bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1966: Cell proliferation-related pathway scores (G2M Checkpoint, E2F Targets, MYC Targets V1 and V2, Mitotic Spindle, p53 pathway) as predictive and prognostic biomarkers in pancreatic cancer
Authors: Oshi Masanori , Le Lan , Tokumaru Yoshihisa , Yan Li , Matsuyama Ryusei , Endo Itaru , Takabe Kazuaki 
Published: July 2021

Abstract
Background: Given the poor survival and severe side effects of treatments for pancreatic cancer, we need prognostic and predictive biomarkers to guide management. We hypothesized that the cell proliferation-related pathway is associated with drug response and survival in pancreatic cancer.
Methods: We studied six hallmark cell proliferation-related gene sets (G2M Checkpoint, E2F Targets, MYC Targets V1 and V2, Mitotic Spindle, p53 pathway) defined by MSigDB in gene set variant analysis (GSVA) was evaluated in 3 independent cohorts, TCGA-PDAC (n = 176), GSE57495 (n = 63), and GSE62452 (n = 69).
Results: We found that although G2M and E2F correlated strongly with each other (spearman's r = 0.976), Mitotic and p53 pathway scores correlated highly with the other cell function gene sets. All pathways were significantly associated with high expression of MKI67 and with proliferation score (all p &gt; 0.001), but none with pathologically complete resection (R0). Mitotic Spindle pathway alone associated with high cytolytic activity (p = 0.020). All pathways were significantly associated with high expression of KRAS and TP53 genes and with high rate of KRAS gene alteration except for MYC v1. The G2M, E2F, and p53 pathway were significantly associated with a high rate of TP53 gene alteration (p = 0.026, 0.011, and 0.07, respectively). Interestingly, different pathway correlated with AUC of different agents, such as Gemcitabine (Mitotic: r=0.706 [p = 0.01]), Paclitaxel (MYC v2: r = -0.636 [p &lt; 0.05]), Apatinib (Mitotic: r = -0.556 [p = 0.03]), Palbociclib (E2F: r =0.675 [p &lt; 0.01]), and Sorafenib (G2M: r = -0.593 [p = 0.03]), for pancreatic cancer. Among all six pathways, only G2M was significantly associated with worse patient survival consistently in all 3 cohorts.
Conclusion: Each proliferation-related pathway was predictive of unique agent, and G2M score predicts survival of pancreatic cancer.
Citation Format: Masanori Oshi, Lan Le, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo, Kazuaki Takabe. Cell proliferation-related pathway scores (G2M Checkpoint, E2F Targets, MYC Targets V1 and V2, Mitotic Spindle, p53 pathway) as predictive and prognostic biomarkers in pancreatic cancer [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 1966.
Abstract 2044: Genomic scar score: a robust model to predict recombination repair deficient based on genomic instability
Authors: Wen Hao , Yang Shuang , Chen Xuejun , Weng Ying , Zhu Changbin , Ruan Li , Dong Hua , Wu Xiaohua 
Published: July 2021

Abstract
Background: Clinical benefit of PARP inhibitors or Platinum-based chemotherapy has been observed and well proved in BRCA mutation patients. However, there are other mechanisms to induce recombination repair deficient (HRD), such as BRCA methylation, ATM expression loss; HRR gene mutation in addition to BRCA mutation. Whether these complicated HRD events or phenotype could be measured by a unified model to accurately identify HRD positive patients is important.
Methods: In this study, we use support vector machine method to build genomic scar (GS) model to predict HRD events, which takes different types of chromosomal copy number into consideration to evaluate genomic instability. The accuracy of GS model was tested by different NGS platform from WGS to two captured SNP Panel. GS status association with Cisplatin-based chemotherapy was also preliminarily validated.
Results: GS model displayed more than 95% accuracy to detect BRCA-ness events and is also able to enrich different types of HRR dysfunction, such as HRR-related mutation or BRCA1 promoter methylation. Moreover, GS model can identify patient benefits from Cisplatin-based chemotherapy, and GS score (GSS) high group had longer progression free survival (PFS) than GSS low group (11 vs 8.5 months, HR=0.5, P=0.05). Meanwhile, GSS showed the high concordance among different NGS platform including WGS; two captured SNP Panels, which implied the high robustness of GS model.
Conclusion: GS was a robust model to predict HRD and had the clinical potential to enrich patients who will response to PARP inhibitors and/or Platinum-based chemotherapy.
Citation Format: Hao Wen, Shuang Yang, Xuejun Chen, Ying Weng, Changbin Zhu, Li Ruan, Hua Dong, Xiaohua Wu. Genomic scar score: a robust model to predict recombination repair deficient based on genomic instability [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 2044.
Abstract 2099: EM-seq enables accurate and precise methylome analysis of challenging DNA samples
Authors: Ponnaluri V K Chaithanya , Williams Louise , Campbell Matthew A. , Panchapakesa Vaishnavi , Vaisvila Romualdas , Langhorst Bradley , Dimalanta Eileen , Davis Theodore B. 
Published: July 2021

