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1.
Blood Adv ; 4(1): 122-126, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31917843

RESUMO

Disease relapse remains the leading cause of failure after autologous stem cell transplantation (ASCT) for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We conducted a phase 2, multicenter, single-arm study of the anti-PD-1 monoclonal antibody pembrolizumab given after ASCT in patients with chemosensitive DLBCL, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary endpoint) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Twenty-nine patients were treated on this study; 62% completed all 8 cycles. Seventy-nine percent of patients experienced at least one grade 3 or higher adverse event, and 34% experienced at least one grade 2 or higher immune-related adverse event. Overall, 59% of patients were alive and progression free at 18 months, which did not meet the primary endpoint. The 18-month overall survival was 93%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with R/R DLBCL, but the PFS did not meet the protocol-specific primary objective and therefore does not support a larger confirmatory study. This trial was registered at www.clinicaltrials.gov as #NCT02362997.

2.
Heart Rhythm ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31918003

RESUMO

BACKGROUND: Atrial fibrillation (AF), the most common sustained arrhythmia, significantly increases cardiovascular and cerebrovascular morbidity and mortality. The pathogenesis and treatment of AF remain a major challenge in the field of cardiology. We previously found that cold-inducible RNA-binding protein (CIRP) regulated ventricular repolarization by post-transcriptionally regulating Kv4.2/4.3 ion channels in rats, but the role of CIRP in AF is not clear. OBJECTIVE: We hypothesize that CIRP participates in atrial electrophysiological remodeling and AF occurrence by regulating atrial channels post-transcriptionally. METHODS: Programmed intra-atrial stimulation was used to induce AF in the wild-type (WT) or the TALEN (transcription activator-like effector nucleases)-based CIRP knockout (KO) rats. Atrial optical mapping, patch clamp, western blotting, RNA immunoprecipitation (RIP) and luciferase reporter assays were performed to evaluate the underlying mechanism of atrial electrical remodeling. RESULTS: First, we observed a shortened atrial effective refractory period (AERP) and increased susceptibility to AF in CIRP KO rats. Second, atria-specific CIRP delivery through an adeno-associated viral vector serotype 9 (AAV9) prolonged the AERP and attenuated AF development in CIRP KO rats. Third, we observed the shortened action potential duration (APD) and enhanced expression of Kv1.5 and Kv4.2/4.3 in the KO rats. Ito blocker (4-AP) and IKur blocker (DPO-1) restored the shortened APD in the KO atria. Finally, we demonstrated that CIRP suppressed Kv1.5 and Kv4.2/4.3 expression by directly targeting their 3'-untranslated regions. CONCLUSION: CIRP plays a protective role in preventing AF onset through the post-transcriptional regulation of Kv1.5 and Kv4.2/4.3.

3.
Science ; 367(6474): 171-175, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31919217

RESUMO

Hydrogen embrittlement of high-strength steel is an obstacle for using these steels in sustainable energy production. Hydrogen embrittlement involves hydrogen-defect interactions at multiple-length scales. However, the challenge of measuring the precise location of hydrogen atoms limits our understanding. Thermal desorption spectroscopy can identify hydrogen retention or trapping, but data cannot be easily linked to the relative contributions of different microstructural features. We used cryo-transfer atom probe tomography to observe hydrogen at specific microstructural features in steels. Direct observation of hydrogen at carbon-rich dislocations and grain boundaries provides validation for embrittlement models. Hydrogen observed at an incoherent interface between niobium carbides and the surrounding steel provides direct evidence that these incoherent boundaries can act as trapping sites. This information is vital for designing embrittlement-resistant steels.

4.
Environ Sci Technol ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31922401

RESUMO

To investigate the effect of nonthermal plasma (NTP) on the microstructure and oxidation characteristics of particulate matter (PM) from diesel engines at different oxidation stages, a self-designed NTP reactor was used to conduct a time-varying oxidation test on PM samples. The oxidized PM samples were analyzed via thermogravimetric analysis and Raman spectra. The results indicated that the effect of NTP could allow the elemental carbon (EC) to more easily start ignition. The oxidation activity of the EC decreased when the action time of the NTP was less than 5 min. Conversely, when the NTP action time was more than 5 min, the EC oxidation activity gradually increased. When the NTP was active for more than 10 min, it rapidly reacted with the EC, and the oxidation priority of the volatile fraction (VF) was higher than that of the EC. During the oxidation process, both the regular and irregular EC structures had a mutual transformation relationship, and the variation trend of graphitization degree was consistent with that of the thermogravimetric results, indicating that the degree of graphitization directly affected the PM oxidation activity.

