotransferase/lactate dehydrogenase levels was found in murine serum. Treatment with VCP979 ameliorated cardiac dysfunction, pathological myocardial fibrosis and hypertrophy in murine MI/R injury models. The administration of VCP979 also inhibited the infiltration of inflammatory cells and the pro­inflammatory cytokine expression in hearts post MI/R injury. Further results revealed that the addition of VCP979 prevented the primary neonatal cardiac fibroblasts (NCFs) from Angiotensin II (Ang II)­induced collagen synthesis and neonatal cardiac myocytes (NCMs) hypertrophy. In addition, VCP979 attenuated the activation of p38­mitogen­activated protein kinase in both Ang II­induced NCFs and hearts subjected to MI/R injury. These findings indicated that the novel small­molecule compound VCP979 can improve ventricular remodeling in murine hearts against MI/R injury, suggesting its potential therapeutic function in patients subjected to MI/R injury.

15.
J Comput Chem ; 41(5): 439-448, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31518010

RESUMO

Cation-π interactions are noncovalent interactions between a π-electron system and a positively charged ion that are regarded as a strong noncovalent interaction and are ubiquitous in biological systems. Similarly, though less studied, anion-ring interactions are present in proteins along with in-plane interactions of anions with aromatic rings. As these interactions are between a polarizing ion and a polarizable π system, the accuracy of the treatment of these interactions in molecular dynamics (MD) simulations using additive force fields (FFs) may be limited. In the present work, to allow for a better description of ion-π interactions in proteins in the Drude-2013 protein polarizable FF, we systematically optimized the parameters for these interactions targeting model compound quantum mechanical (QM) interaction energies with atom pair-specific Lennard-Jones parameters along with virtual particles as selected ring centroids introduced to target the QM interaction energies and geometries. Subsequently, MD simulations were performed on a series of protein structures where ion-π pairs occur to evaluate the optimized parameters in the context of the Drude-2013 FF. The resulting FF leads to a significant improvement in reproducing the ion-π pair distances observed in experimental protein structures, as well as a smaller root-mean-square differences and fluctuations of the overall protein structures from experimental structures. Accordingly, the optimized Drude-2013 protein polarizable FF is suggested for use in MD simulations of proteins where cation-π and anion-ring interactions are critical. © 2019 Wiley Periodicals, Inc.

16.
J Leukoc Biol ; 107(1): 57-67, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31385383

RESUMO

Most information about the immune status of NK cells during sepsis has been obtained from animal models, athough data from clinical septic patients is limited. In this study, we aimed to decipher NK cell immunity of septic patients in a more comprehensive way. We found that cytotoxicity of NK cells dramatically decreased during sepsis, likely due to the reduction of cluster of differentiation (CD)3- CD56+ NK cells and a shift of phenotypic changes of NK group 2 member (NKG2) receptors, natural cytotoxicity receptors (NCRs) and killer immunoglobulin-like receptors (KIRs) toward inhibitory receptors demonstrated by CD3- CD56+ NK cells in septic patients. Expression of the activation indicator CD69 and cytotoxic associated marker CD107a on CD3- CD56+ NK cells in healthy adults was significantly lower than that of septic patients. Although perforin and granzyme B on CD3- CD56+ NK cells from all groups exhibited equivalently high levels, CD3- CD56+ NK cells from septic patients exhibited a much lower fold increase of CD69 and CD107a compared with healthy adults after coculturing with K562 cells in vitro. Cytokine production of IFN-γ and TNF-α on CD3- CD56+ NK cells in septic patients was also impaired after stimulation by PMA and ionomycin. We found that the proportion of NK cells in lymphocytes was negatively associated with patient 28 d death in septic patients. Phenotypic changes of a shift toward inhibitory receptors and impairment of effector functions of NK cells might be an important mechanism of immunosuppression during sepsis.

