bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B012: Genomic and epigenomic drivers of double-negative metastatic prostate cancer
Authors: Lundberg Arian , Zhang Meng , Aggarwal Rahul R. , Li Haolong , Zhang Li , Foye Adam , Sjöström Martin , Chou Jonathan , Chang Kevin , Moreno-Rodriguez Thaidy , Shrestha Raunak , Baskin Avi , Zhu Xiaolin , Weinstein Alana S. , Younger Noah , Alumkal Joshi J. , Beer Tomasz M. , Chi Kim N. , Evans Christopher P. , Gleave Martin , Lara Primo N. , Reiter Robert E. , Rettig Matthew B. , Witte Owen N. , Wyatt Alexander W. , Feng Felix Y. , Small Eric J. , Quigley David A. 
Published: June 2023

Abstract
Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen receptor (AR) signaling. Androgen deprivation therapy and second-generation AR-targeted therapy selectively favor the development of treatment-resistant subtypes of metastatic castration-resistant prostate cancer (mCRPC), defined by whether the tumor expresses either AR or neuroendocrine (NE) markers. Among the subtypes of mCRPC, the molecular drivers of double-negative (AR-/NE-) mCRPC are poorly defined. In this study, we comprehensively characterize genomic and epigenomic features of treatment-emergent mCRPC subtypes in 210 tumors by integrating matched RNA sequencing, whole-genome sequencing, and whole-genome bisulfite sequencing. We show that AR-/NE- tumors exhibit a clinically and molecularly distinct phenotype. Patients with AR-/NE- mCRPC tumors have the shortest survival, and these tumors preferentially harbor amplification of the chromatin remodeler CHD7 and loss of PTEN. We demonstrate that methylation changes in CHD7 candidate enhancers are linked to elevated CHD7 expression in AR-/NE+ tumors. Moreover, we use genome-wide methylation analysis to nominate the Krüppel-like factor gene KLF5 as a driver of the AR-/NE- phenotype and link its activity to loss of the tumor suppressor RB1. These observations reveal the aggressiveness of the AR-/NE- tumors and elucidate genomic and epigenomic drivers of mCRPC subtypes, which may facilitate the identification of novel therapeutic targets in this highly aggressive disease.
Citation Format: Arian Lundberg, Meng Zhang, Rahul R. Aggarwal, Haolong Li, Li Zhang, Adam Foye, Martin Sjöström, Jonathan Chou, Kevin Chang, Thaidy Moreno-Rodriguez, Raunak Shrestha, Avi Baskin, Xiaolin Zhu, Alana S. Weinstein, Noah Younger, Joshi J. Alumkal, Tomasz M. Beer, Kim N. Chi, Christopher P. Evans, Martin Gleave, Primo N. Lara, Robert E. Reiter, Matthew B. Rettig, Owen N. Witte, Alexander W. Wyatt, Felix Y. Feng, Eric J. Small, David A. Quigley. Genomic and epigenomic drivers of double-negative metastatic prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B012.
