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166


Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells

Basu-Roy, Upal; Bayin, N Sumru; Rattanakorn, Kirk; Han, Eugenia; Placantonakis, Dimitris G; Mansukhani, Alka; Basilico, Claudio
The repressive Hippo pathway has a profound tumour suppressive role in cancer by restraining the growth-promoting function of the transcriptional coactivator, YAP. We previously showed that the stem cell transcription factor Sox2 maintains cancer stem cells (CSCs) in osteosarcomas. We now report that in these tumours, Sox2 antagonizes the Hippo pathway by direct repression of two Hippo activators, Nf2 (Merlin) and WWC1 (Kibra), leading to exaggerated YAP function. Repression of Nf2, WWC1 and high YAP expression marks the CSC fraction of the tumor population, while the more differentiated fraction has high Nf2, high WWC1 and reduced YAP expression. YAP depletion sharply reduces CSCs and tumorigenicity of osteosarcomas. Thus, Sox2 interferes with the tumour-suppressive Hippo pathway to maintain CSCs in osteosarcomas. This Sox2-Hippo axis is conserved in other Sox2-dependent cancers such as glioblastomas. Disruption of YAP transcriptional activity could be a therapeutic strategy for Sox2-dependent tumours.
PMCID:4429898
PMID: 25832504
ISSN: 2041-1723
CID: 1519512

Tumors of the spine

Chapter by: Pacione, Donato; Kim, Irene; Placantonakis, Dimitris; Frempong-Boadu, Anthony
in: Spinal disorders and treatments : the NYU-HJD comprehensive textbook by Errico, Thomas J; Cheriyan, Thomas; Varlotta, Gerard P [Eds]
New Delhi : Jaypee Brothers, 2015
pp. 456-481
ISBN: 9351524957
CID: 2709542

A panoramic view of the skull base: systematic review of open and endoscopic endonasal approaches to four tumors

Graffeo, Christopher S; Dietrich, August R; Grobelny, Bartosz; Zhang, Meng; Goldberg, Judith D; Golfinos, John G; Lebowitz, Richard; Kleinberg, David; Placantonakis, Dimitris G
Endoscopic endonasal surgery has been established as the safest approach to pituitary tumors, yet its role in other common skull base lesions has not been established. To answer this question, we carried out a systematic review of reported series of open and endoscopic endonasal approaches to four major skull base tumors: olfactory groove meningiomas (OGM), tuberculum sellae meningiomas (TSM), craniopharyngiomas (CRA), and clival chordomas (CHO). Data from 162 studies containing 5,701 patients were combined and compared for differences in perioperative mortality, gross total resection (GTR), cerebrospinal fluid (CSF) leak, neurological morbidity, post-operative visual function, post-operative anosmia, post-operative diabetes insipidus (DI), and post-operative obesity/hyperphagia. Weighted average rates for each outcome were calculated using relative study size. Our findings indicate similar rates of GTR and perioperative mortality between open and endoscopic approaches for all tumor types. CSF leak was increased after endoscopic surgery. Visual function symptoms were more likely to improve after endoscopic surgery for TSM, CRA, and CHO. Post-operative DI and obesity/hyperphagia were significantly increased after open resection in CRA. Recurrence rates per 1,000 patient-years of follow-up were higher in endoscopy for OGM, TSM, and CHO. Trends for open and endoscopic surgery suggested modest improvement in all outcomes over time. Our observations suggest that endonasal endoscopy is a safe alternative to craniotomy and may be preferred for certain tumor types. However, endoscopic surgery is associated with higher rates of CSF leak, and possibly increased recurrence rates. Prospective study with long-term follow-up is required to verify these preliminary observations.
PMCID:4214071
PMID: 24014055
ISSN: 1386-341x
CID: 590322

Endoscopic Endonasal Resection of Suprasellar Meningiomas: The Importance of Case Selection and Experience in Determining Extent of Resection, Visual improvement and Complications

