Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 167
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Eur Respir J ; 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699841

RESUMO

BACKGROUND: Lung adenocarcinomas (LUADs) that radiologically display as subsolid nodules (SSNs) exhibit more indolent biological behavior than solid LUADs. SSNs, commonly encompassing preinvasive and invasive but early-stage adenocarcinomas, can be categorised as pure ground-glass nodules (pGGNs) and part-solid nodules (PSNs). The genomic characteristics of SSNs remain poorly understood. METHODS: We subjected 154 SSN samples from 120 treatment-naive Chinese patients to whole exome sequencing. Clinical parameters and radiological features of these SSNs were collected. The genomic landscape of SSNs and differences from that of advanced stage LUADs were defined. We also investigated the intratumor heterogeneity and clonal relationship of multifocal SSNs and conducted radiogenomic analysis to link imaging and molecular characteristics of SSNs. Fisher's exact and Wilcoxon rank sum tests were used in the statistical analysis. RESULTS: The median somatic mutation rate across the SSN cohort was 1.12 mutations/Mb. Mutations in EGFR were the most prominent and significant variation, followed by those in RBM10, TP53, STK11, and KRAS. The differences between SSNs and advanced-stage LUADs at a genomic level were unraveled. Branched evolution and remarkable genomic heterogeneity were demonstrated in SSNs. Although multi-centric origin was predominant, we also detected early metastatic events among multifocal SSNs. Using radiogenomic analysis, we found that higher ratios of solid components in SSNs were accompanied by significantly higher mutation frequencies in EGFR, TP53, RBM10, and ARID1B, suggesting that these genes play roles in the progression of LUADs. CONCLUSIONS: Our study provides the first comprehensive description of the mutational landscape and radiogenomic mapping of SSNs.

3.
Vaccine ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31740094

RESUMO

Mycoplasma bovis is an important pathogenic bacterium affecting cows and cattle. Clinically, an inactivated vaccine of M. bovis is mainly used to prevent infection by this bacterium. The changes that occur in the antigen when M. bovis is continuously passaged in vitro remain unknown. Therefore, we performed an in vitro serial passage of the M. bovis NM-28 strain, which was isolated and identified in our laboratory. An isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics method was used to analyse the differences between generations 3 and 60. Many major membrane proteins or protective antigens reported in the literature did not exhibit changes between these generations. We found an imbalance between growth rate and nutrition in the 60th generation. The proteomics results were verified by western blotting and real-time PCR. Growth curves were also prepared based on colony-forming units (CFUs) between the 3rd and 60th generations. The number of colonies in the 60th generation in the stationary phase was 5 × 109 CFU mL-1, which was 10-fold higher than that in the 3rd generation. The 60th generation of the NM-28 strain can be used as an inactivated vaccine strain of M. bovis to lower production costs compared to use of the 3rd generation.

4.
Environ Sci Technol ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31763831

RESUMO

An advanced oxidation process of combining cobalt and peracetic acid (Co/PAA) was developed to degrade sulfamethoxazole (SMX) in this study. The formed acetylperoxy radical (CH3CO3•) through the activation of PAA by Co (Co2+) was the dominant radical responsible for SMX degradation, along with that CH3CO2• might also played roles. Efficient redox cycle of Co3+/Co2+ allows good removal efficiency of SMX even at quite low dosage of Co (< 1 µM). The presence of H2O2 in the Co/PAA process has negative effect on the degradation of SMX due to the competition for reactive radicals. The SMX degradation in the Co/PAA process is pH-dependent, and the optimum reaction pH is near-neutral. Humic acid and HCO3- can inhibit SMX degradation in the Co/PAA process, while the presence of Cl- plays little role in the degradation of SMX in this system. Although transformation products of SMX in the Co/PAA system show higher acute toxicity, the low Co dose and SMX concentration in aquatic solution can efficiently weaken the acute toxicity. After reaction in Co/PAA process, numerous carbon source that could be provided for bacteria and algae growth can be produced, suggesting that the proposed Co/PAA process contains good potential in the combination with bio-treatment processes.

