Δευτέρα 29 Αυγούστου 2022

FKA‐A NPs enhances PTX‐A NPs efficacy to suppress ovarian cancer via regulating Skp2/YAP pathway

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Abstract

Recurrence and distant metastasis after paclitaxel (PTX)-based chemotherapy in ovarian cancer (OC) patients remains a clinical obstacle. Flavokawain A (FKA) is a novel chalcone from kava plant which can induce G2/M arrest and inhibit invasion and metastasis in different tumor cells. In this study, we examined the effects and the molecular mechanism of sodium aescinate (Aes)-stabilized nanoparticles FKA-A NPs in enhancing the efficacy of PTX-A NPs in vitro and in vivo. We showed that FKA-A NPs combined with PTX-A NPs notably inhibited the proliferation, migration and reduced the expression of EMT-related markers in OCs. YAP nuclear translocation and its downstream signaling pathway was remarkably activated after PTX-A NPs treatment in OCs. FKA-A NPs obviously inhibited YAP nuclear translocation and reduced the transcriptional activity of YAP target genes. Simultaneously, FKA-A NPs dose- and time-dependently inhibited Skp2 expression in A2780 and Skov3 cells. In contra st, overexpression of Skp2 significantly attenuated the inhibition of FKA-A NPs on YAP nuclear translocation. In OC homograft mice, treatment with FKA-A NPs and PTX-A NPs significantly suppressed the growth of homograft tumor compared with PTX-A NPs, but did not decrease mice's body weight. In summary, we demonstrate that FKA-A NPs enhance the efficacy of PTX-A NPs against OCs in vitro and in vivo via reducing Skp2 expression, thus suppressing YAP nuclear translocation and activity of its target genes.

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Nelarabine, etoposide, and cyclophosphamide in relapsed pediatric T‐acute lymphoblastic leukemia and T‐lymphoblastic lymphoma (study T2008‐002 NECTAR)

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Abstract

Children with relapse of T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have a dismal prognosis, largely due to difficulty attaining second remission. We hypothesized that adding etoposide and cyclophosphamide to the nucleoside analog nelarabine could improve response rates over single-agent nelarabine for relapsed T-ALL and T-LBL. This phase I dose-escalation trial's primary objective was to evaluate the dose and safety of nelarabine given in combination with etoposide at 100 mg/m2/day and cyclophosphamide at 330–400 mg/m2/day, each for 5 consecutive days in children with either T-ALL (13 patients) or T-LBL (10 patients). Twenty-three patients were treated at three dose levels; 21 were evaluable for dose-limiting toxicities (DLT) and response. The recommended phase II doses (RP2D) for this regimen, when given daily ×5 every 3 weeks, were nelarabine 650 mg/m2/day, etoposide 100 mg/m2/day, and cyclophosphamide 400 mg/m2/day. DLTs included peripheral motor and sensory neuropathies. An expansion cohort to evaluate responses at the RP2D was terminated early due to slow accrual. The overall best response rate was 38% (8/21), with 33% (4/12) responses in the T-ALL cohort and 44% (4/9) responses in the T-LBL cohort. These response rates are comparable to those seen with single-agent nelarabine in this setting. These data suggest that the addition of cyclophosphamide and etoposide to nelarabine does not increase the incidence of neurologic toxicities or the response rate beyond that obtained with single-agent nelarabine in children with first relapse of T-ALL and T-LBL.

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Diverse mutations and structural variations contribute to Notch signaling deregulation in paediatric T‐cell lymphoblastic lymphoma

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Abstract

Background

T-cell lymphoblastic lymphoma (T-LBL) is an aggressive neoplasm closely related to T-cell acute lymphoblastic leukaemia (T-ALL). Despite their similarities, and contrary to T-ALL, studies on paediatric T-LBL are scarce and, therefore, its molecular landscape has not yet been fully elucidated. Thus, the aims of this study were to characterize the genetic and molecular heterogeneity of paediatric T-LBL and to evaluate novel molecular markers differentiating this entity from T-ALL.

Procedure

Thirty-three paediatric T-LBL patients were analyzed using an integrated approach, including targeted next-generation sequencing, RNA-sequencing transcriptome analysis and copy-number arrays.

