tbuckley/cabot-search huggingface dataset:
Abstract 2823: Exploring the role of neutrophil myeloperoxidase in lung cancer
Authors: Paulina Valadez-Cosmes, Nejra Cosic, Melanie Kienzl, Kathrin Maitz, Sofia Raftopoulou, A. McGarry Houghton, Akos Heinemann, Michael J. Davies, Julia Kargl
Journal: Cancer Research (2021)

Abstract The aim of this study is to investigate whether myeloperoxidase, a neutrophil-derived molecule in the tumor microenvironment, can influence tumor growth in lung cancer. Lung cancer is the leading cause of cancer related deaths worldwide. Chronic inflammation plays a key role in lung cancer and some studies point out the role of neutrophils as critical mediators of lung carcinogenesis. In this context, some of the neutrophil granule components have been proposed to contribute to tumor development. One of these molecules is myeloperoxidase. Myeloperoxidase is a heme peroxidase enzyme that generates reactive oxygen/nitrogen species and is most abundantly expressed in neutrophils. Upon neutrophil activation, during acute inflammation or in the tumor microenvironment, MPO is secreted into the extracellular milieu during degranulation and utilizes H2O2 to hypochlorous acid that reacts with surrounding proteins and cell surface molecules and thereby can alter signaling pathways and cell functions. So far, we have found some evidence on myeloperoxidase acting in favor of tumor development. In vivo, LSL-K-ras/MPO-/- mice revealed prolonged survival and reduced tumor burden when compared to LSL-K-ras/MPO+/+ mice. Consistently, in a heterotopic syngeneic tumor mouse model, MPO knockout mice (C57/B6-J/MPO-/-) displayed smaller tumors in comparison to the WT littermates. In vitro, myeloperoxidase is able to bind, internalize and preserve its enzymatic activity in human lung adenocarcinoma A549 cells. Furthermore, A549 cells showed increased proliferation and reduced apoptosis after MPO treatment as well as an enhanced phosphorylation of Akt and Erk proteins. According to our current results, myeloperoxidase may play a role in the development of lung cancer by regulating cancer cell function. Moreover, this project sheds light on the role of neutrophil-derived molecules as key players in the context of tumor growth. Citation Format: Paulina Valadez-Cosmes, Nejra Cosic, Melanie Kienzl, Kathrin Maitz, Sofia Raftopoulou, A. McGarry Houghton, Akos Heinemann, Michael J. Davies, Julia Kargl. Exploring the role of neutrophil myeloperoxidase in lung 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 2823.
Abstract 2698: Spatial gene expression profiling in breast cancer
Authors: Melanie Spears, Vida Talebian, Linda Liao, Megan Hopkins, Drashti Jain, Mary Anne Quintayo, Jane Bayani, Alison Cheung, Martin Yaffe, John M. Bartlett
Journal: Cancer Research (2021)

Abstract Over the last decade breast cancer survival has improved, largely due to the therapies offered to patients with the disease. However, despite the advances in diagnosis and treatment of breast cancer, it is still remains the second leading cause of death from cancer in women. Breast cancer is a heterogeneous disease, this in part, explains why the majority of current therapeutic approaches for cancer work best when multiple agents are combined. The interaction between immune and tumor cells is critical in the development and progression of breast cancer. Here we present in situ transcriptomic profiling, using the NanoString Digital Spatial Profiler (DSP) cancer transcriptomic atlas (CTA) assay, of a cohort of breast cancer lumpectomies to reveal the extent of heterogeneity in pathologically defined unifocal and multifocal cancers. In this study, lumpectomies were processed as whole mounts with serial blocks reviewed. Tissue cores were taken from at least three different regions through the lumpectomy for tissue microarray (TMA) construction, focusing on morphologic/histological differences in addition to the spatial orientation of the sampled region within the lumpectomy. In situ quantification of 1800 tumor and immune genes across 60 patients revealed heterogeneity of tumor and immune genes in most patients. Expression of genes such as HER2, ER and AKT were enriched in the tumor compartment. Whereas, genes such as COLA1, CD68 and CD3 were enriched in the immune compartment. Using a SpatialDecon algorithm for mixed cell deconvolution on the immune areas heterogeneity of the tumor infiltrate at a cell type levels was observed. Fibroblasts and macrophages were prevalent in all samples while immune dense areas also contained B-cells and T-cells. While there are a number of clinically validated transcriptional assays available for breast cancer, we have demonstrated that the immune microenvironment needs to be considered to develop rational stratification of patients to currently available targeted therapies. Citation Format: Melanie Spears, Vida Talebian, Linda Liao, Megan Hopkins, Drashti Jain, Mary Anne Quintayo, Jane Bayani, Alison Cheung, Martin Yaffe, John M. Bartlett. Spatial gene expression profiling in breast 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 2698.
Abstract LB193: Lysine demethylase 5A is required for MYC driven transcription in multiple myeloma
Authors: Jun Qi, hiroto Ohguchi, Paul MC Park, tingjian wang, Kenneth C. Anderson, Teru Hideshima, Catrine Johansson, Udo Oppermann, Adam D. Durbin, Berkley Gryder, Javed Khan, xiaofeng zhang
Journal: Cancer Research (2021)

