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2.
Obes Surg ; 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32462436

RESUMO

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is becoming a primary bariatric/metabolic surgical procedure for treating obesity and related type 2 diabetes mellitus (T2D). This study presents the long-term outcome of LSG about the remission and recurrence of T2D. METHODS: A total of 59 obese patients (38 women and 21 male) with T2D (mean body mass index [BMI] 37.6 ± 5.1 kg/m2) who underwent LSG from 2006 to 2014 with complete 5 years followed up were selected for present study. The remission of T2D was evaluated in stratified groups using the ABCD scoring system which is composed of the age, BMI, C-peptide, and duration of T2D. RESULTS: The weight loss at 5 years after surgery was 23.5% and the mean BMI decreased to 27.7 ± 4.5 kg/m2. The mean HbA1c decreased from 8.1 to 6.1% at 5 years. The 1-year and 5-year complete remission rate (HbA1c < 6.0%) was 62.7% and 42.4%. Thirteen patients (35.1%) out of 37 patients who had their T2D remission at 1 year had their T2D recurrent at 5 years. Patients with ABCD score higher than 5 had a higher long-term T2D remission rate and less recurrence of their T2D than those with ABCD score less than 5. The remission and recurrence of T2D after were associated with a weight loss more than 20%. CONCLUSION: LSG is an effective procedure for T2D treatment but a significant portion of patients had their T2D recurrence at long-term. LSG is better recommended to patients with their ABCD score ≥ 5 and dedication to maintain a good weight loss is important.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32360983

RESUMO

BACKGROUND & AIMS: Aspirin therapy has been associated with reduced risk of colon cancer, but there is only limited evidence for its affects on risk of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). We aimed to investigate the association of daily aspirin therapy with HCV-related HCC risk. METHODS: In this cohort study, based on Taiwan's National Health Insurance Research Database, we screened 237,963 patients with chronic HCV infection for the period of 1997 through 2011. We excluded patients with confounding conditions and 2478 patients who continuously received daily aspirin therapy for 90 days or more (treated group), were randomly matched 1:2 with 4956 patients who had never received antiplatelet therapy (untreated group) by means of propensity scores. Cumulative incidence of, and hazard ratio (HR) for, HCC development were analyzed after we adjusted for patient mortality as a competing risk event. RESULTS: The cumulative incidence of HCC in the treated group was significantly lower than that in the untreated group over 5 years (4.67%; 95% CI, 3.74%-5.59% vs 7.32%; 95% CI, 6.33%-8.30%; P<.001). In the multivariable regression analysis, aspirin therapy was independently associated with a reduced HCC risk (HR, 0.78, 95% CI, 0.64-0.95; P=.011), after adjustment for age per year, male sex, cirrhosis, liver decompensation, hyperlipidemia, statin use, and interferon therapy. Sensitivity subgroup analyses also verified this association (all HRs<1.0). In addition, older age (HR, 1.03 per year; 95% CI, 1.02-1.04), male sex (HR, 1.46; 95% CI, 1.21-1.77), and cirrhosis (HR, 3.13; 95% CI, 2.55-3.84) were independently associated with an increased HCC risk. CONCLUSIONS: In a nationwide cohort study in Taiwan, we found aspirin therapy to be significantly associated with a reduced risk of HCV-related HCC.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32398493