5.
Mater Sci Eng C Mater Biol Appl ; 108: 110192, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31923966

RESUMO

This study provided an eco-friendly manufacturing method for Ti implants by combining machining and surface treatment processes. Ti was machined by electrical discharge machining (EDM) in a water-based dielectric in order to reduce environmental impact and improve operational health. The feasibility of this eco-friendly EDM was evaluated by tested the bioactivity and cytocompatibility of the EDM-treated Ti and the commercially micro-arc oxidation (MAO)-treated Ti was used as a control group. Pulsed MAO and EDM treatments were applied on Ti in an aqueous solution containing hydroxyapatite (HA) with the same concentration (30 g/L) under the same voltage and treatment period. The two surface modification processes were compared from the aspects of surface composition, coating structure, and coating adhesion. Furthermore, in vitro bioactivity and cellular biocompatibility of the MAO- and EDM-treated Ti films were tested. Both treatments produced Ti oxide containing Ca and P on Ti, and the EDM-formed film possessed more Ca, with its Ca/P value closer to HA, as compared to the MAO-formed film. The MAO-formed films had micropores and nanopores in the middle region and film/substrate interface, respectively. Pores only existed on the surface of the EDM-formed films. The MAO-formed films were fractured, but the EDM-formed films maintained their original structure under tensile stress, tested according to the ASTM C633 standard. The bioactivity of the EDM-treated surface was higher than that of the MAO-treated and untreated Ti surface. After 24 h cell incubation, the EDM-treated surface exhibited a significantly higher number of cells than untreated Ti and the MAO-treated surface.

6.
Am J Chin Med ; : 1-18, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31903779

RESUMO

Oral squamous cell carcinoma (OSCC) is a leading cause of cancer-related deaths worldwide. It has a very poor prognosis with over a 5-year survival rate of only 50%. Thus, it is important to identify effective therapeutic interventions against oral cancer. Apoptosis and autophagy have reported genetically regulated in physiology and diseases, which close relationship. Many natural compound study objects anticancer effect have been studied between apoptosis and autophagy relationship. The present study was designed to evaluate the effect of erianin on human oral cancer cell proliferation. Results of the study revealed that treatment with erianin significantly reduced the viability of different OSCC cell lines. Erianin exerted its cytotoxic effect by inducing cell cycle arrest and caspase-dependent apoptotic pathways. Both intrinsic and extrinsic pathways were found to be involved in erianin-mediated cell death. In addition, treatment with erianin also increased autophagy in OSCC cells. With further analysis, it was found that erianin induced both apoptosis and autophagy by regulating MAPK signaling pathways. Taken together, our study indicates that erianin plays an important role in reducing oral cancer cell viability, and thus, can be considered as a potential anticancer agent.

7.
PLoS One ; 15(1): e0227124, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31905222

RESUMO

OBJECTIVES: Immune non-responders (INR) have poor CD4 recovery and are associated with increased risk of serious events despite antiretroviral therapy (ART). A clinically relevant definition for INR is lacking. METHODS: We conducted a retrospective analysis of three large cohorts: Infectious Disease Clinic at the Atlanta Veterans Affairs Medical Center, the US Military HIV Natural History Study and Infectious Disease Program of the Grady Health System in Atlanta, Georgia. Two-stage modeling and joint model (JM) approaches were used to evaluate the association between CD4 (or CD4/CD8 ratio) slope within two years since ART initiation and a composite endpoint (AIDS, serious non-AIDS events and death) after two years of ART. We compared the predictive capacity of four CD4 count metrics (estimated CD4 slope, estimated CD4/CD8 ratio slope during two years following ART initiation and CD4 at 1 and 2 years following ART initiation) using Cox regression models. RESULTS: We included 2,422 patients. Mean CD4 slope (±standard error) during two years of ART was 102 ± 2 cells/µl/year (95% confidence interval: 98-106 cells/µl/year), this increase was uniform among the three cohorts (p = 0.80). There were 267 composite events after two years on ART. Using the JM approach, a CD4 slope ≥100 cells/µL/year or CD4/CD8 ratio slope >0.1 higher rate per year were associated with lower composite endpoint rates (adjusted hazard ratio [HR] = 0.80, p = 0.04 and HR = 0.75 p<0.01, respectively). All four CD4 metrics showed modest predictive capacity. CONCLUSIONS: Using a complex JM approach, CD4 slope and CD4/CD8 ratio slope the first two years after ART initiation were associated with lower rates of the composite outcome. Moreover, the uniformity observed in the mean CD4 slope regardless of the cohort suggests a common CD4 response pattern independent of age or CD4 nadir. Given the consistency observed with CD4 slope, availability and ease of interpretation, this study provides strong rationale for using CD4 gains <100 cells/µl/year to identify patients at risk for adverse events.