Abstract Multiple myeloma (MM) is a malignant plasma cell disorder accounting for 10% of hematologic malignancies. Although high dose chemotherapy and targeted agents have improved patient outcomes, MM remains an incurable disorder. Thus, there is an urgent need to develop novel therapeutic strategies. We discovered that the distinct lysine demethylase 5A (KDM5A) plays a critical role in MM cell growth, through a unique link to MYC-driven transcriptional programs. KDM5A is a dominant regulator of histone H3K4 trimethylation, a histone mark associated with activated gene transcription. We identify that KDM5A interacts with P-TEFb complex and cooperates with MYC to control MYC targeted genes in MM cells. We develop a novel, cell-permeable and selective KDM5 inhibitor, JQKD82 that increases histone H3K4me3, and inhibits downstream MYC-driven transcriptional output in vitro and in vivo. Utilizing genetic ablation together with our inhibitor, we established a detail mechanism that KDM5A is required for transcriptional pause release by P-TEFb at MYC target genes. These data identify KDM5A as a unique vulnerability in MM through regulation of the driving MYC oncogene in MM, and defined JQKD82 as a tool compound to block KDM5A function as a potential therapeutic strategy for MM. Citation Format: Jun Qi, hiroto Ohguchi, Paul MC Park, tingjian wang, Kenneth C. Anderson, Teru Hideshima, Catrine Johansson, Udo Oppermann, Adam D. Durbin, Berkley Gryder, Javed Khan, xiaofeng zhang. Lysine demethylase 5A is required for MYC driven transcription in multiple myeloma [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 LB193.
Abstract 1749: DRAK1 suppresses inflammation-induced cervical cancer progression by targeting TRAF6 protein
Authors: Kyoungwha Pang, Jihee Lee, Jinah Park, Akira Ooshima, Kyung-Min Yang, Seong-Jin Kim
Journal: Cancer Research (2021)

