scholarly journals PATH-65. MOLECULAR SIGNATURE OF FAT1 RELATED MOLECULES IN GLIOMAS IN THE CONTEXT OF THE WHO 2016 CLASSIFICATION

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi158-vi158
Author(s):  
Kunzang Chosdol ◽  
Manvi Arora ◽  
Nargis Malik ◽  
Prerana Jha ◽  
Jyotsna Singh ◽  
...  
Keyword(s):  
Molecular Markers ◽  
In Silico Analysis ◽  
Molecular Signature ◽  
World Health ◽  
Low Grade ◽  
Who Grade ◽  
Inflammatory Microenvironment ◽  
Molecular Features

Abstract Glioblastoma (GBM, WHO grade-IV) being the most malignant and aggressive form of glioma remains a major clinical challenge, with an overall 5-year survival rate of only 9.8%. Till recently, glioma diagnosis and grading were solely dependent on the phenotypic and histological features. However, with the advancement in the understanding of the molecular biology of glioma several molecules have been identified. The importance of these molecular/genotypic features of the tumor became evident by the inclusion of these molecular features by World Health Organization (WHO) in 2016 in glioma sub-grouping. Our lab is focused on studying the role of FAT1 gene (human ortholog of Drosophila tumor suppressor gene, fat) in glioma biology and aggressiveness. We observed FAT1 gene to have an oncogenic role in glioma where it has been found to upregulate migration/invasion, inflammatory microenvironment of the tumors, HIF1α expression/activity in the tumor-cells under severe hypoxia and in regulating EMT/stemness properties of GBM-cells under hypoxia. Here, we have characterized the molecular relationship between FAT1 related molecules and known- molecular markers of glioma with the hope of identifying glioma subgroup with a molecular signature of clinical significance by (i) analyzing the expression correlation of FAT1 and FAT1 regulated pro-inflammatroy molecules like COX2, IL1b and IL6 with the known- molecular markers of glioma like p53, IDH1, MGMT, EGFR, TERT in low-grade (grade-II) and high-grade (grade-III/IV) gliomas (n=50) by real-time PCR, sequencing, immunohistochemistry and in-silico analysis of TCGA-GBM-data (ii) Analyzed the regulatory role of FAT1 on the above known markers by siRNA mediated knockdown of FAT1 in in-vitro cell-culture system and (iii) further analyzed the identified molecular signature for their correlation with the patients prognosis/survival in the follow up patients. We observed a novel molecular signature with significant correlation with patients’ clinical outcome. Therapeutic targetting of FAT1 may benefit patients with high FAT1 expressing tumors.

scholarly journals BIOM-15. SUBVENTRICULAR ZONE INVOLVEMENT IS ASSOCIATED WITH WORSE OUTCOME IN GLIOMA WHO GRADE II INDEPENDENT OF MOLECULAR MARKERS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii4-ii5
Author(s):  
Philipp Karschnia ◽  
Jonathan Weller ◽  
Jens Blobner ◽  
Veit M Stoecklein ◽  
Mario M Dorostkar ◽  
...  
Keyword(s):  
Overall Survival ◽  
Molecular Markers ◽  
Subventricular Zone ◽  
Malignant Progression ◽  
Molecular Signature ◽  
Low Grade ◽  
First Line ◽  
Who Grade ◽  
Early Therapy ◽  
Grade Ii

