tbuckley/cabot-search huggingface dataset:
Abstract B30: ARID1A is a haploinsufficient tumor suppressor for N-Myc transformation of neural crest cells
Authors: Kirby Wallace, Jesus Garcia-Lopez, Joel Otero, Rachelle Olsen, Chelsea DeVaux, Ashton King, Andrew Davidoff, Kevin Freeman
Journal: Cancer Research (2020)

Abstract Large segmental chromosomal alterations are common to cancer and a feature of high-risk neuroblastoma (NBL). Though they are early or initiating events in cancer, including often being found in precancerous lesions, their contribution to tumorigenesis is poorly understood. An unproven model is that these changes promote cancer through the cumulative effect of multiple dosage-sensitive genes. Loss of heterozygosity (LOH) at 1p36 is a frequent structural rearrangement in a broad range of human cancers including NBL. Approximately 70% of MYCN amplified NBL have 1p36 LOH with both mutations independently contributing to tumor aggressiveness in NBL. Two tumor suppressor regions have been proposed to exist in 1p36, a distal and proximal region, which have MYCN-independent and dependent roles. Through CRISPR/Cas9 genome editing of primary mouse neural crest cells (NCCs), a source for NBL, we found that loss of the chromatin remodeling factor Chd5 conferred most of the tumor-suppressor effects of 1p36 LOH in in vitro cell transformation assays in cells with endogenous levels of N-Myc. In contrast, when N-Myc was overexpressed, tumor evolution of NCCs genome edited to have randomly sized 1p36 deletions showed a reduction in tumor latency that significantly correlated with deletion of Arid1a. The Arid1a deletions that were selected for ranged from small indels up to large 1p36 deletions, indicating that large deletions are tolerated to achieve loss of a single critical tumor suppressor. Further, using lentiviral Cre-induced deletion of floxed Arid1a in isolated NCCs, we found that Arid1a is a haploinsufficient tumor suppressor in MYCN-driven transformation of NCCs. As Arid1a is a subunit of the chromatin remodeling complex SWI/SNF, which is mutated in 20% of cancers, Arid1a synthetic lethal therapies are being developed for adult malignancies. We are currently verifying those proposed therapies in NBL and are using small-molecule screening of cells lines derived from Arid1a wild-type, het, or null tumors to identify additional synthetic lethalities. Our findings indicate that context, such as the status of MYCN as an oncogene, dictates which 1p36 gene is the critical tumor suppressor, establishing 1p36 LOH as multifaceted not cumulative, as was previously believed. Citation Format: Kirby Wallace, Jesus Garcia-Lopez, Joel Otero, Rachelle Olsen, Chelsea DeVaux, Ashton King, Andrew Davidoff, Kevin Freeman. ARID1A is a haploinsufficient tumor suppressor for N-Myc transformation of neural crest cells [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B30.
Abstract A31: Podxl as therapeutic target for metastasis
Authors: Anne-Chloe Dhez, Irene Paassen, Poul Sorensen
Journal: Cancer Research (2020)

Abstract Osteosarcoma (OS) is the most common bone tumor in pediatric patients. Metastasis is a major cause of mortality and morbidity. The rarity of this disease coupled with the challenges of drug development for metastatic cancers have slowed the delivery of improvements in long-term outcomes for these patients. Recently, we found that high podocalyxin (gene name PODXL, protein name Podxl) expression is associated with high metastatic profile in OS cell lines. Consistent with this data, we found a significant association between high Podxl expression and poor outcome in pediatric OS patients. Podxl is a cell surface transmembrane glycoprotein belonging to the CD34 family. The functional role of Podxl in tumorigenesis is largely unknown, but it has been demonstrated to promote cancer cell invasion and migration and to enhance metastatic potential. Podxl is upregulated on a variety of human tumors, facilitates disease progression, and is a promising target for immunotherapy as an approach to blocking metastatic disease. Accordingly, in collaboration for the Centre for Drug Research and Development, Kelly McNagny and his collaborators have developed a novel panel of monoclonal antibodies to human Podxl and have explored their utility in suppressing tumor cell growth in vitro and in vivo. To define the relevance of Podxl in the biology of metastasis, we examined Podxl expression in different OS cell lines with different metastatic profiles. Then, we studied the importance of Podxl in migration and invasion processes and in in vitro 3D cell system formation. To assess Podxl’s role in metastatic progression we performed the Pulmonary Metastasis Assay (PuMA). PuMA is an ex vivo lung explant and closed cell culture system that permits to study the biology of lung colonization by fluorescence microscopy. With PuMA model, we assessed the effects of antimetastatic therapeutics over time. In the present study, we found that suppression of Podxl profoundly impairs cell proliferation, migration, invasion properties, and tumorsphere formation in OS cells in vitro. With PuMA model, we found that Podxl is required for the progression of metastasis disease. These data tend to validate podocalyxin as a regulator of tumor progression and a novel therapeutic target in OS. It is necessary to perform in vivo experiments to further explore the functions of Podxl and the effect of the podocalyxin-specific monoclonal antibody (coupled or not to a toxic payload) to suppress the metastasis progression in our model. Citation Format: Anne-Chloe Dhez, Irene Paassen, Poul Sorensen. Podxl as therapeutic target for metastasis [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A31.
