Person: Agar, Nathalie
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Agar
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Nathalie
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Agar, Nathalie
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Publication A Unique Subset of Glycolytic Tumour-Propagating Cells Drives Squamous Cell Carcinoma(Springer Science and Business Media LLC, 2021-02-22) Choi, Jeeeun; Sebastian, Carlos; Ferrer, Christina M.; Lewis, Caroline A.; Sade-Feldman, Moshe; LaSalle, Thomas; Gonye, Anna; Gimenez-Cassina Lopez, Begona; Abdelmoula, Walid M.; Regan, Michael S.; Cetinbas, Murat; Pascual, Gloria; Wojtkiewicz, Gregory; Silveira, Giorgia G.; Boon, Ruben; Ross, Kenneth; Tirosh, Itay; Saladi, Srinivas V.; Ellisen, Leif; Sadreyev, Ruslan; Benitah, Salvador Aznar; Agar, Nathalie; Hacohen, Nir; Mostoslavsky, RaulPublication Development of Stereotactic Mass Spectrometry for Brain Tumor Surgery(Oxford University Press (OUP), 2011) Agar, Nathalie; Golby, Alexandra; Ligon, Keith; Norton, Isaiah Hakim; Mohan, Vandana; Wiseman, Justin M; Tannenbaum, Allen; Jolesz, FerencBACKGROUND: Surgery remains the first and most important treatment modality for the majority of solid tumors. Across a range of brain tumor types and grades, postoperative residual tumor has a great impact on prognosis. The principal challenge and objective of neurosurgical intervention is therefore to maximize tumor resection while minimizing the potential for neurological deficit by preserving critical tissue. OBJECTIVE: To introduce the integration of desorption electrospray ionization mass spectrometry into surgery for in vivo molecular tissue characterization and intraoperative definition of tumor boundaries without systemic injection of contrast agents. METHODS: Using a frameless stereotactic sampling approach and by integrating a 3-dimensional navigation system with an ultrasonic surgical probe, we obtained image-registered surgical specimens. The samples were analyzed with ambient desorption/ionization mass spectrometry and validated against standard histopathology. This new approach will enable neurosurgeons to detect tumor infiltration of the normal brain intraoperatively with mass spectrometry and to obtain spatially resolved molecular tissue characterization without any exogenous agent and with high sensitivity and specificity. RESULTS: Proof of concept is presented in using mass spectrometry intraoperatively for real-time measurement of molecular structure and using that tissue characterization method to detect tumor boundaries. Multiple sampling sites within the tumor mass were defined for a patient with a recurrent left frontal oligodendroglioma, World Health Organization grade II with chromosome 1p/19q codeletion, and mass spectrometry data indicated a correlation between lipid constitution and tumor cell prevalence. CONCLUSION: The mass spectrometry measurements reflect a complex molecular structure and are integrated with frameless stereotaxy and imaging, providing 3-dimensional molecular imaging without systemic injection of any agents, which can be implemented for surgical margins delineation of any organ and with a rapidity that allows real-time analysis.Publication Ambient mass spectrometry for the intraoperative molecular diagnosis of human brain tumors(Proceedings of the National Academy of Sciences, 2013) Eberlin, L. S.; Norton, I.; Orringer, D.; Dunn, Ian; Liu, X.; Ide, J. L.; Jarmusch, A. K.; Ligon, Keith; Jolesz, Ferenc; Golby, Alexandra; Santagata, Sandro; Agar, Nathalie; Cooks, R. G.The main goal of brain tumor surgery is to maximize tumor resection while preserving brain function. However, existing imaging and surgical techniques do not offer the molecular information needed to delineate tumor boundaries. We have developed a system to rapidly analyze and classify brain tumors based on lipid information acquired by desorption electrospray ionization mass spectrometry (DESI-MS). In this study, a classifier was built to discriminate gliomas and meningiomas based on 36 glioma and 19 meningioma samples. The classifier was tested and results were validated for intraoperative use by analyzing and diagnosing tissue sections from 32 surgical specimens obtained from five research subjects who underwent brain tumor resection. The samples analyzed included oligodendroglioma, astrocytoma, and meningioma tumors of different histological grades and tumor cell concentrations. The molecular diagnosis derived from mass-spectrometry imaging corresponded to histopathology diagnosis with very few exceptions. Our work demonstrates that DESI-MS technology has the potential to identify the histology type of brain tumors. It provides information on glioma grade and, most importantly, may help define tumor margins by measuring the tumor cell concentration in a specimen. Results for stereotactically registered samples were correlated to preoperative MRI through neuronavigation, and visualized over segmented 3D MRI tumor volume reconstruction. Our findings demonstrate the potential of ambient mass spectrometry to guide brain tumor surgery by providing rapid diagnosis, and tumor margin assessment in near–real time.Publication Discrimination of Human Astrocytoma Subtypes by Lipid Analysis Using Desorption Electrospray Ionization Imaging Mass Spectrometry(Wiley-Blackwell, 2010) Eberlin, Livia S.; Dill, Allison L.; Golby, Alexandra; Ligon, Keith; Wiseman, Justin M.; Cooks, R. Graham; Agar, NathaliePublication Multiple spatially related pharmacophores define small molecule inhibitors of OLIG2 in glioblastoma(Impact Journals LLC, 2017) Tsigelny, Igor F.; Mukthavaram, Rajesh; Kouznetsova, Valentina L.; Chao, Ying; Babic, Ivan; Nurmemmedov, Elmar; Pastorino, Sandra; Jiang, Pengfei; Calligaris, David; Agar, Nathalie; Scadeng, Miriam; Pingle, Sandeep