Abstract Cervical cancer is a major cause of mortality in women worldwide and strongly associated with persistent infection with high-risk (HR) human papillomavirus (HPV), mainly HPV16 and HPV18. Most HPV viruses can be cleared by the immune system, and a preventive and effective vaccine against HPV infection decreases the development of cervical cancer. The adaptor protein TNF receptor-associated factor 6 (TRAF6) is a key mediator in inflammation. However, the molecular mechanisms controlling its activity and stability in cancer progression remain unclear. Here we show that death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK1) specifically decreases the stability of the TRAF6 protein via an autophagy-mediated degradation pathway by interfering with the homo-oligomerization of TRAF6, eventually suppressing tumor growth and metastasis in inflammation-associated advanced cervical cancer cells. DRAK1 bounds directly to the TRAF domain of TRAF6, preventing its autoubiquitination by interfering homo-oligomerization, eventually leading to autophagy-mediated degradation of TRAF6. Depletion of DRAK1 in cervical cancer cells resulted in markedly increased levels of TRAF6 protein, promoting activation of the IL1β signaling-associated pathway and pro-inflammatory cytokine production. DRAK1 knockdown accelerated cervical cancer tumorigenesis and metastasis whereas DRAK1 overexpression suppressed that phenomenon. DRAK1 was specifically underexpressed in metastatic cervical cancers and inversely correlated with TRAF6 expression in mouse xenograft model tumor tissues and human cervical tumor tissues. Collectively, our findings highlight DRAK1 as a novel potential biomarker and novel therapeutic target for treatment of TRAF6-associated advanced cervical cancers. [This work was supported by National R&amp;D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (HA17C0037).] Citation Format: Kyoungwha Pang, Jihee Lee, Jinah Park, Akira Ooshima, Kyung-Min Yang, Seong-Jin Kim. DRAK1 suppresses inflammation-induced cervical cancer progression by targeting TRAF6 protein [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 1749.
Negative trade-off between neoantigen repertoire breadth and the specificity of HLA-I molecules shapes antitumor immunity
Authors: Máté Manczinger, Balázs Koncz, Gergő Mihály Balogh, Benjamin Tamás Papp, Leó Asztalos, Lajos Kemény, Balázs Papp, Csaba Pál
Journal: Nature Cancer (2021)
Perioperative use of anticholinergic medication in patients undergoing surgery for male urinary stress incontinence
Authors: M.T. Grabbert, T. Huesch, A. Kretschmer, R. Anding, R. Kirschner-Hermanns, C.M. Naumann, F. Queissert, R. Homberg, C. Gratzke, W. Khoder, A. Katzenwadel, T. Hofmann, T. Pottek, H. Loertzer, W. Huebner, A. Haferkamp, R.M. Bauer
Journal: European Urology (2021)
Abstract 2110: Platinum-inducedBRCA1 promoter DNA hypermethylation and altered metabolic profile promotes chemoresistance in ovarian cancer
Authors: Riddhi Sood, Sikai Xiao, Shruthi Sriramkumar, Christiane Hassel, Kenneth Nephew, Heather O'Hagan
Journal: Cancer Research (2021)

Abstract High grade serous ovarian cancer (HGSOC) is the most common and aggressive type of ovarian cancer (OC). Platinum resistance is a common occurrence in HGSOC leading to tumor relapse and patient mortality. Multiple mechanisms contribute to platinum resistance in OC, including enrichment of ovarian cancer stem cells (OCSCs), which is observed in relapsed tumors. Platinum treatment activates the DNA damage response (DDR) and the DNA repair protein BRCA1 is an OC susceptibility factor. In our study, we demonstrate that platinum treatment induces a decrease in BRCA1 levels that leads to an increase in activity of ALDH, an OCSC marker. In a parallel pathway that is associated with G2/M arrest, platinum treatment also induces an increase in NAMPT expression and NAD+ levels, the cofactor required for ALDH activity. BRCA1 is repressed through platinum-induced promoter DNA hypermethylation. Importantly, combination of platinum with decitabine, a DNA methyltransferase (DNMT) inhibitor, prevents the platinum-induced increase in OCSCs. This study uniquely provides preclinical support for the use of DNMT inhibitors in the neoadjuvant setting in combination with platinum treatment for OC patients. Citation Format: Riddhi Sood, Sikai Xiao, Shruthi Sriramkumar, Christiane Hassel, Kenneth Nephew, Heather O'Hagan. Platinum-inducedBRCA1 promoter DNA hypermethylation and altered metabolic profile promotes chemoresistance in ovarian 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 2110.
Abstract 2301: Atomic-level insights into PI3K activation
Authors: Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov
Journal: Cancer Research (2021)

Abstract PI3Kα (PIK3CA) is the second highly mutated oncogene in cancer. It is activated by the receptor tyrosine kinases (RTKs) and Ras on the membrane, regulating the PI3K/Akt/mTOR pathway for the cell growth and proliferation. PI3Kα is an obligate dimer with p110α catalytic subunit and p85α regulatory subunit. Their interactions stabilize and maintain PI3Kα in the inactive state. At the molecular level, the activation of PI3Kα requires two events, (i) the release of nSH2 by phosphorylated tyrosine (pY) motif in the RTK and (ii) the membrane localization facilitated by Ras. The mechanism of PI3Kα activation at the atomic level suggests that PI3Kα undergoes the significant conformational change upon nSH2 release. The iSH2 in p85α subunit moves, which facilitates the membrane interactions and catalysis. The activation loop (a-loop) in the kinase domain becomes more flexible, exposing the basic residues for the substrate binding. The activation mechanism expedites our understanding of the PI3K autoinhibition, activation, and catalysis. By collecting and analyzing the available PI3K structures, we have identified the structural features that distinguish the inactive and active class IA PI3Ks. The a-loop is “collapsed” with kα11 in the regulatory arch “IN” in the inactive PI3Ks. Upon activation, the a-loop becomes “extended” and kα11 moves “OUT”. These features provide the functional explanations for both hotspot and weak oncogenic mutations and indicate their additive effects. The mechanism reveals a principle for PI3K allosteric drug discovery. The inhibitors that may modulate the iSH2 dynamics can allosterically prevent PI3K activation in the signaling pathways. Funded by Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. Citation Format: Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov. Atomic-level insights into PI3K activation [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 2301.
Abstract 2829: Identifying germline variants for metastatic risk assessment in sporadic colorectal carcinomas
Authors: PehYean Cheah, Lai Fun Thean, Michelle Wong, Michelle Lo, Emile Tan, Choong Leong Tang
Journal: Cancer Research (2021)

