bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2706: Ultra-Low Input High-Fidelity (ULI-HiFi) long-reads uncover variants in genomic dark matter from pre-cancer polyp and tumor samples
Authors: Lee Hayan , Erwin Graham , Horning Aaron , Kirtikar Raushun , Griffin-Baldwin Emmett , Rowell William , Li Philip , Kingan Sarah , Snyder Michael P. 
Published: June 2022

Abstract
Long-read sequencing technologies have been constrained by high error rates and large sample input requirements. The recent introduction of HiFi sequencing has enabled highly accurate detection of single-nucleotide variants (SNVs) from long reads (10-15 kb). However, a major limiting factor is the amount of sample input required, where current protocols require ≥15 micrograms of DNA. Here we report Ultra-Low Input High Fidelity Sequencing (ULI-HiFi), an amplification-based library preparation that reduces this input to 10 nanograms of DNA, a more than 10,000-fold reduction in sample input. When the ultra-low input method was tested using a benchmark genome, HG002, we observed high precision and improved recall of structural variants compared to a ground truth dataset from the Genome in a Bottle Consortium. We also benchmarked small variants and reported the accurate analysis of many variants in clinically important genes that are unmappable with short reads. We used this strategy to sequence tumor and polyp samples from a patient with familial adenomatous polyposis, a hereditary form of colon cancer, which revealed SNVs and structural variants not detected by short-read techniques. This strategy will enable the improved characterization of genetic variants from limited clinical samples.
Citation Format: Hayan Lee, Graham Erwin, Aaron Horning, Raushun Kirtikar, Emmett Griffin-Baldwin, William Rowell, Philip Li, Sarah Kingan, Michael P. Snyder. Ultra-Low Input High-Fidelity (ULI-HiFi) long-reads uncover variants in genomic dark matter from pre-cancer polyp and tumor samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2706.
Abstract 2709: Transcriptomic meta-analysis of non-Hodgkin’s B-cell lymphomas reveals reliance on pathways associated with extracellular matrix
Authors: Rapier-Sharman Naomi , Pickett Brett E. 
Published: June 2022

Abstract
We report here the results of a transcriptomic meta-analysis of public data for B-cell Non-Hodgkin’s Lymphomas (BCNHL). In 2016, there were 461,000 cases of Non-Hodgkin’s lymphoma worldwide, resulting in 240,000 deaths that year. BCNHLs pose a significant disease burden worldwide, making up 85-90% of BCNHL cases. BCNHL subtypes include Burkitt’s lymphoma, marginal-zone B-cell lymphomas, follicular lymphoma, diffuse large B-cell lymphoma, and mantle cell lymphoma. There is a growing need to understand the mechanisms of BCNHL pathology. The scientific community has spent a great deal of time and effort to identify the hallmarks of cancer. Since cancers of different subtypes can be considered parallel systems, we have performed a meta-analysis including as many BCNHL subtypes as possible to determine common underlying mechanisms. We performed a transcriptomic meta-analysis of publicly available RNA-sequencing data for BCNHL, consisting of 322 relevant samples across seven distinct studies in the NCBI Gene Expression Omnibus (GEO). To our knowledge, no BCNHL meta-analysis of this magnitude has previously been performed. We found ~10,400 significant differentially expressed genes (FDR p-value &lt;= 0.05) and 33 significantly modulated pathways (FDR p-value &lt;= 0.05). We observed potential common mechanisms for BCNHL’s differentially expressed genes and signaling pathways. Our findings include a significant class of proteoglycans not previously associated with lymphomas as well as significant upregulation of extracellular matrix-associated proteins. This meta-analysis offers fresh insights into the inner workings and mechanisms of B-cell lymphomas that could give rise to improved diagnostics and/or therapeutics.
Citation Format: Naomi Rapier-Sharman, Brett E. Pickett. Transcriptomic meta-analysis of non-Hodgkin’s B-cell lymphomas reveals reliance on pathways associated with extracellular matrix [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2709.
Abstract 272: Effective treatment of colorectal peritoneal metastases by exploiting a molecular subtype specific vulnerability
Authors: Bootsma Sanne , Dings Mark P. , Moreno Leandro Ferreira , Lenos Kristiaan J. , Vermeulen Louis , Bijlsma Maarten F. 
Published: June 2022

