Publications by authors named "Natalie J Serkova"

98 Publications

Preclinical Applications of Multi-Platform Imaging in Animal Models of Cancer.

Cancer Res 2021 03 1;81(5):1189-1200. Epub 2020 Dec 1.

Department of Radiology, University of Texas Southwestern, Dallas, Texas.

In animal models of cancer, oncologic imaging has evolved from a simple assessment of tumor location and size to sophisticated multimodality exploration of molecular, physiologic, genetic, immunologic, and biochemical events at microscopic to macroscopic levels, performed noninvasively and sometimes in real time. Here, we briefly review animal imaging technology and molecular imaging probes together with selected applications from recent literature. Fast and sensitive optical imaging is primarily used to track luciferase-expressing tumor cells, image molecular targets with fluorescence probes, and to report on metabolic and physiologic phenotypes using smart switchable luminescent probes. MicroPET/single-photon emission CT have proven to be two of the most translational modalities for molecular and metabolic imaging of cancers: immuno-PET is a promising and rapidly evolving area of imaging research. Sophisticated MRI techniques provide high-resolution images of small metastases, tumor inflammation, perfusion, oxygenation, and acidity. Disseminated tumors to the bone and lung are easily detected by microCT, while ultrasound provides real-time visualization of tumor vasculature and perfusion. Recently available photoacoustic imaging provides real-time evaluation of vascular patency, oxygenation, and nanoparticle distributions. New hybrid instruments, such as PET-MRI, promise more convenient combination of the capabilities of each modality, enabling enhanced research efficacy and throughput.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026542PMC
March 2021

Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG.

Cell Rep 2020 10;33(3):108286

Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA.

Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.
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http://dx.doi.org/10.1016/j.celrep.2020.108286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574900PMC
October 2020

Complement factor H-deficient mice develop spontaneous hepatic tumors.

J Clin Invest 2020 08;130(8):4039-4054

Department of Medicine, Nephrology and Hypertension, University of Colorado School of Medicine, Aurora, Colorado, USA.

Hepatocellular carcinoma (HCC) is difficult to detect, carries a poor prognosis, and is one of few cancers with an increasing yearly incidence. Molecular defects in complement factor H (CFH), a critical regulatory protein of the complement alternative pathway (AP), are typically associated with inflammatory diseases of the eye and kidney. Little is known regarding the role of CFH in controlling complement activation within the liver. While studying aging CFH-deficient (fH-/-) mice, we observed spontaneous hepatic tumor formation in more than 50% of aged fH-/- males. Examination of fH-/- livers (3-24 months) for evidence of complement-mediated inflammation revealed widespread deposition of complement-activation fragments throughout the sinusoids, elevated transaminase levels, increased hepatic CD8+ and F4/80+ cells, overexpression of hepatic mRNA associated with inflammatory signaling pathways, steatosis, and increased collagen deposition. Immunostaining of human HCC biopsies revealed extensive deposition of complement fragments within the tumors. Investigating the Cancer Genome Atlas also revealed that increased CFH mRNA expression is associated with improved survival in patients with HCC, whereas mutations are associated with worse survival. These results indicate that CFH is critical for controlling complement activation in the liver, and in its absence, AP activation leads to chronic inflammation and promotes hepatic carcinogenesis.
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http://dx.doi.org/10.1172/JCI135105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410061PMC
August 2020

Super Elongation Complex as a Targetable Dependency in Diffuse Midline Glioma.

Cell Rep 2020 04;31(1):107485

Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, CO, USA; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA; Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA. Electronic address:

Histone 3 gene mutations are the eponymous drivers in diffuse midline gliomas (DMGs), aggressive pediatric brain cancers for which no curative therapy currently exists. These recurrent oncohistones induce a global loss of repressive H3K27me3 residues and broad epigenetic dysregulation. In order to identify therapeutically targetable dependencies within this disease context, we performed an RNAi screen targeting epigenetic/chromatin-associated genes in patient-derived DMG cultures. This identified AFF4, the scaffold protein of the super elongation complex (SEC), as a molecular dependency in DMG. Interrogation of SEC function demonstrates a key role for maintaining clonogenic potential while promoting self-renewal of tumor stem cells. Small-molecule inhibition of SEC using clinically relevant CDK9 inhibitors restores regulatory RNA polymerase II pausing, promotes cellular differentiation, and leads to potent anti-tumor effect both in vitro and in patient-derived xenograft models. These studies present a rationale for further exploration of SEC inhibition as a promising therapeutic approach to this intractable disease.
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http://dx.doi.org/10.1016/j.celrep.2020.03.049DOI Listing
April 2020

Electromagnetic wave propagation in a fast pulse line ion accelerator.

Med Phys 2019 Dec 4;46(12):5714-5721. Epub 2019 Nov 4.

Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.

Purpose: The pulse line ion accelerator (PLIA) is a low-cost accelerator concept originally designed to accelerate heavy ions. Our group has been investigating the use of PLIA to accelerate light ions and believe a multi-stage PLIA could be useful for short half-life PET isotope production. The goal of this work was to develop a single prototype fast PLIA structure and demonstrate electromagnetic wave propagation using a high-voltage pulser.

Materials And Methods: A 1.6 m fast PLIA structure (wave speed > 10  m/s) was constructed along with a high-voltage, sinusoidal pulse generator. The latter uses capacitive voltage doubling and spark gap switching. A step-up transformer couples voltage from the pulser to the PLIA coil. Voltage measurements on the coil were made in air using a high-voltage resistive probe, while capacitive probes placed along the length of the PLIA were used to measure wave propagation with the PLIA structure filled with transformer oil.

Results: Voltage measurements acquired on the primary and secondary coils of the transformer coupler in air demonstrated a peak-to-peak voltage step-up of 4.2 relative to the pulser DC charging voltage. The maximum voltage time-rate-of-change on the PLIA coil was 0.76 × 10  V/s. Capacitive probe measurements indicated voltage oscillations on the PLIA coil with half-period equal to 43 ± 0.9 ns and wave speed (with oil) of 1.2 × 10  m/s. Average and peak accelerating gradients were conservatively estimated to be 0.44 and 0.60 MV/m, respectively, with a charging voltage of 55 kV. Wave propagation was demonstrated at these gradients without flashover at a vacuum pressure of 9 × 10  Torr. Submerging the pulser in oil would allow for charging voltages up to 150 kV and produce accelerating gradients >1.2 MV/m.

