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Τρίτη 11 Οκτωβρίου 2022

FBXO6 regulates the anti‐viral immune‐responses via mediating alveolar macrophages survival

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Abstract

Inducing early apoptosis in alveolar macrophages is one of the strategies influenza A virus (IAV) evolved to subvert host immunity. Correspondingly, the host mitochondrial protein nucleotide-binding oligomerization domain-like receptor (NLR)X1 is reported to interact with virus polymerase basic protein 1-frame 2 (PB1-F2) accessory protein to counteract virus induced apoptosis. Herein, we report that one of the F-box proteins, FBXO6, promotes proteasomal degradation of NLRX1, and thus facilitates IAV-induced alveolar macrophages apoptosis and modulates both macrophage survival and type I interferon (IFN) signaling. We observed that FBXO6-deficient mice infected with IAV exhibited decreased pulmonary viral replication, as well as alleviated inflammatory-associated pulmonary dysfunction and morbidity. Analysis of the lungs of IAV-infected mice revealed markedly reduced leukocyte recruitment but enhanced production of type I IFN in Fbxo6 -/- mice. Furthermore, increased type I IFN production and decreased viral replication were recapitulated in FBXO6 knockdown macrophages and was associated with reduced apoptosis. Through gain- and loss-of-function studies, we found lung resident macrophages but not bone marrow derived macrophages play the key role in the differences FBXO6 signaling pathway brings in the antiviral immune response. In further investigation, we identified that FBXO6 interacted with and promoted the proteasomal degradation of NLRX1. Together, our results demonstrate that FBXO6 negatively regulates immunity against IAV infection by enhancing the degradation of NLRX1 and thus impairs the survival of alveolar macrophages and antiviral immunity of the host.

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A novel MAP3K20 mutation causing centronuclear myopathy-6 with fiber-type disproportion in a Pakistani family

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Imaging of pediatric pancreas tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper

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Abstract

Primary pancreatic tumors in children are rare with an overall age-adjusted incidence of 0.018 new cases per 100,000 pediatric patients. The most prevalent histologic type is the solid pseudopapillary neoplasm, followed by pancreatoblastoma. This paper describes relevant imaging modalities and presents consensus-based recommendations for imaging at diagnosis and follow-up.
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Phase 1b study of carfilzomib with induction chemotherapy in pediatric relapsed/refractory acute lymphoblastic leukemia

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Abstract

Background

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in childhood. Survival for patients following relapse remains poor, and achieving complete remission (CR) after relapse is the first critical step to cure. Carfilzomib is a proteasome inhibitor with an acceptable safety profile and clinical activity in adults with multiple myeloma but has not been assessed in children. The primary objective of this phase 1b study was to assess the safety and tolerability of carfilzomib combined with vincristine, dexamethasone, asparaginase, and daunorubicin (VXLD) in children with relapsed and/or refractory ALL.

Methods

Patients aged 1–21 years (n = 24) received 4-week induction therapy with carfilzomib at dose levels of 27 mg/m2 (n = 3), 36 mg/m2 (n = 7), 45 mg/m2 (n = 4), and 56 mg/m2 (n = 10) in combination with VXLD. Patients achieving stable disease were offered further consolidation chemotherapy. Analyses were based on the safety evaluable population.

Results

Following dose escalation of carfilzomib, the recommended phase 2 carfilzomib dose was identified as 56 mg/m2. Grade ≥3 hematological adverse events were common (83%, 20/24 patients), and serious treatment-emergent adverse events occurred in 58% (14/24) of patients. At the end of induction, CR/CR with incomplete platelet recovery (CRp)/CR with incomplete blood count recovery (CRi) was identified in 50% of patients (n = 12/24). By the end of consolidation, cumulative CR/CRp/CRi was identified in 58% of patients (n = 14/24).

Conclusion

These data support the use of carfilzomib in pediatric patients with relapsed and/or refractory ALL.
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High-Resolution Single Tooth MRI With an Inductively Coupled Intraoral Coil—Can MRI Compete With CBCT?

