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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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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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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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Coinfections in hospitalized patients with severe fever with thrombocytopenia syndrome: a retrospective study

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Abstract

Background

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease with a high case fatality rate. Few studies have been performed on bacterial or fungal coinfections or the effect of antibiotics therapy.

Study design

A retrospective, observational study was performed to assess the prevalence of bacterial and fungal coinfections in patients hospitalized for SFTSV infection. The most commonly involved microorganisms and the effect of antimicrobial therapy were determined by the site and source of infection.

Results

A total of 1201 patients hospitalized with SFTSV infection were included; 359 (29.9%) had microbiologically confirmed infections, comprised of 292 with community-acquired infections (CAIs) and 67 with healthcare-associated infections (HAIs). Death was independently associated with HAIs, with a more significant effect than that observed for CAIs. For bacterial infections, only those acquired in hospital were associated with fatal outcomes, while fungal infection, whether acquired in hospital or community, was related to an increased risk of fatal outcomes. The infections in respiratory tract and bloodstream were associated with a higher risk of death than that in urinary tract. Both antibiotic and antifungal treatments were associated with improved survival for CAIs, while for HAIs, only antibiotic therapy was related to improved survival, and no effect from antifungal therapy was observed. Early administration of glucocorticoids was associated with an increased risk of HAIs.

Conclusion

The study provided novel clinical and epidemiological data and revealed risk factors, such as bacterial coinfections, fungal coinfections, infection sources, and treatment strategies associated with SFTS deaths/survival. This report might be helpful in curing SFTS and reducing fatal SFTS.

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Fra‐1 induces apoptosis and neuroinflammation by targeting S100A8 to modulate TLR4 pathways in spinal cord ischemia/reperfusion injury

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Fra-1 induces apoptosis and neuroinflammation by targeting S100A8 to modulate TLR4 pathways in spinal cord ischemia/reperfusion injury

Schematic illustration depicting the mechanism by which Fra-1-mediated S100A8/TLR4/NF-κB and ERK signaling in the regulation of apoptosis and neuroinflammation during spinal I/R.


Abstract

Spinal cord ischemia/reperfusion injury (SCII) is a severe complication driven by apoptosis and neuroinflammation. An increase in the expression of c-Fos, a member of the AP-1 family, is known as a neuronal activation marker in SCII. The AP-1 family is composed of Jun, Fos, and is associated with the regulation of cytokines expression and apoptosis. Fra-1 is a member of the Fos family, however, the contribution of Fra-1 to SCII is still unclear. In our study, Fra-1 was highly upregulated especially in neurons and microglia and promoted apoptosis by changing the expression of Bax/Bcl-2 after SCII. Furthermore, we found that Fra-1 directly regulated the transcription expression of S100A8. We demonstrated that knockdown of Fra-1 alleviated S100A8 mediated neuronal apoptosis and inflammatory factor release, thus improved motor function after SCII. Interestingly, we showed that administration of TAK-242, the TLR4 inhibitor, to the ischemia/reperfusion (I/R) injury induced rats suppress ed the activation of the ERK and NF-κB pathways, and further reduced Fra-1 expression. In conclusion, we found that Fra-1-targeted S100A8 was expressed the upstream of Fra-1, and the Fra-1/S100A8 interaction formed a feedback loop in the signaling pathways activated by SCII.
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The emergence, spread and vanishing of a French SARS‐CoV‐2 variant exemplifies the fate of RNA virus epidemics and obeys the Mistigri rule

alexandrossfakianakis shared this article with you from Inoreader

Abstract

The nature and dynamics of mutations associated with the emergence, spread and vanishing of SARS-CoV-2 variants causing successive waves are complex. We determined the kinetics of the most common French variant ("Marseille-4") for 10 months since its onset in July 2020. Here, we analysed and classified into subvariants and lineages 7,453 genomes obtained by next-generation sequencing. We identified two subvariants, Marseille-4A, which contains 22 different lineages of at least 50 genomes, and Marseille-4B. Their average lifetime was 4.1±1.4 months, during which 4.1±2.6 mutations accumulated. Growth rate was 0.079±0.045, varying from 0.010 to 0.173. Most of the lineages exhibited a bell-shaped distribution. Several beneficial mutations at unpredicted sites initiated a new outbreak, while the accumulation of other mutations resulted in more viral heterogenicity, increased diversity and vanishing of the lineages. Marseille-4B emerged when the other Marse ille-4 lineages vanished. Its ORF8 gene was knocked out by a stop codon, as reported in SARS-CoV-2 of mink and in the Alpha variant. This subvariant was associated with increased hospitalization and death rates, suggesting that ORF8 is a nonvirulence gene. We speculate that the observed heterogenicity of a lineage may predict the end of the outbreak.