Conclusions: Use of a multi-stage, fast PLIA for light ion acceleration could provide a low-cost complement to cyclotrons for the production of short half-life isotopes used for PET imaging, including carbon-11, nitrogen-13, oxygen-15, and fluorine-18.
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http://dx.doi.org/10.1002/mp.13875DOI Listing
December 2019

Feraheme (Ferumoxytol) Is Recognized by Proinflammatory and Anti-inflammatory Macrophages via Scavenger Receptor Type AI/II.

Mol Pharm 2019 10 26;16(10):4274-4281. Epub 2019 Sep 26.

Colorado Center for Nanomedicine and Nanosafety , University of Colorado Anschutz Medical Campus , Aurora , Colorado 80045 , United States.

Feraheme (ferumoxytol), a negatively charged, carboxymethyl dextran-coated ultrasmall superparamagnetic iron oxide nanoparticle (USPIO, 30 nm, -16 mV), is clinically approved as an iron supplement and is used off-label for magnetic resonance imaging (MRI) of macrophage-rich lesions, but the mechanism of recognition is not known. We investigated mechanisms of uptake of Feraheme by various types of macrophages and . The uptake by mouse peritoneal macrophages was not inhibited in complement-deficient serum. In contrast, the uptake of larger and less charged SPIO nanoworms (60 nm, -5 mV; 120 nm, -5 mV, respectively) was completely inhibited in complement deficient serum, which could be attributed to more C3 molecules bound per nanoparticle than Feraheme. The uptake of Feraheme was blocked by scavenger receptor (SR) inhibitor polyinosinic acid (PIA) and by antibody against scavenger receptor type A I/II (SR-AI/II). Antibodies against other SRs including MARCO, CD14, SR-BI, and CD11b had no effect on Feraheme uptake. Intraperitoneally administered PIA inhibited the peritoneal macrophage uptake of Feraheme . Nonmacrophage cells transfected with SR-AI plasmid efficiently internalized Feraheme but not noncharged ultrasmall SPIO of the same size (26 nm, -6 mV), suggesting that the anionic carboxymethyl groups of Feraheme are responsible for the SR-AI recognition. The uptake by nondifferentiated bone marrow derived macrophages (BMDM) and by BMDM differentiated into M1 (proinflammatory) and M2 (anti-inflammatory) types was efficiently inhibited by PIA and anti-SR-AI/II antibody. Interestingly, all BMDM types expressed similar levels of SR-AI/II. In conclusion, Feraheme is efficiently recognized via SR-AI/II but not via complement by different macrophage types. The recognition by the common phagocytic receptor has implications for specificity of imaging of macrophage subtypes.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513579PMC
October 2019

Establishment of patient-derived orthotopic xenograft model of 1q+ posterior fossa group A ependymoma.

Neuro Oncol 2019 12;21(12):1540-1551

Department of Pediatrics, University of Colorado Denver, Aurora, Colorado.

Background: Treatment for pediatric posterior fossa group A (PFA) ependymoma with gain of chromosome 1q (1q+) has not improved over the past decade owing partially to lack of clinically relevant models. We described the first 2 1q+ PFA cell lines, which have significantly enhanced our understanding of PFA tumor biology and provided a tool to identify specific 1q+ PFA therapies. However, cell lines do not accurately replicate the tumor microenvironment. Our present goal is to establish patient-derived xenograft (PDX) mouse models.

Methods: Disaggregated tumors from 2 1q+ PFA patients were injected into the flanks of NSG mice. Flank tumors were then transplanted into the fourth ventricle or lateral ventricle of NSG mice. Characterization of intracranial tumors was performed using imaging, histology, and bioinformatics.

Results: MAF-811_XC and MAF-928_XC established intracranially within the fourth ventricle and retained histological, methylomic, and transcriptomic features of primary patient tumors. We tested the feasibility of treating PDX mice with fractionated radiation or chemotherapy. Mice tolerated radiation despite significant tumor burden, and follow-up imaging confirmed radiation can reduce tumor size. Treatment with fluorouracil reduced tumor size but did not appear to prolong survival.

Conclusions: MAF-811_XC and MAF-928_XC are novel, authentic, and reliable models for studying 1q+ PFA in vivo. Given the successful response to radiation, these models will be advantageous for testing clinically relevant combination therapies to develop future clinical trials for this high-risk subgroup of pediatric ependymoma.
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http://dx.doi.org/10.1093/neuonc/noz116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917412PMC
December 2019

Bitter melon juice-intake modulates glucose metabolism and lactate efflux in tumors in its efficacy against pancreatic cancer.

Carcinogenesis 2019 Sep;40(9):1164-1176

Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver-Anschutz Medical Campus, Aurora, CO, USA.

The established role of bitter melon juice (BMJ), a natural product, in activating master metabolic regulator adenosine monophosphate-activated protein kinase in pancreatic cancer (PanC) cells served as a basis for pursuing deeper investigation into the underlying metabolic alterations leading to BMJ efficacy in PanC. We investigated the comparative metabolic profiles of PanC cells with differential KRAS mutational status on BMJ exposure. Specifically, we employed nuclear magnetic resonance (NMR) metabolomics and in vivo imaging platforms to understand the relevance of altered metabolism in PanC management by BMJ. Multinuclear NMR metabolomics was performed, as a function of time, post-BMJ treatment followed by partial least square discriminant analysis assessments on the quantitative metabolic data sets to visualize the treatment group clustering; altered glucose uptake, lactate export and energy state were identified as the key components responsible for cell death induction. We next employed PANC1 xenograft model for assessing in vivo BMJ efficacy against PanC. Positron emission tomography ([18FDG]-PET) and magnetic resonance imaging on PANC1 tumor-bearing animals reiterated the in vitro results, with BMJ-associated significant changes in tumor volumes, tumor cellularity and glucose uptake. Additional studies in BMJ-treated PanC cells and xenografts displayed a strong decrease in the expression of glucose and lactate transporters GLUT1 and MCT4, respectively, supporting their role in metabolic changes by BMJ. Collectively, these results highlight BMJ-induced modification in PanC metabolomics phenotype and establish primarily lactate efflux and glucose metabolism, specifically GLUT1 and MCT4 transporters, as the potential metabolic targets underlying BMJ efficacy in PanC.
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http://dx.doi.org/10.1093/carcin/bgz114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384253PMC
September 2019

Quantitative NMR-Based Metabolomics on Tissue Biomarkers and Its Translation into In Vivo Magnetic Resonance Spectroscopy.

