bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2227: Streamlined workflow for analyzing and reporting hematological malignancies in Bionano VIATM software
Authors: Clifford Benjamin , Hauenstien Jen , Pang Andy Wing Chun , Burnside Rachel D. , Miller Neil , Hastie Alex , Chaubey Alka 
Published: April 2023

Abstract
Cytogenetic analysis for hematological malignancies most often includes karyotyping, fluorescence in situ hybridization, and rarely, chromosomal microarray (CMA). While considered the gold standard, karyotyping and FISH have significant limitations in resolution of structural variants (SVs). CMA has a much higher resolution, but cannot detect balanced SVs, and is less commonly used in the hematologic oncology setting. Optical genome mapping (OGM) can detect all classes of SVs at high resolution (duplications, deletions, inversions, insertions, translocations), and as such, detects many copy number variants (CNVs) and SVs that have not been previously described. Although these novel SVs will help better describe genetic contributions to disease, analysis, interpretation and curation can take considerable time. A streamlined workflow has been developed for use with Bionano VIA™ software for a comprehensive analysis of relevant SVs in a hematological malignancy genome. First, by employing disease-specific decision trees for variants published in guidelines for those conditions, the software automatically flags Tier 1A variants detected according to ACMG/AMP/CGC criteria. Second, the overall genome complexity is assessed by observing chromosomal abnormalities detected by OGM. Large events (&gt;5Mb) are counted, and complex genomes are assigned if there are more than 3 or 5 events, depending on the cancer type. Third, calls are further refined by filtering on a pan-cancer specific list to capture those variants that are then manually classified as Tier 1B or 2 by the analyst. The Bionano VIA software allows case-specific and disease subtype-specific information to be added to various sections within the software, such as the Knowledgebase, Event Table, and Sample Info fields to facilitate autopopulation of reportable data and interpretations into a formatted report template. Bionano VIA software can also accommodate multiple platforms simultaneously (e.g., NGS panels) to provide users with a comprehensive view of genomic aberrations relevant to hematological malignancies. This workflow is intended to streamline analysis and automate reporting of oncology samples, which can be extremely complex and often require extensive research.
Citation Format: Benjamin Clifford, Jen Hauenstien, Andy Wing Chun Pang, Rachel D. Burnside, Neil Miller, Alex Hastie, Alka Chaubey. Streamlined workflow for analyzing and reporting hematological malignancies in Bionano VIATM software [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 2227.
Abstract 2229: Cell state transitions shape the intratumoral composition of small cell lung carcinoma
Authors: Gopal Priyanka , Petty Aaron , Rogacki Kevin , Bera Titas , Bareja Rohan , Peacock Craig , Abazeed Mohamed 
Published: April 2023

Abstract
Introduction: Small cell lung carcinoma (SCLC) is characterized by rapid growth, early metastases, and initial response followed by almost invariable resistance to therapy. Studies to date have not determined the extent that diverse transcriptional programs drive SCLC and contribute to its lethality. We sought to characterize the intra-tumoral transcriptional heterogeneity of SCLC. We identify multivalent, distinct, and commutable transcriptional states that confer discrete functions in individual SCLC tumors.
Methods: We developed a biorepository of patient-derived xenografts (PDX) (n = 64) and matched PDX-derived ex vivo lines. We used multi-omic profiling (RNAseq, scRNAseq, and ATAC seq), single-cell fluorescence tracking of fate-defining transcription factor (TF)-driven states, and mathematical and statistical models (Markov chain) to study the topology of the SCLC transcriptional landscape and its plasticity. Human tumor material and associated clinical data were obtained after informed written consent on an IRB-approved prospective registry.
Results: We show that individual SCLC tumors are more heterogenous than previously appreciated, displaying distinctive equilibria in the proportion of cells within well-delimited cellular states (ASCL1, NEUROD1 and YAP1). We also show that transcriptional states undergo transitions, which we identified as a mechanism for maintaining cell state diversity. We measured the kinetics of state transitions using single-cell fluorescence tracking of ex vivo cultures and found that these measure were associated significantly with transition estimates using stochastic transition theory (i.e. Markov chains). ATAC-seq profiling indicated a role for the epigenome in the state diversity of SCLC. Namely, there was preferential promoter accessibility to Ascl1, NeuroD1, and Yap1 in a manner consistent with gene and protein expression in the respective subpopulations. Our results indicate that the transition rates between cell types in individual tumors were largely governed by tendencies to reach an equilibrium state that are critical for configuring intratumoral cell state proportions.
Conclusion: In conclusion, we demonstrate that TF driven cell states can transition to maintain an equilibrium in cell state proportions. Our work advances a model of cellular states and program diversity in SCLC and nominates new therapeutic strategies designed to limit the plasticity of this lethal cancer.
Citation Format: Priyanka Gopal, Aaron Petty, Kevin Rogacki, Titas Bera, Rohan Bareja, Craig Peacock, Mohamed Abazeed. Cell state transitions shape the intratumoral composition of small cell lung carcinoma [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 2229.
Abstract 2237: Inhibition of HSF1 demonstrates therapeutic efficacy in preclinical models of cholangiocarcinoma
Authors: Carlson Danielle M. , Abdelrahman Amro , Fogliati Alessandro , Lynch Isaac , Tomlinson Jennifer , Truty Mark , Smoot Rory 
Published: April 2023

