bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2222: The molecular landscape of acral lentiginous melanoma in Mexican patients
Authors: Vázquez-Cruz Martha E. , Basurto-Lozada Patricia , Molina-Aguilar Christian , Castaneda-Garcia Carolina , Ferreira Ingrid , Martínez-Said Héctor , Álvarez-Cano Alethia , Tavares-de la Paz Luis Alberto , Hinojosa-Ugarte Diego , García-Ortega Dorian Y. , Martínez-Gómez Julia M. , Levesque Mitchell P. , Adams David J. , Robles-Espinoza Carla D. 
Published: July 2021

Abstract
Acral lentiginous melanoma (ALM) is the most common melanoma subtype in several countries in Africa, Asia, and Latin America, including Mexico. Comparatively fewer studies have been published of ALM than other subtypes of the disease. However, it is becoming clear that complex DNA structural aberrations, as well as several genes, such as NOTCH2, KIT, PTEN and TYRP1, in addition to the established melanoma drivers, play a role in its development. To date, no comprehensive genomic characterization has been performed on tumors from Latin American patients. The causes of ALM are unknown, and little is known about its transcriptomic profile and immune landscape. Because of these factors, therapeutic options are limited, while approaches such as immunotherapy are too costly for most patients in Latin American countries, and are of unknown efficacy in rarer forms of melanoma such as ALM. A better understanding of the molecular and immune profile of ALM would allow us to identify potential therapeutic targets and treatment strategies in this population.
We have sequenced the exomes and transcriptomes of 113 ALM tumors (primaries, metastases and recurrences) from 86 patients being treated at the National Cancer Institute of Mexico, a national reference hospital. We have performed analyses to define the genomic landscape of the disease, its mutational signatures, the biological pathways involved in its development, and its immune profile. From these analyses, we have identified recurrently amplified and deleted genomic regions, potential causal agents, and the involvement of specific interleukins and cell-adhesion proteins in ulcerated and metastatic tumors.
This study is one of the first to profile the molecular landscape of ALM in a Latin American population. We hope that it will contribute to increasing the diversity of cancer genomics datasets, help highlight differences in disease biology, and provide insights that may inform therapeutic strategies for all patients with this lethal malignancy.
Citation Format: Martha E. Vázquez-Cruz, Patricia Basurto-Lozada, Christian Molina-Aguilar, Carolina Castaneda-Garcia, Ingrid Ferreira, Héctor Martínez-Said, Alethia Álvarez-Cano, Luis Alberto Tavares-de la Paz, Diego Hinojosa-Ugarte, Dorian Y. García-Ortega, Julia M. Martínez-Gómez, Mitchell P. Levesque, David J. Adams, Carla D. Robles-Espinoza. The molecular landscape of acral lentiginous melanoma in Mexican patients [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 2222.
Abstract 2234: Detection of structural variation and analysis on HuKemia models by Using Bionano optical mapping
Authors: Chen Xiaobo , Tian Huan , Qian Wubin , Li Henry Q. , Guo Sheng 
Published: July 2021

Abstract
Background: Genomic Structural variation (SV) refer to abnormalities in chromosome structure, is a normal part of variation in the human genome. Now Genomics SVs are recognized as the largest source of interindividual genetic variation and are closely associated with oncogenesis. The ability to identify constitutive and low-allelic fraction SVs is crucial. Standard SV detection method include chromosome banding, fluorescence in situ hybridization (FISH), and array comparative genome hybridization (CGH), which are manually intensive and have trouble finding low-frequency mutations. In recent year, genome physical mapping technologies have received increasing attention and optical mapping-based methods can well-accomplish sufficient to detect large size SVs or SVs within repetitive regions. Lately, Bionano optical mapping technology rapidly expanded its applications in the detection of structural variations. As well known, Acute Leukemia show distinct patterns of genetic aberrations including chromosome translocations, mutations, and aneuploidies in genes responsible for cell cycle regulation and lymphoid cell development.
