Wisconsin Institutes for Medical Research

Madison, WI, United States

Wisconsin Institutes for Medical Research

Madison, WI, United States

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Aziz M.H.,Wisconsin Institutes for Medical Research | Hafeez B.B.,Wisconsin Institutes for Medical Research | Sand J.M.,Wisconsin Institutes for Medical Research | Sand J.M.,Wisconsin Institutes of Medical Research | And 4 more authors.
Oncogene | Year: 2010

Protein kinase C epsilon (PKC), a novel calcium-independent PKC isoform, has been shown to be a transforming oncogene. PKC-mediated oncogenic activity is linked to its ability to promote cell survival. However, the mechanisms by which PKC signals cell survival remain elusive. We found that signal transducers and activators of transcription 3 (Stat3), which is constitutively activated in a wide variety of human cancers, is a protein partner of PKC. Stat3 has two conserved amino-acid (Tyr705 and Ser727) residues, which are phosphorylated during Stat3 activation. PKC interacts with Stat3α isoform, which has Ser727, and not with Stat3Β isoform, which lacks Ser727. PKC-Stat3 interaction and Stat3Ser727 phosphorylation was initially observed during induction of squamous cell carcinomas and in prostate cancer. Now we present that (1) PKC physically interacts with Stat3α isoform in various human cancer cells: skin melanomas (MeWo and WM266-4), gliomas (T98G and MO59K), bladder (RT-4 and UM-UC-3), colon (Caco-2), lung (H1650), pancreatic (PANC-1), and breast (MCF-7 and MDA:MB-231); (2) inhibition of PKC expression using specific siRNA inhibits Stat3Ser727 phosphorylation, Stat3-DNA binding, Stat3-regulated gene expression as well as cell invasion; and (3) PKC mediates Stat3Ser727 phosphorylation through integration with the MAPK cascade (RAF-1, MEK1/2, and ERK1/2). The results indicate that PKC-mediated Stat3Ser727 phosphorylation is essential for constitutive activation of Stat3 and cell invasion in various human cancers. © 2010 Macmillan Publishers Limited All rights reserved.


Pusztai E.,University of Wisconsin - Madison | Toulokhonova I.S.,University of Wisconsin - Madison | Temple N.,University of Wisconsin - Madison | Albright H.,University of Wisconsin - Madison | And 5 more authors.
Organometallics | Year: 2013

Several 1,3-diphenyl-substituted silafluorene compounds were synthesized and characterized as potential fluorescent materials for OLED fabrication and bioimaging. Introducing phenyl groups into the silafluorene ring at the 1- and 3-positions led to a red shift in the emission, resulting in blue light emitting compounds (λmax 368-375 nm in solution; λ max 362-371 and 482 nm in the solid state), and improved the quantum yield efficiency both in solution and as solids. Aggregation enhanced emission of the silafluorenes (AEE) was also investigated. Theoretical MO calculations were carried out to aid in understanding the optical properties of these molecules. Since these compounds might be useful in bioimaging, their toxicity was also investigated in skin fibroblast cells. All compounds were found to be nontoxic to the investigated cell cultures. © 2013 American Chemical Society.


Liu F.,Wisconsin Institutes for Medical Research | Choi K.W.,University of Wisconsin - Madison | Samsonov A.,Wisconsin Institutes for Medical Research | Samsonov A.,University of Wisconsin - Madison | And 4 more authors.
Radiology | Year: 2015

