Infection phase‐dependent dynamics of the viral and host N6‐methyladenosine epitranscriptome in the lifecycle of an oncogenic virus in vivo

alexandrossfakianakis shared this article with you from Inoreader Infection phase‐dependent dynamics of the viral and host N6‐methyladenosine epitranscriptome in the lifecycle of an oncogenic virus in vivo via Journal of Medical Virology ABSTRACT Dynamic alteration of the epitranscriptome exerts regulatory effects on the lifecycle of oncogenic viruses in vitro. However, little is known about these effects in vivo because of the general lack of suitable animal infection models of these viruses. Using a model of rapid-onset Marek's disease lymphoma in chickens, we investigated changes in viral and host mRNA N6-methyladenosine (m6A) modification during Marek's disease virus (MDV) infection in vivo. We found that the expression of major epitranscriptomic proteins varies among viral infection phases, reprogramming both the viral and the host epitranscriptomes. Specifically, the METTL3/14 complex was suppressed during the lytic and reactivation phases of the MDV lifecycle, whereas its expression was increased during the latent phase and in MDV-induced tumors. METTL3/14 overexpression inhibits, whereas METTL3/14 knockdown enhances, MDV gene expression and replication. These f indings reveal the dynamic features of the mRNA m6A modification program during viral replication in vivo, especially in relation to key pathways involved in tumorigenesis. This article is protected by copyright. All rights reserved. View on Web

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Inverted repeats in the monkeypox virus genome are hot spots for mutation

alexandrossfakianakis shared this article with you from Inoreader Inverted repeats in the monkeypox virus genome are hot spots for mutation via Journal of Medical Virology Abstract The current monkeypox virus (MPXV) strain differs from the strain arising in 2018 by 50+ single nucleotide polymorphisms (SNPs) and is mutating much faster than expected. The cytidine deaminase apolipoprotein B mRNA editing enzyme, catalytic subunit B (APOBEC3) was hypothesised to be driving this increased mutation. APOBEC has recently been identified to preferentially mutate cruciform DNA secondary structures formed by inverted repeats (IRs). IRs were recently identified as hot spots for mutation in SARS-CoV-2, and we aimed to identify whether IRs were also hot spots for mutation within MPXV genomes. We found that MPXV genomes were replete with IR sequences. Of the 50+ SNPs identified in the 2022 outbreak strain, 63.9% of these were found to have arisen within IR regions in the 2018 reference strain (MT903344.1). Notably, IR sequences found in the 2018 reference strain were significantly lost over time, with an average of 32.5% of these sequences being cons erved in the 2022 MPXV genomes. This evidence was highly indicative that mutations were arising within IRs. This data provides further support to the hypothesis that APOBEC may be driving MPXV mutation and highlights the necessity for greater surveillance of IRs of MPXV genomes to detect new mutations. This article is protected by copyright. All rights reserved. View on Web

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Sodium‐glucose co‐transporter 2 inhibitors: A comprehensive review from cells to bedside

alexandrossfakianakis shared this article with you from Inoreader Sodium‐glucose co‐transporter 2 inhibitors: A comprehensive review from cells to bedside via Fundamental & Clinical Pharmacology Abstract Sodium-glucose co-transporter 2 (SGLT2) inhibitors (SGLT2is) are oral medications approved for type 2 diabetes mellitus. Interestingly, during recent years they have been promisingly considered as new medications for cardiovascular and kidney diseases. However, the mechanisms underlying these new benefits are not fully understood. Thanks to the discovery of multiple modes of action, the simple picture about mechanisms of action of SGLT2is has become more and more complex. Besides their effects in diabetes, there is increasing evidence for their beneficial effects in heart failure and chronic kidney diseases. In addition, many studies have provided evidence for the fruitful effects of SGLT2is in atherosclerotic cardiovascular disease. In this study, we present mounting evidence for the complex action modes of SGLT2is and their current applications in clinical practice. View on Web