Method: We use our liver cancer model LI6671 to establish the Bionano Saphyr Gen2 genome imaging platform. DNA &gt;100kbp is extracted, “CTTAAG” sequences were labelled across the entire genome by using Direct-Label-Enzyme (DLE) and linearized through chips for visualizations. Saphyr was loaded, linearized, and imaged labeled DNA in repeated cycles. Assembly Algorithms covert collected DNA images into constructing consensus genome maps. And this assay platform will be used to comprehensively identify SVs for studying our 21 HuKemia models.
Results: By using this fluorescence labels distribution patterns, we find different structure variants among genome. We used filtered data for genome map assembly and compared with human genome hg38 for SV detection. In LI6671, we found out 3952 SVs in LI667 including 1166 deletion, 2497 insertion, 101 duplication, 78 inversion breakpoints, 66 interchr. translocation breakpoints and intrachr. translocation. Oncogenesis related SVs, such as a ~13Kb heterozygous deletion at KCNQ1 region, EPC1::SP1 gene fusions have be founded.
Conclusion: Saphyr is a comprehensive platform, can discover a broad range of Genomic SVs and further improves our understanding of Acute Lymphocytic Leukemia (ALL) and Acute Myelocytic Leukemia (AML).
Citation Format: Xiaobo Chen, Huan Tian, Wubin Qian, Henry Q. Li, Sheng Guo. Detection of structural variation and analysis on HuKemia models by Using Bionano optical mapping [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 2234.
Abstract 2259: Single-cell multi-omics analysis of SNV, CNV, and protein expression
Authors: Ooi Aik , Dhingra Dalia , Sciambi Adam , Thompson Kate , Marin Jacqueline , Parikh Saurabh , Manivannan Mani , Ruff David 
Published: July 2021

Abstract
Recent advancements in precision medicine, while highly promising, presents a major technical challenge to researchers due to disease heterogeneity. The emergence of single-cell technologies has greatly refined the resolution in which sample diversity can be investigated, enhancing the efficiency of selecting appropriate molecular targets. Additionally, applying multi-omics analysis on single cells would further improve the understanding of cell-to-cell heterogeneity by providing unique insights on cellular and genetic composition. Using a two-step droplet microfluidic technology, the Mission Bio Tapestri Platform enables multiplex-PCR based high-throughput targeted DNA sequencing in single cells to obtain single-nucleotide variation (SNV) and copy number variation (CNV) information. By leveraging this technology, a new workflow is developed to detect protein expression in addition to DNA genotype in the same single cells. In this approach, cells are labeled with a pool of oligonucleotide-conjugated antibodies prior to loading the cells into the Tapestri Instrument. Sequencing libraries are then prepared from both antibody oligonucleotides and the amplified DNA sequences, followed by identification of single-cell DNA genotypes and protein signatures from the sequencing readout. The number of protein targets can be in the range from 6 to over 40, which is beyond the limit for a single flow cytometry run. This method has been successfully performed on cell lines, fresh and frozen PBMCs, as well as clinical samples. In an acute myeloid leukemia (AML) sample, combined single-cell SNV, CNV, and protein expression data illustrated the heterogeneity within the sample. The data clearly identified CD3+ T cells and CD19+ B cells without pathogenic SNVs and CNVs. CD34hiCD11blo and CD34loCD11bhi subpopulations were also identified within the cells carrying the same pathogenic SNVs and CNVs. We believe that this novel multi-omics technology will facilitate new discoveries in the complex relationship between genotype and phenotype, enable a better understanding of disease biology, and subsequently improve the design of diagnostics and therapies.
Citation Format: Aik Ooi, Dalia Dhingra, Adam Sciambi, Kate Thompson, Jacqueline Marin, Saurabh Parikh, Mani Manivannan, David Ruff. Single-cell multi-omics analysis of SNV, CNV, and protein 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 2259.
