Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.133
Filtrar
1.
Opt Lett ; 45(3): 665, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32004279

RESUMO

This publisher's note contains corrections to Opt. Lett.44, 2081 (2019)OPLEDP0146-959210.1364/OL.44.002081.

2.
J Cell Mol Med ; 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32064783

RESUMO

Airway epithelial apoptosis and epithelial mesenchymal transition (EMT) are two crucial components of asthma pathogenesis, concomitantly mediated by TGF-ß1. RACK1 is the downstream target gene of TGF-ß1 shown to enhancement in asthma mice in our previous study. Balb/c mice were sensitized twice and challenged with OVA every day for 7 days. Transformed human bronchial epithelial cells, BEAS-2B cells were cultured and exposed to recombinant soluble human TGF-ß1 to induced apoptosis (30 ng/mL, 72 hours) and EMT (10 ng/mL, 48 hours) in vitro, respectively. siRNA and pharmacological inhibitors were used to evaluate the regulation of RACK1 protein in apoptosis and EMT. Western blotting analysis and immunostaining were used to detect the protein expressions in vivo and in vitro. Our data showed that RACK1 protein levels were significantly increased in OVA-challenged mice, as well as TGF-ß1-induced apoptosis and EMT of BEAS-2B cells. Knockdown of RACK1 (siRACK1) significantly inhibited apoptosis and decreased TGF-ß1 up-regulated EMT related protein levels (N-cadherin and Snail) in vitro via suppression of JNK and Smad3 activation. Moreover, siSmad3 or siJNK impaired TGF-ß1-induced N-cadherin and Snail up-regulation in vitro. Importantly, JNK gene silencing (siERK) also impaired the regulatory effect of TGF-ß1 on Smad3 activation. Our present data demonstrate that RACK1 is a concomitant regulator of TGF-ß1 induces airway apoptosis and EMT via JNK/Smad/Snail signalling axis. Our findings may provide a new insight into understanding the regulation mechanism of RACK1 in asthma pathogenesis.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32017343

RESUMO

Hybrid solid/liquid electrolyte with superior security facilitates the implementation of high-energy-density storage devices, while suffers from inferior chemical compatibility with cathodes. Herein, an optimal lithium difluoro(oxalato)borate salt was introduced to in situ build an amorphous cathode electrolyte interphase (CEI) between Ni-rich cathodes and hybrid electrolyte. The formed CEI preserves the surface structure with high compatibility, leading to enhanced interfacial stability. Meanwhile, the space-charge layer can be prominently mitigated at the solid/solid interface via harmonized chemical potentials, acquiring promoted interfacial dynamics that revealed by COMSOL simulation. Consequently, the amorphous CEI integrates the bifunctionality to provide an excellent cycling stability, high Coulombic efficiency and favourable rate capability in high-voltage Li-metal batteries, innovating the design philosophy of functional CEI strategy for future high-energy-density batteries.

4.
Nat Biotechnol ; 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32042168

RESUMO

Several cancer immunotherapy approaches, such as immune checkpoint blockade and adoptive T-cell therapy, boost T-cell activity against the tumor, but these strategies are not effective in the absence of T cells specific for displayed tumor antigens. Here we outline an immunotherapy in which endogenous T cells specific for a noncancer antigen are retargeted to attack tumors. The approach relies on the use of antibody-peptide epitope conjugates (APECs) to deliver suitable antigens to the tumor surface for presention by HLA-I. To retarget cytomegalovirus (CMV)-specific CD8+ T cells against tumors, we used APECs containing CMV-derived epitopes conjugated to tumor-targeting antibodies via metalloprotease-sensitive linkers. These APECs redirect pre-existing CMV immunity against tumor cells in vitro and in mouse cancer models. In vitro, APECs activated specifically CMV-reactive effector T cells whereas a bispecific T-cell engager activated both effector and regulatory T cells. Our approach may provide an effective alternative in cancers that are not amenable to checkpoint inhibitors or other immunotherapies.

