bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 405: The role of GALNT14 in chemoresistant and metastatic osteosarcoma
Authors: Prudowsky Zachary D. , Patel Tajhal , Rajapakshe Kimal , Coarfa Christian , Shuck Ryan , Rainusso Nino , Yustein Jason 
Published: July 2021

Abstract
Introduction: Osteosarcoma is the most common bone tumor in children and adolescents. Many patients have disease progression through standard chemotherapy regimens of methotrexate, cisplatin, and doxorubicin. Presently, there are no salvage therapies that have added significant survival benefits, leaving minimal options for relapsed and resistant disease. Additionally, there are no clinically significant biomarkers for this disease that would predict treatment failures. N-acetylgalactosaminyltransferase 14 (GALNT14) is an enzyme that initiates O-linked glycosylation to outer membrane-bound and extracellular proteins. Using transcriptomic analyses, we identified GALNT14 overexpression correlated with poor tumor necrosis and survival outcomes. Therefore, we hypothesize that GALNT14 contributes to metastatic and chemoresistant phenotypes in pediatric osteosarcoma.
Methods: Transcriptomic data from the Therapeutically Applicable Research for Generating Effective Treatments (TARGET) database and RNA-sequencing of institutional patient-derived xenografts (PDXs) revealed that overexpression of GALNT14 correlated to poor necrosis rates. Gene Set Enrichment Analysis (GSEA) also identified upregulation of glycosylation pathways. Aberrant expression of GALNT14 was confirmed using quantitative polymerase chain reaction (qPCR) and Western blot analyses in various osteosarcoma cell lines. Transient GALNT14 knockdown and overexpression were then analyzed for effects on proliferation, invasion, migration, and chemotherapy response in vitro. Kaplan-Meier curves demonstrating overall survival (OS) and event-free survival (EFS) were established using data from the TARGET database.
Results: GALNT14 expression was higher in both commercial and PDX cell lines that were known to be more prone for chemoresistance and invasiveness. The highest quartile of patients based on GALNT14 overexpression had 40% OS and 25% EFS, compared to 80% (p=0.002) and 75% (p&lt;0.001) for the lowest quartile of expression, respectively.
Summary: GALNT14 shows promise as a predictive marker of chemoresistance and metastasis for pediatric osteosarcoma. Future functional genomic studies through gain and loss-of-function assays will evaluate the role of GALNT14 in osteosarcoma chemoresistance and metastatic potential.
Citation Format: Zachary D. Prudowsky, Tajhal Patel, Kimal Rajapakshe, Christian Coarfa, Ryan Shuck, Nino Rainusso, Jason Yustein. The role of GALNT14 in chemoresistant and metastatic osteosarcoma [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 405.
Abstract 407: Belantamab Mafodotin detection by protein electrophoresis: Assessing interference for defining clinical response
Authors: McClure Fiona J. 
Published: July 2021

Abstract
Multiple Myeloma (MM) is a life threatening incurable cancer of the bone marrow resulting in plasma cell expansion and over production of plasma proteins or ‘M' proteins. Belantamab Mafodotin (Belamaf) is an antibody drug conjugate (ADC) for the treatment of multiple myeloma. The antibody component is an afucosylated IgG1 directed against B-cell maturation antigen (a protein expressed on normal B lymphocytes and multiple myeloma cells) conjugated to the microtubule inhibitor monomethylauristatin F (MMAF).Current criteria for assessing clinical response include changes in serum or urine M-protein levels by serum protein electrophoresis and immunofixation electrophoresis (IFE). Therapeutic use of ADC's has the potential to interfere with M-protein assessment by electrophoresis thus confounding clinical trial results. We aimed to modify an existing electrophoresis (EPS) platform (SAS-1 plus) to identify Belamaf in both saline and patients sera using a specific Anti-mcMMAF antibody.Objectives:1)To determine if Belamaf can be detected by serum protein electrophoresis and/or immunofixation electrophoresis methods that are used to measure ‘M' protein in MM patients. 2)If Belamaf can be detected by this assay, then determine if the detectable levels could interfere with defining clinical outcomes such as complete response*.By modifying an existing platform and using an mcMMAF specific antibody we were able to detect Belamaf in patients sera with no ‘M' protein at concentrations down to 0.5g/L by IFE. In multiple myeloma patients whose total protein concentrations were in excess of 90g/L Belamaf could be detected at 1.5g/L. Belamaf in patients sera can only be identified by anti-mcMMAF as anti-IgG and anti-IgKappa will detected those proteins present in sera in both MM and healthy patients.Belamaf could not be detected below 0.5g/L either by EPS or IFE using Anti-mcMMAF. As therapeutic Cmax levels of Belamaf are expected to be 0.04g/L, it will not be identified by EPS or IFE using the SAS-1 plus system. Further refinement of the SAS-1 plus system may achieve greater sensitive down to 0.2g/L (0.2g/L was detected using anti- IgG) however increased sensitivity and optimisation is highly unlikely to detected therapeutic concentrations of Belamaf.* Complete Response: Patients with CR must show that no abnormal monoclonal proteins (also called M-proteins) are present in the blood serum or urine.
Citation Format: Fiona J. McClure. Belantamab Mafodotin detection by protein electrophoresis: Assessing interference for defining clinical response [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 407.
Abstract 411: New estimators for mediation effects in complex sampling schemes: A comparison with applications
Authors: Mai Yujiao , Srivastava Deo Kumar 
Published: July 2021

