scholarly journals Cerebral Glioblastoma: A Review on Genetic Alterations, Signaling Pathways, and Clinical Management

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Nima Hasanzadeh ◽  
Azadeh Niknejad
Keyword(s):  
Radiation Therapy ◽  
Signaling Pathways ◽  
Tp53 Mutation ◽  
Genetic Alterations ◽  
Idh1 Mutation ◽  
Review Article ◽  
Cellular Mechanisms ◽  
Isocitrate Dehydrogenase 1 ◽  
Secondary Glioblastoma ◽  
Cellular Pathways

Context: Glioblastoma, previously known as glioblastoma multiforme (GBM), is a grade IV astrocytoma common in patients over the age of 45, on average. It is generally categorized into primary and secondary subtypes, based on research conducted by Hans Joachim Scherer. Evidence Acquisition: This review concentrates on cellular and genetic drawbacks that can lead to the appearance of glioblastoma. National Center for Biotechnology Information (NCBI) was the main source used for writing this review article, followed by Google scholar. The following keywords were used to retrieve articles: 'glioblastoma', 'brain tumors', 'glioma', 'LOH', and 'cellular and signaling pathways in glioblastoma'. Results: Several genetic alterations and cellular pathways are involved in the appearance and progression of glioblastoma, including loss of heterozygosity (LoH), TP53 mutation, isocitrate dehydrogenase 1 (IDH1) mutation, P16INK4/RB1 pathway, and EGFR/PTEN/Akt/mTOR pathway. The majority (70%) of primary glioblastomas are caused by (LoH), and it mostly occurs in older people. Secondary glioblastoma is mainly manifested by TP53 mutation and usually affects younger people. Understanding the alterations and cellular mechanisms involved in glioblastoma is important to develope new therapeutic regimes. Surgery, radiation therapy, temozolomide, and TTFields are the four most important therapeutic options available for treating patients. Conclusions: In this review, the genetic alterations and cellular pathways which could lead to the appearance of this tumor were highlighted, and the latest options for treating patients dealing with glioblastoma were discussed.

scholarly journals IDH1 Mutation in Gliomas in Mosul City - Iraq

2015 ◽  
Vol 3 (2) ◽  
pp. 250-255 ◽  
Author(s):  
Mohammed Sami Saeed
Keyword(s):  
Case Series ◽  
Idh1 Mutation ◽  
Teaching Hospitals ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Secondary Glioblastoma ◽  
Idh1 R132h ◽  
Case Series Study ◽  
Idh1 Mutations ◽  
Prospective Case Series

BACKGROUND: IDH1 (isocitrate dehydrogenase 1) mutation might be encounter in the low grade glioma and directs the progression of the tumor to a higher grade.OBJECTIVE: To assess the frequency of IDH1 mutations in gliomas and to correlate the IDH1 positivity with the type and grade of tumors, the age and sex of the patients.MATERIAL AND METHODS: A retro– and prospective case series study. One hundred and nine cases of intracranial gliomas were collected between 2008 and 2014 from Mosul Private Laboratories and Al-Jamboree Teaching Hospitals in Mosul. IDH1 mutations were assessed immunohistochemically using anti-IDH1 R132H mouse monoclonal antibody.RESULTS: IDH1 mutation was perceived in 34.86% of gliomas. In adult gliomas, the secondary glioblastoma and the low-grade astrocytoma had the greatest values of IDH1 positivity (88.88% and 62.5% respectively), followed by oligoastrocytoma/oligodendroglioma (50.0%), and anaplastic astrocytoma (47.36%). The primary glioblastomsa showed 17.64% IDH1 positivity. Males and females expressed the IDH1 equally. While, there was no role of IDH1 in pediatric gliomas.CONCLUSION: IDH1 mutation is commonly present in adult gliomas particularly in low-grade gliomas, and secondary glioblastoma, with equal sex distribution, but it has no role in pediatric gliomas.

Biological role of AKT, and regulation of AKT signaling pathway by thymoquinone: perspectives in cancer therapeutics

2020 ◽  
Vol 20 ◽  
Author(s):  
Md. Junaid ◽  
Yeasmin Akter ◽  
Syeda Samira Afrose ◽  
Mousumi Tania ◽  
Md. Asaduzzaman Khan
Keyword(s):  
Clinical Trials ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Inhibitory Effect ◽  
Akt Signaling ◽  
Review Article ◽  
Therapeutic Drug ◽  
Akt Signaling Pathway ◽  
Anti Cancer