Results

Copy number and mutational analyses allowed the detection of recurrent homozygous deletions of 9p/CDKN2A (78%), trisomy 20 (19%) and gains of 17q24-q25 (16%), as well as frequent mutations of NOTCH1 (62%), followed by the BCL11B (23%), WT1 (19%) and FBXW7, PHF6 and RPL10 genes (15%, respectively). This genetic profile did not differ from that described in T-ALL in terms of mutation incidence and global genomic complexity level, but unveiled virtually exclusive 17q25 gains and trisomy 20 in T-LBL. Additionally, we identified novel gene fusions in paediatric T-LBL, including NOTCH1–IKZF2, RNGTT–SNAP91 and DDX3X–MLLT10, the last being the only one previously described in T-ALL. Moreover, clinical correlations highlighted the presence of Notch pathway alterations as a factor related to favourable outcome.

Conclusions

In summary, the genomic landscape of paediatric T-LBL is similar to that observed in T-ALL, and Notch signaling pathway deregulation remains the cornerstone in its pathogenesis, including not only mutations but fusion genes targeting NOTCH1.

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Antiviral activities of Polygonum Perfoliatum L. extract and related phenolic acid constituents against hepatitis B virus

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Abstract

Chronic hepatitis B virus (HBV) infection is an important public health problem. Polygonum perfoliatum L. is a traditional medicinal herb and has been reported having pharmacological activities such as anti-inflammatory, antibacterial and antiviral. In this study, the antiviral activities and mechanisms of Polygonum perfoliatum L. extract against HBV and the effective components were investigated. The results showed that, the total extract of Polygonum perfoliatum L. reduced the levels of HBV e antigen (HBeAg) secretion and the viral covalently closed circular DNA (CCC DNA) formation, but had little or no negative effects on viral capsid assembly and pregenomic RNA (pgRNA) packaging. Further fractionation showed that the water extract fraction exerted comparable anti-HBV activities with the total extract, especially in inhibiting the CCC DNA formation and HBeAg production, indicating that the effective antiviral components are mainly dis tributed in this fraction. Further study showed that the phenolic acids constituents, protocatechuic acid and gallic acid, but not ethyl caffeate, which are reported enriched in the water extract fraction, showed strong anti-HBV activities in inhibiting viral core DNA synthesis, CCC DNA formation and HBeAg production. These results suggested that the Polygonum perfoliatum L. total extract and the related phenolic acids like protocatechuic acid and gallic acid could inhibit HBV replication and also indicated the potential utility of Polygonum perfoliatum L. and related constituents as sources of novel antivirals against HBV.

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Discovery of a small‐molecule inhibitor targeting the OTU domain of a novel Tamdy orthonairoviruse associated with human febrile illness

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Abstract

Tick-borne orthonairoviruses have been characterized as a global health threat to humans and animals. Tacheng Tick virus 1 (TcTV-1) from this family was provided evidence that is associated with the febrile illness syndrome. Here, we first identify and demonstrate that the OTU domain of TcTV-1 has remarkable deubiquitinating activity both in vitro and in vivo. By solving the crystal structure of TcTV-1 OTU (tcOTU) domain and comparing it to that of human deubiquitinating enzymes, we found that overall structures of tcOTU and human OTU family are similar, but the residues involved in the catalytic pocket vary widely. Based on the tcOTU domain we screened 5090 bioactive compounds and found mecobalamin had a good effect on suppressing the deubiquitinating activity. The structural model of tcOTU and mecobalamin suggests that mecobalamin occupies the site of the substrate Ub, by blocking the substrate bind to the enzyme. Thus, our results showed OTU domain of TcTV-1 has the robust deubiquitinating activity and mecobalamin or its derivatives might be promising candidates for the treatment or prevention of disease caused by TcTV-1 virus.

