bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2058: Identifications of novel variants using system biology-based approaches in NT5C2, its association to relapse acute lymphoblastic leukaemia
Authors: V Sugunakar , Bandapalli Obul Reddy , Sharma Ramita 
Published: April 2023

Abstract
Acute Lymphoblastic Leukaemia (ALL) patients experience relapse despite having a good prognosis; approximately 90% of children and 75% to 85% of adolescents and young adults survive for five years. Chemotherapy resistance and a poor prognosis are linked to relapsed acute lymphoblastic Leukaemia (R-ALL). Evidence suggests that the cytosolic 5 nucleotidase II (NT5C2) gene mutations play a crucial role in the emergence of recurrent ALL; The early R-ALL is usually accompanied by 6-MP resistance, which is typically brought on by gain-of-function mutations impacting NT5C2-driven mutation in relapse mutations by different mechanisms is still unknown. The study aims to identify novel top missense variants of NT5C2 that play a crucial role in the resistance of chemotherapy drugs, altered biological pathways and their impact on the treatment of relapse leukaemia. NT5C2 (5'-Nucleotidase, Cytosolic II) is a Protein Coding gene. This gene induces resistance to chemotherapeutic drug 6 mercaptopurine Which causes leukaemia cell growth and leukaemia-initiating cell activity. The NT5C2 gene variants are extracted from Genome Aggregation Database (gnomAD) and ExAC. The extracted data contained 2280 variants with chromosome number, position reference allele, and altered allele and these were functionally annotated using the ANNOVAR tool. The variants are screened through various computational tools to narrow down based on non-synonymous and stopgain mutations in the exonic region. The predicted 519 variants narrow down by scoring GERP (&gt;2.0) and CADD PHRED (cut-off score &gt;10), ClinVar, SIFT score, Polyphen, PhyloP, PhastCons, LRT score predictions and which indicates the top 10% deleterious variants including reported and unknown variants. The SNPs, insertions, deletions, CNVs or structural variants of top missense variants on genes, transcripts, and protein sequence determined on Variants Effect Predictor on the ensemble. These variants were verified on dbSNP and Clinvar through their variant IDs. The functional prediction of these variants was made to detect their significant role in R-ALL. These findings examine the future role of NT5C2 mutations in the chemoresistance of relapse ALL. This may help to find a new therapeutic combination of drugs to treat relapse acute lymphoblastic leukaemia to improve overall survival.
Citation Format: Sugunakar V, Obul Reddy Bandapalli, Ramita Sharma. Identifications of novel variants using system biology-based approaches in NT5C2, its association to relapse acute lymphoblastic leukaemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2058.
Abstract 2086: ISCVAM, an Interactive Single Cell Visual Analytics for Multiomics, accelerates the identification of novel rare cell populations
Authors: Nguyen Thanh N. M. 
Published: April 2023

Abstract
BACKGROUND Emergent single cell technologies have accelerated the discovery of rare cell populations and characterization of complex tumor microenvironment (TME). We developed an Interactive Single Cell Visual Analytics for Multiomics, ISCVAM, a bioinformatics infrastructure to integrate and visualize high-dimensional sparse multiome single cell data.
METHODS We built an interactive tool, ISCVAM with react.js for the web frontend, and node.js in the backend, with a data bridge to portable HDF5 storage. Commonly used R packages including Seurat, Signac, SingleR, and scType, were used offline for data processing and analyses. We investigated cell populations using two Multiome datasets for proof of principle:1) ~22K cells from the matched pairs of sorted CD8+Tissue resident memory (TRM) and recirculating (ReCir) T cells from 4 ovarian cancer patients in (Anadon, Yu et al. 2022) and 2) ~11K cells from a PBMC sample (from 10X Genomics).
RESULTS ISCVAM enables users to investigate both user-defined markers in multiple modalities (RNA and ATAC) individually and jointly (through weighted nearest neighbor), in different dimension reduction projections and on multiple panels. It also allows discovery of novel signatures of unidentified cell populations using unsupervised clustering algorithms in multiple resolutions. Using the paired TRM and ReCir samples from a single patient as the discovery set, ISCVAM identified a small cluster of mucosal-associated invariant T (MAIT) cells with unique gene and open chromatin peak profiles in both samples (2.18% of the ReCir T cells and 1.50% of the TRM T cells), which was not reported in the original study. Using the identified signature (with SLC4A10, TLE1 and their linked peaks), the MAIT cells were observed in remaining 6 ovarian samples (5.39 ±4.05% cells in 3 ReCir samples and 1.05 ± 1.02% cells in 3 TRM samples) from the same study. The markers are robust and also validated in an independent PBMC 10X Genomics dataset.
CONCLUSION The tool ISCVAM enables the discovery of rare immune cell populations by integrating transcriptional and epigenic profiles simultaneously at multiple resolutions. This information rich tool with multiple panels and modalities with high interactivity enables rapid identification of rare cell populations. This will accelerate the understanding of complex TME in cancer research.
Citation Format: Thanh N. M. Nguyen. ISCVAM, an Interactive Single Cell Visual Analytics for Multiomics, accelerates the identification of novel rare cell populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2086.
Abstract 2179: The role of ATP-binding cassette transporter A5 in colorectal cancer progression
Authors: Bajbouj Khuloud , Alketbi Latifah , Hamid Qutayba , Talaat Iman 
Published: April 2023