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Radiological anatomical variations of the lateral nasal wall and anterior skull base amongst different populations: A systematic review and meta‐analysis

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Abstract

Objectives

To determine the anatomical variations of the lateral nasal wall and anterior skull base amongst populations in different geographical regions.

Design

Systematic review and meta-analysis.

Methods

Using PRISMA guidelines, SCOPUS and PUBMED databases were searched from inception until 1st March 2022. The regions and populations identified were from Europe, Asia, Middle East, Australia-New Zealand-Oceania, South America, North America and Africa. Random-effects model was used to estimate the pooled prevalence with 95% confidence intervals (CIs). Heterogeneity was assessed using the I 2 statistic and Cochran's Q test.

Main outcome measures

Anatomical variations of the lateral nasal wall and anterior skull base confirmed by computed tomography scan.

Results

56 articles were included with a total of 11805 persons. The most common anatomical variation of the ostiomeatal complex was pneumatization of the agger nasi (84.1%), olfactory fossa was Keros type 2 (53.8%) and ethmoids was asymmetry of the roof (42.8%). Sphenoethmoidal and suprabullar cells have a higher prevalence in North Americans (53.7%, 95% CI: 46.00-61.33) while asymmetry of ethmoid roof more common in Middle Easterns (85.5%, 95% CI: 0.00-100). Bent uncinate process has greater prevalence in Asians while supraorbital ethmoid cells and Keros type 3 more common in non-Asians. The overall studies have substantial heterogeneity and publication bias.

Conclusions

Certain anatomic variants are more common in a specific population. The 'approach of analysis' plays a role in the prevalence estimates and consensus should be made in future studies regarding the most appropriate 'approach of analysis' either by persons or by sides.
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Epidemiology and Etiology of Chronic Rhinosinusitis in Asia – a Narrative Review

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Background

Despite having a similar prevalence to Western populations, literature on chronic rhinosinusitis (CRS) in the Asian population is sparse. There is limited data on the epidemiology and etiology of CRS in Asia.

Objectives

To review the current literature on the epidemiology and etiology of chronic rhinosinusitis (CRS) in Asia.

Methods

This is a narrative review of published data on the epidemiology and etiology of CRS. Studies on CRS in Asian countries, published in English and indexed on PubMed or Google Scholar were reviewed. Where available, data extracted included epidemiology, endotype and cytokine profiles and genetic profiles.

Results and Conclusion

The prevalence of CRS in Asia ranges widely from 2.1% -28.4%. Type 2 inflammation has been reported in 5-55% of Asian patients, with lower levels of Type 2 cytokines reported in head to head comparisons of Western vs Asian patients. Notably, there exists marked heterogeneity in criterion of the tissue eosinophilic infiltration for diagnosis of type 2 chronic rhinosinusitis. Our review suggests that differences in prevalence of CRS and proportion of eosinophilic CRS between Asia and Europe and the Americas requires further study. Large-scale Asian studies utilizing standardized definitions are needed to bridge this gap. Head to head genetic and microbiomal analysis may also be useful in understanding differences in CRS between the Asian and Western populations.
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The analgesic and anti‐hemorrhagic efficacy of platelet‐rich plasma in tonsillectomy: A systematic review and meta‐analysis of randomized controlled trials

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Abstract

Aim

To conduct a systematic review and meta-analysis of all randomized controlled trials (RCTs) that evaluated the analgesic and anti-hemorrhagic efficacy of platelet-rich plasma (PRP) among patients undergoing tonsillectomy.

Methods

PubMed, Scopus, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar databases were screened from inception until July 2021, and updated in December 2021. Risk of bias of the included studies was evaluated according to the Cochrane Collaboration tool. The efficacy endpoints were summarized as risk ratio (RR) or standardized mean difference (SMD) with 95% confidence interval (CI).

Results

Seven RCTs were analyzed, comprising a total of 392 patients. Risk of bias evaluation showed an overall high risk in one RCT, low risk in four RCTs, and some concerns in two RCTs. The pooled results revealed that the mean postoperative pain score was significantly reduced in favor of the PRP group compared with the control group (SMD=-1.38, 95% CI [-1.91, -0.85], p<0.001). Subgroup analysis showed the effect estimate was statistically significant for early postoperative pain (day 0 to day 3), without substantial difference between both groups on late postoperative pain (day 5 and day 7). Moreover, the rate of postoperative hemorrhage was significantly reduced in favor of the PRP group compared with the control group (RR=0.16, 95% CI [0.05, 0.50], p=0.001). Subgroup analysis showed the effect estimate was statistically significant for the rate of primary and secondary hemorrhage.

Conclusion

PRP was associated with significant reduction in postoperative pain and hemorrhage among patients undergoing tonsillectomy.

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