tbuckley/cabot-search huggingface dataset:
Inhibition of GSK3β by Postconditioning Is Required to Prevent Opening of the Mitochondrial Permeability Transition Pore During Reperfusion
Authors: LudovicGomez, MélaniePaillard, HélèneThibault, GenevièveDerumeaux, MichelOvize
Journal: Circulation (2008)

Background— Opening of the mitochondrial permeability transition pore (mPTP) is a crucial event in lethal reperfusion injury. Phosphorylation (inhibition) of glycogen synthase kinase-3β (GSK3β) has been involved in cardioprotection. We investigated whether phosphorylated GSK3β may protect the heart via the inhibition of mPTP opening during postconditioning. Methods and Results— Wild-type and transgenic GSK3β-S9A mice (the cardiac GSK3β activity of which cannot be inactivated) underwent 60 minutes of ischemia and 24 hours of reperfusion. At reperfusion, wild-type and GSK3β-S9A mice received no intervention (control), postconditioning (3 cycles of 1 minute ischemia and 1 minute of reperfusion), the mPTP inhibitor cyclosporine A (CsA; 10 mg/kg IV), or the GSK3β inhibitor SB216763 (SB21; 70 μg/kg IV). Infarct size was assessed by triphenyltetrazolium chloride staining. The resistance of the mPTP to opening after Ca2+ loading was assessed by spectrofluorometry on mitochondria isolated from the area at risk. In...
Abstract 9747: Truth in Advertising: Are We Providing Consumers With the Proper Information to Participate in Decision Making About Hypoplastic Left Heart Therapies?
Authors: Richard A Friedman
Journal: Circulation (2015)

Introduction: Consumer Health Informatics has become an integral part of healthcare in 2015. The purpose of this survey study is to examine the information available on the internet to a parent(s) of a fetus diagnosed in utero with hypoplastic left heart disease (HLHD) and compare those to scientific, peer reviewed published data. Specifically, is the the provider data complete enough for prospective parent(s) to make a rational decision as to whether to proceed with a 3 stage repair or choose another option. Hypothesis: The formally untested hypothesis is that there is a signifcant "gap" between what is actually known to providers and what is presented to prospective parent(s)on provider websites. Methods: Using the list of the top 10 rated Pediatric Cardiovascular programs as ranked by the U.S. News World Report (USNWR) we collected the published information with respect to: # cases of HLHD operated on for Stage 1 Norwood at the hospital/program in question, Stage 2 Glenn shunt and Stage 3 Fontan; mortality at each stage ; interstage mortality ; mortality data for patients completing all 3 stages ; neurodevelopemntal outcomes and other morbidities. For comparison, we used published data on outcomes of HLHD surgery and follow-up from the Society for Thoracic Surgery as it encompasses the largest collection of datasets from many U.S. programs. We compared the STS data set to the publsihed information from the websites.. Results: Websites did not present the statistical data presented by the STS. In addition, no website listed the exact incidence of their interstage mortality, neurodevelopemntal outcomes nor morbidities at their site. Conclusions: 1. Information published on websites of the top 10 USNWR programs provide information that tell only part of the story of outcomes for HLHD. 2. Critical pieces of information such as interstage mortality and significant morbidities, are not reported. 3.We must reasses the amount and type of data presented on hospital/program websites
Abstract B22: Uncovering the role of lysyl oxidase-like 2 in rhabdomyosarcoma
Authors: Olga Almacellas Rabaiget, Juan Huertas Martínez, Silvia Garcia Monclús, Santiago Rello Varona, Herrero Martín, Roser López Alemany, Oscar M. Tirado
Journal: Clinical Cancer Research (2018)

