The overall goal of the Ivy Neurological Science Internship Program is to inspire high school and undergraduate students to pursue a career in bioscience, particularly in the areas of glioma research, neuroscience or neurogenomics, by providing an opportunity to conduct hands-on biomedical research under the direct mentorship of a TGen investigator.

Program Summary

Modeled after the Helios Scholars Program, the Ivy Neurological Sciences Internship Program replicates three key features that we have found instrumental to that training program’s success:

  1. Fully-funded research internships for promising high school and undergraduate students
  2. Exposure to translational/clinical medicine leveraging existing community based partnerships
  3. Presentation of research results at the end of the program to faculty, peers, parents and community members

Ivy Neurological Science Internship Program

2017-2018

RITA BYBEE

Attending Grand Canyon University
Mentored by Drs. Michael Berens and Harshil Dhruv in TGen’s
Brain Tumor Unit, Cancer and Cell Biology Division

Research Summary

Pevonedistat (MLN4924; Millenium Pharmaceuticals, Inc.) is currently under investigation for treatment of several cancer types including metastatic melanoma, acute myeloid leukemia, and various advanced solid tumors. Despite its proposed efficacy, the exact mechanism of vulnerability in glioblastoma is not well understood. My project seeks to understand the genomic context of vulnerability to Pevonedistat in glioblastoma cells. Our aim is to utilize the findings from this work to improve our understanding of which patients are most likely to respond to Pevonedistat treatment.

SIDHARTH KULKARNI

Attending Arizona State University
Mentored by Dr. Rebecca Halperin in TGen’s
Quantitative Medicine and Systems Biology Division

Research Summary

My work is centered around my mentor Dr. Halperin’s variant caller, a tool that reads genome sequence data and decides where mutations are. Such tools are of great importance to cancer research as they provide valuable information that enables precision treatment. The work I’m doing to improve the quality of said variant caller is increasing the breadth of information it uses to decide where the mutations are. The accuracy will be measured and optimized with samples from GBM tumors in mind.

SYDNEY CONNOR

Attending Arizona State University
Mentored by Dr. Muhammad Murtaza in TGen’s
Center for Noninvasive Diagnostics, Cancer and Cell Biology Department

Research Summary

A blood test to detect and monitor glioblastoma can help improve its treatment. To develop such a blood test, I am optimizing an assay to detect glioblastoma in the blood using a mouse model. Using this assay, we plan to test how the blood brain barrier affects what biomarkers are shed into blood and whether there are opportunities to improve our diagnostic accuracy.

Ivy Neurological Science Internship Program

2016-2017

ALENA GLADWIN

Currently attending Grand Canyon University
Mentored by Drs. Michael Berens and Harshil Dhruv in TGen’s
Brain Tumor Unit, Cancer and Cell Biology Division

Research Summary

Glioblastoma multiforme (GBM) is the most common and most lethal primary malignant brain tumor, affecting 25,000 patients per year. Despite major research efforts and advances in diagnosis and treatment, overall survival of patients has improved little over the last 30 years and remains at a mean of 14.6 months. Two major aspects of glioma biology that contribute to its poor prognosis are microvascular proliferation and diffuse infiltration of glioma cells. Invasion of normal brain by infiltrating tumor cells makes complete surgical removal of the tumor very challenging and underlies therapeutic failures. To date, no specific treatment has been developed targeting this lethal tumor cell phenotype. My project seeks to improve our understanding of how glioma cells residing at the edge of the tumor mass invade in the normal brain. This improved understanding will aid in the development of novel therapeutics that can be used to target invading glioma cells.

TRISTAN NEAL

Currently attending Arizona State University
Mentored by Drs. Michael Berens and Harshil Dhruv in TGen’s
Brain Tumor Unit, Cancer and Cell Biology Division

Research Summary

My project focuses on evaluating the efficacy of selected repurposed drugs identified from the Ben and Catherine Ivy Foundation-funded “Genomics Enabled Medicine for Glioblastoma” run-in feasibility trial in GBM patient-derived xenograft mouse models. The majority (13/15 patients) of genomics-guided treatment recommendations in this trial included at least one repurposed agent. The most frequently recommended repurposed agents included metformin (diabetes medication), chlorpromazine (antipsychotic medication), propranolol (heart medication), and minocycline (antibiotic). These agents were attractive options for the tumor board to consider given they are known to cross the blood brain barrier, have minimal toxicity, and are reported to display activity against cancer-relevant gene targets.