Methods Mol Biol 2019 ;1978:369-387

Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA.

Nuclear magnetic resonance (NMR) spectroscopy is an established analytical platform for analyzing metabolic profiles of cells, tissues, and body fluids. There are several advantages in introducing an NMR-based study design into metabolomics studies, including a fast and comprehensive detection, characterization, and quantification of dozens of endogenous metabolites in a single NMR spectrum. Quantitative proton H-NMR is the most useful NMR-based platform for metabolomics. The frozen tissues can be analyzed noninvasively using a high-resolution magic angle spinning (HR-MAS) H-NMR spectroscopy; or several extraction techniques can be applied to detect additional metabolites using a conventional liquid-based NMR technique. In this chapter, we report on tissue collection, handling, extraction methods, and H-NMR acquisition protocols developed in the past decades for a precise and quantitative NMR-metabolomics approach. The NMR acquisition protocols (both HR-MAS and conventional H-NMR spectroscopy) and spectral analysis steps are also presented. Since NMR can be applied "in vivo" using horizontal bore MRI scanners, several in vivo sequences for localized H-MRS (magnetic resonance spectroscopy) are presented which can be directly applied for noninvasive detection of brain metabolites.
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http://dx.doi.org/10.1007/978-1-4939-9236-2_23DOI Listing
November 2019

Inhibition of EphB4-Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers.

Cancer Res 2019 05 20;79(10):2722-2735. Epub 2019 Mar 20.

Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.

Identifying targets present in the tumor microenvironment that contribute to immune evasion has become an important area of research. In this study, we identified EphB4-ephrin-B2 signaling as a regulator of both innate and adaptive components of the immune system. EphB4 belongs to receptor tyrosine kinase family that interacts with ephrin-B2 ligand at sites of cell-cell contact, resulting in bidirectional signaling. We found that EphB4-ephrin-B2 inhibition alone or in combination with radiation (RT) reduced intratumoral regulatory T cells (Tregs) and increased activation of both CD8 and CD4Foxp3 T cells compared with the control group in an orthotopic head and neck squamous cell carcinoma (HNSCC) model. We also compared the effect of EphB4-ephrin-B2 inhibition combined with RT with combined anti-PDL1 and RT and observed similar tumor growth suppression, particularly at early time-points. A patient-derived xenograft model showed reduction of tumor-associated M2 macrophages and favored polarization towards an antitumoral M1 phenotype following EphB4-ephrin-B2 inhibition with RT. , EphB4 signaling inhibition decreased Ki67-expressing Tregs and Treg activation compared with the control group. Overall, our study is the first to implicate the role of EphB4-ephrin-B2 in tumor immune response. Moreover, our findings suggest that EphB4-ephrin-B2 inhibition combined with RT represents a potential alternative for patients with HNSCC and could be particularly beneficial for patients who are ineligible to receive or cannot tolerate anti-PDL1 therapy. SIGNIFICANCE: These findings present EphB4-ephrin-B2 inhibition as an alternative to anti-PDL1 therapeutics that can be used in combination with radiation to induce an effective antitumor immune response in patients with HNSCC.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522285PMC
May 2019

Differential effects of intrauterine growth restriction and a hypersinsulinemic-isoglycemic clamp on metabolic pathways and insulin action in the fetal liver.

Am J Physiol Regul Integr Comp Physiol 2019 05 13;316(5):R427-R440. Epub 2019 Feb 13.

Perinatal Research Center, Department of Pediatrics, University of Colorado School of Medicine , Aurora, Colorado.

Intrauterine growth-restricted (IUGR) fetal sheep have increased hepatic glucose production (HGP) that is resistant to suppression during a hyperinsulinemic-isoglycemic clamp (insulin clamp). We hypothesized that the IUGR fetal liver would have activation of metabolic and signaling pathways that support HGP and inhibition of insulin-signaling pathways. To test this, we used transcriptomic profiling with liver samples from control (CON) and IUGR fetuses receiving saline or an insulin clamp. The IUGR liver had upregulation of genes associated with gluconeogenesis/glycolysis, transcription factor regulation, and cytokine responses and downregulation of genes associated with cholesterol synthesis, amino acid degradation, and detoxification pathways. During the insulin clamp, genes associated with cholesterol synthesis and innate immune response were upregulated in CON and IUGR. There were 20-fold more genes differentially expressed during the insulin clamp in IUGR versus CON. These genes were associated with proteasome activation and decreased amino acid and lipid catabolism. We found increased , , and expression and decreased expression as molecular targets for increased HGP in IUGR. As candidate genes for resistance to insulin's suppression of HGP, expression of , , and increased more during the insulin clamp in CON compared with IUGR. Metabolites were measured with H-nuclear magnetic resonance and support increased amino acid concentrations, decreased mitochondria activity and energy state, and increased cell stress in the IUGR liver. These results demonstrate a robust response, beyond suppression of HGP, during the insulin clamp and coordinate responses in glucose, amino acid, and lipid metabolism in the IUGR fetus.
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http://dx.doi.org/10.1152/ajpregu.00359.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589601PMC
May 2019

Subversion of Systemic Glucose Metabolism as a Mechanism to Support the Growth of Leukemia Cells.

Cancer Cell 2018 10 27;34(4):659-673.e6. Epub 2018 Sep 27.