Abstract
DNA isolated from blood draws (cell-free DNA (cfDNA)) or from archival material like formalin fixed paraffin embedded (FFPE) tissues have advanced the field of cancer genetics. DNA methylation (5-methylcytosines (5mC) and 5-hydroxymethylcytosines (5hmC)) is a key epigenetic factor that plays an important role in cellular processes and it's misregulation results in diseased states like cancer. Advances in the field of sample preparation from biological matrices and genomics have enabled cancer biomarker identification based on methylation profiling. Bisulfite sequencing has been the gold standard for detection of methylation and is employed for both targeted and whole genome methylation analysis. However, the chemical based bisulfite conversion of cytosines to uracils leads to DNA damage which subsequently translates to shorter DNA insert sizes as well as biases in the data. DNA obtained from cfDNA and FFPE samples is typically of low quality and quantity making DNA methylation profiling using the harsh bisulfite conversion challenging. Robust biomarker detection relies primarily on the ability to profile methylation accurately. To overcome the drawbacks of bisulfite sequencing, we developed an enzyme based methylation detection technology, called NEBNext® Enzymatic Methyl-Seq (EM-Seq™), that minimizes damage to DNA enabling longer insert sizes, lower duplication rates and minimal GC bias resulting in more accurate quantification of methylation in the sample DNA. Using EM-Seq, we profiled cfDNA and lung FFPE DNA. Results for these challenging DNA types showed that the EM-Seq libraries had longer inserts, lower duplication rates, higher percentages of mapped reads and less GC bias compared to WGBS libraries. EM-seq libraries also identified a higher number of CpG's with even coverage facilitating accurate methylation calling. In conclusion, EM-Seq libraries have superior sequencing metrics resulting in robust methylation profiling for these types of challenging DNA samples.
Citation Format: V K Chaithanya Ponnaluri, Louise Williams, Matthew A. Campbell, Vaishnavi Panchapakesa, Romualdas Vaisvila, Bradley Langhorst, Eileen Dimalanta, Theodore B. Davis. EM-seq enables accurate and precise methylome analysis of challenging DNA samples [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 2099.
Abstract 2112: Epigenetic control of heparanase expression using CRISPR/dCas9
Authors: Chen Zixin , Zeng Guihua , Li Xiaogang , Liang Fu-Sen , Cui Lina 
Published: July 2021

Abstract
Heparanase (HPSE) is the only known enzyme that cleaves the polymeric heparan sulfate (HS), a key component of the extracellular matrix (ECM). Heparanase has been implicated in various pathophysiological conditions involving ECM remodeling, such as tumor progression, metastasis angiogenesis, and inflammation. To study the role of heparanase in diseases, we developed a strategy to epigenetically modulate its expression in cells based on the clustered regularly interspaced short palindromic repeats (CRISPR) system. A fusion protein of dCAS9 can be directed to the HPSE gene via one or a combination of single guide RNAs. By linking dCas9 with different histone modification enzymes (eg. P300, hHDAC3, LSD1), the expression of heparanase can be up- or down-regulated through histone acetylation, deacetylation and demethylation. This approach allows us to tune heparanase expression in various cell lines on demand, enabling the study of heparanase activity in real-time. This work will also lead to novel therapeutics targeting heparanase.
Citation Format: Zixin Chen, Guihua Zeng, Xiaogang Li, Fu-Sen Liang, Lina Cui. Epigenetic control of heparanase expression using CRISPR/dCas9 [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 2112.
Abstract 2161: A transcriptomic signature for measuring YAP1 activity in patient samples and tumor models
Authors: Spanakis Emmanuel , Calvet Loreley , Santos Odette Dos , Dib Colette , Sidhu Sukhvinder , Moll Jurgen , Debussche Laurent , Pollard Jack , Valtingojer Iris 
Published: July 2021