Abstract
Introduction: Cholangiocarcinoma (CCA) is a highly lethal, and biologically heterogenous malignancy arising from the biliary tree. With only moderate responses to cytotoxic chemotherapy and despite the development of targeted therapies, treatment success has been hindered by primary or acquired resistance. New therapeutic strategies are necessary to improve outcomes in these patients. NXP800 is a heat shock factor 1 (HSF1) small-molecule inhibitor with activity previously noted in ovarian cancers with ARID1A mutations. ARID1A mutations are common, well-known players in cholangiocarcinoma. In preclinical exploratory studies, we examined treatment responses in validated cholangiocarcinoma patient derived xenograft (PDX) models.
Methods: In our preliminary studies we evaluated response to HSF1 inhibition in a single, ARID1A wildtype PDX model. Xenografts were expanded into the flank of NOD/SCID mice and treatment begun when tumors averaged 120mm3. 16 tumor bearing mice were randomized and 8 mice were grouped into both the treatment and control arms. Mice were then treated with either NXP800 (35 mg/kg), in the treatment arm, or vehicle, in the control arm, via oral gavage 5 days on, 2 days off, for 28 days. Tumor volume and animal weight were collected twice weekly.
Results: After screening of our Human CCA PDX library of 57 patients, we identified an established and histologically validated PDX from a patient with intrahepatic cholangiocarcinoma obtained at surgical resection. Molecular characterization of the tumor identified NRAS Q61 mutation, FGFR1 and FGFR2 overexpression, androgen receptor overexpression, microsatellite stability, and a total tumor mutational burden of 2.6. RNA sequencing was completed and an evaluation of a 21-gene signature of YAP activity had identified this PDX as having an elevated activity signature compared to a cohort of 27 additional PDX tumors. Treatment with NXP800 was associated with a statistically significant decrease in tumor size compared to control tumor bearing mice, with a mean difference of the delta in tumor volume (852.6 mm3; 95% CI: 321 - 1384; P-value = 0.0057).
Conclusion: NXP800, a HSF1 inhibitor, demonstrated significant therapeutic activity in a cholangiocarcinoma PDX. Further studies are needed and being performed to determine the role of HSF1 inhibition in human cholangiocarcinoma.
Citation Format: Danielle M. Carlson, Amro Abdelrahman, Alessandro Fogliati, Isaac Lynch, Jennifer Tomlinson, Mark Truty, Rory Smoot. Inhibition of HSF1 demonstrates therapeutic efficacy in preclinical models of cholangiocarcinoma [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 2237.
Abstract 2241: Transcriptomic analysis of tetraspanins in colorectal cancer
Authors: Suwatthanarak Thanawat , Tanjak Pariyada , Chaiboonchoe Amphun , Acharayothin Onchira , Thanormjit Kullanist , Suwatthanarak Tharathorn , Tangkullayanone Watsaphon , Pithukpakorn Manop , Chinswangwatanakul Vitoon 
Published: April 2023