Abstract B46: CATACOMB: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb Repressive complex 2 via a H3K27M-like mechanism
Authors: Andrea Piunti, Edwin Smith, Marc Morgan, Michal Ugarenko, Natalia Khaltyan, Kathryn Helmin, Caila Ryan, David Murray, Ryan Rickels, Bahar Yilmaz, Emily Rendleman, Jeffrey Savas, Benjamin Singer, Serdar Bulun, Ali Shilatifard
Journal: Cancer Research (2020)

Abstract Dysregulation of Polycomb Repressive Complex 2 (PRC2) function is a common feature of many cancer types, including both solid and hematologic malignancies. A number of chromosomal translocations involving Polycomb group proteins have been identified; however, the molecular function of these fusion proteins remains largely unexplored. Here we characterize two endometrial stromal sarcoma (ESS) associated fusion proteins: JAZF1-SUZ12 and MBTD1-CXORF67. We identify JAZF1 as a previously unreported subunit of the NuA4 complex, which when fused to SUZ12 creates a bridge between the NuA4 and PRC2 complexes. Intriguingly, the MBTD1-CXORF67 fusion binds to PRC2 and leads to strongly reduced levels of the PRC2 catalytic products H3K27me2/3. We demonstrate that this inhibitory function is mediated by the CXORF67 half of the fusion protein. Because of this striking property, we propose a new gene name: CATACOMB (CATalytic Antagosnist of polyCOMB; official gene name: EZHIP). We map CATACOMB’s inhibitory function to a short, highly conserved region and identify a single methionine residue essential for diminution of H3K27me2/3 levels. Remarkably, the amino acid sequence surrounding this critical methionine resembles that of the oncogenic histone H3 lysine-27-to-methionine (H3K27M) mutation found in high-grade pediatric gliomas. Finally, we show CATACOMB expression is silenced through DNA methylation and upon treatment with DNA demethylating agents, CATACOMB is expressed, binds to PRC2, and antagonizes its catalytic activity. In conclusion, we have identified an endogenous inducible gene, CATACOMB, which can regulate the catalytic activity of PRC2 and propose that such mechanism of regulation of histone modifications through the expression of antagonistic subunits may also exist for other histone-modifying enzyme complexes. Citation Format: Andrea Piunti, Edwin Smith, Marc Morgan, Michal Ugarenko, Natalia Khaltyan, Kathryn Helmin, Caila Ryan, David Murray, Ryan Rickels, Bahar Yilmaz, Emily Rendleman, Jeffrey Savas, Benjamin Singer, Serdar Bulun, Ali Shilatifard. CATACOMB: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb Repressive complex 2 via a H3K27M-like mechanism [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B46.