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imageObjectives The aims of this study were to quantify T1/T2-relaxation times of the dental pulp, develop a realistic tooth model, and compare image quality between cone-beam computed tomography (CBCT) and high-resolution magnetic resonance imaging (MRI) of single teeth using a wireless inductively coupled intraoral coil. Methods T1/T2-relaxometry was performed at 3 T in 10 healthy volunteers (283 teeth) to determine relaxation times of healthy dental pulp and develop a realistic tooth model using extracted human teeth. Eight MRI sequences (DESS, CISS, TrueFISP, FLASH, SPACE, TSE, MSVAT-SPACE, and UTE) were optimized for clinically applicable high-resolution imaging of the dental pulp. In model, image quality of all sequences was assessed quantitatively (contrast-to-noise ratio) and qualitatively (visibility of anatomical structures and extent of susceptibility artifacts using a 5-point scoring scale). Cone-beam computed tomography served as the reference modality for qualitative assessment. Statistical analysis was performed using 2-way analysis of variance, Fisher exact test, and Cohen κ. Results In vivo, relaxometry of dental pulps revealed T1/T2 relaxation times at 3 T of 738 ± 100/171 ± 36 milliseconds. For all sequences, an isotropic resolution of (0.21 mm)3 was achieved, with acquisition times ranging from 6:19 to 8:02 minutes. In model, the highest contrast-to-noise ratio values were observed for UTE, followed by TSE and CISS. The best image/artifact quality, however, was found for DESS (mean ± SD: 1.3 ± 0.3/2.2 ± 0.0), FLASH (1.5 ± 0.3/2.4 ± 0.1), and CISS (1.5 ± 0.4/2.5 ± 0.1), at a level comparable to CBCT (1.2 ± 0.3/2.1 ± 0.1). Conclusions Optimized MRI protocols using an intraoral coil at 3 T can achieve an image quality comparable to reference modality CBCT within clinically applicable acquisition times. Overall, DESS revealed the best results, followed by FLASH and CISS.
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Length of Stay in Patients Undergoing Tracheoplasty: A NSQIP Study

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Background

Prolonged length of stay (LOS) has been associated with increased morbidity and resource utilization in various surgical procedures. We aim to determine factors associated with increased hospital stay in patient undergoing tracheoplasty.

Methods

The 2012–2018 National Surgical Quality Improvement Program (NSQIP) database was queried for patients undergoing tracheoplasty. Patient LOS was the primary clinical outcome. A LOS >75th percentile was considered as prolonged and was utilized for bivariate analysis of demographic, comorbidity, and operative characteristics. LOS was utilized as a continuous variable for multivariate linear regression analysis.

Results

A total of 252 patients were queried. The majority of patients were female (67.5%), white (82.4%), and over the age of 65 (77.0%). Patients had a median LOS of 7 days with the 75th percentile cutoff being defined at 10 days. On bivariate analysis of associated comorbidities, patients with prolonged LOS were more commonly obese (72.4% vs. 53.1%, p = 0.009), diabetic (37.9% vs. 16.5%, p < 0.001), dyspneic (58.6% vs. 40.7%, p = 0.016), and had chronic steroid use (25.9% vs. 12.9%, p = 0.018). Multivariable logistic regression analysis demonstrated significant associations between prolonged LOS and both chronic obstructive pulmonary disorder (COPD) (OR: 3.43, p = 0.020) and chronic steroid use (OR: 3.81, p = 0.018).

Conclusions

This study elucidates factors associated with prolonged LOS in patients undergoing tracheoplasty. Patients with COPD and chronic steroid use were significantly associated with prolonged LOS.

Level of Evidence

4 Laryngoscope, 2022
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The influence of low insertion torque values on survival rate of immediately loaded dental implants: a systematic review and meta‐analysis

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Abstract

Introduction

The aim was to systematically evaluate the effect of low insertion torque values on the survival rate of immediately loaded dental implants.

Methods

The protocol was registered (PROSPERO ID CRD42020189499), with an electronic search performed in the PubMed, Embase, Web of Science and Cochrane Central Register of Controlled Trials until June 2022 in English and Spanish. Studies analysing the failure or survival rate of immediately loaded dental implants according to different insertion torque values were included.

Results

Five hundred seventy-three articles were assessed of eligibility, of which 7 articles, 4 randomised clinical trials (RTCs), 1 controlled clinical trial and 2 prospective case series studies, were included in the qualitative analysis. The RCTs were classified as low risk of bias, and the non-RCTs as moderate and serious risk of bias. The mean survival rate for implants with low insertion toque (≤35 Ncm) was 96% (p>0.001, 95% CI: 0.91–0.98), and that for implants with medium or high insertion torque (>35 Ncm) was 92% (p>0.001, 95% CI: 0.86–0.96) (IRR = 1.05, 95% CI: 0.79–1.39, p=0.175, I2=0.0%). Splinted implants with insertion torque >20 Ncm and single implants with insertion torque >35 Ncm had a higher survival rate than implants with lower insertion torque values (IRR = 1.05, 95% CI: 0.78–1.43, p=0.956, I2=0.0%, and IRR = 0.92, 95% CI: 0.48–1.75, p=0.799, I2=0.0%, respectively). Different in sertion torque values achieved equivalent outcomes. The mean follow-up was 24 months.

Conclusion

Low insertion torque values have no significant effect on survival rates of immediate loading implants at a mean follow-up of 24 months.
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Efficacy of access flap and pocket elimination procedures in the management of peri‐implantitis – a systematic review and meta‐analysis

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Abstract

Objectives

To evaluate the efficacy of access flap and pocket elimination procedures in the surgical treatment of peri-implantitis.

