tbuckley/cabot-search huggingface dataset:
Abstract 2435: Transcription Factor AP2 enhances malignancy of non-small cell lung cancer through upregulation of USP22 gene expression
Authors: Keqiang Zhang, Ting Sun, Wendong Li, Rajendra Pangeni, Dan Raz
Journal: Cancer Research (2021)

Abstract Ubiquitin-specific peptidase 22 (USP22), a putative cancer stem cell marker, is frequently upregulated in various human cancers, and USP22 overexpression is associated with aggressive growth, metastasis, and therapy resistance in a number of human cancers including lung cancer. However, USP22 gene amplification seldom occurs, and the mechanism underlying USP22 upregulation in human cancers remains largely unknown. We set out to characterize and identify potential transcription factors that regulate USP22 expression in human non-small cell lung cancers (NSCLC). A luciferase reporter driven by the promoter region from -5085 to +55 of USP22 gene was constructed to screen a customized siRNA library targeting about 100 selected transcription factors that are expected to bind to the USP22 promoter. Luciferase reporter assays have revealed that knockdown of SP1 and activating transcription factor 3 (ATF3) promote USP22 expression, while knockdown of transcription factor 2α, 2β (TFAP2α and TFAP2β), cMyc, and PPAR α suppress USP22 expression. The specific binding of TFAP2α and TFAP2β to the USP22 promoter was further validated by binding site-directed mutagenesis and chromosome immunoprecipitation (Chip) assays. Furthermore, overexpression of TFAP2α and TFAP2β significantly up-regulate USP22 expression and downstream molecules of USP22, concurrently enhance the proliferation, migration and invasion of NSCLC A549 and H1299 cells in a partially USP22-dependent manner. In addition, TFAP2 was demonstrated to be associated with a poor prognosis of NSCLC patients. Moreover, TFAP2 protein expression correlated with USP22 protein expression in human NSCLC tissues. Taken together, the findings of this study indicate TFAP2 is an important transcription factor driving USP22 gene expression, and it promotes the progression of NSCLC partially through enhancing USP22 expression. Citation Format: Keqiang Zhang, Ting Sun, Wendong Li, Rajendra Pangeni, Dan Raz. Transcription Factor AP2 enhances malignancy of non-small cell lung cancer through upregulation of USP22 gene expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2435.
Abstract 995: Alpelisib and vorinostat modulate critical genes in basal-2 triple negative breast cancer cells and inhibit cell growth and invasion
Authors: Beverly D. Lyn-Cook, Beverly Word, George Hammons, Fatemeh Nouri Emamzadeh
Journal: Cancer Research (2021)

Abstract Triple negative breast cancer (TNBC) is a heterogeneous disease that continues to be an unmet medicine need. It has a high mortality rate in younger women, especially African Americans. African American women are not sufficiently involved in clinical trials in which novel drugs are being tested. The aggressive and biology of subtypes of this cancer are being researched; however, no targeted therapy has been successful to date. Alpelisib is a selective inhibitor of PIK3 in the PIK3/ATK pathway and has been approved for treatment of advanced metastatic breast cancer. This study was conducted to investigate the effects of Alpelisib and vorinostat (an HDAC inhibitor), either alone or in combination, in the basal-2, a subtype of TNBC, cell line, HCC1806 from a African American woman. Alpelisib alone decreased protein expression of GSKβ, crk and DDX5. Alpelisib significantly upregulated the expression of AKT1 protein. In combination with vorinostat, a synergistic effect was noted with AKT1 protein expression. Different isoforms of AKT has been shown to exert anti-cancer effects. Also, the combination significantly decreased GSKβ protein expression. GSKβ regulates epithelial-mesenchymal transition and cancer stem cell properties. Decreased expression of DDX5 has been shown to result in decreased cell growth. These drugs also decreased invasion. Results from this study suggest that Alpelisib should be further investigated in basal-2 TNBC, alone or in combination with vorinostat. Citation Format: Beverly D. Lyn-Cook, Beverly Word, George Hammons, Fatemeh Nouri Emamzadeh. Alpelisib and vorinostat modulate critical genes in basal-2 triple negative breast cancer cells and inhibit cell growth and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 995.
FDA calls for investigation into industry influence during Alzheimer’s drug approval
Authors: Owen Dyer
Journal: BMJ (2021)

The acting commissioner of the US Food and Drug Administration (FDA) has asked the health department’s inspector general to investigate allegations of improper contact between FDA regulators and a company whose Alzheimer’s disease treatment won a controversial approval last month.