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CTIM-22. THE COMBINATION OF LOMUSTINE AND THE IMMUNOCYTOKINE L19TNF IS A PROMISING TREATMENT FOR RECURRENT GLIOBLASTOMA

alexandrossfakianakis shared this article with you from Inoreader CTIM-22. THE COMBINATION OF LOMUSTINE AND THE IMMUNOCYTOKINE L19TNF IS A PROMISING TREATMENT FOR RECURRENT GLIOBLASTOMA via # Neuro-Oncology Current Issue Abstract Glioblastoma is the most aggressive primary brain tumor and adults and poorly immunogenic. Treatment options for recurrent glioblastoma after standard of care chemoradiation are limited Several immunotherapeutic strategies including peptide vaccination and immune checkpoint inhibition have so far failed to improve survival and except from potentially regorafenib, no other agent has demonstrated superior activity to lomustine. Therefore, there is an urgent need for more effective treatment strategies for recurrent glioblastoma. Here, we investigate a new treatment combination based on the alkylating chemotherapy lomustine and the tumor-stroma targeting antibody-cytokine fusion protein L19TNF in preclinical glioma models and patients with recurrent glioblastoma. The combination treatment with lomustine and L19TNF demonstrated strong synergistic anti-tumor activity in several immunocompetent orthotopic glioma models curing the majority of tumor-bear ing mice, whereas other mono- or combination therapies for example with anti-PD1 had only limited anti-glioma activity. Investigations of the mechanism of action revealed that lomustine plus L19TNF led to intratumoral necrosis, DNA damage and triggered a strong local anti-tumor immune response with increased MHC-I expression, presentation of neoepitopes and increased abundance of tumor-infiltrating lymphoid cells. In the first patients treated within a phase I/II clinical trial (NCT04573192), the treatment was well tolerated, and durable objective tumor responses and disease stabilizations could be observed also in patients with an unmethylated MGMT promoter. View on Web

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STEM-28. THE ROLE OF LONP1 IN DRIVING ENHANCED PMT IN THE 'LEADING EDGE' NICHE IN GLIOBLASTOMA

alexandrossfakianakis shared this article with you from Inoreader STEM-28. THE ROLE OF LONP1 IN DRIVING ENHANCED PMT IN THE 'LEADING EDGE' NICHE IN GLIOBLASTOMA via # Neuro-Oncology Current Issue Abstract Glioblastoma (GBM), a high grade brain tumor, possesses poor overall survival with less than 5% surviving past five years. Previously, the TCGA classifications for GBM have included the mesenchymal, proneural, classical and neural subtypes with their own respective expression profiles and survival. Recent omics analysis has revealed other key aspects of GBM pathology, including intratumoral heterogeneity spanning all subtypes and enhanced stemness and treatment resistance and other hallmarks of proneural mesenchymal transition (PMT) following treatment with first-line standard of care treatment with radiation therapy and temozolomide (TMZ). Invading glioma stem cells (GSC) with high Nestin and hypoxia-inducible factor 1 alpha (HIF-1α) expression have been theorized to contribute to recurrence. HIF-1α acts as a master regulator driving increased stemness, invasiveness and angiogenesis. Interestingly, HIF-1α and nuclear respiratory factor-2 both upregulate Lon peptidase 1 (LonP1) in response to increased hypoxia or reactive oxygen species (ROS) production. LonP1 has been shown to drive increased metastasis, tumor growth and epithelial-mesenchymal transition (EMT), an analog of PMT, in colon cancer, melanoma and other cancer types. In a recently elucidated GBM organoid model, we present new findings demonstrating the importance of LonP1 in driving enhanced, transient PMT near the 'invading edge'. This includes the enhanced expression of several key drivers of PMT and phenotypic hallmarks, such as increased invasiveness, proliferation and poorer survival. View on Web