Abstract
Mediation analysis examines the indirect effects via a third variable on the pathway between exposures and outcomes. For the finite-population surveys, that often use stratified cluster sampling, the conventional methods assuming simple random sampling are not appropriate. The point estimation of the effect can be corrected using sampling weights, but the standard error needs further improvement. Recent studies have integrated mediation analysis with balanced repeated replication for standard error estimation. Alternative estimators include Jackknife repeated replication (JRR), bootstrap, and Taylor series linear approximation (TSE). This study proposes new standard error estimators by incorporating the classic linear mediation analysis with JRR, bootstrap, and TSE for complex surveys and compares them using Monte Carlo simulations. The preliminary results show that replication methods have lower Type-I error rates and higher confidence-interval coverage rates than conventional methods. The proposed methods are applied to National Health Interview Surveys to explore the mediation effects on the pathway between cancer survivors' health status and employment status.
Citation Format: Yujiao Mai, Deo Kumar Srivastava. New estimators for mediation effects in complex sampling schemes: A comparison with applications [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 411.
Abstract 412: Blockade of beta-catenin pathway combined with Aurora kinase activity inhibition enhances antitumor effects in adrenocortical cancer cells
Authors: Maria Andrea G. , Borges Kleiton S. , Lira Regia C. , Thome Carolina H. , Berthon Annabel , Drougat Ludivine , Faucz Fabio R. , Faca Vitor M. , Tone Luiz G. , Stratakis Constantine A. 
Published: July 2021

Abstract
Adrenocortical cancer (ACC) is a rare and aggressive type of endocrine tumor with high risk of recurrence and metastasis. The overall survival of patients diagnosed with ACC is very low and current treatment for metastatic stages remain limited to mitotane, which has low efficiency in advanced stages of the disease and is associated with high toxicity and side effects. Therefore, identification of new biological targets to improve ACC treatment is crucial. Beta-catenin alterations have been found in approximately 30% of ACCs and blockade of Wnt-beta-catenin showed to decrease adrenal steroidogenesis and increase apoptosis of ACC cells, NCI-H295, in vitro and in a mouse model. Aurora kinases are known to play an important role in cell division during G1-M phase and their aberrant expression is correlated with poor prognosis in different types of tumors. Hence, we hypothesized that inhibition of aurora kinase activity combined with beta-catenin pathway blockade could promote better antitumor effects in NCI-H295 cells. We studied the in vitro effects of AMG 900, an aurora kinase activity inhibitor and PNU-74654, a beta-catenin pathway blocker, in proliferation, migration, colony establishment and invasion of NCI-H295 and SW-13 ACC cell lines. Our results show that the combination of AMG 900 with PNU-74654, decreases cell proliferation and viability, compared to either one of the single treatments. Regarding cell invasion and clonogenesis inhibition, AMG 900 was more efficient than PNU-74654, and its combination with the latter did not improve these effects. On the other hand, PNU-74654 was more effective in decreasing cortisol secretion. Taken together, our data suggest that inhibition of aurora kinases activity combined with blockade of the beta-catenin pathway could bring new approaches for designing new drugs to treat certain ACCs.
Citation Format: Andrea G. Maria, Kleiton S. Borges, Regia C. Lira, Carolina H. Thome, Annabel Berthon, Ludivine Drougat, Fabio R. Faucz, Vitor M. Faca, Luiz G. Tone, Constantine A. Stratakis. Blockade of beta-catenin pathway combined with Aurora kinase activity inhibition enhances antitumor effects in adrenocortical cancer cells [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 412.
Abstract 458: Characterization of ATRX polyclonal, application of immunohistochemical analysis on astrocytoma and glioblastoma
Authors: Diaz Jose Jonathan , Scoggin Tatiana , Ramos Jason 
Published: July 2021