“Given the ongoing interest and questions,” Janet Woodcock wrote on Twitter, “today I requested that the inspector general conduct an independent review and assessment of interactions between representatives of Biogen and FDA during the process that led to the approval of Aduhelm.”1

The request came hours after the agency restricted the potential market of aducanumab (Aduhelm), retreating from a June approval2 that would have made it available to all US patients with Alzheimer’s disease, estimated at over six million people. Instead, the drug’s labelling will indicate its use only in those who have not progressed beyond mild cognitive impairment or early …
Abstract 3151: β Hydroxy β Methylbutyrate synergizes with cytotoxic chemotherapy and immunotherapy in a mouse model of pancreatic cancer
Authors: Michael F. Coleman, Kristyn A. Liu, Suhas K. Etigunta, Alex J. Pfeil, Xiaohu Tang, Salvador Fabela, Laura M. Lashinger, Zhengrong Cui, Stephen D. Hursting
Journal: Cancer Research (2021)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) remains the 4th most deadly cancer in the US. Current chemotherapeutic regimens poorly control PDAC progression and no approved immunotherapeutic options currently exist. PDAC incidence and progression are increased by obesity, which promotes a potently protumor PDAC microenvironment characterized by inflammation, fibrosis, and immunosuppression. β Hydroxy β Methylbutyrate, found to be safe and well-tolerated in clinical trials over many years, blunts cancer cachexia; however it has not been tested in PDAC. Further, the role of HMB in modifying existing therapies has been understudied. We sought to determine if HMB treatment would alter therapeutic response of lean and obese mice to gemcitabine or anti-PD1 immunotherapy. Methods: Lean and obese C57BL/6 mice were treated with HMB alone or in combination with gemcitabine or anti-PD1 immunotherapy following subcutaneous injection of Panc02 PDAC cells. In addition, bone marrow-derived macrophages (BMDM) were treated with HMB in vitro with or without LPS. Tumor/macrophage transcriptomic analysis, followed by gene set enrichment analysis and enrichment mapping identified transcriptional responses. CIBERSORTx determined microenvironment immune cell composition. Results: a) HMB reduces obesity-associated PDAC progression; b) HMB treatment and gemcitabine together suppress PDAC growth in obese mice; c) HMB mitigates PDAC immunosuppression and promotes tumor immune surveillance; d) HMB enhances the efficacy of anti-PD1 immunotherapy; e) HMB promotes M1 polarization of BMDM. Conclusion: Overall, HMB evokes antitumor immune responses in the context of pro-inflammatory stimuli such as obesity or immunotherapy. Moreover, HMB promotes immune surveillance in PDAC, synergizing with both cytotoxic chemotherapy and immunotherapy. HMB has been found to be safe and well tolerated in clinical trials for many years. Hence, HMB-induced suppression of PDAC tumor growth and promotion of immune surveillance may offer significant synergy with chemotherapies or immunotherapies in PDAC. This research was supported by R35CA197627 to S. Hursting. Citation Format: Michael F. Coleman, Kristyn A. Liu, Suhas K. Etigunta, Alex J. Pfeil, Xiaohu Tang, Salvador Fabela, Laura M. Lashinger, Zhengrong Cui, Stephen D. Hursting. β Hydroxy β Methylbutyrate synergizes with cytotoxic chemotherapy and immunotherapy in a mouse model of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3151.
Diabetes Care and Glycemic Control During the COVID-19 Pandemic in the United States
Authors: Sadiq Y. Patel, Rozalina G. McCoy, Michael L. Barnett, Nilay D. Shah, Ateev Mehrotra
Journal: JAMA Internal Medicine (2021)