Ottenhausen, Malte; Banu, Matei; Placantonakis, Dimitris G; Tsiouris, A John; Khan, Osaama H; Anand, Vijay K; Schwartz, Theodore H
OBJECTIVE: Suprasellar meningiomas have been resected via various open cranial approaches. Over the past two decades the endoscopic endonasal approach has been shown to be an option in selected patients. We wished to examine the learning curve for parameters such as extent of resection, visual outcome and complications. METHODS: We retrospectively reviewed a consecutive series of patients suprasellar meningiomas resected through an endonasal endoscopic approach between 2005 and 2013 at our Institution. After 6/08, our surgical technique matured. Using this timepoint, we divided our case series into two chronological groups, Group 1 (n=8) and Group 2 (n=12). This cut-off was also used to examine rates of gross-total resection (GTR) and visual improvement. Case selection criteria in successful and unsuccessful cases were examined to determine important principals for case selection. RESULTS: Mean age at surgery was 57.05 years (range 31 - 81 years). Mean tumor volume was 11.98cm3 (range 0.43 - 28.93 cm3). Overall, gross total resection (GTR) was achieved in 80% and vision improved or normalized in fourteen patients (82.4%) with no occurrence of postoperative visual deterioration. GTR rates went from 62.5% (Group 1) to 91.7% (Group 2). Visual improvement went from 75% (Group 1) to 88.9% (Group 2). CSF leak rates were 25% in Group 1 and 0% in Group 2. Average follow up was 51.5 month (range 3 to 96 month). CONCLUSION: Once the learning curve is overcome, endonasal endoscopic resection of suprasellar meningiomas can achieve high rates of GTR with low complication rates in well-selected cases.
PMID: 24657254
ISSN: 1878-8750
CID: 941752

The transplanum transtuberculum approaches for suprasellar and sellar-suprasellar lesions. Avoidance of CSF leak and lessons learned

Mascarenhas, Lino; Moshel, Yaron A; Bayad, Fatema; Szentirmai, Oszkar; Salek, Al Amin; Leng, Lewis Z; Hofstetter, Christoph P; Placantonakis, Dimitris G; Tsiouris, Apostolos J; Anand, Vijay K; Schwartz, Theodore H
OBJECTIVE: To present a large series of patients and examine the learning curve of the endonasal endoscopic transplanum, transtuberculum approach for primarily suprasellar or sellar-suprasellar tumors.. METHODS: We identified 122 patients who underwent 126 surgeries using the transplanum, transtuberculum approach . Extent of resection was determined with volumetric analysis of MRI's. Results concerning vision, endocrine function and complications were noted. RESULTS: Average tumor volume was 14 cm3. The most frequent pathologies were pituitary macroadenoma (51.6%), craniopharyngioma (20.6%) and meningioma (15.9%). 73% presented with visual compromise. Rates of GTR and NTR for the group as a whole were 58.1% and 13.7%, and for the patients in whom GTR was intended (n=90), rates of GTR and NTR were 77.5% and 12.5% for a total of 90%. Extent of resection in this group was 97.6%. Vision improved in 52.4% and deteriorated in 4.8%. Favorable endocrine outcome occurred in 63.5%. CSF leak rate was 3.1% for the series as a whole. It improved from 6.3% in the first half of the series to 0% in the second half. Leak rates varied with technique from 11% (fat graft only) to 4.2% (gasket seal only) to 1.8% (fat plus nasoseptal flap) to 0% (gasket plus nasoseptal flap). The rate of other complications was 14.3% in the first half of the series and 1.6% in the second half. There was one infection (0.8%). CONCLUSION: The endonasal endoscopic transtuberculum transplanum approach is a safe and effective minimal access approach to midline pathology in the suprasellar cistern.
PMID: 23403355
ISSN: 1878-8750
CID: 240312

Brain stem cells as the cell of origin in glioma

Modrek, Aram S; Bayin, N Sumru; Placantonakis, Dimitris G
Glioma incidence rates in the United States are near 20000 new cases per year, with a median survival time of 14.6 mo for high-grade gliomas due to limited therapeutic options. The origins of these tumors and their many subtypes remain a matter of investigation. Evidence from mouse models of glioma and human clinical data have provided clues about the cell types and initiating oncogenic mutations that drive gliomagenesis, a topic we review here. There has been mixed evidence as to whether or not the cells of origin are neural stem cells, progenitor cells or differentiated progeny. Many of the existing murine models target cell populations defined by lineage-specific promoters or employ lineage-tracing methods to track the potential cells of origin. Our ability to target specific cell populations will likely increase concurrently with the knowledge gleaned from an understanding of neurogenesis in the adult brain. The cell of origin is one variable in tumorigenesis, as oncogenes or tumor suppressor genes may differentially transform the neuroglial cell types. Knowledge of key driver mutations and susceptible cell types will allow us to understand cancer biology from a developmental standpoint and enable early interventional strategies and biomarker discovery.
PMCID:3927013
PMID: 24567787
ISSN: 1948-0210
CID: 820902

