Pancreatic Cancer Action Network-AACR Innovative Grants are available to independent junior and senior investigators to develop and study new ideas and approaches that have direct application and relevance to pancreatic cancer. The research proposed for funding may be basic, translational, clinical or epidemiological in nature. The Pancreatic Cancer Action Network-AACR Innovative Grants were formally known as the Pancreatic Cancer Action Network-AACR Pilot Grants and have been renamed to emphasize the focus on funding new, creative, and cutting-edge ideas and approaches.
- Lisa A. Cannon-Albright, Ph.D. (2011)
- James R. Eshleman, M.D., Ph.D. (2011)
- Matthias Hebrok, Ph.D. (2011)
- Hidde L. Ploegh, Ph.D. (2011)
- Frank McCormick, Ph.D., F.R.S. (2010)
- Diane M. Simeone, M.D. (2010)
- Gloria H. Su, Ph.D. (2010)
- Amy H. Tang, Ph.D. (2010)
- George A. Calin, M.D., Ph.D. (2009)
- Qingshen Gao, M.D. (2009)
- Brian Lewis, Ph.D. (2009)
- Jiayuh Lin, Ph.D. (2009)
- Nabeel Bardeesy, Ph.D. (2008)
2011 GRANTEES
Lisa A. Cannon-Albright, Ph.D.Professor, University of Utah Health Science Center, Salt Lake City, UT
Informative Linkage Analysis of High-Risk Pancreatic Cancer Pedigrees
Nearly every person to be diagnosed with pancreatic cancer will eventually die from it, usually in less than four to six months. Not only does this highlight pancreatic cancer as a clinically significant disease, but it has also resulted in significantly limited resources for genome-wide linkage studies. About 10 percent of pancreatic cancer is recognized to have a familial component. Although pedigrees with multiple pancreatic cancer cases have been identified, they are typically small, and few DNA samples from cases are available. It is well recognized that the late age at onset and short survival have made it difficult or impossible to build resources of high-risk pancreatic cancer pedigrees. Since few collections of powerful high-risk pedigrees exist, informative linkage studies of high-risk pancreatic cancer pedigrees have not been performed.
Genome-wide association studies (GWAS) have been performed for pancreatic cancer. Such studies are expected to find common variants with low penetrance, but are not informative for rare variants. A rare variant(s) hypothesis may be one explanation for the relatively small amount of heritability that is explained by current GWAS findings in pancreatic cancer. An important aspect of this proposal is that an optimal search for genes affecting pancreatic cancer risk has not been completed. A genome-wide linkage scan could identify rare segregating variants.
“We will create the first powerful linkage resource for pancreatic cancer, making innovative use of existing resources in Utah. We will use a computerized genealogy of Utah, linked to cancer registration in Utah from 1966, to identify extended high-risk pancreatic cancer pedigrees. The difficulty will be in obtaining DNA samples for the cases in these extended pedigrees, most of whom are deceased. We will collect stored DNA samples from the two largest health care systems in Utah, together serving 80-90 percent of the state, which have collected and stored DNA and tissue samples for over six decades. We will identify and collect DNA samples from cases seen locally since 2000, and for all other cases we will extract DNA from normal tissue, stored as part of FFPE tissue blocks, from two statewide bio-repositories that together serve the entire state of Utah. The largest bio-repository has stored all tissue samples for over six decades, and serves 60-70 percent of Utah. We will identify and gather DNA samples in 15 informative extended high-risk pedigrees with at least six sampled cases each. We innovatively propose that sufficient genotyping data for a linkage analysis can be derived from these DNA samples, and that an informative linkage scan can thus be performed for the first time in multiple high-risk pancreatic cancer pedigrees.”
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James R. Eshleman, M.D., Ph.D.Professor, Johns Hopkins University, School of Medicine, Baltimore, MD
Identifying Familial Pancreatic Cancer Predisposition Genes
Pancreatic cancer is generally a lethal cancer with a five-year survival of less than 5 percent. One bright spot is the discovery of several genes, in which defective copies are inherited and these are the direct cause of pancreatic cancer in these families. Since these genes are critical for one way that our cells repair DNA (so called double-strand break repair), and since the cancer cells have inactivated the second normal copy of the same gene, this creates a potential Achilles’ heel for the cancer. Parp inhibitor drugs inhibit a second type of DNA repair (single-strand break repair) and others have recently demonstrated that these drugs are synergistically toxic to cancer cells with double-strand break repair defects.
