bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6608: High-sensitivity detection of specific ultra low-frequency somatic mutations for minimal residual disease monitoring
Authors: Liu Tong , Bocek Michael , Cherry Patrick , Gorda Shawn , Challacombe Jean , Murphy Derek , Toro Esteban 
Published: April 2023

Abstract
Minimal/Molecular residual disease (MRD) refers to the small number of tumor cells which may remain within a patient after therapeutic intervention. The detection of these remnants and monitoring of their abundance is a promising prognostic marker to identify individuals at risk of recurrence or in need of adjuvant therapy. Due to the low abundance of ctDNA present in samples obtained during remission, MRD assays need to be highly sensitive. In addition, each individual will have a different set of somatic variants, requiring personalized solutions for detection. Therefore, personalized NGS assays with high sensitivity and specificity are needed for MRD diagnostics.
To address this need and empower accurate assessments of MRD, Twist Bioscience has developed the MRD Rapid 500 Panels. This product enables customers to design, manufacture and ship fully personalized MRD panels (up to 500 targets) in as little as six days.
To demonstrate the detection sensitivity of Twist Rapid 500 MRD panels, we designed five custom MRD panels which specifically target somatic variants found in Breast, Lung, CRC, Melanoma and Renal Cell Carcinoma. Each of these MRD panels were designed to include 197 targets, with 3-5 variants per tissue origin and a selection of passenger mutations. To create the sample set, we blended synthetic variant sequences with fragmented cell line gDNA (NA12878) to form a contrived specimen which approximates the profile cell-free and circulating tumor DNA. Five frequency levels were created with average VAFs of 0% (WT), 0.01%, 0.05%, 0.1% and 2%. Libraries were prepared with UMI adapters and target enrichment was performed using the MRD panels.
With a sequencing depth of 80,000x, variant calling results revealed that an average of 20 SNV targets can be detected with confidence in the 0.01% VAF samples for each MRD panel, clearly distinguishable from the WT control samples. In addition to demonstrating the accuracy of variant calling, we showcase the utility of targeting a large number of variants for the detection of an MRD signature at very low levels (e.g. 0.01% VAF).
In summary, the performance of the Twist MRD Rapid 500 Panels showed high detection sensitivity of ultra low-frequency somatic mutations while maintaining high specificity for the purposes of MRD monitoring.
*For Research Use Only. Not for use in diagnostic procedures.
Citation Format: Tong Liu, Michael Bocek, Patrick Cherry, Shawn Gorda, Jean Challacombe, Derek Murphy, Esteban Toro. High-sensitivity detection of specific ultra low-frequency somatic mutations for minimal residual disease monitoring. [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 6608.
Abstract 6609: Detection of rare mutations, copy number variation, and DNA methylation in the same template DNA molecules
Authors: Wang Yuxuan , Douville Christopher , Cohen Joshua , Bettegowda Chetan , Papadopoulos Nick , Kinzler Ken , Vogelstein Bert 
Published: April 2023

Abstract
The analysis of cell-free DNA (cfDNA) from plasma offers great promise for the earlier detection of cancer. At present, changes in DNA sequence, methylation, or copy number are the most sensitive ways to detect the presence of cancer. To increase the sensitivity of such assays, it would be useful to be able evaluate the same template molecules for all these changes. Here we report an approach, called MethylSaferSeqS, that achieves this goal, and can be applied to any standard library preparation method suitable for massively parallel sequencing. The innovative step was to copy both strands of each DNA-barcoded molecule with a primer that allows the subsequent separation of the original strands (retaining their 5-methylcytosine residues) from the copied strands (in which the 5-methylcytosine residues are replaced with unmodified cytosine residues). The original and copied strands are queried for epigenetic and genetic alterations, respectively. We applied this approach to plasma from 265 individuals, including 198 with cancers of the pancreas, ovary, lung or colon, and found the expected patterns of mutations, copy number alterations, and methylation. Furthermore, we could determine which original template DNA molecules were methylated and/or mutated. MethylSaferSeqS should be useful for addressing a variety of questions relating genetics and epigenetics in the future.
Citation Format: Yuxuan Wang, Christopher Douville, Joshua Cohen, Chetan Bettegowda, Nick Papadopoulos, Ken Kinzler, Bert Vogelstein. Detection of rare mutations, copy number variation, and DNA methylation in the same template DNA molecules. [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 6609.
Abstract 665: Repetitive elements and viral mimicry co-evolve with the immune microenvironment in pancreatic ductal adenocarcinoma
Authors: Sun Siyu 
Published: April 2023