Ivy Neurological Science Internship Program

2015-2016

HEATHER SONNEMANN

Currently attending Arizona State University
Studying Biological Science with a concentration in Genetics
Mentored by Drs. Nhan Tran and Harshil Dhruv in TGen’s Brain Tumor Unit in the Cancer

Research Summary

Glioblastoma Multiforme (GBM) is the most common and aggressive brain tumor in adults with a median patient survival of 14.6 months with treatment. Frequent genetic alternations in GBMs result in activation of signaling pathways involving Ras, AKT, and other growth-promoting factors. The dysregulation or uncontrolled activation of the Ras pathway leads to proliferation and the formation of tumors. NF1 encodes a tumor suppressor protein that can inactivate the Ras pathway when it is active. Unfortunately in GBM, the tumor suppressor protein is being degraded or genetic mutations in NF1 render it inactive, allowing the Ras pathway to be uncontrollably active. We are currently investigating ways to stabilize the NF1 protein which will allow it to control the Ras pathway.
My additional project investigated arsenic trioxide (ATO) susceptibility in GBM cell lines. ATO is a drug that induces cell differentiation and can cross the blood brain barrier in low doses. We have shown that, at high doses, ATO induces apoptosis. We are currently investigating how ATO affects cells at lower doses.
My experience at TGen has shaped the way I view research. Every person is unique and we can’t give them all the same treatment. Personalized medicine is the way of the future and TGen is leading the way. I am so honored to be able to say that I got to work with these amazing scientists.

NGHIA MILLARD

Currently attending Arizona State University
Double Majoring in Microbiology and Mathematics
Mentored by Drs. Nhan Tran and Harshil Dhruv in TGen’s Brain Tumor Unit in the Cancer and Cell Biology Division

Research Summary

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. A significant challenge in treating GBM is the ability of glioma cells to invade normal brain tissue, escape surgical resection and resist radiotherapy and chemotherapy. Our lab has demonstrated that the TWEAK-Fn14 signaling axis plays an important role in glioma cell invasion and discovered a small molecule, L524-0366, that specifically disrupts the TWEAK-Fn14 interaction.
However, TWEAK’s binding affinity to Fn14 is significantly higher than L524-0366’s binding affinity to Fn14, limiting L524’s clinical feasibility. After analyzing the structure-activity relationship (SAR) of L524-0366, structurally similar small molecules were obtained and screened using a cell-based assay, yielding small molecules that showed promising activity in inhibiting TWEAK induced Fn14 signaling.
In this project, we utilize migration and invasion assays to investigate the efficacy of these small molecules in suppressing glioma cell migration and invasion respectively. Small molecules that show promising activity in suppressing glioma cell migration and invasion will be further examined in cell signaling assays and tested for their ability to sensitize glioma cells to radiation and chemotherapy. Overall, this project seeks to find clinically relevant novel small molecules that suppress Fn14-TWEAK signaling.
My experience at TGen has given me a passion for biomedical research. Despite not having interest in attending medical school, I am inspired to pursue a career in biomedical research where I can develop novel treatments to help treat patients and improve their quality of life.

MARYA SABIR

Graduated Arizona State University
Pursuing Medical School
Mentored by Drs. Michael Berens and Harshil Dhruv in TGen’s Brain Tumor Unit in the Cancer and Cell Biology Division

