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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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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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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Risk Factors for Recurrence of Peritonsillar Abscess

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Objectives

This study aimed to investigate the risk factors associated with peritonsillar abscess (PTA) recurrence in adult patients.

Methods

This retrospective cohort study used a nationwide insurance claims database in Japan. Adult patients (aged ≥ 20 years) who received intravenous antibiotics or surgical therapy within 5 days of their first PTA diagnosis were included. Multivariable Cox proportional modeling was used to investigate the risk factors for PTA recurrence using the variables: age, sex, comorbidities, tobacco use, history of recurrent tonsillitis, duration of intravenous antibiotics, and surgical therapy for PTA.

Results

This study included 12,012 patients (8784 men, 73.1%). Of them, 1358 (11.3%) experienced PTA recurrence. An age ≥40 years and treatment with intravenous antibiotics for 3 days or more were associated with a lower risk of PTA recurrence (aged ≥ 40 years: adjusted hazard ratio [HR]: 0.69; 95% confidence interval [CI]: 0.62–0.78, treated with intravenous antibiotics for 3 days or more: adjusted HR: 0.85; 95% CI: 0.76–0.96). Patients with a history of recurrent tonsillitis were associated with a higher risk of recurrence (adjusted HR: 1.79; 95% CI: 1.47–2.19).

Conclusion

A median age of 20–39 years, a history of recurrent tonsillitis, and less than 3 days of intravenous antibiotic therapy may be risk factors for PTA recurrence among adult patients. Further studies exploring more detailed clinical data are necessary to confirm the risk factors for PTA recurrence.

Level of Evidence

3 Laryngoscope, 2022

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Monovalent rotavirus vaccine efficacy against different rotavirus genotypes: a pooled analysis of Phase II and III trial data

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Abstract
Background
Rotavirus vaccine performance appears worse in countries with high rotavirus genotype diversity. Evidence suggests diminished vaccine efficacy (VE) against G2P[4], which is heterotypic with existing monovalent rotavirus vaccine formulations. Most studies assessing genotype-specific VE have been underpowered and inconclusive.
Methods
We pooled individual-level data from ten Phase II and III clinical trials of rotavirus vaccine containing G1 and P[8] antigens (RV1) conducted between 2000 and 2012. We estimated VE against both any-severity and severe (Vesikari score ≥11) rotavirus gastroenteritis (RVGE) using binomial and multinomial logistic regression models for non-specific VE against any RVGE, genotype-specific VE, and RV1-typic VE against genotypes homotypic, partially heterotypic, or fully heterotypic with RV1 antigens. We adjusted models for concomitant oral poliovirus and RV1 vaccination and the country's de signated child mortality stratum.
Results
Analysis included 87,644 infants from 22 countries in the Americas, Europe, Africa, and Asia. For VE against severe RVGE, non-specific VE was 91% (95% confidence interval (CI): 87-94%). Genotype-specific VE ranged from 96% (95% CI: 89-98%) against G1P[8] to 71% (43-85%) against G2P[4]. RV1-typic VE was 92% (95% CI: 84-96%) against partially heterotypic genotypes but 83% (67-91%) against fully heterotypic genotypes. For VE against any-severity RVGE, non-specific VE was 82% (95% CI: 75-87%). Genotype-specific VE ranged from 94% (95% CI: 86-97%) against G1P[8] to 63% (41-77%) against G2P[4]. RV1-typic VE was 83% (95% CI: 72-90%) against partially heterotypic genotypes but 63% (40-77%) against fully heterotypic genotypes.
Conclusions
RV1 VE is comparatively diminished against fully heterotypic genotypes including G2P[4].
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Infants Receiving Very Early ART Have High CD4 Counts in the First Year of Life

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ABSTRACT
We followed 54 infants with in utero HIV after initiating very early antiretroviral treatment. At Weeks 24 and 48, ≥80% had CD4 ≥ 1500 cells/mm3 and CD4% ≥25%. Routine Pneumocystis jirovecii pneumonia prophylaxis in the first year of life may not be necessary for all very early treated infants.
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Effect of Repeat Vaccination on Immunogenicity of Quadrivalent Cell-Culture and Recombinant Influenza Vaccines Among Healthcare Personnel Aged 18-64 Years: A Randomized, Open-Label Trial

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Abstract
Background
Antibody responses to non-egg-based standard-dose cell-culture influenza vaccine (containing 15 µg hemagglutinin (HA)/component) and recombinant vaccine (containing 45 µg HA/component) during consecutive seasons have not been studied in the United States.
Methods
In a randomized trial of immunogenicity of quadrivalent influenza vaccines among healthcare personnel (HCP) aged 18–64 years over two consecutive seasons, HCP who received recombinant-hemagglutinin (RIV) or cell-culture-based vaccine (ccIIV) during the first season (Y1) were re-randomized the second season of 2019-2020 (Y2) to receive ccIIV or RIV, resulting in four ccIIV-RIV combinations. In Y2, hemagglutination inhibition (HI) antibody titers against reference cell-grown vaccine viruses were compared in each ccIIV-RIV group with titers among HCP randomized both seasons to receive egg-based, standard-dose inactivated influenza vaccine (IIV), using geome tric mean titer (GMT) ratios of Y2-post-vaccination titers.
Results
Y2 data from 414 HCPs were analyzed per-protocol. Compared to 60 IIV/IIV recipients, 74 RIV/RIV and 106 ccIIV/RIV recipients showed significantly elevated GMT ratios (Bonferroni corrected P <.007) against all components except A (H3N2). Post-vaccination GMT ratios for ccIIV/ccIIV and RIV/ccIIV were not significantly elevated compared to IIV/IIV except for RIV/ccIIV against A(H1N1)pdm09.
Conclusions
In adult HCPs, receipt of RIV two consecutive seasons or the second season was more immunogenic than consecutive egg-based IIV for three of the four components of quadrivalent vaccine. Immunogenicity of ccIIV/ccIIV was similar to that of IIV/IIV. Differences in hemagglutinin antigen content may play a role in immunogenicity of influenza vaccination in consecutive seasons.
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