5.
Cell ; 179(5): 1160-1176.e24, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31730855

RESUMO

Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn's disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD.

6.
J Immunol Res ; 2019: 2546161, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583255

RESUMO

Background: The role of interleukin-12 (IL-12), interleukin-23 (IL-23), and interleukin-17 (IL-17) has been recognized in psoriasis pathogenesis, and new drugs targeting this axis have already been developed which may provide a new therapeutic approach for patients with moderate to severe psoriasis. Objective: To compare the direct and indirect evidences of the efficacy and safety of brodalumab, secukinumab, ixekizumab, ustekinumab, guselkumab, tildrakizumab, and risankizumab in the short-term treatment of moderate to severe plaque psoriasis using network meta-analysis (NMA). Methods: A comprehensive literature search was performed in PubMed, EMBASE, and Cochrane Central Register of Controlled Trials for the available relevant studies. NMA was conducted by Stata 15.0 software using relative risks (RR) with 95% confidence interval to assess the clinical effectiveness and safety. Ranked the efficacy and safety for each drug accordance with the surface under the cumulative ranking curve (SUCRA). Results: This meta-analysis included 28 studies. All the interventions performed better than placebo in short-term achievement. Based on the result of SUCRA, ixekizumab 80 mg every 2 weeks ranked the highest in short-term achievement of PASI 75 (SUCRA = 93.0%). Brodalumab 210 mg ranked the highest in short-term achievement of PASI 100 (SUCRA = 85.0%). Secukinumab 300 mg ranked the highest in short-term achievement of sPGA 0/1 or IGA 0/1 or PGA 0/1 (SUCRA = 98.1%). In terms of having a risk of adverse events, the rates were higher in brodalumab, secukinumab, ixekizumab, and ustekinumab 45 mg compared with placebo. Ixekizumab 80 mg every 4 weeks ranked the highest in the risk of adverse events during short-term treatment (SUCRA = 4.5%). Guselkumab 50 mg ranked the highest in the risk of serious adverse events during short-term treatment (SUCRA = 25.9%). Ixekizumab 80 mg every 4 weeks ranked the highest in the risk of discontinuations due to adverse events during short-ter treatment (SUCRA = 10.7%). Conclusions: IL-17, IL-12/23, and IL-23 inhibitors had high efficacy in the achievement of PASI 75, PASI 100, and sPGA 0/1 or IGA 0/1 or PGA 0/1 in moderate to severe plaque psoriasis after 12 or 16 weeks of treatment. IL-17 inhibitors showed superior efficacy. However, its clinical safety was poor. Risankizumab appeared to have relatively high efficacy and low risk. The clinical tolerance of other biological agents needs to be further observed.

7.
Proc Natl Acad Sci U S A ; 116(45): 22624-22634, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31636214

RESUMO

The reactivation of quiescent cells to proliferate is fundamental to tissue repair and homeostasis in the body. Often referred to as the G0 state, quiescence is, however, not a uniform state but with graded depth. Shallow quiescent cells exhibit a higher tendency to revert to proliferation than deep quiescent cells, while deep quiescent cells are still fully reversible under physiological conditions, distinct from senescent cells. Cellular mechanisms underlying the control of quiescence depth and the connection between quiescence and senescence are poorly characterized, representing a missing link in our understanding of tissue homeostasis and regeneration. Here we measured transcriptome changes as rat embryonic fibroblasts moved from shallow to deep quiescence over time in the absence of growth signals. We found that lysosomal gene expression was significantly up-regulated in deep quiescence, and partially compensated for gradually reduced autophagy flux. Reducing lysosomal function drove cells progressively deeper into quiescence and eventually into a senescence-like irreversibly arrested state; increasing lysosomal function, by lowering oxidative stress, progressively pushed cells into shallower quiescence. That is, lysosomal function modulates graded quiescence depth between proliferation and senescence as a dimmer switch. Finally, we found that a gene-expression signature developed by comparing deep and shallow quiescence in fibroblasts can correctly classify a wide array of senescent and aging cell types in vitro and in vivo, suggesting that while quiescence is generally considered to protect cells from irreversible arrest of senescence, quiescence deepening likely represents a common transition path from cell proliferation to senescence, related to aging.