Research Summary

Glioblastoma (GBM) is the most common malignant brain tumor in adults. Most GBM patients succumb to the disease less than one-year post diagnosis due to the highly invasive nature of the tumor, which prevents complete surgical resection and gives rise to tumor recurrence. The invasive phenotype also confers radio-and chemoresistant properties to the tumor cells; therefore, there is a need to develop new therapeutics that target drivers of GBM invasion.
Amplification of EGFR is observed in over 50 percent of GBM tumors, of which half concurrently overexpress the variant EGFRvIII, and expression of both receptors confers a worse prognosis. EGFR and EGFRvIII cooperate to promote tumor progression and invasion, in part, through activation of the JAK/STAT-signaling pathway.
Here we report that GBM cells expressing EGFRvIII show increased expression of a previously established mediator of glioma cell invasion and survival, fibroblast growth factor-inducible 14 (Fn14), at the mRNA and protein level. Treatment with STAT3, STAT5, JAK, or Src inhibitors decreased Fn14 mRNA and protein expression. Finally, knockdown of Fn14 levels in the EGFRvIII-expressing glioma cells decreased both cell survival after temozolomide (TMZ) treatment and cell invasion, which suggests that Fn14, in part, mediates the oncogenic phenotypes conferred by EGFRvIII signaling. Since EGFR inhibitors display limited therapeutic efficacy in GBM patients, we hypothesize that Fn14-targeted therapies could potentially limit invasiveness and chemoresistance in EGFRvIII-dependent GBM tumors.
My participation has greatly inspired my interests in biomedical research. Beyond learning and performing critical molecular biology techniques, this internship has allowed me to continue honing my problem-solving and critical thinking skills with respect to the current breadth of literature. I have learned immensely, but most importantly that collaboration and the sharing of ideas through scientific dialog are the keys to making breakthroughs. At the end of the day, the foundation of good medicine is research. The most important principle I have learned is that it is all about improving the quality of life and longevity of individuals suffering from debilitating ailments. In the future, I want to play an integral role in “bench-to-bedside” medical research and translating scientific discoveries into the clinic.

Ivy Neurological Science Internship Program

2014-2015

MICHAEL PINEDA

Attending Arizona State University
Majoring in Biomedical Engineering
Mentored by Dr. Harshil Dhruv in TGen’s Brain Tumor Unit in the Cancer and Cell Biology Division

Research Summary

The most common, lethal primary brain tumor is glioblastoma (GBM). Profiling individual patient tumors to arrive at optimal treatment recommendations (Precision Medicine) is an emerging practice. The task of translating molecular subtyping of glioblastoma into therapeutically actionable guidance remains an unfulfilled opportunity for GBM due to the few drug choices. We proposed to repurpose currently approved FDA drugs for use against GBM through drug screening of preclinical models of GBM. Earlier work showed that GBM can be sub-grouped into distinct categories based on genomic changes; because the genes that place the tumors into these subgroups have driving functions, we refer to the subgroups as molecular contexts (mC). Utilizing a technique we term Chemical Biology Fingerprinting (CBF), we screened 8 GBM patient-derived xenograft (PDX) models using a small chemical library of clinically relevant anti-cancer agents seeking to discover whether there was context-specific sensitivity. Preliminary data demonstrated that mC14 shows distinct vulnerability to Arsenic Trioxide (ATO) as compared to mC4. To validate ATO vulnerability signature in GBM, we acquired 22 treatment-naïve archival patient samples that were part of Phase I/II clinical trial to study efficacy of ATO and Temozolomide (TMZ) in combination with radiation in the treatment of high-grade gliomas and determined their molecular classification via RNAseq. In summary, we demonstrate a subclassification of GBM into novel contexts and we also show that these contexts are differentially sensitive to clinically relevant drugs. The study suggests that molecular profiling of GBM may guide treatment selection for patients.

EMILY HERRING

Attending Arizona State University
Majoring in Biomedical Engineering
Mentored by Dr. Sara Byron in TGen’s Integrated Cancer Genomics

Research Summary

Glioblastoma (GBM) is an extremely malignant form of brain cancer that is characterized by rapid progression and poor patient survival. The treatment plan for patients diagnosed with GBM is maximally safe resection (when possible) followed by radiation and chemotherapy. However, even with these treatments, less than 10 percent of patients with this disease survive five years. More effective therapeutic options are urgently needed to improve outcomes for patients with glioblastoma. With the advancement of genomic profiling, new therapeutic targets have been identified and new investigational agents have been developed and are currently being evaluated in clinical trials. Though several of these agents have been tested in clinical trials in glioblastoma, they have shown minimal efficacy. Adequate drug delivery is a critical challenge in glioblastoma treatment, as drugs delivered systemically must be able to penetrate the blood-brain barrier (BBB). Therefore, we sought to develop a resource to catalog known BBB penetration information for all investigational agents currently in clinical trials in cancer. Using an in silico prediction model and manual annotation to capture existing knowledge from the literature, BBB content for ~500 investigational drugs was added to the database. In addition to BBB content, the database also includes information on the drug target and the clinical trial phase and disease type in which the drug is currently being tested. The BBB database was used to identify investigational agents with evidence for BBB penetration, matched to the genomic alterations identified in samples from the Ivy Foundation Genomics Enabled Medicine for Glioblastoma clinical trial at TGen. By prioritizing investigational agents for further study based on evidence for BBB penetration, this resource can help the GBM research community pursue more effective treatments for glioblastoma.

