Αρχειοθήκη ιστολογίου

Αλέξανδρος Γ. Σφακιανάκης
ΩτοΡινοΛαρυγγολόγος
Αναπαύσεως 5
Άγιος Νικόλαος Κρήτη 72100
2841026182
6032607174

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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Reliable fluorescence technique to detect the antibiotic colistin, a possible environmental threat due to its overuse

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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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