Abstract BACKGROUND The subventricular zone represents a niche of adult neural stem cells. Involvement of the subventricular zone is associated with decreased survival in malignant glioma. We aimed to determine whether a similar association applies to low-grade gliomas. METHODS A retrospective institutional database search was performed for patients with glioma WHO grade II according to the 2016 classification. Demographic data, histology and molecular signature, imaging, and therapy were recorded and outcome was analysed for tumors with and without infiltration of the subventricular zone. RESULTS 182 patients with glioma WHO grade II were identified, including 97 oligodendrogliomas and 85 astrocytomas. 78 of 182 patients (43%) presented with subventricular zone involvement. Demographics, histopathology, and molecular signature did not differ between patients with and without subventricular zone involvement. First-line management included surgery, chemotherapy, radiotherapy, brachytherapy, and wait-and-scan approaches. Median follow-up was 43 months. Median time to malignant progression was 122 months; median overall survival was not reached. Subventricular zone involvement was a negative prognostic marker for time to malignant progression (p = 0.002) and overall survival (p = 0.023) in the entire cohort as well as in the subgroup of patients who were managed with wait-and-scan approaches. Among patients in which early therapy was provided, subventricular zone involvement was not prognostic for overall survival but for time to malignant progression. In multivariate analysis, subventricular zone involvement was associated with worse prognosis independent of molecular markers or treatment approaches including use of resection. CONCLUSION Subventricular zone involvement represents a key risk factor for worse outcome in glioma WHO grade II. Early first-line therapy may improve outcome in such patients.

Treatment Options in COVID-19: The Role of Bioavailable Antiviral Ribonucleoside Analog on NHC in vitro

2020 ◽  
Author(s):  
Lara Bittmann
Keyword(s):  
World Health Organization ◽  
Clinical Picture ◽  
Treatment Options ◽  
World Health ◽  
Wuhan City ◽  
The World ◽  
Novel Coronavirus ◽  
Health Organization

On December 31, 2019, WHO was informed of cases of pneumonia of unknown cause in Wuhan City, China. A novel coronavirus was identified as the cause by Chinese authorities on January 7, 2020 and was provisionally named "2019-nCoV". This new Coronavirus causes a clinical picture which has received now the name COVID-19. The virus has spread subsequently worldwide and was explained on the 11th of March, 2020 by the World Health Organization to the pandemic.

scholarly journals A 25-year retrospective, single center analysis of 343 WHO grade II/III glioma patients: implications for grading and temozolomide therapy

2021 ◽  
Author(s):  
Eike Steidl ◽  
Katharina Filipski ◽  
Pia S. Zeiner ◽  
Marlies Wagner ◽  
Emmanouil Fokas ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Molecular Markers ◽  
Treatment Time ◽  
Real Life ◽  
Patient Characteristics ◽  
Low Grade ◽  
Who Grade ◽  
Idh1 R132h ◽  
Treatment Data ◽  
Grade Ii

Abstract Purpose Classification and treatment of WHO grade II/III gliomas have dramatically changed. Implementing molecular markers into the WHO classification raised discussions about the significance of grading and clinical trials showed overall survival (OS) benefits for combined radiochemotherapy. As molecularly stratified treatment data outside clinical trials are scarce, we conducted this retrospective study. Methods We identified 343 patients (1995–2015) with newly diagnosed WHO grade II/III gliomas and analyzed molecular markers, patient characteristics, symptoms, histology, treatment, time to treatment failure (TTF) and OS. Results IDH-status was available for all patients (259 mutant, 84 IDH1-R132H-non-mutant). Molecular subclassification was possible in 173 tumors, resulting in diagnosis of 80 astrocytomas and 93 oligodendrogliomas. WHO grading remained significant for OS in astrocytomas/IDH1-R132H-non-mutant gliomas (p < 0.01) but not for oligodendroglioma (p = 0.27). Chemotherapy (and temozolomide in particular) showed inferior OS compared to radiotherapy in astrocytomas (median 6.1/12.1 years; p = 0.03) and oligodendrogliomas (median 13.2/not reached (n.r.) years; p = 0.03). While radiochemotherapy improved TTF in oligodendroglioma (median radiochemotherapy n.r./chemotherapy 3.8/radiotherapy 7.3 years; p < 0.001/ = 0.06; OS data immature) the effect, mainly in combination with temozolomide, was weaker in astrocytomas (median radiochemotherapy 6.7/chemotherapy 2.3/radiotherapy 2.0 years; p < 0.001/ = 0.11) and did not translate to improved OS (median 8.4 years). Conclusion This is one of the largest retrospective, real-life datasets reporting treatment and outcome in low-grade gliomas incorporating molecular markers. Current histologic grading features remain prognostic in astrocytomas while being insignificant in oligodendroglioma with interfering treatment effects. Chemotherapy (temozolomide) was less effective than radiotherapy in both astrocytomas and oligodendrogliomas while radiochemotherapy showed the highest TTF in oligodendrogliomas.