Abstract
Overexpression of repetitive RNA is an emerging hallmark of human cancers. These diverse repetitive elements, including SINEs (Short Interspersed Nuclear Elements) and LINEs (Long Interspersed Nuclear Elements), can mimic viruses by replicating in the genome through retrotransposition and displaying pathogen-associated molecular patterns, potentially triggering inflammatory responses. However, our knowledge of how specific repeats affect tumor evolution and shape the tumor immune microenvironment in a pro- or anti-tumorigenic manner remains incomplete. We integrated evolutionary analysis on whole genome and total RNA sequencing data from a unique cohort of multiregion-sampled human primary and metastatic pancreatic ductal adenocarcinoma (PDAC). We find that the more recently evolved SINEs are more likely to form double-strand RNAs (dsRNAs), a structure known to stimulate innate immune response. Consistently, these younger SINEs are highly associated with a RIG-I associated type-I interferon signature. LINE-1 (L1) retrotransposition activity in these samples tracks with tumor phylogenetic branching and is depended on the status of TP53 mutations, supporting active differential surveillance of L1 mobility by mutant TP53 during tumor evolution. Lastly, we discovered that immunostimulatory SINE expression is anti-correlated with both ADAR1 expressions, exonuclease DIS3 expression, and L1 retrotransposons activity, suggesting a cooperative relationship between ADAR1 and L1 activity in regulating immunogenic SINE expression. We propose that pancreatic tumors modulate immunogenic SINE abundance to their pro-tumorigenic inflammatory advantage through hyperactive L1 activity via accelerated exonuclease degradation when ADAR1 is not activated. Our analysis illustrates for the first time the evolutionary role of dark matter genomic repeats in allowing tumors to actively leverage viral-like innate immune responses to manipulate their immune microenvironment for selective advantage.
Citation Format: Siyu Sun. Repetitive elements and viral mimicry co-evolve with the immune microenvironment 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 665.
Abstract 6650: Cell-based assay to support development and characterization of new drugs in immuno-oncology
Authors: Haque Mohammad , Salam Safnas Abdul , McGinley Shawn , Ma Haiching , Wu jianghong 
Published: April 2023

Abstract
The years since 2009 have seen tremendous progress in unlocking the curative potential of the immune system for the treatment of cancer. Much of that revolution in immuno-oncology has been fueled by the clinical success of immune checkpoint inhibitors, targeting cytokines, antibody dependent cell cytotoxicity and complement dependent cytotoxicity via the T cell activation. Reaction biology has established state-of-art high throughput screening procedures for measuring the ability of new Biologics or compounds to activate T cells. Antibody Dependent Cell Cytotoxicity (ADCC), T cell activation assay (NFAT), immune checkpoint inhibitor assay (PD-1/PD-L1 blockade bioassay), cytokines activation assay and Complement Dependent Cytotoxicity (CDC) are commonly used for drug discovery industry. ADCC is a desirable mechanism for killing target cells using antibody-based drugs. T cell activation assay can be used for the discovery and development of novel biologics and cell therapies aimed at inducing, strengthening and/or engineering T cell response. Blocking of immune inhibitory receptors by their respective ligands on an adjacent cell inhibits TCR mediated proliferation, transcriptional activation and cytokines production. Biologics or compounds designed for measuring the stimulatory or inhibitory function of cytokines are promising in the field of immune oncology. Reaction Biology developed biochemical assays for PD-1/PD-L1, CTLA4/CD80 and CTLA4/CD86 to screen immune checkpoint inhibitors. All of these screening procedures and experimental methods will help to identify new therapeutic biologics or compounds for drug discovery in immune-oncology field.
Citation Format: Mohammad Haque, Safnas Abdul Salam, Shawn McGinley, Haiching Ma, jianghong Wu. Cell-based assay to support development and characterization of new drugs in immuno-oncology [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 6650.
Abstract 6666: Multispectral imaging to detect immune phenotypes in pre and post therapy breast cancer patient specimens
Authors: Patel Bhavika , Allen Stephanie , Dennison Brenna , Stapleton Jacob , Archuleta Roni , Rath Mary Lou , Mehra Navi , Talwalkar Sameer S. 
Published: April 2023