Abstract
In colorectal cancer, peritoneal metastases (PMs) associate with severe morbidity and dismal prognosis. Given the incidence of this disease and the lack of adequate treatments currently available, PMs pose a large unmet clinical need. Although PMs can be accompanied by more widespread metastatic disease, it often occurs as the only sign of dissemination. This implies that the route of metastatic spread to the peritoneum differs from that to distant organs. PMs are thought to result from cancer cells that spill into the abdominal cavity, and are able to attach to the peritoneal lining and form tumor deposits. This cascade places specific demands on the cancer cells.
Here, we report that colorectal cancers that present with PMs almost universally classify as consensus molecular subtype 4 (CMS4). This previously recognized disease entity is characterized by mesenchymal features, poor prognosis, and resistance to therapies currently used against peritoneal metastases, which explains their limited efficacy. By leveraging disease models that capture CMS4-specific features, including the ability to form PMs in vivo, we identified elesclomol as a highly effective agent. Elesclomol kills cancer cells in a copper-dependent fashion by targeting the oxidative phosphorylation machinery, which we found to be a specific vulnerability of CMS4 cancers. Elesclomol-Cu2+ was effective following only minutes of exposure to CMS4 cell lines and organoids, supporting its use in intra-abdominal treatment procedures. It is therefore a promising candidate for the local treatment of peritoneal metastases of colorectal cancer.
Citation Format: Sanne Bootsma, Mark P. Dings, Leandro Ferreira Moreno, Kristiaan J. Lenos, Louis Vermeulen, Maarten F. Bijlsma. Effective treatment of colorectal peritoneal metastases by exploiting a molecular subtype specific vulnerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 272.
Abstract 2740: Stochastic modeling uncovers the interplay between early cancer progression and adaptive immune-specific cancer escape
Authors: George Jason T. 
Published: June 2022

Abstract
The lack of durable therapeutic interventions continues to limit cancer treatment efficacy. While breakthroughs in immunotherapy have improved patient survival for some disease subtypes, immune escape is an unfortunate and common hallmark of cancer evasion. Understanding the dynamic interplay between an evolving and heterogeneous malignant population and the adaptive immune system, consisting of millions of unique T cells, is therefore required for designing optimized treatment strategies. We begin by describing the implications of cancer escape via durable evasion events, such as major histocompatibility antigen presentation down-regulation. Durable escape is then applied to relate observed cancer age-specific incidence to physiologic impairments in T cell turnover and diversity. We then discuss a more generalized stochastic process that enables transient escape and recurrent recognition via distinct T cell subclones. This co-evolutionary model predicts repeated immune recognition and cancer evasion prior to disease manifestation. Using this model, we find that T cell turnover and cancer mutation rates explain differences in early age incidence data across nearly all cancer types. Lastly, we introduce a modeling approach for understanding the extent of optimality occurring in cancer evasion via tumor-associated antigen downregulation, emphasizing the utility of foundational modeling frameworks for optimizing cancer T cell immunotherapy.
Citation Format: Jason T. George. Stochastic modeling uncovers the interplay between early cancer progression and adaptive immune-specific cancer escape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2740.
Abstract 2772: A novel bio-physical based CDA approach for evaluating lung cancer therapeutic responses
Authors: Wu Junjie , Zou Zixiu , Du Xuedong , Lin Yue , Tang Xing , Chen Jie , Peng Lan , Yu Chris 
Published: June 2022

Abstract
Background: Lung cancer is the world's highest mortality and incidence rate of malignancy, and the prognosis survival rate is significantly lower than other tumors. A novel bio-physics based multi (pan)-cancer test technology named Cancer Differentiation Analysis Technology (CDA) has been developed and investigated for evaluating and monitoring lung cancer therapeutic responses.
Methods: A total of 686 patients diagnosed with different sub-types of lung cancer were included in this study. CDA levels were concurrently measured in peripheral blood obtained from 686 patients during the treatment. According to the response evaluation criteria in solid tumors (RECIST) 1.1 standard, the efficacy of 686 patients after treatment was evaluated, and the diagnostic efficacy of CDA technology was evaluated by receiver operating characteristic (ROC) curve.
Results: Clinical pathological parameters of the patients are listed in Table 1. The higher the CDA value, the worse the curative effect. CDA value of lung cancer in CR (complete response) group was significantly lower than that in other 3 groups (p&lt;0.05). CDA value of adenocarcinoma lung cancer in CR group were significantly lower than that in SD (stable disease) group (p&lt;0.05). For non - metastatic lung cancer, CDA value in CR group was significantly lower than that in SD group (p&lt;0.05) The receiver ROC analysis showed that the area under curve (AUC) of lung cancer group, NSCLC group, adenocarcinoma lung cancer group, were 0.756, 0.772, and 0.792, respectively. The AUC of early lung cancer group, and non - metastatic lung cancer group were 0.794, and 0.851.
Conclusions: CDA appears to have the ability to predict and monitor therapeutic responses to lung cancer surgery and chemotherapy treatments. In most cases, the CDA of CR patients is low, and there is a good correlation between CDA and curative effect in early lung cancer. CDA could be a potential candidate for evaluating lung cancer, especially for early stage lung cancer therapeutic response.
Citation Format: Junjie Wu, Zixiu Zou, Xuedong Du, Yue Lin, Xing Tang, Jie Chen, Lan Peng, Chris Yu. A novel bio-physical based CDA approach for evaluating lung cancer therapeutic responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2772.
Abstract 2832: Identifying tumor specific surface protein markers for glioblastoma immunotherapy by single-nuclei RNA-seq
Authors: Ibrahim Omar M. , Wang Liang-Bo , Yao Lijun , Caravan Wagma , Deen Nataly Naser Al , Jayasinghe Reyka G. , Chheda Milan G. , Ding Li 
Published: June 2022

