bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 830: Validity and reproducibility of immunohistochemical scoring by trained non-pathologists on Tissue MicroArrays
Authors: Offermans Kelly , Jenniskens Josien C. , Samarska Iryna , Fazzi Gregorio E. , Simons Colinda C. , Smits Kim M. , Schouten Leo J. , Weijenberg Matty P. , van den Brandt Piet A. , Grabsch Heike I. 
Published: July 2021

Abstract
Aims: Scoring of immunohistochemical (IHC) staining is often done by non-pathologists, especially in large-scale Tissue MicroArray (TMA)-based studies. Studies on the validity of scoring results from non-pathologists are very limited. Therefore, our main aim was to assess inter-observer agreement between trained non-pathologists and an experienced histopathologist for three IHC markers with different subcellular localisation (nucleus/membrane/cytoplasm).
Methods and results: Three non-pathologists were trained in recognizing adenocarcinoma and IHC scoring by a senior histopathologist. Kappa statistics were used to analyse inter- and intra-observer agreement for 6249 TMA cores from a colorectal cancer (CRC) series. Inter-observer agreement between non-pathologists (independently scored) and the histopathologist was “substantial” for nuclear and membranous IHC markers (κrange=0.67-0.75 and κrange=0.61-0.69, respectively), and “moderate” for the cytoplasmic IHC marker (κrange=0.43-0.57). Scores of the three non-pathologists were also combined into a combination score (if at least two non-pathologists independently assigned the same score to a core, this was the combination score). This increased agreement with the pathologist (κnuclear=0.74; κmembranous=0.73; κcytopasmic=0.56). Inter-observer agreement between non-pathologists was “substantial” (κnuclear=0.78; κmembranous=0.72; κcytopasmic=0.61). Intra-observer agreement of non-pathologists was “substantial” to “almost perfect” (κnuclear,range=0.83-0.87; κmembranous,range=0.75-0.82; κcytopasmic,range=0.69-0.69). Overall, agreement was lowest for the cytoplasmic IHC marker.
Conclusions: This study shows that adequately trained non-pathologists are able to produce similar IHC scoring results as an experienced histopathologist. Considering the histopathologist's score as the golden standard, we can conclude that trained non-pathologists can produce valid IHC results on TMA sections. A combination score of at least two non-pathologists yielded optimal results.
Citation Format: Kelly Offermans, Josien C. Jenniskens, Iryna Samarska, Gregorio E. Fazzi, Colinda C. Simons, Kim M. Smits, Leo J. Schouten, Matty P. Weijenberg, Piet A. van den Brandt, Heike I. Grabsch. Validity and reproducibility of immunohistochemical scoring by trained non-pathologists on Tissue MicroArrays [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 830.
Abstract 86: O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation
Authors: Ciraku Lorela , Bacigalupa Zachary , Moeller Rebecca , Ju Jing , Lee Rusia H. , Ferrer Christina , Trefely Sophie , Snyder Nathaniel W. , D'Agostino Luca , Katsetos Christos D. , Shi Wenyin , Reginato Mauricio J. 
Published: July 2021

