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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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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Phosphatase and tensin homolog determines inflammatory status by differentially regulating the expression of Akt1 and Akt2 in macrophage alternative polarization of periodontitis

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Abstract

Aims

Macrophages are closely involved in periodontitis; however, the molecular mechanism by which macrophages influence periodontitis is not well understood. We investigated the effects of phosphatase and tensin homolog (PTEN) on macrophage polarization, the underlying mechanism, and the regulatory roles in periodontium regeneration.

Materials and Methods

PTEN expression in periodontitis macrophages was detected ex vivo. The effects of PTEN on macrophage polarization and the underlying mechanisms were investigated in vitro. We also analyzed the ability of PTEN inhibitors to repair periodontitis in vivo, in a ligature-induced mouse model of periodontitis.

Results

Macrophage PTEN expression in periodontitis patients was significantly higher than that of controls. PTEN inhibition in macrophages induced alternative macrophage polarization, whereas PTEN overexpression facilitated classical polarization. PTEN inhibition facilitated activation of Akt1 while inhibited expression of Akt2. Furthermore, Akt2 overexpression could rescue the effects of PTEN inhibition on NF-κB. Treatment with PTEN inhibitor significantly attenuated the local inflammatory status and prevented alveolar bone resorption in mouse model.

Conclusions

Our findings suggest that PTEN inhibition could induce alternative macrophage polarization by differentially regulating Akt1 and Akt2. This also changed a pro-inflammatory microenvironment to an anti-inflammatory environment, by subsequently regulating the expression of NF-κB, and thereby attenuated inflammatory alveolar bone resorption induced by ligature.
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SARS‐CoV‐2 evolves to reduce but not abolish neutralizing action

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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) have prolonged coronavirus disease 2019 (COVID-19) pandemic by escaping pre-existing immunity acquired by natural infection or vaccination. Elucidation of VOCs' mutation trends and evasion of neutralization is required to update current control measures. Mutations and the prevalence of VOCs were analyzed in the global immunization coverage rate context. Lentivirus-based pseudovirus neutralization analysis platforms for SARS-CoV-2 prototype strain (PS) and VOCs, containing Alpha, Beta, Gamma, Delta and Omicron, were constructed based on the spike protein of each variant and HEK 293T cell line expressing the hACE2 (human angiotensin-converting enzyme 2) receptor on the surface, and an eGFP reporter. Serum samples from 65 convalescent individuals and 20 WIBP-CorV vaccine recipients and four therapeutic monoclonal antibodies (mAbs) namely imdevimab, casirivimab, bamlanivima b, and etesevimab were used to evaluate the neutralization potency against the variants. Pseudovirus-based neutralization assay platforms for PS and VOCs were established, and multiplicity of infection (MOI) was the key factor influencing the assay result. Compared to PS, VOCs may enhance the infectivity of hACE2-293T cells. Except for Alpha, other VOCs escaped neutralization to varying degrees. Attributed to favorable and emerging mutations, the current pandemic Omicron variant of all VOCs demonstrated the most significant neutralization-escaping ability to the sera and mAbs. Compared with the PS pseudovirus, Omicron had 15.7-fold and 3.71-fold decreases in the NT50 value (the highest serum dilution corresponding to a neutralization rate of 50%); and correspondingly, 90% and 43% of immunization or convalescent serum samples lost their neutralizing activity against the Omicron variant, respectively. Therefore, SARS-CoV-2 has evolved persistently with a strong ability to escape neutr alization and prevailing against the established immune barrier. Our findings provide important clues to controlling the COVID-19 pandemic caused by new variants.