RESUMO

OBJECTIVE: Transjugular intrahepatic portosystemic shunt (TIPS) and endoscopic therapy (ET) have been recommended to prevent variceal rebleeding due to cirrhotic portal hypertension. However, which one is better for patients with hepatocellular carcinoma (HCC) remains controversial. Hence, we aimed to compare the clinical outcomes of these two treatments for these subpopulation. METHODS: This retrospective study was approved by the institutional review board. The data of 98 consecutive patients with HCC meeting the Milan criteria (mean age 54.1 years) who had received TIPS placement (34 patients) or ET (64 patients) between June 2010 and December 2017 were reviewed. The clinical outcomes were evaluated and were calculated by the Kaplan-Meier method and compared by using the log-rank test. A matched cohort composed of 34 patients from each group was selected after adjustment with propensity score matching to verify the robustness of the results. RESULTS: The median follow-up time was 33.1 months. The rebleeding rate was significantly lower in TIPS group (P = 0.016). A matched cohort composed of 34 patients from each group after adjustment with propensity score matching showed that TIPS reduced the risk of rebleeding (P = 0.030) without increasing long-term overt hepatic encephalopathy (P = 0.151), while there was no significant difference in overall liver transplant-free survival (P = 0.120). Thereafter, 25 patients in TIPS group (73.5%) and 42 patients in ET group (65.6%) received locoregional therapies for HCC (P = 0.431). CONCLUSION: TIPS reduced the risk of rebleeding without improving survival. Locoregional therapies can be performed safely to manage HCC after sufficient prevention of variceal rebleeding.

5.
Med Ultrason ; 22(2): 255-256, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32399533

RESUMO

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6.
J Am Heart Assoc ; 9(10): e015742, 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32370590

RESUMO

Background The current study aims to validate the accuracy of 3-dimensional speckle-tracking echocardiography (3D-STE) in evaluating biventricular functions against the accuracy of cardiac magnetic resonance (CMR) and to explore the comprehensive characteristics and normal values for 3D-biventricular functions in transplanted hearts. Methods and Results A cohort of 35 heart transplant (HT) patients underwent both 3D echocardiography and CMR examination to validate the accuracy of 3D-STE in evaluating biventricular functions (Protocol 1). Then, 3D-STE derived biventricular functions were compared between 46 HT patients and 46 non-HT controls (Protocol 2). Protocol 1, validated that 3D-STE showed excellent accuracy in evaluating biventricular functions of transplanted hearts against CMR. Protocol 2, revealed lower (normal range) 3D-biventricular ejection fractions in HT patients than in controls (P<0.001). 3D-left ventricular global longitudinal strain, left ventricular-global circumferential strain, left ventricular-global radial strain, left ventricular-global performance index and right ventricular free-wall longitudinal strain were all lower in the HT patients than in healthy controls (P<0.001). Further, these strain values were all good for differentiating between groups (areas under the curve: 0.80-0.94, P<0.001). Moreover, left ventricular-lateral-wall radial displacement was higher and septal-wall radial displacement was lower in the HT group than in control group (P<0.001). Conclusions Compared with cardiac magnetic resonance, 3D-STE can evaluate biventricular functions of transplanted hearts accurately; 3D-biventricular mechanical functions are reduced even in clinically well HT patients. The provided characteristics and appropriate normal values of biventricular functions can be the basis for detection of ventricular dysfunction during follow-ups and further studies on transplanted hearts.

