bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3630: Comprehensive integrated HBV DNA profiling in HCC patients with GGH by HBV-targeted NGS and PacBio sequencing analysis
Authors: Kao Yu-Lan , Su Yih-Ping , Tsai Hung-Wen , Su Ih-Jen , Lin Selena , Song Wei , Su Ying-Hsiu 
Published: September 2020

Abstract
Despite current antiviral therapy success in reducing viral load in patients with chronic hepatitis B virus (HBV), persistent viral surface antigen (HBsAg) remains a risk factor of HCC. Recent evidence has shown that integrated HBV can serve as a source for continued viral antigen expression, despite the lack of detectable replication. Given the oncogenicity of pre-S mutant proteins and its expression in type II ground glass hepatocytes (GGH) even in the absence of viral replication, we assessed the likelihood of GGH as a pre-malignant state as compared to other adjacent-to-tumor non-GGH “normal” tissue by investigating the integrity of integrated HBV DNA. We developed a sensitive HBV-targeted NGS and downstream bioinformatics pipeline, ChimericSeq, to identify HBV-host junctions. A pilot study of 10 HBV-HCC patients, each with six micro-dissected FFPE tissue sections (2 tumor, 2 GGH, 2 HBsAg-negative), was subjected to HBV-targeted NGS and ChimericSeq analysis. We identified integrated HBV DNA in 90% of HCC as well as its matched GGH, and identified PreS2 deletions, for instance, deletion at nt. 43-52. Surprisingly, the recurrent insertional driver mutations of TERT, CCNE1, and ABCC13 integration were detected in 9 of 10 (90%) of this GGH/HCC patient cohort. Next we performed PacBio amplicon sequencing of integrated HBV DNA including Pre-S sequences to comprehensively profile the integrity of the integrated HBV DNA, such as insertional mutations or deletion, and mutations across the different frozen tissue sections (tumor, GGH, HBsAg-negative). Our data suggest that HBV integration of cancer driver genes occurs early during course of infection and integrated DNA evolved over time during carcinogenesis. Overall, a sensitive workflow to comprehensively profile integrated HBV DNA in HCC patients enables further investigation of the role of HBV integration during tumorigenesis.
Citation Format: Yu-Lan Kao, Yih-Ping Su, Hung-Wen Tsai, Ih-Jen Su, Selena Lin, Wei Song, Ying-Hsiu Su. Comprehensive integrated HBV DNA profiling in HCC patients with GGH by HBV-targeted NGS and PacBio sequencing analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3630.
Abstract 3662: FiTAc-seq: Fixed-Tissue ChIP-seq for H3K27Ac profiling and super-enhancer analysis on FFPE tissues
Authors: Font-Tello Alba , Kesten Nikolas , Xie Yingtian , Taing Len , Bellmunt Joaquim , Brown Myles , Cejas Paloma , Long Henry 
Published: September 2020

Abstract
FiTAc-seq is an epigenetic method for profiling of active enhancers and promoters in FFPE clinical samples. The protocol is optimized to generate high-quality H3K27Ac ChIP-seq maps from FFPE macrodissected or cored tissues within 4 days. We previously developed FiT-seq, a modified ChIP-seq protocol for chromatin profiling in FFPE. FiT-seq produces high-quality chromatin profiles particularly for methylated histone marks but is not optimized to resolve H3K27Ac signal. To overcome this limitation, we have modified the tissue homogenization and sonication steps by replacing the proteinase K digestion applied in FiT-seq with extended heating at 65°C in more stringent detergent conditions and minimizing the sonication step. FiTAc-seq produces high-quality genome wide H3K27Ac profiles, and it is suitable to generate enhancer landscapes and super-enhancer annotation. We demonstrate FiTAc-seq applicability for a wide variety of human tumor types, including bladder cancers, breast cancer brain metastasis, melanomas, pancreatic neuroendocrine tumors and seminomas. The unsupervised hierarchical analyses of both enhancer and super-enhancer only H3K27Ac signal clearly identify clusters according to the different tumor types. Moreover, super-enhancer annotation shows lineage-specific transcription factors for the distinct tumor samples. We demonstrate that FiTAc-seq is a robust method suitable for the epigenetic interrogation of archived FFPE clinical samples. The results generated allow the identification of tissue-specific enhancer and SE landscapes, with potential immediate impact on ongoing basic and translational research.
Citation Format: Alba Font-Tello, Nikolas Kesten, Yingtian Xie, Len Taing, Joaquim Bellmunt, Myles Brown, Paloma Cejas, Henry Long. FiTAc-seq: Fixed-Tissue ChIP-seq for H3K27Ac profiling and super-enhancer analysis on FFPE tissues [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3662.
Abstract 3670: Development of cfDNA-based methylation assay for early cancer detections
Authors: Xiang Binggang , Zhao Zhixin , Stevens Maya , Dai Chao , Xie Feng , Wang Xiaohong , Zhou Kemin , Jia Shidong , Du Pan , Yu Jianjun 
Published: September 2020