Abstract
Cancer cells alter their metabolism to increase cell growth. A subset of the glucose taken up is shunted into the hexosamine biosynthetic pathway where it is used to synthesize UDP-GlcNAc, a substrate of O-GlcNAc transferase (OGT), which modifies cytoplasmic and nuclear proteins with O-linked sugar moieties. Here, we show that OGT and O-GlcNAcylation are elevated in glioblastoma (GBM) cancer cells and in GBM patient samples that correlates with disease progression. Reduction of OGT expression in GBM cells led to significant reduction in anchorage-independent growth, acetyl-CoA levels, and decrease in free fatty acids. Conversely, overexpressing OGT in GBM cells had the opposite effect. Reducing OGT expression in GBMcells transplanted in an orthotopic intracranial mouse model reduced tumor growth and extended survival. Mechanistically, we show that OGT overexpression increases carbon-flux of acetate to acetyl-CoA, a reaction carried by the enzyme acetyl-CoA synthetase 2 (ACSS2). Indeed, OGT regulates ACSS2 protein levels and O-GlcNAcylation increases ACSS2phosphorylation on Ser-267 in a cyclin dependent kinase 5 (CDK5)-dependent manner, which regulates its stability by reducing polyubiquitination and degradation. ACSS2 Ser-267 is critical for OGT-mediated GBM growth as overexpression of ACSS2 Ser-267 phospho-mimetic rescues growth in vitro and in vivo. Using an ex vivo GBM brain slice model we show that treatment of GBM-transplanted slices with OGT inhibitor Ac-GlcNAc-5S or pan-cdk inhibitor dinaciclib reduced growth of pre-formed tumors in cultured brain slices. These results suggest a crucial role for O-GlcNAc signaling in transducing nutritional state to regulate acetate metabolism and identify OGT and CDK5 as novel therapeutic targets for treatment of glioblastoma.
Citation Format: Lorela Ciraku, Zachary Bacigalupa, Rebecca Moeller, Jing Ju, Rusia H. Lee, Christina Ferrer, Sophie Trefely, Nathaniel W. Snyder, Luca D'Agostino, Christos D. Katsetos, Wenyin Shi, Mauricio J. Reginato. O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation [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 86.
Abstract 862: Transcriptomics analysis reveals unique immunoinflammatory signatures of nigerian prostate cancer
Authors: Rotimi Solomon Oladapo , Omonisi Abidemi E. , Mohammed Faruk , Jibrin Paul , Duduyemi Babatunde , Olusina Daniel B. , Xu Yili , Jin Yuxin , Liu Xiyu , Xiao Guang Q. , Odedina Folakemi , Carpten John , Reams Renee , Manojlovic Zarko 
Published: July 2021

Abstract
Background: Prostate cancer (PCa) is the leading cause of cancer death among Nigerian men, with most men presenting late and with high grade disease. Furthermore, improved PCa diagnosis and treatment could rely on genomics-driven precision approaches. Mounting evidence supports potential population enriched molecular features of cancer, however the extent of which is hampered due to a dearth of genomic data in diverse cohorts. This study, therefore, aims at utilizing transcriptomics analysis to deduce transcriptional states in PCa from Nigerian men.
Methodology: RNA was extracted from macro-dissected prostate tumor and adjacent normal tissue from 35 archival formalin fixed paraffin-embedded (FFPE) blocks from Gleason 8-9 cancers, of which 25 had cribriform morphologic architecture. High resolution hybrid-capture mRNA-seq libraries were sequenced using Illumina NovaSeq 6000 system and generated an average of 124 million read pairs per sample. Raw reads were processed using a custom pipeline based upon industry standard algorithms along with the deduction of genetic ancestry. Molecular annotation was also performed to investigate tumor and immune cell heterogeneity.
Result: The Nigerian data were compared with high grade PCa data of Caucasian obtained from TCGA. The Nigerian PCa tumors where characterized with uniquely enriched immune-inflammatory microenvironment which include crosstalk between dendritic cells and natural killer cells, and natural killer cell signaling. While the Nigerian tumors share more features of distal metastatic tumor, their enrichment in NKT Cells is a unique feature.
Conclusion: This represents the first report of RNA-seq analysis of PCa in Sub-Saharan Africa and the unique transcriptomics features of Nigerian PCa presents opportunities for precision intervention in addressing its burden in Nigeria.
Citation Format: Solomon Oladapo Rotimi, Abidemi E. Omonisi, Faruk Mohammed, Paul Jibrin, Babatunde Duduyemi, Daniel B. Olusina, Yili Xu, Yuxin Jin, Xiyu Liu, Guang Q. Xiao, Folakemi Odedina, John Carpten, Renee Reams, Zarko Manojlovic. Transcriptomics analysis reveals unique immunoinflammatory signatures of nigerian prostate 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 862.
Abstract 871: KYNU expression is a prognostic factor in KEAP1/STK11 co-mutated lung adenocarcinoma
Authors: Cai Ling , Rogers Thomas J. , Li Huiyu , Kim Jiyeon , Xie Yang , Xiao Guanghua , Minna John , DeBerardinis Ralph J. 
Published: July 2021