8.
Ocul Immunol Inflamm ; : 1-6, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906767

RESUMO

Purpose: To report the long-term prognosis of punctate inner choroidopathy (PIC) or multifocal choroiditis (MFC) and associated zonal outer retinopathy (ZOR).Method: Retrospective study in patients with PIC/MFC and ZOR with a clinical follow-up of 4 years or longer.Results: There were 14 patients in this study (M: F = 11:3). All patients received systemic steroid therapy. The initial and final median logarithm of minimal angle of resolution of BCVA were 1.00 and 0.22 (p = .002). Ellipsoid zone recovery was noted in all patients. The median visual field loss improved from -6.38 dB to -3.41 dB (p = .035). The median of total area of PIC/MFC lesions enlarged from 6.82 mm2 to 8.77 mm2 (p = .005). Recurrent disease was noted in 4 eyes and maintenance steroid was needed in 3 eyes.Conclusion: With steroid therapy, most patients with PIC/MFC and ZOR had good visual prognosis.

9.
Nat Neurosci ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907437

RESUMO

Temporal lobe epilepsy causes severe cognitive deficits, but the circuit mechanisms remain unknown. Interneuron death and reorganization during epileptogenesis may disrupt the synchrony of hippocampal inhibition. To test this, we simultaneously recorded from the CA1 and dentate gyrus in pilocarpine-treated epileptic mice with silicon probes during head-fixed virtual navigation. We found desynchronized interneuron firing between the CA1 and dentate gyrus in epileptic mice. Since hippocampal interneurons control information processing, we tested whether CA1 spatial coding was altered in this desynchronized circuit, using a novel wire-free miniscope. We found that CA1 place cells in epileptic mice were unstable and completely remapped across a week. This spatial instability emerged around 6 weeks after status epilepticus, well after the onset of chronic seizures and interneuron death. Finally, CA1 network modeling showed that desynchronized inputs can impair the precision and stability of CA1 place cells. Together, these results demonstrate that temporally precise intrahippocampal communication is critical for spatial processing.

10.
J Mater Chem B ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31909406

RESUMO

Since its launch in 1997, rituximab (RTX) has extensively improved the treatment of CD20-positive follicular and diffuse large B cell non-Hodgkin lymphoma (NHL). The application of RTX is limited usually by the failed therapy because of resistance. Iron oxide nanomaterials have been explored for cancer detection and treatment in recent years. In this study, a multivalent nanoprobe comprising one Fe3O4 nanoparticle and several RTX antibodies was constructed for the targeted imaging and enhanced treatment of NHL. Poly(ethylene glycol) (PEG)-coated Fe3O4 nanoparticles were fabricated via a thermal decomposition method and ligand exchange. RTX was conjugated onto the surface of the Fe3O4-PEG nanoparticles to form Fe3O4-PEG-nAb (n = 2, 5 or 8) multivalent nanoprobes. These multivalent nanoprobes, with a core size of approximately 11 nm and a hydrodynamic diameter of about 22 nm, showed colloidal stability in buffer solution. The r2 relaxation rate of Fe3O4-PEG-nAb was similar to that of Fe3O4-PEG (309 ± 3.08 mM-1 s-1). The specificity of nanoprobes for CD20-positive Raji cells was assessed on a clinical magnetic resonance imaging scanner. The receptor binding site of one multivalent nanoprobe was more than that of one RTX, exhibiting valence-dependent induction of Raji cell apoptosis, and this effect could be enhanced by complement activation from blood serum added. A similar activity was observed in vivo in a NHL xenograft model. The multivalent nanoprobe treatment significantly reduced tumor burden and enhanced survival in comparison to the RTX group. Our studies demonstrate that the appropriate design and preparation of anticancer antibody-nanoparticle conjugates enable the generation of improved anticancer nanomedicines and could thus provide an efficient cancer theranostic strategy.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31910346