17.
Menopause ; 27(3): 326-332, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31834159

RESUMO

OBJECTIVE: To determine the effect of metformin on marrow adiposity in postmenopausal women with newly diagnosed type 2 diabetes mellitus (T2DM). METHODS: We enrolled 25 postmenopausal T2DM women who satisfied the requirement of having been on 1 year of metformin therapy and 26 age-matched healthy women receiving a placebo. All participants were analyzed for marrow fat fraction (FF) by magnetic resonance spectroscopy, vertebral volumetric bone mineral density (vBMD) by quantitative computed tomography, blood glucose, lipid profiles, and bone biomarkers to compare values before and after the interventions. Differences between groups were assessed using a Student's t test and chi-square test or an analysis of covariance adjusted for covariates. Twelve-month change in within-group difference was assessed using paired t tests. Correlations were determined by Pearson's correlation. RESULTS: Vertebral vBMD was lower in T2DM than in nondiabetic controls (105.6 ±â€Š13.8 vs 112.8 ±â€Š15.2 mg/cm; P = 0.029). T2DM women had a higher marrow FF than those without diabetes (66.3 ±â€Š7.2% vs 58.9 ±â€Š7.5%; P < 0.001), even after adjusting for covariates. From baseline to month 12 in the T2DM group, metformin was associated with a reduction in marrow FF (-12.0%; P < 0.001) and an increase in vBMD (3.7%; P = 0.020). For metformin-treated T2DM women, the 12-month change in marrow FF was inversely associated with change in vBMD (r = -0.771, P < 0.001), but not with changes in bone biomarkers, whereas change in vBMD or FF was not significant in the control group. CONCLUSION: Postmenopausal women with newly diagnosed T2DM have a higher marrow fat content compared with nondiabetic women. Metformin treatment reduced marrow adiposity in T2DM.

18.
Neuropharmacology ; 164: 107910, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31838171

RESUMO

Alzheimer's disease (AD) starts with memory impairments that can be observed before the appearance of significant neuropathology; thus, identifying mechanisms to stop AD progression is an urgent priority. Epidemiological and clinical data show that the consequences of vitamin D deficiency are relevant to disease risk and can be observed in the progression of many diseases, especially AD, whereas higher serum levels of vitamin D are associated with better cognitive test performance. However, the potential therapeutic strategy and underlying mechanisms of vitamin D supplementation against AD still need to be further investigated. In the present study, we found that 3xTg-AD mice with vitamin D supplementation exhibited an increase in serum vitamin D concentrations and improved cognition. We measured serum vitamin D binding protein (VDBP) concentrations and found that serum VDBP levels were increased in 3xTg-AD mice compared to B6129S control mice, but there was no significant difference between control- and vitamin D-treated 3xTg-AD groups. The vitamin D-mediated memory improvement may be accompanied by the suppression of increased hippocampal collapsin response mediator protein-2 (CRMP2) phosphorylation, and the restoration of CRMP2 phosphorylation by okadaic acid (OA) could abolish the beneficial effects of vitamin D. In addition, we found that CRMP2 was associated with NR2B and PSD-95 in 3xTg-AD mice with vitamin D supplementation. This CRMP2-NR2B interaction could be disrupted by a TAT-CBD3 peptide or OA, leading to attenuated memory protection in vitamin D-treated 3xTg-AD mice. Therefore, CRMP2 may be involved in vitamin D-mediated memory improvement in AD.