Abstract Rhabdomyosarcoma (RMS) is the most common soft-tissue malignancy in childhood and adolescence that originates as a consequence of regulatory disruption in the growth and differentiation of muscle precursor cells. Members of the lysyl oxidase family of proteins (LOX and LOXL1-4) are amine oxidases that catalyze the covalent crosslinking of collagen and elastin in the extracellular matrix. Apart from their traditional role, novel functions have been attributed to these proteins related to tumor progression. In this study we sought to unravel the potential role of this family of proteins during the progression of RMS. By qRT-PCR and Western blot, lysyl oxidase-like 2 (LOXL2) was found overexpressed in RMS cell lines compared to other sarcoma cells. Then we characterized LOXL2 in RMS cell lines by analyzing the subcellular localization by immunofluorescence and subcellular fractionation. Post-translational modifications were also analyzed: glycosylation and proteolytic processing by tunicamycin treatment and secretion by analysis of the conditioned media by Western blot. Moreover, we characterized the neoplastic phenotype after silencing LOXL2 in two RMS cell lines (RH4 and CW9019). Stable LOXL2 knockdown resulted in a decrease in their clonogenic, proliferative, and cell migratory capabilities. On the other hand, reexpression of LOXL2 in RH28 cells using wild-type or mutated (catalytically inactive) constructs resulted in an increase in cell proliferation and migration, independently of its catalytic activity. Finally, in vivo experiments using an orthotopic model of tumor generation inside the muscle will be carried out to further evaluate the tumorigenic role of LOXL2. Taking all into consideration, our results suggest an oncogenic role of LOXL2 in RMS. Citation Format: Olga Almacellas Rabaiget, Juan Huertas Martínez, Silvia Garcia Monclús, Santiago Rello Varona, David Herrero Martín, Roser López Alemany, Oscar M. Tirado. Uncovering the role of lysyl oxidase-like 2 in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B22.
Abstract B46: DICER1 and FOXL2 mutations correlate with clinicopathologic features of ovarian Sertoli-Leydig cell tumors
Authors: Anthony N. Karnezis, Yemin Wang, Jamie Magrill, Jacqueline Keul, Stefan Kommoss, Basile Tessier-Cloutier, Lily Proctor, Dietmar Schmidt, C Blake Gilks, David G. Huntsman, Friedrich Kommoss
Journal: Clinical Cancer Research (2018)

Abstract Sertoli-Leydig cell tumors are rare mixed ovarian sex cord-stromal neoplasms consisting of a mixture of Sertoli cells, Leydig cells, and occasionally heterologous elements or retiform differentiation. The only known recurrent genetic abnormality is mutations in DICER1, with rare mutations reported in FOXL2. We set out to determine the DICER1 and FOXL2 mutation status in a series of 51 SLCTs with the goal of establishing a molecular classifier using mutation status and clinicopathologic features. Five tumors were well differentiated, 39 moderately differentiated, and 7 poorly differentiated. Nine tumors had heterologous elements (8 epithelial, one mesenchymal), and four showed retiform differentiation; all of these were moderately differentiated. DICER1 mutations were identified in 16/45 of successfully genotyped tumors (36%, 15 moderately differentiated, 1 poorly differentiated), including 7 with heterologous elements and 3 of 4 with retiform differentiation. FOXL2 c.402C&amp;gt;G mutation was identified in 10/51 tumors (20%, 8 moderately differentiated, 2 poorly differentiated). DICER1 and FOXL2 mutations were mutually exclusive. Median age for the entire cohort was 44 years (range 15-90). Patients with DICER1 mutations were younger (median 23.5 years, range 15-62) than patients with neither DICER1 nor FOXL2 mutation (median 41.5 years, range 16-74). Tumors with FOXL2 mutation occurred exclusively in postmenopausal patients (median 78 years, range 54-90), whereas 11/13 tumors with either heterologous elements (median 26 years, range 16-62) or retiform differentiation (median 38 years, range 18-57) occurred in premenopausal patients. Our data suggest the existence of at least three molecular subtypes of SLCT: DICER1 mutant (younger, moderately/poorly differentiated, including heterologous elements or retiform differentiation), FOXL2 mutant (postmenopausal, moderately/poorly differentiated, no heterologous elements or retiform differentiation), and DICER1/FOXL2 wild-type (no specific age, no heterologous elements, including all well-differentiated tumors). These findings suggest that well-differentiated and moderately/poorly differentiated SLCTs may be different histomolecular entities with different etiologies. Citation Format: Anthony N. Karnezis, Yemin Wang, Jamie Magrill, Jacqueline Keul, Stefan Kommoss, Basile Tessier-Cloutier, Lily Proctor, Dietmar Schmidt, C Blake Gilks, David G. Huntsman, Friedrich Kommoss. DICER1 and FOXL2 mutations correlate with clinicopathologic features of ovarian Sertoli-Leydig cell tumors. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B46.
Linking Heart Failure to Cancer
Authors: Edoardo Bertero, Marco Canepa, Christoph Maack, Pietro Ameri
Journal: Circulation (2018)