“We recently discovered another such gene by “brute force” sequencing all genes that a familial pancreatic cancer patient received at birth, in addition to all genes in their cancer. Based on the work of the human genome project, we were able to identify genes where this patient inherited one defective copy, and their cancer had mutated the second copy. In this way, we were able to identify the Partner and Localizer of BRCA2 (Palb2) gene.”
“Because of our longstanding interest in this problem, over the past eight years, the Eshleman lab has been producing familial pancreatic cancer cell lines. Using this panel of nine familial pancreatic cancer cell lines and the corresponding patient DNA, we will use the same approach to identify the predisposition gene defect in these cases. We will then confirm any candidate familial predisposition genes in a panel of 96 additional cases. This work only can be accomplished because of the Pancreatic Cancer Action Network-AACR Innovation Grant funding and an outstanding collaborative team, including Drs. Kinzler, Vogelstein, Velculescu, Klein, Goggins, Kern and Hruban.”
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Pancreatic Cancer Action Network-AACR Innovative Grant, in memory of Abby Sobrato
Mattias Hebrok, Ph.D.Professor, University of California, San Francisco, San Francisco, CA
Role of miRNAs in Pancreatic Adenocarcinoma
“In this proposal, we aim to analyze the functions of novel regulators of gene activity in the development and progression of pancreatic adenocarcinoma (PDA). We have recently learned that micro RNAs (miRNAs), small sequences of nucleic acid, can affect the activity of a variety of other genes. We also know that the expression of these miRNAs changes during the initiation and progression of many cancers, including PDA. Therefore, miRNAs might not only serve as novel biomarkers for specific early stages of PDA formation, information that could be used for early diagnosis before the cancer has grown too big or already spread, but also to better understand what signaling cascades are activated at different stages. This latter information should be useful to instruct development of novel therapeutic strategies to combat this aggressive cancer in human patients.
In this proposal, we take advantage of extensive prior information that we have gathered in my laboratory with the aim to understand which miRNAs are expressed during what stages of cancer progression. Furthermore, others have previously established excellent mouse models in which all aspects of human PDA formation are present. In one of these mouse models, we have shown that elimination of miRNAs speeds up the development of metaplastic/pre-neoplastic tissue. Importantly, loss of miRNAs does block the progression towards cancer at a critical stage in these mice. Therefore, our results clearly indicate that miRNAs play different roles during early and late stages of this cancer.
In addition, we have developed tools in collaboration with colleagues at our university to eliminate individual miRNAs in a mouse model of PDA. This is a critical advance and we have already started to look at cancer formation in a transgenic mouse lacking one specific miRNA. The results are astonishing as they reveal a requirement for this particular miRNA to block the development of early defects associated with cancer formation. While this is a very interesting and encouraging result that demonstrates our strategy is working, we need to understand the function of this miRNA in more detail and propose to do so in this application.”
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Pancreatic Cancer Action Network-AACR Innovative Grant, in honor of the Kovler Family
Hidde L. Ploegh, Ph.D.Professor, Whitehead Institute for Biomedical Research, Cambridge, MA
Generation of Transnuclear Mice from Pancreatic Cancer Infiltrating T Cells
“There is strong evidence that the immune system protects us from certain types of cancer. The immune system almost certainly evolved to deal with bacteria and viruses first and foremost, but there is increasing optimism that its discriminatory powers and precision of recognition may be used also to attack different types of cancer. It may even be possible to provide the immune system with the proverbial shot in the arm, so that it can fight cancers that would not normally be attacked by immune cells. To bring such methods closer to a practical application in man, animal models remain very important. Two post-docs, Oktay Kirak and Stepahnie Dougan, in a collaboration between my lab and that of Rudi Jaenisch, have applied a technique called somatic cell nuclear transfer to generate cloned mice (in a procedure not unlike that used to generate the cloned sheep Dolly) from immune cells. Such immune cells make use of indelible alterations in their genetic material to learn not only how to recognize foreign invaders (viruses, bacteria), but also cancer cells. We already have evidence that this technology can be used to study the immune response against melanoma, and we now intend to extend this approach to pancreatic cancer. At the Koch Center for Cancer Research/MIT, investigators led by Tyler Jacks have developed a mouse model for pancreatic cancer that should allow us to examine the presence and specificity of immune cells that recognize pancreatic cancer. Such cells will be "turned into mice" and should then serve as a small animal model for immune recognition of pancreatic cancer. Support from the Pancreatic Cancer Action Network will be used to launch these efforts.”