ZACH MAYO

Graduated from the University of Iowa in Iowa City, IA
Majored in Human Physiology/Pre-Medicine
Mentored by Dr. Nhan Tran in TGen’s Brain Tumor Unit in the Cancer and Cell Biology Division

Research Summary

Glioblastoma Multiforme (GBM) is the most common malignant brain tumor in adults. Most GBM patients succumb to the disease less than one-year post diagnosis due to the highly invasive nature of the tumor, which prevents complete surgical resection and gives rise to tumor recurrence. The invasive phenotype also confers radio-and chemoresistant properties to the tumor cells; therefore, there is a need to develop new therapeutics that target drivers of GBM invasion. Amplification of EGFR is observed in over 50 percent of GBM tumors, of which half concurrently overexpress the variant EGFRvIII, and expression of both receptors confers a worse prognosis. EGFR and EGFRvIII cooperate to promote tumor progression and invasion, in part, through activation of the JAK/STAT-signaling pathway. We report that GBM cells expressing EGFRvIII show increased expression of a previously established mediator of glioma cell invasion and survival, fibroblast growth factor-inducible 14 (Fn14), at the mRNA and protein level. Treatment with a STAT3, STAT5, or JAK inhibitor decreases Fn14 mRNA and protein expression. Finally, knockdown of Fn14 levels in the EGFRvIII-expressing glioma cells decreases both cell survival after temozolomide (TMZ) treatment and cell invasion, which suggests that Fn14, in part, mediates the oncogenic phenotypes conferred by EGFRvIII signaling. Since EGFR inhibitors display limited therapeutic efficacy in GBM patients, we hypothesize that Fn14-targeted therapies could potentially limit invasiveness and chemoresistance in these tumor subtypes.

Ivy Neurological Science Internship Program

2013

JUSTIN BESSANT

Attending Arizona State University
Pursuing a B.S. in Chemical Engineering
Mentored by Drs. Harshil Dhruv and Nhan Tran in TGen’s Brain Tumor Unit, Cancer and Cell Biology Division

Research Summary

The key barriers to the improved treatment of Glioblastoma Multiform include: 1) the molecular heterogeneity of tumors across patients, 2) lack of systematic utilization of existing knowledge of molecular data for target discovery, and 3) lack of relevant, rapid and systematic testing of hypotheses. Previously, the Brain Tumor Unit at TGen has identified molecularly homogeneous subsets of glioma patients by analyzing gene expression, gene copy number, and miRNA data available in TCGA. Additionally, in an ongoing collaborative effort with Sanford Burnham Medical Research Institute (SBMRI) our group has identified that two specific molecularly homogeneous subsets of glioma present therapeutic vulnerability to currently used chemotherapeutic agents including Tamoxifen and Arsenic Trioxide. My project focuses on validating these findings in short-term glioma cultures developed from patient-derived xenograft (PDX) models belonging to molecularly homogeneous subsets of interest. I have been successful in developing short-term cultures of 6 glioma PDX models, which will be utilized for validating their therapeutic vulnerability to Tamoxifen and Arsenic Trioxide in vitro and in vivo.

ETHAN HOLLIDAY

Arizona State University
Pursuing a B.S. in Molecular Biosciences & Biotechnology
Mentored by Drs. Harshil Dhruv and Nhan Tran in TGen’s Brain Tumor Unit, Cancer and Cell Biology Division