Dramatic reductions in outpatient visits and laboratory testing early in the COVID-19 pandemic1,2 raised concerns about gaps in diabetes management and glycemic control.3 We therefore compared weekly rates of diabetes-related outpatient visits, screening tests, medication fills, and patients’ hemoglobin A1c (HbA1c) levels in 2020 vs 2019 in a national cohort of adults with type 2 diabetes.
Non-TBI Based Conditioning Regimen in Peripheral Blood Stem Cell Transplantation (PBSCT) for Adult Acute Lymphoblastic Leukemia Patients: A Single Center Experience
Authors: Gamal Fathy, Yasser Elnahass, Omar Fahmy, Mohamed Abdel Mooti Samra, Raafat Abdel El Fattah, Alaa Elhaddad, Ali Sobhy, Shymaa Mohamed, Mahmoud Bokhary, Hossam K Mahmoud
Journal: Blood (2017)
Abstract 2602: Leveraging cell-free methylome markers for early cancer detection
Authors: Nicholas Cheng, Kimberly Skead, David Soave, Jocelyn Meng, Elias Gbeha, Ilinca Lungu, Bernard Lam, Scott Bratman, Daniel De Carvalho, Philip Awadalla
Journal: Cancer Research (2021)

Abstract Cancer survival rates are significantly improved when detected at early stages, particularly when the tumor is still localized to the tissue of origin. However, effective screening tools for early cancer detection is currently limited to a subset of cancer types. The early development of human malignancies are difficult to observe as cancers are often detected once it becomes symptomatic, as such many cancer biomarker and evolution studies to date have primarily examined the genomics from solid tumor or liquid biopsies following a diagnosis. Investigating early tumor evolution in the pre-diagnosis context could allow us to better understand how to prevent or detect cancers in the earliest stage when survival rates are significantly higher, however this requires application of new technologies to biologics collected prior to a cancer diagnosis. Here, we leverage blood samples collected from participants in the Canadian Partnership for Tomorrow Project (CPTP), a longitudinal population cohort, prior to the onset of a cancer. Specifically, we utilize hybrid capture approaches to enrich for and characterize early mutations and methylation changes in circulating tumor DNA (ctDNA) of pre-cancer plasma samples collected from patients several months to years prior to clinical diagnosis. Here, we identify the earliest detectability of aberrant genetic and epigenetic events in ctDNA and describe the molecular evolution of these events at various stages prior to clinical detection of cancers. Further, we develop molecular biomarkers and implement machine learning tools to classify individuals with early cancers, and to develop risk scores from survival analyses predictive of cancer development up to 5 years prior to diagnosis. In our current study, we focus specifically on breast, prostate, lung and pancreatic cancer cases, and are extending this to pan-cancer applications in subsequent studies. Citation Format: Nicholas Cheng, Kimberly Skead, David Soave, Jocelyn Meng, Elias Gbeha, Ilinca Lungu, Bernard Lam, Scott Bratman, Daniel De Carvalho, Philip Awadalla. Leveraging cell-free methylome markers for early cancer detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2602.
Molecular characterization of fast-growing melanomas
Authors: Caroline Gaudy-Marqueste, Nicolas Macagno, Anderson Loundou, Eric Pellegrino, L'houcine Ouafik, Timothy Budden, Piyushkumar Mundra, Gabriela Gremel, Victoria Akhras, Lijing Lin, Martin Cook, Rajiv Kumar, Jean-Jacques Grob, Eduardo Nagore, Richard Marais, Amaya Virós
Journal: Journal of the American Academy of Dermatology (2021)
Coordinated changes in gene expression kinetics underlie both mouse and human erythroid maturation
Authors: Melania Barile, Ivan Imaz-Rosshandler, Isabella Inzani, Shila Ghazanfar, Jennifer Nichols, John C. Marioni, Carolina Guibentif, Berthold Göttgens
Journal: Genome biology (2021)