Division of Hematology, University of Colorado Anschutz Medical Campus, 12700 E 19(th) Avenue, Aurora, CO 80045, USA. Electronic address:

From an organismal perspective, cancer cell populations can be considered analogous to parasites that compete with the host for essential systemic resources such as glucose. Here, we employed leukemia models and human leukemia samples to document a form of adaptive homeostasis, where malignant cells alter systemic physiology through impairment of both host insulin sensitivity and insulin secretion to provide tumors with increased glucose. Mechanistically, tumor cells induce high-level production of IGFBP1 from adipose tissue to mediate insulin sensitivity. Further, leukemia-induced gut dysbiosis, serotonin loss, and incretin inactivation combine to suppress insulin secretion. Importantly, attenuated disease progression and prolonged survival are achieved through disruption of the leukemia-induced adaptive homeostasis. Our studies provide a paradigm for systemic management of leukemic disease.
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http://dx.doi.org/10.1016/j.ccell.2018.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177322PMC
October 2018

Cabozantinib Exhibits Potent Antitumor Activity in Colorectal Cancer Patient-Derived Tumor Xenograft Models via Autophagy and Signaling Mechanisms.

Mol Cancer Ther 2018 10 19;17(10):2112-2122. Epub 2018 Jul 19.

Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.

Antiangiogenic therapy used in treatment of metastatic colorectal cancer (mCRC) inevitably succumbs to treatment resistance. Upregulation of MET may play an essential role to acquired anti-VEGF resistance. We previously reported that cabozantinib (XL184), an inhibitor of receptor tyrosine kinases (RTK) including MET, AXL, and VEGFR2, had potent antitumor effects in mCRC patient-derived tumor explant models. In this study, we examined the mechanisms of cabozantinib sensitivity, using regorafenib as a control. The tumor growth inhibition index (TGII) was used to compare treatment effects of cabozantinib 30 mg/kg daily versus regorafenib 10 mg/kg daily for a maximum of 28 days in 10 PDX mouse models. angiogenesis and glucose uptake were assessed using dynamic contrast-enhanced (DCE)-MRI and [F]-FDG-PET imaging, respectively. RNA-Seq, RTK assay, and immunoblotting analysis were used to evaluate gene pathway regulation and Analysis of TGII demonstrated significant antitumor effects with cabozantinib compared with regorafenib (average TGII 3.202 vs. 48.48, respectively; = 0.007). Cabozantinib significantly reduced vascularity and glucose uptake compared with baseline. Gene pathway analysis showed that cabozantinib significantly decreased protein activity involved in glycolysis and upregulated proteins involved in autophagy compared with control, whereas regorafenib did not. The combination of two separate antiautophagy agents, SBI-0206965 and chloroquine, plus cabozantinib increased apoptosis Cabozantinib demonstrated significant antitumor activity, reduction in tumor vascularity, increased autophagy, and altered cell metabolism compared with regorafenib. Our findings support further evaluation of cabozantinib and combinational approaches targeting autophagy in colorectal cancer. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168336PMC
October 2018

The cysteine-rich whey protein supplement, Immunocal®, preserves brain glutathione and improves cognitive, motor, and histopathological indices of traumatic brain injury in a mouse model of controlled cortical impact.

Free Radic Biol Med 2018 08 27;124:328-341. Epub 2018 Jun 27.

University of Denver, Department of Biological Sciences and Knoebel Institute for Healthy Aging, 2155 E. Wesley Ave., Denver, CO 80208, United States. Electronic address:

Traumatic brain injury (TBI) is a major public health problem estimated to affect nearly 1.7 million people in the United States annually. Due to the often debilitating effects of TBI, novel preventative agents are highly desirable for at risk populations. Here, we tested a whey protein supplement, Immunocal®, for its potential to enhance resilience to TBI. Immunocal® is a non-denatured whey protein preparation which has been shown to act as a cysteine delivery system to increase levels of the essential antioxidant glutathione (GSH). Twice daily oral supplementation of CD1 mice with Immunocal for 28 days prior to receiving a moderate TBI prevented an ~ 25% reduction in brain GSH/GSSG observed in untreated TBI mice. Immunocal® had no significant effect on the primary mechanical injury induced by TBI, as assessed by MRI, changes in Tau phosphorylation, and righting reflex time or apnea. However, pre-injury supplementation with Immunocal® resulted in statistically significant improvements in motor function (beam walk and rotarod) and cognitive function (Barnes maze). We also observed a significant preservation of corpus callosum width (axonal myelination), a significant decrease in degenerating neurons, a reduction in Iba1 (microglial marker), decreased lipid peroxidation, and preservation of brain-derived neurotrophic factor (BDNF) in the brains of Immunocal®-pretreated mice compared to untreated TBI mice. Taken together, these data indicate that pre-injury supplementation with Immunocal® significantly enhances the resilience to TBI induced by a moderate closed head injury in mice. We conclude that Immunocal® may hold significant promise as a preventative agent for TBI, particularly in certain high risk populations such as athletes and military personnel.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211803PMC
August 2018

Design considerations for a pulse line ion accelerator (PLIA)-based PET isotope generator.

Med Phys 2018 Jun 15. Epub 2018 Jun 15.

Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.

Purpose: Positron emission tomography (PET) imaging remains limited due to the cost associated with on-site production of short half-life, positron-emitting isotopes. In this work, we examine the use of a pulse line ion accelerator (PLIA) to accelerate protons for single-dose PET isotope production.

Methods: Time-domain electromagnetic field and particle-in-cell (PIC) simulations were performed for a 1.5-m PLIA structure modeled in CST Microwave Studio and Particle Studio software. Scaled measurements from a kV ramp-pulse generator were incorporated into the simulations to accelerate a 1 A, 50 ns proton beam injected with initial kinetic energy of 100 keV. A uniform, 3 T, solenoidal magnetic field was used to provide external beam focusing. Electromagnetic fields and particle phase space were recorded with ns resolution for subsequent analysis.

Results: Applying a scaled 100 kV, 20 ns ramped voltage pulse to the PLIA input resulted in a travelling electric field wave inside the structure with accelerating gradient of 2.4 MV/m. The observed wave speed was 1.2 × 10 m/s and is in good agreement with theoretical predictions. Phase space monitors showed both acceleration and bunching of the proton beam, with a maximum kinetic energy of 2.5 MeV, observed at the exit of the single PLIA stage. Evaluation of beam position monitors at different locations in the accelerator showed bunch compression and minimal beam divergence, illustrating that the 3 T field is adequate to contain the beam over the length of the PLIA structure.