7.
Int J Surg ; 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32417463

RESUMO

BACKGROUND: Vault RNA 2-1 (VTRNA2-1, also called nc886) is a 108-nucleotide noncoding transcript that is epigenetically controlled via 18 CpG dinucleotide modifications of its promoter, and can exert either tumor suppressor or oncogenic functions depending on cell types of cancers. In hepatocellular carcinoma (HCC), the role of VTRNA2-1 in prognosis of patients remains unexplored. Here, we analysed the methylation status of the VTRNA2-1 promoter and its correlation with clinical parameters in patients with HCC. PATIENTS AND METHODS: A total of 92 patients with HCC were enrolled, genomic DNA of tumor versus normal tissues were extracted and bisulfite modified. VTRNA2-1 promoter regions chr5: 135416381 (cg06536614), 135416388, 135416394 (cg26328633), and 135416398 (cg25340688) were PCR amplified and pyrosequenced. The methylation status of VTRNA2-1 in patients was further analysed with other clinical parameters via univariate and multivariate analysis. RESULTS: The differential hypermethylation status (tumor- normal) of the VTRNA2-1 promoter in HCC correlated well with the presence of large tumor size (p=0.001), pathological vascular invasion (p=0.036), tumor recurrence (p=0.007) and more advanced tumor stage (stage III AJCC) in patients (p=0.03). In addition, the methylation of the VTRNA-2-1 promoter increased in stage III HCC tumor compared with stage I & II tumor (64.7% versus 36.0%, p=0.030). Furthermore, the differential hypermethylation status of the VTRNA2-1 promoter was an independent factor for patient outcome after partial hepatectomy using multivariate Cox regression analysis (p=0.011, HR=2.305). Using another public dataset (GES89852), we found that the differential hypermethylation of the VTRNA2-1 promoter was also significantly associated with tumor recurrence. CONCLUSIONS: Patients had unfavourable outcomes when the VTRNA2-1 promoter was differentially hypermethylated in tumor tissues compared to its adjacent normal tissues. These findings suggest that such patients should receive intensive follow-up care or possible adjuvant therapy after liver resection.

8.
Oncogene ; 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404985

RESUMO

The overexpression of SOX4 in various kinds of cancer cells was associated with poor prognosis for patients. The role of SOX4 in angiogenesis and tumor microenvironment modulation was recently documented in breast cancer but remains unclear in hepatocellular carcinoma (HCC). In our study, the clinical relevance of SOX4 overexpression in HCC and its role in the tumor microenvironment were investigated. The overexpression of SOX4 (SOX4high) in tumor lesions was associated with higher microvessel density (P = 0.012), tumor thrombosis formation (P = 0.012), distant metastasis (P < 0.001), and an independent prognostic factor for disease-free survival in HCC patients (P = 0.048). Endogenous SOX4 knockout in Hep3B cells by the CRISPR/cas9 system reduced the expression of CXCL12, which, in turn, attenuated chemotaxis in human umbilical vein endothelial cells, tube formation in vitro, reduced tumor growth, reticular fiber production, and angiogenesis in vivo in a xenograft mouse model. Treatment with an antagonist targeting CXCR4 (AMD3100), a receptor of CXCL12, inhibited chemotaxis and tube formation in endothelial cells in vitro. The CXCL12 promoter was activated by ectopic expression of a Flag-tagged SOX4 plasmid, endogenous SOX4 knockdown abolished promoter activity of CXCL12 as shown by luciferase assays, and an association with the CXCL12 promoter was identified via chromatin immunoprecipitation in HCC cells. In conclusion, SOX4 modulates the CXCL12 promoter in HCC cells. The secretory CXCL12, in turn, modulates CXCR4 in endothelial cells, reticular fibers to regulate the tumor microenvironment and modulate neovascularization, which might contribute to the distant metastasis of tumors.

9.
J Autoimmun ; : 102483, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32446704

RESUMO

BACKGROUND: The long-term renal outcome in patients with primary Sjögren's syndrome (pSS) remains uncertain. We aimed to determine the absolute incidence and relative risk of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in patients with pSS at the general population level. METHODS: We performed a retrospective cohort study using a national health insurance database in Taiwan from 2000 to 2013. We calculated the cumulative incidence of CKD and ESRD in our pSS and age-, sex- and entry time-matched control cohorts. Cox regression analyses were used to estimate adjusted hazard ratios (aHRs) after adjusting for comorbidities and medications. RESULTS: Among 17 505 patients with incident pSS, 1008 (5.8%) developed CKD and 38 (0.22%) developed ESRD. Of the 87 525 non-pSS controls, 3173 (3.6%) developed CKD and 256 (0.29%) developed ESRD. The risk of CKD was higher in patients with pSS than in the non-pSS controls (adjusted hazard ratio [HR] 1.49, 95% confidence interval [95% CI] 1.38-1.59). Notably, the risk of ESRD was similar in both pSS and non-pSS cohorts (aHR 0.82, 95% CI 0.58-1.16). CONCLUSIONS: Renal prognosis among patients with pSS and renal involvement is good. Although the risk of ESRD did not increase in patients with pSS, a significantly increased risk of CKD was observed in these patients, indicating the need for increased vigilance in regular monitoring for renal complications in patients with pSS.