Abstract B063: Interplay between PARP and the RB/E2F axis in prostate cancer
Authors: Evans Latese , Cunningham Moriah , Gonzalez Jasibel Vasquez , Schiewer Matthew 
Published: June 2023

Abstract
Retinoblastoma (RB) protein is a tumor suppressor that represses the transcriptional activity of E2Fs by forming an RB-E2F repressor complex. The phosphorylation of RB by CDK4/6 results in dissociation of the complex and subsequent E2F transcriptional activity, leading to cell cycle progression. RB loss occurs in 10-15% of castration-resistant prostate cancer (CRPC) which is associated tumor aggressiveness and poor clinical outcomes. RB loss is also associated differential treatment response to an array of treatment modalities, including hormone therapy and DNA damage inducing chemotherapy. RB depletion leads to enhanced expression of DNA repair proteins due to increased transcriptional activity of E2F1. PARP-1 is an enzyme that plays a role in multiple nuclear processes including DNA repair, transcriptional regulation, and chromatin dynamics. Increased PARP-1 activity is associated with and correlates to poor clinical outcomes in CRPC. E2F1 transcriptional activity is supported by PARP enzymatic activity, but the consequences of the functional interaction between the RB/E2F axis and PARP remains an open line of inquiry, which may yield novel treatment strategies and/or biomarkers of response. Isogenic models of RB1 knockdown were used to evaluate the impact of RB loss on PARP enzymatic activity. PARP-1 protein increases upon RB1 depletion with a concomitant increase in PARP activity. Growth curve assays were conducted to examine the biological response to PARP inhibition in the isogenic models. Results suggest a differential response between control and RB1 depleted cells when treated with Olaparib. RB1depleted cells also exhibit differential PARP activity in response to treatment with the IC50 dose of Olaparib. Future studies have been designed to evaluate the impact of RB alteration and manipulation of PARP activity on biological and molecular processes that are governed by RB/E2F and PARP.
Citation Format: Latese Evans, Moriah Cunningham, Jasibel Vasquez Gonzalez, Matthew Schiewer. Interplay between PARP and the RB/E2F axis in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B063.
Abstract B076: IGFBP3 promotes resistance to olaparib via modulating EGFR signaling in advanced prostate cancer
Authors: Leslie Amy R. , Gao Allen C. , Lombard Alan P. , Ning Shu 
Published: June 2023

Abstract
Background: Castration-resistant prostate cancer (CRPC) is an incurable disease and a leading cause of cancer death in men worldwide. Olaparib (Lynparza) was among the first PARP inhibitors (PARPi) approved for the treatment of CRPC tumors harboring DNA repair defects. However, clinical resistance to PARPi’s has been documented. The mechanisms underlying resistance to PARPi’s remain elusive. To study acquired resistance, we developed olaparib-resistant LN-OlapR and 2B-OlapR cell lines generated through chronic olaparib treatment of the olaparib-sensitive cell lines LNCaP and C4-2B, respectively. RNA-seq revealed IGFBP3 is overexpressed in both OlapR cell lines. IGFBP3 overexpression is correlated with poor clinical outcome and is thought to participate in DNA repair pathways. IGFBP3 plays a key role in nonhomologous end joining (NHEJ) repair through a ternary complex with EGFR and DNA-PKcs. The IGFBP3/EGFR signaling axis is thought to modulate NHEJ repair and could have implications for PARPi sensitivity. We hypothesize that increased IGFBP3 expression promotes PARPi resistance by enhancing DNA repair capacity. Methods: RNA-sequencing and gene set enrichment analysis were used to determine the expression profile changes in resistant cells compared to parental cells. Real time PCR and western blots confirmed the expression of DNA damage repair genes such as γH2AX, EGFR, and DNA-PKcs. ELISA was used to determine IGFBP3 secretion. RNAi was used to inhibit IGFBP3 and EGFR expression. Gefitinib was used to inhibit EGFR activity. Cell viability assays were used to assess cell growth. Results: Transcriptomic profiling revealed that IGFBP3 is highly expressed in resistant models. We verified increased levels of IGFBP3 RNA and protein in both OlapR models. We found that RNAi inhibition of IGFBP3 increases γH2AX and cleaved-PARP protein levels in the resistant models, which suggests accumulation of DNA double strand breaks (DSBs) leading to genomic instability and cell death. We discovered increased phosphorylation of EGFR and DNA-PKcs in the resistant cells. Furthermore, silencing/inhibiting IGFBP3 and EGFR reduces OlapR cell viability and resensitizes resistant cells to treatment. Conclusions: Our findings demonstrated that inhibiting IGFBP3 and EGFR aids in PARPi sensitivity in the resistant setting. Future work will utilize OlapR models to study how the IGFBP3/EGFR/DNA-PKcs protein complex promotes the development of resistance. Understanding the role of IGFBP3 in PARPi resistance will enhance our ability to re-sensitize resistant CRPC to PARPi therapeutics.