Plasma LRG1 Protein Are Overexpressed in Acute Myeloid Leukemia with High Sensitivity and High Specificity in Differentiating Leukemic Plasma from Normal Plasma — a Potential Biomarker for Minimal Residual Disease Detection
Authors: Chin Hin Ng, Xu Liang, Jianbiao Zhou, Elaine Seah, Baohong Lin, Wee-Joo Chng, Yoon-Pin Lim
Journal: Blood (2017)
Abstract #1215: The protective role of 2-Deoxy-D-Glucose (2DG) against high-dose chemotherapy induced toxicity
Authors: Qian Liu, Jessica Sun, Damien Ferraro, Dharmendra Ahluwalia, Yan Wang, Charles Hart, John Curd
Journal: Cancer Research (2009)

Caloric restriction (CR) has been reported to increase lifespan in many species. Short-term starvation or low glucose could protect mammalian cells against high dose of chemotherapy. 2-Deoxy-D-Glucose (2DG) is a synthetic glucose analog that inhibits intracellular utilization of glucose and inhibits ATP synthesis. 2DG has been used as a CR mimetic compound that reduces the energy availability at the cellular level and provides protection from radiotherapy, excitotoxicity and cardiovascular risk factors. The purpose of this study is to investigate whether 2DG, particularly with oral administration, can protect animals against the toxicity induced by high dose chemotherapy. Female nude mice were used in the study. The maximum dose of chemotherapeutic agents was determined to be that producing 20% animal body weight loss and not causing drug related lethality. Animals were dosed with Docetaxel (40mg/kg, iv) or Cisplatin (10mg/kg, iv) alone or in combination with 2DG (500 to 2000mg/kg, po). All drugs were administered on Day 1 and Day 8. Body weight (BW) was monitored daily and hematological toxicity was examined on Day 14. The BW loss was 12.4% on Day 14 in the Docetaxel alone group and in 1 of 5 mice the BW loss was more than 20%. 2DG 500mg/kg and 1000mg/kg in combination with Docetaxel showed 5.7% and 8.3% BW decrease respectively. No animals lost more than 20% weight in the 2DG groups. Increasing the dose of 2DG to 2000mg/kg did not enhance the protective activity. Cisplatin alone gave 9.6% BW loss on Day 11, while only a loss of 1.4% was observed when 2DG 1000mg/kg was combined with the Cisplatin. Hematologically, Docetaxel alone significantly decreased white blood cells (WBC), 3.4 ± 0.5 vs 6.0 ± 0.6 in Vehicle (p  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1215.
Abstract A68: Optical coherence tomography improves subclinical retinoblastoma management
Authors: Sameh E. Soliman, Cynthia VandenHooven, Leslie MacKeen, Brenda Gallie
Journal: Cancer Research (2020)

Abstract Purpose: Optical coherence tomography (OCT) improved retinal assessment that is comparable to histopathologic sections. In retinoblastoma, OCT was reported to detect fovea-tumor relation, diagnose subclinical (new, residual and recurrent tumors), and suspect tumor spread into the optic nerve. We hypothesized that strategic incorporation of OCT into retinoblastoma management will improve outcomes and managing retinoblastoma at the subclinical level (clinically undetectable) provides means for less treatment burden. Methods: A single-center, noncomparative retrospective review of all eyes with subclinical retinoblastoma was conducted. Any eye that had an OCT-guided procedure, whether diagnostic or therapeutic, utilizing OCT software was included. OCT-guided management included projecting embedded OCT software tools (scan cube size and direction, multiple scan frames, localizing and measuring vertical and horizontal calipers, enhanced depth imaging frames, and/or red free fundus photograph) on a separate colored fundus image to guide management to improve visual, life, and eye salvage outcomes. Results: We used OCT-guided strategies in 83 children (114 eyes). Diagnostic strategies included posterior pole screening for invisible retinoblastoma (37 eyes), topographic localization of invisible tumors (15 eyes) or subclinical recurrence (29 tumors), topographic localization of fovea-tumor relation (31 eyes), and mapping of potential choroidal or optic nerve invasion to determine subsequent management (2 eyes each). Therapeutic strategies included laser photocoagulation for perifoveal residual (26) and invisible (11) tumors and verification of photocoagulation adequacy for invisible (11) new and recurrent (11) tumors. These procedures were scored for their influence to changed therapy. Conclusion: Detailed OCT assessment improves retinoblastoma management and facilitates precision therapy to preserve vital visual structures (e.g., the center of vision), detect subtle subclinical tumors (new or recurrent), allow administration and adequacy of laser treatment, and map subclinical high-risk features. Developing OCT-guided strategies with full technical description facilitates reproducibility and allows precision therapy to be a reality. Citation Format: Sameh E. Soliman, Cynthia VandenHooven, Leslie MacKeen, Brenda Gallie. Optical coherence tomography improves subclinical retinoblastoma management [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A68.