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2010 GRANTEES
Frank McCormick, Ph.D., F.R.S. Professor, University of California, San Francisco, San Francisco, CA
Specific K-Ras Inhibitors for Treating Pancreatic Cancer
"Mutations in the K-Ras gene play a direct causal role in the majority of pancreatic cancers, and the mutant K-Ras protein has been a prime target for therapy of this disease for many years. However, no drugs have yet been developed that target K-Ras effectively. The K-Ras protein needs to be inserted into the cell plasma membrane to retain activity and drive cancer cell proliferation. An enzyme called farnesyl transferase attaches a small lipid tail to the K-Ras protein, and this anchors it in the membrane. Many years ago, this was seen as the Achilles' heel of the K-Ras protein and many farnesyl transferase inhibitors were developed as potential cancer therapies. Unfortunately, they did not work, because, unexpectedly, cells contain a back-up system that attaches a different lipid to K-Ras after farnesyl transferase has been blocked, allowing K-Ras activity to be restored.
"We propose a new strategy to preventing lipid tails from being attached to the K-Ras protein. We will identify small molecules that bind to K-Ras directly at the site of lipid attachment, thus blocking modification and permanently shutting down K-Ras function. We will use an approach pioneered by UCSF scientists called tethering, in which a low affinity binding compound is coupled to an active group that covalently attacks nearly cysteines. The C-terminal cysteine residue in K-Ras, which is the site of lipid modification, is an ideal target. If successful, these experiments could lead to the generation of new therapies for pancreatic cancer by directly targeting the major single cause of the pancreatic cancer, activated K-Ras."
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Pancreatic Cancer Action Network-AACR Innovative Grant, supported by The Randy Pausch Family
Diane M. Simeone, M. D. Professor, University of Michigan, Ann Arbor, MI
Targeting Notch Signaling in Pancreatic Cancer Stem Cells
"Pancreatic cancer is a deadly disease and current therapies remain largely ineffective. This may be due to the fact that existing therapies target primarily a cancer cell population with limited tumorigenic potential. Recent data supports the existence of pancreatic cancer stem cells (CSC), a small population of cancer cells with stem cell-like properties, that are resistant to chemotherapy and radiation. Recent preclinical studies in our laboratory suggest that targeting the notch signaling pathway may help eradicate pancreatic CSC within human pancreatic cancers. In this PanCAN-AACR Innovative Grant, we propose to characterize pancreatic CSC in a neoadjuvant clinical setting and to determine the effect of inhibition of notch signaling on that CSC compartment. We have received approval from the NCI (CTEP) to lead a multi-institutional neoadjuvant clinical trial to test the effects of the R0 gamma secretase inhibitor on patient outcomes and CSC metrics in human patients. Eligible patients with resectable pancreatic cancer will be randomized to receive either the notch inhibitor R0 or placebo for two weeks. Operative evaluation and surgical resection will occur on week three. Resected surgical specimens from the treatment and the placebo groups will be compared and analyzed for extent of Notch inhibition and effects on pancreatic CSC number and function. Following resection and recovery, patients in the RO arm of the trial will receive adjuvant RO and gemcitabine compared to the control arm which will receive gemcitabine alone. Clinical outcomes will be measured. This grant will support the translational research accompanying this clinical trial."