10.
J Formos Med Assoc ; 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32446756

RESUMO

BACKGROUND/PURPOSE: Rosacea has been linked to inflammatory bowel disease and small bowel bacterial overgrowth. We aimed to investigate the fecal microbial profiling and the potential gene functions between rosacea and non-rosacea subjects. METHODS: A case-control study. Fecal microbiome and predicted genetic function inferred from high-throughput 16S ribosomal RNA sequencing were analyzed between rosacea (n = 11) and age-, gender- and body mass index-matched non-rosacea subjects (n=110). The correlation between altered microbiome as well as lifestyle and diet were also investigated. RESULTS: A significant reduction of fecal microbial richness was found in rosacea patients. A distinct fecal microbial community structure was demonstrated in rosacea patients. The discriminating enriched genera in rosacea patients included Rhabdochlamydia, CF231, Bifidobacterium, Sarcina, Ruminococcus, belonging to the phylum of Chlamydiae, Bacteroidetes, Actinobacteria, and Lentisphaerae. The discriminating reduced abundant genera included Lactobacillus, Megasphaerae, Acidaminococcus, Hemophilus, Roseburia, Clostridium, belong to the phylum of Firmicutes; and Citrobacter, belonging to the phylum of Proteobacteria. The distinct fecal microbial composition might be related to sulfur metabolism, cobalamin, and carbohydrate transport. CONCLUSION: An altered fecal microbial richness and composition were observed in rosacea patients. The distinct microbial composition might be related to sulfur metabolism, cobalamin and carbohydrate transport.

11.
Circulation ; 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32421381

RESUMO

Background: To investigate deep vein thrombosis (DVT) in hospitalized patients with coronavirus disease 2019 (COVID-19), we performed a single institutional study to evaluate its prevalence, risk factors, prognosis, and potential thromboprophylaxis strategies in a large referral and treatment center. Methods: We studied a total of 143 patients with COVID-19 from January 29 to February 29, 2020. Demographic and clinical data, laboratory data, including ultrasound scans of the lower extremities, and outcome variables were obtained, comparisons were made between DVT and non-DVT groups. Results: Of the 143 patients hospitalized with COVID-19 (aged 63 ± 14 years; 74 [51.7%] man), 66 patients developed lower extremity DVT (46.1%, included 23 [34.8%] with proximal DVT and 43 [65.2%] with distal DVT).Compared with patients who with no DVT, patients with DVT were older and had a lower oxygenation index, a higher rate of cardiac injury, and worse prognosis including an increased proportion of deaths (23 [34.8%] vs 9 [11.7%], P = 0.001) and a decreased proportion of patients discharged (32 [48.5%] vs 60 [77.9%], P < 0.001). Multivariant analysis only showed an association between CURB-65 score 3-5 (OR = 6.122, P = 0.031), Padua prediction score ≥ 4 (OR = 4.016, P = 0.04), and D-dimer >1.0 (µg/ml) (OR = 5.818, P < 0.014) and DVT in this cohort, respectively. The combination of a CURB-65 score 3-5, a Padua prediction score ≥ 4, and D-dimer > 1.0 (µg/ml) has a sensitivity of 88.52% and a specificity of 61.43% for screening for DVT. In the subgroup of patients with a Padua prediction score ≥ 4 and whose ultrasound scans were performed ˃72 hours after admission, DVT was present in 18 (34.0%) of the subgroup receiving venous thromboembolism prophylaxis vs 35 (63.3%) in the nonprophylaxis group (P = 0.010). Conclusions: The prevalence of DVT is high and is associated with adverse outcomes in hospitalized patients with COVID-19. Prophylaxis for venous thromboembolism may be protective in patients with a Padua protection score ≥ 4 after admission. Our data seem to suggest that COVID-19 is probably an additional risk factor for DVT in the hospitalized patients.