Abstract Background Single-cell technologies are transforming biomedical research, including the recent demonstration that unspliced pre-mRNA present in single-cell RNA-Seq permits prediction of future expression states. Here we apply this RNA velocity concept to an extended timecourse dataset covering mouse gastrulation and early organogenesis. Results Intriguingly, RNA velocity correctly identifies epiblast cells as the starting point, but several trajectory predictions at later stages are inconsistent with both real-time ordering and existing knowledge. The most striking discrepancy concerns red blood cell maturation, with velocity-inferred trajectories opposing the true differentiation path. Investigating the underlying causes reveals a group of genes with a coordinated step-change in transcription, thus violating the assumptions behind current velocity analysis suites, which do not accommodate time-dependent changes in expression dynamics. Using scRNA-Seq analysis of chimeric mouse embryos lacking the major erythroid regulator Gata1, we show that genes with the step-changes in expression dynamics during erythroid differentiation fail to be upregulated in the mutant cells, thus underscoring the coordination of modulating transcription rate along a differentiation trajectory. In addition to the expected block in erythroid maturation, the Gata1-chimera dataset reveals induction of PU.1 and expansion of megakaryocyte progenitors. Finally, we show that erythropoiesis in human fetal liver is similarly characterized by a coordinated step-change in gene expression. Conclusions By identifying a limitation of the current velocity framework coupled with in vivo analysis of mutant cells, we reveal a coordinated step-change in gene expression kinetics during erythropoiesis, with likely implications for many other differentiation processes.
Abstract 1004: Defining stearoyl-CoA desaturase 1 as a molecular therapeutic target against cholangiocarcinoma
Authors: Justyna J. Gleba, Laura A. Marlow, Erin E. Miller, James L. Miller, Aylin Alasonyalilar-Demirer, Yi Guo, Kabir Mody, Lewis R. Roberts, Steven R. Alberts, Mark J. Truty, Tushar C. Patel, John A. Copland
Journal: Cancer Research (2021)

Abstract Cancer cells increase lipid metabolism by up-regulation lipogenic enzymes such as stearoyl-CoA desaturase 1 (SCD1). It is the rate-limiting enzyme in the de novo synthesis of fatty acids (FAs), catalyzing the conversion and biosynthesis of saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs). We developed SSI-4, a novel highly specific SCD1 inhibitor. The anti-tumor activity ofSSI-4 was examined against different cholangiocarcinoma (CCA) models that included human and mouseCCA cell lines, CCA patient-derived xenografts (PDX) NOD SCID gamma (NSG) mouse models, and CCA PDX derived organoids. Using cell proliferation assay, we examined twelve CCA cell lines and 4 were very sensitive to SSI-4 (1-40 nM IC50). The remaining CCA cell lines showed moderate to no sensitivity to SSI-4. Studies at the protein level have shown that SCD1 is present in both sensitive and non-sensitive cells. Thus, SCD1 must be present in sensitive cells but is not predictive of response to an SCD1 inhibitor. In an effort to identify biomarkers predicting response to therapy, we performed assays, such as lipid, lactate, or energy phenotype which identified elevated lactate and unsaturated fatty acid levels as well as a glycolytic energy phenotype. In vivo, CCA PDX models have demonstrated that SSI-4strongly inhibited tumor growth. Immunohistochemical analysis of CCA tumors revealed elevated glycolytic genes in sensitive cells and thus, a potential predictive biomarker. We are currently pursuing a better understanding of the relationship between glycolysis and fatty acid synthesis/metabolism. We are also testing novel combination therapy of SSI-4 with the standard of care and other drugs to develop novel treatments for CCA. Using CCA PDX derived organoids showed synergistic antitumor activity of SSI-4in combination with cancer standard of care drugs such as gemcitabine and cisplatin. Collectively, we expect to develop a biomarker-driven selection of CCA patients sensitive to SCD1 inhibitors and novel SSI-4 combination therapy leading to improved patient survival. Citation Format: Justyna J. Gleba, Laura A. Marlow, Erin E. Miller, James L. Miller, Aylin Alasonyalilar-Demirer, Yi Guo, Kabir Mody, Lewis R. Roberts, Steven R. Alberts, Mark J. Truty, Tushar C. Patel, John A. Copland. Defining stearoyl-CoA desaturase 1 as a molecular therapeutic target against cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1004.
Alpha-blockers adverse events: Analysis of real-life data from Eudra-Vigilance
Authors: C. De Nunzio, A. Nacchia, R. Lombardo, A. Franco, G. Tema, V. Baldassarri, L.M. Rovesti, E. Mancini, G. Guarnotta, F. Di Giacomo, S. D’Annunzio, O.A. Voglino, G. Disabato, A.F.M. Cicione, A. Tubaro
Journal: European Urology (2021)
Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse
Authors: Stacey Richardson, Rebecca M Hill, Christopher Kui, Janet C Lindsey, Yura Grabovksa, Claire Keeling, Louise Pease, Matthew Bashton, Stephen Crosier, Maria Vinci, Nicolas André, Dominique Figarella-Branger, Jordan R Hansford, Maria Lastowska, Krzysztof Zakrzewski, Mette Jorgensen, Jessica C Pickles, Michael D Taylor, Stefan M Pfister, Stephen B Wharton, Barry Pizer, Antony Michalski, Abhijit Joshi, Thomas S Jacques, Debbie Hicks, Edward C Schwalbe, Daniel Williamson, Vijay Ramaswamy, Simon Bailey, Steven C Clifford
Journal: Neuro-Oncology (2021)