Conclusion: Simulations performed in this work demonstrate the feasibility of using a PLIA structure to accelerate protons with MV/m level gradients. Combining several PLIA stages in series could allow for a low-cost accelerator suitable for dose-on-demand PET isotope production.
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http://dx.doi.org/10.1002/mp.13050DOI Listing
June 2018

Unique Heterogeneous Topological Pattern of the Metabolic Landscape in Rabbit Fetal Lungs following Tracheal Occlusion.

Fetal Diagn Ther 2019 18;45(3):145-154. Epub 2018 Apr 18.

Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA.

Introduction: Fetal tracheal occlusion (TO) is currently an experimental approach to drive accelerated lung growth. It is stimulated by mechanotransduction that results in increased cellular proliferation and growth. However, it is currently unknown how TO affects the metabolic landscape of fetal lungs.

Materials And Methods: TO or sham was performed on fetal rabbits at 26 days followed by lung harvest on day 30. Mass spectrometry was performed to evaluate global metabolic changes. Fluorescence lifetime intensity microscopy (FLIM) was performed to estimate local free/bound NADH relative ratio as an indicator of aerobic glycolysis versus oxidative phosphorylation (glycolysis/OXPHOS).

Results: TO results in a metabolic shift from tricarboxylic acid cycle towards glycolysis. FLIM reveals uniform structures in control lungs characterized by similar ratios of free/bound NADH indicating a homogenous topological pattern. Similar uniform structures are observed in shams with some variability in the glycolysis/OXPHOS ratio. In contrast, lungs following TO demonstrate different types of unique distinct topological zones: one with enlarged alveoli and a shift towards glycolysis; the other maintains balance between glycolysis/OXPHOS similar to control lungs.

Conclusion: We demonstrate for the first time a unique variable topological pattern of metabolism in fetal lungs following TO with a wide variation of metabolism between zones.
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http://dx.doi.org/10.1159/000487752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314905PMC
July 2019

Development of Novel Patient-Derived Xenografts from Breast Cancer Brain Metastases.

Front Oncol 2017 2;7:252. Epub 2017 Nov 2.

Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.

Brain metastases are an increasing burden among breast cancer patients, particularly for those with HER2 and triple negative (TN) subtypes. Mechanistic insight into the pathophysiology of brain metastases and preclinical validation of therapies has relied almost exclusively on intracardiac injection of brain-homing cells derived from highly aggressive TN MDA-MB-231 and HER2 BT474 breast cancer cell lines. Yet, these well characterized models are far from representing the tumor heterogeneity observed clinically and, due to their fast progression , their suitability to validate therapies for established brain metastasis remains limited. The goal of this study was to develop and characterize novel human brain metastasis breast cancer patient-derived xenografts (BM-PDXs) to study the biology of brain metastasis and to serve as tools for testing novel therapeutic approaches. We obtained freshly resected brain metastases from consenting donors with breast cancer. Tissue was immediately implanted in the mammary fat pad of female immunocompromised mice and expanded as BM-PDXs. Brain metastases from 3/4 (75%) TN, 1/1 (100%) estrogen receptor positive (ER), and 5/9 (55.5%) HER2 clinical subtypes were established as transplantable BM-PDXs. To facilitate tracking of metastatic dissemination using BM-PDXs, we labeled PDX-dissociated cells with EGFP-luciferase followed by reimplantation in mice, and generated a BM-derived cell line (F2-7). Immunohistologic analyses demonstrated that parental and labeled BM-PDXs retained expression of critical clinical markers such as ER, progesterone receptor, epidermal growth factor receptor, HER2, and the basal cell marker cytokeratin 5. Similarly, RNA sequencing analysis showed clustering of parental, labeled BM-PDXs and their corresponding cell line derivative. Intracardiac injection of dissociated cells from BM-E22-1, resulted in magnetic resonance imaging-detectable macrometastases in 4/8 (50%) and micrometastases (8/8) (100%) mice, suggesting that BM-PDXs remain capable of colonizing the brain at high frequencies. Brain metastases developed 8-12 weeks after ic injection, located to the brain parenchyma, grew around blood vessels, and elicited astroglia activation characteristic of breast cancer brain metastasis. These novel BM-PDXs represent heterogeneous and clinically relevant models to study mechanisms of brain metastatic colonization, with the added benefit of a slower progression rate that makes them suitable for preclinical testing of drugs in therapeutic settings.
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http://dx.doi.org/10.3389/fonc.2017.00252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673842PMC
November 2017

Folate dietary insufficiency and folic acid supplementation similarly impair metabolism and compromise hematopoiesis.

Haematologica 2017 12 7;102(12):1985-1994. Epub 2017 Sep 7.

Department of Biochemistry and Molecular Genetics, University of Colorado AMC, Aurora, CO, USA

While dietary folate deficiency is associated with increased risk for birth defects and other diseases, evidence suggests that supplementation with folic acid can contribute to predisposition to some diseases, including immune dysfunction and cancer. Herein, we show that diets supplemented with folic acid both below and above the recommended levels led to significantly altered metabolism in multiple tissues in mice. Surprisingly, both low and excessive dietary folate induced similar metabolic changes, which were particularly evident for nucleotide biosynthetic pathways in B-progenitor cells. Diet-induced metabolic changes in these cells partially phenocopied those observed in mice treated with anti-folate drugs, suggesting that both deficiency and excessive levels of dietary folic acid compromise folate-dependent biosynthetic pathways. Both folate deficiency and excessive dietary folate levels compromise hematopoiesis, resulting in defective cell cycle progression, persistent DNA damage, and impaired production of lymphocytes. These defects reduce the reconstitution potential in transplantation settings and increase radiation-induced mortality. We conclude that excessive folic acid supplementation can metabolically mimic dietary folate insufficiency, leading to similar functional impairment of hematopoiesis.
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http://dx.doi.org/10.3324/haematol.2017.171074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709097PMC
December 2017

MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer.

Cancer Cell 2017 07;32(1):71-87.e7

Department of Anesthesiology, University of Colorado Denver, Aurora, CO 80045, USA.

Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. We also demonstrate that MUC1-regulated stabilization of hypoxia inducible factor-1α (HIF-1α) mediates such metabolic reprogramming. Targeting HIF-1α or de novo pyrimidine biosynthesis, in combination with gemcitabine, strongly diminishes tumor burden. Finally, reduced expression of TKT and CTPS, which regulate flux into pyrimidine biosynthesis, correlates with better prognosis in pancreatic cancer patients on fluoropyrimidine analogs.
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http://dx.doi.org/10.1016/j.ccell.2017.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533091PMC
July 2017

Nanoparticle-Based Magnetic Resonance Imaging on Tumor-Associated Macrophages and Inflammation.

Front Immunol 2017 22;8:590. Epub 2017 May 22.

Department of Anesthesiology, Anschutz Medical Center, Aurora, CO, USA.

The inflammatory response, mediated by tissue-resident or newly recruited macrophages, is an underlying pathophysiological condition for many diseases, including diabetes, obesity, neurodegeneration, atherosclerosis, and cancer. Paradoxically, inflammation is a double-edged sword in oncology. Macrophages are, generally speaking, the major drivers of inflammatory insult. For many solid tumors, high density of cells expressing macrophage-associated markers have generally been found in association with a poor clinical outcome, characterized by inflamed microenvironment, a high level of dissemination and resistance to conventional chemotherapies. On another hand, radiation treatment also triggers an inflammatory response in tumors (often referred to as pseudoprogression), which can be associated with a positive treatment response. As such, non-invasive imaging of cancer inflammation and tumor-associated macrophages (TAMs) provides a revolutionary diagnostic tool and monitoring strategy for anti-inflammatory, immuno- and radiotherapies. Recently, quantitative T2-weighted magnetic resonance imaging (qT2wMRI), using injection of superparamagnetic iron oxide nanoparticles (SPIONs), has been reported for the assessment of TAMs non-invasively in animal models and in human trials. The SPIONs are magnetic resonance imaging (MRI) contrast agents that significantly decrease T2 MR relaxation times in inflamed tissues due to the macrophage-specific uptake and retention. It has been shown that macrophage-populated tumors and metastases will accumulate iron oxide nanoparticles and decrease T2-relaxation time that will result in a negative (dark) contrast in qT2wMRI. Non-invasive imaging of TAMs using SPION holds a great promise for staging the inflammatory microenvironment of primary and metastatic tumors as well monitoring the treatment response of cancer patients treated with radiation and immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2017.00590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439008PMC
May 2017

Mechanisms and Barriers in Cancer Nanomedicine: Addressing Challenges, Looking for Solutions.

ACS Nano 2017 01 9;11(1):12-18. Epub 2017 Jan 9.

Sanford Burnham Prebys Medical Discovery Institute , La Jolla, California 92037, United States.

Remarkable progress has recently been made in the synthesis and characterization of engineered nanoparticles for imaging and treatment of cancers, resulting in several promising candidates in clinical trials. Despite these advances, clinical applications of nanoparticle-based therapeutic/imaging agents remain limited by biological, immunological, and translational barriers. In order to overcome the existing status quo in drug delivery, there is a need for open and frank discussion in the nanomedicine community on what is needed to make qualitative leaps toward translation. In this Nano Focus, we present the main discussion topics and conclusions from a recent workshop: "Mechanisms and Barriers in Nanomedicine". The focus of this informal meeting was on biological, toxicological, immunological, and translational aspects of nanomedicine and approaches to move the field forward productively. We believe that these topics reflect the most important issues in cancer nanomedicine.
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http://dx.doi.org/10.1021/acsnano.6b08244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542883PMC
January 2017

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia.

Proc Natl Acad Sci U S A 2016 10 10;113(43):E6669-E6678. Epub 2016 Oct 10.

Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, CO 80045; School of Medicine, University of Colorado, Aurora, CO 80045; Integrated Department of Immunology, University of Colorado, Aurora, CO 80045; Cancer Biology Program, University of Colorado, Aurora, CO 80045; Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado, Aurora, CO 80045

Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.
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http://dx.doi.org/10.1073/pnas.1603876113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5086999PMC
October 2016

Metabolic Reprogramming Regulates the Proliferative and Inflammatory Phenotype of Adventitial Fibroblasts in Pulmonary Hypertension Through the Transcriptional Corepressor C-Terminal Binding Protein-1.

Circulation 2016 10 25;134(15):1105-1121. Epub 2016 Aug 25.

From Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics and Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO (M.L., S.R., H.Z., A.F., B.A.M., M.F., S.K., M.A.F., K.R.S.); Department of Biochemistry and Molecular Genetics and Biological Mass Spectrometry Shared Resource (A.D., K.C.H.), Department of Anesthesiology (N.J.S.), Advanced Light Microscopy Core Facility (R.M.), Department of Dermatology (H.L., H.L., Q.Z.), and Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition (K.C.E.K.), University of Colorado, Denver; Department of Mitochondrial Physiology, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (L.P.-H., P.J.); Department of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (D.I., S.P.); Center for Genetic Improvement of Livestock, Department of Animal Bioscience, University of Guelph, Guelph, ON, Canada (A.C.); Department of Animal Science, University of California-Davis, Davis (J.F.M.); and Department of Animal Science, Colorado State University, Fort Collins (M.G.T.).

Background: Changes in metabolism have been suggested to contribute to the aberrant phenotype of vascular wall cells, including fibroblasts, in pulmonary hypertension (PH). Here, we test the hypothesis that metabolic reprogramming to aerobic glycolysis is a critical adaptation of fibroblasts in the hypertensive vessel wall that drives proliferative and proinflammatory activation through a mechanism involving increased activity of the NADH-sensitive transcriptional corepressor C-terminal binding protein 1 (CtBP1).

Methods: RNA sequencing, quantitative polymerase chain reaction,C-nuclear magnetic resonance, fluorescence-lifetime imaging, mass spectrometry-based metabolomics, and tracing experiments with U-C-glucose were used to assess glycolytic reprogramming and to measure the NADH/NAD ratio in bovine and human adventitial fibroblasts and mouse lung tissues. Immunohistochemistry was used to assess CtBP1 expression in the whole-lung tissues. CtBP1 siRNA and the pharmacological inhibitor 4-methylthio-2-oxobutyric acid (MTOB) were used to abrogate CtBP1 activity in cells and hypoxic mice.