12.
Chemistry ; 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32378767

RESUMO

Herein, we describe the synthesis of a dithiophosphate-protected copper(I) hydride-rich nanocluster (NC), [Cu30H18{S2P(O n Pr)2}12] (1H), fully characterized by various spectroscopic methods and single crystal X-ray diffraction. The X-ray structure of 1H reveals an unprecedented central Cu12 hollow icosahedron. Six faces of this icosahedron are capped by Cu3 triangles, the whole Cu30 core being wrapped by twelve dithiophosphate ligands and the whole cluster has ideal S6 symmetry. The locations of the 18 hydrides in 1H was ascertained by a single crystal neutron diffraction. They are composed of three types: capping µ3-H, interstitial µ4-H (seesaw) and µ5-H ligands (square pyramidal), in good agreement with the DFT simulations. The numbers of hydrides and ligand resonances in the 1H NMR spectrum of 1H are in line with their coordination environment in the solid-state, retaining the S6 symmetry in solution. Furthermore, two new Se-protected polyhydrido copper nanoclusters, [Cu30H18{Se2P(OR)2}12] (2H: R = i Pr 3H: R = i Bu) were synthesized from their sulfur relative 1Hvia ligand displacement reaction and their X-ray structures feature the exceptional case where both the NC shape and size are fully conserved during the course of ligand exchange. In addition, the reaction of 1H with [Pd(PPh3)2Cl2] in the presence of terminal alkynes led to the formation of new bimetallic Cu-Pd alloy clusters [PdCu14H2{S2P(O n Pr)2}6(C≡CR)6] (4: R = Ph; 5: R = C6H4F).

13.
Cell Death Dis ; 11(4): 265, 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327633

RESUMO

RAGE (receptor for advanced glycation end-product) is thought to be associated with metastasis and poor prognosis of various types of cancer. However, RAGE is constitutively expressed in the normal lung and down-regulated in cancerous lung, while the opposite evidence shows that RAGE-mediated signaling contributes to the tumorigenesis of lung cancer. Therefore, the role of RAGE in lung cancer progression is still unclear to be further investigated. In this study, RAGE-overexpressed stable clones of human lung cancer A549 cells and two local lung adenocarcinoma cell lines CL1-0 and CL1-5 were utilized to verify the effect of RAGE on lung cancer cells while the in vivo xenograft animal model was further performed to evaluate the role of RAGE in the progression of lung cancer. The growth of A549 cells was inhibited by RAGE overexpression. p53-dependent p21CIP1 expression contributed to RAGE-induced growth inhibition by suppressing CDK2 kinase activity and retinoblastoma protein (RB) phosphorylation in vitro. On the other hand, RAGE overexpression promoted migration, invasion, and mesenchymal features of lung adenocarcinoma cells through ERK signaling. Furthermore, an in vivo xenograft experiment indicated that RAGE promoted the metastasis of lung cancer cells with p21CIP1 up-regulation, ERK activation, and the changes of EMT markers. Regarding to the involvement of tumor-associated macrophage (TAM) in the microenvironment, we monitored the expressions of TAM markers including CD68 and CD163 as well as angiogenesis marker CD31 in xenograft slice. The data showed that RAGE might induce the accumulation of TAM in lung cancer cells and further accelerate the in vivo tumor growth. In summary, our study provides evidence indicating the distinct in vitro and in vivo effects of RAGE and related mechanisms on tumor growth and metastasis, which shed light on the oncogenic role of RAGE in lung cancer.