Abstract
Background: Colorectal cancer (CRC) is one of the most common malignancies worldwide; it is the fourth leading cause of cancer-related deaths. The lack of novel diagnostic and therapeutic targets and the development of chemoresistance are major issues when dealing with CRC. The overexpression of ATP-binding cassette (ABC) transporters is considered one facilitating mechanism for chemoresistance. Furthermore, several ABCA superfamily transporters have been shown to mediate cancer development and multidrug resistance. However, the role of ABCA5 in CRC development and progression is elusive. The current study aimed at profiling the expression of ABCA5 at the different grades of CRC.
Experimental Methods: Forty-nine (9 Well differentiated, 26 moderately differentiated and 14 poorly differentiated) primarily diagnosed CRC cases, and 15 normal colonic tissues were included in the study. Formalin-fixed paraffin-embedded samples were interpreted for the differential expression of ABCA5 by immunohistochemistry. The immunoreactivity of ABCA5 was assessed in the cells based on the staining intensity and the percentage of the positively stained cells to create the immunoreactive score.
Results: In total, 49 CRC cases were recruited, with a mean age of 63.77 years (range 33-86); 21 female and 28 male patients. All specimens were diagnosed as adenocarcinoma (NOS). Immunohistochemical analysis of the 49 CRC samples revealed diffuse ABCA5 immunoreactivity in the majority of cases. Seven cases showed mild expression, 25 showed moderate expression, whereas 17 cases revealed intense ABCA5 expression. Intriguingly, negative to a mild expression of ABCA5 was noted in the normal colonic tissues. ABCA5 intensity was higher in poorly differentiated CRC compared to the other grades.
Conclusion: Higher expression of ABCA5 is associated with CRC differentiation, indicating that it might contribute to CRC development and progression. Thus, it may be a novel diagnostic biomarker.
Citation Format: Khuloud Bajbouj, Latifah Alketbi, Qutayba Hamid, Iman Talaat. The role of ATP-binding cassette transporter A5 in colorectal cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2179.
Abstract 2185: Septin isoform expression as a potential biomarker for differential response to microtubule targeted chemotherapy in breast cancer
Authors: Essif Jacob N. , Yee Samantha S. , Risinger April 
Published: April 2023