Abstract 2261: A multimodal single-cell workflow to interrogate cellular responses to cancer therapy
Authors: Dhingra Dalia , Ooi Aik , Li Alex , Sciambi Adam , Wang Shu , Gulati Saurabh , Ruff David 
Published: July 2021

Abstract
Understanding the genomic landscape of cancer in single cells can be valuable for the characterization of molecular events that drive evolution of tumorigenesis and fostering progress in identifying druggable regimens for patient treatment scenarios. We report a new approach to measure multiple modalities simultaneously from up to 10,000 individual cells using microfluidics paired with next generation sequencing. Our procedure determines targeted protein levels, mRNA transcript levels and somatic gDNA sequence variations including copy number variants. This approach can resolve over 20 proteins, 100s of targeted transcripts and DNA amplicons. We employ oligo-conjugated antibody panels to probe cell surface markers and targeted RNA and DNA amplification to resolve gene expression levels and genomic variants. Cell suspensions are first stained with the antibody panel then loaded onto the Mission Bio Tapestri for generation of a droplet. This droplet biochemistry allows for concurrent cell lysis and release of gDNA/mRNA. A second droplet formation event brings together a barcoded bead and multiplex PCR amplification reagents. After amplification, the combined libraries are sequenced yielding a multimodal readout. We applied this technique to several dynamic immunology and oncology in vitro models. As fusion gene detection has long been a focus of cancer research, we demonstrate this multi-modal workflow on cell lines containing variants of BCR-ABL transcripts with high sensitivities and specificities. We further explored the relationship between genotype-to-phenotype in imatinib impact on retinoblastoma and BCR-ABL driven leukemic cells. Our pilot studies demonstrate the utility of multimodal resolution in further illuminating cellular states and biological responses in cancer cells.
Citation Format: Dalia Dhingra, Aik Ooi, Alex Li, Adam Sciambi, Shu Wang, Saurabh Gulati, David Ruff. A multimodal single-cell workflow to interrogate cellular responses to cancer therapy [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 2261.
Abstract 2262: Comprehensive characterization of cancer drivers and therapeutic targets
Authors: Li Yize ,   Oncogenic Drivers and Pathways GroupClinical Proteomic Tumor Analysis Consortium
Published: July 2021

Abstract
Cancer is a family of diseases caused primarily by genetic “driver” mutations. Building upon a large-scale Pan-cancer study of ours, we expand our investigation to the proteogenomic level (including global proteome and phosphoproteome data) drawing &gt;1,000 cases over 10 cancer types (BR, ccRCC, CO, EC, GBM, HNSCC, LSCC, LUAD, OV, PDAC) from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). We concentrate on 6 aspects of drivers: (1) We identify genomic & epigenomic drivers (mutations, SVs, CNVs, fusions, etc.), estimate their frequencies, and investigate their exclusivities & co-occurrences. (2) We investigate the proteogenomic impact of drivers, especially recurrent ones, e.g. cis/trans effects, on miRNA, RNA, and protein expression. (3) We investigate their impact on Post Transcriptional Modifications (PTMs), comparing levels of protein and PTM, e.g. for one- and two-hit events. For example, we found upregulation of PTPN11 phosphorylation sites in EGFR-altered LUAD, GBM, and HNSCC samples, suggesting a pan-cancer effect, and observed high NRF2 phosphorylation and activation of antioxidant pathways in KEAP1 or NRF2-altered samples in lung cancer (LSCC and LUAD); (4) We compare tumors and normal adjacent tissues (NATs) to identify key protein level changes and regulations for oncogenic pathways and further examine cell type composition, proteomic variation, and association with driver mutations. For instance, we found VHL mutations often signify enrichment of endothelial cells. (5) We capture potential Significant Protein Drivers (SPRDs), independent of DNA level changes, to uncover hidden drivers in cause-ambiguous tumors. (6) We examine actionable driver alterations and expression changes across proteogenomic levels and associations with immune infiltration and immunogenic peptides to understand targeting, therapeutic implications and, influence on tumor micro-environment. We comment upon the clinical utility of comprehensive proteogenomics, especially in cases where a strictly genomic assessment is inconclusive. Proteomics can further prioritize gene targets with additional layers of evidence for differential expression among features such as cell-type composition, anatomical location, disease stage, and immune infiltration. Our approach has the potential for identifying cancer-type-specific and non-specific novel druggable targets, which would provide new biological and clinical insights into cancer.