Abstract
Introduction: Alpha thalassemia/mental retardation syndrome X-linked (ATRX) plays a role in chromatin regulation and maintenance of telomeres. It regulates incorporation of histone H3.3 into telomeric chromatin. ATRX is also a major component of various essential cellular pathways such as DNA replication and repair, chromatin higher-order structure regulation, and gene transcriptional regulation. ATRX loss was observed in grades II/III astrocytomas, oligoastrocytomas, oligodendrogliomas, and glioblastomas. In grades II/III gliomas, most ATRX-loss cases had IDH1/2 mutations. Assessment of ATRX loss by IHC staining captures the majority of mutations, giving a reasonable sensitivity in neuropathology diagnostics. In this study, the specificity and sensitivity of ATRX were analyzed on multiple tissues focusing on Astrocytoma and Glioblastoma tissues.
Materials and Methods: IHC staining has been performed by using formalin-fixed paraffin-embedded tissue with standard deparaffinization steps and a heat-induced retrieval method using a citrate buffer solution in a pressure cooker (Decloaking chamber). Antibody was incubated for 30 minutes, followed by HRP detection and DAB solution for visualization. Slides were stained using semi-automated staining system (intelliPATH). ATRX polyclonal antibody [Biocare Medical, California, USA] diluted in a carrier at an optimal concentration with standard protocol.
Results: ATRX stained 44% of diffuse and anaplastic astrocytoma and 57% of glioblastoma. Also, cross-reactivity testing determined ATRX polyclonal may stain normal brain in some cases. A more comprehensive data evaluation shown below:
Conclusions: ATRX polyclonal shows a potential advantage when diagnosing brain tumors (especially astrocytoma and glioblastomas) even if some cross reactivity can be observed. ATRX in conjunction with other brain marker antibodies can offer a better tool in diagnosing brain tumors.
Diseased Tissue Specificity and SensitivityTissuePositive CasesTotal Cases% +Astrocytoma163644Glioblastoma4757Breast Cancer132748Colon Cancer84020Lung Cancer245246Prostate Cancer164238Normal Tissue Cross-ReactivityCerebrum51145Cerebellum2367
Citation Format: Jose Jonathan Diaz, Tatiana Scoggin, Jason Ramos. Characterization of ATRX polyclonal, application of immunohistochemical analysis on astrocytoma and glioblastoma [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 458.
Abstract 461: Pan-liver disease single cell-based deconvolution reveals γδ2 T cells as a marker in hepatocellular carcinoma development
Authors: Shankar Rama , Haskins Jeremy , Paithankar Shreya , Chen Bin 
Published: July 2021

Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary adult liver cancer and the fourth leading cause of cancer-related death worldwide. HCC incidence is highest most often in people with chronic liver diseases, yet the effect of cell composition on the progression of chronic liver diseases to HCC remains unknown. Using gene biomarkers of twenty cell-types identified from healthy liver scRNA-seq data, we estimated cell compositions of six chronic liver diseases and HCC based on their bulk RNA-seq samples. We observed a decrease in the enrichment of various health cells as the progression of liver diseases. Compared to a healthy state, liver fibrosis and HCC present higher enrichment of γδ2 T cells and lower enrichment of central venous liver sinusoidal endothelial cells (LSECs). High enrichment of γδ2 T cells was specifically observed in HCV and/or HBV positive HCC and advanced HCC. γδ2 T cell is one of the nine cell types that are associated with HCC prognosis. The analysis of multiple independent datasets confirmed that γδ2 T cells enrichment is more associated with poor prognosis in patients with lower Alpha-fetoprotein (AFP) level and HCV/HBV positive patients. Following pan-cancer analysis suggested enrichment of γδ2 T cells is associated with poor prognosis in kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, and low grade gliomas. In addition, this type of cells is also enriched in the blood samples of various chronic liver diseases and HCC, indicating the potential of being diagnostic markers. In summary, the integrative bioinformatics analysis identified γδ2 T cells as a marker for HCC progression.
Citation Format: Rama Shankar, Jeremy Haskins, Shreya Paithankar, Bin Chen. Pan-liver disease single cell-based deconvolution reveals γδ2 T cells as a marker in hepatocellular carcinoma development [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 461.
Abstract 463: Features consistent with a small-cell neuroendocrine like (SC/NE-L) transformation can be readily detected and quantified in circulating tumor cells (CTCs)
Authors: Scher Howard I. , Jendrisak Adam , Gilbertson Cole , Gill Audrey , Barnett Ethan , Gopalan Anuradha , Keegan Niamh , Zaidi Samir , Benoliel Hannah , Emily Carbone , Wang Eva , Lu James , Tubbs Alisa , Anderson Amanda , Jones Joshua , Schonhoft Joseph D. , Wenstrup Rick 
Published: July 2021

