Σφακιανάκης Αλέξανδρος
ΩτοΡινοΛαρυγγολόγος
Αναπαύσεως 5 Άγιος Νικόλαος
Κρήτη 72100
00302841026182
00306932607174
alsfakia@gmail.com

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Κυριακή 5 Ιουνίου 2022

DIPG-40. Combined pharmacological and genetic screening to identify dependencies and combinations in ACVR1-mutant diffuse midline glioma

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Abstract
Somatic mutations in ACVR1, which encodes the serine/threonine kinase ALK2, are found in 20-25% of DMG-H3K27 patients. Treatment of ACVR1-mutant patient-derived models with multiple chemotypes of ALK2 inhibitors (ALK2i) results in reduced cell viability in vitro and extended survival in orthotopic xenografts in vivo but, as single agents, these inhibitors were unable to achieve a complete anti-tumour response. Recently we reported that combinatorial treatment of ACVR1-mutant DIPG cells with vandetanib (RTK inhibitor) and everolimus (mTOR/ABC transporter inhibitor) was synergistic both in vitro and in vivo and was shown to be a feasible combination to trial clinically in this setting. To identify specific dependencies in ACVR1-mutant cells which may be translatable with novel synergistic drug combinations alongside ALK2i, we have implemented both candidate and unbiased drug and genetic screening approaches. Using a panel of patient-derived ACVR1-m utant and wild-type models, we identified synergy between multiple chemotypes of ALK2i (M4K2009/LDN-214117) and PI3K/mTOR (AZD8055/everolimus) and MEK inhibitors (trametinib), reflecting the common co-segregation of PIK3CA/PIK3R1 alterations in these tumours. Whole-genome CRISPR/Cas9 screening of ACVR1-mutant SU-DIPG-IV cells in combination with two ALK2i (M4K2009/LDN-193189), confirmed a specific MTOR genetic dependency, as well as for the protein phosphatase regulatory subunit PPP2R1A, known to play a role in MAPK pathway activation. Additional hits include the serine/threonine kinase PKMYT1, a negative regulator of the G2/M checkpoint via a functionally redundant phosphorylation of CDK1/CCNB1 alongside WEE1; confirmatory drug assays with the WEE1 inhibitor AZD1775 resulted in a synergistic interaction with ALK2i in ACVR1-mutant cells. Hits were integrated with DepMap using 'gene-effect' scores (Chronos) enabling filtering of common essential genes. Preliminary pathway enrichm ent analysis (MAGeCKFlute) identified ALK2i-specific vulnerabilities involving TGFB1/SMAD signalling and histone deacetylation. These data highlight functionally rational and novel combinatorial possibilities for children with ACVR1-mutant DMG, with systematic preclinical assessment required for prioritisation for the clinic.
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Management of Neurofibromatosis Type 1-Associated Plexiform Neurofibromas

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Abstract
Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multi-disciplinary NF1 experts.
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The clinical and bioinformatics analysis for the role of anti‐hypertension drugs on mortality among patients with hypertension hospitalized with COVID‐19

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Abstract

Comorbidities such as hypertension could exacerbate symptoms of COVID-19 infection. Patients with hypertension may receive both anti-COVID-19 and anti-hypertension therapies when infected with COVID-19. However, it is not clear how different classes of anti-hypertension drugs impact the outcome of COVID-19 treatment. Herein, we explore the association between the inpatient use of different classes of anti-hypertension drugs and mortality among patients with hypertension hospitalized with COVID-19. We totally collected data from 278 patients with hypertension diagnosed with COVID-19 admitted to hospitals in Wuhan from February 01 to April 01, 2020. A retrospective study was conducted and single cell RNA-Seq analysis of treatment-related genes was performed. The results showed that angiotensin II receptor blockers (ARB) and calcium channel blockers (CCB) drugs significantly increased the survival rate but the use of ACEI/beta-block/diuretic drugs did not affec t the mortality caused by COVID-19. Based on the analysis of four public datasets of single-cell RNA-seq on COVID-19 patients, we concluded that JUN, LST1 genes may play a role in the effect of ARB on COVID-19 related mortality while CALM1 gene may contribute to the effect of CCB on COVID-19 related mortality. Our results provide guidance on the selection of anti-hypertension drugs for hypertensive patients infected with COVID-19.