Citation Format: Yize Li, Oncogenic Drivers and Pathways GroupClinical Proteomic Tumor Analysis Consortium. Comprehensive characterization of cancer drivers and therapeutic targets [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 2262.
Abstract 2270: Membrane organization of KRas4B with regulatory domain of Raf-1
Authors: Jang Hyunbum , Zhang Mingzhen , Nussinov Ruth 
Published: July 2021

Abstract
A major pathway in RAS-driven cell proliferation is the MAPK (Raf/MEK/ERK) pathway. In cancer, membrane-anchored, proximally located, oncogenic Ras isoforms promote Raf dimerization and fully activate MAPK signaling. Among Ras isoforms, KRas4B is frequently mutated in cancer. In the MAPK pathway, active KRas4B dimer or nanocluster can lead to dimerization of Raf kinase domain enhancing the affinity of the KRas4B-Raf interaction. Recently, we modeled the binary KRas4B-Raf-1 complex and its quaternary assembly with the regulatory domain of Raf-1 containing the Ras binding domain (RBD) and cysteine-rich domain (CRD), and suggested that Raf-1 CRD bolsters the high-affinity interaction of Raf-1 with KRas4B by reducing the KRas4B-RBD fluctuations. For the quaternary assembly, recent in silico studies suggested that KRas4B dimer is aligned through the α3 and α4 helical interface, not the α4 and α5 helical interface due to hindrance to the membrane contact of Raf-1 CRD. The Raf-1 regulatory domain contains the N-terminal region (residues 1-55), RBD, and CRD. However, previous modeling efforts were conducted for the KRas4B-Raf-1 complex in the absence of the N-terminal region. Here, computational studies were performed for the KRas4B-Raf-1 complex with full sequence of Raf-l regulatory domain interacting with monomeric and dimeric KRas4B-GTP at the membrane. Increasing experimental evidences suggested that the N-terminal region of Raf plays a significant role in the Ras interaction and the membrane anchorage of Raf. The membrane interaction of isolated N-terminal segment was investigated as the first step toward the complex model construction. Since oncogenic KRas4B mutants form dimers/nanoclusters at the membrane microdomains that provide the signaling platform for Raf, KRas4B in different mutation states interacting with the membrane microdomains with different lipid composition was also studied. The presence of the N-terminal segment of Raf-1 regulatory domain at the membrane can enhance the stability of KRas4B-Raf-1 and thereby relieving Raf's autoinhibition toward a kinase domain-accessible state, providing a complete mechanistic picture of the KRas4B-Raf-1 interaction. Our recent work uncovers the mechanism of Raf-1 activation by KRas4B at atomic resolution and highlight how this may help in elucidating vital mechanistic questions in Ras biology. Funded by Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E.
Citation Format: Hyunbum Jang, Mingzhen Zhang, Ruth Nussinov. Membrane organization of KRas4B with regulatory domain of Raf-1 [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 2270.