Background: AKT/PKB is an important enzyme with numerous biological functions, and its overexpression is related to the carcinogenesis. AKT stimulates different signaling pathways that are downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase, hence functions as an important target for anti-cancer drugs. Objective: In this review article, we have interpreted the role of AKT signaling pathways in cancer and natural inhibitory effect of Thymoquinone (TQ) in AKT and its possible mechanism. Method: We have collected the updated information and data on AKT, their role in cancer and inhibitory effect of TQ in AKT signaling pathway from google scholar, PubMed, Web of Science, Elsevier, Scopus and many more. Results: There are many drugs already developed, which can target AKT, but very few among them have passed clinical trials. TQ is a natural compound, mainly found in black cumin, which has been found to have potential anti-cancer activities. TQ targets numerous signaling pathways, including AKT, in different cancers. In fact, many studies revealed that AKT is one of the major targets of TQ. The preclinical success of TQ suggests its clinical studies on cancer. Conclusion: This review article summarizes the role of AKT in carcinogenesis, its potent inhibitors in clinical trials, and how TQ acts as an inhibitor of AKT and TQ’s future as a cancer therapeutic drug.

scholarly journals A Phase Ib Clinical Trial of Metformin and Chloroquine in Patients with IDH1-Mutated Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2474
Author(s):  
Mohammed Khurshed ◽  
Remco J. Molenaar ◽  
Myra E. van Linde ◽  
Ron A. Mathôt ◽  
Eduard A. Struys ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Intrahepatic Cholangiocarcinoma ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Idh1 Mutation ◽  
Resonance Spectroscopy ◽  
Isocitrate Dehydrogenase 1 ◽  
Who Grade ◽  
Phase Ib

Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid IDH1-mutated tumors produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are more vulnerable to disruption of their metabolism. Methods: Patients with IDH1-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with the antidiabetic drug metformin and the antimalarial drug chloroquine. The primary objective was to determine the occurrence of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Radiological and biochemical tumor responses to metformin and chloroquine were investigated using CT/MRI scans and magnetic resonance spectroscopy (MRS) measurements of D-2HG levels in serum. Results: Seventeen patients received study treatment for a median duration of 43 days (range: 7–74 days). Of twelve evaluable patients, 10 patients discontinued study medication because of progressive disease and two patients due to toxicity. None of the patients experienced a DLT. The MTD was determined to be 1500 mg of metformin two times a day and 200 mg of chloroquine once a day. A serum D/L-2HG ratio of ≥4.5 predicted the presence of an IDH1 mutation with a sensitivity of 90% and a specificity of 100%. By utilization of digital droplet PCR on plasma samples, we were able to detect tumor-specific IDH1 hotspot mutations in circulating tumor DNA (ctDNA) in investigated patients. Conclusion: Treatment of advanced IDH1-mutated solid tumors with metformin and chloroquine was well tolerated but did not induce a clinical response in this phase Ib clinical trial.

scholarly journals NCOG-38. CLINICAL CHARACTERISTICS OF LOW GRADE GLIOMA PATIENTS WITH NON-CANONICAL IDH1 AND IDH2 MUTATIONS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii137-ii137
Author(s):  
Katherine Peters ◽  
Eric Lipp ◽  
Gloria Broadwater ◽  
James Herndon ◽  
Margaret Johnson ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Point Mutations ◽  
Progression Free Survival ◽  
Idh1 Mutation ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Who Grade ◽  
Targeted Mutation ◽  
Kaplan Meier ◽  
Idh1 And Idh2 Mutations

Abstract BACKGROUND Low grade gliomas (LGGs) develop in young adults and represent 10-15% of all glial tumors. While LGG patients can have longer survival than higher grade tumors, progression, transformation, and ultimately mortality occurs. Mutations in Isocitrate dehydrogenase 1/2 (IDH1/IDH2) are prevalent in LGG and are responsible for gliomagenesis. The classic IDH1 mutation is located at 132 codon and represented as p.Arg132His, but there are non-canonical IDH1 and IDH2 mutations. We sought to compare clinical characteristics of LGG patients with classic IDH1 p.Arg132His mutation to LGG patients with non-canonical IDH1 and IDH2 mutations. METHODS We queried an IRB-approved registry retrospectively from 12/2004- 9/2019. We included IDH1/IDH2 mutant LGG (WHO grade II) and known IDH1 and IDH2 targeted mutation analysis using standard PCR followed by DNA sequencing to detect point mutations in IDH1/IDH2 genes. We obtained available clinical and histopathological data. We estimated progression-free survival (PFS), time to transformation (TT), and overall survival (OS) using Kaplan-Meier methods. RESULTS We identified 267 LGG patients with median follow-up of 9.1 yrs (95%CI 8.4-9.9 yrs). Classic IDH1 p.Arg132His mutation occurred in 223 (83.9%) patients. IDH2 mutations occurred in 14 (5.2%) patients. Non-canonical IDH1 mutations were in 30 (11.2%) patients and included the following mutations: p.Arg132Cys (13), p.Arg132Gly (10), p.Arg132Ser (4), p.Arg132Leu (1), p.Arg119Gln (1), and p.Arg172Met (1). Initial presentation, OS, and TT did not differ between IDH1/IDH2 groups. PFS differed significantly between groups with improved median PFS in IDH2 mutant LGG (5.4 yrs; 95%CI 3.5-25.2) versus classic IDH1 mutant LGG (4.1 yrs; 95%CI 3.7-4.9 yrs) and non-canonical IDH1 mutant LGG (2.6 yrs; 95%CI 2.1-4.8) (log-rank p=0.019). Notably, non-canonical mutations were more common in astrocytoma (22/30; 73.3%) than other LGG histologies (p=0.018). CONCLUSIONS In this cohort, LGG patients with non-canonical mutations have a shorter time to progression than patients with classic p.Arg132His mutation and IDH2 mutations.