19.
Biomed Pharmacother ; 121: 109644, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31766099

RESUMO

BACKGROUND: The molecular mechanisms of gastric cancer (GC) development are very complicated. Recent studies revealed that DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)-related protein (DC-SIGNR) is involved in colon cancer and GC biological processes. However, the exact roles of DC-SIGN in GC remain unrevealed. METHODS: DC-SIGN overexpression and knockdown experiments were performed by using DC-SIGN shRNA or DC-SIGN plasmid to investigate the biological roles of DC-SIGN in proliferation, cell cycle progression, migration and invasion of GC cells in vitro. Furthermore, the lncRNA profiles of SGC-7901 cells with control shRNA and DC-SIGN shRNA were generated by using microarray analysis. Mechanistically, the relationship between DC-SIGN, RP11-181G12.2 and the JAK2/STAT3 signaling pathway was then investigated using qRT-PCR and western blot assays. Additionally, we analyzed DC-SIGN and RP11-181G12.2 expression levels in GC specimens based on the Cancer Genome Atlas database. RESULTS: In this study, the results showed that DC-SIGN was highly expressed in GC cells and significantly correlated with advanced clinical stage and lymphatic metastasis. Downregulation of DC-SIGN significantly inhibited the proliferation, cell cycle progression, migration and invasion of GC cells in vitro. The reverse results could partly be seen with the upregulation of DC-SIGN. Mechanistically, knockdown of DC-SIGN inactivated the JAK2/STAT3 signaling pathway, and overexpression of DC-SIGN activated the JAK2/STAT3 signaling pathway. In addition, through LncPath microarray analysis, we identified a lncRNA, RP11-181G12.2, that was significantly upregulated after knockdown of DC-SIGN; this was also confirmed by qRT-PCR. Furthermore, RP11-181G12.2 knockdown enhanced DC-SIGN expression in GC cells, further activating the JAK2/STAT3 signaling pathway. In contrast, DC-SIGN overexpression suppressed RP11-181G12.2 expression. CONCLUSIONS: Our study suggests that DC-SIGN might be involved in the progression of GC by regulating the JAK2/STAT3 signaling pathway and affecting lncRNA RP11-181G12.2 expression.

20.
Lancet Diabetes Endocrinol ; 8(1): 27-35, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31862149

RESUMO

BACKGROUND: Cardiovascular and kidney outcome trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors slow progression of chronic kidney disease in patients with type 2 diabetes with or without chronic kidney disease. The aim of this study was to assess whether these benefits extend to patients with type 2 diabetes treated in routine clinical practice. METHODS: CVD-REAL 3 was a multinational observational cohort study in which new users of SGLT2 inhibitors and other glucose-lowering drugs with measurements of estimated glomerular filtration rate (eGFR) before and after (within 180 days) initiation were identified via claims, medical records, and national registries in Israel, Italy, Japan, Taiwan, and the UK. Propensity scores for SGLT2 inhibitor initiation were developed in each country, with 1:1 matching with initiators of other glucose-lowering drugs. Propensity score included (in addition to other clinical and demographic variables) baseline eGFR and eGFR slope before SGLT2 inhibitor or other glucose-lowering drug initiation. The main outcome measure was rate of eGFR decline (slope) calculated with a linear mixed regression model. Differences in eGFR slope between SGLT2 inhibitors and other glucose-lowering drugs were calculated and pooled. We also assessed a composite outcome of 50% eGFR decline or end-stage kidney disease. FINDINGS: After propensity matching, there were 35 561 episodes of treatment initiation in each group, from 65 231 individual patients. Dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin accounted for 57·9%, 34·1%, 5·7%, 1·4%, 0·5%, and 0·4% of SGLT2 inhibitor initiation episodes, respectively. At baseline, 29 363 (41·3%) of 71 122 initiations were in women, mean age was 61·3 years, mean HbA1c was 72 mmol/mol (8·71%), and mean eGFR was 90·7 mL/min per 1·73 m2. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs other glucose-lowering drugs 1·53 mL/min per 1·73 m2 per year, 95% CI 1·34-1·72, p<0·0001). During a mean follow-up of 14·9 months, 351 composite kidney outcomes occurred: 114 (3·0 events per 10 000 patient-years) among initiators of SGLT2 inhibitors and 237 (6·3 events per 10 000 patient-years) among initiators of other glucose-lowering drugs (hazard ratio 0·49, 95% CI 0·35-0·67; p<0·0001). These findings were consistent across countries (pheterogeneity 0·10) and prespecified subgroups. INTERPRETATION: In this large, international, real-world study of patients with type 2 diabetes, initiation of SGLT2 inhibitor therapy was associated with a slower rate of kidney function decline and lower risk of major kidney events compared with initiation of other glucose-lowering drugs. These data suggest that the benefits of SGLT2 inhibitors on kidney function identified in clinical trials seem to be largely generalisable to clinical practice. FUNDING: AstraZeneca.

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