Association of Childhood Intrafamilial Aggression and Childhood Peer Bullying With Adult Depressive Symptoms in China
Authors: Qing Wang
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Childhood intrafamilial aggression, a series of aggressive behaviors inflicted by family members, and adulthood mental health are associated with childhood peer bullying (eg, in the neighborhood or in school). However, few studies have been able to identify the contribution of childhood peer bullying to the association between childhood intrafamilial aggression and adult depression. <h3>Objective</h3> To examine the mediating role of childhood peer bullying in the association between childhood intrafamilial aggression and depression in adulthood. <h3>Design, Setting, and Participants</h3> This population-based cross-sectional study used data from the China Health and Retirement Longitudinal Study (CHARLS). Middle-aged and older adults (≥45 years) participated in a CHARLS wave from July 1 to September 30, 2015, and the CHARLS life history survey from June 1 to December 31, 2014, with complete data. A 4-step mediation model with logistic regression was run to test the mediating role of peer bullying. Data analysis was performed from October 1 to 30, 2019. <h3>Exposures</h3> Childhood intrafamilial aggression, including parental physical maltreatment and sibling aggression, and peer bullying. <h3>Main Outcomes and Measures</h3> Depressive symptoms measured by a categorical variable derived from the Center for Epidemiologic Studies Depression Scale, based on a cutoff score of 12. <h3>Results</h3> Among the 15 450 respondents (mean [SD] age, 59.5 [9.9] years; 7987 women [51.7%]), 4422 (28.6%) were exposed to parental physical maltreatment; 986 (6.4%), to sibling aggression; and 2504 (16.2%), to peer bullying in childhood. Respondents experiencing intrafamilial aggression were more likely to be bullied by peers (parental physical maltreatment odds ratio [OR], 2.53 [95% CI, 2.25-2.83]; sibling aggression OR, 3.05 [95% CI, 2.46-3.78]). Children with these adverse experiences were at a higher risk of adult depression symptoms (parental physical maltreatment OR, 1.28 [95% CI, 1.15-1.42]; sibling aggression OR, 1.40 [95% CI, 1.13-1.74]; peer bullying OR, 1.78 [95% CI, 1.56-2.01]). Peer bullying mediated 30% (95% CI, 19%-42%) of the association between childhood parental maltreatment and adult depression and 35% (95% CI, 15%-54%) of the association between sibling aggression and depression symptoms in adulthood. <h3>Conclusions and Relevance</h3> This study found that being bullied by peers was a mediator of the association between childhood intrafamilial aggression and depression in adulthood. The findings have important implications to mitigate the effect of early-life stress and promote life-course mental health through dealing with childhood intrafamilial aggression and peer bullying experiences coordinately.
Abstract IA05: Circulating tumor DNA as a tool for prognostication, translational discovery, and early cancer detection
Authors: Brian Crompton
Journal: Cancer Research (2020)

Abstract New sequencing technologies have facilitated the detection and profiling of circulating tumor DNA (ctDNA) in the blood of patients with cancer. Recent efforts have demonstrated that ctDNA can be detected in the blood of pediatric patients with solid malignancies, using assays specifically designed for the unique somatic profiles observed in these cancers. Once identified in a blood sample, ctDNA levels appear to correlate with outcome and can be tracked over time to measure response to therapy and detect recurrence. Deep profiling of ctDNA can identify subclonal somatic variants that are not detectable in single-tumor biopsy samples, enabling a broader understanding of tumor heterogeneity and the ability to discover novel patterns of tumor evolution and treatment resistance. Validation of the prognostic and translational value of these assays requires leveraging large prospective studies, and this work is ongoing. One obvious application of this new technology is the potential to detect the presence of cancer in pediatric patients with increased cancer risks, including cancer predisposition syndromes. Collaborative multi-institutional efforts are under way to collect samples and develop new ctDNA assays for early cancer detection. Citation Format: Brian Crompton. Circulating tumor DNA as a tool for prognostication, translational discovery, and early cancer detection [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA05.