RESUMO

Background: M5A is a humanized monoclonal antibody (mAb) directed against carcinoembryonic antigen (CEA) The purpose of this first in human phase I dose-escalation trial was to characterize the toxicities and determine the maximum tolerated dose (MTD) of yttrium-90 (90Y)-DOTA-M5A as a single agent and in combination with gemcitabine (gem). Methods: Patients with advanced metastatic CEA-producing malignancies who had progressed on standard therapies were first administered indium-111 (111In)-DOTA-M5A. If tumor targeting was observed, the patient then received the therapy dose of 90Y-DOTA-M5A. Serial scans, blood sampling, and 24 h urine collections were then performed to estimate radiation doses to organs and total body. Assays for human antihuman antibody (HAHA) responses were performed out to 6 months. Results: Of the 18 patients who received 111In-DOTA-M5A, 16 received 90Y-DOTA-M5A therapy; 1 patient at 14 mCi/m2 with gem (150 mg/m2 days 1and 3), 3 patients at 12 mCi/m2 with gem, 6 patients at 12 mCi/m2 without gem, and 6 at 10 mCi/m2 without gem. Prolonged cytopenias resulted in discontinuation of dose escalation with gemcitabine. A single agent MTD of 10 mCi/m2 was established based on dose-limiting hematopoietic toxicities. HAHA immune response was identified in 2 of 16 patients (12.5%). Stable disease at 3 months was seen in 10 patients and 2 patients demonstrated an 88% and 64% decrease in CEA back to normal levels. In 2 patients 111In-DOTA-M5A imaging revealed previously unknown brain metastases. Conclusion: This study demonstrates the potential utility of the 90Y-DOTA-M5A anti-CEA mAb as a therapeutic antibody. There is decreased immunogenicity compared with murine and chimeric mAbs, allowing for the potential of multiple administrations. Combined modality therapy approaches incorporating this agent should continue to be evaluated.

12.
Diabetes Res Clin Pract ; : 108005, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31911248

RESUMO

AIMS: The objective of this study was to investigate the different associations of the serum urate (SUA) level with cardiovascular and cerebrovascular diseases (CVD), diabetic kidney disease (DKD) and diabetic retinopathy (DR) in Chinese adults. METHODS: We analyzed 4,767 participants out of 4813 adults with diabetes enrolled from seven communities in a cross-sectional survey. Participants underwent several medical examinations, including the measurement of anthropometric factors, blood pressure, SUA, glucose, lipid profiles, urine albumin/creatinine ratio (ACR) and fundus photographs. RESULTS: Compared with the first SUA tertile, the third tertile increased the prevalence of CVD by 22% (OR 1.22; 95% CI 1.01, 1.46) (P for trend <0.05) and increased the prevalence of DKD by 59% (OR 1.59; 95% CI 1.28, 1.97) for KDOQI definition. Compared with the first tertile, the OR (95% CI) of the number of diabetic complications, ranging from 0 to 2, associated with SUA level in ordinal logistic regression was 1.75 (1.44, 2.12) for the third tertile (P for trend< 0.01). These associations were all fully adjusted. No association was found between the prevalence of DR and the SUA level. CONCLUSIONS: A higher SUA level was associated with an increased prevalence of CVD and DKD and a variety of diabetic complications, other than DR, in men and postmenopausal women with T2DM. However, the causation remains to be demonstrated.

13.
J Nat Med ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31912311

RESUMO

Three new benzylisoquinoline alkaloids, (1'S)-12'-hydroxyl-linderegatine (1), (1S)-5'-O-p-hydroxybenzoyl norreticuline (2), (1R, 1'R)-11,11'-biscoclaurine (3), along with 18 known compounds were isolated from the roots of Lindera aggregata (Sims) Kosterm. Their structures were determined on the basis of extensive spectroscopic analysis (IR, UV, HR-ESI-MS, 1D and 2D NMR). The absolute configurations of three new compounds were determined by comparing their experimental and calculated ECD for the first time. Compounds (4) and (9) showed cytotoxic activities against human colon carcinoma cell line (HCT-116), with IC50 values of 51.4 and 27.1 µM, respectively. Furthermore, compounds (10) and (11) showed inhibitory activities on nitric oxide production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells, with IC50 values of 37.8 and 38.7 µM, respectively.

