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Abedalthagafi, Malak

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Abedalthagafi

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Malak

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Abedalthagafi, Malak

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2014 - 20189

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Author's Publications: search.filters.isAuthorOfPublication.33bf7701-9d2d-4863-9e64-be040148a8b0

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Now showing 1 - 9 of 9
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    Myelodysplastic syndrome with progressive multifocal predominantly pontine demyelination
    (Lippincott Williams & Wilkins, 2015) Bhattacharyya, Shamik; Wong, Janice C.; Abedalthagafi, Malak; Wahlster, Sarah; Vaitkevicius, Henrikas
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    Cancer diagnostics: The journey from histomorphology to molecular profiling
    (Impact Journals LLC, 2016) Ahmed, Atif A.; Abedalthagafi, Malak
    Although histomorphology has made significant advances into the understanding of cancer etiology, classification and pathogenesis, it is sometimes complicated by morphologic ambiguities, and other shortcomings that necessitate the development of ancillary tests to complement its diagnostic value. A new approach to cancer patient management consists of targeting specific molecules or gene mutations in the cancer genome by inhibitory therapy. Molecular diagnostic tests and genomic profiling methods are increasingly being developed to identify tumor targeted molecular profile that is the basis of targeted therapy. Novel targeted therapy has revolutionized the treatment of gastrointestinal stromal tumor, renal cell carcinoma and other cancers that were previously difficult to treat with standard chemotherapy. In this review, we discuss the role of histomorphology in cancer diagnosis and management and the rising role of molecular profiling in targeted therapy. Molecular profiling in certain diagnostic and therapeutic difficulties may provide a practical and useful complement to histomorphology and opens new avenues for targeted therapy and alternative methods of cancer patient management.
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    Osteoglycin promotes meningioma development through downregulation of NF2 and activation of mTOR signaling
    (BioMed Central, 2017) Mei, Yu; Du, Ziming; Hu, Changchen; Greenwald, Noah; Abedalthagafi, Malak; Agar, Nathalie Y.R.; Dunn, Gavin P.; Bi, Wenya; Santagata, Sandro; Dunn, Ian
    Background: Meningiomas are the most common primary intracranial tumors in adults. While a majority of meningiomas are slow growing neoplasms that may cured by surgical resection, a subset demonstrates more aggressive behavior and insidiously recurs despite surgery and radiation, without effective alternative treatment options. Elucidation of critical mitogenic pathways in meningioma oncogenesis may offer new therapeutic strategies. We performed an integrated genomic and molecular analysis to characterize the expression and function of osteoglycin (OGN) in meningiomas and explored possible therapeutic approaches for OGN-expressing meningiomas. Methods: OGN mRNA expression in human meningiomas was assessed by RNA microarray and RNAscope. The impact of OGN on cell proliferation, colony formation, and mitogenic signaling cascades was assessed in a human meningioma cell line (IOMM-Lee) with stable overexpression of OGN. Furthermore, the functional consequences of introducing an AKT inhibitor in OGN-overexpressing meningioma cells were assessed. Results: OGN mRNA expression was dramatically increased in meningiomas compared to a spectrum of other brain tumors and normal brain. OGN-overexpressing meningioma cells demonstrated an elevated rate of cell proliferation, cell cycle activation, and colony formation as compared with cells transfected with control vector. In addition, NF2 mRNA and protein expression were both attenuated in OGN-overexpressing cells. Conversely, mTOR pathway and AKT activation increased in OGN-overexpressing cells compared to control cells. Lastly, introduction of an AKT inhibitor reduced OGN expression in meningioma cells and resulted in increased cell death and autophagy, suggestive of a reciprocal relationship between OGN and AKT. Conclusion: We identify OGN as a novel oncogene in meningioma proliferation. AKT inhibition reduces OGN protein levels in meningioma cells, with a concomitant increase in cell death, which provides a promising treatment option for meningiomas with OGN overexpression. Electronic supplementary material The online version of this article (10.1186/s12964-017-0189-7) contains supplementary material, which is available to authorized users.