Abstract
We searched for gene expression prognostic markers with bimodal distribution in lung adenocarcinoma (LUAD) that might help specify molecular subtypes and identified a highly consistent biomarker KYNU, an enzyme in the pathway that converts tryptophan to nicotinamide adenine dinucleotide (NAD+). KYNU performed better in predicting LUAD outcomes than genes in related pathways. High KYNU expression is particularly observed in tumors with mutations in the tumor suppressor genes KEAP1 and STK11, but not in the oncogene KRAS. From clinical data of LUAD, we found more frequent co-mutation of KEAP1 and STK11 than KRAS with either KEAP1 or STK11. Tumors with mutations in both KEAP1 and STK11 had poorer outcomes than tumors with mutations in neither or only one of these genes, regardless of KRAS status. Importantly, KYNU expression associated with poor outcomes regardless of KEAP1/STK11 status and other covariates. We also assessed clinical features associated with KEAP1/STK11 mutations with AACR GENIE data. By examining co-expression of KYNU with other genes, we determined that high KYNU expression had low expression of gene sets related to macrophages.
Citation Format: Ling Cai, Thomas J. Rogers, Huiyu Li, Jiyeon Kim, Yang Xie, Guanghua Xiao, John Minna, Ralph J. DeBerardinis. KYNU expression is a prognostic factor in KEAP1/STK11 co-mutated lung adenocarcinoma [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 871.
Abstract 872: Pathogenesis underlying the bidirectional relationship between non-Hodgkin lymphomas and primary Sjögren's Syndrome
Authors: Ma Kevin Sheng-Kai , Chiang Cho-Han , Wang Li-Tzu 
Published: July 2021

Abstract
Introduction: Bidirectional relationship between non-Hodgkin lymphomas (NHLs) and Sjögren's syndrome (SS) has been recognized in large scale cohort studies. To investigate the underlying pathogenesis of this association, we identified highly expressed genes and altered pathways with RNA-sequencing (RNA-seq) data from SS and NHLs patients.
Methods: Canonical pathway analysis was conducted by comparing RNA-seq data from whole-transcriptome expression profiling to identify underlying pathogenesis among NHL patients with Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL), and SS patients. Collected biopsies included lymphoma biopsies for NHLs, including BL (n = 59), DLBCL (n = 88), FL (n = 65), MCL (n = 43), and MZL (n = 23), sorted B cells from healthy donors (n=10), as well as parotid gland tissues for SS (n=17). Fold changes and z-scores were derived after normalized by the expression levels among controls. RNA-seq data with P values less than 0.05 or -log10(P) values larger than 1.3 were considered significantly expressed. Positive z-scores indicated up-regulation while negative z-scores indicated down-regulation.
Results: There were 17 identified significantly expressed genes (P &lt; 0.05 for all NHLs and SS), including well-known cancer-associated genes CXCL13, COL1A1, IGFBP7, COL3A1, CXCL9, CXCL12, CCL19, and CLU. Among them, CXCL13 was the most expressed gene involved in NHLs and SS. The fold changes of CXCL13 were 14.09, 465.57, 319.51, 369.70, 817.63, and 4.03 for BL, DLBCL, FL, MCL, MZL, and SS, respectively. Among all identified pathways underlying SS and NHL development, which were ordered based on the sum of z-scores, the endocannabinoid system-driven cancer inhibition pathways were the most significantly altered in both SS and NHLs, followed by interferon-involved antiviral responses, when compared to matched healthy controls. The z-scores of the cancer inhibition pathways were -0.14 for BL (-log10(P) = 4.54), -1.30 for DLBCL (-log10(P) = 3.00), -0.33 for FL (-log10(P) = 4.67), -0.87 for MCL (-log10(P) =3.77), -2.61 for MZL (-log10(P) = 4.31), and -1 for SS (-log10(P) = 1.44).
Conclusion: The underlying pathogenesis for SS-associated NHL development involved 17 highly expressed genes, including CXCL13, and down-regulated cancer inhibition pathways.
Citation Format: Kevin Sheng-Kai Ma, Cho-Han Chiang, Li-Tzu Wang. Pathogenesis underlying the bidirectional relationship between non-Hodgkin lymphomas and primary Sjögren's Syndrome [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 872.
Abstract 875: Associations of aspirin and other anti-inflammatory medications with breast cancer risk by the status of COX2 receptor
Authors: Yaghjyan Lusine Na , Eliassen Heather , Colditz Graham , Rosner Bernard , Wijayabahu Akemi , Tamimi Rulla 
Published: July 2021