Abstract
Glioblastoma (GBM) is one of the deadliest adult brain tumors, in which the typical treatments of surgery, chemotherapy, and/or radiotherapy yield generally poor median survival. GBM is categorized into IDH-mutant subtype and IDH-wildtype subtype, which is subcategorized into proneural, classical, and mesenchymal subtypes, yet few personalized treatment options are available. The use of genetically modified chimeric antigen receptor T cells (CAR-T), such as CD19 CAR-T, has shown significant clinical efficacy in the treatment of hematological malignancies due to specific antitumor response; however, CAR-T response in GBM has been poor. Single nuclei RNA-seq (snRNA-seq) technology offers high-resolution profiling of different cell populations and their specific differential patterns. Accordingly, we developed a robust genomic analysis pipeline that can be applied to external datasets, tumor, and healthy samples. This was followed by unbiased systematic analysis of GBM tumor-specific cell surface markers using 18 single nuclei RNA sequencing (snRNA-seq) samples to identify GBM specific CAR-T targets allowing efficient tumor cells targeting and minimum off-target effects by CAR-T (1). We identified key potential targetable cell surface-specific markers and we also identified subtype-specific targets. Our findings provide insights into tumor-specific cell surface proteins that may be potential targets for engineered immunotherapy. References:(1) Wang, Liang-Bo, Alla Karpova, Marina A. Gritsenko, Jennifer E. Kyle, Song Cao, Yize Li, Dmitry Rykunov, et al. "Proteogenomic and metabolomic characterization of human glioblastoma." Cancer cell 39, no. 4 (2021): 509-528.
Citation Format: Omar M. Ibrahim, Liang-Bo Wang, Lijun Yao, Wagma Caravan, Nataly Naser Al Deen, Reyka G. Jayasinghe, Milan G. Chheda, Li Ding. Identifying tumor specific surface protein markers for glioblastoma immunotherapy by single-nuclei RNA-seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2832.
Abstract 2866: BAY 3375968: An afucosylated anti-CCR8 antibody depleting activated intratumoral regulatory T cells as a cancer immunotherapy
Authors: Roider Helge , Tseng Su-Yi , Hoff Sabine , Berndt Sandra , Filarski Katharina , Gritzan Uwe , Stelte-Ludwig Beatrix , Nadler Wiebke M. , Grudzinska-Goebel Joanna , Ellinger Philipp , Trautwein Mark , Gorjanacz Matyas 
Published: June 2022

Abstract
Regulatory T cells (Tregs) play an indispensable role in mediating peripheral tolerance to self-antigens. They can also promote tumor growth by suppressing the function of effector CD8+ and CD4+ T cells in the tumor microenvironment (TME). Furthermore, Tregs are identified as one of the key resistance mechanisms hampering the efficacy of immune checkpoint inhibitors (ICIs) across many tumor types. Therefore, there is a high need for safe and effective agents that would specifically deplete tumor-infiltrating Tregs while sparing both peripheral Tregs and effector T cells.
Chemokine receptor 8 (CCR8) is predominantly expressed on activated tumor-infiltrating Tregs and marks the most suppressive and proliferative Treg population. CCR8+ Tregs are associated with high tumor grade and poor overall survival across many tumor types such as lung, breast, or head-neck cancer. Thus, unlike other approaches directed against Tregs, targeting CCR8 offers the opportunity to specifically deplete intra-tumoral Tregs without impacting peripheral Tregs or other immune cells.
BAY 3375968 is a non-internalizing fully human glycoengineered (afucosylated) monoclonal IgG1 antibody, which in vitro selectively depleted human CCR8+ Tregs via antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). In vivo efficacy studies using mouse surrogate antibodies showed strong monotherapeutic efficacy across a variety of murine tumor models with clear correlation of intratumoral CCR8+ Treg depletion and CD8+ T cell increase. The monotherapeutic efficacy of CCR8 depleting antibodies was further enhanced by combinations with ICIs. BAY 3375968 also showed a good safety profile in cynomolgus monkeys. In conclusion, CCR8 is a novel Treg depleting immunotherapy target, and due to its highly tumor-restricted expression profile, BAY 3375968 may provide superior clinical safety and efficacy profile comparing to other less specific Treg targeting approaches.
Based on the promising pre-clinical data, preparations for a phase I clinical trial investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of BAY 3375968 are underway.
Citation Format: Helge Roider, Su-Yi Tseng, Sabine Hoff, Sandra Berndt, Katharina Filarski, Uwe Gritzan, Beatrix Stelte-Ludwig, Wiebke M. Nadler, Joanna Grudzinska-Goebel, Philipp Ellinger, Mark Trautwein, Matyas Gorjanacz. BAY 3375968: An afucosylated anti-CCR8 antibody depleting activated intratumoral regulatory T cells as a cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2866.
Abstract 2926: Structure-based design of quadruplex-binding small molecule compounds: The essential role of water molecules
Authors: Neidle Stephen 
Published: June 2022