8.
Sensors (Basel) ; 19(21)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31653040

RESUMO

In order to reduce the cost of the flight controller and improve the control accuracy of solar-powered unmanned aerial vehicle (UAV), three state estimation algorithms based on the extended Kalman filter (EKF) with different structures are proposed: Three-stage series, full-state direct and indirect state estimation algorithms. A small hand-launched solar-powered UAV without ailerons is used as the object with which to compare the algorithm structure, estimation accuracy, and platform requirements and application. The three-stage estimation algorithm has a position accuracy of 6 m and is suitable for low-cost small, low control precision UAVs. The precision of full-state direct algorithm is 3.4 m, which is suitable for platforms with low-cost and high-trajectory tracking accuracy. The precision of the full-state indirect method is similar to the direct, but it is more stable for state switching, overall parameters estimation, and can be applied to large platforms. A full-scaled electric hand-launched UAV loaded with the three-stage series algorithm was used for the field test. Results verified the feasibility of the estimation algorithm and it obtained a position estimation accuracy of 23 m.

9.
Clin Chim Acta ; 499: 4-12, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31473195

RESUMO

Atrial fibrillation (AF) is the most common sustained arrhythmia. Atrial remodeling, including electrical/structural/autonomic remodeling, plays a vital role in AF pathogenesis. All of these have been shown to contribute continuously to the self-perpetuating nature of AF. The Warburg effect was found to play important roles in tumor and non-tumor disease. Recently, lots of studies documented altered atrial metabolism in AF, but the specific mechanism and the impact of these changes upon AF initiation/progression remain unclear. In this article, we review the metabolic consideration in AF comprehensively and observe the footprints of the Warburg effect. We also summarize the signaling pathway involved in the Warburg effect during AF-HIF-1α and AMPK, and discuss their potential roles in AF maintenance and progression. In conclusion, we give the innovative idea that the Warburg effect exists in AF and promotes the progression of AF. Targeting it may provide new therapies for AF treatment.

10.
Food Funct ; 10(7): 3890-3897, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31187836

RESUMO

Gelatin was extracted from the swim bladder of Amur sturgeon with hot water at 50 °C with acceptable yield (76.54%) and it showed type I collagen features. The degree of hydrolysis reached 70.42%, and 26.55% of collagen peptides (380.76 Da) survived, after simulating digestion, absorption and peripheral blood circulation in vitro. In situ single-pass intestinal perfusion showed that the AMW of the collagen peptides was about 1100 Da in the intestine and they were mainly absorbed in the jejunum (61.11%). A 12-month feeding experiment using rats demonstrated that gelatin improved the histological structure, increased the thickness of the dermis (18.45%) and the density of collagen fibers (22.17%), and decreased the ratio of type III to type I collagen (43.44%) of chronologically aged skin at 3.85 g per kg bw per d. Moreover, the antioxidant enzyme activities in skin were significantly enhanced, while the malondialdehyde content was reduced by 31.99%. These results provided new insights into the development of new nutraceuticals and functional foods for the anti-skin-aging effect.