Abstract
Introduction: DNA methylation is the essential epigenetic mechanism of cell regulation, and one of the earliest signatures in cancer development. Blood-based DNA methylation has been tested for cancer early detection. Several methods have been used for DNA methylation sequencing, which include whole genome bisulfite sequencing (WGBS) and antibody-dependent DNA immunoprecipitation (MeDIP). However, WGBS has known issues of DNA loss and fragmentations, and MeDIP only captures the methylated DNA regions and are biased. Therefore, methods that can accurately quantify DNA methylation status while keeping DNA less damaged and loss are highly needed, especially for liquid biopsy at early cancer stages (due to its low cfDNA amount).
Methods: We developed a probe capture-based cfDNA methylation assay using proprietary in-house developed liquid biopsy NGS platform and DeepSEA software algorithm. Analytic assay validation has been conducted using reference materials with known methylation profiles. Both cell line gDNA with known methylation profiles and plasma cfDNA from patients were used for this methylation study. Methylation profiles, DNA damages, and losses were evaluated and compared. Fragment distribution and copy number variations (CNV) were compared between untreated and treated samples.
Results: In this study, we developed a cfDNA-based methylation assay that measures DNA methylation status and genomic profiling simultaneously. Using both cell line gDNA and plasma cfDNA, the assay detects both methylation change and genomic alterations, including fragment size distribution and CNV in a single test.
Discussion: The successful development of cfDNA methylation assay could help identify cancer at its early stage. It also enables the detection and monitoring of minimal residual disease (MRD) and in obtaining information on therapeutic targets and resistance mechanisms relevant to the management of personalized cancer care.
Citation Format: Binggang Xiang, Zhixin Zhao, Maya Stevens, Chao Dai, Feng Xie, Xiaohong Wang, Kemin Zhou, Shidong Jia, Pan Du, Jianjun Yu. Development of cfDNA-based methylation assay for early cancer detections [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3670.
Abstract 3685: Sustained Ret expression during mammary gland post-lactation induces premature involution and enhances cancer potential
Authors: Vallone Sabrina A. , Solá Martín García , Cardiff Robert D. , Meiss Roberto P. , Chodosh Lewis A. , Shere-Levy Carolina , Kordon Edith C C. , Hynes Nancy E. , Gattelli Albana 
Published: September 2020

Abstract
Loss of normal development is a hallmark of cancer. Thus, understanding the mechanisms of tissue-specific developmental regulation and the changes that occur during tumorigenesis may provide insights of both diagnostic and therapeutic importance. In breast cancer, several members of the receptor tyrosine kinases (RTK) family that are well known to promote aggressive breast cancers also have roles in normal breast. We found that Ret, a RTK member, is normally expressed in the mouse glands in lactation. We determined that inhibition of Ret activity in vivo does not alter lactation, however impacts in the transition to involution. Involution is the period with high inflammation which returns the lactating mammary gland to a quiescent state after weaning. Involution has been well described as a post-lactation stage that drives cancer progression. Ret is overexpressed in about 40% of human breast tumors. Previously, using a doxycycline-inducible transgenic mouse model (Ret/MTB) we determined that chronic expression of Ret is oncogenic in the mammary epithelium. However, the stage of development at which Ret expression results in increase mammary tumor incidence has not been identified. To address this, we used the Ret/MTB system, to conditionally overexpress Ret during discrete periods of mammary gland development. We found that Ret is required for efficient transition to involution. We determined that the induction of Ret in Ret/MTB females promotes the expression of factors that drives involution, including premature Stat3 activation. RNA-seq data in Ret-overexpressing glands is supporting these findings, which were confirmed by several techniques. In addition, sustained expression of Ret during post-lactation enhances cancer potential showing a significant increase in pre-neoplastic lesions, defective milk recycling and disrupting Stat3 signaling. These results demonstrate that Ret deregulation increases cancer potential in post-lactation and might be considered as a prognostic marker for post-partum breast cancer.
Citation Format: Sabrina A. Vallone, Martín García Solá, Robert D. Cardiff, Roberto P. Meiss, Lewis A. Chodosh, Carolina Shere-Levy, Edith C C. Kordon, Nancy E. Hynes, Albana Gattelli. Sustained Ret expression during mammary gland post-lactation induces premature involution and enhances cancer potential [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3685.
Abstract 3691A: Targeting MARK2-HDAC-YAP signaling to overcome paclitaxel resistance in PDAC
Authors: Zeng Yongji , Chen Yuanhong , Dong Jixin 
Published: September 2020