Purpose: To compare multicomponent T2 parameters of the articular cartilage of the knee joint measured by using multicomponent driven equilibrium single-shot observation of T1 and T2 (mcDESPOT) in asymptomatic volunteers and patients with osteoarthritis. Materials and Methods: This prospective study was performed with institutional review board approval and with written informed consent from all subjects. The mcDESPOT sequence was performed in the knee joint of 13 asymptomatic volunteers and 14 patients with osteoarthritis of the knee. Singlecomponent T2 (T2Single), T2 of the fast-relaxing water component (T2F) and of the slow-relaxing water component (T2S), and the fraction of the fast-relaxing water component (FF) of cartilage were measured. Wilcoxon rank-sum tests and multivariate linear regression models were used to compare mcDESPOT parameters between volunteers and patients with osteoarthritis. Receiver operating characteristic analysis was used to assess diagnostic performance with mcDESPOT parameters for distinguishing morphologically normal cartilage from morphologically degenerative cartilage identified at magnetic resonance imaging in eight cartilage subsections of the knee joint. Results: Higher cartilage T2Single (P <.001), lower cartilage FF (P <.001), and similar cartilage T2F (P =.079) and T2S (P =.124) values were seen in patients with osteoarthritis compared with those in asymptomatic volunteers. Differences in T2Single and FF remained significant (P <.05) after consideration of age differences between groups of subjects. Diagnostic performance was higher with FF than with T2Single for distinguishing between normal and degenerative cartilage (P <.05), with greater areas under the curve at receiver operating characteristic analysis. Conclusion: Patients with osteoarthritis of the knee had significantly higher cartilage T2Single and significantly lower cartilage FF than did asymptomatic volunteers, and receiver operating characteristic analysis results suggested that FF may allow greater diagnostic performance than that with T2Single for distinguishing between normal and degenerative cartilage. © 2015 RSNA.


Hwang B.,Richard Roudebush Veterans Affairs Medical Center | Hwang B.,Indiana University | Hwang B.,Wisconsin Institutes for Medical Research | Wu P.,Richard Roudebush Veterans Affairs Medical Center | And 3 more authors.
FEBS Journal | Year: 2012

Although improving glucose metabolism by inhibition of pyruvate dehydrogenase kinase 4 (PDK4) may prove beneficial in the treatment of type 2 diabetes or diet-induced obesity, it may have detrimental effects by inhibiting fatty acid oxidation. Peroxisome proliferator-activated receptor α (PPARα) agonists are often used to treat dyslipidemia in patients, especially in type 2 diabetes. Combinational treatment using a PDK4 inhibitor and PPARα agonists may prove beneficial. However, PPARα agonists may be less effective in the presence of a PDK4 inhibitor because PPARα agonists induce PDK4 expression. In the present study, the effects of clofibric acid, a PPARα agonist, on blood and liver lipids were determined in wild-type and PDK4 knockout mice fed a high-fat diet. As expected, treatment of wild-type mice with clofibric acid resulted in less body weight gain, smaller epididymal fat pads, greater insulin sensitivity, and lower levels of serum and liver triacylglycerol. Surprisingly, rather than decreasing the effectiveness of clofibric acid, PDK4 deficiency enhanced the beneficial effects of clofibric acid on hepatic steatosis, reduced blood glucose levels, and did not prevent the positive effects of clofibric acid on serum triacylglycerols and free fatty acids. The metabolic effects of clofibric acid are therefore independent of the induction of PDK4 expression. The additive beneficial effects on hepatic steatosis may be due to induction of increased capacity for fatty acid oxidation and partial uncoupling of oxidative phosphorylation by clofibric acid, and a reduction in the capacity for fatty acid synthesis as a result of PDK4 deficiency. Here we tested whether the lipid lowering effects of clofibric acid, a PPARα agonist, are affected by PDK4 deficiency. PDK4 deficiency enhanced the beneficial effects of clofibric acid on hepatic steatosis and did not prevent its hypolipidemic effects. Therefore, PDK4 inhibitor and clofibric acid could potentially be used in combination to lower blood glucose and ameliorate hepatic steatosis. © Journal compilation © 2012 FEBS. No claim to original US government works.


Kosoff D.,University of Wisconsin - Madison | Krueger T.,University of Wisconsin - Madison | Lang J.M.,University of Wisconsin - Madison | Lang J.M.,Wisconsin Institutes for Medical Research
Immunotherapy | Year: 2013

The ability to evade host immune surveillance is critical for the survival of tumor cells and is correlated with poor clinical outcomes. Many tumor types have been found to downregulate expression of genes involved in antigen production, processing and presentation to evade immune detection. Recent findings suggest that the mechanisms underlying these immune evasion phenomena extend beyond alterations in DNA sequence to include epigenetic modifications of DNA and associated proteins, including hypermethylation of DNA and altered histone acetylation patterns. This review will summarize alterations in antigen presentation machinery identified in malignant cells, epigenetic mechanisms that can be employed in the downregulation of genes relevant for antigen presentation and translational strategies to target these processes to enhance the efficacy of antitumor immunotherapies. © 2013 Future Medicine Ltd.