11.
Clin Interv Aging ; 14: 959-968, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213783

RESUMO

Objective: To bridge the efficacy and compare the safety of the 24-week teriparatide treatment in a Chinese osteoporosis study (NCT00414973) to a large international trial (FPT, NCT00670501) to determine whether long-term results from the international study were applicable to Chinese patients. Methods: In this post-hoc analysis, a propensity score matching method was used to select patients with similar baseline characteristics. Patients were female with osteoporosis at high risk of fracture, aged ≥55 years, and had no history of rheumatoid arthritis or corticosteroid use. Outcomes included percentage changes in lumbar-spine bone mineral density (LS-BMD) from baseline to 24 weeks, safety in matched-pair patients, and long-term percentage changes in LS-BMD and fragility fracture incidence in the matched fracture prevention trial (FPT) population. The determination of the acceptability of bridging results was based on the International Conference on Harmonization E5 guidelines. Results: A total number of 228 patients from each study were matched and paired. Patients were similar at baseline (P-values >0.33) except for ethnicity (98% Caucasian for FPT). For changes in LS-BMD from baseline to week 24, treatment with teriparatide showed significantly greater increases (P-values <0.001; least-squares mean difference: 5.0% in the Chinese study and 5.4% in FPT) than comparator (calcitonin/placebo). The safety profiles over 24 weeks were similar between two studies. For matched-pair FPT patients, long-term changes in LS-BMD were significantly greater (least-squares mean difference: 11.5%, P<0.001) and the fragility fracture rate was marginally lower in the teriparatide group compared with the placebo group (13.1% vs 22.3%, P=0.070). Conclusion: Assuming similar pharmacokinetic profiles for teriparatide between populations, comparable increases in LS-BMD and consistent safety profiles within 24 weeks of the treatment suggest long-term LS-BMD results from the FPT may be applicable to Chinese population.


Assuntos
Densidade Óssea/efeitos dos fármacos , Hormônios e Agentes Reguladores de Cálcio , Vértebras Lombares/diagnóstico por imagem , Fraturas por Osteoporose/prevenção & controle , Teriparatida , Idoso , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Calcitonina/uso terapêutico , Hormônios e Agentes Reguladores de Cálcio/administração & dosagem , Hormônios e Agentes Reguladores de Cálcio/efeitos adversos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Humanos , Análise por Pareamento , Pessoa de Meia-Idade , Osteoporose/complicações , Osteoporose/diagnóstico , Osteoporose/tratamento farmacológico , Teriparatida/administração & dosagem , Teriparatida/efeitos adversos , Resultado do Tratamento
12.
Genomics ; 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31071461

RESUMO

Mycoplasma capricolum subsp. capripneumoniae (Mccp), belongs to Mycoplasma mycoides cluster and is a causal pathogen of contagious caprine pleuropneumonia (CCPP). This paper presents the complete annotated genome sequence of Mccp Strain 87001-a strain that was isolated from pneumonia affected goats on a farm in China, and comparative genomics analysis of five Mccp genomes in addition to comparative genomics within Mycoplasma mycoides cluster. The Mccp strain 87001 genome consists of a single circular chromosome 1017333 bp in length and encodes 898 open reading frames (orfs) averaging 944 bp in length. Fifty eight potential virulence genes were identified, including variable surface lipoproteins, hemolysin A, and P60 surface lipoprotein. Comparative genomic analysis revealed eight virulence genes and four extracellular genes which remained unchanged in five Mccp genomes for forty years, which can be used as potential target for drug development and vaccine design. We revealed 183 Mccp unique genes as markers to distinguish Mccp with other mycoplasma strains from goats, and different virulence factors contributing to host specificity and different syndrome of bovine pathogens and caprine pathogens.