DISTANCE-WISE PATHWAY DISCOVERY FROM PROTEIN–PROTEIN INTERACTION NETWORKS WEIGHTED BY SEMANTIC SIMILARITY

2014 ◽  
Vol 12 (01) ◽  
pp. 1450004 ◽  
Author(s):  
SLAVKA JAROMERSKA ◽  
PETR PRAUS ◽  
YOUNG-RAE CHO
Keyword(s):  
Signaling Pathways ◽  
Semantic Similarity ◽  
Protein Interaction ◽  
Protein Pair ◽  
Semantic Analysis ◽  
Topological Analysis ◽  
Cellular Mechanisms ◽  
Semantic Similarity Measure ◽  
Protein Protein Interaction ◽  
Ppi Networks

Reconstruction of signaling pathways is crucial for understanding cellular mechanisms. A pathway is represented as a path of a signaling cascade involving a series of proteins to perform a particular function. Since a protein pair involved in signaling and response have a strong interaction, putative pathways can be detected from protein–protein interaction (PPI) networks. However, predicting directed pathways from the undirected genome-wide PPI networks has been challenging. We present a novel computational algorithm to efficiently predict signaling pathways from PPI networks given a starting protein and an ending protein. Our approach integrates topological analysis of PPI networks and semantic analysis of PPIs using Gene Ontology data. An advanced semantic similarity measure is used for weighting each interacting protein pair. Our distance-wise algorithm iteratively selects an adjacent protein from a PPI network to build a pathway based on a distance condition. On each iteration, the strength of a hypothetical path passing through a candidate edge is estimated by a local heuristic. We evaluate the performance by comparing the resultant paths to known signaling pathways on yeast. The results show that our approach has higher accuracy and efficiency than previous methods.

scholarly journals The Impact of IDH1 Mutation and MGMT Promoter Methylation on Recurrence-Free Interval in Glioblastoma Patients Treated With Radiotherapy and Chemotherapeutic Agents

2021 ◽  
Vol 27 ◽  
Author(s):  
Maher Kurdi ◽  
Nadeem Shafique Butt ◽  
Saleh Baeesa ◽  
Badrah Alghamdi ◽  
Yazid Maghrabi ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Tumor Recurrence ◽  
Dna Methyltransferase ◽  
Chemotherapeutic Agents ◽  
Idh1 Mutation ◽  
Treatment Modalities ◽  
Isocitrate Dehydrogenase 1 ◽  
Free Interval ◽  
Significant Difference ◽  
The Impact

The aim of this study is to investigate the relationship between isocitrate dehydrogenase-1 (IDH1) mutation and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with recurrence-free interval in glioblastoma patients treated with chemoradiotherapies. Clinical data were collected from 82 patients with totally resected glioblastoma and treated with adjuvant therapies from 2014 to 2019. IDH1 mutation was assessed by immunohistochemistry and MGMT promoter methylation was assessed by different sequencing methods. IDH1 mutation was present in 32 cases and 50 cases were IDH1 wildtype; 54 and 28 patients had unmethylated and methylated MGMT promoter, respectively, Of the 82 patients, 62 patients received chemoradiotherapy while 20 patients only received radiation. Approximately, 61% of patients had a tumor recurrence after 1 year, and 39% showed a recurrence before 1 year of treatment. There was no significant relationship between IDH1 mutation and MGMT promoter methylation (p-value = 0.972). Patients with IDH1 mutation and their age <50 years showed a significant difference in recurrence-free interval (p-value = 0.014). Difference in recurrence-free interval was also statistically observed in patients with unmethylated MGMT promoter and treated with chemoradiotherapies (p-value = 0.031), by which they showed a late tumor recurrence (p-value = 0.016). This revealed that IDH1 mutation and MGMT methylation are independent prognostic factors in glioblastoma. Although IDH1-mutant glioblastomas showed late tumor recurrence in patients less than 50 years old, the type of treatment modalities may not show additional beneficial outcome. Patients with unmethylated MGMT and IDH1 mutation, treated with different chemoradiotherapies, showed a late tumor recurrence.