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Safety and Immunogenicity of a Recombinant Receptor Binding Domain‐Based Protein Subunit Vaccine (Noora Vaccine™) Against COVID‐19 in Adults: A Randomized, Double‐Blind, Placebo‐Controlled, Phase 1 Trial

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Abstract

The development of a safe and effective vaccine is essential to protect populations against COVID-19. There are several vaccine candidates under investigation with different mechanisms of action. In the present study, we have evaluated the safety and immunogenicity of a recombinant RBD-based protein subunit vaccine (Noora vaccine) against COVID-19 in adults. This phase 1 trial is a randomized, double-blind, placebo-controlled study to evaluate the safety and immunogenicity of the recombinant RBD-based protein subunit vaccine (Noora vaccine) against COVID-19 in healthy adults volunteers. Eligible participants were included in this study after evaluating their health status and considering the exclusion criteria. They were then randomized into three groups and received three doses of vaccine (80 µg, 120 µg, and placebo) on days 0, 21, and 35. Primary outcomes including solicited, unsolicited, and medically attended adverse events were recorded during this st udy. Secondary outcomes including the humoral and cellular immunity (including anti-RBD IgG antibody and neutralizing antibody) were measured on days 0, 21, 28, 35, 42, and 49 by using the ELISA kit and the Virus Neutralization Test (VNT) was performed on day 49. Totally 70 cases were included in this phase 1 trial and 60 of them completed the study. Safety assessments showed no severe adverse events. Local pain at the vaccine injection site occurred in 80% of the vaccinated volunteers. Induration and redness at the injection site were the other adverse reactions of this vaccine. There was no significant difference between the studied groups regarding adverse reactions. Anti-RBD IgG antibody and neutralizing antibody assessment showed significant seroconversion in comparison to the placebo group (80%, and 100% respectively, P<0.001). The cellular immunity panel also showed mild to moderate induction of TH1 responses and the VNT showed 78% of seroprotection. The results of this ph ase 1 trial showed acceptable safety without serious adverse events and significant seroconversions in the humoral and cellular immunity panel. The dose of 80 µg is an appropriate dose for injection in the next phases of the trial.

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Elevated preradiotherapy serum lactate dehydrogenase predicts distant metastasis for lymphoepithelial carcinoma of major salivary gland following postoperative radiotherapy

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Abstract

Background

To evaluate the predicting factors associated with distant metastasis (DM) for lymphoepithelial carcinoma of salivary gland (LECSG) following postoperative radiotherapy (PORT).

Methods

We retrospectively collected 160 eligible patients from two cancer institutions. The DM rate was evaluated using competing risk method.

Results

The median follow-up time was 65.6 months. Elevated preradiotherapy serum LDH (ratio >0.5) (p = 0.006) and N classification (N2-3) (p = 0.001) were independently associated with DM for the LECSG. After the risk stratification, the high-risk subgroup was defined as the patients presented higher risk score (score >0), whereas 5-year cumulative incidence of DM in the high- and low-risk group was 30.9% and 6.0%, respectively (p < 0.001). Moreover, a significantly worse overall survival (OS) was observed in the high-risk patients compared with the low-risk subgroup (5-year OS: 83.9% vs. 97.8%, p = 0.006).

Conclusion

Elevated preradiotherapy serum LDH could serve as a predictive factor for DM in the LECSG following PORT.

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Curcumin reduces inflammation in rat apical periodontitis

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Abstract

Aim

To evaluate the effect of systemic curcumin administration on the severity of apical periodontitis (AP).

Methodology

Forty male Wistar rats weighing 250-280g each, age 2.5 months, were distributed into four groups (n=10): control untreated rats (C), control rats treated with curcumin (CUR), rats with pulp exposure-induced apical periodontitis (AP), and rats with pulp exposure-induced apical periodontitis treated with curcumin (AP-CUR). Curcumin treatment was administered orally once daily for 15 days before pulp exposure and continued for 30 days after pulp exposure. The rats were sacrificed at 30 days, and the jaws were collected and reconstructed in a program specific for micro-CT. The jaws were processed for analysis of the inflammatory process using Haemotoxylin and Eosin staining and immunohistochemical assays for interleukin tumour necrosis factor alpha (TNF-α), interleukin (Il)-6, and Il-1β. Tartrate-resistant acid phosphatase (TRAP) and osteocalcin (OCN) staining were used to analyze the resorptive process on the bone surface of periapical area. Kruskal–Wallis with Dunn's test was performed for nonparametric data, and ANOVA with Tukey's test for parametric data, p < .05.