5.
Medicine (Baltimore) ; 99(3): e18729, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011451

RESUMO

BACKGROUND: Patients with mechanical heart valves (MHV) have an increased risk of thromboembolic complications. Low molecular weight heparin (LMWH) and unfractionated heparin (UFH) are often recommended for bridging anticoagulation; however, it is not clear which strategy is more beneficial. METHODS: The PubMed, EMBASE, and Cochrane databases were searched from January 1960 to March 2019. Randomized controlled trials and observational studies were analyzed. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the studies. Stata 11.0 was used for the meta-analysis. RESULTS: A total of 6 publications were included; 1366 events were selected, involving 852 events with LMWH and 514 events with UFH. The thromboembolism risk of the LMWH group was lower than that of the UFH group (risk ratio [RR] = 0.34, 95% confidence interval [CI] 0.12-0.95, P = .039). The incidence of major bleeding was lower in the LMWH group than in the UFH group, albeit without statistical significance (RR = 0.94, 95% CI 0.68-1.30, P = .728), as was mortality (RR = 0.52, 95% CI 0.16-1.66, P = .271). Subgroup analysis showed that LMWH cardiac surgery patients had a higher risk of major bleeding compared with UFH cardiac surgery patients (RR = 1.17, 95% CI 0.72-1.90, P = .526); but among non-cardiac surgery patients, the LMWH group had a lower risk of major bleeding than the UFH group (RR = 0.79, 95% CI 0.51-1.22, P = .284), although the difference was not statistically significant. CONCLUSION: Our meta-analysis suggests that LMWH not only reduces the risk of thromboembolism in patients with MHV but also does not increase the risk of major bleeding. LMWH may provide safer and more effective bridging anticoagulation than UFH in patients with MHV. It is still necessary to conduct future randomized studies to verify this conclusion.

6.
Int J Lab Hematol ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31958215

RESUMO

INTRODUCTION: To assess the clinical performance and correlations of automated chemiluminescence assay (CIA) and enzyme-linked immunosorbent assay (ELISA) for detecting antiphospholipid (aPL) antibodies in the diagnosis of antiphospholipid syndrome (APS). METHODS: The study recruited 505 subjects, including 192 with APS, 193 with connective tissue diseases other than APS, and 120 healthy donors. We measured anticardiolipin (aCL) and anti-ß2-glycoprotein I (anti-ß2GPI) antibodies IgG, IgM, and IgA in all the samples using both CIA and ELISA. RESULTS: Total agreement between the two methods ranged from 83.50% for anti-ß2GPI IgG antibodies to 92.76% for anti-ß2GPI IgM antibodies in all the groups. Anti-ß2GPI and aCL IgG assays showed the highest Spearman's rho coefficients (anti-ß2GPI IgG = 0.742, aCL IgG = 0.715). Anti-ß2GPI IgG CIA showed the highest sensitivity for diagnosis of APS at 80.21%, which was significantly higher than the sensitivity of anti-ß2GPI IgG ELISA (52.08%). For diagnosis of APS, anti-ß2GPI IgG CIA had the best discrimination power with the area under the curves (AUC) of 0.922, followed by aCL IgG CIA (AUC of 0.905). While the CIA AUC was slightly higher in all cases, the difference was not statistically significant. CONCLUSION: CIA measurements had a good agreement and correlation with comparative ELISA assays. The CIA anti-ß2GPI IgG however was significantly more sensitive for APS diagnosis. The two assay methodologies showed comparable predictive powers and support the value of the CIA method for improved diagnosis and management of patients with APS.

7.
Chem Commun (Camb) ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31965121

RESUMO

We demonstrated a rechargeable aqueous Al-S battery based on a water-in-salt electrolyte with the configuration Al‖Al(OTF)3 + LiTFSI + HCl‖S/C. The superconcentrated LiTFSI trapped water molecules to inhibit the hydrolysis of aluminum polysulfides in the cathode, and the HCl additive provided a mild acidic environment to enable repeatable oxidation-reduction reactions in the anode.

8.
J Cell Mol Med ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31965704

RESUMO

It is an increasing evidence that long non-coding RNAs (lncRNAs) are involved in tumour initiation and progression. Here, we analysed RNA-sequencing data from the Cancer Genome Atlas (TCGA) datasets. Totally, 1176lncRNAs, 245miRNAs and 2081mRNAs were identified to be differentially expressed (DE) in colon cancer tissues compared with normal tissues. CASC21, a novel lncRNA located in 8q24.21 locus, was significantly overexpressed in 30 colon cancer tissues compared with matched normal tissues by qRT-PCR assay. CASC21 tended to higher expression as the increase of the tumour-node-metastasis (TNM) classification. Functionally, CASC21 promoted cell proliferation by regulating cell cycle and enhanced tumour metastasis by epithelial-mesenchymal transition (EMT) in colon cancer. Mechanism study indicated that CASC21 might be involved in activating WNT/ß-catenin pathway in colon cancer. In addition, we also built a competing endogenous RNA (ceRNNA) network by bioinformatic analysis using TCGA datasets. Together, our results not only provide novel lncRNAs as potential candidates for further study but also prove that CASC21 is an oncogenic regulator through activating WNT/ß-catenin signalling in colon cancer.