scholarly journals Molecular Signaling and Cellular Pathways for Virus Entry

ISRN Virology ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Pei-I Chi ◽  
Hung-Jen Liu
Keyword(s):  
Signaling Pathways ◽  
Viral Entry ◽  
Virus Entry ◽  
Host Cells ◽  
Target Cells ◽  
Molecular Signaling ◽  
Cellular Processes ◽  
Cellular Pathways ◽  
Host Life ◽  
Endocytic Vesicles

The cell signaling plays a pivotal role in regulating cellular processes and is often manipulated by viruses as they rely on the functions offered by cells for their propagation. The first stage of their host life is to pass the genetic materials into the cell. Although some viruses can directly penetrate into cytosol, in fact, most virus entry into their host cells is through endocytosis. This machinery initiates with cell type specific cellular signaling pathways, and the signaling compounds can be proteins, lipids, and carbohydrates. The activation can be triggered in a very short time after virus binds on target cells, such as receptors. The signaling pathways involved in regulation of viral entry are wide diversity that often cross-talk between different endocytosis results. Furthermore, some viruses have the ability to use the multiple internalization pathways which leads to the regulation being even more complex. In this paper, we discuss some recent advances in our understanding of cellular pathways for virus entry, molecular signaling during virus entry, formation of endocytic vesicles, and the traffic.

scholarly journals Herpes simplex virus triggers activation of calcium-signaling pathways

2003 ◽  
Vol 163 (2) ◽  
pp. 283-293 ◽  
Author(s):  
Natalia Cheshenko ◽  
Brian Del Rosario ◽  
Craig Woda ◽  
Daniel Marcellino ◽  
Lisa M. Satlin ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Signaling Pathways ◽  
Focal Adhesion ◽  
Calcium Concentration ◽  
Pharmacological Agents ◽  
Viral Therapy ◽  
Cellular Pathways ◽  
Simplex Virus ◽  
Anti Viral Therapy

The cellular pathways required for herpes simplex virus (HSV) invasion have not been defined. To test the hypothesis that HSV entry triggers activation of Ca2+-signaling pathways, the effects on intracellular calcium concentration ([Ca2+]i) after exposure of cells to HSV were examined. Exposure to virus results in a rapid and transient increase in [Ca2+]i. Pretreatment of cells with pharmacological agents that block release of inositol 1,4,5-triphosphate (IP3)–sensitive endoplasmic reticulum stores abrogates the response. Moreover, treatment of cells with these pharmacological agents inhibits HSV infection and prevents focal adhesion kinase (FAK) phosphorylation, which occurs within 5 min after viral infection. Viruses deleted in glycoprotein L or glycoprotein D, which bind but do not penetrate, fail to induce a [Ca2+]i response or trigger FAK phosphorylation. Together, these results support a model for HSV infection that requires activation of IP3-responsive Ca2+-signaling pathways and that is associated with FAK phosphorylation. Defining the pathway of viral invasion may lead to new targets for anti-viral therapy.

scholarly journals Understanding MAPK Signaling Pathways in Apoptosis

2020 ◽  
Vol 21 (7) ◽  
pp. 2346 ◽  
Author(s):  
Jicheng Yue ◽  
José M. López
Keyword(s):  
Signaling Pathways ◽  
Positive Feedback ◽  
Cell Model ◽  
Mapk Signaling ◽  
Feedback Loops ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Mechanisms ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis ◽  
Mapk Signaling Pathways

MAPK (mitogen-activated protein kinase) signaling pathways regulate a variety of biological processes through multiple cellular mechanisms. In most of these processes, such as apoptosis, MAPKs have a dual role since they can act as activators or inhibitors, depending on the cell type and the stimulus. In this review, we present the main pro- and anti-apoptotic mechanisms regulated by MAPKs, as well as the crosstalk observed between some MAPKs. We also describe the basic signaling properties of MAPKs (ultrasensitivity, hysteresis, digital response), and the presence of different positive feedback loops in apoptosis. We provide a simple guide to predict MAPKs’ behavior, based on the intensity and duration of the stimulus. Finally, we consider the role of MAPKs in osmostress-induced apoptosis by using Xenopus oocytes as a cell model. As we will see, apoptosis is plagued with multiple positive feedback loops. We hope this review will help to understand how MAPK signaling pathways engage irreversible cellular decisions.

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