Abstract
Purpose: We investigated the associations of aspirin and other non-steroid anti-inflammatory drugs (NSAIDs) with breast cancer risk by the status of COX2 receptor expression.
Methods: This study included 421 cases and 3,166 controls from a nested case-control study within the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII) cohorts. Information on medication use was first collected in 1980 (NHS) and 1989 (NHSII) and was updated biennially. Medication use was defined as none, past or current; average cumulative dose and frequency were calculated for all past or current users using data collected from all bi-annual questionnaires preceding the reference date. Immunochemistry for COX2 expression was performed using commercial antibody (Cayman Chemical and Thermo Fisher Scientific). We used polychotomous logistic regression to quantify associations of aspirin and NSAIDs with the risk of COX2+ and COX2- breast cancer tumors, while adjusting for known breast cancer risk factors. All tests of statistical significance were two-sided.
Results: In multivariate analysis, heterogeneity tests indicated statistically significant differences in associations of most of the aspirin exposures and regular use of NSAIDs with breast cancer risk by COX2 receptor status. However, we observed no distinct differences in the patterns of associations between COX2+ and COX2- tumors for any of the exposure variables. Significant associations of these medications with breast cancer risk were observed for dosage of aspirin among current users in COX2- tumors (OR for &gt;5 tablets per week vs. none 1.71, 95% CI 1.01-2.88, p-trend 0.04) Regular aspirin use was marginally associated with the risk of COX2- tumors (p-trend=0.06) only (p-heterogeneity&lt;0.0001).
Conclusions: Our findings suggested no differences in associations of aspirin and other NSAIDs with COX2+ and COX2- tumors.
Citation Format: Lusine Na Yaghjyan, Heather Eliassen, Graham Colditz, Bernard Rosner, Akemi Wijayabahu, Rulla Tamimi. Associations of aspirin and other anti-inflammatory medications with breast cancer risk by the status of COX2 receptor [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 875.
Abstract 911: In vitro and in vivo activity of DHES0815A, an antibody-drug conjugate targeting HER2/neu in uterine serous carcinoma
Authors: Tymon-Rosario Joan Tymon R. , Bonazzoli Elena , Bellone Stefania , Manzano Arancha , Manara Paola , Zammataro Luca , Pelligra Silvia , Guglielmi Adele , Gnutti Barbara , Zeybek Burak , Harold Justin , Mauricio Dennis , Ratner Elena , Schwartz Peter , Santin Alessandro D. 
Published: July 2021

Abstract
Objective: Uterine serous carcinoma (USC) is an aggressive histologic variant of endometrial cancer which portends a poor prognosis. DHES0815A is a novel antibody-drug-conjugate (ADC) which binds specifically to HER2 overexpressing tumors at a distinct epitope from that bound by trastuzumab and pertuzumab after which it delivers the toxic payload, PBD-MA, a DNA mono-alkylating agent. The objective of this study was to evaluate the preclinical activity of DHES0815A against primary USC cell lines and xenografts.
Methods: Twelve primary USC cell lines were assessed by immunohistochemistry (IHC) for HER2 protein expression and for C-erbB2 gene amplification using fluorescent in situ hybridization (FISH) analysis. Cell viability and bystander killing in USC cell lines after exposure to DHES0815A, the non-targeted ADC, and the unconjugated antibody (i.e. MHES0488A) were evaluated using flow cytometry-based-assays. In vivo activity of DHES0815A was tested against HER2/neu overexpressing USC xenografts.
Results: High HER2/neu protein expression was seen in 25% (3/12) of the primary USC cell lines. USC cell lines overexpressing HER2/neu were significantly more sensitive to DHES0815A when compared to the non-targeted control ADC (p&lt;0.001). DHES0815A did not induce significant bystander killing of HER2/neu negative tumors when admixed with HER2/neu positive tumors. DHES0815A caused growth-inhibition and increased survival in USC HER2/neu overexpressing xenografts when compared to controls (p&lt;0.01).
Conclusions: DHES0815A is both highly selective and toxic to USC tumors overexpressing HER2/neu both in vitro and in vivo. HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy.
Citation Format: Joan Tymon R. Tymon-Rosario, Elena Bonazzoli, Stefania Bellone, Arancha Manzano, Paola Manara, Luca Zammataro, Silvia Pelligra, Adele Guglielmi, Barbara Gnutti, Burak Zeybek, Justin Harold, Dennis Mauricio, Elena Ratner, Peter Schwartz, Alessandro D. Santin. In vitro and in vivo activity of DHES0815A, an antibody-drug conjugate targeting HER2/neu in uterine serous carcinoma [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 911.
Abstract 922: End-to-end discovery to support the development of safe and efficacious engineered cell therapies
Authors: Vousden Katherine , Holt Sanne , Vermond Sophie , Hazenoot Monique , Ives Sarah , Youssef Sawsan , Glanville Jake 
Published: July 2021