Research Summary

I have been working on two very exciting and worthwhile projects. Both of my projects center around small molecule inhibitors targeted at slowing the spread of glioma in the human brain. The first of these is, Propentofylline (PPF), has been shown to readily cross the blood-brain barrier and is already FDA approved. PPF targets TNFR19 (TROY), an orphan member of the tumor necrosis factor superfamily receptors. We have shown that TROY is associated with the Rac-1 signal transduction pathway, and has been shown to stimulate glioma invasion as well as other cell survival activities. Our data showed that inhibition of TROY by PPF increases the sensitivity of glioma cells to Temozolomide (TMZ), the current standard of chemotherapy for glioma patients. My project is to evaluate PPF’s ability to decrease the ability of glioma cells to invade into adjacent brain tissues by treating the cells with achievable concentrations of PPF, and understanding the mechanism by which PPF suppresses TROY expression. This work may ultimately help improve the prognosis for patients with tumors that have elevated levels of TROY expression.
The second project I have been working on involves another FDA approved drug, Aurintricarboxylic Acid (ATA), which we have identified to interfere with Fn14 and TWEAK signaling in glioblastoma. The TWEAK-Fn14 signaling cascade is hyperactive in glioblastoma cells and drives glioma cell survival and invasion. My role on this project is to characterize the mechanism by which ATA specifically inhibits TWEAK-Fn14 signaling in glioblastoma cells. Methods of testing this are similar to the invasion experiments conducted with PPF. ATA has shown a very low level of cellular toxicity, which adds to the promise of the drug for the future. This drug could potentially improve the life expectancy of patients suffering from glioblastoma expressing high Fn14.

IAN MATHEWS

Attending Arizona State University
Pursuing a B.S. in Molecular Biosciences & Biotechnology
Mentored by Drs. Harshil Dhruv and Nhan Tran in TGen’s Brain Tumor Unit, Cancer and Cell Biology Division

Research Summary

The TGen CNS Tumor Lab has a primary focus in the protein Fn14 and its role in promoting GB cell invasion and survival phenotypes. Fn14 is frequently present in advanced gliomas while being almost entirely absent in normal brain cells, and is often present in greater abundance in the invasive population of GB tumor cells at the tumor rim compared to the cells in the tumor core. Further, Fn14 is a viable target for therapy because of its response to stimuli at the cell membrane and the propagation of signals within the cell. These Fn14-induced signals promote the dynamic rearrangement of internal cell structures necessary for cell movement, in addition to promoting resistance to apoptosis, the cellular equivalent of suicide, induced by damage from chemotherapy.
My research has focused on a particular signaling target of Fn14 named SGEF. Data I have contributed to have shown SGEF recruitment to Fn14 at the cell membrane is necessary for rearrangement of an internal structure of the cell, the actin cytoskeleton, in cell migration. Our continued research intends to characterize SGEF as a key mediator of Fn14 signaling in other compartments of the cell, promoting repair of DNA damage following chemotherapy. Further elucidation of SGEF’s role in GB will inform new approaches to targeted therapy design for the Fn14 signaling axis as well as planning treatment strategies to improve the standard of care for patients with GB.

KYLE JOHNSON

Attending Arizona State University
Pursuing a B.S. in Molecular Biosciences & Biotechnology
Mentored by Drs. Harshil Dhruv and Nhan Tran in TGen’s Brain Tumor Unit, Cancer and Cell Biology Division

Research Summary

Metastases to the central nervous system (CNS) are the most common intracranial malignancy, with up to one in five cancer patients eventually developing a brain or spine metastasis. These tumors are typically associated with survival times of four to five months. Lung and breast are the most common primary cancer sites for CNS metastasis, representing approximately 60 percent of such tumors. Chemotherapeutic choices are limited and rarely effective, and management is typically limited to surgery and either stereotactic or whole-brain radiotherapy. The molecular characteristics of these tumors, as well as the factors driving cancers to metastasize to the CNS, are not well understood. This is due in part to inaccessibility of clinical samples and a lack of established, well-characterized models. This has resulted in a continued lack of predictive biomarkers and preventative measures. My project revolves around the goal of shedding light on the molecular biology of these highly heterogeneous tumors and establishing resources for preclinical testing. This involves the creation of both in vivo and in vitro models of CNS metastases originating from lung or breast cancer.

In vivo models of each tumor are being developed in immunodeficient mice in a collaborative lab. My responsibility has been for the development of a cell line from each tumor, creating an in vitro model. I have maintained as many as ten tumor-derived cell lines in culture over the past nine months and have worked to characterize each line. My initial characterization has been performed using antibody-specific microscopic staining techniques, allowing us to verify that the cells I have cultured exhibit the same staining profile seen by pathologists in the initial tumor. This confirms the presence of the desired cancer cells in each culture. I have also worked to extract analytes such as DNA, RNA, and protein so that detailed molecular analysis can begin. Each step in this process has required a large amount of literature review, optimization, experimentation and trial, and error, as models of CNS metastasis have not been previously established. Working with cells derived from metastatic sites has provided additional challenges as it is sometimes difficult to know if they maintain the characteristics of their primary tumor of origin. I am now in the process of characterizing the growth patterns of each cell line so that I can begin using them in drug studies on compounds of interest.