Citation Format: Amy R. Leslie, Allen C. Gao, Alan P. Lombard, Shu Ning. IGFBP3 promotes resistance to olaparib via modulating EGFR signaling in advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B076.
Abstract PR005: Multi-level functional genomics reveals molecular and cellular oncogenicity of patient-based 3’ untranslated region mutations
Authors: Schuster Samantha L. , Arora Sonali , Wladyka Cynthia L. , Corey Lukas , Stackhouse Bethany L. , Kollath Lori , Corey Eva , True Lawrence D. , Young Dave , Paddison Patrick J. , Hsieh Andrew C. 
Published: June 2023

Abstract
It is clear from the high mortality rate in advanced cancers that we need a more complete understanding of the many sources of oncogenic dysregulation in tumors. The importance of the non-coding genome in disease has recently begun to be revealed through expanded use of whole genome sequencing. In particular, 3’ untranslated region (3’UTR) somatic mutations represent an important but largely unexplored avenue of alternative oncogenic gene dysregulation. Individual instances of 3’UTR-mediated oncogenicity are known, including oncogenic RNA binding proteins and microRNAs. However, a comprehensive, high-throughput study of patient-based 3’UTR mutations and their effect on post-transcriptional gene regulation in cancer has yet to be undertaken. To determine the significance of 3’UTR mutations in advanced disease, we identify 3’UTR somatic variants across 185 metastatic castration-resistant prostate tumors, discovering 14,497 single-nucleotide mutations, which are enriched in oncogenic pathways and 3’UTR regulatory elements. We develop two complementary massively parallel reporter assays (MPRAs) to measure how thousands of these patient-based mutations affect two distinct levels of post-transcriptional gene regulation: mRNA translation and stability. These MPRAs identify hundreds of functional variants that allow us to define three determinants of mutation significance: sequence conservation, known regulatory elements, and RNA structure. Furthermore, we demonstrate the clinical relevance of these mutations, observing that CRISPR-Cas9 base editing of distinct patient 3’UTR mutations into endogenous cellular loci increases oncogenic mRNA translation and cellular stress resistance. Finally, we go back to patients, illustrating that those harboring oncogenic 3’UTR mutations discovered by our methods display particularly poor prognosis. This work represents an unprecedented view of the extent to which disease-relevant 3’UTR mutations affect mRNA stability, translation, and cancer progression, uncovering principles of regulatory functionality and potential therapeutic targets in previously unexplored regulatory regions.
Citation Format: Samantha L. Schuster, Sonali Arora, Cynthia L. Wladyka, Lukas Corey, Bethany L. Stackhouse, Lori Kollath, Eva Corey, Lawrence D. True, Dave Young, Patrick J. Paddison, Andrew C. Hsieh. Multi-level functional genomics reveals molecular and cellular oncogenicity of patient-based 3’ untranslated region mutations [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR005.
Abstract PR007: ERG-driven luminal prostate cancers emerge from Ck5+/Nkx3.1+ basal cells
Authors: Feng Weiran , Ladewig Erik , Salsabeel Nazifa , Zhao Huiyong , Lee Young Sun , Gopalan Anuradha , Luo Hanzhi , Kang Wenfei , Fan Ning , Rosiek Eric , Masilionis Ignas , Manova-Todorova Katia , Chaligné Ronan , de Stanchina Elisa , Carver Brett S. , Chen Yu , Gao Dong , Leslie Christina S. , Sawyers Charles L. 