Abstract Colorectal carcinoma (CRC) is the third highest incidence cancer and leading cause of cancer mortality worldwide. Metastasis to distal organ is the major cause of cancer mortality. This trend is expected to be exacerbated by an aging population in the developed world. Genetic predisposition plays a greater role in disease progression than disease etiology in sporadic CRC. However, the underlying genetic factors for metastasis are currently unclear. We identified germline single nucleotide polymorphism (SNP) variants contributing to metastasis risk from a case-case (metastasis-positive vs metastasis-negative) genome-wide association study (GWAS) comprising 3,000 sporadic Chinese CRC cases with definitive metastasis status. Metastasis-positive case is defined as one with distal-organ involvement attributable to primary CRC; metastasis-negative case is defined as metastasis-free with 5 years or more follow-up. By interrogating summarized SNP statistics from the case-case GWAS using the Functional Mapping and Annotation (FUMA) software, we identified 5 genomic risk loci and 74 disease-relevant genes based on gene set enrichment analysis and the Molecular Signatures Database. These genes are in various pathways implicated in different metastasis steps, from epithelial-mesenchymal transition (EMT) to implantation at distal organs. They are different from the risk variants identified by case-control GWAS for disease occurrence. We will expression-profile 250 metastasis-positive vs metastasis negative cases from the GWAS panel to validate the bioinformatics analysis by quantitative real-time PCR. We will focus first on the five genes implicated in glycolysis as this is a biochemical fingerprint of malignant cells that represents one of the ‘hallmarks of cancer'. Expression profile of these genes will be validated in a second independent panel. Kaplan Meier survival analysis as function of the median expression value will be performed to assess prognostic value of these genes. The ultimate goal is to improve metastasis risk assessment for secondary prevention to reduce cancer mortality and morbidity for individual patient as well as reducing public health expenditure. Citation Format: PehYean Cheah, Lai Fun Thean, Michelle Wong, Michelle Lo, Emile Tan, Choong Leong Tang. Identifying germline variants for metastatic risk assessment in sporadic colorectal carcinomas [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 2829.
GP data scheme may face further delay as practices refuse to hand over patient information
Authors: Stephen Armstrong
Journal: BMJ (2021)

A group of GPs have told the government they will refuse to hand over patients’ data to NHS Digital under the agency’s data extraction programme unless the Department of Health and Social Care for England commits to a list of demands, amid ongoing concerns about patient consent and confidentiality.

The BMJ has learnt that NHS Digital has quietly withdrawn the data provision notice for its GP data extraction scheme and will reissue it at a later date. Privacy campaigners believe that the extraction, which had already been deferred once after a legal challenge, could be further delayed beyond the 1 September deadline that had been set.

An open letter to the government coordinated by GPs in the east London borough of Tower Hamlets said there had been a lack of informed consent about the proposals.1 It urged NHS Digital to write to every patient telling them what is to be done with their data and to enshrine their right in legislation to opt out.