9.
Reg Anesth Pain Med ; 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31898581

RESUMO

BACKGROUND AND OBJECTIVES: Neuropathic pain is partially refractory to currently available treatments. Although some studies have reported that apoptosis signal-regulating kinase 1 (ASK1) may inhibit chronic pain, the mechanisms underlying this process have not been fully elucidated. METHODS: Chronic constriction injury (CCI) of the rat sciatic nerve was used to establish a neuropathic pain model. Nociception was assessed using von Frey hair and Hargreaves' methods. Western blot and immunofluorescence were used to detect the cell signaling pathway. BV2 cell line was cultured for in vitro evaluation. RESULTS: Our results indicated that spinal ASK1 was co-expressed with the microglia marker ionized calcium binding adaptor 1. Additionally, intrathecal administration of ASK1 inhibitor suppressed the activation of spinal microglia and attenuated CCI-induced neuropathic pain. The ASK1 inhibitor also decreased the levels of phosphorylated ASK1 (p-ASK1), p65, p38 mitogen-activated protein kinase (MAPK) and tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) messenger RNA in lipopolysaccharide-stimulated BV2 microglia cells. Intragastric administration of levo-corydalmine (l-CDL) significantly attenuated CCI-induced neuropathic pain and inhibited the expression of p-ASK1 in the spinal cord. l-CDL conspicuously suppressed the activation of spinal microglia in vitro and in vivo. Translocation of nuclearfactor-kappa B (NF-κB) and upregulation of p-p65, TNF-α, IL-1ß were inhibited by l-CDL. Further, the analgesic effects of l-CDL were associated with reduced levels of phosphorylated protein kinase C (PKC γ), c-JunNH2-terminal kinase, and extracellular signal-regulated kinase. CONCLUSIONS: This study showed that the expression of ASK1 in spinal microglia and ASK1 inhibitor suppressed microglia activation via suppression of p38 MAPK/NF-κB, which ultimately attenuated CCI-induced neuropathic pain. l-CDL also inhibited the ASK1-P38 MAPK/NF-κB axis to attenuate CCI-induced neuropathic pain.

10.
J Matern Fetal Neonatal Med ; : 1-4, 2020 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-31928263

RESUMO

Objective: To investigate the effect of unique skill of perineum protection in forceps delivery on the maternal and neonatal morbidity.Methods: A case-control study was conducted. Singleton pregnancies with forceps-assisted and normal vaginal deliveries were recruited. The maternal and neonatal complications were compared between forceps and normal deliveries.Results: Five hundred forty participants were included. The prevalence of maternal anal sphincter injury, postpartum hemorrhage, vaginal hematoma, cervical laceration, perineal wound infection, perineal wound dehiscence, dyspareunia, urinary incontinence, and anal incontinence were not significantly different between forceps and normal deliveries (p > .05). However, the rate of neonatal facial injury was higher in the forceps group (2.9% versus 0, p = .004).Conclusions: Cooperation according to the tension of perineum and labor process between obstetrician and midwife is important for perineum protection. Forceps-assisted delivery concentrating on perineum protection is an effective alternative in decreasing maternal morbidity.

11.
J Cardiovasc Nurs ; 35(2): 156-164, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31904693

RESUMO

BACKGROUND: The health behaviors and blood pressure control of patients with hypertension who have had a stroke are unsatisfactory. A protocol of a comprehensive reminder system has been published, and the results of 3 months of implementation have demonstrated improved patient health behaviors and blood pressure control. The continuity of the intervention effect on these variables after 3 months was not clear. OBJECTIVE: The aim of this study was to determine the impact of a comprehensive reminder system intervention on health behaviors, medication adherence, blood pressure, disability, and stroke recurrence in patients with hypertension who have had a stroke from baseline to 6 months after discharge. METHOD: A multicenter, assessor-blinded, randomized controlled trial was conducted with 174 patients with hypertension who have had a stroke. The intervention consisted of health belief education, a calendar handbook, weekly short message services, and telephone interviews. Data were collected at baseline and at 3 and 6 months after discharge. RESULTS: Repeated-measures analysis of variance and single-effect analysis revealed that, compared with the control group, improvements of health behaviors, medication adherence, blood pressure, and disability of participants in the intervention group were superior. From 3 to 6 months after discharge, these trends remained or continually improved, whereas a downward trend was observed in the control group. There were only 2 stroke recurrences within 6 months, and no statistically significant difference between groups was found. CONCLUSION: The comprehensive reminder system improved patients' health behaviors and medication adherence and reduced blood pressure and disability; the effect extended to 6 months after discharge.