Published: June 2023

Abstract
TMPRSS2-ERG translocations are initiating lesions in nearly 50% of human prostate adenocarcinomas, often in conjunction with PTEN loss. In mice, prostate-specific expression of ERG using a Probasin-Cre driver (Pb-Cre4) is sufficient to induce invasive Ck8+ luminal adenocarcinoma with high penetrance in the context of Pten loss. Because TMPRSS2 expression in the human prostate is androgen-regulated and thereby largely restricted to luminal epithelial cells, it has been assumed that luminal cells are the likely cell of origin for TMPRSS2-ERG positive prostate cancers. To gain further support for this hypothesis, we examined the early stages of luminal adenocarcinoma initiation in the Pb-Cre ERG/Pten model at a single cell level. To our surprise, we found a highly proliferative population of ERG+ Ck5+ (a putative basal marker) cells that are enriched at the invasive front in a background of more canonical ERG+/Ck8+/Ck5- luminal tumor cells. We next performed lineage tracing experiments using Ck5-, Ck8- as well as Nkx3.1-Cre drivers, introduced via viral injection or tamoxifen induction, which collectively support the hypothesis that ERG-driven tumors originate in a subset of basal cells defined by Ck5+/Nkx3.1+. This conclusion is further supported by orthotopic transplantation of freshly isolated primary mouse prostate basal (Cd49f high) or luminal (Cd24 high) cells showing that ERG+/Ck8+ tumors arise preferentially from basal cells following ex vivo ERG/Pten activation. Time course experiments in organoids and in vivo show that ERG promotes Ck8+ luminal differentiation from highly proliferative Ck5+ cells, progressing through a Ck5+/Ck8+ intermediate cell state. Collectively, these data implicate a tumor initiating cell population defined by a mix of basal (Ck5) and luminal (Nkx3.1) markers that, under the influence of ERG expression, can expand and invade while retaining full luminal differentiation potential. Our results also suggest that widely held assumptions regarding luminal-specific expression of canonical markers such as Nkx3.1 and Probasin may need revision.
Citation Format: Weiran Feng, Erik Ladewig, Nazifa Salsabeel, Huiyong Zhao, Young Sun Lee, Anuradha Gopalan, Hanzhi Luo, Wenfei Kang, Ning Fan, Eric Rosiek, Ignas Masilionis, Katia Manova-Todorova, Ronan Chaligné, Elisa de Stanchina, Brett S. Carver, Yu Chen, Dong Gao, Christina S. Leslie, Charles L. Sawyers. ERG-driven luminal prostate cancers emerge from Ck5+/Nkx3.1+ basal cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR007.
Abstract PR013: Unlocking the proteome of metastatic prostate cancer circulating tumor cells
Authors: Drake Justin M. , Sychev Zoi , Horrmann Alec , Smith Kaylee Judith , Galeano-Garces Catalina , Arafa Ali , Heller Nicholas , Ahmadi Mahdi , Hong Jiarong , Ludwig Megan , Hwang Justin , Antonarakis Emmanuel S. , Parthasarathy Jayant 
Published: June 2023

Abstract
In recent years, liquid biopsies have emerged to provide improved insights on the current disease state of a patient, but they generally rely on a small number of protein markers from immunofluorescent staining or cell-free DNA, which provides limited information especially around drug targets. As more targeted therapies and immunotherapies enter the market, selecting the optimal drug target could improve patient outcomes drastically. One way to achieve this goal is to generate multi-omic datasets from the cancer cells in circulation, known as circulating tumor cells (CTCs). In this study, we collaborated with Astrin Biosciences and used their patented isolation technology to enrich CTCs with high purity from the blood of 15 metastatic castration resistant prostate cancer (mCRPC) patients. The enriched CTCs and a patient matched control sample consisting primarily of white blood cells were divided such that RNA and protein could be interrogated from the same patient. Label free unbiased mass spectrometry-based proteomics was used to identify the CTC-enriched proteins and marks the first time a global proteomic assessment has been performed on CTCs from cancer patients. Initial analysis identified over 1,500 peptides corresponding to greater than 500 proteins from each patients’ CTCs; including increased epithelial cell markers in the CTC-enriched sample and increased WBC markers in the control sample. Hallmarks of androgen response and detection of the androgen receptor were also identified in the CTC-enriched proteome. Overall, this study was designed to show the feasibility of obtaining large scale proteomic data from a liquid biopsy and future studies will provide more insight into the clinical utility of such data with a focus on cancer signaling mechanisms and biomarkers. Importantly, as we analyze more patients, we plan to compare the proteomic data with future RNA signatures across mCRPC patients to eventually be able to correlate them with drug response with the overall goal to improve treatment selection and patient outcomes.