Recent epidemiological analyses suggest that incident cancer may be more common among patients with preexisting heart failure (HF) than in patients without HF. Arguments against this notion have been the increased chance of co-occurrence of 2 high-prevalence conditions and increased tumor detection in patients with HF because of intensified medical observation. However, biological data lend support to the hypothesis that HF is an oncogenic condition. Neurohormonal activation has been related to cancer initiation, progression, and dissemination by studies not specifically focusing on HF, which are now reappraised in the light of the emerging evidence that tumors are diagnosed more often in HF than control cohorts. Furthermore, a thought-provoking scenario to be considered is that a systemically perturbed milieu, where low-grade inflammation plays a primary role, leads to both HF and malignancy, thus connecting 1 disease to another. Postischemic HF has been shown to promote tumor growth in an animal model. Exploring these and other pathways potentially linking HF to malignancy is a new and exciting field of research, with the ultimate goal of answering the question of whether HF does promote cancer.
Abstract 2070: The prevalence of <i>DICER1</i> pathogenic variation in cancer population databases
Authors: Jung Kim, Kris Ann P. Schultz, D. Ashley A. Hill, Douglas R. Stewart
Journal: Cancer Research (2018)

Abstract DICER1 is an RNaseIII endonuclease that is crucial for processing pre-microRNA into mature microRNA. The DICER1 syndrome is a rare, autosomal dominant tumor-predisposition disorder associated with pleuropulmonary blastoma, a rare pediatric lung cancer. Somatic missense variation in “hotspot” codons in the RNaseIIIb domain (E1705, D1709, G1809, D1810, E1813) is observed in DICER1-associated tumors. Previously, we found in the general population (non-TCGA ExAC) that the prevalence of pathogenic DICER1 variation is approximately 1:10,000. In this study, we investigated the prevalence of pathogenic DICER1 variation in common adult and pediatric cancers. We examined two publicly-available cancer datasets: TCGA (adult; 32 cancer types; 9,173 exomes) and TARGET (pediatric; 3 cancer types; 236 exomes). TCGA bam files were downloaded and germline variants were called. Germline VCF files were obtained from TARGET investigators. All datasets were annotated with snpEff and ANNOVAR. Variants were binned into 4 categories: likely benign (LB), variant of unknown significance (VUS), likely pathogenic (LP), or pathogenic (P). We reviewed publicly-available pathology images for the TCGA tumors. The prevalence of DICER1 P/LP variants (in all cancers combined) was 1:834 and 1:118 in TCGA and TARGET, respectively. To reduce potential prevalence inflation, we conducted a more stringent prevalence calculation by only considering loss-of-function and hotspot variants. The prevalence of P variants was approximately 1:4586 in TCGA and 1:236 in TARGET. With these more stringent criteria, a single participant with a uterine corpus endometrial carcinoma (UCEC in TCGA) harbored a two pathogenic germline DICER1 (hotspot and splice donor) variants, and a second UCEC harbored a somatic DICER1 (hotspot) variant. In TARGET, a single participant with a neuroblastoma harbored a germline DICER1 canonical splice variant. There were no atypical or unusual features noted on pathology review of publicly-available slides from TCGA tumors. In TCGA, across many types of cancer, the prevalence of pathogenic DICER1 variation was higher compared with the general population (~1:4,600 vs. ~1:10,000), a finding driven by one cancer type (UCEC). In the smaller TARGET dataset, we observed a single pathogenic germline variant in neuroblastoma. This is the first comprehensive analysis of DICER1 pathogenic variation in large adult and pediatric cancer populations. The novel association of DICER1 variation with UCEC merits additional investigation. Citation Format: Jung Kim, Kris Ann P. Schultz, D. Ashley A. Hill, Douglas R. Stewart. The prevalence of DICER1 pathogenic variation in cancer population databases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2070.
Abstract 5629: Preclinical characterization of Sym023 a human anti-TIM3 antibody with a novel mechanism of action
Authors: Trine Lindsted, Monika Gad, Michael V. Grandal, Camilla Frölich, Vikram K. Bhatia, Torben Gjetting, Johan Lantto, Ivan D. Horak, Michael Kragh, Klaus Koefoed, Mikkel W. Pedersen
Journal: Cancer Research (2018)