The letter has been signed by Tower Hamlets Local Medical Committee, Solihull LMC, and Gateshead and South Tyneside LMC, which represent a total of 113 general practices, and also the North East London Clinical Commissioning Group and North Central London CCG. GPs who coordinated the letter said …
Abstract 86: O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation
Authors: Lorela Ciraku, Zachary Bacigalupa, Rebecca Moeller, Jing Ju, Rusia H. Lee, Christina Ferrer, Sophie Trefely, Nathaniel W. Snyder, Luca D'Agostino, Christos D. Katsetos, Wenyin Shi, Mauricio J. Reginato
Journal: Cancer Research (2021)

Abstract Cancer cells alter their metabolism to increase cell growth. A subset of the glucose taken up is shunted into the hexosamine biosynthetic pathway where it is used to synthesize UDP-GlcNAc, a substrate of O-GlcNAc transferase (OGT), which modifies cytoplasmic and nuclear proteins with O-linked sugar moieties. Here, we show that OGT and O-GlcNAcylation are elevated in glioblastoma (GBM) cancer cells and in GBM patient samples that correlates with disease progression. Reduction of OGT expression in GBM cells led to significant reduction in anchorage-independent growth, acetyl-CoA levels, and decrease in free fatty acids. Conversely, overexpressing OGT in GBM cells had the opposite effect. Reducing OGT expression in GBMcells transplanted in an orthotopic intracranial mouse model reduced tumor growth and extended survival. Mechanistically, we show that OGT overexpression increases carbon-flux of acetate to acetyl-CoA, a reaction carried by the enzyme acetyl-CoA synthetase 2 (ACSS2). Indeed, OGT regulates ACSS2 protein levels and O-GlcNAcylation increases ACSS2phosphorylation on Ser-267 in a cyclin dependent kinase 5 (CDK5)-dependent manner, which regulates its stability by reducing polyubiquitination and degradation. ACSS2 Ser-267 is critical for OGT-mediated GBM growth as overexpression of ACSS2 Ser-267 phospho-mimetic rescues growth in vitro and in vivo. Using an ex vivo GBM brain slice model we show that treatment of GBM-transplanted slices with OGT inhibitor Ac-GlcNAc-5S or pan-cdk inhibitor dinaciclib reduced growth of pre-formed tumors in cultured brain slices. These results suggest a crucial role for O-GlcNAc signaling in transducing nutritional state to regulate acetate metabolism and identify OGT and CDK5 as novel therapeutic targets for treatment of glioblastoma. Citation Format: Lorela Ciraku, Zachary Bacigalupa, Rebecca Moeller, Jing Ju, Rusia H. Lee, Christina Ferrer, Sophie Trefely, Nathaniel W. Snyder, Luca D'Agostino, Christos D. Katsetos, Wenyin Shi, Mauricio J. Reginato. O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation [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 86.
Cutaneous Human Papillomaviruses and the Risk of Keratinocyte Carcinomas
Authors: Dana E. Rollison, Rossybelle P. Amorrortu, Yayi Zhao, Jane L. Messina, Michael J. Schell, Neil A. Fenske, Basil S. Cherpelis, Anna R. Giuliano, Vernon K. Sondak, Michael Pawlita, Sandrine McKay-Chopin, Tarik Gheit, Tim Waterboer, Massimo Tommasino
Journal: Cancer Research (2021)

Abstract Cutaneous human papillomavirus (cuHPV) infections may be novel targets for skin cancer prevention and treatment, but critical information regarding the development of virus-positive skin cancers following cuHPV infection has been lacking. In this study, baseline cuHPV infection was measured by serology and viral DNA detection in eyebrow hairs (EBH) and forearm skin swabs (SSW) among 1,008 individuals undergoing routine skin cancer screening exams and followed for incidence of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cuSCC). Baseline β-HPV detection, particularly in SSW, significantly predicted cuSCC (HR = 4.32; 95% confidence interval, 1.00–18.66), whereas serologic evidence of past β-HPV infection was not associated with cuSCC. Less than 5% of baseline β-HPV types detected in SSW were present in subsequent cuSCC tumors, and cuHPV detected in SSW with higher mean fluorescence intensity values were more likely to be present in cuSCC compared with those with lower levels (P &amp;lt; 0.001). β-HPV-positive cuSCC occurred more often in areas of highly sun-damaged skin than did β-HPV-negative cuSCC. Overall, no clear patterns were observed between baseline β-HPV detection and subsequent development of BCC, or between baseline γ-HPV detection and either cuSCC or BCC. Collectively, these results demonstrate that β-HPV detection in SSW is a significant predictor of cuSCC risk, although evidence suggests only a small subset of cuSCC is etiologically linked to β-HPV infection. Significance: β-HPV positivity may be a useful biomarker for identifying individuals who could benefit from increased screening or novel cutaneous squamous cell carcinoma prevention strategies.