Abstract
Over the past years, the HIPPO tumor suppressor pathway and its downstream effector Yes1-associated transcriptional regulator (YAP1) present increasing interest in cancer research. The YAP1-TEAD complex regulates transcription for cell proliferation, survival, plasticity, and migration. Aberrant activation of YAP1 has been reported for multiple different cancer types. To estimate the proportion of cases where YAP1/TEAD-dependent transcription may be responsible for tumor development or evolution and evaluate the pharmacodynamics of novel TEAD-inhibitors, we have identified a transcriptional signature of YAP1 activity. The signature comprises 500 genes, positive and negative downstream effectors at about equal proportions, selected by differential expression analyses from 10 published datasets reporting, in total, 19 YAP1-activation and 18 YAP1-inhibition experiments. YAP1/TEAD-dependent transcription was scored in single samples as the difference Rp - Rn, where Rp is the mean fractional rank of the positive YAP1-effectors, and Rn, that of the negative effectors. We so scored, and called, YAP1 activation in normal tissues (GTEx collection; N~9000), in primary, recurrent, or metastatic tumors (TCGA; N~10000), and in cell lines (CCLE; N~1000) for the selection of models. We further applied the signature to follow the degree of YAP1 inhibition in cell and tumor models either after genetic knockdown of HIPPO-YAP1 pathway components or by pharmacologic inhibition using small-molecule TEAD-inhibitors. Our data confirm the robustness of the YAP1-transcription signature as a biomarker for both, tumor indication selection and pharmacodynamics of YAP1-TEAD activity.
Citation Format: Emmanuel Spanakis, Loreley Calvet, Odette Dos Santos, Colette Dib, Sukhvinder Sidhu, Jurgen Moll, Laurent Debussche, Jack Pollard, Iris Valtingojer. A transcriptomic signature for measuring YAP1 activity in patient samples and tumor models [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 2161.
Abstract 2413: POLE gene mutations in African Americans colorectal cancer
Authors: Brim Hassan , Shokrani Babak , Azimi Hamed , Varma Sudhir , Lee Edward , Ashktorab Hassan 
Published: July 2021

Abstract
Background: Most focus in genetic instability in colon carcinogenic transformation was on DNA Mismatch Repair (MMR) genes alterations as they relate to the microsatellite instability phenotype. However, POLE gene mutations can also be instrumental in triggering genetic instability, at even higher magnitude of genome mutation rate.
Aim: To assess POLE gene mutations in African Americans with colorectal cancer (CRC).
Methods: Data from Whole exome sequencing of 12 CRC African American tumors was searched to scan POLE gene mutations. All detected mutations were checked in tumors and matched normal. The detected mutations were validated in a second set of samples that were sequenced using POLE gene targeted sequencing. Detected and validated mutations were checked in available databases such as COSMIC and dbSNP to determine novel mutations in our population that is at high risk of aggressive CRC.
Results: Six out of 12 patients (50%) displayed mutations in POLE gene. There were 41 detected mutations, 11 are novel mutations and 15 are amino-acid changing. Nine of these were non-synonymous and predicted to have deleterious effects. All these mutations were validated using targeted sequencing. In comparison to DNA MMR, POLE gene has four folds more mutations than MSH2gne (10 mutations and MSH6 (11 mutations and two fold more than MSH3 gene (20 mutations) in the same set of 12 cancer/matched normals. The POLE mutations heterozygous/homozygous status was overall similar in normal and matched normal. However, most of the mutations were homozygous.
Conclusion: POLE gene mutations are increasingly recognized as another important element in genetic instability. Our data shows that mutations affecting this gene are likely more significant than those affecting DNA MMR genes. Moreover, POLE mutations might be more consequential, especially those affecting its exonuclease domain of polymerase epsilon, proofreading catalytic subunit. Microsatellite-stable, hypermutated CRCs might need to be explored for POLE gene mutations to track the origin of high mutation rates.
Citation Format: Hassan Brim, Babak Shokrani, Hamed Azimi, Sudhir Varma, Edward Lee, Hassan Ashktorab. POLE gene mutations in African Americans colorectal cancer [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 2413.
Abstract 2425: Prevalence of NTRK fusions and clinico-pathological characteristics of Middle Eastern papillary thyroid cancer revealed enrichment in BRAF wild-type PTC
Authors: Siraj Abdul K. , Bu Rong , Parvathareddy Sandeep K. , Kong Yan , Annaiyappanaidu Padmanaban , Ahmed Saeeda O. , Al-Rasheed Maha , Al-Kuraya Khawla S. 
Published: July 2021