Abstract
The primary cause of cancer-associated death is due to the development of metastatic disease. Metastasis is a multistage process requiring displacement of cells from the primary tumor, survival in circulation, and adhesion and growth in a secondary location. Reorganization of both the actin and microtubule cytoskeleton is critical for metastasis of solid tumors. Drugs that inhibit microtubule dynamics, including microtubule stabilizers and destabilizers, are used to treat metastatic breast cancer, however there is no rationale to guide the choice among these drugs. Septins, a class of small GTPases, interact with both microtubules and actin to functionally link these cytoskeletal components. Expression of a specific isoform, septin9_i1, is associated with breast cancer development, migration, and drug resistance. This isoform is unique among septins in that it contains a specific microtubule binding domain required for association of septins with microtubules. We found that microtubule stabilizing or destabilizing chemotherapeutics currently used to treat metastatic breast cancer promoted respective microtubule or actin localization of oncogenic septins, particularly when septin9_i1 was expressed. This differential cellular distribution correlated with our finding that microtubule destabilizers were more effective than stabilizers at inhibiting the migration of septin9_i1 expressing breast cancer cells in vitro whereas the drugs were equally effective in isogenic cells depleted of septin9_i1. We are currently testing the hypothesis that septin9_i1 promotes in vivo metastasis of breast tumors and that microtubule destabilizers will be more effective than stabilizers at inhibiting this metastasis. This supports our ongoing clinical investigations to determine whether septin9_i1 expression could be used as a predictive biomarker to guide the selection among microtubule-targeted chemotherapeutics, which is significant as there is currently no molecular guidance to inform on this choice. Our findings will promote the more targeted and rational use of this highly used but mechanistically underappreciated class of chemotherapy.
Citation Format: Jacob N. Essif, Samantha S. Yee, April Risinger. Septin isoform expression as a potential biomarker for differential response to microtubule targeted chemotherapy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2185.
Abstract 2218: The molecular mechanism underlying KRAS regulation on STK31 expression in pancreatic ductal adenocarcinoma
Authors: Liu Yuting , Tang Shing Chun , Chen Yangchao 
Published: April 2023

Abstract
KRAS is frequently mutated in pancreatic ductal adenocarcinoma (PDAC). However, targeting mutant KRAS is still challenging. Kinase inhibitors are ideal targeted therapeutics for mutant KRAS-driven cancer. In our previous study, an esiRNA screening was prepared to identify some vital kinases that took part in KRAS mutant-driven pancreatic cancer. The STK31 was identified as a potential therapeutic target in KRAS mutant PDAC. This study aimed to investigate the underlying mechanism of STK31 in KRAS mutant PDAC as well as its therapeutic potential. The results demonstrated that STK31 was upregulated in KRAS mutant PDAC patients with poor survival. STK31 was also highly expressed in PDAC cell lines with KRAS mutant background. Inhibition of STK31 in KRAS mutant cell lines significantly reduced PDAC cell proliferation, colony formation, and migration. Gain and loss of function experiments revealed that STK31 was a downstream target of KRAS in PDAC. Pharmacological inhibition of several signaling pathways involved in KRAS showed MAPK/ERK signaling involved in STK31 regulation. Then, further mechanistic study validated that c-Jun, regulated by KRAS/MAPK/ERK signaling, directly regulated the transcription level of STK31 by binding to its promoter region. In summary, our results show that STK31 promotes PDAC cell proliferation under the control of the KRAS/MAPK/ERK/c-Jun transcriptional axis in PDAC. STK31 may act as a potential target in PDAC treatment.
Citation Format: Yuting Liu, Shing Chun Tang, Yangchao Chen. The molecular mechanism underlying KRAS regulation on STK31 expression in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2218.
Abstract 2226: Modeling the role of Tet-deficiency and restoration in Bcl2-driven B cell lymphoma progression
Authors: Lam Minh Quang , Cimmino Luisa 
Published: April 2023

Abstract
Loss of function in DNA methylation regulators such as the Ten-eleven translocation (TET1-3) proteins, have been implicated in the progression of lymphoma. TET enzymes constitute a family of iron and αKG-dependent dioxygenases that oxidize 5-methylcytosine in DNA to promote demethylation and the reversal of gene silencing. The TET enzymes require vitamin C for their optimal catalytic activity, however, many patients with hematological malignancies are vitamin C deficient. Enhancing and restoring TET function with high-dose vitamin C has been shown to block the progression of solid tumors and blood malignancies. A combination of genetic and epigenetic diversity in lymphoma can result in the aberrant overexpression of oncogenes, loss of tumor suppressor function, and genomic instability. Our research models Bcl2-driven B cell lymphoma with Tet-deficiency using transgenic RNAi for the knockdown of Tet1 or Tet2. In vitro, our results have shown that this model shows increased self-renewal capacity of early B cell progenitors and precursors that can be suppressed by genetic restoration of Tet expression or upon treatment with vitamin C. In vivo, the B cell compartment of mice with Bcl2 overexpression and Tet1 or Tet2 deficiency exhibit a block in B cell maturation during a long period of pre-malignancy, and a decreased frequency of follicular B cells in the spleen from 3 months of age. Our aim is to determine mechanistically the effects of Tet-deficiency on B cell lymphoma progression and whether vitamin C can restore Tet activity to suppress lymphoma progression.
Citation Format: Minh Quang Lam, Luisa Cimmino. Modeling the role of Tet-deficiency and restoration in Bcl2-driven B cell lymphoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2226.
Abstract 2233: Clinical validation of a methylation array-based diagnostic assay for improved classification of CNS tumors
Authors: Soucy Melissa , Renzette Nick , Zhuo Xinming , Nuni Prasanti , Herlth Kristi , Kelly Kevin , Omerza Gregory , Li Lei 
Published: April 2023