C.; Wrasidlo, Wolfgang; Makale, Milan T.; Kesari, SantoshTranscription factors (TFs) are a major class of protein signaling molecules that play key cellular roles in cancers such as the highly lethal brain cancer—glioblastoma (GBM). However, the development of specific TF inhibitors has proved difficult owing to expansive protein-protein interfaces and the absence of hydrophobic pockets. We uniquely defined the dimerization surface as an expansive parental pharmacophore comprised of several regional daughter pharmacophores. We targeted the OLIG2 TF which is essential for GBM survival and growth, we hypothesized that small molecules able to fit each subpharmacophore would inhibit OLIG2 activation. The most active compound was OLIG2 selective, it entered the brain, and it exhibited potent anti-GBM activity in cell-based assays and in pre-clinical mouse orthotopic models. These data suggest that (1) our multiple pharmacophore approach warrants further investigation, and (2) our most potent compounds merit detailed pharmacodynamic, biophysical, and mechanistic characterization for potential preclinical development as GBM therapeutics.Publication Structural Characterization of Pandoraea pnomenusa B-356 Biphenyl Dioxygenase Reveals Features of Potent Polychlorinated Biphenyl-Degrading Enzymes(Public Library of Science, 2013) Colbert, Christopher L.; Agar, Nathalie; Kumar, Pravindra; Chakko, Mathew N.; Sinha, Sangita C.; Powlowski, Justin B.; Eltis, Lindsay D.; Bolin, Jeffrey T.The oxidative degradation of biphenyl and polychlorinated biphenyls (PCBs) is initiated in Pandoraea pnomenusa B-356 by biphenyl dioxygenase \((BPDO_{B356})\). \(BPDO_{B356}\), a heterohexameric \((αβ)_3\) Rieske oxygenase (RO), catalyzes the insertion of dioxygen with stereo- and regioselectivity at the 2,3-carbons of biphenyl, and can transform a broad spectrum of PCB congeners. Here we present the X-ray crystal structures of \(BPDO_{B356}\) with and without its substrate biphenyl 1.6-Å resolution for both structures. In both cases, the Fe(II) has five ligands in a square pyramidal configuration: H233 Nε2, H239 Nε2, D386 Oδ1 and Oδ2, and a single water molecule. Analysis of the active sites of \(BPDO_{B356}\) and related ROs revealed structural features that likely contribute to the superior PCB-degrading ability of certain BPDOs. First, the active site cavity readily accommodates biphenyl with minimal conformational rearrangement. Second, M231 was predicted to sterically interfere with binding of some PCBs, and substitution of this residue yielded variants that transform 2,2′-dichlorobiphenyl more effectively. Third, in addition to the volume and shape of the active site, residues at the active site entrance also apparently influence substrate preference. Finally, comparison of the conformation of the active site entrance loop among ROs provides a basis for a structure-based classification consistent with a phylogeny derived from amino acid sequence alignments.Publication Rapid, Label-Free Detection of Brain Tumors with Stimulated Raman Scattering Microscopy(American Association for the Advancement of Science (AAAS), 2013) Ji, Minbiao; Orringer, Daniel A.; Freudiger, Christian Wilhelm; Ramkissoon, Shakti H.; Liu, Xiaohui; Lau, Darryl; Golby, Alexandra; Norton, Isaiah Hakim; Hayashi, Marika; Agar, Nathalie; Young, Geoffrey; Spino, Cathie; Santagata, Sandro; Camelo-Piragua, Sandra; Ligon, Keith; Sagher, Oren; Xie, XiaoliangSurgery is an essential component in the treatment of brain tumors. However, delineating tumor from normal brain remains a major challenge. We describe the use of stimulated Raman scattering (SRS) microscopy for differentiating healthy human and mouse brain tissue from tumor-infiltrated brain based on histoarchitectural and biochemical differences. Unlike traditional histopathology, SRS is a label-free technique that can be rapidly performed in situ. SRS microscopy was able to differentiate tumor from nonneoplastic tissue in an infiltrative human glioblastoma xenograft mouse model based on their different Raman spectra. We further demonstrated a correlation between SRS and hematoxylin and eosin microscopy for detection of glioma infiltration (κ = 0.98). Finally, we applied SRS microscopy in vivo in mice during surgery to reveal tumor margins that were undetectable under standard operative conditions. By providing rapid intraoperative assessment of brain tissue, SRS microscopy may ultimately improve the safety and accuracy of surgeries where tumor boundaries are visually indistinct.Publication Protein Aggregation and Protein Instability Govern Familial Amyotrophic Lateral Sclerosis Patient Survival(Public Library of Science, 2008) Agar, Jeffrey N.; Wang, Qi; Johnson, Joshua L.; Agar, NathalieThe nature of the “toxic gain of function” that results from amyotrophic lateral sclerosis (ALS)-, Parkinson-, and Alzheimer-related mutations is a matter of debate. As a result no adequate model of any neurodegenerative disease etiology exists. We demonstrate that two synergistic properties, namely, increased protein aggregation propensity (increased likelihood that an unfolded protein will aggregate) and decreased protein stability (increased likelihood that a protein will unfold), are central to ALS etiology. Taken together these properties account for 69% of the variability in mutant Cu/Zn-superoxide-dismutase-linked familial ALS patient survival times. Aggregation is a concentration-dependent process, and spinal cord motor neurons have higher concentrations of Cu/Zn-superoxide dismutase than the surrounding cells. Protein aggregation therefore is expected to contribute to the selective vulnerability of motor neurons in familial ALS.