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

alexandrossfakianakis shared this article with you from Inoreader DIPG-40. Combined pharmacological and genetic screening to identify dependencies and combinations in ACVR1-mutant diffuse midline glioma via Neuro-Oncology Current Issue 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. View on Web

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

alexandrossfakianakis shared this article with you from Inoreader Reliable fluorescence technique to detect the antibiotic colistin, a possible environmental threat due to its overuse via Earth and environmental sciences : nature.com subject feeds View on Web

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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

alexandrossfakianakis shared this article with you from Inoreader The clinical and bioinformatics analysis for the role of anti‐hypertension drugs on mortality among patients with hypertension hospitalized with COVID‐19 via Journal of Medical Virology 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. This article is protected by copyright. All rights reserved. View on Web

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

alexandrossfakianakis shared this article with you from Inoreader Clinical efficacy and in vitro neutralization capacity of monoclonal antibodies for SARS‐CoV‐2 delta and omicron variants via Journal of Medical Virology 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. This article is protected by copyright. All rights reserved. View on Web

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An Artificial Intelligence‐Based Cosmesis Evaluation for Temporomandibular Joint Reconstruction

alexandrossfakianakis shared this article with you from Inoreader An Artificial Intelligence‐Based Cosmesis Evaluation for Temporomandibular Joint Reconstruction via The Laryngoscope 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 View on Web

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

alexandrossfakianakis shared this article with you from Inoreader Successful isavuconazole salvage therapy for cerebral mucormycosis in a child with relapsed leukemia: A light in the dark tunnel via Pediatric Blood & Cancer View on Web

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Nucleus pulposus cell senescence is regulated by substrate stiffness and is alleviated by LOX possibly through the integrin β1-p38 MAPK signaling pathway

alexandrossfakianakis shared this article with you from Inoreader Nucleus pulposus cell senescence is regulated by substrate stiffness and is alleviated by LOX possibly through the integrin β1-p38 MAPK signaling pathway via ScienceDirect Publication: Experimental Cell Research Publication date: Available online 3 June 2022 Source: Experimental Cell Research Author(s): Runze Zhao, Li Yang, Shuangjian He, Tingting Xia View on Web

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

alexandrossfakianakis shared this article with you from Inoreader Polyamine synthesis enzyme AMD1 is closely related to the tumorigenesis and prognosis of human breast cancer via ScienceDirect Publication: Experimental Cell Research 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 View on Web

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Discoidin domain receptor 1 may be involved in biological barrier homeostasis

alexandrossfakianakis shared this article with you from Inoreader Discoidin domain receptor 1 may be involved in biological barrier homeostasis via Journal of Clinical Pharmacy and Therapeutics 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. View on Web

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

alexandrossfakianakis shared this article with you from Inoreader Physical, mechanical and anti‐biofilm formation properties of CAD‐CAM milled or 3D printed denture base resins: In Vitro analysis via Journal of Prosthodontics 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. This article is protected by copyright. All rights reserved View on Web

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