13.
Clin Chim Acta ; 495: 345-354, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31059701

RESUMO

BACKGROUND: Previous studies have suggested that proteomic modifications are closely associated with cardiovascular diseases. The aim of this study was to identify potential mechanisms by profiling the changes in succinylated protein expression in left appendage tissues from patients with valvular heart disease and atrial fibrillation (AF). METHODS: Using dimethyl labeling for relative and absolute quantification-coupled high-performance liquid chromatography-tandem mass spectrometry, we analyzed the proteomics profiles and succinylation events in 18 left atrial appendage tissue samples from patients who underwent cardiac valvular surgery, including nine patients with permanent AF and nine patients with sinus rhythm (SR). RESULTS: In total, after setting the quantification ratio > 1.3 and < 1:1.3 representing the up- and downregulated cutoff values, respectively, 132 proteins were classified as targets of upregulation and 117 proteins as targets of downregulation. Within these proteins, 246 sites exhibited upregulated succinylation and 45 sites exhibited downregulated succinylation. Protein-protein interaction networks showed that the proteins exhibiting lysine succinylation and AF status were highly enriched in energy metabolism, extracellular matrix-related, and cellular structure-related proteins. These results were confirmed by western blot. CONCLUSIONS: The differences in succinylation level of energy metabolism-related proteins indicates the possible involvement of these proteins in AF of valvular heart disease patients, and provide insight for further analysis of their biological functions.

14.
J Innate Immun ; : 1-16, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31141808

RESUMO

Prostaglandin E2 (PGE2), an essential endogenous lipid mediator for normal physiological functions, can also act as an inflammatory mediator in pathological conditions. We determined whether Staphylococcus aureus lipoproteins are essential for inducing PGE2 secretion by immune cells and whether pattern recognition receptors mediate this process. PGE2 levels secreted by mouse peritoneal macrophages infected with the S. aureus isogenic mutant, lgt::ermB (Δlgt; deficient in lipoprotein maturation), decreased compared with those from macrophages infected with wild-type (WT) S. aureus. Experiments using toll-like receptors 2 (TLR2)-deficient, TLR4-deficient, and NLRP3-deficient mice indicated that these 3 proteins are involved in macrophage PGE2 secretion in response to S. aureus, and lipoproteins were essential for S. aureus invasion and survival within macrophages. Inhibition of endogenous PGE2 synthesis had no effect on bacterial invasion. Exogenous PGE2 inhibited phagocytosis in the WT S. aureus and its isogenic mutant but increased intracellular killing accompanied by enhanced IL-1ß secretion. Our data demonstrate that S. aureus can induce macrophage TLR/mitogen-activated protein kinase/NF-κB signaling and that PGE2 treatment upregulates NLRP3/caspase-1 signaling activation. Thus, macrophage PGE2 secretion after S. aureus infection depends on bacterial lipoprotein maturation and macrophage receptors TLR2, TLR4, and NLRP3. Moreover, exogenous PGE2 regulates S. aureus-induced macrophage activation through TLRs and NLRP3 inflammasome signaling.

15.
MBio ; 10(3)2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138746

RESUMO

Bacterial antibiotic resistance modulation by small signaling molecules is an emerging mechanism that has been increasingly reported in recent years. Several studies indicate that indole, an interkingdom signaling molecule, increases bacterial antibiotic resistance. However, the mechanism through which indole reduces antibiotic resistance is largely unknown. In this study, we demonstrated a novel mechanism for indole-mediated reversal of intrinsic antibiotic resistance in Lysobacter This reversal was facilitated by a novel BtuD-associated dual-function importer that can transfer both vitamin B12 and antibiotics. Indole stimulated btuD overexpression and promoted efficient absorption of extracellular vitamin B12; meanwhile, the weak selectivity of the importer caused cells to take up excessive doses of antibiotics that resulted in cell death. Consistently, btuD deletion and G48Y/K49D substitution led to marked reductions in the uptake of both antibiotics and vitamin B12 This novel mechanism is common across multiple bacterial species, among which the Q-loop amino acid of BtuD proteins is Glu (E) instead of Gln (Q). Interestingly, the antibiotic resistance of Lysobacter spp. can be restored by another small quorum sensing signaling factor, 13-methyltetradecanoic acid, designated LeDSF, in response to bacterial population density. This work highlights the mechanisms underlying dynamic regulation of bacterial antibiotic resistance by small signaling molecules and suggests that the effectiveness of traditional antibiotics could be increased by coupling them with appropriate signaling molecules.IMPORTANCE Recently, signaling molecules were found to play a role in mediating antibiotic resistance. In this study, we demonstrated that indole reversed the intrinsic antibiotic resistance (IRAR) of multiple bacterial species by promoting the expression of a novel dual-function importer. In addition, population-dependent behavior induced by 13-methyltetradecanoic acid, a quorum sensing signal molecule designated LeDSF, was involved in the IRAR process. This study highlights the dynamic regulation of bacterial antibiotic resistance by small signaling molecules and provides direction for new therapeutic strategies using traditional antibiotics in combination with signaling molecules.