Abstract Background Less than 5% of medulloblastoma (MB) patients survive following failure of contemporary radiation-based therapies. Understanding the molecular drivers of medulloblastoma relapse (rMB) will be essential to improve outcomes. Initial genome-wide investigations have suggested significant genetic divergence of the relapsed disease. Methods We undertook large-scale integrated characterization of the molecular features of rMB—molecular subgroup, novel subtypes, copy number variation (CNV), and driver gene mutation. 119 rMBs were assessed in comparison with their paired diagnostic samples (n = 107), alongside an independent reference cohort sampled at diagnosis (n = 282). rMB events were investigated for association with outcome post-relapse in clinically annotated patients (n = 54). Results Significant genetic evolution occurred over disease-course; 40% of putative rMB drivers emerged at relapse and differed significantly between molecular subgroups. Non-infant MBSHH displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MBGroup4 demonstrated the greatest genetic divergence, enriched for targetable (eg, CDK amplifications) and novel (eg, USH2A mutations) events. Importantly, many hallmark features of MB were stable over time; novel subtypes (&amp;gt;90% of tumors) and established genetic drivers (eg, SHH/WNT/P53 mutations; 60% of rMB events) were maintained from diagnosis. Critically, acquired and maintained rMB events converged on targetable pathways which were significantly enriched at relapse (eg, DNA damage signaling) and specific events (eg, 3p loss) predicted survival post-relapse. Conclusions rMB is characterised by the emergence of novel events and pathways, in concert with selective maintenance of established genetic drivers. Together, these define the actionable genetic landscape of rMB and provide a basis for improved clinical management and development of stratified therapeutics, across disease-course.
Abstract 2189: Subtype-specific epigenomic landscape and 3D genome structure in bladder cancer
Authors: Tejaswi Tejaswi, Baozhen Zhang, Qixuan Wang, Ye Hou, Qiushi Jin, Jie Xu, Hongbo Yang, Tingting Liu, David J. DeGraff, Feng Yue
Journal: Cancer Research (2021)

Abstract Urinary bladder cancers (BLCA) are commonly diagnosed urologic malignancy in the United States. Muscle invasive BLCA is a morbid and expensive disease to treat, thus increased molecular understanding is necessary. BLCA has recently been characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. Transcriptionally, FOXA1, GATA3, and PPARg have been shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63, STAT3, and TFAP2 family members are critical for regulation of basal subtype specific genes. Despite these advances, the underlying epigenetic mechanisms and 3D chromatin architecture responsible for subtype-specific regulation in bladder cancer remains unknown. Here, we determined the genome-wide transcriptome, enhancer landscape, and transcription factor binding profiles (FOXA1 and GATA3) in luminal and basal subtypes of bladder cancers. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct TF binding at distal-enhancers of luminal and basal bladder cancers. Finally, we identified a novel clinically relevant transcriptional factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration. In summary, our work identifies a subtype-specific epigenomic and 3D genome structure in urinary bladder cancers and suggests a novel link between the circadian TF NPAS2 and a clinical bladder cancer subtype. Citation Format: Tejaswi Tejaswi, Baozhen Zhang, Qixuan Wang, Ye Hou, Qiushi Jin, Jie Xu, Hongbo Yang, Tingting Liu, David J. DeGraff, Feng Yue. Subtype-specific epigenomic landscape and 3D genome structure in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2189.