12.
Am J Chin Med ; 48(1): 77-90, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31918565

RESUMO

Post inflammatory irritable bowel syndrome (PI-IBS), a subset of IBS, is characterized by symptoms of visceral pain, bloating, and changed bowel habits that occur post initial episode of intestinal infection. Gut microbial dysbiosis or inflammation plays a key role in the pathogenesis of abdominal hypersensitivity of PI-IBS. Electroacupuncture (EA) stimulation results in an alleviated PI-IBS-associated symptom. This study investigated the effect of EA on IL-18 and gut microbial dysbiosis in one visceral hypersensitive rat models with PI-IBS. A trinitrobenzene sulfonic acid (TNBS)-induced visceral hypersensitivity rat model was developed. EA stimulation was applied to the ST25 and ST36 acupoints. Animals were assessed using abdominal withdrawal reflex (AWR) scores to determine the development of colonic visceral hypersensitivity. The 16S rRNA was used to correlate microbial diversity. IL-18 expression in colon was quantified by quantitative real-time PCR and western blotting. We identified that model rats had an increased visceral hypersensitivity to colorectal distention at different distention pressures compared with the normal group. Sensitivity to colorectal distention decreased after EA stimulation. The composition of the fecal microbiota was different between groups. Specifically, in the model group Empedobacter, Psychrobacter, Enterococcus, Butyricimonas, Vampirovibrio, Kurthia, Intestinimonas, Neisseria, Falsiporphyromonas, Bilophila, Fusobacterium, Alistipes, Veillonella, Flavonifractor, Clostridium XlVa were more abundant affected genera, whereas Lactobacillus was enriched in normal rats. EA stimulation was correlated with significant decrease in the phyla of Fusobacteria. The mRNA and protein levels of IL-18 were higher in the model group. Meanwhile, EA stimulation attenuated this response. In a word, our findings suggest that PI-IBS is associated with significant increase in IL-18 levels as well as an alteration in microbiome diversity. These changes can be reversed with EA treatment. EA stimulation has a positive effect in alleviating symptoms of visceral hypersensitivity and protecting the gastrointestinal tract.

13.
Neurochem Int ; 133: 104613, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31785347

RESUMO

Trigeminal neuropathic pain (TNP) remains a tremendous clinical challenge due to its elusive mechanisms. Previous studies showed that peripheral nerve injury facilitated a selective GABAergic neuronal apoptosis in the superficial dorsal horn and contributed to the development and maintenance of neuropathic pain. It has also demonstrated that downregulation of the anaphase-promoting complex/cyclosome(APC/C) and its coactivator Cdh1 contribute to neuronal apoptosis in diverse neurodegenerative diseases. However, whether APC/C-Cdh1 downregulation could induce GABAergic neuronal apoptosis in trigeminal caudalis nucleus (Vc), and then contribute to the development and maintenance of TNP remains unknown. In this study, we aimed to investigate the role of APC/C-Cdh1 in a TNP rat model and its underlying mechanisms. Our results showed that Cdh1 was primarily distributed in superficial laminae of Vc and significantly downregulated in Vc at day 14 post trigeminal nerve injury. Furthermore, trigerminal nerve injury leads to neuronal apoptosis, especially GABAergic interneurons in the superficial of Vc. Upregulating Cdh1 in Vc ameliorated mechanical allodynia and inhibited GABAergic neuronal apoptosis induced by chronic constriction injury of trigeminal infraorbital nerve (CCI-ION).

14.
Biochem Biophys Res Commun ; 522(4): 845-851, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31801666

RESUMO

Mesenchymal cells in the liver provide the microenvironment for hepatoblasts expansion and differentiation. We have previously demonstrated that myofibroblasts (MFs) promoted hepatoblasts differentiation into cholangiocytes, whereas its role in controlling the proliferation of hepatoblasts and their differentiated cholangiocytes remains elusive. Here, we investigated the role of MFs in regulating the proliferation of hepatoblasts and their differentiated cholangiocytes using an indirect coculture system. When cocultured with hepatoblasts, MFs promoted hepatoblasts differentiation into cholangiocytes and inhibited the proliferation and stemness of hepatoblasts. However, when hepatoblasts already differentiated into cholangiocytes, MFs promoted the differentiated cholangiocytes proliferation. In addition, hepatoblast proliferation genes such as hepatocyte growth factor (HGF), insulin-like growth factor-1 and 2 (IGF-1 and 2), midkine 1 (Mdk1), and pleiotrophin (Ptn) expression in MFs were down-regulated compared with their levels in fibroblasts. Our findings uncover the role of MFs in controlling the proliferation of hepatoblasts and their differentiated cholangiocytes, potentially providing a novel therapeutic strategy for cholangiocyte regeneration.