Abstract
Current cIMPACT-NOW and WHO guidelines state that the accurate diagnosis of many central nervous system (CNS) tumors must not only incorporate traditional histological findings but also include additional molecular data derived from sequence and methylation profiling techniques. To address this clinical need, our group has adapted and clinically validated the CNS tumor classifier that was pioneered and developed by the German Cancer Research Network (DKFZ) and University Hospital Heidelberg for both adult and pediatric CNS tumors. The classifier analyzes whole genome methylation data derived from the Illumina EPIC array system with a machine learning algorithm trained on a large reference set to provide a tumor family and class (a more granular classification than family) along with calibrated scores to aid in determining confidence in the assigned classifications. Around this core algorithm, we have generated a computational and reporting pipeline to generate a mid-throughput clinical diagnostic assay. We have validated this assay using a combination of adult and pediatric CNS tumor samples and have established reliable run-level and sample-level quality control metrics with empirically defined thresholds. With these thresholds, approximately 90% of samples with a neoplastic content of 70% or greater were “classifiable”, such that a result could be returned by the CNS tumor diagnostic assay. The performance of the assay was exceptional, with a sensitivity, specificity and accuracy each greater than 98% as determined with a validation sample set of 105 specimens. Further, 4 discordant calls between the original diagnosis and the output of the new methylation-based diagnostic were identified and underwent further histopathologic review. This additional analysis led to the re-classification of 2 specimens due to molecular analysis, highlighting the clinical utility of the assay. The new assay is currently offered for clinical testing under the name JAX OncoMethyl ArrayTM and addresses a clear need in the field of CNS tumor diagnostics.
Citation Format: Melissa Soucy, Nick Renzette, Xinming Zhuo, Prasanti Nuni, Kristi Herlth, Kevin Kelly, Gregory Omerza, Lei Li. Clinical validation of a methylation array-based diagnostic assay for improved classification of CNS tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2233.
Abstract 2238: RAS activity-related features of metastatic pancreatic cancer
Authors: Mitsunaga Shuichi , Masuda Mari , Yoshimatsu Hiroki , Kamei Yoichi , Sasaki Mitsuhito , Watanabe Kazuo , Ikeda Masafumi 
Published: April 2023