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INNV-25. ASSESSING SLEEP AND CIRCADIAN RHYTHMS IN PRIMARY BRAIN TUMORS PATIENTS: AN OBSERVATIONAL STUDY

alexandrossfakianakis shared this article with you from Inoreader INNV-25. ASSESSING SLEEP AND CIRCADIAN RHYTHMS IN PRIMARY BRAIN TUMORS PATIENTS: AN OBSERVATIONAL STUDY via # Neuro-Oncology Current Issue Abstract Sleep-wake disturbances are among the most common and severe symptoms in primary brain tumor (PBT) patients. Currently, no studies have quantified their physiological sleep measurements or compared these assessments to established patient reported outcome measures (PROs). Smart wearable devices, such as Fitbits, continuously monitor patient behaviors at home and provide detailed physiological measurements of sleep, activity, and heart rate. We hypothesized that smart wearable devices can accurately determine physiological sleep disturbances and circadian disruptions and will complement established PROs in a PBT patient population. This observational, cross-sectional trial monitors sleep and circadian rhythm variables using Fitbit smart wearable devices worn for 1 month. Additionally, participants will answer PROs questionnaires (PROMIS Sleep Disturbance and Sleep Related Impairment-Short Forms, Sleep Hygiene Index, Morningness-Eveningness questio nnaire, and Consensus Sleep Diary) at study entry and during the last week on-study. The present study is a planned interim analysis of 54 patients to assess feasibility, including evaluation of enrollment, attrition, study parameter completion and data missingness. 73 PBT patients were screened and approached. Of these patients, 54 (74%) were enrolled on study and 19 (26%) declined participation (8 lacked interest, 3 discomfort wearing watches, 3 lacked smart phone, 2 unable to wear device at work, 2 unable to attend consent calls, 1 pregnancy and 1 cognitive complication). The accrued patients were 56% male, 56%³ 50 years of age, and 81% had a KPS³ 90. Patients represented different stages of treatment: 6% of patients were newly diagnosed, 24% on active treatment (11% 1st recurrence, 13% 2nd recurrence), and 70% were on imaging surveillance. Feasibility was confirmed as there were no deviations reported and 100% of PROs and study timep oints completed. Quantified Fitbit data including percent time worn and physiologic sleep parameters will be reported. Study enrollment for efficacy measures continues. View on Web

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LTBK-08. Inferring cell type and cell state composition in glioblastoma from bulk DNA methylation profiles using multi-omic single-cell analyses

alexandrossfakianakis shared this article with you from Inoreader LTBK-08. Inferring cell type and cell state composition in glioblastoma from bulk DNA methylation profiles using multi-omic single-cell analyses via # Neuro-Oncology Current Issue Abstract OBJECTIVE Cellular heterogeneity determines tumor phenotype and response to therapy. This is particularly pronounced in glioblastoma (GBM), which is characterized by multiple malignant cell states with distinct proliferation potentials, and different cell types of the microenvironment. Ideally, cellular heterogeneity is characterized using single cell genomic profiling techniques. However, these techniques remain challenging to apply in a diagnostic setting and to large retrospective patient cohorts (TCGA, GLASS, DKFZ and clinical trials). Instead, clinicians routinely support their diagnosis with bulk DNA methylation profiling, which generates robust results from low quality material but does not inform on cellular heterogeneity. We have developed a powerful new computational method to deconvolute bulk DNA methylation data and infer cellular heterogeneity within individual tumors, to support prognostic accuracy and personalized treatme nt decisions. METHODS Using both bulk and single-cell multi-omic datasets, we created a DNA methylation-based reference of cell types (malignant, glial, neuronal, and immune) within GBM tumors, and the state of malignant cells therein (stem-like vs. differentiated-like). Using this reference, our computational approach accurately deconvolutes bulk DNA methylation profiles of individual query samples. RESULTS High deconvolution accuracy of GBM heterogeneity was achieved from frozen and FFPE tissue samples, including those of low quality or purity (Jensen Shannon divergence for composition similarity < 0.05). Our approach eliminates bias derived from the microenvironment, and results in patient stratification that harmonizes the DNA methylation- and RNA-based classifications of GBM. It also reveals the inter- and intra-tumoral links between the genetic, DNA methylation, and transcriptomic components of GBM pathology, and suggests their specific impacts on treatmen t efficacy. To facilitate clinical translation, we created a public website that allows clinicians to infer the relative abundance of different cell states within a tumor at the click of a button. View on Web