Results: We found that adventitial fibroblasts from calves with severe hypoxia-induced PH and humans with idiopathic pulmonary arterial hypertension (PH-Fibs) displayed aerobic glycolysis when cultured under normoxia, accompanied by increased free NADH and NADH/NAD ratios. Expression of the NADH sensor CtBP1 was increased in vivo and in vitro in fibroblasts within the pulmonary adventitia of humans with idiopathic pulmonary arterial hypertension and animals with PH and cultured PH-Fibs, respectively. Decreasing NADH pharmacologically with MTOB or genetically blocking CtBP1 with siRNA upregulated the cyclin-dependent genes (p15 and p21) and proapoptotic regulators (NOXA and PERP), attenuated proliferation, corrected the glycolytic reprogramming phenotype of PH-Fibs, and augmented transcription of the anti-inflammatory gene HMOX1. Chromatin immunoprecipitation analysis demonstrated that CtBP1 directly binds the HMOX1 promoter. Treatment of hypoxic mice with MTOB decreased glycolysis and expression of inflammatory genes, attenuated proliferation, and suppressed macrophage numbers and remodeling in the distal pulmonary vasculature.

Conclusions: CtBP1 is a critical factor linking changes in cell metabolism to cell phenotype in hypoxic and other forms of PH and a therapeutic target.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069179PMC
http://dx.doi.org/10.1161/CIRCULATIONAHA.116.023171DOI Listing
October 2016

Silibinin inhibits hypoxia-induced HIF-1α-mediated signaling, angiogenesis and lipogenesis in prostate cancer cells: In vitro evidence and in vivo functional imaging and metabolomics.

Mol Carcinog 2017 03 5;56(3):833-848. Epub 2016 Sep 5.

Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado.

Hypoxia is associated with aggressive phenotype and poor prognosis in prostate cancer (PCa) patients suggesting that PCa growth and progression could be controlled via targeting hypoxia-induced signaling and biological effects. Here, we analyzed silibinin (a natural flavonoid) efficacy to target cell growth, angiogenesis, and metabolic changes in human PCa, LNCaP, and 22Rv1 cells under hypoxic condition. Silibinin treatment inhibited the proliferation, clonogenicity, and endothelial cells tube formation by hypoxic (1% O ) PCa cells. Interestingly, hypoxia promoted a lipogenic phenotype in PCa cells via activating acetyl-Co A carboxylase (ACC) and fatty acid synthase (FASN) that was inhibited by silibinin treatment. Importantly, silibinin treatment strongly decreased hypoxia-induced HIF-1α expression in PCa cells together with a strong reduction in hypoxia-induced NADPH oxidase (NOX) activity. HIF-1α overexpression in LNCaP cells significantly increased the lipid accumulation and NOX activity; however, silibinin treatment reduced HIF-1α expression, lipid levels, clonogenicity, and NOX activity even in HIF-1α overexpressing LNCaP cells. In vivo, silibinin feeding (200 mg/kg body weight) to male nude mice with 22Rv1 tumors, specifically inhibited tumor vascularity (measured by dynamic contrast-enhanced MRI) resulting in tumor growth inhibition without directly inducing necrosis (as revealed by diffusion-weighted MRI). Silibinin feeding did not significantly affect tumor glucose uptake measured by FDG-PET; however, reduced the lipid synthesis measured by quantitative H-NMR metabolomics. IHC analyses of tumor tissues confirmed that silibinin feeding decreased proliferation and angiogenesis as well as reduced HIF-1α, FASN, and ACC levels. Together, these findings further support silibinin usefulness against PCa through inhibiting hypoxia-induced signaling. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/mc.22537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637733PMC
March 2017

Metabolic Imaging to Assess Treatment Response to Cytotoxic and Cytostatic Agents.

Front Oncol 2016 15;6:152. Epub 2016 Jul 15.

Developmental Therapeutics Program, University of Colorado Comprehensive Cancer Center, Aurora, CO, USA; Division of Medical Oncology, Anschutz Medical Center, University of Colorado Denver, Aurora, CO, USA.

For several decades, cytotoxic chemotherapeutic agents were considered the basis of anticancer treatment for patients with metastatic tumors. A decrease in tumor burden, assessed by volumetric computed tomography and magnetic resonance imaging, according to the response evaluation criteria in solid tumors (RECIST), was considered as a radiological response to cytotoxic chemotherapies. In addition to RECIST-based dimensional measurements, a metabolic response to cytotoxic drugs can be assessed by positron emission tomography (PET) using (18)F-fluoro-thymidine (FLT) as a radioactive tracer for drug-disrupted DNA synthesis. The decreased (18)FLT-PET uptake is often seen concurrently with increased apparent diffusion coefficients by diffusion-weighted imaging due to chemotherapy-induced changes in tumor cellularity. Recently, the discovery of molecular origins of tumorogenesis led to the introduction of novel signal transduction inhibitors (STIs). STIs are targeted cytostatic agents; their effect is based on a specific biological inhibition with no immediate cell death. As such, tumor size is not anymore a sensitive end point for a treatment response to STIs; novel physiological imaging end points are desirable. For receptor tyrosine kinase inhibitors as well as modulators of the downstream signaling pathways, an almost immediate inhibition in glycolytic activity (the Warburg effect) and phospholipid turnover (the Kennedy pathway) has been seen by metabolic imaging in the first 24 h of treatment. The quantitative imaging end points by magnetic resonance spectroscopy and metabolic PET (including 18F-fluoro-deoxy-glucose, FDG, and total choline) provide an early treatment response to targeted STIs, before a reduction in tumor burden can be seen.
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http://dx.doi.org/10.3389/fonc.2016.00152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946377PMC
July 2016

Clinical translation of ferumoxytol-based vessel size imaging (VSI): Feasibility in a phase I oncology clinical trial population.

Magn Reson Med 2017 02 26;77(2):814-825. Epub 2016 Feb 26.

Clinical Imaging Group, Genentech, Inc., South San Francisco, California, USA.

