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1.  Astrocyte and Macrophage Regulation of YKL-40 Expression and Cellular Response in Neuroinflammation 
Numerous inflammatory conditions are associated with elevated YKL-40 expression by infiltrating macrophages. Thus, we were surprised to observe minimal macrophage and abundant astrocyte expression of YKL-40 in neuroinflammatory conditions. The aims of the current study were to better delineate this discrepancy, characterize the factors that regulate YKL-40 expression in macrophages and astrocytes and study whether YKL-40 expression correlates with cell morphology and/or activation state. In vitro, macrophages expressed high levels of YKL-40 that was induced by classical activation and inhibited by alternative activation. Cytokines released from macrophages induced YKL-40 transcription in astrocytes that was accompanied by morphological changes and altered astrocytic motility. Because coculturing of astrocytes and macrophages did not reverse this in vitro expression pattern, additional components of the in vivo central nervous system (CNS) milieu must be required to suppress macrophage and induce astrocyte expression of YKL-40.
doi:10.1111/j.1750-3639.2011.00550.x
PMCID: PMC3557465  PMID: 22074331
astrocytes; macrophages; neuroinflammation; YKL-40
2.  Utilisation of a thoracic oncology database to capture radiological and pathological images for evaluation of response to chemotherapy in patients with malignant pleural mesothelioma 
BMJ Open  2012;2(5):e001620.
Objective
An area of need in cancer informatics is the ability to store images in a comprehensive database as part of translational cancer research. To meet this need, we have implemented a novel tandem database infrastructure that facilitates image storage and utilisation.
Background
We had previously implemented the Thoracic Oncology Program Database Project (TOPDP) database for our translational cancer research needs. While useful for many research endeavours, it is unable to store images, hence our need to implement an imaging database which could communicate easily with the TOPDP database.
Methods
The Thoracic Oncology Research Program (TORP) imaging database was designed using the Research Electronic Data Capture (REDCap) platform, which was developed by Vanderbilt University. To demonstrate proof of principle and evaluate utility, we performed a retrospective investigation into tumour response for malignant pleural mesothelioma (MPM) patients treated at the University of Chicago Medical Center with either of two analogous chemotherapy regimens and consented to at least one of two UCMC IRB protocols, 9571 and 13473A.
Results
A cohort of 22 MPM patients was identified using clinical data in the TOPDP database. After measurements were acquired, two representative CT images and 0–35 histological images per patient were successfully stored in the TORP database, along with clinical and demographic data.
Discussion
We implemented the TORP imaging database to be used in conjunction with our comprehensive TOPDP database. While it requires an additional effort to use two databases, our database infrastructure facilitates more comprehensive translational research.
Conclusions
The investigation described herein demonstrates the successful implementation of this novel tandem imaging database infrastructure, as well as the potential utility of investigations enabled by it. The data model presented here can be utilised as the basis for further development of other larger, more streamlined databases in the future.
doi:10.1136/bmjopen-2012-001620
PMCID: PMC3488720  PMID: 23103606
Basic Sciences
3.  Quantitative Measurement of Lung Re-Expansion in Malignant Pleural Mesothelioma Patients Undergoing Pleurectomy/Decortication 
Academic radiology  2010;18(3):294-298.
Rationale and Objectives
Malignant pleural mesothelioma (MPM) is a neoplasm that grows circumferentially along the pleura. The tumor and concurrent pleural effusion may reduce lung function by restricting or preventing lung expansion. The purpose of this study was to provide objective evidence that pleurectomy/decortication (P/D) allows trapped lung to re-expand, quantify the re-expansion based on computed tomography (CT) scans, and investigate whether the expansion persists after surgery.
Materials and Methods
A database of 12 patients demonstrating unilateral MPM was collected. Each patient underwent a pre-surgical CT scan, surgical debulking by P/D, and two post-surgical CT scans (at one and four months). The lung volume was measured in each scan using an automated algorithm and compared for each patient across time.
Results
An increase in the ipsilateral post-surgical lung volume was observed for 10 of 12 patients (83%) one month after surgery. The median ipsilateral volume increase was 44% relative to the pre-surgical ipsilateral volume and 21% relative to the contralateral volume. A statistically significant change in ipsilateral lung volume was not observed between 1 -month and 4-month post-surgical scans, implying that the volume improvement persisted months after surgery.
Conclusions
Debulking of MPM with P/D substantially increased the ipsilateral lung volume relative to both the pre-surgical, ipsilateral volume and the contralateral lung volume. This improvement persisted months after surgery.
doi:10.1016/j.acra.2010.10.009
PMCID: PMC3075578  PMID: 21145765
4.  YKL-40 Expression in Traumatic Brain Injury: An Initial Analysis 
Journal of Neurotrauma  2010;27(7):1215-1223.