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Efficacy and Safety of Radiofrequency Ablation of Thyroid Nodules: A Multi-institutional Prospective Cohort Study

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imageBackground: Radiofrequency ablation (RFA) has been recently adopted into the practice of thyroidology in the United States, although its use as an alternative to traditional thyroid surgery in Asia and Europe came near the turn of the 21st century. In the United States, only a few studies with small sample sizes have been published to date. We examined outcomes of benign thyroid nodules treated with RFA from 2 North American institutions. Methods: We performed a prospective, multi-institutional cohort study of thyroid nodules treated with RFA between July 2019 and January 2022. Demographics, sonographic characteristics of thyroid nodules, thyroid function profiles, procedural details, complications, and nodule volume measurements at 1, 3, 6, and 12 months follow-up were evaluated. Adjusted multivariate logistic regression analysis was performed to identify sonographic features associated with treatment failure. Results: A total of 233 nodules were included. The median and interquartile range of volume reduction rate (VRR) at 1, 3, 6, and 12 months were 54% [interquartile range (IQR): 36%–73%], 58% (IQR: 37%–80%), 73% (IQR: 51%–90%), and 76% (IQR: 52%–90%), respectively (P
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Prevention of Incisional Hernias by Prophylactic Mesh-augmented Reinforcement of Midline Laparotomies for Abdominal Aortic Aneurysm Treatment: Five-year Follow-up of a Randomized Controlled Trial

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imageIntroduction: The incidence of incisional hernias (IHs) after open repair of an abdominal aortic aneurysm (AAA) is high. Several randomized controlled trials have reported favorable results with the use of prophylactic mesh to prevent IHs, without increasing complications. In this analysis, we report on the results of the 60-month follow-up of the PRIMAAT trial. Methods: In a prospective, multicenter, open-label, randomized design, patients were randomized between prophylactic retrorectus mesh reinforcement (mesh group), and primary closure of their midline laparotomy after open AAA repair (no-mesh group). This article reports on the results of clinical follow-up after 60 months. If performed, ultrasonography or computed tomography were used for the diagnosis of IHs. Results: Of the 120 randomized patients, 114 were included in the intention-to-treat analysis. Thirty-three patients in the no-mesh group (33/58—56.9%) and 34 patients in the mesh group (34/56—60.7%) were evaluated after 5 years. In each treatment arm, 10 patients died between the 24-month and 60-month follow-up. The cumulative incidence of IHs in the no-mesh group was 32.9% after 24 months and 49.2% after 60 months. No IHs were diagnosed in the mesh group. In the no-mesh group, 21.7% (5/23) underwent reoperation within 5 years due to an IH. Conclusions: Prophylactic retrorectus mesh reinforcement after midline laparotomy for the treatment of AAAs safely and effectively decreases the rate of IHs. The cumulative incidence of IHs after open AAA repair, when no mesh is used, continues to increase during the first 5 years after surgery, which leads to a substantial rate of hernia repairs.
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HOXA3 and KDM6A cooperate in transcriptional control of aerobic glycolysis and glioblastoma progression

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Abstract
Background
Alterations in transcriptional regulators of glycolytic metabolism have been implicated in brain tumor growth, but the underlying molecular mechanisms remain poorly understand.
Methods
Knockdown and overexpression cells were used to explore the functional roles of HOXA3 in cell proliferation, tumor formation and aerobic glycolysis. Chromatin immunoprecipitation, luciferase assays and western blotting were performed to verify the regulation of HK2 and PKM2 by HOXA3. PLA, Immunoprecipitation and GST pull down assays were used to examine the interaction of HOXA3 and KDM6A.
Results
We report that transcription factor homeobox A3 (HOXA3), which is aberrantly highly expressed in glioblastoma (GBM) patients and predicts poor prognosis, transcriptionally activates aerobic glycolysis, leading to a significant acceleration in cell proliferation and tumor growth. Mechanically, we identified KDM6A, a lysine-specific dem ethylase, as an important cooperator of HOXA3 to regulating aerobic glycolysis. HOXA3 activates KDM6A transcription and recruits KDM6A to genomic binding sites of glycolytic genes, targeting glycolytic genes for transcriptional activation by removing the suppressive histone modification H3K27 trimethylation. Further evidences demonstrate that HOXA3 requires KDM6A for transcriptional activation of aerobic glycolysis and brain tumor growth.
Conclusion
Our findings provide a novel molecular mechanism linking HOXA3-mediated transactivation and KDM6A-coupled H3K27 demethylation in regulating glucose metabolism and GBM progression.
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