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    A case of molecularly profiled extraneural medulloblastoma metastases in a child
    (BioMed Central, 2018) Mobark, Nahla Ali; Al-Harbi, Musa; Mosleh, Othman; Santagata, Sandro; Snuderl, Matija; Abedalthagafi, Malak
    Background: Extraneural metastases are relatively rare manifestations of medulloblastoma. Case presentation: We present the case of a young boy with group three MYCN-amplified medulloblastoma. He received multimodal chemotherapy consisting of gross total resection followed by postoperative craniospinal radiation and adjuvant chemotherapy. The patient developed extraneural metastases 4 months after the end of therapy. Literature review identifies the poor prognosis of MYCN-amplified medulloblastomas as well as extraneural metastases; we review the current limitations and future directions of medulloblastoma treatment options. Conclusion: To the best of our knowledge, this is the first molecularly characterized report of extraneural metastases of medulloblastoma in a child.
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    Angiomatous meningiomas have a distinct genetic profile with multiple chromosomal polysomies including polysomy of chromosome 5
    (Impact Journals LLC, 2014) Abedalthagafi, Malak; Merrill, Parker H.; Bi, Wenya; Jones, Robert T.; Listewnik, Marc L.; Ramkissoon, Shakti H.; Thorner, Aaron R.; Dunn, Ian; Beroukhim, Rameen; Alexander, Brian; Brastianos, Priscilla; Francis, Joshua M.; Folkerth, Rebecca D.; Ligon, Keith; Hummelen, Paul Van; Ligon, Azra; Santagata, Sandro
    Meningiomas are a diverse group of tumors with a broad spectrum of histologic features. There are over 12 variants of meningioma, whose genetic features are just beginning to be described. Angiomatous meningioma is a World Health Organization (WHO) meningioma variant with a predominance of blood vessels. They are uncommon and confirming the histopathologic classification can be challenging. Given a lack of biomarkers that define the angiomatous subtype and limited understanding of the genetic changes underlying its tumorigenesis, we compared the genomic characteristics of angiomatous meningioma to more common meningioma subtypes. While typical grade I meningiomas demonstrate monosomy of chromosome 22 or lack copy number aberrations, 13 of 14 cases of angiomatous meningioma demonstrated a distinct copy number profile – polysomies of at least one chromosome, but often of many, especially in chromosomes 5, 13, and 20. WHO grade II atypical meningiomas with angiomatous features have both polysomies and genetic aberrations characteristic of other atypical meningiomas. Sequencing of over 560 cancer-relevant genes in 16 cases of angiomatous meningioma showed that these tumors lack common mutations found in other variants of meningioma. Our study demonstrates that angiomatous meningiomas have distinct genomic features that may be clinically useful for their diagnosis.
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    Sporadic hemangioblastomas are characterized by cryptic VHL inactivation
    (Springer Nature, 2014) Shankar, Ganesh; Taylor-Weiner, Amaro; Lelic, Nina; Jones, Robert T; Kim, James C; Francis, Joshua M; Abedalthagafi, Malak; Borges, Lawrence; Coumans, Jean-Valery; Curry, William; Nahed, Brian; Shin, John; Paek, Sun Ha; Park, Sung-Hye; Stewart, Chip; Lawrence, Michael S; Cibulskis, Kristian; Thorner, Aaron R; Van Hummelen, Paul; Stemmer-Rachamimov, Anat; Batchelor, Tracy; Carter, Scott; Hoang, Mai; Santagata, Sandro; Louis, David; Barker, Frederick; Meyerson, Matthew; Getz, Gad; Brastianos, Priscilla; Cahill, Daniel
    Hemangioblastomas consist of 10-20% neoplastic “stromal” cells within a vascular tumor cell mass of reactive pericytes, endothelium and lymphocytes. Familial cases of central nervous system hemangioblastoma uniformly result from mutations in the Von Hippel-Lindau (VHL) gene. In contrast, inactivation of VHL has been previously observed in only a minority of sporadic hemangioblastomas, suggesting an alternative genetic etiology. We performed deep-coverage DNA sequencing on 32 sporadic hemangioblastomas (whole exome discovery cohort n = 10, validation n = 22), followed by analysis of clonality, copy number alteration, and somatic mutation. We identified somatic mutation, loss of heterozygosity and/or deletion of VHL in 8 of 10 discovery cohort tumors. VHL inactivating events were ultimately detected in 78% (25/32) of cases. No other gene was significantly mutated. Overall, deep-coverage sequence analysis techniques uncovered VHL alterations within the neoplastic fraction of these tumors at higher frequencies than previously reported. Our findings support the central role of VHL inactivation in the molecular pathogenesis of both familial and sporadic hemangioblastomas.