Goel S.,University of Wisconsin - Madison | Chen F.,University of Wisconsin - Madison | Ehlerding E.B.,Wisconsin Institutes for Medical Research | Cai W.,University of Wisconsin - Madison | Cai W.,Wisconsin Institutes for Medical Research
Small | Year: 2014

Although chelator-based radiolabeling techniques have been used for decades, concerns about the complexity of coordination chemistry, possible altering of pharmacokinetics of carriers, and potential detachment of radioisotopes during imaging have driven the need for developing a simple yet better technique for future radiolabeling. Here, the emerging concept of intrinsically radiolabeled nanoparticles, which could be synthesized using methods such as hot-plus-cold precursors, specific trapping, cation exchange, and proton beam activation, is introduced. Representative examples of using these multifunctional nanoparticles for multimodality molecular imaging are highlighted together with current challenges and future research directions. Although still in the early stages, design and synthesis of intrinsically radiolabeled nanoparticles has shown attractive potential to offer easier, faster, and more specific radiolabeling possibilities for the next generation of molecular imaging. © 2014 Wiley-VCH Verlag GmbH & Co. KGaA.


Goel S.,University of Wisconsin - Madison | Chen F.,University of Wisconsin - Madison | Ehlerding E.B.,Wisconsin Institutes for Medical Research | Cai W.,University of Wisconsin - Madison
Small | Year: 2014

Although chelator-based radiolabeling techniques have been used for decades, concerns about the complexity of coordination chemistry, possible altering of pharmacokinetics of carriers, and potential detachment of radioisotopes during imaging have driven the need for developing a simple yet better technique for future radiolabeling. Here, the emerging concept of intrinsically radiolabeled nanoparticles, which could be synthesized using methods such as hot-plus-cold precursors, specific trapping, cation exchange, and proton beam activation, is introduced. Representative examples of using these multifunctional nanoparticles for multimodality molecular imaging are highlighted together with current challenges and future research directions. Although still in the early stages, design and synthesis of intrinsically radiolabeled nanoparticles has shown attractive potential to offer easier, faster, and more specific radiolabeling possibilities for the next generation of molecular imaging. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Artz N.S.,Wisconsin Institutes for Medical Research | Wentland A.L.,Wisconsin Institutes for Medical Research | Sadowski E.A.,University of Wisconsin - Madison | Djamali A.,University of Wisconsin - Madison | And 5 more authors.
Investigative Radiology | Year: 2011

Objective: The purpose of this study was to assess the ability of a flow-sensitive alternating inversion recovery-arterial spin labeling (FAIR-ASL) technique to track renal perfusion changes during pharmacologic and physiologic alterations in renal blood flow using microspheres as a gold standard. Materials and Methods: Fluorescent microsphere and FAIR-ASL perfusion were compared in the cortex of the kidney for 11 swine across 4 interventional time points: (1) under baseline conditions, (2) during an acetylcholine and fluid bolus challenge to increase perfusion, (3) initially after switching to isoflurane anesthesia, and (4) after 2 hours of isoflurane anesthesia. In 10 of the 11 swine, a bag of ice was placed on the hilum of 1 kidney at the beginning of isoflurane administration to further reduce perfusion in 1 kidney. Results: Both ASL and microspheres tracked the expected cortical perfusion changes (P < 0.02) across the interventions, including an increase in perfusion during the acetylcholine challenge and decrease during the administration of isoflurane. Both techniques also measured lower cortical perfusion in the iced compared with the noniced kidneys (P Currency sign 0.01). The ASL values were systematically lower compared with microsphere perfusion. Very good correlation (r ≤ 0.81, P < 0.0001) was observed between the techniques, and the relationship appeared linear for perfusion values in the expected physiologic range (microsphere perfusion <550 mL/min/100 g) although ASL values saturated for perfusion >550 mL/min/100 g. Conclusion: Cortical perfusion measured with ASL correlated with microspheres and reliably detected changes in renal perfusion in response to physiologic challenge. © 2011 by Lippincott Williams & Wilkins.