Defining persistent Staphylococcus aureus bacteraemia: secondary analysis of a prospective cohort study
Authors: Richard Kuehl, Laura Morata, Christian Boeing, Isaac Subirana, Harald Seifert, Siegbert Rieg, Winfried V Kern, Hong Bin Kim, Eu Suk Kim, Chun-Hsing Liao, Robert Tilley, Luis Eduardo Lopez-Cortés, Martin J Llewelyn, Vance G Fowler, Guy Thwaites, José Miguel Cisneros, Matt Scarborough, Emmanuel Nsutebu, Mercedes Gurgui Ferrer, José L Pérez, Gavin Barlow, Susan Hopkins, Hugo Guillermo Ternavasio-de la Vega, M Estée Török, Peter Wilson, Achim J Kaasch, Alex Soriano, Richard Kuehl, Laura Morata, Christian Boeing, Isaac Subirana, Harald Seifert, Siegbert Rieg, Winfried V. Kern, Hong Bin Kim, Eu Suk Kim, Chun-Hsing Liao, Robert Tilley, Luis Eduardo Lopez-Cortés, Martin J. Llewelyn, Vance G. Fowler, Guy Thwaites, José Miguel Cisneros, Matt Scarborough, Emmanuel Nsutebu, Mercedes Gurgui Ferrer, José L. Pérez, Gavin Barlow, Susan Hopkins, Hugo Guillermo Ternavasio-de la Vega, Estée Török, Peter Wilson, Achim J. Kaasch, Alex Soriano, Christian Bernasch, Norma Jung, Karuna Lamarca Soria, Maria Alba Rivera Martínez, Nuria Prim, José Antonio Martínez, Miguel Marcos, Jesús Rodríguez Baño, Marina De Cueto, Kyoung-Ho Sung, Chung-Jong Kim, Chang Kyung Kang, Jung In Park, Stephen Morris-Jones, Musa Kamfose, Bernadette Young, Hannah Gott, Theodore Gouliouris, Luke Bedford, James Price
Journal: The Lancet Infectious Diseases (2020)
Annals Graphic Medicine - Dr. Mom: Work–Life Balance
Authors: Grace E. Farris
Journal: Annals of Internal Medicine (2020)

Web Exclusives4 August 2020Annals Graphic Medicine - Dr. Mom: Work–Life BalanceFREEGrace E. Farris, MDGrace E. Farris, MDMount Sinai School of Medicine, New York, New York (G.E.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G20-0071 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Mount Sinai School of Medicine, New York, New York (G.E.F.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G18-0042.Author/Illustrator Information: Grace E. Farris, MD, is an assistant professor of medicine at Icahn School of Medicine at Mount Sinai and chief of hospital medicine at Mount Sinai West hospital in New York, New York. You can view her work at her Web site: www.farrisgrace.com.About Dr. Mom: In Dr. Mom, physician and cartoonist Grace Farris examines work–life balance while mothering and doctoring. Dr. Mom appears monthly in Annals Graphic Medicine at Annals.org. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 4 August 2020Volume 173, Issue 3Page: W52-W54KeywordsConflicts of interestDisclosureHospital medicineHospitalists ePublished: 4 August 2020 Issue Published: 4 August 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract B24: Dysregulated Transcription Drives Splicing Defect in Ewing Sarcoma
Authors: L. Lawrence, A. Gorthi, H. Miller, A. J. R. Bishop
Journal: Cancer Research (2020)

Abstract Ewing sarcoma (EwS) is a pediatric and young adult cancer that is driven by the EWSR1-FLI1 translocation. Despite decades of work, this cancer is still an enigma, with poorly understood biology and no targeted treatments. Our recent work published in Nature demonstrated a previously overlooked consequence of EWSR1-FLI1, that this fusion causes hyperphosphorylated RNA polymerase II (pRNAPII) due to loss of EWSR1 inhibition of CDK7 and CDK9. We observed high levels of transcription, with high levels of R-loops present in locations that R-loops normally (physiologically) occur. Based upon these findings, we began to reconsider cellular phenotypes of EwS to identify the molecular basis of these phenotypes and ask whether these changes provide a fundamental defect in all EwS. One phenotype that was previously identified in EwS is that these cells display altered splicing profiles. In our prior work we reported that the normal dephosphorylation of pRNAP in response to damage does not occur, and this results in trapping of BRCA1 protein with the active transcription complex. It was recently shown that the splicing machinery is bound to pRNAPII. This observation raises the interesting possibility that in EwS, like BRCA1 protein, the splicing machinery is also sequestered with pRNAPII. Interestingly, in recent years, there have been several reports linking R-loops to splicing, with splicing defects causing R-loop accumulation and R-loops being associated with sites of alternative splicing. We therefore asked if there is an association between the R-loops and alternative splicing phenotype in EwS cells and whether this results in a defect that can be leveraged to specifically target EwS cells and tumors. Citation Format: L. Lawrence, A. Gorthi, H. Miller, A. J. R. Bishop. Dysregulated Transcription Drives Splicing Defect in Ewing Sarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B24.