Abstract
Background: The increasing availability and earlier use of life prolonging drugs targeting the androgen receptor signaling axis (ARSI) has resulted in an increase in the frequency of late state tumors with “small cell/neuroendocrine like (SC/NE-L) phenotypes” similar to small-cell lung cancer (SCLC). These tumors are typically heterogenous wherein the small-cell component represents only a portion of CTC's present. Definitive pathologic criteria to diagnose small-cell neuroendocrine transformation are lacking, and the eligibility criteria across trials in this space inconsistent, limiting the ability to relate outcomes between studies. We hypothesize that an analytically validated assay for a rigorously defined “small-cell CTC” phenotype would clarify the identification and diagnosis of SC/NE-L tumors.
Methods: Using the WHO guidelines for small-cell diagnosis in tissue as reference, we defined an equivalent set of single-cell criteria for defining a CTC with small cell or neuroendocrine like (SC/NE) histology that include: a circulating CD45- cell with a high nuclear to cytoplasm area ratio, small size, high circularity, lack of detectable nucleoli, salt and pepper chromatin, SC/NE or tumor-related protein expression (DLL3, CD56, CK etc.), and other features associated with lineage plasticity (i.e., CK speckling). Clinical feasibility of feature extraction was explored on CTCs detected using the Epic Sciences platform in the blood of patients with small-cell lung and late state prostate cancers.
Results: Using the Epic Sciences platform, morphologic features associated with small-cell or neuroendocrine transformation can be readily identified and quantified automatically in CTCs in a liquid biopsy from patients with small-cell lung and prostate cancers.
Conclusions: Identifying small-cell to neuroendocrine like (SC/NE-L) CTC subtypes may aid in establishing that lineage transformation to a SC/NE-L phenotype has occurred where invasive single site tissue biopsies may not be informative or feasible.
Citation Format: Howard I. Scher, Adam Jendrisak, Cole Gilbertson, Audrey Gill, Ethan Barnett, Anuradha Gopalan, Niamh Keegan, Samir Zaidi, Hannah Benoliel, Carbone Emily, Eva Wang, James Lu, Alisa Tubbs, Amanda Anderson, Joshua Jones, Joseph D. Schonhoft, Rick Wenstrup. Features consistent with a small-cell neuroendocrine like (SC/NE-L) transformation can be readily detected and quantified in circulating tumor cells (CTCs) [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 463.
Abstract 477: Elevated EVL methylation level in the normal colon mucosa is a potential risk biomarker for developing metachronous polyps
Authors: Yu Ming , Wang Ting , Carter Kelly T. , Baker Kelsey , Redman Mary W. , Vickers Kathy , Dzubinski Lynda Ann , Schoen Robert E. , Grady William M. 
Published: July 2021