Abstract 2271: Potential small-molecule inhibitors of the Tiam1 oncogene product
Authors: Fritz Claire , Stamper Michaela , Valentino Stephen , Ulatowski Lynn , Gupta Meghana , Thakur Varsha , Chung Stacey , DeHann Nick , Laggner Christian , Manor Danny 
Published: July 2021

Abstract
T-cell lymphoma invasion and metastasis-inducing factor (Tiam)1 is an established proto-oncogene that drives cancer cell migration and metastasis. The correlation between Tiam1 integrity and patient survival, epithelial-mesenchymal transition, and angiogenesis, render it as an important prognostic factor in multiple human malignancies. Tiam1 is a guanine nucleotide exchange factor (GEF) that facilitates the activation of the small GTPase Rac1, thereby controlling cytoskeletal organization, cell polarity, motility, and invasion. In light of the clinical relevance of Tiam1 signaling, we investigated the utility of small molecule inhibitors that target Tiam1 as a therapeutic intervention strategy. We used an in silico computational approach to screen 10 million compounds for candidate drugs that bind to a select patch on Tiam1's surface. We then identified 13 compounds that inhibit the migration of Tiam1-expressing A549 cells without affecting overall viability. Our studies open the door for a new targeted therapy approach in Tiam1-relevant cancers.
Citation Format: Claire Fritz, Michaela Stamper, Stephen Valentino, Lynn Ulatowski, Meghana Gupta, Varsha Thakur, Stacey Chung, Nick DeHann, Christian Laggner, Danny Manor. Potential small-molecule inhibitors of the Tiam1 oncogene product [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 2271.
Abstract 2273: MAPK signaling pathway disruption explains the anticancer mechanism for polyisoprenylated cysteinyl amide inhibitors (PCAIs)
Authors: Tawfeeq Nada , Jin Yonghao , Lamango Nazarius 
Published: July 2021

Abstract
The Mitogen-activated protein kinase (MAPK) pathway is one of the key signaling pathways that regulates normal cell proliferation, differentiation, and survival. Abnormalities of the pathway play vital roles in cancer initiation and progression. Ras small GTPases that are key upstream mediators of the MAPK pathway are mutated in 20%-30% of human tumors. KRAS is the most frequently mutated isoform of the RAS proteins, accounting for up to 86% of RAS mutant cancer cases. Mutant KRAS is prevalent in lung, colon, and pancreatic cancers, which considered to be the most aggressive and account for the most cancer deaths in the US. To help mitigate this problem and fill the therapeutic need that has lingered for decades, polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed and synthesized to target the hyperactivity of aberrant monomeric G-Proteins. Recently, the PCAIs underwent a synthetic optimization to mitigate the excessive hydrophobicity of the earlier analogs. While the newer agents are more polar and have maintained the effectiveness of the earlier PCAIs against cancer cell lines driven by mutant KRAS proteins, the specific anticancer mechanisms are still unclear. Thus, we explored the effects of the newer PCAIs on the MAPK pathway using lung cancer A549 cells which harbor the KRAS mutation. When the cells were treated with NSL-YHJ-2-27 for 48 h, the KRAS protein levels dropped by 40% at 5μM compared to the controls. However, no significant difference was observed in the levels of total or phosphorylated B- and C-Raf proteins. Moreover, it was observed that the PCAIs immensely stimulated the MAPK pathway in a concentration-dependent manner following treatment with 1, 2, and 5μM of NSL-YHJ-2-27. The phosphorylation of MEK1/2, ERK1/2, and p90RSK significantly increased by 84%, 59%, and 160%, respectively, relative to controls following treatment for 48h at 5 µM of NSL-YHJ-2-27. Interestingly, a non-farnesylated analog, NSL-YHJ-2-62, did not elicit similar effects on the MAPK pathway. Although ERK stimulation has mostly been associated with cell survival and proliferation, various studies show that ERK activation can also mediate apoptosis depending on the intensity and duration of the stimulation. These data reveal that the Ras-MAPK signaling axis is involved in the anticancer effects of the PCAIs. The PCAIs may thus be considered as possible agents for the unmet therapeutic needs of patients with aberrantly hyperactive G-proteins.
Citation Format: Nada Tawfeeq, Yonghao Jin, Nazarius Lamango. MAPK signaling pathway disruption explains the anticancer mechanism for polyisoprenylated cysteinyl amide inhibitors (PCAIs) [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 2273.