scholarly journals Pan-cancer analysis reveals tumor-associated macrophage communication in the tumor microenvironment

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Linbang Wang ◽  
Tao He ◽  
Jingkun Liu ◽  
Jiaojiao Tai ◽  
Bing Wang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Hub Genes ◽  
Tumor Associated Macrophage ◽  
Molecular Features ◽  
Receptor Interactions ◽  
Tumor Types ◽  
Pan Cancer

Abstract Background Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment (TME). However, their contribution to the immunosuppressive status of the TME remains unclear. Methods We integrated single-cell sequencing and transcriptome data from different tumor types to uncover the molecular features of TAMs. In vitro experiments and prospective clinical tests confirmed the results of these analysis. Results We first detected intra- and inter-tumoral heterogeneities between TAM subpopulations and their functions, with CD86+ TAMs playing a crucial role in tumor progression. Next, we focused on the ligand-receptor interactions between TAMs and tumor cells in different TME phenotypes and discovered that aberrant expressions of six hub genes, including FLI1, are involved in this process. A TAM-tumor cell co-culture experiment proved that FLI1 was involved in tumor cell invasion, and FLI1 also showed a unique pattern in patients. Finally, TAMs were discovered to communicate with immune and stromal cells. Conclusion We determined the role of TAMs in the TME by focusing on their communication pattern with other TME components. Additionally, the screening of hub genes revealed potential therapeutic targets.

scholarly journals The Role of Extent of Resection in IDH1 Wild-Type or Mutant Low-Grade Gliomas

Neurosurgery ◽  
2017 ◽  
Vol 82 (6) ◽  
pp. 808-814 ◽  
Author(s):  
Toral Patel ◽  
Evan D Bander ◽  
Rachael A Venn ◽  
Tiffany Powell ◽  
Gustav Young-Min Cederquist ◽  
...  
Keyword(s):  
Cox Regression ◽  
Extent Of Resection ◽  
World Health ◽  
Low Grade ◽  
Wild Type ◽  
Who Grade ◽  
Cox Regression Analysis ◽  
Low Grade Gliomas ◽  
Grade Ii ◽  
The Impact

Abstract BACKGROUND Maximizing extent of resection (EOR) improves outcomes in adults with World Health Organization (WHO) grade II low-grade gliomas (LGG). However, recent studies demonstrate that LGGs bearing a mutation in the isocitrate dehydrogenase 1 (IDH1) gene are a distinct molecular and clinical entity. It remains unclear whether maximizing EOR confers an equivalent clinical benefit in IDH mutated (mtIDH) and IDH wild-type (wtIDH) LGGs. OBJECTIVE To assess the impact of EOR on malignant progression-free survival (MPFS) and overall survival (OS) in mtIDH and wtIDH LGGs. METHODS We performed a retrospective review of 74 patients with WHO grade II gliomas and known IDH mutational status undergoing resection at a single institution. EOR was assessed with quantitative 3-dimensional volumetric analysis. The effect of predictor variables on MPFS and OS was analyzed with Cox regression models and the Kaplan–Meier method. RESULTS Fifty-two (70%) mtIDH patients and 22 (30%) wtIDH patients were included. Median preoperative tumor volume was 37.4 cm3; median EOR of 57.6% was achieved. Univariate Cox regression analysis confirmed EOR as a prognostic factor for the entire cohort. However, stratifying by IDH status demonstrates that greater EOR independently prolonged MPFS and OS for wtIDH patients (hazard ratio [HR] = 0.002 [95% confidence interval {CI} 0.000-0.074] and HR = 0.001 [95% CI 0.00-0.108], respectively), but not for mtIDH patients (HR = 0.84 [95% CI 0.17-4.13] and HR = 2.99 [95% CI 0.15-61.66], respectively). CONCLUSION Increasing EOR confers oncologic and survival benefits in IDH1 wtLGGs, but the impact on IDH1 mtLGGs requires further study.