14.
Food Funct ; 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913387

RESUMO

Growing attention has been paid to the importance of bound polyphenols in dietary fiber. This study aimed to elucidate the effect of bound polyphenols on the fermentation and antioxidant properties of carrot dietary fiber (CDF) in vivo and in vitro. Compared with CDF treatment, 16S rRNA pyrosequencing of in vivo mice feces and in vitro human fecal fermentation samples showed that dephenolized carrot dietary fiber (CDF-DF) treatment decreases operational taxonomic units (OTUs), ACE and Chao1 indexes, increases Firmicute/Bacteroidetes ratio and relative abundance (RA) of Parabacteroides at phylum, restrains RAs of typical beneficial bacteria as well as improves RAs of various harmful bacteria at genus. Meanwhile, short-chain fatty acid (SCFA) contents were lower, while the pH value was higher in the CDF-DF group than those in the CDF group. Interestingly, the combination of bound polyphenols and CDF-DF (CDDP) could recover these indexes influenced by the removal of bound polyphenols in in vitro fermentation samples. Furthermore, the CDF-DF-fed mice exhibited higher MDA content and lower SOD and GSH-Px activities in the colon. The cellular antioxidant activity (CAA) value of CDF-DF was lower than that of CDF and CDDP. These results revealed that bound polyphenols significantly contribute to the fermentation and antioxidant properties of CDF.

15.
Theranostics ; 10(1): 201-217, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31903115

RESUMO

Carcinomatous progression and recurrence are the main therapeutic challenges frequently faced by patients with refractory tumors. However, the underlined molecular mechanism remains obscure. Methods: We found Musashi-1 (MSI1) transported into cytosol under stress condition by confocal microscopy and cell fractionation. Argonaute 2 (AGO2) was then identified as a cytosolic binding partner of MSI1 by Mass Spectrametry, immunoprecipitation, and recombinant protein pull-down assay. We used RNA-IP to determine the MSI1/AGO2 associated regions on downstream target mRNAs. Finally, we overexpressed C-terminus of MSI1 to disrupt endogenous MSI1/AGO2 interaction and confirm it effects on tmor progression. Results: Malignant tumors exhibit elevated level of cytosolic Musashi-1 (MSI1), which translocates into cytosol in response to stress and promote tumor progression. Cytosolic MSI1 forms a complex with AGO2 and stabilize or destabilize its target mRNAs by respectively binding to their 3´ untranslated region or coding domain sequence. Both MSI1 translocation and MSI1/AGO2 binding are essential for promoting tumor progression. Blocking MSI1 shuttling by either chemical inhibition or point mutation attenuates the growth of GBM-xenografts in mice. Importantly, overexpression of the C-terminus of MSI1 disrupts endogenous MSI1/AGO2 interaction and effectively reduces stress-induced tumor progression. Conclusion: Our findings highlight novel molecular functions of MSI1 during stress-induced carcinomatous recurrence, and suggest a new therapeutic strategy for refractory malignancies by targeting MSI1 translocation and its interaction with AGOs.

16.
Medicine (Baltimore) ; 99(2): e18709, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914079

RESUMO

Kidney handling of electrolytes varies in different stages of chronic kidney disease (CKD). Diabetes mellitus (DM) plays an important role in CKD. Fractional excretion (FE) is an important means in clinical practice. The relationship between FE of electrolytes in patients at different stages of CKD is worth further investigating.We designed a cross-sectional study in 1 teaching hospital, consecutive CKD patients were enrolled between February 2016 and January 2017. Including clinical demographic features, laboratory examination including spot urine electrolytes, blood biochemistries, and relevant medications were determined.A total of 762 CKD patients completed the study. Of these, 218 (28.6%) had DM. Participants were grouped according to estimated glomerular filtration rate into 7 categories: hyperfiltration (HF), CKD1, CKD2, CKD3a, CKD3b, CKD4, and CKD5. Groups HF, CKD1, 2, 3a, 3b, 4 and 5 contained 83, 143, 192, 94, 82, 82, and 86 patients, respectively. FE of electrolytes tended to increase along with the decline of renal function (CKD1-CKD5) (P < .001). The relationship was similar between the DM and non-DM groups. Diabetic patients demonstrated higher FE of magnesium compared with non-DM subjects at CKD2 and CKD5 (P < .05).CKD patients showed a progressive increase in the FE of electrolytes; FE of magnesium seemed to increase more among diabetic patients with CKD, and could be a potential predictor of CKD progression.