Abstract
Nanoparticle albumin-bound (Nab)-paclitaxel (taxol) combined with gemcitabine has been approved as a first-line chemotherapy for advanced pancreatic ductal adenocarcinoma (PDAC) patients. However, the response rate is still very low due to the occurrence of drug resistance and attempts in reversing the resistance have not been successful in the clinic.
MARK (microtubule affinity-regulating kinase) proteins (MARK1-4) are critical for microtubule dynamics by modulating MAPs (microtubule-associated proteins). They are members of the AMPK/Snf1 family and control cell polarity and asymmetric cell division. Dysregulation of MARKs has also been associated with pathological conditions such as cancer and Alzheimer disease. Several recent studies showed that MARK family members are important regulators of Hippo-YAP (Yes-associated protein) signaling, which is critical in cancer development, drug resistance, and stem cell biology.
Through Phos-tag-based kinome-wide screens, we identified MARK2 as a critical determinant for mitotic progression and paclitaxel chemosensitivity. MARK2 is phosphorylated by cyclin-dependent kinase 1 (CDK1) during paclitaxel-induced mitotic arrest and normal mitosis. MARK2 inhibition did not affect growth under normal conditions, but greatly sensitized PDAC cells to paclitaxel-induced apoptosis. Mechanistically, our findings also suggest that MARK2 controls paclitaxel chemosensitivity by regulating class IIa HDACs (histone deacetylase). MARK2 directly phosphorylates HDAC4 on multiple sites upon paclitaxel treatment. Inhibition (with knockdown or inhibitors) of HDACs significantly enhanced paclitaxel-induced cell death in a MARK2-phosphorylation dependent manner in PDAC cells. MARK2-phosphorylated HDAC4 positively regulates YAP (the transcriptional coactivator of the Hippo pathway) activity and controls expression of YAP target genes induced by paclitaxel. MARK2, class IIa HDACs, and YAP expression levels are upregulated and positively correlated in PDAC patients. Importantly, combination of HDAC inhibition (Vorinostat/SAHA, FDA-approved) and paclitaxel overcomes paclitaxel-resistance in preclinical PDAC animal models. Together, our findings reveal the MARK2-HDAC-YAP axis as a druggable target for overcoming paclitaxel resistance in PDAC.
Citation Format: Yongji Zeng, Yuanhong Chen, Jixin Dong. Targeting MARK2-HDAC-YAP signaling to overcome paclitaxel resistance in PDAC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3691A.
Abstract 3721: Relationship between insulin resistance and chemosensitivity of high grade bone sarcoma
Authors: Boudou-Rouquette Pascaline , Gataa Ithar , De Percin Sixtine , Tlemsani Camille , Biau David , Dumaine Valerie , Audard Virginie , Larousserie Frédérique , Anract Philippe , Jouinot Anne , Goldwasser François 
Published: September 2020