Abstract
Introduction: Transmembrane proteins and their overexpression have been highly involved in malignancies. In particular, Tetraspanins (TSPANs)—a family of four-span transmembrane proteins—have been proposed as “master organizers” of multi-molecular membrane complexes by associating with specific partners and thus contributed to the progression of many cancer types. To date, transcriptomic analysis of all human TSPANs in colorectal cancer (CRC) has remained unclear. Here, we focused on utilizing next-generation RNA sequencing (RNA-Seq) to explore the expression level of TSPANs in primary tumor tissues of CRC, which is a complex disease and the second cause of cancer mortality worldwide.
Experimental Procedures: Resected primary tumor tissues of CRC were collected from 100 patients along with the written informed consents. Later, total RNA was extracted from all frozen patient tissues. RNA-Seq of those RNA samples was next done before the transcriptomic analysis of TSPANs in CRC was performed. Immunofluorescence (IF) and Immunohistochemistry (IHC) stains were also employed to confirm the target protein expression in formalin-fixed paraffin-embedded tissue (FFPE) slides from CRC patients.
Results: As a result of transcriptomic analysis of TSPANs in CRC tissues, among 33 human TSPANs, the high expression levels (transcript per million above the average of all TSPANs) of TSPAN1, TSPAN8, TSPAN24, TSPAN29 and TSPAN30 were observed in the patient-derived CRC tissues. Notably, the expression level of TSPAN8 was comparable with that of EPCAM, which is a well-known tumor marker. Moreover, the high expression of TSPAN8 protein could be clearly observed in both IF and IHC-stained FFPE slides from CRC patients. Our result highlights the possible relevance of these overexpressed TSPANs in CRC development.
Conclusions: This study is the first RNA-Seq-based transcriptomic analysis of all human TSPANs in CRC. Our finding suggests the significant overexpression of particular TSPANs, especially TSPAN8, in CRC. Further analyses will be beneficial for translational research in CRC. The overexpression of TSPANs may suggest a framework to further explore diagnostic, prognostic, and predictive surface biomarkers, therapeutic targets, and other applications for CRC.
Citation Format: Thanawat Suwatthanarak, Pariyada Tanjak, Amphun Chaiboonchoe, Onchira Acharayothin, Kullanist Thanormjit, Tharathorn Suwatthanarak, Watsaphon Tangkullayanone, Manop Pithukpakorn, Vitoon Chinswangwatanakul. Transcriptomic analysis of tetraspanins in colorectal 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 2241.
Abstract 2340: Development of a CCR8 monoclonal antibody which blocks CCR8 signaling and abolishes the immunosuppressive function of Treg for the treatment of cancer
Authors: Fan Guohuang , Wang Jianfei , Wang Na , Zhang Yuanyuan , Zhang Yong , Tian Binle , Jia Xuebing 
Published: April 2023

Abstract
Within the tumor microenvironment (TME), regulatory T (Treg) cells are one attractive cell type for targeting as they play a critical role in immunosuppression. Therapeutic strategies that specifically inhibit tumor-infiltrating Tregs while sparing peripheral and normal tissue Tregs are highly desirable. The tumor-associated Tregs express the chemokine receptor CCR8, which plays a role in the induction, expansion, chemotactic migration, and immunosuppression of tumor-associated Tregs. Thus, targeted inhibition of CCR8 is a potential therapeutic strategy against cancer. We have developed a monoclonal antibody antagonist of CCR8, IPG0521, which potently inhibited the receptor-mediated signaling and chemotaxis in Treg cells with single digital nanomolar IC50. RNA sequencing (RNA-seq)analysis indicated that CCL1-induced up-regulation of immunosuppressive genes, including PD-1, CTLA4, IL-10, TIGIT etc., were reversed by IPG0521 in tumor-derived Treg cells. IPG0521 potently inhibited the growth of multiple tumor types in both syngeinic and immune-humanized mouse models, including lung cancer, liver cancer, breast cancer, via inhibiting Treg and activating CD8+ T cells. These data pave the way for the development of IPG0521, which is under IND filing, as a novel therapeutic agent against cancer.
Citation Format: Guohuang Fan, Jianfei Wang, Na Wang, Yuanyuan Zhang, Yong Zhang, Binle Tian, Xuebing Jia. Development of a CCR8 monoclonal antibody which blocks CCR8 signaling and abolishes the immunosuppressive function of Treg for the treatment of 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 2340.
Abstract 2341: Group 2 innate lymphoid cells influence pancreatic stromal cell composition in homeostasis and pancreatic cancer
Authors: Yip Thomas , Lee Sheng , Stockis Julie , Garcia Celine , Raghunathan Shwetha , Lim Bram , Pinaud Silvain , Png Shaun , Halim Timotheus 
Published: April 2023

Abstract
Background: Group 2 Innate Lymphoid Cells (ILC2s) are tissue-resident innate immune cells critical in orchestrating type-2 immune responses. Cancer-associated fibroblasts are increasingly recognized as having important pro- and anti-tumorigenic roles. While type-2 immunity has been linked to fibrosis and tumor development, how ILC2s influence the stromal microenvironment in these settings is poorly understood. Here, we investigated the role of ILC2s on pancreatic stromal cell (PSC) behavior in healthy and tumor-bearing mice.
Methods: Naive, inflamed, and tumor-bearing pancreata of WT or ILC2-deficient mice were profiled by flow cytometry, histology, or multiplex immunofluorescence imaging. We assessed two-way communication between ILC2s and stromal cells using in silico analysis of single-cell RNAseq or in vitro coculture transcriptomic data. Putative crosstalk mechanisms were tested with in vitro and in vivo assays. Additionally, we performed two-photon microscopy of reporter mice pancreata and multiplex immunofluorescent imaging of tumor sections.
Results: Imaging studies show that ILC2s co-localize with IL-33+ stromal cells in the naïve, inflamed and tumor-bearing pancreas. In vivo and in vitro studies indicate that ILC2s are critical mediators of stromal cell proliferation and density in homeostatic and inflamed conditions, while influencing stromal cell-driven immune modulation in cancer. Single-cell transcriptomic analysis reveal distinct Il33+ and Il33- stromal cell clusters, which may engage in different crosstalk mechanisms with ILC2s, as determined by in silico inferential analysis, in vitro co-culture and in vivo studies.
Conclusion: ILC2s strongly influence stromal cell composition in both the healthy pancreas and pancreatic tumors. Given the importance attributed to the characteristic desmoplasia of pancreatic tumors, ILC2-driven modulation of the stromal compartment may affect tumor progression.
Citation Format: Thomas Yip, Sheng Lee, Julie Stockis, Celine Garcia, Shwetha Raghunathan, Bram Lim, Silvain Pinaud, Shaun Png, Timotheus Halim. Group 2 innate lymphoid cells influence pancreatic stromal cell composition in homeostasis and 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 2341.
Abstract 2386: Label free imaging for rapid assessment of tumor viability in live tumor fragments
Authors: Ouellette Jonathan , Wargowski Ellen , Wait Eric , Zahm Chris , Johnson Scott , Oliner Jon 
Published: April 2023