Abstract
YKL-40 (chitinase 3-like protein 1) is expressed in a broad spectrum of inflammatory conditions and cancers. We have previously reported that YKL-40 levels are elevated in the cerebrospinal fluid (CSF) of macaques and humans with lentiviral encephalitis, as well as multiple sclerosis (MS). The current study assessed temporal CSF YKL-40 levels in subjects with severe traumatic brain injury (TBI; Glasgow Coma Scale [GCS] score ≤8). We also evaluated temporal expression of YKL-40 after parasagittal controlled cortical impact (CCI) injury over the parietal cortex (2.8 mm deep, 4 m/sec). We demonstrate that CSF YKL-40 levels are elevated after acute TBI, and that YKL-40 levels are higher in patients who died following injury than in patients who survived. YKL-40 levels significantly correlate with CSF levels of inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), as well as the inflammatory marker C-reactive protein (CRP). After CCI, in situ hybridization (ISH) showed that YKL-40 transcription is primarily associated with reactive astrocytes in pericontusional cortex. Tissue YKL-40 transcription time course analysis after CCI showed that YKL40 transcription in astrocytes began 1 day after injury, remained elevated for several days, and then declined by day 12. Similarly to our temporal CSF measurements in humans, YKL-40 induction after CCI is coincident with IL-1β expression. Taken together these findings demonstrate that YKL-40 is induced in astrocytes during acute neuroinflammation, is temporally related to inflammatory mediator expression, and may be a useful biomarker for understanding secondary injury and for patient prognosis.
doi:10.1089/neu.2010.1310
PMCID: PMC2942903  PMID: 20486806
chitinase; controlled cortical impact; cytokine; gliosis; neuroinflammation; traumatic brain injury; YKL-40
5.  In vivo CHI3L1 (YKL-40) expression in astrocytes in acute and chronic neurological diseases 
Background
CHI3L1 (YKL-40) is up-regulated in a variety of inflammatory conditions and cancers. We have previously reported elevated CHI3L1 concentration in the cerebrospinal fluid (CSF) of human and non-human primates with lentiviral encephalitis and using immunohistochemistry showed that CHI3L1 was associated with astrocytes.
Methods
In the current study CHI3L1 transcription and expression were evaluated in a variety of acute and chronic human neurological diseases.
Results
ELISA revealed significant elevation of CHI3L1 in the CSF of multiple sclerosis (MS) patients as well as mild elevation with aging. In situ hybridization (ISH) showed CHI3L1 transcription mostly associated with reactive astrocytes, that was more pronounced in inflammatory conditions like lentiviral encephalitis and MS. Comparison of CHI3L1 expression in different stages of brain infarction showed that YKL40 was abundantly expressed in astrocytes during acute phases and diminished to low levels in chronic infarcts.
Conclusions
Taken together, these findings demonstrate that CHI3L1 is induced in astrocytes in a variety of neurological diseases but that it is most abundantly associated with astrocytes in regions of inflammatory cells.
doi:10.1186/1742-2094-7-34
PMCID: PMC2892443  PMID: 20540736
6.  Systemic and Brain Macrophage Infections in Relation to the Development of Simian Immunodeficiency Virus Encephalitis▿  
Journal of Virology  2008;82(10):5031-5042.
The brains of individuals with lentiviral-associated encephalitis contain an abundance of infected and activated macrophages. It has been hypothesized that encephalitis develops when increased numbers of infected monocytes traffic into the central nervous system (CNS) during the end stages of immunosuppression. The relationships between the infection of brain and systemic macrophages and circulating monocytes and the development of lentiviral encephalitis are unknown. We longitudinally examined the extent of monocyte/macrophage infection in blood and lymph nodes of pigtailed macaques that did or did not develop simian immunodeficiency virus encephalitis (SIVE). Compared to levels in macaques that did not develop SIVE, more ex vivo virus production was detected from monocyte-derived macrophages and nonadherent peripheral blood mononuclear cells (PBMCs) from macaques that did develop SIVE. Prior to death, there was an increase in the number of circulating PBMCs following a rise in cerebrospinal fluid viral load in macaques that did develop SIVE but not in nonencephalitic macaques. At necropsy, macaques with SIVE had more infected macrophages in peripheral organs, with the exception of lymph nodes. T cells and NK cells with cytotoxic potential were more abundant in brains with encephalitis; however, T-cell and NK-cell infiltration in SIVE and human immunodeficiency virus encephalitis was more modest than that observed in classical acute herpes simplex virus encephalitis. These findings support the hypothesis that inherent differences in host systemic and CNS monocyte/macrophage viral production are associated with the development of encephalitis.
doi:10.1128/JVI.02069-07
PMCID: PMC2346725  PMID: 18337567
7.  Evaluation of Lung MDCT Nodule Annotation Across Radiologists and Methods1 
Academic radiology  2006;13(10):1254-1265.
Rationale and Objectives
Integral to the mission of the National Institutes of Health–sponsored Lung Imaging Database Consortium is the accurate definition of the spatial location of pulmonary nodules. Because the majority of small lung nodules are not resected, a reference standard from histopathology is generally unavailable. Thus assessing the source of variability in defining the spatial location of lung nodules by expert radiologists using different software tools as an alternative form of truth is necessary.
Materials and Methods
The relative differences in performance of six radiologists each applying three annotation methods to the task of defining the spatial extent of 23 different lung nodules were evaluated. The variability of radiologists’ spatial definitions for a nodule was measured using both volumes and probability maps (p-map). Results were analyzed using a linear mixed-effects model that included nested random effects.
Results
Across the combination of all nodules, volume and p-map model parameters were found to be significant at P < .05 for all methods, all radiologists, and all second-order interactions except one. The radiologist and methods variables accounted for 15% and 3.5% of the total p-map variance, respectively, and 40.4% and 31.1% of the total volume variance, respectively.
Conclusion
Radiologists represent the major source of variance as compared with drawing tools independent of drawing metric used. Although the random noise component is larger for the p-map analysis than for volume estimation, the p-map analysis appears to have more power to detect differences in radiologist-method combinations. The standard deviation of the volume measurement task appears to be proportional to nodule volume.
doi:10.1016/j.acra.2006.07.012
PMCID: PMC1994157  PMID: 16979075
LIDC drawing experiment; lung nodule annotation; edge mask; p-map; volume; linear mixed-effects model

Results 1-7 (7)