Κυριακή 20 Νοεμβρίου 2022

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

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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.

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

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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.

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The effect of SARS‐CoV‐2 infection on cardiac function in post‐COVID‐19 survivors: A systematic review and meta‐analysis

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Abstract

Objective

The longitudinal trajectories of cardiac structure and function following SARS-CoV-2 infection are unclear. Therefore, this meta-analysis aims to elucidate the effect of SARS-CoV-2 infection on cardiac function in COVID-19 survivors after recovery.

Methods

PubMed/MEDLINE, CENTRAL, and EMBASE were systematically searched for articles published up to 1st August 2022. A systematic review and meta-analysis were performed to calculate the pooled effects size and 95% confidence interval (CI) of each outcome.

Results

Twenty-one studies including 2394 individuals (1436 post-COVID-19 cases and 958 controls) were included in the present meta-analysis. The pooled analyses compared with control groups showed a significant association between post-COVID-19 and reduced left ventricular ejection fraction (LV EF), LV end-diastolic volume (LV EDV), LV stroke volume (LV SV), mitral annular plane systolic excursion (MAPSE), global longitudinal strain (GLS), right ventricular EF (RV EF), RV EDV, RV ESV, RV SV, tricuspid annular plane systolic excursion (TAPSE), and increased LV mass. Subgroup analysis based on the severity of COVID-19 in the acute phase and subsequent chronic outcomes revealed that LV EF, MAPSE, RV EF, and RV ESV only decreased in studies including patients with a history of intensive care unit (ICU) admission.

Conclusion

Cardiac impairment after SARS-CoV-2 infection persisted in recovered COVID-19 patients even after one year. Future studies are warranted to determine the biological mechanisms underlying the long-term cardiovascular consequences of COVID-19.

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

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

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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.
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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

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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.
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Pediatric cancer‐associated thrombosis

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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.
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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

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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.
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