Abstract
Live tumor fragments (LTF) that maintain a patient's relevant tumor microenvironment provides an opportunity to study treatment response. To verify viability of the fragments over time, we have devised and applied a label-free quantitative microscopy-based approach to monitor LTF health. This method directly assesses intrinsic fluorescence from metabolic co-factors and allows the spatial and temporal visualization of cell status. Using the label-free method of multiphoton fluorescence lifetime microscopy (MP-FLIM), we can assess excised tumor samples over 48 hours to determine the health of individual cells. Specifically, with MP-FLIM, we can analyze signals generated by the intrinsically fluorescent metabolic co-factor NAD(P)H which correlates with mitochondrial outer membrane permeabilization and the irreversible cascades leading to cell death. Our findings using MP-FLIM were confirmed using a standard caspase 3/7 live apoptosis assay. These data demonstrate MP-FLIM can detect and quantify cell viability without the use of potentially toxic dyes, thus enabling longitudinal multi-day studies assessing the effects of therapeutic agents on LTF.
Citation Format: Jonathan Ouellette, Ellen Wargowski, Eric Wait, Chris Zahm, Scott Johnson, Jon Oliner. Label free imaging for rapid assessment of tumor viability in live tumor fragments [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 2386.
Abstract 239: Whole-genome sequencing based homologous recombination deficiency testing for precision oncology of breast cancers
Authors: Kim Ryul , Park Seongyeol , Lim Joonoh , Yi Boram , Koo Jaemo , Lee Sangmoon , Lee Jeong Seok , Park Yeon Hee , Ju Young Seok 
Published: April 2023

Abstract
Breast cancers (BCs) with defects in homologous recombination repair (HRR) pathway depend on the Poly (ADP-ribose) polymerase enzymes (PARP) for their survival and thus are sensitive to PARP inhibitors (PARPi). To screen out BCs with homologous recombination deficiency (HRD), germline mutations in BRCA genes have been tested, which constitute approximately 5% of unselected BC patients. However, a substantial proportion of BCs show HRD phenotypes despite the absence of BRCA inactivating mutations in germline. Herein, we apply whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS) in 332 samples from 325 BC patients for characterizing their HRD phenotypes for PARPi treatments. Of 325 BC patients, 75 cases (23.1%) showed remarkable HRD phenotypes, based on mutational signatures of HRR abrogation. Intriguingly, 51 cases do not harbor any germline mutations in HR-related genes including BRCA1 and BRCA2. The whole-genome portrait of these samples was similar to that of HRD-positive BCs with germline mutation in HRR pathway, but showed markedly distinctive features from HRD-negative BCs. With a notable exception of BRCA1, the second most common somatic mutation in HRD-positive BCs without germline mutation, the mutational landscape of the whole study samples was primarily determined by hormone receptor and HER2 positivity, not by HRD status. Likewise, WTS-based clusters determined in an unsupervised manner were highly dependent on the histological subtype of BC, not on HRD status or germline mutations in the HRR pathway. Notably, differentially expressed gene and gene set enrichment analysis revealed that HRD-positive BCs had an increased inflammatory activity compared to BCs with proficient HR. Overall, our analysis demonstrate that WGS enables better classification of the HR status in BC than conventional BRCA germline testing, suggesting WGS as a rapid and sensitive tool for screening breast cancers for PARPi treatment.
Citation Format: Ryul Kim, Seongyeol Park, Joonoh Lim, Boram Yi, Jaemo Koo, Sangmoon Lee, Jeong Seok Lee, Yeon Hee Park, Young Seok Ju. Whole-genome sequencing based homologous recombination deficiency testing for precision oncology of breast cancers [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 239.