scholarly journals Piezo1-Mediated Mechanotransduction Promotes Cardiac Hypertrophy by Impairing Calcium Homeostasis to Activate Calpain/Calcineurin Signaling

Hypertension ◽  
2021 ◽  
Author(s):  
Yuhao Zhang ◽  
Sheng-an Su ◽  
Wudi Li ◽  
Yuankun Ma ◽  
Jian Shen ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Ion Channel ◽  
Calcium Homeostasis ◽  
Pressure Overload ◽  
Cell Physiology ◽  
Hypertrophic Growth ◽  
Molecular Features ◽  
Mechanosensitive Ion Channel

Hemodynamic overload induces pathological cardiac hypertrophy, which is an independent risk factor for intractable heart failure in long run. Beyond neurohumoral regulation, mechanotransduction has been recently recognized as a major regulator of cardiac hypertrophy under a myriad of conditions. However, the identification and molecular features of mechanotransducer on cardiomyocytes are largely sparse. For the first time, we identified Piezo1 (Piezo type mechanosensitive ion channel component 1), a novel mechanosensitive ion channel with preference to Ca 2+ was remarkably upregulated under pressure overload and enriched near T-tubule and intercalated disc of cardiomyocyte. By applying cardiac conditional Piezo1 knockout mice (Piezo1 fl/fl Myh6Cre+, Piezo1 Cko ) undergoing transverse aortic constriction, we demonstrated that Piezo1 was required for the development of cardiac hypertrophy and subsequent adverse remodeling. Activation of Piezo1 by external mechanical stretch or agonist Yoda1 lead to the enlargement of cardiomyocytes in vitro, which was blocked by Piezo1 silencing or Yoda1 analog Dooku1 or Piezo1 inhibitor GsMTx4. Mechanistically, Piezo1 perturbed calcium homeostasis, mediating extracellular Ca 2+ influx and intracellular Ca 2+ overload, thereby increased the activation of Ca 2+ -dependent signaling, calcineurin, and calpain. Inhibition of calcineurin or calpain could abolished Yoda1 induced upregulation of hypertrophy markers and the hypertrophic growth of cardiomyocytes in vitro. From a comprehensive view of the cardiac transcriptome, most of Piezo1 affected genes were highly enriched in muscle cell physiology, tight junction, and corresponding signaling. This study characterizes an undefined role of Piezo1 in pressure overload induced cardiac hypertrophy. It may partially decipher the differential role of calcium under pathophysiological condition, implying a promising therapeutic target for cardiac dysfunction.

miR-9-1 Is a New Circulating Biomarker for Higher-grade Meningioma Regulated via the EGFR-FOS Network

2020 ◽  
Author(s):  
Daniele Baiz ◽  
Caterina Negroni ◽  
Sara Ferluga ◽  
Emanuela Ercolano ◽  
Claire L Adams ◽  
...  
Keyword(s):  
Tumor Grade ◽  
World Health ◽  
Tumor Growth Rate ◽  
Low Grade ◽  
Serum Samples ◽  
Circulating Biomarker ◽  
Mirna Array ◽  
Malignant Grade ◽  
Health Organization

Abstract Background: Meningiomas are the most common primary CNS tumors. According to the World Health Organization Classification (WHO), they are classified as benign (grade I), atypical (grade II), and anaplastic/malignant (grade III). Chemotherapy has proven ineffective in treating these tumors, which are primarily managed by surgery, radiotherapy, or a combination of them. Morbidity and mortality correlate with meningioma grade. Currently, risk assessment for treatment is based on the radiological assessment of tumor size, tumor growth rate, and/or clinical progression of symptoms. Methods: We performed a cancer miRNA array in an in vitro model of meningioma in order to identify circulating biomarkers in meningioma patients. We validated the miRNA biomarker candidate in cells and tissues and analyzed its regulation. We then investigated expression in tissues and blood. Results: We identified miR-9-1 as significantly overexpressed in atypical and anaplastic cells compared to benign. We further demonstrated that miR-9-1 overexpression is due to increased levels of FOS via upregulation of the EGFR receptor, and showed that miR-9-1 and FOS are upregulated in a cohort of higher-grade meningioma biopsies. Next, we isolated circulating exosomes from meningioma patients’ serum samples, and found higher levels of miR-9-1 in higher-grade compared to low-grade meningiomas patients. Conclusions: Overall, our study shows overexpression and the mechanism of miR-9-1 regulation and suggests miR-9-1 as a novel circulating biomarker candidate to identify tumor grade in meningioma.