Abstract
The compounds CM03 and SOP1812 are tri- and tetra-substituted naphthalene diimide derivatives with high affinity for several human DNA quadruplexes. They have been designed by computer modelling based on co-crystal structures of 1st-generation substituted naphthalene diimides with human intramolecular telomeric quadruplexes. CM03 and SOP1812 have single-digit 1-20 nM anti-proliferative activity in a panel of human pancreatic ductal adenocarcinoma (PDAC) cell lines (Marchetti et al., J. Med. Chem, 2018, 61, 2500-2517: Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644) and significant anti-tumor activity in the MIA-PACA2 xenograft model for PDAC as well as in the more demanding KPC model. SOP1812 is bio-available at therapeutic doses and is well tolerated at these levels in animal models. It is currently being evaluated as a candidate for clinical development by Qualigen Therapeutics Inc. The role of water in protein-drug binding is well documented and known to be important for accurate estimates of drug binding energies and for docking/virtual screening studies. To date this factor has not been seriously considered in studies of ligand-quadruplex interactions even though virtual screening has emerged as an important tool for finding new chemotypes and optimizing compound libraries in silico. A high-resolution crystal structure of a naphthalene diimide quadruplex complex (PDB id 3UYH: Micco et al., J. Med. Chem., 2013, 56, 2959-2974) has now been analyzed in detail. Patterns of water molecules have been found in each of the four quadruplex grooves, associated with the cationic side chains. Only a nitrogen atom on each N-methyl-piperazine cationic end groups is in direct hydrogen bonded contact with a phosphate group. The morpholino groups each have a small and well-defined cluster of water molecules mediating between cationic nitrogen atom and phosphate group. The rest of each groove is filled by a second cluster of waters, suggesting that larger substituents can be accommodated. Data from a library of naphthalene diimide derivatives is being examined to validate the role of these waters, especially with respect to their relative mobilities and ease of displacement.
Citation Format: Stephen Neidle. Structure-based design of quadruplex-binding small molecule compounds: The essential role of water molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2926.
Abstract 2931: Optical genome mapping workflow for identification and annotation of variants in hematological diseases
Authors: Hauenstein Jennifer , Pang Andy , Chaubey Alka , Hastie Alex 
Published: June 2022

Abstract
Guidelines from WHO, NCCN and others, for the genetic analysis of hematological malignancies included structural variation analysis. Traditionally, this has relied on a combination of three cytogenetic technologies for structural variation analysis: karyotyping, FISH, and microarray, are used to detect copy number variants, translocations, inversions. Next generation sequencing is also applied for mutation analysis but has not been successful for structural variation analysis. These traditional methods have many very manual aspects and require extensive expertise. Optical genome mapping (OGM) consolidates assays into a single laboratory assay in which the output provides the visualization of structural and copy number variants at one time. OGM is able to comprehensively detect structural variations genome wide down to 5% variant allele fraction for CNVs, inversions, and translocations from blood and bone marrow aspirates making it an attractive choice for hematologic malignancy genomic analysis. Preanalytical and analytical steps require approximately 4-5 days from sample to processed data with structural variation calls. Dynamic filtering in the user interface can be configured to remove most polymorphic variants and prioritize relevant variants. In addition, the OGM graphical user interface software, Bionano Access 1.7, allows for the user to assign classification/relevance to the variants for each case. For example, an ALL sample with t(9;22), deletion of CDKN2A, and whole chromosome gains of 4,6, and 10 can be easily visualized with the Circos plot and, then, can be further examined and annotated as needed. A second analyst can repeat the process blind to the first analysis and a supervisor can adjudicate the classifications. A variety of cases with hallmark abnormalities from various leukemias will be presented with the filtering and prioritization workflow used to derive them. This comprehensive technology allows for a quicker, more reliable output than traditional cytogenetic approaches.
Citation Format: Jennifer Hauenstein, Andy Pang, Alka Chaubey, Alex Hastie. Optical genome mapping workflow for identification and annotation of variants in hematological diseases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2931.