Abstract
The immune microenvironment is an important component in cancer therapy. Immune cells can encourage tumor growth, leading to disease progression. A high number of immune cells may be predictive of disease prognosis and response to therapies. Therefore, understanding the immune cell phenotypes present within cancerous tissue can be valuable in developing strategies that aid in the treatment of cancer. In this study, we analyzed pre-and post-therapy samples from breast cancer patients, treated with neoadjuvant chemotherapy, using a 6-plex immunofluorescence assay which included clinically relevant immuno-oncology biomarkers (FoxP3, PD-L1, PanCK, CD4, CD8 and CD163). This assay was developed and optimized in-house prior to testing the cohort. Endpoints for this analysis were characterization of the tumor microenvironment and analysis of the individual immune cell subsets pre and post treatment. Staining was completed on the Leica Bond RX autostainer (Leica Biosystems) and slides were scanned using the PhenoImager™ Fusion (Akoya Biosciences). Using Visiopharm® software, the multiplex phenotyping module was used to analyze the high dimensional human tissue and cell phenotypes were detected using artificial intelligence. Qualitative and quantitative results revealed a change in immune cell phenotypes between pre- and post-therapy samples. These included an increase in intra-tumoral and stromal T cells, no significant difference in PD-L1 positive cells, and an increase in the FOXP3 positive T cells in post-treatment samples. Our data provides insights into the development and application of multispectral imaging for characterization of tumor microenvironment and its dynamics before and after treatment in breast cancer. This can be applied to other cancer types and can aid in making treatment decisions.
Citation Format: Bhavika Patel, Stephanie Allen, Brenna Dennison, Jacob Stapleton, Roni Archuleta, Mary Lou Rath, Navi Mehra, Sameer S. Talwalkar. Multispectral imaging to detect immune phenotypes in pre and post therapy breast cancer patient specimens [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 6666.
Abstract 6787: Vaccinia virus harboring TRAIL (vTRAIL) for in vivo lung cancer therapy
Authors: Yoo So Young 
Published: April 2023

Abstract
While oncolytic virotherapy has shown promising results for uncured patients with cancer, its effects on lung cancer remain unclear. Lung cancer is mostly unlikely to respond to conventional anticancer drug, therefore, oncolytic virotherapy can be the best option. Herein, we evaluated the anti-cancer activity of the previously developed three oncolytic vaccinia viruses encoding TNF-related apoptosis-inducing ligand (TRAIL), angiopoietin 1 (Ang1) and both genes, especially on killing lung cancer (LC). In this study, we confirmed that our engineered vaccinia viruses showed overall higher anti-cancer activity on lung cancer cells, compared to WT. Vaccinia virus engineered with both Ang1 and TRAIL (vTRAN) showed the highest oncolytic activity and selectivity in vitro (WT &lt; vTRAIL &lt; vAng1 &lt; vTRAN). However, In vivo LLC1 murine lung cancer syngeneic model showed highest attenuated tumor growth when vTRAIL was treated (WT &lt; vAng1 &lt; vTRAN &lt; vTRAIL), which was in accordance with CD8 high PD1 low expression levels in the tissues. It concludes that engineered vaccinia virus harboring TRAIL (vTRAIL) is the promising therapeutic option for in vivo lung cancer therapy.
Citation Format: So Young Yoo. Vaccinia virus harboring TRAIL (vTRAIL) for in vivo lung cancer therapy [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 6787.
Abstract 746: Disparities in factors affecting access to palliative care in patients with stage IV breast cancer
Authors: Itani Mira , Sabbagh Saad , Mohanna Mohamed , Dominguez Barbara , Liang Hong , Nahleh Zeina 
Published: April 2023

