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Phoenix, AZ, United States

Liu J.T.C.,State University of New York at Stony Brook | Meza D.,State University of New York at Stony Brook | Sanai N.,Barrow Brain Tumor Research Center
Neurosurgery | Year: 2014

Mounting evidence suggests that a more extensive surgical resection is associated with an improved life expectancy for both low-grade and high-grade glioma patients. However, radiographically complete resections are not often achieved in many cases because of the lack of sensitivity and specificity of current neurosurgical guidance techniques at the margins of diffuse infiltrative gliomas. Intraoperative fluorescence imaging offers the potential to improve the extent of resection and to investigate the possible benefits of resecting beyond the radiographic margins. Here, we provide a review of wide-field and high-resolution fluorescence-imaging strategies that are being developed for neurosurgical guidance, with a focus on emerging imaging technologies and clinically viable contrast agents. The strengths and weaknesses of these approaches will be discussed, as well as issues that are being addressed to translate these technologies into the standard of care. Copyright © 2014 by the Congress of Neurological Surgeons. Source

Baumgart S.,University of Marburg | Chen N.-M.,University of Gottingen | Zhang J.-S.,Schulze Center for Novel Therapeutics | Billadeau D.D.,Schulze Center for Novel Therapeutics | And 13 more authors.
Molecular Cancer Therapeutics | Year: 2016

We aimed to investigate the mechanistic, functional, and therapeutic role of glycogen synthase kinase 3β (GSK-3β) in the regulation and activation of the proinflammatory oncogenic transcription factor nuclear factor of activated T cells (NFATc2) in pancreatic cancer. IHC, qPCR, immunoblotting, immunofluorescence microscopy, and proliferation assays were used to analyze mouse and human tissues and cell lines. Protein-protein interactions and promoter regulation were analyzed by coimmunoprecipitation, DNA pulldown, reporter, and ChIP assays. Preclinical assays were performed using a variety of pancreatic cancer cells lines, xenografts, and a genetically engineered mouse model (GEMM). GSK-3β-dependent SP2 phosphorylationmediates NFATc2 protein stability in the nucleus of pancreatic cancer cells stimulating pancreatic cancer growth. In addition to protein stabilization, GSK-3β also maintains NFATc2 activation through a distinct mechanism involving stabilization of NFATc2-STAT3 complexes independent of SP2 phosphorylation. For NFATc2-STAT3 complex formation, GSK-3β-mediated phosphorylation of STAT3 at Y705 is required to stimulate euchromatin formation of NFAT target promoters, such as cyclin-dependent kinase-6, which promotes tumor growth. Finally, preclinical experiments suggest that targeting the NFATc2-STAT3-GSK-3β module inhibits proliferation and tumor growth and interferes with inflammationinduced pancreatic cancer progression in KrasG12D mice. In conclusion, we describe a novel mechanism by which GSK-3b fine-tunes NFATc2 and STAT3 transcriptional networks to integrate upstream signaling events that govern pancreatic cancer progression and growth. Furthermore, the therapeutic potential of GSK-3β is demonstrated for the first time in a relevant Kras and inflammation-induced GEMM for pancreatic cancer. © 2016 American Association for Cancer Research.3. Source

Baumgart S.,University of Marburg | Chen N.-M.,University of Marburg | Chen N.-M.,University of Gottingen | Siveke J.T.,TU Hamburg - Harburg | And 25 more authors.
Cancer Discovery | Year: 2014

Cancer-associated inflammation is a molecular key feature in pancreatic ductal adenocarcinoma. Oncogenic KRAS in conjunction with persistent inflammation is known to accelerate carcinogenesis, although the underlying mechanisms remain poorly understood. Here, we outline a novel pathway whereby the transcription factors NFATc1 and STAT3 cooperate in pancreatic epithelial cells to promote Kras G12D - driven carcinogenesis. NFATc1 activation is induced by inflammation and itself accelerates inflammation-induced carcinogenesis in KrasG12D mice, whereas genetic or pharmacologic ablation of NFATc1 attenuates this effect. Mechanistically, NFATc1 complexes with STAT3 for enhancer-promoter communications at jointly regulated genes involved in oncogenesis, for example, Cyclin, EGFR and WNT family members. The NFATc1-STAT3 cooperativity is operative in pancreatitis-mediated carcinogenesis as well as in established human pancreatic cancer. Together, these studies unravel new mechanisms of inflammatory-driven pancreatic carcinogenesis and suggest beneficial effects of chemopreventive strategies using drugs that are currently available for targeting these factors in clinical trials. SIGNIFICANCE: Our study points to the existence of an oncogenic NFATc1-STAT3 cooperativity that mechanistically links inflammation with pancreatic cancer initiation and progression. Because NFATc1-STAT3 nucleoprotein complexes control the expression of gene networks at the intersection of inflammation and cancer, our study has signifi cant relevance for potentially managing pancreatic cancer and other inflammatory-driven malignancies. © 2014 American Association for Cancer Research. Source

Kusne Y.,Barrow Brain Tumor Research Center | Sanai N.,Barrow Brain Tumor Research Center
Advances in Experimental Medicine and Biology | Year: 2015

Gliomas are primary cancers of the brain and the most lethal cancers known to man. In recent years the discovery of germinal regions in the postnatal brain containing neuronal stem and progenitor cell populations has led to the hypothesis that these cells may themselves serve as an origin of brain tumors. Stem cells that reside within the glioma tumor have been shown to display nonneoplastic stem-like characteristics, including expression of various stem cell markers, as well as capacity for self-renewal and multipotency. Furthermore, glioma tumors display marked similarities to the germinal regions of the brain. Investigations of human neural stem cells and their potential for malignancy may fi nally identify a cell-oforigin for human gliomas. This, in turn, may facilitate better therapeutic targeting leading to improved prognosis for glioma patients. © Springer International Publishing Switzerland 2015. Source

Chen Y.,University of Washington | Wang D.,State University of New York at Stony Brook | Khan A.,State University of New York at Stony Brook | Wang Y.,University of Washington | And 3 more authors.
Journal of Biomedical Optics | Year: 2015

Video-rate optical-sectioning microscopy of living organisms would allow for the investigation of dynamic biological processes and would also reduce motion artifacts, especially for in vivo imaging applications. Previous feasibility studies, with a slow stage-scanned line-scanned dual-axis confocal (LS-DAC) microscope, have demonstrated that LS-DAC microscopy is capable of imaging tissues with subcellular resolution and high contrast at moderate depths of up to several hundred microns. However, the sensitivity and performance of a video-rate LS-DAC imaging system, with low-numerical aperture optics, have yet to be demonstrated. Here, we report on the construction and validation of a video-rate LS-DAC system that possesses sufficient sensitivity to visualize fluorescent contrast agents that are topically applied or systemically delivered in animal and human tissues. We present images of murine oral mucosa that are topically stained with methylene blue, and images of protoporphyrin IX-expressing brain tumor from glioma patients that have been administered 5-aminolevulinic acid prior to surgery. In addition, we demonstrate in vivo fluorescence imaging of red blood cells trafficking within the capillaries of a mouse ear, at frame rates of up to 30 fps. These results can serve as a benchmark for miniature in vivo microscopy devices under development. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI. © 2015 The Authors. Source

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