Abstract
Background: Neoadjuvant chemotherapy with intercalated surgery is the standard of care for resectable high-grade bone sarcoma (BS) but identification of biomarkers for chemosensitivity prediction is still needed. Insulin-like Growth Factor (IGF) pathway was first linked with sarcoma biology approximately 30 years ago (El-Brady OM, 1990).
Methods: We recruited 138 pts with newly diagnosed primary localized or metastatic BS. We measured fasting blood glucose and insulin, body mass index (BMI). The HOMA-IR (Homeostasis Model Assessment) score ((Glucose (mmol/l) x Insulin) / 22.5), which has been proven to reliably detect insulin resistance IR was calculated, and patients with HOMA-IR &gt; 2.6 were considered as IR. We collected characteristics usually associated with insulin resistance: age, obesity, diabetes, dyslipidemia and hypertension.
Results: Out of 138 pts, 50 (36%) were insulin resistant: HOMA-IR &gt;2.6. Thirty-two IR patients (64%) had no cardiovascular risk factor. In univariate analysis, IR was associated with obesity (BMI &gt; 30 kg/m2)(22% vs 3%, p=0.0015), but not with age (median 36,8 vs 41 years, p=0.19). IR was more prevalent in Ewing sarcoma (14/29; 48%) and chondrosarcoma (7/16; 44%) followed by osteosarcoma (25/67; 37%) and other rare bone sarcomas (4/26; 15.3%), but not significantly (p=0.097). After neoadjuvant chemotherapy and surgery of Ewing tumor and osteosarcoma, pathologic tumor necrosis was higher in IR pts (88.9 vs 75%, p= 0.028).
Conclusion: Our results suggest that metabolic profile may help to discriminate best candidates for neoadjuvant chemotherapy in high-grade bone sarcomas. Further studies are needed to confirm and explain these results.
Citation Format: Pascaline Boudou-Rouquette, Ithar Gataa, Sixtine De Percin, Camille Tlemsani, David Biau, Valerie Dumaine, Virginie Audard, Frédérique Larousserie, Philippe Anract, Anne Jouinot, François Goldwasser. Relationship between insulin resistance and chemosensitivity of high grade bone sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3721.
Abstract 3732: Characterization of tumor relevant isocitrate dehydrogenase 1 (IDH1)
Authors: Coleman Nalani J. , Thornberg Ella , Caliger Danielle , Luna Lucas , Sohl Christal D. 
Published: September 2020

Abstract
Isocitrate dehydrogenase 1 (IDH1) is found commonly mutated in grade II and III gliomas and secondary glioblastomas. Normally, IDH1 catalyzes the conversion of isocitrate and NADP+ to α-ketoglutarate and NADPH. However, in mutated form, IDH1 catalyzes α-ketoglutarate and NADPH into NADP+ and D-2-hydroxyglutarate, an oncometabolite. D-2-hydroxyglutarate is toxic to cells and drives a number of pro-tumorigenic pathways. To understand the molecular mechanisms of how mutated IDH1 can lead to brain cancer, we created point mutations in IDH1 to understand the effects on enzyme activity. Site-directed mutagenesis was used to generate mutations at residue 132, the most common site of mutations in cancer patients. Wild type (WT) IDH1 and mutant IDH1 were heterologously expressed in bacteria . Following purification using affinity column chromatography, steady-state kinetic assays were used to compare the catalytic activity of WT versus mutant IDH1. By elucidating the types of mutations at R132 that facilitate D2HG production, we can have a better understanding of how IDH1 mutations affect prognosis and therapeutic response.
This work was funded by a Research Scholar Grant, RSG-19-075-01-TBE, from the American Cancer Society (CDS), National Institutes of Health R00 CA187594 (CDS), National Institutes of Health U54CA132384 (SDSU) & U54CA132379 (UC San Diego), MARC 5T34GM008303 (SDSU), and IMSD 5R25GM058906 (SDSU), and the California Metabolic Research Foundation (SDSU).
Citation Format: Nalani J. Coleman, Ella Thornberg, Danielle Caliger, Lucas Luna, Christal D. Sohl. Characterization of tumor relevant isocitrate dehydrogenase 1 (IDH1) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3732.
Abstract 3748: Tyrosine kinase inhibition of fibroblast growth factor receptor 1 in advanced prostate cancer
Authors: Bengtsson Louise Medina , Labanca Estefania , Navone Nora 
Published: September 2020