Noninvasive diagnosis and management of spontaneous intracranial hypotension in patients with marfan syndrome: Case Report and Review of the Literature

Bassani, Luigi; Graffeo, Christopher S; Behrooz, Navid; Tyagi, Vineet; Wilson, Taylor; Penaranda, Saul; Zagzag, David; Rifkin, Daniel B; Barcellos-Hoff, Mary Helen; Fatterpekar, Girish; Placantonakis, Dimitris
BACKGROUND: Spontaneous intracranial hypotension is an uncommon clinical entity. Heritable connective tissue disorders (HCTD), such as Marfan syndrome, are frequently implicated as an underlying cause, due to dural structural weaknesses that predispose patients to spontaneous cerebrospinal fluid (CSF) leak. Due to the high prevalence of multi-system disease in HCTD, diagnosis and treatment are often complicated. CASE DESCRIPTION: We present a 58-year-old female with Marfan syndrome on anticoagulation for a mechanical aortic valve replacement who came to medical attention with severe, acute-onset headache following a straining episode. Noninvasive magnetic resonance (MR) myelography confirmed thoracic CSF extravasations and multiple lumbar diverticula. The patient was treated conservatively and her symptoms resolved. CONCLUSION: We discuss the common presentation, diagnostic tools, and treatment options for spontaneous CSF leaks in patients with Marfan syndrome or related HCTD with an emphasis on noninvasive modalities and a review of the major radiographic criteria used to diagnose dural abnormalities, such as dural ectasia.
PMCID:3927088
PMID: 24575323
ISSN: 2152-7806
CID: 820792

Selective Lentiviral Gene Delivery to CD133-Expressing Human Glioblastoma Stem Cells

Bayin, N Sumru; Modrek, Aram S; Dietrich, August; Lebowitz, Jonathan; Abel, Tobias; Song, Hae-Ri; Schober, Markus; Zagzag, David; Buchholz, Christian J; Chao, Moses V; Placantonakis, Dimitris G
Glioblastoma multiforme (GBM) is a deadly primary brain malignancy. Glioblastoma stem cells (GSC), which have the ability to self-renew and differentiate into tumor lineages, are believed to cause tumor recurrence due to their resistance to current therapies. A subset of GSCs is marked by cell surface expression of CD133, a glycosylated pentaspan transmembrane protein. The study of CD133-expressing GSCs has been limited by the relative paucity of genetic tools that specifically target them. Here, we present CD133-LV, a lentiviral vector presenting a single chain antibody against CD133 on its envelope, as a vehicle for the selective transduction of CD133-expressing GSCs. We show that CD133-LV selectively transduces CD133+ human GSCs in dose-dependent manner and that transduced cells maintain their stem-like properties. The transduction efficiency of CD133-LV is reduced by an antibody that recognizes the same epitope on CD133 as the viral envelope and by shRNA-mediated knockdown of CD133. Conversely, the rate of transduction by CD133-LV is augmented by overexpression of CD133 in primary human GBM cultures. CD133-LV selectively transduces CD133-expressing cells in intracranial human GBM xenografts in NOD.SCID mice, but spares normal mouse brain tissue, neurons derived from human embryonic stem cells and primary human astrocytes. Our findings indicate that CD133-LV represents a novel tool for the selective genetic manipulation of CD133-expressing GSCs, and can be used to answer important questions about how these cells contribute to tumor biology and therapy resistance.
PMCID:4277468
PMID: 25541984
ISSN: 1932-6203
CID: 1419672

NON-UNIFORM NOTCH SIGNALING UNDERLIES HETEROGENEITY WITHIN THE GLIOBLASTOMA STEM CELL POPULATION [Meeting Abstract]

Bayin, NSumru; Si, Sheng; Modrek, Aram; Song, Hae-Ri; Zagzag, David; Dung Minh Hoang; Wadghiri, Youssef Z; Dolgalev, Igor; Baysan, Mehmet; Heguy, Adriana; Barcellos-Hoff, Mary Helen; Placantonakis, Dimitris
ISI:000350452200804
ISSN: 1523-5866
CID: 2340682

ERG AS A RELIABLE MARKER OF VASCULAR CELLS IN BRAIN TUMORS [Meeting Abstract]

Iranmahboob, Amir; Haber, Matthew; Esencay, Mine; Fatterpekar, Girish; Raz, Eytan; Placantonakis, Dimitris; Zagzag, David
ISI:000310971300012
ISSN: 1522-8517
CID: 204932