Abstract
Background: Palliative care is an essential component of cancer care; however, factors hindering its reach to the target population remain understudied. We aim to explore whether an association exists between socioeconomic and geographic factors and access to palliative care (PC) in patients with Stage IV breast cancer in the US.
Methods: This 2004-2017 National Cancer Database analysis includes patients with Stage IV breast cancer who received palliative care. Access to PC is defined as being either at the patient’s primary healthcare facility or at a referral site. Chi-square tests and a multivariate logistic regression were performed to determine the independent factors predicting access to PC. SAS version 9.4 was used to analyze the data.
Results: A total of 18,903 patients were included in the analysis: 15,111 received palliative care services at the same facility and 3,792 were referred elsewhere. Patient age, race, insurance status, Charlson-Deyo score, setting, high school diploma status, median income, facility type, facility location, and distance from healthcare centers were all significantly different between the two groups. On logistic regression, better odds for access to PC were predicted by urban settings (OR: 1.47; 95% CI: 1.30 - 1.67) and being in the Middle Atlantic region (OR: 1.27; 95% CI: 1.07 - 1.52). Distance from the healthcare facility of 4 miles or greater predicted worse odds for access to PC. Comprehensive cancer programs (OR: 1.60; 95% CI: 1.43 - 1.80) and academic/research programs (OR: 2.40; 95% CI: 2.11 - 2.73) held higher odds for access to PC. Having Medicaid/other government insurance (OR: 1.43; 95% CI: 1.24 - 1.65) predicted better odds for access to PC. However, having no insurance was also found to increase access to PC (OR: 1.30; 95% CI: 1.08 - 1.55). Median income and high school diploma status were not significantly associated with the outcome.
Conclusion: PC was positively affected by having access to urban settings, nearby healthcare centers, non-community care centers, Medicaid/other governmental insurance, and by being in the Middle Atlantic region of the US. Having no insurance appears to increase palliative care use, which was unexpected but could be explained if patients with no insurance did not receive standard treatment and were instead offered palliative care. This needs to be investigated in future research.
Citation Format: Mira Itani, Saad Sabbagh, Mohamed Mohanna, Barbara Dominguez, Hong Liang, Zeina Nahleh. Disparities in factors affecting access to palliative care in patients with stage IV 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 746.
Abstract 759: Genome-wide cell-free DNA fragmentation in early detection and disease monitoring of hepatocellular carcinoma
Authors: Lian Shifeng , Fang Fang , Liu Zhiwei , Ji Mingfang , Zheng Zongli 
Published: April 2023

Abstract
Background: Genome-wide cell-free DNA fragmentation profiling was suggested to be useful for early cancer detection. However, it still needed to be evaluated using sample before cancer diagnosis.
Methods: A prospective cohort with hepatitis B virus (HBV)-seropositive participants were enrolled in 2012 and followed-up biannually with blood sample collections till 31 December 2019. A case-control study with hospital hepatocellular carcinoma (HCC) cases were conducted to identify potential biomarkers for HCC detection (Discovery). We adapted the DELFI method (Cristiano et al, Nature, 2019) and evaluated cfDNA fragmentation profile (AdaptDelfi) for detecting HCC at the Discovery phase and validated AdaptDelfi in an independent prospective population cohort (Validation).
Results: Of 18,373 participants, 2,893 were HBV-seropositive and developed 81 incident HCC cases. In Discovery, the AdaptDelfi model distinguished HCC cases from controls excellently (AUC [95% confidence interval] = 0.999 [0.997 - 1.0]), while the serum alpha-fetoprotein (AFP) had an AUC of 0.851 (95% CI = 0.796 - 0.906). High AdaptDelfi was associated with advanced tumor stage (P = 0.038). The hazard of death increased in high AdaptDelfi (hazard ratio 2.43, 95% CI = 1.13 - 5.2) after adjustment for tumor stage. In Validation, AdaptDelfi showed slightly increasing performance using pre-HCC samples collected ≥4 years (AUC = 0.530), 3-4 years (0.615), 2-3 years (0.781), 1-2 years (0.711), and 0-1 year (0.770) before diagnosis. These were comparable with the traditional biomarker - AFP that showed corresponding AUCs of 0.521, 0.525, 0.517, 0.575 and 0.727, respectively. Using a fixed cutoff value from Discovery, AdaptDelfi had a specificity of 88.0% and a sensitivity of 32.5% within one year before diagnosis in detecting early HCC, yielding an estimated positive predict value (PPV) of 1.4% (95% CI = 0.8% - 2.4%) among HBV-seropositive male population.
Conclusions: The genome-wide cell-free DNA fragmentation is correlated with HCC stage and may be a useful biomarker for diagnosing clinical HCC and predict patient survival. However, the low PPV suggests its utility in HCC screening in high-risk populations so far may be limited.
Citation Format: Shifeng Lian, Fang Fang, Zhiwei Liu, Mingfang Ji, Zongli Zheng. Genome-wide cell-free DNA fragmentation in early detection and disease monitoring of hepatocellular 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 759.
Abstract 760: Characteristics of fatty liver disease-related hepatocellular carcinoma and genetic background in Japan
Authors: Kogiso Tomomi , Ogasawara Yuri , Horiuchi Kentaro , Taniai Makiko , Tokushige Katsutoshi 
Published: April 2023