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Pancreatic Cancer Action Network-AACR Innovative Grant, funded in part by an Anonymous Family Foundation
Gloria H. Su, Ph.D. Assistant Professor, Columbia University Medical Center, New York, NY
Notch Decoy Targeting the Notch Signaling Pathway in Pancreatic Cancer
"Notch receptors are involved in regulating the balance between cell differentiation and stem cell proliferation during organogenesis of the pancreas, and their expressions are absent in adult pancreas. However, upregulation of Notch1, Notch2, Notch3, and Notch4 receptors and their ligands are frequently observed in human pancreatic cancer and PanIN (pancreatic intraepithelial neoplasia). This notion that the Notch pathway is dysregulated in pancreatic cancer is further supported by a genomic analysis revealing that at least one of the genes in the Wnt/Notch signaling pathway is mutated in 100 percent human pancreatic ductal adenocarcinoma (PDA). The upregualtion of the Notch genes are also observed in a genetically engineered mouse model, LSL-KrasG12D; PDX1-Cre, which has been validated to simulate human pancreatic cancer. Recent reports show that the development of PanINs in this mouse model is aided by activated Notch signaling and the synergy between Notch and Kras. All of these evidences suggest that the reactivation of the Notch signaling in adult human pancreas is not a mere bystander effect, but an active contributor to pancreatic tumorigenesis. This leads us to hypothesize that inhibition of Notch pathway activation may diminish the growth or progression of pancreatic tumor and serves as an effective therapeutic option. In this proposal, we will explore if blocking the Notch signaling in genetically engineered mouse models will mitigate the growth or progression of PanIN to invasive cancer and metastasis. This will be accomplished by either deleting the Notch1 gene or blocking the Notch signaling using a novel Notch1 decoy. These two complimentary approaches will allow us to evaluate the impacts of Notch1 inactivation on the tumor and/or its microenvironment. This proposal will be the first step to investigate the utility of the Notch1 decoy in treating pancreatic cancer. This AACR/PanCAN grant will provide the vital support for our team of research scientists with diverse expertise in pancreatic cancer, the Notch signaling pathway, and angiogenesis to advance a novel therapeutic agent for pancreatic cancer."
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Amy H. Tang, Ph.D. Assistant Professor, Eastern Virginia Medical School, Norfolk, VA
SIAH is a Novel and Effective anti-K-RAS Drug Target in Pancreatic Cancer
"Hyperactive K-RAS signaling is a major menace that drives aggressive tumor growth and metastasis in pancreatic cancer. Currently, there are no effective ways to treat pancreatic cancers that have oncogenic K-RAS mutations that confer drug resistance, aggressive tumor growth and metastasis and poor clinical outcome. Therefore, finding effective means and new molecular targets to inhibit oncogenic K-RAS is an urgent goal and major challenge in pancreatic cancer therapy. Hyperactive K-RAS protein acts like a car’s gas pedal that is permanently stuck in the ACCELERATION position and propels the pancreatic cancer cells to grow and metastasize uncontrollably. Instead of targeting the upstream signaling modules, we attempt to stop “such runaway cars” by attacking the downstream signal transmission – the SIAH E3 ligases – in the K-RAS signaling pathway, and find that an anti-SIAH-based anti-K-RAS strategy is very effective in stopping pancreatic tumorigenesis and metastasis. Through our work, SIAH has begun to emerge as a new and effective drug target against oncogenic K-RAS activation in pancreatic cancer. Using anti-SIAH molecules to block K-RAS signaling in human pancreatic cancer is an excellent example of science going “from the bench (basic science in fruit flies) to the bedside (preclinical and ultimately clinical studies)." Arising from the extensive genetic studies of the RAS signal transduction pathway in Drosophila, SIAH is uniquely positioned to become the next generation anti-K-RAS drug target. Our preclinical studies have demonstrated that “SIAH-dependent proteolysis” is an Achilles' heel in human pancreatic cancer. Albeit at an early preclinical stage, knowledge gained from this study has great promise and immediate translational value. Inhibiting SIAH function may represent an innovative way to inhibit K-RAS activation, halt tumor growth and metastasis and provide novel strategies for therapeutic intervention in pancreatic cancer. This generous AACR grant will endow us with a coveted opportunity to contribute to the great mission of AACR-Pancreatic Cancer Action Network to accelerate pancreatic cancer research as fast as possible."