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Pediatric cancer‐associated thrombosis

alexandrossfakianakis shared this article with you from Inoreader Pediatric cancer‐associated thrombosis: Analysis from a tertiary care cancer center in India via Pediatric Blood & Cancer Abstract Background and aims Thrombotic events (TEs) have been extensively studied in adult cancer patients, but data in children are limited. We prospectively analyzed pediatric cancer-associated thrombosis (PCAT) in children with malignancies. Methods Children below 15 years of age with confirmed malignancies, treated at a large tertiary cancer center in India from July 2015 to March 2020 developing any TE were eligible. A standardized approach for detection and management was followed. Data were collected after informed consent. Results Of 6132 eligible children, 150 (2.44%) had 152 TEs, with median age 8.5 years and male:female of 1.83:1. Most TEs occurred on chemotherapy: 111 (74.0%). The most common site was central nervous system (CNS) 59 (39.3%), followed by upper-limb venous system 37 (24.7%). Hemato-lymphoid (HL) malignancies were more prone to PCAT than solid tumors (ST) (incidence 3.23% vs. 1.58%; odds ratio [OR] = 2.06, 95% confidence interval [CI] [1.36–2.88]; p < .001). Malignancies associated with PCAT were acute lymphoblastic leukemia (ALL) 2.94%, acute myeloid leukemia (AML) 6.66%, and non-Hodgkin lymphomas 5.35%. Response imaging done in 106 (70.7%) children showed complete to partial resolution in almost 90% children. Death was attributable to TE in seven (4.66%) children. Age above 10 years (OR 2.33, 95% CI [1.59–3.41]; p < .001), AML (OR 4.62, 95% CI [1.98–10.74]; p = .0062), and non-Hodgkin lymphoma (OR 4.01, 95 % CI [1.15–14.04]; p = .029) were significantly associated with TEs. In ALL, age more than 10 years (OR 1.86, 95% CI [1.06–3.24]; p < .03), T-ALL (OR 3.32, 95% CI [1.69–6.54]; p = .001), and intermediate-risk group (OR 4.97, 95% CI [1.12–22.02]; p = .035) were significantly associated with thrombosis. The 2-year event-free survival (EFS) for HL malignancies with PCAT was 55.3% versus 72.1% in those without PCAT (p = .05), overall survival (OS) being 84.6% versus 80.0% (p = .32). Conclusion Incidence of PCAT was 2.4%, and occurred predominantly in older children with hematolymphoid malignancies early in treatment. Most resolved completely with low molecular weight heparin (LMWH) and mortality was low. In hematolymphoid malignancies, PCAT reduce EFS, highlighting the need for prevention. View on Web

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18F‐fludeoxyglucose positron emission computed tomography (18F‐FDG‐PET/CT) versus 68Ga‐DOTATATE‐PET/CT in patients with head and neck cancer: Comparisons and implications for treatment

alexandrossfakianakis shared this article with you from Inoreader 18F‐fludeoxyglucose positron emission computed tomography (18F‐FDG‐PET/CT) versus 68Ga‐DOTATATE‐PET/CT in patients with head and neck cancer: Comparisons and implications for treatment via Head & Neck Abstract Background Tumor-specific molecular imaging in head and neck squamous cell carcinoma (HNSCC) is not well established. Somatostatin receptors (SSTRs) are found in solid tumors, including HNSCC. 68Ga-DOTATATE, a commercially available radionuclide that binds SSTRs, may have utility in imaging HNSCC. Methods Patients with HNSCC received pretreatment imaging with 18F-FDG-PET/CT and 68Ga-DOTATATE. Imaging was compared for concordance. When available, surgical resection specimens were compared to pretreatment imaging findings. Historic HNSCC tumor specimens were assessed for both SSTR and p16/human papilloma virus (HPV) expression. Results Twenty patients were imaged. Fifteen had oropharyngeal cancer. Primary tumor site was concordant between imaging modalities for all patients. One of 45 lymph nodes was discordant. Retrospective specimen review showed a significant correlation with SSTR expression and HPV/p16 expression. No adverse events occurred. Conclusions 68Ga-DOTATATE imaging is safe and effective in HNSCC. SSTR expression may be increased in HPV-mediated tumors. Targeted therapies to SSTR should be explored. View on Web

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