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Clinical efficacy and in vitro neutralization capacity of monoclonal antibodies for SARS‐CoV‐2 delta and omicron variants

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Abstract

We aimed to provide in vitro data on the neutralization capacity of different monoclonal antibody (mAb) preparations against the SARS-CoV-2 delta and omicron variant, respectively, and describe the in vivo RNA kinetics of COVID-19 patients treated with the respective mAbs. Virus neutralization assays were performed to assess the neutralizing effect of the mAb formulations casirivimab/imdevimab and sotrovimab on the SARS-CoV-2 delta and omicron variant. Additionally, respiratory tract SARS-CoV-2 RNA kinetics are provided for 25 COVID-19 patients infected with either delta variant (n=18) or omicron variant (n=7) treated with the respective mAb formulations during their hospital stay. In the virus neutralization assay, sotrovimab exhibits neutralizing capacity at therapeutically achievable concentrations against the SARS-CoV-2 delta and omicron variant. In contrast, casivirimab/imdevimab had neutralizing capacity against the delta variant but fail ed neutralization against the omicron variant except for a very high concentration above the currently recommended therapeutic dosage. In patients with delta variant infections treated with casivirimab/imdevimab, we observed a rapid decrease of respiratory viral RNA at day three after mAb therapy. In contrast, no such prompt decline was observed in patients with delta variant or omicron variant infections receiving sotrovimab.

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An Artificial Intelligence‐Based Cosmesis Evaluation for Temporomandibular Joint Reconstruction

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An Artificial Intelligence-Based Cosmesis Evaluation for Temporomandibular Joint Reconstruction

A state-of-the-art AI facial recognition system was applied to the symmetry evaluation of the faces underwent mandibular reconstruction surgery with free vascularized fibular flaps. Temporomandibular joint reconstruction with fibular bone was found to match the original joint in terms of symmetry as well as function.


Objective

Management of the temporomandibular joint (TMJ) following condylar resection remains challenging in the field of mandibular reconstruction. A simple reconstruction of the TMJ with a contoured end of a fibular graft placed into the joint space is a potential option, but its efficacy is unknown partly because there are only few objective assessment systems for aesthetic outcome. This study aimed to develop an artificial intelligence (AI)-based aesthetic outcome evaluation system for the simple TMJ reconstruction method and evaluate its functional outcomes.

Methods

Patients who underwent segmental mandibular resection and reconstruction with fibular flaps at our institution between 2011 and 2020 were retrospectively reviewed. The mandibular asymmetry value was introduced as a primary aesthetic outcome measure, calculated for each patient's photograph using facial recognition AI. The outcomes of the simple TMJ reconstruction method were compared with those of cases in which the native condyle was preserved.

Results

Ten patients underwent condylar resection followed by simple TMJ reconstruction, while the native condyle was preserved in 18 patients. No significant difference was observed in the postoperative mandibular asymmetry value between the two treatment groups. No significant differences were found in the functional outcomes of deglutition and speech.

Conclusion

The AI-based asymmetry evaluation system was useful as an aesthetic outcome measure in mandibular reconstruction. Simple TMJ reconstruction with a fibular end seemed to be a promising option, as there were no significant differences in both aesthetic and functional outcomes between this method and those cases in which the native condyle was preserved. Laryngoscope, 2022

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Successful isavuconazole salvage therapy for cerebral mucormycosis in a child with relapsed leukemia: A light in the dark tunnel

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Polyamine synthesis enzyme AMD1 is closely related to the tumorigenesis and prognosis of human breast cancer

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Publication date: Available online 4 June 2022

Source: Experimental Cell Research

Author(s): Hongyu Gao, Hanjun Li, Jingjie Wang, Cheng Xu, Yueyun Zhu, Dilihumaer Tuluhong, Xinfang Li, Shaohua Wang, Jieshou Li

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Discoidin domain receptor 1 may be involved in biological barrier homeostasis

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Discoidin domain receptor 1 may be involved in biological barrier homeostasis

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase may involved in biological barrier homeostasis, such as epithelial barrier, vascular barrier, glomerular filtration barrier, blood–brain barrier and blood-labyrinth barrier. And DDR1-targeted inhibition has emerged as an attractive research option.


Abstract

What is known and objective

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase involved in the pathological processes of several diseases, such as keloid formation, renal fibrosis, atherosclerosis, tumours, and inflammatory processes. The biological barrier is the first line of defence against pathogens, and its disruption is closely related to diseases. In this review, we attempt to elucidate the relationship between DDR1 and the biological barrier, explore the potential biological value of DDR1, and review the current research status and clinical potential of DDR1-selective inhibitors.