14.
J Colloid Interface Sci ; 574: 293-299, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32334294

RESUMO

We propose an efficient and convenient procedure for estimating the thermodynamic equilibrium constants of the surface dissociation/association reactions of metal oxide particles through electrophoresis measurements and a general electrophoresis model, which takes account of essentially all the relevant factors. These constants are usually estimated experimentally through a tedious potentiometric acid-base titration procedure. In addition, since several assumptions need be made in applying this procedure, the results obtained can be unreliable, especially when the difference between the equilibrium constant of the dissociation reaction and that of the association reaction is small. Another merit of the procedure proposed is that the site density of the surface dissociation/associations functional groups need not be known in advance so that it becomes much more convenient and efficient than previous procedures. The applicability of the present procedure is examined by applying it to the cases of SiO2 and TiO2 nanoparticles dispersed in an aqueous NaCl solution.

15.
Brain Stimul ; 13(3): 786-799, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32289709

RESUMO

BACKGROUND: Non-virus genetic treatment for Parkinson's disease (PD) via plasmid glial cell-line derived neurotrophic factor (pGDNF) has shown potential for repairing damaged dopaminergic neurons. However, development of this gene therapy is largely hampered by the insufficient transfection efficiency as a result of the cell membrane, lysosome, and cytoskeleton meshwork. METHODS: In this study, we propose the use of polyethylenimine (PEI)-superparamagnetic iron oxide-plasmid DNA (pDNA)-loaded microbubbles (PSp-MBs) in conjunction with focused ultrasound (FUS) and two-step magnetic navigation to provide cavitation, proton sponge effect and magnetic effects to increase the efficiency of gene delivery. RESULTS: The gene transfection rate in the proposed system was 2.2-fold higher than that of the commercial agent (TransIT®-LT1). The transfection rate could be boosted ∼11%, ∼10%, and 6% by cavitation-magnetic hybrid enhanced cell membrane permeabilization, proton sponge effect, and magnetic-assisted cytoskeleton-reorganization, respectively. In vivo data suggested that effective gene delivery with this system results in a 3.2-fold increase in recovery of dopaminergic neurons and a 3.9-fold improvement in the motor behavior when compared to untreated genetic PD mice. CONCLUSIONS: We proposed that this novel FUS-magnetic hybrid gene delivery platform could be integrated with a variety of therapeutic genes for treating neurodegenerative diseases in the future.

16.
Phys Chem Chem Phys ; 22(18): 10123-10131, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32347228

RESUMO

This work presents a series of molecular dynamics simulations of argon adsorption on a silicon substrate with different lattice orientations. From the simulation results, the density profiles are discussed and the amount of adsorbed particles is obtained at different pressures. It is found that the solid surface orientation has a great influence on the density distributions and atomic arrangements near the surface. With the collected data, the thermal constants derived from the expression of zeta adsorption isotherms are determined. The calculated isotherms agree well with the simulation results. Also, from a microscopic point of view, the molecular insights show that the structures of the adsorbates are present as clusters with different numbers of particles. The size of the clusters changes with pressure. At a relatively small pressure ratio, most of the clusters consist of a single molecule. As the pressure ratio increases, larger sized clusters appear, forming various cluster-types. The molecular cluster distributions are closely consistent with the basic approximation of the zeta adsorption isotherm. Furthermore, the surface adsorption sites determined from molecular dynamics simulation show good agreement with that predicted by the zeta isotherm model, which reaffirms the effectiveness of the theoretical model. When the isotherm is extended to a pressure ratio greater than unity, a finite amount of adsorption is predicted and the wetting conditions are obtained. Affected by the solid surface orientations, the pressure ratio at wetting for the silicon substrate with the (111) surface plane is larger than those of the (100) and (110) surfaces, indicating that a higher subcooling is required for the wetting transition.