15.
Angew Chem Int Ed Engl ; 59(6): 2318-2322, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31750970

RESUMO

Black phosphorus (BP) is a desirable anode material for alkali metal ion storage owing to its high electronic/ionic conductivity and theoretical capacity. In-depth understanding of the redox reactions between BP and the alkali metal ions is key to reveal the potential and limitations of BP, and thus to guide the design of BP-based composites for high-performance alkali metal ion batteries. Comparative studies of the electrochemical reactions of Li+ , Na+ , and K+ with BP were performed. Ex situ X-ray absorption near-edge spectroscopy combined with theoretical calculation reveal the lowest utilization of BP for K+ storage than for Na+ and Li+ , which is ascribed to the highest formation energy and the lowest ion diffusion coefficient of the final potassiation product K3 P, compared with Li3 P and Na3 P. As a result, restricting the formation of K3 P by limiting the discharge voltage achieves a gravimetric capacity of 1300 mAh g-1 which retains at 600 mAh g-1 after 50 cycles at 0.25 A g-1 .

16.
Neural Netw ; 122: 231-238, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31698201

RESUMO

This paper is concerned with multistability and attraction basins of discrete-time neural networks with nonmonotonic piecewise linear activation functions. Under some reasonable conditions, the addressed networks have (2m+1)n equilibrium points. (m+1)n of which are locally asymptotically stable, and the others are unstable. The attraction basins of the locally asymptotically stable equilibrium points are given in the form of hyperspherical regions. These results here, which include existence, uniqueness, locally asymptotical stability, instability and attraction basins of the multiple equilibrium points, generalize and improve the earlier publications. Finally, an illustrative example with numerical simulation is given to show the feasibility and the effectiveness of the theoretical results. The theoretical results and illustrative example indicate that the activation functions improve the storage capacity of neural networks significantly.

17.
J Cell Biochem ; 121(2): 1716-1727, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31595566

RESUMO

BACKGROUND: Since several long noncoding RNAs (lncRNAs) have been implicated in the development of chemoresistance in non-small cell lung carcinoma (NSCLC), the aim of this study was to investigate whether antisense noncoding RNA in the INK4 locus (ANRIL) was associated with the chemoresistance of NSCLC. METHOD: Real-time polymerase chain reaction was performed to identify potential lncRNAs involved in the chemoresistance of NSCLC, while in-silicon analyses and luciferase assays were carried out to explore the regulatory relationship among ANRIL, miR-125a, and aminopeptidase N (APN). RESULTS: Ubenimex resistant cells were associated with a high expression of ANRIL, which directly binds to miR-125a. MiR-125a directly targeted APN expression. In addition, miR-125a and ANRIL small interfering RNA inhibited the expression of APN but promoted the expression of beclin-1 and LC3, whereas ANRIL, by competing with miR-125a, promoted cell proliferation and inhibited cell apoptosis. CONCLUSION: The data of this study suggested that, by targeting ANRIL and the APN signaling pathway, miR-125a inhibited the proliferation of NSCLC cells and promoted their apoptosis, thus attenuating the chemoresistance of NSCLC against Ubenimex.

18.
Cancer Biol Ther ; 21(2): 157-169, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31619123

RESUMO

Long noncoding RNAs (lncRNAs) have been shown to play important roles in various tumors including colorectal cancer (CRC). Here, we obtained data from RNA-sequencing analysis using 3 paired of CRC tissues and corresponding normal tissues. Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, the biological functions of these dysregulated genes were identified. Moreover, we analyzed the expression levels of lncRNA PGM5-AS1 and B3GALT5-AS1 by quantitative real-time PCR (qRT-PCR) assay. To evaluate the accuracy of the lncRNA-mRNA co-expression network we built, we also detected PGM5 expression and analyzed the relationship between PGM5-AS1 and PGM5 in CRC. In addition, we explored the potential function of PGM5-AS1 in vitro and in vivo. In conclusion, we identified dysregulated lncRNAs and constructed the lncRNA-mRNA co-expression network in CRC. Then, we showed that the expression levels of PGM5-AS1, B3GALT5-AS1 and PGM5 were significantly downregulated in CRC tissues compared with corresponding normal tissues. Besides, PGM5-AS1 expression was positively associated with PGM5 expression. These findings were consistent with our RNA-sequencing data. Functionally, overexpression of PGM5-AS1 could induce cell apoptosis and cell cycle arrest in CRC. Animal study indicated that PGM5-AS1 overexpression inhibited CRC growth in vivo. This work provides dysregulated lncRNAs as candidates for further study in CRC. The lncRNA-mRNA co-expression network brings novel insights into further function research. More importantly, PGM5-AS1 is a critical tumor suppressor in CRC.