Methods

We conducted an extensive literature search on PubMed to collect studies on the relevance of DDR1 to biological barriers and DDR1-selective inhibitors. With these studies, we explored the relationship between DDR1 and biological barriers and briefly reviewed representative DDR1-selective inhibitors that have been reported in recent years.

Results and discussion

First, the review of the potential mechanisms by which DDR1 regulates biological barriers, including the epithelial, vascular, glomerular filtration, blood-labyrinth, and blood–brain barriers. In the body, DDR1 dysfunction and aberrant expression may be involved in the homeostasis of the biological barrier. Secondly, the review of DDR1 inhibitors reported in recent years shows that DDR1-targeted inhibition is an attractive and promising pharmacological intervention.

What is new and conclusions

This review shows that DDR1 is involved in various physiological and pathological processes and in the regulation of biological barrier homeostasis. However, studies on DDR1 and biological barriers are still scarce, and further studies are needed to elucidate their specific mechanisms. The development of targeted inhibitors provides a new direction and idea to study the mechanism of DDR1.

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Physical, mechanical and anti‐biofilm formation properties of CAD‐CAM milled or 3D printed denture base resins: In Vitro analysis

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Abstract

Purpose

To investigate surface characteristics (roughness and contact angle), anti-biofilm formation, and mechanical properties (mini-flexural strength) of computer-aided design and computer-aided manufacturing (CAD-CAM) PMMA polymer, and three-dimensional (3D) printed resin for denture base fabrication compared with conventional heat polymerized denture base resins.

Materials and Methods

A total of 60 discs and 40 rectangular specimens were fabricated from one CAD-CAM (AvaDent), one 3D printed (Cosmos Denture), and two conventional heat polymerized (Lucitone 199 and VipiWave) materials for denture base fabrication. Roughness was determined by Ra value; the contact angle was measured by the sessile drop method; the biofilm formation inhibition behavior was analyzed through C. albicans adhesion, while mini-flexural strength test was done using a three-point bending test. The data were analyzed using descriptive and analytical statistics (α = 0.05).

Results

The CAD-CAM PMMA group showed the lowest C. albicans adhesion (log CFU/mL: 3.74 ±0.57) and highest mini-flexural strength mean (114.96 ±16.23 MPa). 3D printed specimens presented the highest surface roughness (Ra: 0.317 ±0.151 μm) and lowest mini-flexural strength values (57.23 ±9.07 MPa). However, there was no statistical difference between CAD-CAM PMMA and conventional groups for roughness, contact angle, and mini-flexural strength.

Conclusions

CAD-CAM milled materials present surface and mechanical properties similar to conventional resins and show improved behavior preventing C. albicans adhesion. Nevertheless, 3D printed resins present decreased mini-flexural strength.

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Pharyngeal tongue base augmentation for dysphagia therapy: A prospective case series in patients post head and neck cancer treatment

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Abstract

Background

Dysphagia post head and neck cancer (HNC) multimodality treatment is attributed to reduced pharyngeal strength. We hypothesized that pharyngeal tongue base augmentation for dysphagia (PAD therapy) would increase pharyngeal pressures during swallowing thereby improving swallow symptoms.

Methods

Adults with moderate–severe dysphagia post-HNC treatment had PAD therapy using a temporary filler (hyaluronic acid [HA]), with follow-up long-lasting lipofilling. Swallowing preprocedure and postprocedure was assessed with the Sydney Swallow Questionnaire (SSQ), High-Resolution Pharyngeal Manometry (HRPM), and Videofluoroscopic Swallowing Study (VFSS). Statistical comparison utilized paired tests.

Results

Six participants (all male; median age 64 years [IQR 56, 71]) underwent PAD therapy at a median of 47 [IQR 8, 95] months post-treatment. SSQ scores reduced from baseline (mean 1069 [95%CI 703, 1434]) to post-HA (mean 579 [76, 1081], p > 0.05), and post-lipofilling (491 [95%CI 913, 789], p = 0.003, n = 4). Individual participants demonstrated reduced Swallow Risk Index, Bolus Presence Time, and increased Upper Esophageal Sphincter opening, but mesopharyngeal contractile pressures were unchanged. VFSS measures of aspiration, residue, and severity were unchanged.

Conclusions

Novel PAD therapy is safe and improves dysphagia symptoms. Biomechanical swallowing changes are suggestive of more efficacious bolus propulsion with conservative filler volume, but this was unable to resolve residue or aspiration measures.

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