Abstract
Fusions involving neurotrophic tyrosine receptor kinase (NTRK) are known oncogenic drivers in a broad range of tumor types. It recently gained attention as predictor of targeted therapy, since selective NTRK inhibitor are now approved in US and Europe for patients with solid tumor harboring gene fusions. However, estimation of NTRK gene fusion/alteration frequency and its clinico-pathological characteristics in papillary thyroid cancer (PTC) is limited, especially in a population with high incidence for PTC like Middle Eastern population. This study aims to characterize the NTRK gene fusion frequency using FISH analysis and investigate the utility of pan-Trk immunohistochemistry as predictor of NTRK fusion in a large cohort of Middle Eastern PTC. FISH analysis for NTRK gene fusions as well as immunohistochemical (IHC) staining was conducted on a cohort of 315 Middle Eastern PTC. Correlation of NTRK with clinico-pathological markers and patient outcome were determined. 6.0% (19/315) patients were identified with NTRK gene fusions and significantly associated with pediatric PTC, lymph node metastasis and BRAF wild-type. Pan-Trk IHC was positive in 9.2% (29/315) and significantly associated with NTRK gene fusion with a sensitivity of 73.7% and specificity of 94.9% in this cohort. In conclusion, this study confirms the presence of NTRK fusions in Middle Eastern PTC and mostly enriched in BRAF wild-type and pediatric age group and propose the usefulness of IHC to screen for PTC patients with NTRK fusion that might benefit from TRK inhibitors.
Citation Format: Abdul K. Siraj, Rong Bu, Sandeep K. Parvathareddy, Yan Kong, Padmanaban Annaiyappanaidu, Saeeda O. Ahmed, Maha Al-Rasheed, Khawla S. Al-Kuraya. Prevalence of NTRK fusions and clinico-pathological characteristics of Middle Eastern papillary thyroid cancer revealed enrichment in BRAF wild-type PTC [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 2425.
Abstract 2568: Use of kinase inhibitors in Fanconi anemia oral cancercell lines
Authors: Jungbauer Walter N. , Ali Mustafa M. , Wuertz Beverly R. , Ondrey Frank G. 
Published: July 2021