Liu F.,Wisconsin Institutes for Medical Research | Samsonov A.,Wisconsin Institutes for Medical Research | Samsonov A.,University of Wisconsin - Madison | Wilson J.J.,University of Wisconsin - Madison | And 3 more authors.
Journal of Magnetic Resonance Imaging | Year: 2015

Purpose To compare multicomponent T2 parameters of menisci measured using Multicomponent Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT) in asymptomatic volunteers and osteoarthritis (OA) patients with intact and torn menisci. Materials and Methods The prospective study was performed with Institutional Review Board approval and with all subjects signing written informed consent. mcDESPOT was performed on the knee joint of 12 asymptomatic volunteers and 14 patients with knee OA. Single-component T2 relaxation time (T2Single), T2 relaxation time of the fast relaxing water component (T2F), and the slow relaxing water component (T2S), and fraction of the fast relaxing water component (FF) of the medial and lateral menisci were measured. Multivariate linear regression models were used to compare mcDESPOT parameters between normal menisci in asymptomatic volunteers, intact menisci in OA patients, and torn menisci in OA patients with adjustment for differences in age between subjects. Results The mean mcDESPOT parameters for normal menisci in asymptomatic volunteers, intact menisci in OA patients, and torn menisci in OA patients were respectively 16.1 msec, 18.8 msec, and 22.7 msec for T2Single; 9.0 msec, 10.0 msec, and 11.1 msec for T2F; 24.4 msec, 27.7 msec, and 31.4 msec for T2S; and 34%, 32%, 27% for FF. There were significant differences (P<0.05) in T2Single, T2F, T2S, and FF between the three groups of menisci. Conclusion The menisci of OA patients had significantly higher T2Single, T2F, and T2S and significantly lower FF than normal menisci in asymptomatic volunteers with greater changes in multicomponent T2 parameters noted in torn than intact menisci in OA patients. © 2015 Wiley Periodicals, Inc.


Forouzan O.,University of Wisconsin - Madison | Warczytowa J.,University of Wisconsin - Madison | Wieben O.,University of Wisconsin - Madison | Wieben O.,Wisconsin Institutes for Medical Research | And 2 more authors.
Journal of Cardiovascular Magnetic Resonance | Year: 2015

Background: Exercise stress tests are commonly used in clinical settings to monitor the functional state of the heart and vasculature. Large artery stiffness is one measure of arterial function that can be quantified noninvasively during exercise stress. Changes in proximal pulmonary artery stiffness are especially relevant to the progression of pulmonary hypertension (PH), since pulmonary artery (PA) stiffness is the best current predictor of mortality from right ventricular failure. Methods: Cardiovascular magnetic resonance (CMR) was used to investigate the effect of exercise stress on PA pulse wave velocity (PWV) and relative area change (RAC), which are both non-invasive measures of PA stiffness, in healthy subjects. All 21 subjects (average age 26 ± 4 years; 13 female and 8 male) used a custom-made MR-compatible stepping device to exercise (two stages of mild-to-moderate exercise of 3-4 min duration each) in a supine position within the confines of the scanner. To measure the cross-sectional area and blood flow velocity in the main PA (MPA), two-dimensional phase-contrast (2D-PC) CMR images were acquired. To measure the reproducibility of metrics, CMR images were analyzed by two independent observers. Inter-observer agreements were calculated using the intraclass correlation and Bland-Altman analysis. Results: From rest to the highest level of exercise, cardiac output increased from 5.9 ± 1.4 L/min to 8.2 ± 1.9 L/min (p < 0.05), MPA PWV increased from 1.6 ± 0.5 m/s to 3.6 ± 1.4 m/s (p < 0.05), and MPA RAC decreased from 0.34 ± 0.11 to 0.24 ± 0.1 (p < 0.05). While PWV also increased from the first to second exercise stage (from 2.7 ± 1.0 m/s to 3.6 ± 1.4 m/s, p < 0.05), there was no significant change in RAC between the two exercise stages. We found good inter-observer agreement for quantification of MPA flow, RAC and PWV. Conclusion: These results demonstrate that metrics of MPA stiffness increase in response to acute moderate exercise in healthy subjects and that CMR exercise stress offers great potential in clinical practice to noninvasively assess vascular function. © 2015 Forouzan et al.

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