Abstract
Background: RAS activity might play crucial roles in the aggravation of KRAS-mutated pancreatic cancer (PC), including systemic inflammatory reactions, tumor-driven inflammation, chemo-refractoriness and anorexia. We aimed to identify RAS activity-related features in PC patients with liver metastasis (LM), to create a murine xenograft model of human PC cells representative of RAS-driven aggravation.
Methods: RAS activities in 77 patients who underwent needle biopsy for LM of treatment-naïve PC were measured using an RAS signature score from a comprehensive cDNA microarray dataset of LM samples. Changes in the sum of the longest diameter of the target lesion in the first month of chemotherapy (ΔSLD), laboratory data and anorexia score at baseline were evaluated. Gene modules to be correlated with RAS activity and aggravation were evaluated using weighted co-expression network analysis (WGCNA). Human PC cells were classified as high and low activity according to in silico analysis of the DepMap CCLE expression dataset for profiling RAS activity and the best hub gene expression in the gene module. Subcutaneous xenograft models of human PC cells with high and low activity in severe combined immunodeficiency mice were compared to explore the RAS-related phenotype.
Results: KRAS-mutated LM was detected in 70 of the 77 PC patients (90.9%). RAS signatures were up-regulated in patients with KRAS-mutated LM (P &lt; 0.01), high serum level of C-reactive protein (P = 0.01) as a systemic inflammatory marker, high expression of IL-6 mRNA by the tumor (P = 0.12) as an index of tumor-driven inflammation, and high level of phospho-Erk (P = 0.03). In 58 PC patients receiving first-line chemotherapy for KRAS-mutated LM, ΔSLD in patients with a high RAS signature was increased as compared to those in patients with a low RAS signature (P = 0.045). WGCNA methods revealed that the green module highly correlated with RAS activity and aggravation. Based on in silico analysis with classification of the human PC cell lines CFPAC-1 and SUIT-2 into high and low activity cells, respectively, CFPAC-1 tumors showed desmoplasia and high expression of tumor IL-6 and liver SAA1 as compared to SUIT-2 tumors (P = 0.046 and P = 0.016, respectively).
Conclusions: Tumor RAS activity is related to inflammation-related aggravation in PC patients. RAS-related inflammation can be accurately presented in a murine model of human PC cells, which might be an effective tool to test the inhibition of RAS-driven inflammation.
Citation Format: Shuichi Mitsunaga, Mari Masuda, Hiroki Yoshimatsu, Yoichi Kamei, Mitsuhito Sasaki, Kazuo Watanabe, Masafumi Ikeda. RAS activity-related features of metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2238.
Abstract 2239: Investigation of the molecular biological significance of YAP/TAZ expression in PNEN
Authors: Shiraishi Yuta , Hayashi Hiromitsu , Ogawa Daisuke , Yumoto Shinsei , Sato Hiroki , Matsumoto Takashi , Takematsu Toru , Maruno Masataka , Tsukamoto Masayo , Miyata Tatsunori , Nakagawa Shigeki , Mima Kosuke , Nitta Hidetoshi , Baba Hideo 
Published: April 2023

Abstract
[Background] Neuroendocrine neoplasms (NEN) developing in the digestive organs are relatively rare tumors, with 3 to 5 new cases per 100,000 population annually, most of which occur in the pancreas and digestive tract. In pancreatic neuroendocrine neoplasms (PNEN), the risk of metastasis and progression varies depending on the grade of the tumor, even when the tumor size is small. In clinical practice, it is often difficult to determine the indication for surgery or multidisciplinary treatment with chemotherapy. The mechanisms of tumor formation and progression in PNEN remain unknown. YAP/TAZ have been known to play an important role in pancreatic development. Here, we explore the biological and clinical significance of YAP/TAZ over-expression in PNEN.
[Methods] Immunostaining for YAP/TAZ was performed using 92 resected specimens in PNEN patients, and the association between YAP/TAZ overexpression and clinicopathological factors was elucidated. Furthermore, we generated a PNEN cell line with YAP and TAZ over-expression using QGP-1, and examined the intracellular signals regulated by YAP/TAZ expression.
[Results and Discussion] The overexpression of YAP, TAZ, and YAP/TAZ were observed in 55, 55, and 32patients, respectively. High YAP expression was significantly associated with positive lymphovascular invasion (p=0.04). YAP/TAZ-high group displayed significantly worse Overall survival (p=0.0023) and recurrence-free survival (p=0.007) compared to those in others. By Western-blotting, YAP/TAZ overexpression in the QGP-1 cell line enhanced phosphorylation of Akt and Erk1/2.
[Conclusions] High expression of YAP/TAZ in PNEN was implicated in poor prognosis, and was also associated with Akt, Erk1/2, and mTOR.
Citation Format: Yuta Shiraishi, Hiromitsu Hayashi, Daisuke Ogawa, Shinsei Yumoto, Hiroki Sato, Takashi Matsumoto, Toru Takematsu, Masataka Maruno, Masayo Tsukamoto, Tatsunori Miyata, Shigeki Nakagawa, Kosuke Mima, Hidetoshi Nitta, Hideo Baba. Investigation of the molecular biological significance of YAP/TAZ expression in PNEN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2239.