Results

Micro-CT revealed no statistically significant differences in bone resorption between the AP and AP-CUR groups (p > .05). The levels of inflammatory cell infiltration and immunoreactivity for the proinflammatory cytokines TNF-α, Il-6, and Il-1β were significantly higher in the periapical lesions of the AP group than in the AP-CUR group (p < .05). The number of TRAP-positive multinucleated cells was higher in the AP group than in the AP-CUR group (p < .05). In OCN-positive cells, no differences were observed between the AP and AP-CUR groups (p > .05).

Conclusions

Oral supplementation with curcumin had a significant effect on the AP severity in rats, suggesting an anti-inflammatory effect of curcumin on AP development.

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Impaired pancreatic beta‐cell function after a single dose of oral iron: a before‐and‐after (pre‐post) study

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Abstract

Introduction

Although in vitro and animal studies have shown that iron loading in pancreatic beta-cells impaired insulin secretion, no human studies have documented the acute effects of oral iron on beta-cell insulin secretory capacity. In this study, we determined beta-cell insulin secretory capacity at baseline and after a single oral dose of iron (ferrous sulphate, 120 mg elemental iron) in healthy male individuals.

Methods

Fifteen healthy male volunteers underwent an oral glucose tolerance test (OGTT) to document baseline glucose tolerance and insulin secretion kinetics (baseline OGTT). One week later, the same subjects underwent a second OGTT, two hours after an oral dose of ferrous sulfate (120 mg of elemental iron) (post-iron OGTT). Changes in disposition index, insulin secretion kinetics, glucose tolerance, insulin resistance, insulin clearance, and iron-related parameters in serum were determined.

Results

Compared to baseline OGT T, the areas under the curve (AUC) for serum iron and transferrin saturation increased by 125% and 118% respectively, in the post-iron OGTT. The disposition index decreased by 20% (p=0.009) and the AUC for glucose concentrations increased by 5.7% (p<0.001) during the post-iron OGTT. The insulin secretion rate was marginally lower during the first hour (-3.5%, p=0.63), but became significantly higher during the second hour (22%, p=0.005) of the post-iron OGTT. Insulin resistance and insulin clearance rate were not affected by iron intake.

Conclusion

The decrease in disposition index and glucose tolerance observed after the oral dose of iron points to an acute iron-induced impairment in pancreatic beta-cell insulin secretory capacity.

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Genotype‐driven NPC1L1 and PCSK9 inhibition and reduced risk of periodontitis

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Abstract

Aim

Epidemiological and preclinical studies suggest a chemoprotective role of lipid-lowering agents in periodontitis. We tested the association of genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), Niemann-Pick C1-Like 1 (NPC1L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9) with periodontitis.

Methods and materials

Genetic variants in HMGCR, NCP1L1 and PCSK9 associated with low-density lipoprotein (LDL) cholesterol in a genome-wide association study (GWAS) meta-analysis (N = 188,578) were used to proxy therapeutic inhibition of HMGCR, NPC1L1, and PCSK9. For these genetic variants, associations with periodontitis were obtained from GWAS of 17,353 cases and 28,210 controls in the GeneLifestyle Interactions in Dental Endpoints consortium. Generalized weighted least squares analysis accounted for linkage disequilibrium of genotypes to derive pooled estimates.

Results

While genetically proxied HMGCR inhibition equivalent to 1-mmol/L reduction in LDL was not associated with odds of periodontitis (odds ratio (OR) = 0.92 [95% CI: 0.73;1.16]; P = 0.4905; FDR = 0.4905), genetically proxied NPC1L1 (OR = 0.53 [95% CI: 0.35; 0.81]; P = 0.0038; FDR = 0.0077) and PCSK9 (OR = 0.84 [95% CI: 0.74; 0.95]; P = 0.0051; FDR = 0.0077) inhibition lowered the odds of periodontitis.

Conclusions

Genetically proxied inhibition of NCP1L1 and PCSK9 was associated with lower odds of periodontitis.

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