Abstract
Aim: A single nucleotide polymorphism (SNP) in PNPLA3 was identified as a disease susceptibility gene for fatty liver disease (FLD) and it’s associated with fibrosis progression and carcinogenesis. Additionally, mutations in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), which encodes hepatic lipid droplet protein, have been found the involvement in various metabolic processes. Loss-of-function mutations in the human HSD17B13 gene may confer a strong protective effect on liver injury, inflammation, fibrosis, and even onset of hepatocellular carcinoma (HCC). Here, we evaluated the characteristics of Japanese patients with FLD- HCC and considered the risk factors of HCC including genetic background.
Methods: We enrolled 402 patients of clinically and pathologically diagnosed with FLD (alcohol: 63, nonalcohol: 339) in our hospital from 1990-2018 (228 males, median age 54.9 [14.6-83.6] years). We analyzed the survival and new-onset HCC rates according to the etiology of FLD (alcohol and nonalcohol), hepatic fibrosis, FIB-4 index, and genetic background of PNPLA3 and HSD17B13 for consideration of the risk factors.
Results: FLD-HCC was observed in 57 cases (14.2%). Comparing to the patients with HSD17B13 wild-type AA (212 cases) and mutant (A/AA or AA/AA, 190 cases), patients with wild type showed significantly increased HCC complication (wild vs. mutant; 39 [18.4%] vs. 18 [9.5%], p = 0.01) and these were tended to be high complication of hypertension (120 [56.6%] vs. 90 [47.4%], p = 0.06). In patients with mutant of HSD17B13, HCC incidence was significantly reduced in alcohol-related FLD, FIB-4 index &lt;2.67, and PNPLA3 CC genotype, however, there was not significant difference in nonalcohol-FLD. Patients with HSD17B13 mutant showed severe steatosis (77% vs. 88.6%). Eleven cases of new HCC were developed during observation period (8.1 [0.5-25.1] years) (n = 370). Five-year incidence of HCC was 3.3% in patients with both PNPLA3 GG/GC and HSD17B13 wild type and it was significantly elevated compared to other SNP profiles (0.6%, p = 0.03). Multivariate analysis identified the risk of FLD-HCC including age, gender, and complication of hypertension.
Conclusions: Genetic background of FLD may associate with onset of HCC. Inhibiting HSD17B13 activity may prevent HCC development, especially in alcohol-related FLD and patients with low risk factors. Therefore, SNPs of gene combination with other risk factors may use for screening tool for FLD-HCC.
Citation Format: Tomomi Kogiso, Yuri Ogasawara, Kentaro Horiuchi, Makiko Taniai, Katsutoshi Tokushige. Characteristics of fatty liver disease-related hepatocellular carcinoma and genetic background in Japan [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 760.