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    Radiographic prediction of meningioma grade by semantic and radiomic features
    (Public Library of Science, 2017) Coroller, Thibaud; Bi, Wenya; Huynh, Elizabeth; Abedalthagafi, Malak; Aizer, Ayal A.; Greenwald, Noah; Parmar, Chintan; Narayan, Vivek; Wu, Winona; Miranda de Moura, Samuel; Gupta, Saksham; Beroukhim, Rameen; Wen, Patrick Y.; Al-Mefty, Ossama; Dunn, Ian; Santagata, Sandro; Alexander, Brian; Huang, Raymond; Aerts, Hugo
    Objectives: The clinical management of meningioma is guided by tumor grade and biological behavior. Currently, the assessment of tumor grade follows surgical resection and histopathologic review. Reliable techniques for pre-operative determination of tumor grade may enhance clinical decision-making. Methods: A total of 175 meningioma patients (103 low-grade and 72 high-grade) with pre-operative contrast-enhanced T1-MRI were included. Fifteen radiomic (quantitative) and 10 semantic (qualitative) features were applied to quantify the imaging phenotype. Area under the curve (AUC) and odd ratios (OR) were computed with multiple-hypothesis correction. Random-forest classifiers were developed and validated on an independent dataset (n = 44). Results: Twelve radiographic features (eight radiomic and four semantic) were significantly associated with meningioma grade. High-grade tumors exhibited necrosis/hemorrhage (ORsem = 6.6, AUCrad = 0.62–0.68), intratumoral heterogeneity (ORsem = 7.9, AUCrad = 0.65), non-spherical shape (AUCrad = 0.61), and larger volumes (AUCrad = 0.69) compared to low-grade tumors. Radiomic and sematic classifiers could significantly predict meningioma grade (AUCsem = 0.76 and AUCrad = 0.78). Furthermore, combining them increased the classification power (AUCradio = 0.86). Clinical variables alone did not effectively predict tumor grade (AUCclin = 0.65) or show complementary value with imaging data (AUCcomb = 0.84). Conclusions: We found a strong association between imaging features of meningioma and histopathologic grade, with ready application to clinical management. Combining qualitative and quantitative radiographic features significantly improved classification power.
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    Increased expression of the immune modulatory molecule PD-L1 (CD274) in anaplastic meningioma
    (Impact Journals LLC, 2015) Du, Ziming; Abedalthagafi, Malak; Aizer, Ayal A.; McHenry, Allison R.; Sun, Heather H.; Bray, Mark-Anthony; Viramontes, Omar; Machaidze, Revaz; Brastianos, Priscilla; Reardon, David; Dunn, Ian; Freeman, Gordon; Ligon, Keith; Carpenter, Anne E.; Alexander, Brian; Agar, Nathalie Y.; Rodig, Scott; Bradshaw, Elizabeth M.; Santagata, Sandro
    There are no effective medical treatments for WHO grade III (anaplastic) meningioma. Patients with this high-grade malignancy have a median survival of less than two years. Therapeutics that modulate the mechanisms that inhibit local immune responses in the tumor microenvironment are showing significant and durable clinical responses in patients with treatment refractory high-grade tumors. We examined the immune infiltrate of 291 meningiomas including WHO grade I-III meningiomas using immunohistochemistry and we examined the expression of PD-L1 mRNA by RNAscope in situ hybridization and PD-L1 protein by immunohistochemistry. In meningioma, the tumor infiltrating lymphocytes are predominantly T cells. In anaplastic meningioma, there is a sharp decrease in the number of T cells, including the numbers of CD4+ and CD8+ T cells and cells expressing PD-1 and there is also an increase in the number of FOXP3 expressing immunoregulatory (Treg) cells. PD-L1 expression is increased in anaplastic meningioma – both mRNA and protein. Using patient derived meningioma cell, we confirm that PD-L1 is expressed in meningioma cells themselves, and not solely in infiltrating immune cells. This work indicates that high-grade meningioma harbor an immunosuppressive tumor microenviroment and that increased Treg cells and elevated PD-L1 may contribute to the aggressive phenotype of these tumors.
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    Erratum: Genomic landscape of high-grade meningiomas
    (Nature Publishing Group UK, 2017) Bi, Wenya; Greenwald, Noah; Abedalthagafi, Malak; Wala, Jeremiah; Gibson, Will J.; Agarwalla, Pankaj Kumar; Horowitz, Peleg; Schumacher, Steven E.; Esaulova, Ekaterina; Mei, Yu; Chevalier, Aaron; A. Ducar, Matthew; Thorner, Aaron R.; van Hummelen, Paul; O. Stemmer-Rachamimov, Anat; Artyomov, Maksym; Al-Mefty, Ossama; Dunn, Gavin P.; Santagata, Sandro; Dunn, Ian; Beroukhim, Rameen