Abstract
Successful Fanconi anemia (FA) treatment allows greater longevity for these patients. However, there is a greatly increased risk of squamous malignancies of the head and neck which are quite deadly in these young patients. There is an unmet need for non DNA damaging therapies for this malignancy which could augment surgery. Our approach has been to examine potential treatments based on known pathophysiology of the disease which would be acceptable for this population so we examined the effects of metformin and pioglitazone, as well as two cell cycle kinase inhibitors, in FA and leukoplakia cell lines. We examined dose-dependent and combination effects on cell proliferation, as judged by MTT assay. We examined metformin, pioglitazone, the polo-like kinase 1 inhibitor, GSK461364, and Wee1 kinase inhibitor, AZD1775.In single agent studies, we observed dose-dependent decreases in cell proliferation with all 4 single agents. We observed decreased cell proliferation in all cell lines at 72 hours at clinically achievable serum levels of 85% to 55% of control levels (P&lt;0.0001). Additionally, we found decreases beyond single agent treatment levels when cells were treated with metformin combined with GSK461364 or AZD1775 and similarly, with combination therapies of pioglitazone and GSK461364 or AZD1775. Our current data demonstrate feasibility and preclinical efficacy of a combined agent approach for FA associated head and neck cancer. The low reported toxicity of these agents clinically allows for all of these agents to potentially move forward clinically, once additional experiments are conducted in mechanistic and animal studies.
Citation Format: Walter N. Jungbauer, Mustafa M. Ali, Beverly R. Wuertz, Frank G. Ondrey. Use of kinase inhibitors in Fanconi anemia oral cancercell lines [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 2568.
Abstract 2630: Meta-analysis of pazopanib and trabectedin in 2L+ metastatic synovial sarcoma (2L+ mSS)
Authors: Carroll Charlotte , Patel Nashita , Gunsoy Necdet B. , Parks Dan , Stirnadel-Farrant Heide A. , Pokras Shibani 
Published: July 2021

Abstract
Background: Pazopanib (P) and trabectedin (T) are approved targeted treatments for metastatic soft tissue sarcoma (mSTS). Our objective was to evaluate the efficacy (from clinical trials [CT]) and effectiveness (from real-world studies [RW]) of P and T in second line (2L+) mSS.
Methods: This meta-analysis included all English language studies assessing P or T efficacy/effectiveness in patients with 2L+ mSS, 1999 onwards, identified by a systematic literature review. Outcomes were overall response rate (ORR) representing the proportion of patients who have achieved CR or PR during the study and median overall survival (mOS) in months (mos) from start of study medication. Proportions from studies were pooled using generalized linear mixed models to account for small sample sizes, zero events and random site effects. Medians were combined using the weighted median of the medians method with 95% confidence intervals from an inverted sign test.
Results: 16 studies with 405 patients with 2L+ mSS met the inclusion criteria. Response was measured variably across studies (CT: RECIST v1.0, v1.1; RW: modified RECIST or clinician assessment). ORR estimates were higher in RW than CTs (Table). OS results were consistent across CTs and RW (Table).
Conclusions: This is the first study to provide estimates for patients with mSS in the 2L+ setting, distinct from mSTS and pool outcomes of targeted therapies. RW estimates of ORR for both treatments were higher than those observed in trials likely due to variable definition of response and in underlying prognostic factors. mOS was consistent across both types of studies and was similar to mOS seen on placebo (10.7 mos in PALETTE study) suggesting a high unmet need in this population.
Funding: GSK (213368).
Outcomes with pazopanib (P) and trabectedin (T) in clinical trials (CT) and real-world (RW) studiesPTP & T pooledORR-ALL (%)N=6, n=96, 18.9 (8.5, 41.8)N=7, n=162, 12.3 (8.0, 18.9)N=13, n=258, 14.7 (9.2, 23.4)ORR-CT (%)N=1, n=38, 13.2 (2.4, 23.9)†N=3, n=57, 7.0 (2.7, 18.1)N=4, n=95, 9.5 (5.1, 17.6)ORR-RW (%)N=5, n=58, 20.2 (7.4, 54.8)N=4, n=105, 15.2 (9.7, 23.9)N=9, n=163, 17.7 (9.9, 31.5)mOS-ALL (mos)N=4, n=96, 10.3 (8.7, 13.8)N=4, n=165, 9.9 (1.5, 13.9)N=8, n=261, 9.9 (9.2, 13.9)mOS-CT (mos)ND*ND*N=3, n=113, 10.3 (8.7, 13.9)mOS-RW (mos)ND*ND*N=5, n=148, 9.9 (9.2, 13.9)*Not done due to small sample size; †results of study since N=1. N=number of studies; n=number of patients. Estimates presented with 95% confidence intervals.
Citation Format: Charlotte Carroll, Nashita Patel, Necdet B. Gunsoy, Dan Parks, Heide A. Stirnadel-Farrant, Shibani Pokras. Meta-analysis of pazopanib and trabectedin in 2L+ metastatic synovial sarcoma (2L+ mSS) [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 2630.