Purpose: To assess the feasibility of acquiring vessel size imaging (VSI) metrics using ferumoxytol injections and stock pulse sequences in a multicenter Phase I trial of a novel therapy in patients with advanced metastatic disease.

Methods: Scans were acquired before, immediately after, and 48 h after injection, at screening and after 2 weeks of treatment. ΔR , ΔR2*, vessel density (Q), and relative vascular volume fractions (VVF) were estimated in both normal tissue and tumor, and compared with model-derived theoretical and experimental estimates based on preclinical murine xenograft data.

Results: R and R2* relaxation rates were still significantly elevated in tumors and liver 48 h after ferumoxytol injection; liver values returned to baseline by week 2. Q was relatively insensitive to changes in ΔR2*, indicating lack of dependence on contrast agent concentration. Variability in Q was higher among human tumors compared with xenografts and was mostly driven by ΔR . Relative VVFs were higher in human tumors compared with xenografts, while values in muscle were similar between species.

Conclusion: Clinical ferumoxytol-based VSI is feasible using standard MRI techniques in a multicenter study of patients with lesions outside of the brain. Ferumoxytol accumulation in the liver does not preclude measurement of VSI parameters in liver metastases. Magn Reson Med 77:814-825, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
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http://dx.doi.org/10.1002/mrm.26167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677523PMC
February 2017

Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors.

J Clin Invest 2015 Dec 9;125(12):4666-80. Epub 2015 Nov 9.

The incidence of cancer is higher in the elderly; however, many of the underlying mechanisms for this association remain unexplored. Here, we have shown that B cell progenitors in old mice exhibit marked signaling, gene expression, and metabolic defects. Moreover, B cell progenitors that developed from hematopoietic stem cells (HSCs) transferred from young mice into aged animals exhibited similar fitness defects. We further demonstrated that ectopic expression of the oncogenes BCR-ABL, NRAS(V12), or Myc restored B cell progenitor fitness, leading to selection for oncogenically initiated cells and leukemogenesis specifically in the context of an aged hematopoietic system. Aging was associated with increased inflammation in the BM microenvironment, and induction of inflammation in young mice phenocopied aging-associated B lymphopoiesis. Conversely, a reduction of inflammation in aged mice via transgenic expression of α-1-antitrypsin or IL-37 preserved the function of B cell progenitors and prevented NRAS(V12)-mediated oncogenesis. We conclude that chronic inflammatory microenvironments in old age lead to reductions in the fitness of B cell progenitor populations. This reduced progenitor pool fitness engenders selection for cells harboring oncogenic mutations, in part due to their ability to correct aging-associated functional defects. Thus, modulation of inflammation--a common feature of aging--has the potential to limit aging-associated oncogenesis.
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http://dx.doi.org/10.1172/JCI83024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665776PMC
December 2015

Non-invasive imaging to monitor lupus nephritis and neuropsychiatric systemic lupus erythematosus.

F1000Res 2015 16;4:153. Epub 2015 Jun 16.

Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect multiple different organs, including the kidneys and central nervous system (CNS). Conventional radiological examinations in SLE patients include volumetric/ anatomical computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound (US). The utility of these modalities is limited, however, due to the complexity of the disease. Furthermore, standard CT and MRI contrast agents are contraindicated in patients with renal impairment. Various radiologic methods are currently being developed to improve disease characterization in patients with SLE beyond simple anatomical endpoints. Physiological non-contrast MRI protocols have been developed to assess tissue oxygenation, glomerular filtration, renal perfusion, interstitial diffusion, and inflammation-driven fibrosis in lupus nephritis (LN) patients. For neurological symptoms, vessel size imaging (VSI, an MRI approach utilizing T2-relaxing iron oxide nanoparticles) has shown promise as a diagnostic tool. Molecular imaging probes (mostly for MRI and nuclear medicine imaging) have also been developed for diagnosing SLE with high sensitivity, and for monitoring disease activity. This paper reviews the challenges in evaluating disease activity in patients with LN and neuropsychiatric systemic lupus erythematosus (NPSLE). We describe novel MRI and positron-emission tomography (PET) molecular imaging protocols using targeted iron oxide nanoparticles and radioactive ligands, respectively, for detection of SLE-associated inflammation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536614PMC
http://dx.doi.org/10.12688/f1000research.6587.2DOI Listing
November 2015

Severe pulmonary hypertension is associated with altered right ventricle metabolic substrate uptake.

Am J Physiol Lung Cell Mol Physiol 2015 Sep 26;309(5):L435-40. Epub 2015 Jun 26.

Department of Medicine, University of Colorado Denver, Aurora, Colorado;

In severe pulmonary hypertension (SPH), prior studies have shown an increase in right ventricle (RV) uptake of glucose, but it is unclear whether there is a change in the relative utilization of fatty acids. We hypothesized that in the RV in SPH, as in left ventricular (LV) failure, there is altered substrate utilization, with increased glucose uptake and decreased fatty acid uptake. SPH was induced in rats by treatment with the VEGF receptor inhibitor SU5416 and 3 wk of hypoxia (10% FiO2 ), followed by an additional 4 wk of normoxia (SU-Hx group). Control rats were treated with carboxymethylcellulose vehicle and 7 wk of normoxia (CMC-Nx group). The rodents then underwent positron emission tomography with sequential administration of two radiotracers, 2-deoxy-2-[(18)F]fluoroglucose ((18)F-FDG) and 14-(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid ((18)F-FTHA), analogs of glucose and fatty acid, respectively. Five CMC-Nx and 3 SU-Hx rats completed the entire experimental protocol. In the RV, there was a mild increase in (18)F-FDG uptake (1.35-fold, P = 0.085) and a significant decrease in (18)F-FTHA uptake (-2.1-fold, P < 0.05) in the SU-Hx rats relative to the CMC-Nx rats. In the LV, SU-Hx rats had less uptake of both radiotracers compared with CMC-Nx rats. Less RV fatty acid uptake in SPH was corroborated by decreased fatty acid transporters and enzymes in the RV tissue, and specifically a decrease in lipoprotein lipase. In the RV in rats with SPH, there is a major shift in metabolic substrate preference, largely due to decreased fatty acid uptake.
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http://dx.doi.org/10.1152/ajplung.00169.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556932PMC
September 2015
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