17.
FASEB J ; 34(1): 1107-1121, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914708

RESUMO

The nucleolus is best known for its cellular role in regulating ribosome production and growth. More recently, an unanticipated role for the nucleolus in innate immunity has recently emerged whereby downregulation of fibrillarin and nucleolar contraction confers pathogen resistance across taxa. The mechanism of this downregulation, however, remains obscure. Here we report that rather than fibrillarin itself being the proximal factor in this pathway, the key player is a fibrillarin-stabilizing deubiquitinylase USP-33. This was discovered by a candidate-gene search of Caenorhabditis elegans in which CED-3 caspase was revealed to execute targeted cleavage of USP-33, thus destabilizing fibrillarin. We also showed that cep-1 and ced-3 mutant worms altered nucleolar size and decreased antimicrobial peptide gene, spp-1, expression rendering susceptibility to bacterial infection. These phenotypes were reversed by usp-33 knockdown, thus linking the CEP-1-CED-3-USP-33 pathway with nucleolar control and resistance to bacterial infection in worms. Parallel experiments with the human analogs of caspases and USP36 revealed similar roles in coordinating these two processes. In summary, our work outlined a conserved cascade that connects cell death signaling to nucleolar control and innate immune response.

18.
Metab Brain Dis ; 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31916204

RESUMO

Postoperative cognitive dysfunction (POCD) is a common neurological disease affecting the elderly patients after surgery. Unfortunately, no effective treatment for this disease has been discovered. Edaravone, a clinical-used free radical scavenger, at 3 mg/kg has been reported to prevent neuroinflammation induced by the combination of surgery and lipopolysaccharide in adult rodents. However, we found that edaravone at such low concentration could not inhibit POCD in aged mice. Instead, edaravone at 33.2 mg/kg significantly prevented recognition and spatial cognitive dysfunctions in 14 month aged mice after abdominal surgery under general anesthesia with isoflurane. Furthermore, edaravone significantly prevented the increase of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) induced by abdominal surgery in aged mice. Edaravone could also decrease glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) positive areas in the hippocampal regions of surgery mice, suggesting that edaravone might inhibit surgery-induced over-activation of microglia and astrocytes. Moreover, edaravone substantially increased the expression of PSD-95 and pSer9-glycogen synthase kinase-3ß (pSer9-GSK3ß) as demonstrated by Western blotting assay. Furthermore, the activity of acetylcholinesterase (AChE) is decreased in the mice in edaravone group. All these results suggested that edaravone at high concentrations could inhibit surgery-induced cognitive impairments in aged animals, possibly via the attenuation of neuroinflammation, the increase of synaptic proteins, and the elevation of cholinergic transmission, providing a further support that edaravone might be developed as a treatment of POCD.

19.
Environ Toxicol ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31916385

RESUMO

Cantharidic acid (CA) is the hydrolysis product of the acid anhydride cantharidin, which is a natural toxin secreted by several species of blister beetles. Several studies have indicated that as an inhibitor of protein phosphatase 2 (PP2A), CA induces apoptosis in various human cancer cells. However, the effect of CA on human nasopharyngeal carcinoma (NPC) cells and the underlying pathways have not been addressed. In our current study, we tested the hypothesis that CA treatment reduces the viability of human NPC cells (HONE-1, NPC-39, and NPC-BM) by inducing apoptosis. Results indicated that CA markedly reduced cell viability, which was revealed by the upregulation of caspase activation in extrinsic and intrinsic apoptosis pathways as well as the upregulation of extracellular-signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase 1/2 (JNK1/2) pathways. Coadministration of a p38 inhibitor (SB203580) with CA abolished the activation of caspase proteins. These findings indicated that CA treatment leads to apoptosis in human NPC cells through the upregulation of caspase activation, mediated particularly by the p38 pathway. Hence, CA is a promising therapeutic agent for human NPC.

20.
Bioinformatics ; 2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31926011

RESUMO

MOTIVATION: In gene expression and genome-wide association studies, the identification of interaction effects is an important and challenging issue owing to its ultrahigh-dimensional nature. In particular, contaminated data and right censored survival outcome make the associated feature screening even challenging. RESULTS: In this paper, we propose an inverse probability-of-censoring weighted Kendall's tau statistic to measure association of a survival trait with biomarkers, as well as a Kendall's partial correlation statistic to measure the relationship of a survival trait with an interaction variable conditional on the main effects. The Kendall's partial correlation is then used to conduct interaction screening. Simulation studies under various scenarios are performed to compare the performance of our proposal with some commonly available methods. In the real data application, we utilize our proposed method to identify epistasis associated with the clinical survival outcomes of non-small-cell lung cancer, diffuse large B-cell lymphoma, and lung adenocarcinoma patients. Both simulation and real data studies demonstrate that our method performs well and outperforms existing methods in identifying main and interaction biomarkers. AVAILABILITY: R-package "IPCWK" is available to implement this method, together with a reference manual describing how to perform the "IPCWK" package. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

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