scholarly journals Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1

2017 ◽  
Vol 114 (40) ◽  
pp. 10743-10748 ◽  
Author(s):  
Tali Mazor ◽  
Charles Chesnelong ◽  
Aleksandr Pankov ◽  
Llewellyn E. Jalbert ◽  
Chibo Hong ◽  
...  
Keyword(s):  
Copy Number ◽  
Cpg Island ◽  
Clonal Expansion ◽  
Low Grade ◽  
Copy Number Alterations ◽  
Wild Type ◽  
Mutant Idh1

IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite d-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients mutant IDH1 and 2HG are not required for later clonal expansions.

Imaging in low-grade glioma: a guide for neurologists

2017 ◽  
Vol 18 (1) ◽  
pp. 27-34 ◽  
Author(s):  
Jennifer Larsen ◽  
Nigel Hoggard ◽  
Fiona M McKevitt
Keyword(s):  
Surgical Planning ◽  
World Health Organisation ◽  
Low Grade Glioma ◽  
World Health ◽  
Low Grade ◽  
The Central Nervous System ◽  
Contemporary Management

The management of low-grade glioma (LGG) is shifting as evidence has emergedthat refutes the previously commonplace imaging-based ‘watch and wait’ approach, in favour of early aggressive surgical resection. This coupled with the recent 2016 update to the World Health Organisation Classification of Tumours of the Central Nervous System is changing LGG imaging and management. Recently in Practical Neurology the contemporary management of low-grade glioma and the changes to this grading system were discussed in detail. 1 In this complementary article, we discuss the role of imaging in the diagnosis, surgical planning and post-treatment follow-up of LGG. We describe the principles of imaging these tumours and use several cases to highlight some difficult scenarios.

scholarly journals The miRNA Content of Exosomes Released from the Glioma Microenvironment Can Affect Malignant Progression

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 564
Author(s):  
Federica Caponnetto ◽  
Emiliano Dalla ◽  
Damiano Mangoni ◽  
Silvano Piazza ◽  
Slobodanka Radovic ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Bioactive Molecules ◽  
Low Grade ◽  
Anaplastic Transformation ◽  
Prognostic Stratification ◽  
Vitro Model ◽  
Mirna Content ◽  
Glioma Microenvironment

Low-grade gliomas (LGG) are infiltrative primary brain tumors that in 70% of the cases undergo anaplastic transformation, deeply affecting prognosis. However, the timing of progression is heterogeneous. Recently, the tumor microenvironment (TME) has gained much attention either as prognostic factor or therapeutic target. Through the release of extracellular vesicles, the TME contributes to tumor progression by transferring bioactive molecules such as microRNA. The aim of the study was to take advantage of glioma-associated stem cells (GASC), an in vitro model of the glioma microenvironment endowed with a prognostic significance, and their released exosomes, to investigate the possible role of exosome miRNAs in favoring the anaplastic transformation of LGG. Therefore, by deep sequencing, we analyzed and compared the miRNA profile of GASC and exosomes obtained from LGG patients characterized by different prognosis. Results showed that exosomes presented a different signature, when compared to their cellular counterpart and that, although sharing several miRNAs, exosomes of patients with a bad prognosis, selectively expressed some miRNAs possibly responsible for the more aggressive phenotype. These findings get insights into the value of TME and exosomes as potential biomarkers for precision medicine approaches aimed at improving LGG prognostic stratification and therapeutic strategies.

Sign in / Sign up

Export Citation Format

Share Document