2009 GRANTEES
Pancreatic Cancer Action Network-AACR Pilot Grant, in memory of Seena Magowitz
George A. Calin, M.D., Ph.D.
Associate Professor, UT MD Anderson Cancer Center, Houston, TX
Roles of MicroRNAs and Ultraconserved Genes in Pancreatic Cancers
"One of the most unexpected and fascinating discoveries of the last few years in molecular oncology is that the interplay between abnormalities in both protein coding genes (PCGs) and non-coding RNAs (ncRNAs), including short microRNAs are causally involved in cancer initiation, progression and dissemination. A growing amount of evidence proves that miRNAs can work as tumor suppressors (blocking the malignant potential) or oncogenes (activating the malignant potential). The pathogenetic mechanisms of the final steps of tumorigenesis - the invasion and the metastases in adjacent or at distance sites for the pancreatic ductal adenocarcinoma (PDAC), the most dangerous form of cancer in the Western world, is still largely unknown. Based on the new concept of direct interaction between miRNAs and long non-coding ultraconserved genes (UCGs), as well as between these ncRNA and PCGs, the broad, long-term purpose of this application is to decipher the roles of miRNAs and UCGs during the metastatic process of PDAC. To achieve this, in collaboration with Dr. Tom Schmittgen from Ohio State University, we will use high-throughput genomics profiling and functional studies applied to cell lines and to laser-microdissected paired normal/tumor samples with and without dissemination. In this way, we will be able to identify new genetic pathways involved in late-stage PDAC by establishing the interactions of non-coding RNA networks with PCGs and their functional consequences. The AACR-PanCAN grant is significant for my work as it offers me a great opportunity to explore this high-risk/high-gain concept of non-coding RNA networks and to reveal new markers for molecular diagnosis and prognosis in PDAC and new targets for drug therapy."
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Qingshen Gao, M.D.
Assistant Professor, Evanston Northwestern Healthcare Research Institute, Evanston, IL
Discovery of Novel Pancreatic Cancer Susceptibility Genes
"Approximately five to 10 percent of individuals with pancreatic cancer report having one or more first- or second-degree relatives with the disease. However, the responsible germline mutation is rarely identified. The failure of traditional genetic approaches such as linkage to identify the remainder of these genes suggests that heterogeneity (many genes) and/or lower prevalence/penetrance (rare and low lifetime cancer risk) are at play. Our objective is to discover novel pancreatic cancer susceptibility genes by dissecting the BRCA2 pathway. BRCA2 mutations likely account for the largest percentage of familial pancreatic carcinoma. BRCA2 cannot work alone. It must coordinate with many other proteins, usually by interacting with them. These components of BRCA2 pathway are also likely direct targets of tumorigenesis. We have identified 13 BRCA2 binding proteins, including DSS1, MAGE-D1 and centrobin that we have published recently. We have strong evidence indicating that genes encoding these 13 BRCA2 binding proteins are likely pancreatic cancer susceptibility genes. In 2002, we created the Pancreatic Cancer Family Registry. We now have 276 participants with DNA samples suitable for analysis, most of them with a family history of pancreatic cancer. Here, we propose to screen all the 13 candidate genes for germline mutations in our collection of samples to uncover novel pancreatic cancer susceptibility genes. If we discover germline mutations of our candidate genes in this group of patients, it will demonstrate that germline mutation of these genes likely predispose to hereditary pancreatic cancer. Sequencing these genes for clinical purposes should have similar value to sequencing BRCA2. This kind of test will likely have important clinical utility for patients with family histories of pancreatic cancers."
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Pancreatic Cancer Action Network-AACR Pilot Grant, in memory of Constance Williams
Brian Lewis, Ph.D.
Associate Professor, University of Massachusetts, Worcester, MA
Involvement of miRNAs in Kras-Induced Pancreatic Tumorigenesis
"Pancreatic cancer, the fourth-leading cause of cancer-related deaths in the United States, is characterized by the presence of activating mutations in the KRAS oncogene. We have previously shown that the expression of an activated Kras allele in isolated primary pancreatic ductal epithelial cells enhances their proliferation, as well as their survival after exposure to death-inducing insults. However, our knowledge of the mechanisms through which Kras exerts these effects remains incomplete. MicroRNAs (miRNAs) are short non-coding RNAs that affect the stability and translation of target messenger RNAs. Previous studies have demonstrated that the levels of several miRNAs are altered in pancreatic cancers, yet the roles of these miRNAs in tumor pathogenesis, and the mechanisms that regulate their expression remain unknown. We have now shown that Kras regulates the levels of several miRNAs in pancreatic epithelial cells, and, therefore, our proposed studies seek to identify whether miRNAs are required for the ability of Kras to enhance the proliferation and survival of pancreatic epithelial cells and the ability of these cells to form tumors when transferred into recipient animals. We will also analyze the roles of individual candidate miRNAs in these processes. Through these experiments, we expect to generate new insights into the mechanisms by which Kras initiates pancreatic tumorigenesis. Such insights will be important for the refinement of new therapeutic approaches. We are very honored to receive support for this project through the AACR/PanCAN pilot grants program. This vital support will allow us to dedicate the effort needed, in personnel and reagents, to make significant progress on these important scientific questions."
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Jiayuh Lin, Ph.D.
Associate Professor, Research Institute at Nationwide Children's Hospital, Columbus, OH
Dual Inhibitors Target JAK2/STAT3 for Novel Pancreatic Cancer Therapy
"Pancreatic cancer is one of the most serious of cancers. There is an urgent need to develop more effective treatments. Patients with any stage of pancreatic cancer can appropriately be considered candidates for clinical trials using new agents because of the poor response to chemotherapy and radiation therapy as conventionally used. The proposed studies are focused on targeting the constitutive Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway in pancreatic cancer cells as a novel therapeutic approach. We will design and synthesize novel small molecules that target JAK2/STAT3 pathway. We will examine the inhibitory effects of the novel small molecule JAK2/STAT3 inhibitors in pancreatic cancer cells in vitro and in a mouse pancreatic tumor model in vivo. Because constitutive activation of STAT3 is frequently activated in pancreatic cancer and can contribute to pancreatic cancer progression and survival, our proposed studies using novel STAT3 inhibitors will provide a promising potential to enhance the efficacy of pancreatic cancer treatment and may make an important contribution to the goal of eradicating pancreatic cancer and reducing the mortality of cancer patients."
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2008 GRANTEE
AACR-PanCAN Pilot Grant, in honor of Randy Pausch, Ph.D.
Nabeel Bardeesy, Ph.D.
Assistant Professor, Massachusetts General Hospital, Boston, MA
Molecular Markers of Drug Sensitivity in Pancreatic Cancer
"I became interested in pancreatic cancer research during my postdoctoral fellowship at the Dana-Farber Cancer Institute. Another postdoctoral fellow in the laboratory had lost two family members to pancreatic cancer and encouraged me to work on this disease. I learned about the critical need for an improved understanding of pancreatic cancer biology. My current project is designed to enable the development of improved approaches to treating pancreatic cancer. In contrast to many other cancer types, there have been no significant improvements in pancreatic cancer therapy over the past decade. In other cancers, progress has come from the observation that some patients respond to certain therapies and that this response is due to specific genetic alterations in the tumor cells. This discovery enables treatments to be ‘tailored' for patients with these genetic changes. In other words, different drugs can be matched to patients who are most likely to benefit from a specific drug. The goal of this proposal is to identify similar drug sensitive subsets of pancreatic cancer. Our approach is to analyze the responsiveness of cells derived from many different pancreatic cancer patients to a large set of anti-cancer drugs. We will then compare the drug sensitivity with the genetic features of the cancer to determine which features predict drug responsiveness. We will test our predictions using a series of mouse models that resemble the human disease. Overall, our studies will define distinct subgroups of PDAC, provide new insights into cancer therapeutics, and directly inform the design of refined clinical trials."
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