Abstract
Advanced prostate cancer (PCa) is one of the leading causes of cancer death in men in the United States. The FGF/FGFR1 signaling axis has been implicated in the progression of PCa. Different isoforms of FGFR1 have been described in PCa (e.g., alpha and beta), which might account for the typical heterogeneity of PCa. The isoforms may also mediate different clinical responses to treatments targeting this pathway. Pan-FGFR tyrosine kinase inhibitor JNJ-42756493 (Janssen) has been demonstrated to have antiproliferative effects in FGFR pathway-activated cancer cell lines and in vivo mouse antitumor activity. Our goal was to study the effects of JNJ-42756493 in PCa growth and signaling in vitro and establish whether these effects differ according to the FGFR1 isoform (alpha or beta) expressed. Using transfected bone-derived PCa cell lines and patient-derived xenografts (PDXs), we measured the effects of FGFR1 expression on cell proliferation and activation of the FGFR1-pMAPK signaling pathway. We then performed drug treatment experiments on FGFR1-expressing sublines and high-FGFR1 PDXs and observed the response in FGFR1-pMAPK signaling pathway activation. Our results showed that FGFR1 isoforms alpha and beta trigger different biological effects (i.e., proliferation), possibly contributing to the heterogeneity of PCa. We found that targeting the tyrosine kinase domain of FGFR1 with JNJ-42756493 results in pMAPK inhibition in PCa sublines. These findings indicate that the presence of specific FGFR1 variants should be considered for treatment selection in advanced PCa. The results also suggest that FGFR1-pMAPK pathway blockade by JNJ-42756493 should be further studied as a strategy to guide the development of therapies to hinder PCa progression.
Citation Format: Louise Medina Bengtsson, Estefania Labanca, Nora Navone. Tyrosine kinase inhibition of fibroblast growth factor receptor 1 in advanced prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3748.
Abstract 3750: STEAP2 is upregulated and necessary for hepatocellular carcinoma progression via increased copper levels and stress-activated MAP kinase activity
Authors: Zeballos Carla R. , Easley Acarizia , Bouamar Hakim , Zheng Guixi , Gu Xiang , Junhua Yang , Chen Yidong , Cigarroa Francisco , Sun LuZhe 
Published: September 2020

Abstract
To understand potential molecular mechanisms that drive hepatocellular carcinoma (HCC) progression, we performed RNA sequencing from paired adjacent non-tumor liver and HCC tumor tissues of nine local HCC patients which revealed significant involvement of a gene coding for Six Transmembrane Epithelial Antigen of Prostate 2 (STEAP2) protein. STEAP2 is a metalloreductase involved in the reduction and indirectly, uptake, of iron and copper ions. We found significantly higher levels of total copper in HCC tissues than those in paired adjacent non-tumor tissues. The upregulation of STEAP2 expression in HCC was confirmed at its protein level and in TCGA and other published HCC gene expression datasets. Hepatic copper overload is associated with Wilson's disease and a known risk factor for HCC, therefore, we hypothesize that STEAP2 upregulation and copper accumulation contribute to HCC progression.
Paired HCC and adjacent non-tumor tissues were collected for RNA sequencing, metal ion measurement, and measurements of STEAP2 levels with RT-qPCR and Western blot. Public HCC datasets were queried for STEAP2 expression in HCC and non-tumor tissues. HCC cell lines with knockdown (KD) and overexpression (OE) of STEAP2 were created to perform mechanistic studies including measurements of copper levels and MAP kinase activities, cell proliferation, migration, and anchorage independent growth in vitro and tumor growth in vivo.
STEAP2 is significantly upregulated in various HCC gene expression datasets; its expression is positively associated with tumor grade. STEAP2 KD in HCC cell lines decreased cell growth, migration, invasion, and xenograft tumor growth, while STEAP2 OE showed opposite effects. STEAP2 KD in HCC cells also reduced intracellular copper levels and activation of stress-activated MAP kinases including p38 and JNK. Treatment with copper rescued the reduced HCC cell migration due to STEATP2 KD and activated p38 and JNK. Furthermore, treatment with p38 or JNK inhibitors significantly inhibited cell migration. Thus, STEAP2 appears to play a malignant-promoting role in HCC cells by driving migration/invasion via increased copper levels and MAP kinase activities. Our study uncovered a novel molecular mechanism contributing to HCC malignancy and a potential therapeutic target for HCC treatment.
Citation Format: Carla R. Zeballos, Acarizia Easley, Hakim Bouamar, Guixi Zheng, Xiang Gu, Yang Junhua, Yidong Chen, Francisco Cigarroa, LuZhe Sun. STEAP2 is upregulated and necessary for hepatocellular carcinoma progression via increased copper levels and stress-activated MAP kinase activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3750.