16.
Clin Cancer Res ; 25(16): 5049-5060, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31113842

RESUMO

PURPOSE: Genomic analyses of small-cell lung cancer (SCLC) are limited by the availability of tumor specimens. This study aimed to investigate the suitability of single-cell sequencing of circulating tumor cells (CTC) as a method of inferring the evolution and progression of SCLCs. EXPERIMENTAL DESIGN: Between July 1, 2011, and July 28, 2014, 48 consecutively diagnosed patients with SCLC were recruited for this study. CTCs were captured from each patient with CellSearch system. Somatic mutations and copy number alterations (CNA) were monitored by single-cell sequencing of CTCs during chemotherapy. RESULTS: Single-cell sequencing of CTCs can provide a mutational atlas for SCLC. A 10-CNA score based on single CTCs was established as a classifier for outcomes of initial chemotherapy in patients with SCLC. The survival analyses demonstrated that patients with low CNA scores (<0) had significantly prolonged progression-free survival (PFS) and overall survival (OS) after first-line chemotherapy in comparison with those with high scores (≥0; PFS: 212 days vs. 110.5 days, P = 0.0042; and OS: 223.5 days vs. 424 days, P = 0.0006). The positive predictive value and negative predictive value of the CNA score for clinical subtype (refractory vs. sensitive) were 80.0% and 93.7%, respectively. By tracing allele-specific CNAs in CTCs isolated at different time points during chemotherapy, we showed that CNA heterogeneity might result from allelic losses of initially consistent CNAs. CONCLUSIONS: Single CTC-based sequencing can be utilized to depict the genomic profiles and evolutionary history of SCLC, thus offering the potential for clinical stratification of patients with SCLC.

17.
Lipids Health Dis ; 18(1): 109, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077199

RESUMO

BACKGROUND: Atrial lipid metabolic remodeling is critical for the process of atrial fibrillation (AF). Abnormal Fatty acid (FA) metabolism in cardiomyocytes is involved in the pathogenesis of AF. MET (Metformin), an AMPK (AMP-activated protein kinase) activator, has been found to be associated with a decreased risk of AF in patients with type 2 diabetes. However, the specific mechanism remains unknown. METHODS: Fifteen mongrel dogs were divided into three groups: SR, ARP (pacing with 800 beats/min for 6 h), ARP plus MET (treated with MET (100 mg/kg/day) for two weeks before pacing). We assessed metabolic factors, speed limiting enzymes circulating biochemical metabolites (substrates and products), atrial electrophysiology and accumulation of lipid droplets. RESULTS: The expression of AMPK increased in the ARP group and significantly increased in the MET+ARP group comparing to the SR group. In the ARP group, the expressions of PPARα、PGC-1α and VLCAD were down-regulated, while the concentration of free fatty acid and triglyceride and the lipid deposition in LAA (left atrial appendage) increased. Moreover, AERP and AERPd have also been found abnormally in this process. Pretreatment with MET before receiving ARP reversed the alterations aforementioned. CONCLUSIONS: The FA metabolism in LAA is altered in the ARP group, mainly characterized by the abnormal expression of the rate-limiting enzyme. Metformin reduces lipid accumulation and promotes ß-oxidation of FA in AF models partially through AMPK/PPAR-α/VLCAD pathway. Our study indicates that MET may inhibit the FA lipid metabolic remodeling in AF.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Fibrilação Atrial/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metformina/farmacologia , PPAR alfa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Fibrilação Atrial/fisiopatologia , Estimulação Cardíaca Artificial , Modelos Animais de Doenças , Cães , Ácidos Graxos/metabolismo , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/patologia , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética/efeitos dos fármacos
18.
Cancer Cell ; 35(6): 932-947.e8, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31130341