Abstract Immunotherapy has become a major focus of research in oncology and blockade of immune checkpoints such as cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4) and programmed cell death protein 1 (PD1) has been some of the most successful immunotherapies. The next wave of immunomodulatory targets that are being explored for cancer therapy include T cell immunoglobulin and mucin domain protein 3 (TIM3). TIM3 is constitutively expressed on cells of myeloid origin whereas the TIM3 expression is induced on T-cells upon activation. The exact function of TIM3 on the different immune cells is not clear and may be context dependent suggesting that TIM3 is not a classical immune check-point. Sym023 is a human anti-TIM3 antibody, which binds human TIM3 and cross-reacts with cynomolgus monkey TIM3. Sym023 blocks binding of phosphatidyl serine but not galectin 9 and stimulates T-cell proliferation in mixed lymphocyte reactions and tumor growth inhibition in vivo. Here, we present data demonstrating that ligation of TIM3 by Sym023 increase cytokine production and T cell proliferation in vitro through a novel mechanism of action. Citation Format: Trine Lindsted, Monika Gad, Michael V. Grandal, Camilla Frölich, Vikram K. Bhatia, Torben Gjetting, Johan Lantto, Ivan D. Horak, Michael Kragh, Klaus Koefoed, Mikkel W. Pedersen. Preclinical characterization of Sym023 a human anti-TIM3 antibody with a novel mechanism of action [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5629.
Abstract 110: PPARγ loss increases the metastatic potential of HER2+ breast cancer
Authors: Elizabeth D. Lightbody, Kathleen MJ O'Connell, Hailey T. Newton, Rachel R. Rubino, Anthony J. Apostoli, Kevin Ren, Sandip K. SenGupta, Christopher J. Nicol
Journal: Cancer Research (2018)

Abstract Breast tumors that overexpress human epidermal growth factor receptor 2 (HER2+) grow and spread faster than HER2-negative tumors, resulting in poor patient prognosis. Peroxisome proliferator-activated receptor (PPAR)γ is a nuclear transcription factor that controls the expression of genes essential for normal metabolism of fats and sugars in the body. Our laboratory previously showed that PPARγ expression suppresses environmental carcinogen DMBA-mediated breast tumor progression in vivo, and PPARγ-activating drugs further enhance this effect. However, the role of PPARγ and PPARγ agonists on HER2+ breast tumorigenesis and patient survival is unclear. We hypothesized that PPARγ loss enhances HER2+ breast tumor progression. To test this, this study generated a novel mouse model referred to as NIC:PPARγ-KO, which has targeted PPARγ deletion in the same HER2+ transformed mammary epithelial cells that drive breast tumorigenesis. Compared to NIC:PPARγ-WT mice, NIC:PPARγ-KO mice have increased mammary tumor incidences and lung metastases. Protein analysis of NIC:PPARγ-KO tumors shows PPARγ loss is inversely correlated with increased HER2 phosphorylation at tyrosine 877 (pY877HER2) in primary and metastatic tumorigenic tissue. Immunofluorescence also showed HER2 H-scores were significantly highest among tumors from NIC:PPARγ-KO mice, but also correlated with targeted PPARγ loss in DMBA-induced primary and metastatic mammary tumors among PPARγ-WT and PPARγ-KO mice (p&amp;lt;0.05). To further investigate the role of PPARγ in the metastatic process, we established cell lines from the freshly isolated lung metastatic tumors harvested from the NIC:PPARγ-KO model (NIC:PPARγ-KO-lmet). In vitro analysis of several human HER2+ breast cancer cells lines and our NIC:PPARγ-KO-lmet cells shows migration, invasion and tumorsphere-forming potential were significantly increased after epidermal growth factor (EGF, 20ng/mL) treatment and, more interestingly, that co-treatment with a PPARγ-activating drug (rosiglitazone, 10μM) significantly abrogated these effects (p&amp;lt;0.05). Together, these data provide the first evidence that PPARγ may be a useful prognostic/predictive biomarker for HER2+ breast tumors, and suggest that the novel inclusion of PPARγ-activating drugs may benefit a subset of HER2+ breast cancer patients. Citation Format: Elizabeth D. Lightbody, Kathleen MJ O'Connell, Hailey T. Newton, Rachel R. Rubino, Anthony J. Apostoli, Kevin Ren, Sandip K. SenGupta, Christopher J. Nicol. PPARγ loss increases the metastatic potential of HER2+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 110.
Abstract 20672: Dynamic Phenommapping in Heart Transplantation Predicts Clinical Outcomes
Authors: Maral Bakir, Nicholas Jackson, Chi-Hong Tseng, Eleanor Chang, David Henriquez-Ticas, Mario Deng, Martin Cadeiras
Journal: Circulation (2016)