Ivy Neurological Science Internship Program

2012

ASHLEY CHAVEZ

 

Attending Arizona State University
Majoring in Nursing
Mentored by Harshil Dhruv, Ph.D. & Nhan Tran, Ph.D.

Research Summary

Glioblastoma (GB) is the most lethal of the advanced glial tumors. While chemotherapeutic agents have been developed to treat it, they have been ineffective in targeting the invading cells. This may be attributed to the overexpression and amplification of EGFR in glioblastoma (>50 percent of the cases). Our lab has shown that the TNFRSF19/TROY gene is significantly overexpressed in invading cells of GB as compared to the matching proliferating tumor cells at the core. Moreover, TROY expression has been inversely correlated with patient survival amongst malignant gliomas. Overexpression of TROY also induces increased glioma cell migration and invasion. Currently, I am currently investigating the role of TROY and an intracellular protein, NHERF-1, as potential molecular “switches” for invading GB cells from a less proliferative, high migratory phenotype to a highly proliferative, less migratory phenotype. Our data shows that TROY interacts with EGFR and enhances EGFR signaling in GB cells. Additionally, I am developing a novel regulatory inducible knockdown system to specifically alter the gene expression of key protein regulators of the EGFR-TROY signaling pathway. This system will allow me to specifically test whether TROY knockdown will inhibit glioma invasion in the orthotopic GB in vivo model and enhanced temozolomide sensitivity of these invading cells. Overall, understanding the mechanism by which GB cells invade will lead to improved targeted therapies against invasive GB cells.

IAN MATHEWS

 

Attending Arizona State University
Majoring in Molecular Biosciences and Biotechnology 
Mentored by Shannon Fortin and Nhan Tran, Ph.D.

Research Summary

Glioblastoma (GB) is the most prevalent and most malignant primary adult brain tumor, its lethality due in large part to the capacity of glioma cells to invade surrounding normal brain. These invasive cells evade surgical resection, chemotherapy with temozolomide (TMZ) and radiation treatment, all of which target the actively proliferative cells within the central tumor mass. There are currently no therapies targeting invading glioma cells, so characterizing genes that promote invasion with subsequent chemotherapeutic resistance will direct the development of future therapies for GB. Our lab has previously characterized the tumor necrosis factor (TNF) receptor, fibroblast growth factor inducible-14 (Fn14) and its ligand, the TNF-like weak inducer of apoptosis (TWEAK), as a potent signaling axis for driving glioma cell invasion and survival. We have shown that TWEAK/Fn14 pro-survival signaling is dependent upon Rac1 and NF-κB, and interestingly, a genome wide analysis of temozolomide-resistant xenografts revealed an increased presence of NF-κB on the promoter sequence of the RhoG-specific guanine nucleotide exchange factor SGEF. Our investigations have shown that SGEF mRNA expression correlates with increased brain tumor grade and is negatively associated with patient survival. SGEF is recruited to the cell membrane by Fn14 and induces membrane ruffling, and shRNA-mediated depletion of SGEF significantly restricts TWEAK-induced glioma cell migration. SGEF is rapidly activated under TWEAK treatment, and its activation and co-immunoprecipitation with Fn14 is dependent on binding to the TNF receptor-association factor 2 (TRAF2). Depletion of SGEF reduces TWEAK-dependent activation of RhoG and, consequently, Rac1. In addition, the stimulation of Fn14 by TWEAK induces SGEF expression in an NF-κB-dependent manner, and SGEF mRNA expression is negatively associated with response to TMZ in patient derived GB xenografts. Furthermore, depletion of SGEF increases sensitivity to TMZ, and impairs the ability for colony formation following TMZ or radiation insult. Continued study of genes regulated by SGEF activity may bring further insight into its role in glioma cell resistance to apoptosis and its significance as a target of anti-invasion therapy.

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