19.
J Thorac Oncol ; 15(1): 91-100, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31605797

RESUMO

INTRODUCTION: Clinical studies have shown that a combination of a tyrosine kinase inhibitor (TKI) and pemetrexed overcame acquired resistance to epidermal growth factor receptor (EGFR) TKI in NSCLC. Previously, pemetrexed+gefintib (P+G) had improved progression-free survival (PFS) compared with gefitinib. We present OS, updated PFS, biomarker analysis, and safety of P+G versus gefitinib. METHODS: This was a phase 2, multicenter, randomized study conducted in East Asian patients with advanced nonsquamous NSCLC with EGFR mutations. Patients were randomized (2:1) to receive P+G (500 mg/m2 intravenously 3-weekly + 250 mg/day orally) or gefitinib. RESULTS: In total, 191 patients (P+G, n=126; gefitinib, n=65) comprised the intent-to-treat and safety populations. Median OS was 43.4 months in P+G versus 36.8 months in gefitinib arm; adjusted HR 0.77 (95% CI, 0.5-1.2); one-sided P=0.105. Median PFS was significantly longer in the P+G (16.2 months) versus gefitinib arm (11.1 months); adjusted HR 0.67 (95% CI, 0.5-0.9); one-sided P=0.009. In the P+G and gefitinib arms, median PFS was 22.6 and 11.0 months, respectively, in patients with low thymidylate synthase (TS) expression, and 12.6 and 9.9 months, respectively, in patients with high TS expression. Common second-line post-discontinuation systemic therapies were EGFR-TKIs and chemotherapy. Most patients experienced at least one adverse event. CONCLUSIONS: Addition of pemetrexed to EGFR TKI gefitinib resulted in significantly improved PFS and numerically longer OS compared with gefitinib in treatment-naïve patients with EGFR-mutated advanced nonsquamous NSCLC. Low TS expression appeared to be a good predictor for treatment outcomes.

20.
Transl Res ; 216: 43-56, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31669150

RESUMO

Macrophage migration inhibitory factor (MIF), a pleiotropic inflammatory cytokine, is highly expressed in patients with atrial fibrillation (AF). CD74 (major histocompatibility complex, class II invariant chain) is the main receptor for MIF. However, the role of the MIF/CD74 axis in atrial arrhythmogenesis is unclear. In this study, we investigated the effects of MIF/CD74 signaling on atrial electrophysiological characteristics and determined its underlying mechanisms. Confocal fluorescence microscopy, patch clamp, and western blot analysis were used to study calcium homeostasis, ionic currents, and calcium-related signaling in MIF-treated HL-1 atrial cardiomyocytes with or without anti-CD74 neutralized antibodies treatment. Furthermore, electrocardiographic telemetry recording and echocardiography were obtained from mice treated with MIF. Compared with controls, MIF-treated HL-1 myocytes had increased calcium transients, sarcoplasmic reticulum (SR) calcium content, Na+/Ca2+ exchanger (NCX) efflux rate, calcium leak, transient outward potassium current, and ultra-rapid delayed rectifier potassium current. Furthermore, MIF could induce expression of SR Ca2+ATPase, NCX, phosphorylation of ryanodine receptor 2 (RyR2), and activation of calcium/calmodulin kinase II (CaMKII) when compared with control cells. MIF-mediated electrical dysregulation and CaMKII-RyR2 signaling activation were attenuated through blocking of CD74. Moreover, MIF-injected mice had lesser left atrium fractional shortening, greater atrial fibrosis, and atrial ectopic beats than control (nonspecific immunoglobulin treated) or MIF combined with anti-CD74 neutralized antibody-treated mice. Consequently, our study on MIF/CD74 signaling has pointed out a new potential therapeutic intervention of AF patients with MIF elevation.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA