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Huang B.,University of Pittsburgh | Sikorski R.,University of Pittsburgh | Sampath P.,University of Pittsburgh | Thorne S.H.,University of Pittsburgh | Thorne S.H.,Hillman Cancer Center
Journal of Immunotherapy | Year: 2011

A variety of immune cell therapies proposed for use in the treatment of cancer, including both autologous cells (Lymphokine Activated Killer, Cytokine Induced Killer) or cell lines (TALL-104, NK-92), rely on recognition of NKG2D ligands on malignant cells for targeting. These ligands, such as MICA and MICB in humans are stress response ligands and are commonly, but not ubiquitously expressed within tumors. Several tumor escape mechanisms have been reported, including ligand downregulation and internalization, or proteolytic cleavage and shedding of their exposed portions (releasing soluble MICA and MICB; sMICA, sMICB). Therefore, an ability to prescreen patients for the level of tumor cell surface expression and shedding of these ligands would prevent needless treatment of patients that are unable to respond, whereas targeted pretreatment of patients to increase surface expression and/or block shedding would enhance the subsequent effectiveness of these therapies. Here, we report that serum tests of sMICA and sMICB in conjunction with tumor measurements might be used to determine rates of shedding from a tumor and that treatment with a selected combination of histone deacetylase inhibitors (to upregulate cell surface MICA/B in some tumors), and metalloproteinase inhibitors (to block MICA/B shedding in others) can be incorporated to regulate cell surface MICA/B levels before immune cell therapy, significantly enhancing their effectiveness (either used alone or as carrier vehicles for oncolytic viruses). Ultimately prescreening patients undergoing such immune cell therapies might be used to personalize cancer treatment regimens based on the NKG2D-ligand status of the tumor. © 2011 by Lippincott Williams & Wilkins.

Liu Y.,University of Pittsburgh | Liu Y.,Hillman Cancer Center | Uttam S.,University of Pittsburgh | Alexandrov S.,National University of Ireland | Bista R.K.,University of Pittsburgh
BMC Biophysics | Year: 2014

Background: The cell and tissue structural properties assessed with a conventional bright-field light microscope play a key role in cancer diagnosis, but they sometimes have limited accuracy in detecting early-stage cancers or predicting future risk of cancer progression for individual patients (i.e., prognosis) if no frank cancer is found. The recent development in optical microscopy techniques now permit the nanoscale structural imaging and quantitative structural analysis of tissue and cells, which offers a new opportunity to investigate the structural properties of cell and tissue below 200-250 nm as an early sign of carcinogenesis, prior to the presence of microscale morphological abnormalities. Identification of nanoscale structural signatures is significant for earlier and more accurate cancer detection and prognosis. Results: Our group has recently developed two simple spectral-domain optical microscopy techniques for assessing 3D nanoscale structural alterations - spectral-encoding of spatial frequency microscopy and spatial-domain low-coherence quantitative phase microscopy. These two techniques use the scattered light from biological cells and tissue and share a common experimental approach of assessing the Fourier space by various wavelengths to quantify the 3D structural information of the scattering object at the nanoscale sensitivity with a simple reflectance-mode light microscopy setup without the need for high-NA optics. This review paper discusses the physical principles and validation of these two techniques to interrogate nanoscale structural properties, as well as the use of these methods to probe nanoscale nuclear architectural alterations during carcinogenesis in cancer cell lines and well-annotated human tissue during carcinogenesis. Conclusions: The analysis of nanoscale structural characteristics has shown promise in detecting cancer before the microscopically visible changes become evident and proof-of-concept studies have shown its feasibility as an earlier or more sensitive marker for cancer detection or diagnosis. Further biophysical investigation of specific 3D nanoscale structural characteristics in carcinogenesis, especially with well-annotated human cells and tissue, is much needed in cancer research. © 2014 Liu et al.; licensee BioMed Central Ltd.

Beumer J.H.,University of Pittsburgh | Fu K.Y.,University of Pittsburgh | Anyang B.N.,University of Pittsburgh | Siegfried J.M.,University of Minnesota | And 2 more authors.
BMC Cancer | Year: 2015

Background: ATM and ATR are kinases implicated in a myriad of DNA-damage responses. ATM kinase inhibition radiosensitizes cells and selectively kills cells with Fanconi anemia (FA) gene mutations. ATR kinase inhibition sensitizes cells to agents that induce replication stress and selectively kills cells with ATM and TP53 mutations. ATM mutations and FANCF promoter-methylation are reported in lung carcinomas. Methods: We undertook functional analyses of ATM, ATR, Chk1 and FA proteins in lung cancer cell lines. We included Calu6 that is reported to be FANCL-deficient. In addition, the cancer genome atlas (TCGA) database was interrogated for alterations in: 1) ATM, MRE11A, RAD50 and NBN; 2) ATR, ATRIP and TOPBP1; and 3) 15 FA genes. Results: No defects in ATM, ATR or Chk1 kinase activation, or FANCD2 monoubiquitination were identified in the lung cancer cell lines examined, including Calu6, and major alterations in these pathways were not identified in the TCGA database. Cell lines were radiosensitized by ATM kinase inhibitor KU60019, but no cell killing by ATM kinase inhibitor alone was observed. While no synergy between gemcitabine or carboplatin and ATR kinase inhibitor ETP-46464 was observed, synergy between gemcitabine and Chk1 kinase inhibitor UCN-01 was observed in 54T, 201T and H460, and synergy between carboplatin and Chk1 kinase inhibitor was identified in 201T and 239T. No interactions between ATM, ATR and FA activation were observed by either ATM or ATR kinase inhibition in the lung cancer cell lines. Conclusions: Analyses of ATM serine 1981 and Chk1 serine 345 phosphorylation, and FANCD2 monoubiquitination revealed that ATM and ATR kinase activation and FA pathway signaling are intact in the lung cancer cell lines examined. As such, these posttranslational modifications may have utility as biomarkers for the integrity of DNA damage signaling pathways in lung cancer. Different sensitization profiles between gemcitabine and carboplatin and ATR kinase inhibitor ETP-46464 and Chk1 kinase inhibitor UCN-01 were observed and this should be considered in the rationale for Phase I clinical trial design with ATR kinase inhibitors. © 2015 Beumer et al.

Whiteside T.L.,University of Pittsburgh | Whiteside T.L.,Hillman Cancer Center
Cancer Immunology, Immunotherapy | Year: 2012

Human tumors can use many different mechanisms to induce dysfunction in the host immune system. Accumulations of inducible regulatory T cells (iTreg, Tr1) are commonly seen in the tumor microenvironment. These Treg express CD39 and up-regulate CD73 ectonucleotidases, hydrolyze exogenous adenosine triphosphate (ATP) to AMP and adenosine and produce prostaglandin E 2 (PGE 2). Most tumors also express CD39/CD73 and COX-2 and thus contribute to immune suppression. Pharmacologic inhibitors can be used to eliminate adenosine/PGE 2 production by Tr1 as well as the tumor or to block binding of these factors to their receptors on Teff or to selectively block cAMP synthesis in Teff. These pharmacologic blocking strategies used alone or in combination with conventional treatments or immunotherapies could disarm Tr1, at the same time restoring antitumor functions of Teff. © 2011 Springer-Verlag.

Pu J.,University of Pittsburgh | Gu S.,University of Pittsburgh | Liu S.,University of Utah | Zhu S.,Henan Provincial Peoples Hospital | And 3 more authors.
Medical Physics | Year: 2012

As one of the most prevalent chronic disorders, airway disease is a major cause of morbidity and mortality worldwide. In order to understand its underlying mechanisms and to enable assessment of therapeutic efficacy of a variety of possible interventions, noninvasive investigation of the airways in a large number of subjects is of great research interest. Due to its high resolution in temporal and spatial domains, computed tomography (CT) has been widely used in clinical practices for studying the normal and abnormal manifestations of lung diseases, albeit there is a need to clearly demonstrate the benefits in light of the cost and radiation dose associated with CT examinations performed for the purpose of airway analysis. Whereas a single CT examination consists of a large number of images, manually identifying airway morphological characteristics and computing features to enable thorough investigations of airway and other lung diseases is very time-consuming and susceptible to errors. Hence, automated and semiautomated computerized analysis of human airways is becoming an important research area in medical imaging. A number of computerized techniques have been developed to date for the analysis of lung airways. In this review, we present a summary of the primary methods developed for computerized analysis of human airways, including airway segmentation, airway labeling, and airway morphometry, as well as a number of computer-aided clinical applications, such as virtual bronchoscopy. Both successes and underlying limitations of these approaches are discussed, while highlighting areas that may require additional work. © 2012 American Association of Physicists in Medicine.

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