Abstract
The purpose of this study is to evaluate the use of molecular markers for more accurately predicting the individual risk of metachronous polyps or cancer during colonoscopic surveillance. Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in the United States. The risk of CRC varies among people; individuals who develop adenomas are at heightened risk of forming metachronous adenomas and interval cancer, compared to those without a personal history of adenoma or CRC. Yet, even in these high risk individuals, only 25-30% will develop subsequent adenomas. To date, few studies have evaluated the use of molecular markers for predicting the risk of metachronous lesions. We have demonstrated that aberrantly methylated mir342/EVL is present at a higher frequency in the normal colon of people with CRC compared to people with no colon cancer or polyps, suggesting it may indicate a field cancerization process. Further, we developed an ultra-sensitive quantitative Methylation-specific ddPCR (MS-ddPCR) assay to accurately determine the level of rare EVL methylation in the normal colon mucosa. To investigate the correlation of EVL methylation in normal mucosa and the risk of developing polyps during the follow-up colonoscopy, we conducted a retrospective cohort study (N=136 subjects) and EVL methylation status was determined in normal colon mucosa samples from these subjects. Among them, 71 subjects had polyps detected within 12 years of the index colonoscopy, and 11 subjects were polyp-free at all subsequent colonoscopic exams done within 8-16 years of the index colonoscopy (54 subjects did not meet the criteria for follow up, so were excluded from the following analysis). Applying the standard Inverse Probability Weighted Logistic Regression (IPWLR) model, we found that higher level of EVL methylation in the normal colon mucosa at the time of the index colonoscopy (which was when the tissue sample was collected) indicated an increased risk of having polyps detected within 12 years, compared to subjects with no polyps detected by colonoscopy done within 8-16 years (Odds Ratio (95% CI) = 4.35 (1.14, 16.60); p-value = 0.0317). Our results suggest that EVL methylation level in the normal colon mucosa can be used as a risk biomarker for metachronous adenomas.
Citation Format: Ming Yu, Ting Wang, Kelly T. Carter, Kelsey Baker, Mary W. Redman, Kathy Vickers, Lynda Ann Dzubinski, Robert E. Schoen, William M. Grady. Elevated EVL methylation level in the normal colon mucosa is a potential risk biomarker for developing metachronous polyps [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 477.
Abstract 494: Novel human B7-H3 knock-in mice demonstrate efficacy of anti-B7-H3 immunotherapy in vivo
Authors: Zhao Lei , Li Huilin , Liu Yujie , Yu Zhaoxue , Lin Eugene 
Published: July 2021

Abstract
In recent years, immune checkpoint inhibitors (ICIs), particularly against PD-1/PD-L1, have revolutionized cancer treatment. However, ICI monotherapy only benefits a portion of cancer patients, while co-blockade of PD-1/PD-L1 and CTLA-4 is associated with increased IrAEs. Combined targeting of other immune checkpoints with PD-1/PD-L1 rather than CTLA-4 may be safer. B7-H3, also known as CD276, is a newer member of the same B7/CD28 superfamily as PD-1 and PD-L1. Its transcripts are ubiquitously expressed in normal tissues and solid tumors, but the protein is expressed in tumor tissues and by antigen-presenting cells, such as DC or macrophages, where it inhibits T cells and contributes to tumor immune evasion. Importantly, B7-H3 is overexpressed on a wide range of human solid cancers and correlates with negative prognosis and poor clinical outcome in patients. Recent studies have shown that B7-H3 also drives tumor growth, invasion, migration, angiogenesis, and metastasis beyond its immune regulatory roles. Thus, B7-H3 is an interesting new target for immunotherapy. To investigate B7-H3 function in vitro and evaluate in vivo efficacy of B7-H3 antibodies, Biocytogen generated a B7-H3 humanized mouse (B-hB7-H3) and B7-H3-expressing MC38 cell line (MC38-hB7-H3). In the mice, exons 3-4 of the mouse B7-H3 gene, which encode the extracellular domain, are replaced by human B7-H3 exons 3-6. Human B7-H3 mRNA was detectable in spleen and bone marrow of only B-hB7-H3 mice, and B7-H3 antibodies bound well to hB7-H3+ MC38 cells. Furthermore, using the MC38-hB7-H3 and EL4 tumor models, we showed robust efficacy of anti-human B7-H3 antibodies in inhibiting tumor growth in vivo, which was amplified in mice receiving combined human B7-H3 and mouse PD-1 blockade. Taken together, B7-H3 humanized mice are a useful tool for in vivo efficacy evaluation and selection of candidate human B7-H3 antibodies for advancement to clinical trials. In addition, Biocytogen has generated B7-H3/PD-1 and B7-H3/PD-1/PD-L1 multi-gene humanized mice to evaluate B7-H3/PD-1/PD-L1 combination therapies in vivo.
Citation Format: Lei Zhao, Huilin Li, Yujie Liu, Zhaoxue Yu, Eugene Lin. Novel human B7-H3 knock-in mice demonstrate efficacy of anti-B7-H3 immunotherapy in vivo [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 494.