Abstract
The global market for cell and gene therapies, including T-cell/Natural Killer cell chimeric antigen receptors (CAR-T/NK), is continuing to grow rapidly - with many clinical success stories for B-cell malignancies in particular. However, the path to clinical success has not been smooth - with early reports of organ damage and even deaths following CAR-T therapy highlighting that there are significant risks involved in their development, and a clear requirement to understand and mitigate for the underlying mechanisms that result in unwanted toxicities. Off-target binding and tonic signalling are indicated in many pre-clinical and clinical cell therapy failures, and it is becoming increasingly apparent that CAR design - particularly the selection of the tumor targeting moiety with exquisite specificity, desirable biophysical attributes and appropriate affinity - is key to developing a successful therapy. Distributed Bio's scFv and VHH phage-display libraries (SuperHuman 2.0 and Tungsten) have been designed to be biophysically stable and non-immunogenic. Their size and clonal diversity, coupled with the use of streamlined work-flows, enable the rapid identification of large panels of VH CDR3 sequence-unique binders which can then be assessed for CAR suitability by exploiting the integrated approach offered by DBio's successful partnership with Charles River. Panels of CAR constructs, covering the diversity of sequences and affinities related to the scFv/VHH domains isolated, can be triaged through Charles River efficacy and safety work-streams to identify the best therapeutic candidates. For example, co-culture experiments with target-expressing carcinoma cell lines and non-target expressing cell lines can be utilized to investigate and compare activity, specificity and potency of the various CAR constructs. Ultimately, combining Distributed Bio discovery with Charles River downstream characterization enables identification of the best lead candidate - balancing efficacy and safety of your CAR-T therapy - for optimal therapeutic outcome.
Citation Format: Katherine Vousden, Sanne Holt, Sophie Vermond, Monique Hazenoot, Sarah Ives, Sawsan Youssef, Jake Glanville. End-to-end discovery to support the development of safe and efficacious engineered cell therapies [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 922.
Abstract 994: Investigating inhibition of nuclear export in breast cancer cells
Authors: Gruener Robert F. , Greene Geoffrey L. , Huang R. Stephanie 
Published: July 2021

Abstract
XPO1 (Exportin aka CRM1) is a mediator of nuclear export that is known to be dysregulated in cancers. Selective inhibitors of nuclear export (SINEs) have shown some promise in cancer treatment, but the mechanism is poorly understood in cancer specific subtypes. Here, we investigated XPO1 inhibition in breast cancer by treating a panel of breast cancer cell lines with a SINE (Selinexor) and saw a bimodal response, with most triple-negative cell lines showing sensitivity and some ER+ cell lines showing resistance to the therapy. Changes in the expression of BIRC5 (Survivin) have been previously implicated in XPO1 inhibitor response. Using RT-qPCR experiments we were able to show that after 24 hours of selinexor treatment, the expression of BIRC5 does change in two sensitive cell lines MDA-MB-231 and MCF7, but is not necessarily changed at earlier time points. To more holistically explore the mechanism of XPO1 inhibition induced cell death, we performed RNA-Seq and differential gene expression analysis on these two cell lines at 2, 8, and 24 hours post treatment with Selinexor (compared to vehicle). Our results indicate that several breast cancer and cell cycle associated genes show expression changes as early as 2 hours post-treatment and showed-consistent changes across the time-points. Overall, our analysis sheds light on the mechanism by which XPO1 inhibition induces cell death in breast cancer, which may help elucidate potential biomarkers as well as to nominate rationale combinations to explore with XPO1 inhibition.
Citation Format: Robert F. Gruener, Geoffrey L. Greene, R. Stephanie Huang. Investigating inhibition of nuclear export in breast 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 994.