Methods

Systematic electronic searches (Central/Medline/Embase) up to March 2022 were conducted to identify prospective clinical studies evaluating surgical therapy (access flap or pocket elimination procedures) of peri-implantitis. Primary outcome measures were reduction of probing depth (PD) and bleeding on probing (BOP). Risk of bias was evaluated according to study design. Meta-analysis and meta-regression were performed. Results were expressed as standardized mean effect with 95% confidence intervals (CI).

Results

Evidence from studies directly comparing surgical with non-surgical therapy is lacking. Based on pre-post data originating from 13 prospective patient cohorts, pronounced reductions of PD (standardized mean effect: 2.2 mm; 95%CI 1.8, 2.7) and BOP% (27.0; 95%CI 19.8, 34.2) as well as MBL gain (0.2 mm; 95%CI -0.0, 0.5) were observed at evaluation time points ranging from 1 to 5 years. Wide prediction intervals suggested a high degree of heterogeneity. Reduction of mean PD increased by 0.7 mm (95%CI 0.5, 0.9) for every mm in increase of mean PD at baseline. During follow-up period ranging from 1 to 5 years, disease recurrence occurred frequently and implant loss was not uncommon.

Conclusions

Access flap and pocket elimination surgery are effective procedures in the management of peri-implantitis, although rates of disease recurrence during 5 years were high. Treatment outcomes were affected by baseline conditions.
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The protective effect of 3‐indolepropanoic acid on aflatoxin B1‐induced systemic perturbation of the liver and kidney function in rats

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Abstract

Aflatoxin B1 (AFB1) is known to derange the hepatorenal system by redox, DNA adduct formation, and apoptotic networks. Endogenous 3-indole propionic acid (3-IPA) is a metabolite of tryptophan metabolism by gut microbiota that can protect against redox imbalance, inflammation, and cellular lipid damage. We investigated the beneficial effect of 3-IPA against AFB1-mediated organ toxicity in male rats post 28 days of consecutive treatment. 3-IPA (25 and 50mg/kg) was orally administered alongside AFB1 (50μg/kg)-treatment. Biochemical and Enzyme-Linked Immunosorbent Assays were utilised to examine biomarkers of hepatorenal function, oxidative status, and inflammation. DNA damage and apoptosis were also assessed, and histological staining techniques were used to investigate hepatorenal tissues for pathological indicators. 3-IPA supplementation abated AFB1-mediated increases in biomarkers of hepatic and renal dysfunction in rat serum. Co-administration of 3-IPA further reduced AFB1-induc ed redox imbalance (by upregulating antioxidant mediators and enzymes (GSH, TSH, Trx, Trx-R, SOD, CAT, GPx, GST); reducing reactive oxygen species, lipid peroxidation and DNA adduct (RONS, LPO & 8-OH-dG) formation; suppressing pro-inflammatory and apoptotic mediators (XO, MPO, NO, IL-1β, & Casp -9 and -3); and upregulating the level of interleukin 10 (IL-10). Moreover, treatment with 3-IPA lessened hepatorenal tissue injuries. These findings suggest that augmenting 3-IPA endogenously from tryptophan metabolism may provide a novel strategy to forestall xenobiotics-mediated hepatorenal toxicity, including AFB1.
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The pathophysiological and immunological background of the monkeypox virus infection: An update

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Abstract

In addition to the COVID-19 waves, the globe is facing global monkeypox (MPX) outbreak. MPX is an uncommon zoonotic infection characterized by symptoms similar to smallpox. It is caused by the monkeypox virus (MPXV), a double-stranded DNA virus that belongs to the genus Orthopoxvirus (OPXV). MPXV, which causes human disease, has been confined to Africa for many years, with only a few isolated cases in other areas. Outside of Africa, the continuing MPXV outbreak in multiple countries in 2022 is the greatest in recorded history. The current outbreak, with over ten thousand confirmed cases in over fifty countries between May and July 2022, demonstrates that MPXV may travel rapidly among humans and pose a danger to human health worldwide. The rapid spread of such outbreaks in recent times has elevated monkeypox to the status of a rising zoonotic disease with significant epidemic potential. While the MPXV is not as deadly or contagious as the variola virus that c auses smallpox, it poses a threat because it could evolve into a more potent human pathogen. This review assesses the potential threat to the human population and provides a brief overview of what is currently known about this re-emerging virus. By analyzing the biological effects of MPXV on human health, its shifting epidemiological footprint, and currently available therapeutic options, this review has presented the most recent insights into the biology of the virus. This study also clarifies the key potential causes that could be to blame for the present MPX outbreak and draw attention to major research questions and promising new avenues for combating the current monkeypox epidemic.

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