RESUMO

We performed genomic and transcriptomic sequencing of 133 combined hepatocellular and intrahepatic cholangiocarcinoma (cHCC-ICC) cases, including separate, combined, and mixed subtypes. Integrative comparison of cHCC-ICC with hepatocellular carcinoma and intrahepatic cholangiocarcinoma revealed that combined and mixed type cHCC-ICCs are distinct subtypes with different clinical and molecular features. Integrating laser microdissection, cancer cell fraction analysis, and single nucleus sequencing, we revealed both mono- and multiclonal origins in the separate type cHCC-ICCs, whereas combined and mixed type cHCC-ICCs were all monoclonal origin. Notably, cHCC-ICCs showed significantly higher expression of Nestin, suggesting Nestin may serve as a biomarker for diagnosing cHCC-ICC. Our results provide important biological and clinical insights into cHCC-ICC.

19.
BMC Pharmacol Toxicol ; 20(1): 18, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-31023386

RESUMO

BACKGROUND: The effects of ß blockers on the primary prevention of anthracycline-induced cardiotoxicity were controversial. METHODS: We searched PubMed, Embase and Cochrane Library for randomized controlled trials of the comparison of ß blockers versus placebo in patients undergoing anthracycline chemotherapy. This meta-analysis was performed by using random-effect models. RESULTS: Nine hundred forty participants from 11 trials were included in this meta-analysis. ß blockers led to a significant reduction in symptomatic heart failure (risk ratio [RR] 0.29, 95% CI 0.10 to 0.85). Compared with placebo, ß blockers were associated with improved left ventricular ejection fraction (mean difference [MD] 4.46, 95% CI 1.77 to 7.15) and s' (MD 0.78, 95% CI 0.01 to 1.55) in parallel with reduced left ventricular diameter (left ventricular end systolic diameter, MD -3.19, 95% CI -6.17 to - 0.21; left ventricular end diastolic diameter, MD -2.28, 95% CI 4.50 to - 0.05). ß blockers also improved strain and strain rate when compared with placebo. There were no significant differences in diastolic function variables between ß blockers and placebo except e' (MD 2.33, 95% CI 0.16 to 4.51). In addition, ß blockers compared with placebo reduced the risk of cardiac troponin I elevation > 0.04 ng/ml (RR 0.60, 95% CI 0.42 to 0.85). There was no marked difference in adverse events (RR 0.94, 95% CI 0.56 to 1.59) between ß blockers and placebo. CONCLUSIONS: In cancer patients with anthracycline therapy, prophylactic ß blockers were associated with reduced risk of heart failure, decreased left ventricular diameter, improved left ventricular systolic function, and alleviative cardiomyocyte injury.

20.
Cancer Cell ; 35(3): 428-440.e5, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30853353

RESUMO

We comprehensively analyzed clinical, genomic, and transcriptomic data of a cohort of 465 primary triple-negative breast cancer (TNBC). PIK3CA mutations and copy-number gains of chromosome 22q11 were more frequent in our Chinese cohort than in The Cancer Genome Atlas. We classified TNBCs into four transcriptome-based subtypes: (1) luminal androgen receptor (LAR), (2) immunomodulatory, (3) basal-like immune-suppressed, and (4) mesenchymal-like. Putative therapeutic targets or biomarkers were identified among each subtype. Importantly, the LAR subtype showed more ERBB2 somatic mutations, infrequent mutational signature 3 and frequent CDKN2A loss. The comprehensive profile of TNBCs provided here will serve as a reference to further advance the understanding and precision treatment of TNBC.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA