23 results on '"Jeannine Garnett"'
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2. Regulation of HGF Expression by ΔEGFR-Mediated c-Met Activation in Glioblastoma Cells
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Jeannine Garnett, Vaibhav Chumbalkar, Brian Vaillant, Anupama E. Gururaj, Kristen S. Hill, Khatri Latha, Jun Yao, Waldemar Priebe, Howard Colman, Lisa A. Elferink, and Oliver Bogler
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The hepatocyte growth factor receptor (c-Met) and a constitutively active mutant of the epidermal growth factor receptor (ΔEGFR/EGFRvIII) are frequently overexpressed in glioblastoma (GBM) and promote tumorigenesis. The mechanisms underlying elevated hepatocyte growth factor (HGF) production in GBM are not understood. We found higher, coordinated mRNA expression levels of HGF and c-Met in mesenchymal (Mes) GBMs, a subtype associated with poor treatment response and shorter overall survival. In an HGF/c-Met–dependent GBM cell line, HGF expression declined upon silencing of c-Met using RNAi or by inhibiting its activity with SU11274. Silencing c-Met decreased anchorage-independent colony formation and increased the survival of mice bearing intracranial GBM xenografts. Consistent with these findings, c-Met activation by ΔEGFR also elevated HGF expression, and the inhibition of ΔEGFR with AG1478 reduced HGF levels. Interestingly, c-Met expression was required for ΔEGFR-mediated HGF production, anchorage-independent growth, and in vivo tumorigenicity, suggesting that these pathways are coupled. Using an unbiased mass spectrometry–based screen, we show that signal transducer and activator of transcription 3 (STAT3) Y705 is a downstream target of c-Met signaling. Suppression of STAT3 phosphorylation with WP1193 reduced HGF expression in ΔEGFR-expressing GBM cells, whereas constitutively active STAT3 partially rescued HGF expression and colony formation in c-Met knockdown cells expressing ΔEGFR. These results suggest that the c-Met/HGF signaling axis is enhanced by ΔEGFR through increased STAT3-dependent HGF expression and that targeting c-Met in Mes GBMs may be an important strategy for therapy.
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- 2013
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3. Cryopreserved human umbilical cord as a meningeal patch during in utero spina bifida repair in a modified ovine model
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Lovepreet K. Mann, Jong H. Won, Jeannine Garnett, Rajan P. Patel, Ponnada A. Narayana, Ranu Jain, Stephen A. Fletcher, and Ramesha Papanna
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General Medicine - Abstract
OBJECTIVE Despite in utero spina bifida (SB) repair, more than two-thirds of patients with SB are unable to ambulate independently, and 1 in 4 children need surgery for tethered cord by school age. The objective of this study was to test the cryopreserved human umbilical cord (HUC) as an antiscarring material to reduce tethering and improve function in a modified in utero SB repair model. METHODS An SB defect (L2–6 levels) without myelotomy was created in fetuses of timed-pregnant ewes at gestational day (GD) 75. On GD 96, the fetal defect was exposed, and the arachnoid layer was removed to disrupt the barrier and expose the spinal cord to simulate human in utero SB repair. The fetuses were randomly assigned to two groups according to the method used to cover the spinal cord: the conventional repair (CR) group, for which myofascial closure was used (n = 7), and the HUC meningeal patch group, for which HUC was used as a meningeal patch (n = 6), followed by primary skin closure. The lambs were delivered at GD 140. Blinded clinical assessment of spinal cord function was performed using the Texas Spinal Cord Injury Scale (TSCIS). Histology of the spine was performed for quantitative assessment of spinal cord tethering, inflammatory markers, and arachnoid layer regeneration. RESULTS The TSCIS scores were significantly lower in the CR than the HUC meningeal patch group (p = 0.0015) and the controls (p = 0.0018). The loss of spinal cord function in the CR group was mainly due to ataxia and loss of proprioception (p = 0.01 and 0.005 vs control and HUC, respectively). The histology at the repair site showed higher rates of spinal cord tethering in the CR lambs than the HUC lambs at all levels of the repair site (p = 0.01 and 0.02 vs control and HUC, respectively). In the CR with tethering compared with the HUC repair, there was a lower arachnoid layer covering at the repair site (p = 0.001). There was greater astrocyte activation in the posterior column in the CR than in the HUC repair group (p = 0.01). CONCLUSIONS In a modified ovine SB model, the HUC as a meningeal patch allows regeneration of the arachnoid layer, prevents spinal cord tethering, and improves spinal cord function after in utero SB repair.
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- 2023
4. The significance of hindbrain herniation reversal following prenatal repair of neural tube defects
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Clifton O. Brock, Eric P. Bergh, Michal Fishel Bartal, Anthony Johnson, Edgar A. Hernandez-Andrade, Jeannine Garnett, KuoJen Tsao, Mary T. Austin, Stephen A. Fletcher, Jennifer H. Johnston, Katrina S. Hughes, Rajan Patel, and Ramesha Papanna
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General Medicine - Abstract
OBJECTIVE The aim of this study was to determine whether reversal of hindbrain herniation (HBH) on MRI following prenatal repair of neural tube defects (NTDs) is associated with reduced rates of ventriculoperitoneal (VP) shunt placement or endoscopic third ventriculostomy (ETV) within the 1st year of life. METHODS This is a secondary analysis of prospectively collected data from all patients who had prenatal open repair of a fetal NTD at a single tertiary care center between 2012 and 2020. Patients were offered surgery according to inclusion criteria from the Management of Myelomeningocele Study (MOMS). Patients were excluded if they were lost to follow-up, did not undergo postnatal MRI, or underwent postnatal MRI without a report assessing hindbrain status. Patients with HBH reversal were compared with those without HBH reversal. The primary outcome assessed was surgical CSF diversion (i.e., VP shunt or ETV) within the first 12 months of life. Secondary outcomes included CSF leakage, repair dehiscence, CSF diversion prior to discharge from the neonatal intensive care unit (NICU), and composite neonatal morbidity. Demographic, prenatal sonographic, and operative characteristics as well as outcomes were assessed using standard univariate statistical methods. Multivariate logistic regression models were fit to assess for independent contributions to the primary and secondary outcomes. RESULTS Following exclusions, 78 patients were available for analysis. Of these patients, 38 (48.7%) had HBH reversal and 40 (51.3%) had persistent HBH on postnatal MRI. Baseline demographic and preoperative ultrasound characteristics were similar between groups. The primary outcome of CSF diversion within the 1st year of life was similar between the two groups (42.1% vs 57.5%, p = 0.17). All secondary outcomes were also similar between groups. Patients who had occurrence of the primary outcome had greater presurgical lateral ventricle width than those who did not (16.1 vs 12.1 mm, p = 0.02) when HBH was reversed, but not when HBH was persistent (12.5 vs 10.7 mm, p = 0.49). In multivariate analysis, presurgical lateral ventricle width was associated with increased rates of CSF diversion before 12 months of life (adjusted OR 1.18, 95% CI 1.03–1.35) and CSF diversion prior to NICU discharge (adjusted OR 1.18, 95% CI 1.02–1.37). CONCLUSIONS HBH reversal was not associated with decreased rates of CSF diversion in this cohort. Predictive accuracy of the anticipated benefits of prenatal NTD repair may not be augmented by the observation of HBH reversal on MRI.
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- 2023
5. Supplementary Data from SAR405838: A Novel and Potent Inhibitor of the MDM2:p53 Axis for the Treatment of Dedifferentiated Liposarcoma
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Raphael E. Pollock, Dina Lev, Hemant Bid, Abbie Zewdu, Gonzalo Lopez, Danielle Braggio, Lucia Casadei, Bethany C. Prudner, Alexander J. Lazar, Laurent Debussche, Cedric Barriere, Svetlana Bolshakov, Chad J. Creighton, XiaoYen Ma, Isabelle Meaux, Jeannine Garnett, and Kate Lynn J. Bill
- Abstract
Supplementary Data from SAR405838: A Novel and Potent Inhibitor of the MDM2:p53 Axis for the Treatment of Dedifferentiated Liposarcoma
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- 2023
6. Differences between myelomeningocele and myeloschisis lesions in patients undergoing open in-utero spina bifida repair
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Jeannine Garnett, Eric P. Bergh, Lovepreet Mann, Kuojen Tsao, Mary Austin, Anthony Johnson, Hope Northrup, Kit Sing Au, Brandon Miller, Stephen A. Fletcher, and Ramesha Papanna
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Obstetrics and Gynecology - Published
- 2023
7. Fetal umbilical artery(UA) doppler changes during laparotomy-assisted fetosocopic spina-bifida repair(FSR) vs. open in-utero spina-bifida repair(OSR)
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Sami Backley, Jeannine Garnett, Edgar Hernandez Andrade, Eric P. Bergh, Ranu Jain, Kuojen Tsao, Mary Austin, Stephen A. Fletcher, Brandon Miller, Brittany Graham, Heinrich Taegtmeyer, Anthony Johnson, Lovepreet Mann, and Ramesha Papanna
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Obstetrics and Gynecology - Published
- 2023
8. Suture techniques and patch materials using an in-vitro model for watertight closure of in-utero spina bifida repair
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Thai Vu, Mary T. Austin, Jeannine Garnett, Manish N. Shah, Ranu Jain, KuoJen Tsao, Kenneth J. Moise, Lovepreet K. Mann, Anthony Johnson, Ramesha Papanna, and Stephen A. Fletcher
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medicine.medical_specialty ,In Vitro Techniques ,Thigh ,Neurosurgical Procedures ,Surgical methods ,In vitro model ,Spina bifida repair ,03 medical and health sciences ,0302 clinical medicine ,Traction ,030225 pediatrics ,medicine ,Animals ,Humans ,Spinal Dysraphism ,Fetal Therapies ,business.industry ,Spina bifida ,Suture Techniques ,General Medicine ,Repair site ,medicine.disease ,Surgery ,medicine.anatomical_structure ,In utero ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Wound edge ,business ,Chickens - Abstract
Purpose Despite proven benefits of in-utero spina bifida (SB) repair, ≥ 30% of children at birth have Chiari II malformation or cerebrospinal fluid (CSF) leakage from the repair site. Our study's purpose was to determine CSF pressures in the myelomeningocele sac during mid-gestation in order to design an in-vitro model for evaluating different surgical methods used for watertight closure during in-utero SB repair. Methods CSF pressures were measured during in-utero SB repair at mid-gestation. An in-vitro chicken thigh model, simulating fetal tissue, tested watertight closure when attached to the base of a water column. Primary closure methods were evaluated using defect sizes of 20 × 3 mm for minimal traction or 20 × 8 mm for moderate traction. Additionally, 3 common in-utero repair patches were compared using 15 × 15 mm defects. Results Using 6–12.5 cm pre-determined CSF pressures, 165 in-vitro experiments were performed. Regardless of methodology we found that in 66 primary-based closures that minimal versus moderate wound edge traction provided better seals. The locking method was superior to the non-locking technique for watertight closure in 99 patch-based closures. Conclusions Minimal wound edge traction was best for primary closures, and locking sutures ideal for patch-based closures, however surgical techniques should be individualized to improve upon clinical outcomes.
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- 2020
9. Cryopreserved human umbilical cord versus acellular dermal matrix patches for in utero fetal spina bifida repair in a pregnant rat model
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Nicholaus J. Trenton, Lovepreet K. Mann, Scheffer C.G. Tseng, Ramesha Papanna, Jeannine Garnett, Jong H. Won, Michael R. Diehl, Stephen A. Fletcher, and Saul Snowise
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Pathology ,medicine.medical_specialty ,Umbilical cord ,Neurosurgical Procedures ,Umbilical Cord ,Rats, Sprague-Dawley ,03 medical and health sciences ,Fetus ,0302 clinical medicine ,Pregnancy ,In vivo ,medicine ,Animals ,Humans ,Spinal Dysraphism ,business.industry ,Mesenchymal stem cell ,General Medicine ,medicine.disease ,Spinal cord ,Rats ,Cellular infiltration ,Disease Models, Animal ,medicine.anatomical_structure ,Spinal Cord ,In utero ,030220 oncology & carcinogenesis ,Female ,business ,Keratinocyte ,030217 neurology & neurosurgery - Abstract
OBJECTIVEDespite significant improvement in spinal cord function after in utero spina bifida (SB) repair compared with traditional postnatal repair, over half of the children who undergo this procedure do not benefit completely. This lack of benefit has been attributed to closure methods of the defect, with subsequent spinal cord tethering at the repair site. Hence, a regenerative patch or material with antiinflammatory and anti-scarring properties may alleviate comorbidities with improved outcomes. The authors’ primary objective was therefore to compare cryopreserved human umbilical cord (HUC) versus acellular dermal matrix (ADM) patches for regenerative repair of in utero SB lesions in an animal model.METHODSIn vivo studies were conducted in retinoic acid–induced SB defects in fetuses of Sprague-Dawley rats. HUC or ADM patches were sutured over the SB defects at a gestational age of 20 days. Repaired SB defect tissues were harvested after 48–52 hours. Tissue sections were immunofluorescently stained for the presence of neutrophils, macrophages, keratinocytes, meningeal cells, and astrocytes and for any associated apoptosis. In vitro meningeal or keratinocyte cell coculture experiments with the ADM and HUC patches were performed. All experiments were scored quantitatively in a blinded manner.RESULTSNeutrophil counts and apoptotic cells were lower in the HUC-based repair group (n = 8) than in the ADM patch repair group (n = 7). In the HUC patch repair group, keratinocytes were present on the outer surface of the patch, meningeal cells were present on the inner surface of the patch adjacent to the neural placode, and astrocytes were noted to be absent. In the ADM patch repair group, all 3 cell types were present on both surfaces of the patch. In vitro studies showed that human meningeal cells grew preferentially on the mesenchymal side of the HUC patch, whereas keratinocytes showed tropism for the epithelial side, suggesting an inherent HUC-based cell polarity. In contrast, the ADM patch studies showed no polarity and decreased cellular infiltration.CONCLUSIONSThe HUC patch demonstrated reduced acute inflammation and apoptosis together with superior organization in regenerative cellular growth when compared with the ADM patch, and is therefore likely the better patch material for in utero SB defect repair. These properties may make the HUC biomaterial useful as a “meningeal patch” during spinal cord surgeries, thereby potentially reducing tethering and improving on spinal cord function.
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- 2020
10. Fetoscopic myelomeningocele (fMMC) repair with human umbilical cord (fMMC-HUC) compared with open in-utero MMC repair (oMMC)
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Ramesha Papanna, Stephen A. Fletcher, Lovepreet Mann, Jeannine Garnett, Eric P. Bergh, Mary Austin, Brandon Miller, Jerrie Refuerzo, Anthony Johnson, Ranu Jain, and Kuojen Tsao
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Obstetrics and Gynecology - Published
- 2023
11. The significance of hindbrain herniation reversal following prenatal surgery for fetal neural tube defects
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Clifton O. Brock, Jeannine Garnett, Samantha Hentosh, Eric P. Bergh, Stephen A. Fletcher, Mary Austin, Kuojen Tsao, Anthony Johnson, Rodrigo Ruano, Katrina Hughes, Rajan Patel, and Ramesha Papanna
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Obstetrics and Gynecology - Published
- 2022
12. Preterm birth after in-utero spina bifida repair: outcomes and risk factors
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Sami Backley, Jeannine Garnett, Samantha Hentosh, Michal Fishel Bartal, Stephen A. Fletcher, Kuojen Tsao, Mary Austin, Ranu Jain, Anthony Johnson, Rodrigo Ruano, Ramesha Papanna, and Eric P. Bergh
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Obstetrics and Gynecology - Published
- 2022
13. Correction: SAR405838: A Novel and Potent Inhibitor of the MDM2:p53 Axis for the Treatment of Dedifferentiated Liposarcoma
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Kate Lynn J. Bill, Jeannine Garnett, Isabelle Meaux, XiaoYen Ma, Chad J. Creighton, Svetlana Bolshakov, Cedric Barriere, Laurent Debussche, Alexander J. Lazar, Bethany C. Prudner, Lucia Casadei, Danielle Braggio, Gonzalo Lopez, Abbie Zewdu, Hemant Bid, Lev Dina, and Raphael E. Pollock
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Cancer Research ,Oncology - Published
- 2022
14. Pentraxin‐3 plasma levels correlate with tumour burden and overall survival in patients with primary myelofibrosis
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Srdan Verstovsek, Jeannine Garnett, Ivo Veletic, Taghi Manshouri, Zeev Estrov, and Kate J. Newberry
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Male ,medicine.medical_specialty ,Kaplan-Meier Estimate ,Gastroenterology ,Internal medicine ,Fibrocyte ,medicine ,Overall survival ,Humans ,In patient ,Myelofibrosis ,Aged ,Pentraxin-3 ,business.industry ,Hematology ,Plasma levels ,Middle Aged ,Serum amyloid P ,Prognosis ,medicine.disease ,Tumor Burden ,Serum Amyloid P-Component ,C-Reactive Protein ,Primary Myelofibrosis ,Case-Control Studies ,Female ,business ,Biomarkers - Published
- 2018
15. Improved prediction of PARP inhibitor response and identification of synergizing agents through use of a novel gene expression signature generation algorithm
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Shiaw Yih Lin, Curtis Chun Jen Lin, Jeannine Garnett, Qinghua Yu, Yiling Lu, Gordon B. Mills, Qingxin Liu, Wei Mo, Zhenlin Ju, Jun Yin, Daniel J. McGrail, Bryan T. Hennessy, Christopher P. Vellano, and Hui Dai
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0301 basic medicine ,QH301-705.5 ,Systems biology ,Bioinformatics ,General Biochemistry, Genetics and Molecular Biology ,Article ,Efficacy ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,medicine ,Biology (General) ,Modality (human–computer interaction) ,business.industry ,Applied Mathematics ,Precision medicine ,medicine.disease ,3. Good health ,Computer Science Applications ,Identification (information) ,030104 developmental biology ,030220 oncology & carcinogenesis ,Modeling and Simulation ,PARP inhibitor ,Personalized medicine ,Ovarian cancer ,business ,Algorithm - Abstract
Despite rapid advancement in generation of large-scale microarray gene expression datasets, robust multigene expression signatures that are capable of guiding the use of specific therapies have not been routinely implemented into clinical care. We have developed an iterative resampling analysis to predict sensitivity algorithm to generate gene expression sensitivity profiles that predict patient responses to specific therapies. The resultant signatures have a robust capacity to accurately predict drug sensitivity as well as the identification of synergistic combinations. Here, we apply this approach to predict response to PARP inhibitors, and show it can greatly outperforms current clinical biomarkers, including BRCA1/2 mutation status, accurately identifying PARP inhibitor-sensitive cancer cell lines, primary patient-derived tumor cells, and patient-derived xenografts. These signatures were also capable of predicting patient response, as shown by applying a cisplatin sensitivity signature to ovarian cancer patients. We additionally demonstrate how these drug-sensitivity signatures can be applied to identify novel synergizing agents to improve drug efficacy. Tailoring therapeutic interventions to improve patient prognosis is of utmost importance, and our drug sensitivity prediction signatures may prove highly beneficial for patient management., Personalized medicine: Signature-guided cancer therapy Personalized cancer therapy is one of the holy grails of oncology, as the ability to determine what treatment would best benefit a patient would serve not only to improve outcomes, but also mitigate side effects from less effective treatments. Here, we develop algorithms to predict what patients will respond to a given therapeutic modality, as well as ways to specifically target any observed phenotype, by integrating large scale data sets that profile cancer cell line gene expression and sensitivity to hundreds of drugs. Furthermore, we show how these gene expression signatures can be used to predict novel synergizing agents to further enhance the efficacy of these therapeutics. Taken together, this work stands to advance the era of personalized medicine by enabling precision medicine approaches in the clinic.
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- 2017
16. Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer
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Chaoyang Sun, Nidhi Sahni, Yulong Liang, Karen H. Lu, Rosemarie Schmandt, Ji Yuan Wu, Yang Li, Limei Hu, David Shih, Scott Kopetz, Russell Broaddus, Yongsheng Li, Truong Nguyen Anh Lam, Melinda S. Yates, Jun Yin, Shiaw Yih Lin, David G. Menter, Hui Dai, Jeannine Garnett, Gordon B. Mills, Eric Jonasch, Daniel J. McGrail, and Guang Peng
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0301 basic medicine ,Cancer Research ,NEDD8 Protein ,Proteome ,Programmed Cell Death 1 Receptor ,Mice, Transgenic ,Cyclopentanes ,Biology ,medicine.disease_cause ,NEDD8 ,DNA Mismatch Repair ,Article ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Mutation ,Protein Stability ,Cell Biology ,HCT116 Cells ,Phenotype ,Xenograft Model Antitumor Assays ,Endometrial Neoplasms ,Mice, Inbred C57BL ,030104 developmental biology ,Pyrimidines ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Immunogenic cell death ,DNA mismatch repair ,Female ,Microsatellite Instability ,Immunotherapy ,Carcinogenesis ,Colorectal Neoplasms - Abstract
Deficient DNA mismatch repair (dMMR) induces a hypermutator phenotype that can lead to tumorigenesis; however, the functional impact of the high mutation burden resulting from this phenotype remains poorly explored. Here, we demonstrate that dMMR-induced destabilizing mutations lead to proteome instability in dMMR tumors, resulting in an abundance of misfolded protein aggregates. To compensate, dMMR cells utilize a Nedd8-mediated degradation pathway to facilitate clearance of misfolded proteins. Blockade of this Nedd8 clearance pathway with MLN4924 causes accumulation of misfolded protein aggregates, ultimately inducing immunogenic cell death in dMMR cancer cells. To leverage this immunogenic cell death, we combined MLN4924 treatment with PD1 inhibition and found the combination was synergistic, significantly improving efficacy over either treatment alone.
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- 2019
17. Abstract NG14: Proteome instability is an immunogenic therapeutic vulnerability in mismatch repair deficient cancer
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Daniel J. McGrail, Nidhi Sahni, Karen H. Lu, Scott Kopetz, Melinda S. Yates, Jun Yin, Guang Peng, Shiaw Y. Lin, Hui Dai, Jeannine Garnett, Gordon B. Mills, Russell Broaddus, David Shih, and David G. Menter
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Cancer Research ,business.industry ,medicine.medical_treatment ,Cancer ,Microsatellite instability ,Immunotherapy ,medicine.disease ,Immune checkpoint ,Transcriptome ,Oncology ,Cancer cell ,Cancer research ,medicine ,Immunogenic cell death ,DNA mismatch repair ,business - Abstract
Deficient DNA mismatch repair (dMMR) induces a hypermutator phenotype, leaving a genomic scar known as microsatellite instability (MSI). MSI is observed in approximately 30% of endometrial cancers, 20% of gastric cancers, 15% of colorectal cancers, and in a smaller fraction of other tumor types. This hypermutator phenotype is thought to produce large numbers of immunogenic neoantigens, leading to the approval of MSI status as a clinical biomarker for immunotherapy. However, more than 60% of patients with MSI tumors fail to respond to immune checkpoint therapy. To uncover alternative therapeutic vulnerabilities for these patients, we used transcriptome signature-guided approaches to identify MLN4924 (pevonedistat), a Nedd8-activating enzyme inhibitor, as a potential therapy for dMMR/MSI cancers. We discover that destabilizing mutations from the dMMR mutation process lead to rampant proteome instability in MSI tumors, resulting in an abundance of misfolded protein aggregates. To compensate, MSI cancer cells activate a Nedd8-mediated degradation pathway to facilitate clearance of misfolded proteins, which is blocked by treatment with MLN4924. The accumulation of misfolded proteins in MSI cancer cells following MLN4924 treatment activated the unfolded protein response, promoted immune cell migration, and induced immunogenic cell death. Antitumor vaccination with MLN4924-treated cells stimulated the generation of endogenous tumor antibodies and prevented tumor incidence upon re-challenge. Based on this immunostimulation, we combined MLN4924 with PD1 blockade, finding that the combination increased recruitment of CD8+ lymphocytes and improved therapeutic efficacy beyond either treatment alone. Taken together, our results indicate that targeting proteome instability is a novel therapeutic avenue for MSI patients and may potentiate immune checkpoint blockade, potentially increasing the depth and duration of response, as well as the fraction of dMMR/MSI patients who can benefit. Citation Format: Nidhi Sahni, Daniel J. McGrail, Jeannine Garnett, Jun Yin, Hui Dai, David J. H. Shih, Guang Peng, David Menter, Melinda S. Yates, Scott Kopetz, Karen Lu, Russell Broaddus, Gordon B. Mills, Shiaw Y. Lin. Proteome instability is an immunogenic therapeutic vulnerability in mismatch repair deficient cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr NG14.
- Published
- 2020
18. Increased H3K9me3 drives dedifferentiated phenotype via KLF6 repression in liposarcoma
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Kunal Rai, Alexander J. Lazar, Jeannine Garnett, Emily Z. Keung, Dina Lev, Kadir C. Akdemir, Ghadah A. Al Sannaa, Lynda Chin, and Keila E. Torres
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Male ,Cellular differentiation ,Kruppel-Like Transcription Factors ,Piperazines ,Epigenesis, Genetic ,Histones ,Histone H3 ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Adipocytes ,Biomarkers, Tumor ,Kruppel-Like Factor 6 ,Humans ,Epigenetics ,Epigenomics ,Regulation of gene expression ,biology ,Liposarcoma ,General Medicine ,Cell Dedifferentiation ,Phenotype ,Gene Expression Regulation, Neoplastic ,Histone ,KLF6 ,biology.protein ,Cancer research ,Female ,Research Article - Abstract
Liposarcoma (LPS) can be divided into 4 different subtypes, of which well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) are the most common. WDLPS is typically low grade, whereas DDLPS is high grade, aggressive, and carries a worse prognosis. WDLPS and DDLPS frequently co-occur in patients. However, it is not clear whether DDLPS arises independently from WDLPS, or whether epigenomic alterations underly the histopathological differences of these subtypes. Here, we profiled 9 epigenetic marks in tumor samples from 151 patients with LPS and showed elevated trimethylation of histone H3 at Lys9 (H3K9me3) levels in DDLPS tumors. Integrated ChIP-seq and gene expression analyses of patient-derived cell lines revealed that H3K9me3 mediates differential regulation of genes involved in cellular differentiation and migration. Among these, Kruppel-like factor 6 (KLF6) was reduced in DDLPS, with increased H3K9me3 at associated regulatory regions. Pharmacologic inhibition of H3K9me3 with chaetocin decreased DDLPS proliferation and increased expression of the adipogenesis-associated factors PPARγ, CEBPα, and CEBPβ, suggesting that increased H3K9me3 may mediate DDLPS-associated aggressiveness and dedifferentiation properties. KLF6 overexpression partially phenocopied chaetocin treatment in DDLPS cells and induced phenotypic changes that were consistent with adipocytic differentiation, suggesting that the effects of increased H3K9me3 may be mediated through KLF6. In conclusion, we provide evidence of an epigenetic basis for the transition between WDLPS and DDLPS.
- Published
- 2015
19. EZH2-miR-30d-KPNB1 pathway regulates malignant peripheral nerve sheath tumour cell survival and tumourigenesis
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Chang Gong Liu, Davis R Igram, Raphael E. Pollock, Jeannine Garnett, Xiuping Liu, Chad J. Creighton, Alexander J. Lazar, Ghadah A. Al Sannaa, and Pingyu Zhang
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Gene knockdown ,Downregulation and upregulation ,Apoptosis ,microRNA ,EZH2 ,Cancer research ,Beta Karyopherins ,macromolecular substances ,Biology ,Signal transduction ,Hedgehog signaling pathway ,Pathology and Forensic Medicine - Abstract
Malignant peripheral nerve sheath tumours (MPNSTs), which develop sporadically or from neurofibromatosis, recur frequently with high metastatic potential and poor outcome. The polycomb group protein enhancer of zeste homologue 2 (EZH2) is an important regulator for various human malignancies. However, the function of EZH2 in MPNSTs is unknown. Here we report that the EZH2–miR-30d–KPNB1 signalling pathway is critical for MPNST tumour cell survival in vitro and tumourigenicity in vivo. Up-regulated EZH2 in MPNST inhibits miR-30d transcription via promoter binding activity, leading to enhanced expression of the nuclear transport receptor KPNB1 that is inhibited by miR-30d targeting of KPNB1 3′ UTR region. Furthermore, inhibition of EZH2 or KPNB1, or miR-30d over-expression, induces MPNST cell apoptosis in vitro and suppresses tumourigenesis in vivo. More importantly, forced over-expression of KPNB1 rescues MPNST cell apoptosis induced by EZH2 knockdown. Immunohistochemical analyses show that EZH2 and KPNB1 over-expression is observed in human MPNST specimens and is negatively associated with miR-30d expression. Our findings identify a novel signalling pathway involved in MPNST tumourigenesis, and also suggest that EZH2–miR-30d–KPNB1 signalling represents multiple potential therapeutic targetable nodes for MPNST. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
- Published
- 2014
20. SAR405838: A Novel and Potent Inhibitor of the MDM2:p53 Axis for the Treatment of Dedifferentiated Liposarcoma
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Abbie Zewdu, Dina Lev, Jeannine Garnett, Xiao Yen Ma, Isabelle Meaux, Alexander J. Lazar, Bethany C. Prudner, Laurent Debussche, Lucia Casadei, Gonzalo Lopez, Danielle Braggio, Chad J. Creighton, Kate Lynn J. Bill, Cedric Barriere, Svetlana Bolshakov, Raphael E. Pollock, and Hemant K. Bid
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0301 basic medicine ,Cancer Research ,Cell cycle checkpoint ,Indoles ,Microarray ,DNA damage ,Apoptosis ,Article ,Piperazines ,03 medical and health sciences ,Mice ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,Animals ,Humans ,Spiro Compounds ,Cell Proliferation ,biology ,Microarray analysis techniques ,Cell growth ,Imidazoles ,Proto-Oncogene Proteins c-mdm2 ,Liposarcoma ,Microarray Analysis ,Xenograft Model Antitumor Assays ,In vitro ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Mdm2 ,Neoplasm Recurrence, Local ,Tumor Suppressor Protein p53 ,Signal Transduction - Abstract
Purpose: Dedifferentiated liposarcoma (DDLPS) is an aggressive malignancy that can recur locally or disseminate even after multidisciplinary care. Genetically amplified and expressed MDM2, often referred to as a “hallmark” of DDLPS, mostly sustains a wild-type p53 genotype, substantiating the MDM2:p53 axis as a potential therapeutic target for DDLPS. Here, we report on the preclinical effects of SAR405838, a novel and highly selective MDM2 small-molecule inhibitor, in both in vitro and in vivo DDLPS models. Experimental Design: The therapeutic effectiveness of SAR405838 was compared with the known MDM2 antagonists Nutlin-3a and MI-219. The effects of MDM2 inhibition were assessed in both in vitro and in vivo. In vitro and in vivo microarray analyses were performed to assess differentially expressed genes induced by SAR405838, as well as the pathways that these modulated genes enriched. Results: SAR405838 effectively stabilized p53 and activated the p53 pathway, resulting in abrogated cellular proliferation, cell-cycle arrest, and apoptosis. Similar results were observed with Nutlin-3a and MI-219; however, significantly higher concentrations were required. In vitro effectiveness of SAR405838 activity was recapitulated in DDLPS xenograft models where significant decreases in tumorigenicity were observed. Microarray analyses revealed genes enriching the p53 signaling pathway as well as genomic stability and DNA damage following SAR405838 treatment. Conclusions: SAR405838 is currently in early-phase clinical trials for a number of malignancies, including sarcoma, and our in vitro and in vivo results support its use as a potential therapeutic strategy for the treatment of DDLPS.
- Published
- 2015
21. The hepatocyte growth factor receptor as a potential therapeutic target for dedifferentiated liposarcoma
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Jeannine Garnett, Xiaoyan Ma, Raphael E. Pollock, Kate Lynn J. Bill, Svetlana Bolshakov, Alexander J. Lazar, Caitlin D. May, and Dina Lev
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MAPK/ERK pathway ,medicine.medical_specialty ,Antineoplastic Agents ,Biology ,Article ,Pathology and Forensic Medicine ,Mice ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Gene knockdown ,Kinase ,Cell growth ,Hepatocyte Growth Factor ,Cell Biology ,Liposarcoma ,Proto-Oncogene Proteins c-met ,3. Good health ,Pyridazines ,Endocrinology ,Pyrimidines ,Hepatocyte Growth Factor Receptor ,Gene Knockdown Techniques ,Cancer research ,Hepatocyte growth factor ,Female ,Proto-Oncogene Proteins c-akt ,medicine.drug - Abstract
Dedifferentiated liposarcomas (DDLPS) are highly resistant to conventional chemo- and radiotherapies, with surgical resection remaining the classic treatment strategy; therefore, there is a pressing need for novel anti-DDLPS-targeted chemotherapeutics. Hepatocyte growth factor receptor (Met) expression is elevated in DDLPS, but the functional role of Met signaling in this disease is not known. We found that the in vitro stimulation of DDLPS cells with hepatocyte growth factor (HGF) elevated the degree of PI3K/AKT and MAPK pathway signaling, and that pro-tumorigenic phenotypes such as cell proliferation, invasion, and migration were significantly enhanced. Conversely, Met knockdown using shRNA-mediated interference decreased HGF-induced Met signaling, the invasive and migratory nature of DDLPS cells in vitro, and the tumorigenicity of DDLPS cells in vivo. These data strongly support the role for Met as a DDLPS therapeutic target. To that end, using EMD1214063, an ATP-competitive kinase inhibitor that targets Met more specifically than other kinases, inhibited Met-dependent signaling, reduced the oncogenicity of DDLPS cells in vitro, and significantly increased the survival of nude mice bearing subcutaneous DDLPS xenografts. These findings support further investigations of HGF-induced Met signaling inhibition in DDLPS, as a potential strategy to enhance clinical outcomes for this disease.
- Published
- 2014
22. Identification of Kruppel-Like Factor 6 (KLF6) as a Differentially Expressed Transcription Factor and Tumor Suppressor in Well Differentiated and Dedifferentiated Liposarcoma (WDLPS, DDLPS) through Unbiased Epigenetic Approaches
- Author
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Jeannine Garnett, Emily Z. Keung, Ghadah A. Al Sannaa, Kadir C. Akdemir, Keila E. Torres, Lynda Chin, Kunal Rai, and Alexander J. Lazar
- Subjects
Dedifferentiated liposarcoma ,business.industry ,law.invention ,Well differentiated ,KLF6 ,law ,Cancer research ,Medicine ,Suppressor ,Surgery ,Identification (biology) ,Kruppel-Like Factor 6 ,Epigenetics ,business ,Transcription factor - Published
- 2014
23. AXL is a potential therapeutic target in dedifferentiated and pleomorphic liposarcomas
- Author
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Dina Lev, Svetlana Bolshakov, Caitlin D. May, Lixia Han, Fuguo Zhou, Xiaoyan Ma, Davis R. Ingram, Yi Zhang, Elizabeth G. Demicco, Azad Abul Kalam, Dominique Broccoli, Alexander J. Lazar, Tona Vu, Jeannine Garnett, Raphael E. Pollock, Ghadah A. Al Sannaa, Wei-Lien Wang, Sharon M. Landers, Keila E. Torres, Juehui Liu, and Christine M. Kivlin
- Subjects
Cancer Research ,Receptor tyrosine kinase ,Cellular differentiation ,Enzyme-Linked Immunosorbent Assay ,Small hairpin RNA ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Genetics ,Humans ,Neoplasm Invasiveness ,Cell Proliferation ,030304 developmental biology ,Soft tissue sarcoma ,0303 health sciences ,Gene knockdown ,Tissue microarray ,biology ,Cell growth ,GAS6 ,AXL ,Receptor Protein-Tyrosine Kinases ,Cell Differentiation ,Liposarcoma ,Immunohistochemistry ,Axl Receptor Tyrosine Kinase ,Neoplasm Proteins ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Intercellular Signaling Peptides and Proteins ,Research Article - Abstract
Background AXL is a well-characterized, protumorigenic receptor tyrosine kinase that is highly expressed and activated in numerous human carcinomas and sarcomas, including aggressive subtypes of liposarcoma. However, the role of AXL in the pathogenesis of well-differentiated (WDLPS), dedifferentiated (DDLPS), and pleomorphic liposarcoma (PLS) has not yet been determined. Methods Immunohistochemical analysis of AXL expression was conducted on two tissue microarrays containing patient WDLPS, DDLPS, and PLS samples. A panel of DDLPS and PLS cell lines were interrogated via western blot for AXL expression and activity and by ELISA for growth arrest-specific 6 (GAS6) production. AXL knockdown was achieved by siRNA or shRNA. The effects of AXL knockdown on cell proliferation, migration, and invasion were measured in vitro. In addition, AXL shRNA-containing DDLPS cells were assessed for their tumor-forming capacity in vivo. Results In this study, we determined that AXL is expressed in a subset of WDLPS, DDLPS, and PLS patient tumor samples. In addition, AXL and its ligand GAS6 are expressed in a panel of DDLPS and PLS cell lines. We show that the in vitro activation of AXL via stimulation with exogenous GAS6 resulted in a significant increase in cell proliferation, migration, and invasion in DDLPS and PLS cell lines. Transient knockdown of AXL resulted in attenuation of these protumorigenic phenotypes in vitro. Stable AXL knockdown not only decreased migratory and invasive characteristics of DDLPS and PLS cells in vitro but also significantly diminished tumorigenicity of two dedifferentiated liposarcoma xenograft models in vivo. Conclusions Our results suggest that AXL signaling contributes to the aggressiveness of DDLPS and PLS, and that AXL is therefore a potential therapeutic target for treatment of these rare, yet devastating tumors.
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