Introduction: A major limitation of long-term survival in Heart Transplantation (HTx) is determined by the effects of the immune system on the cardiac allograft as well as the consequences of the b...
Abstract 5109: Somatic CRISPR/Cas9-mediated gene editing enables versatile brain tumor modeling
Authors: Marc Zuckermann, Britta Ismer, Volker Hovestadt, Christiane B. Knobbe-Thomsen, Marc Zapatka, Paul A. Northcott, Martine F. Roussel, Guido Reifenberger, Peter Lichter, Stefan M. Pfister, Daisuke Kawauchi, Jan Gronych, David T. Jones
Journal: Cancer Research (2018)

Abstract Despite substantial advances in the molecular classification of pediatric brain tumors over the last decade, many tumors are still incurable, have a poor prognosis or therapy-related detrimental long term effects. To develop innovative and modern therapy approaches, sophisticated mouse models, faithfully reflecting the human disease are urgently needed. However, the development of transgenic mouse lines is a time consuming process that is confronted with an increasing number of candidate genes resulting from next generation sequencing of tumor specimens. To cope with this discrepancy, more adaptable animal models are needed. Using somatic gene transfer to manipulate cells in situ holds great advantages in terms of speed and flexibility. We therefore established a system in which we are using the CRISPR/Cas9 system for somatic disruption of candidate tumor suppressor genes (TSGs) in combination with transposon-mediated overexpression of candidate oncogenes to induce murine brain tumors. By deleting Ptch1 in murine cerebella, we induced Sonic Hedgehog (SHH) subgroup medulloblastoma with high penetrance and short latency. We characterized the induced mutations in depth and did not detect recurrent off-targets using unsupervised whole genome sequencing. We further demonstrated that this method is suited to induce other brain tumor entities by targeting multiple TSGs at the same time or by combining TSG targeting with overexpression of certain oncogenes. To date we established five novel mouse models using this system. Two of these resulted from simultaneous deletion of Nf1, Pten and Trp53 or from combining overexpression of a MET fusion with a loss of Trp53, respectively. Both of these combinations led to efficient glioblastoma induction in the murine forebrain. Our results demonstrate a fast and flexible system for validating novel candidate genes and for generating faithful animal models of human cancer. Citation Format: Marc Zuckermann, Britta Ismer, Volker Hovestadt, Christiane B. Knobbe-Thomsen, Marc Zapatka, Paul A. Northcott, Martine F. Roussel, Guido Reifenberger, Peter Lichter, Stefan M. Pfister, Daisuke Kawauchi, Jan Gronych, David T. Jones. Somatic CRISPR/Cas9-mediated gene editing enables versatile brain tumor modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5109.