18.
J Clin Endocrinol Metab ; 105(7)2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32285127

RESUMO

OBJECTIVE: This study retrospectively characterized the immune infiltrating profile in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs). METHODS: Tumor tissues from the 109-patient Fudan cohort and a 73-patient external validation set were evaluated by immunohistochemistry for 9 immune cell types: tumor-infiltrating neutrophils (TINs), tumor-associated macrophages (TAMs), CD11c+ dendritic cells, anti-NCR1+ natural killer (NK) cells, CD4+ and CD8+ T cells, CD45RO+ memory T cells, FOXP3+ regulatory T cells (Tregs), and CD20+ B cells. RESULTS: TINs were primarily distributed in the intratumoral area, dendritic cells and NK cells were scattered evenly in intratumoral and stromal areas, and Tregs were rarely detected. The remaining 5 cell types were primarily present in peritumoral stroma. Total TINs (P < .001) and TAMs (P = .002) increased as NF-PanNET grade rose. Kaplan-Meier analyses showed that high intratumoral TINs, total TAMs, and stromal CD4+ T-cell infiltration correlated with shorter recurrence-free survival (RFS, P = .010, P = .027, and P = .035, respectively) and overall survival (OS, P = .017, P = .029, and P = .045, respectively). Additionally, high intratumoral CD8+ T cell infiltration correlated with prolonged RFS (P = .039). Multivariate Cox regression demonstrated that intratumoral TINs, World Health Organization (WHO) classification, and eighth edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (AJCC8th TNM) were independent factors for RFS (P = .043, P = .023, and P = .029, respectively), whereas intratumoral TINs and WHO classification were independent factors for OS (P = .010 and P = .007, respectively). Furthermore, the combination of TINs, WHO classification, and AJCC8th TNM remarkably improved prognostic accuracy for RFS. These results have been verified in the external validation set. CONCLUSION: Intratumoral TINs are an independent and unfavorable predictor of postoperative NF-PanNETs. A combination of TINs, WHO classification, and AJCC8th TNM could improve prognostic accuracy for RFS.

19.
Life Sci ; 252: 117643, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32298738

RESUMO

AIMS: Non-peptide ligands of oxytocin receptor (OTR) have promising potentialities as therapeutic agents with improved pharmacological properties. WAY-267,464 is a non-peptide agonist which loses its agonist activity when its resorcinol moiety is methylated, yielding a partial antagonist (denoted here, WAY-Methylated). This study attempts to rationalize these opposing activities by comparative analyses of structural dynamicsof OTR in complex with these ligands. MAIN METHODS: Glide extra precision (XP) docking with and without positional constraints was employed to probe alternative binding poses of both WAY-267,464 and WAY-Methylated. The more preferred configuration of each system was subjected to an extended 2 µs MD simulation and the physics-based Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) binding energy was used to rank the complexes with improved accuracy, in addition to empirical-based Glide docking score. Network analysis was performed, and the identified critical residues were cross-referenced with the experimental mutagenesis data. KEY FINDINGS: The added methyl groups in the antagonist WAY-Methylated enhanced hydrophobicity, resulting in a flipped binding pose deeper in the binding pocket. Interestingly, OTR responded to the methylation by stabilizing the initial inactive conformation, decreasing fluctuations and increasing the overall secondary structural composition. Conversely, the agonist WAY-267,464 produced larger fluctuations to allow the receptor to change from the default inactive state to a state of partial activation. These transitions were further supported by the identified critical residues overlapping with experimental mutagenesis data. SIGNIFICANCE: These findings provide insights into the activation mechanism of OTR by WAY-267.464 and its antagonism by WAY-Methylated.

20.
Carbohydr Res ; 492: 108012, 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32305627

RESUMO

Three new acylphloroglucinol glucosides, rhodosides A-C (1-3), and three known ones (4-6) were isolated from the roots of Lysidice rhodostegia. The new structures were identified by MS, NMR, and acid hydrolysis. In addition, the antioxidant capacities of the isolated compounds were evaluated using DPPH radical-scavenging assay, and compounds 1-6 exhibited obvious antioxidant activities with IC50 values of 24.65 ± 1.27 to 38.11 ± 1.35 µM.

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