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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Management of Neurofibromatosis Type 1-Associated Plexiform Neurofibromas

alexandrossfakianakis shared this article with you from Inoreader Management of Neurofibromatosis Type 1-Associated Plexiform Neurofibromas via Neuro-Oncology Advance Access 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. 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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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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