Citation Format: Justin M. Drake, Zoi Sychev, Alec Horrmann, Kaylee Judith Smith, Catalina Galeano-Garces, Ali Arafa, Nicholas Heller, Mahdi Ahmadi, Jiarong Hong, Megan Ludwig, Justin Hwang, Emmanuel S. Antonarakis, Jayant Parthasarathy. Unlocking the proteome of metastatic prostate cancer circulating tumor cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR013.
The Problem of Modal Upgrading in Aristotle’s Apodictic Syllogistic
Authors: Botting David 
Published: June 2023

This is another contribution to the unending controversy over the two Barbaras. My approach to the problem is hopefully quite new: I wish to view the issue through the prism of modal upgrading. Modal upgrading occurs when a subject term that has only been predicated of assertorically in the premises is predicated of apodictically either: i) in the conclusion of a given syllogism, or; ii) in some proposition that is derived from either the premises of the given syllogism alone or the premises in combination with other propositions that do not refer to the proposition’s subject term. I call the proposition after it has been upgraded the upgraded proposition.
When a conclusion is the upgraded proposition, it is obviously a different predicate being predicated than was predicated in the premises. Aristotle endorses this kind of upgrading; it is effectively what happens in any valid mixed modal syllogism when the minor premise is not apodictic (e.g., Barbara LXL).
In other cases the upgraded proposition is not a conclusion but still follows from the premises alone. In these cases it is the same predicate being predicated in the upgraded proposition as in the premises, although the quantity of the propositions are different (one is universal, another particular). Aristotle rejects this kind of upgrading and takes its occurrence as sufficient to deny the validity of the given syllogism (e.g., Barbara XLL).
I will describe a third type where both the predicate remains the same and the quantity of the proposition remains the same as in the premise, e.g., the upgrading of “All C are B” to “All C are necessarily B”. In these cases it will turn out that the upgraded proposition is not derived from the premises alone, or at least, not syllogistically from the premises alone. This kind of upgrading too is reason for denying the validity of any syllogism from which the upgraded proposition follows as a consequence. I will show that Barbara LXL entails this kind of modal upgrading and should be rejected for this reason.
Armed with this notion of modal upgrading I want to attack the problem of the two Barbaras in Aristotle’s apodictic syllogistic. Aristotle himself endorses mixed modal Barbara when the major is necessary and the minor is assertoric, thereby endorsing the first kind of modal upgrading, but rejects Barbara when the minor is necessary and the major is assertoric on the grounds that it leads to the second kind of modal upgrading. Theophrastus endorses the peioram rule which rejects both Barbaras on the grounds that the conclusion can only be as strong as the weakest premise. Łukasiewicz endorses both Barbaras. I will argue that both Barbaras lead to unacceptable modal upgrading and should be taken to be invalid for that reason. Hence, I agree with Theophrastus about the two Barbaras; however, I do not endorse the peioram rule because I think that the negative mixed modal syllogisms generally avoid this problem and is mostly correct.
Porphyry’s Life of Pythagoras and Athanasius’ Life of Antony
Authors: Cain Andrew 
Published: June 2023

Abstract
A little over a century ago, it was discovered that Athanasius’ Life of Antony echoes Porphyry’s Life of Pythagoras in two different passages, and scholars have since debated the implications of this clear intertextual linkage. Building on these initial findings, the present article adduces a previously undiscovered third echo of the Porphyrian Life and argues that Athanasius deploys this intertext in order simultaneously to subvert Porphyry’s idealized portraiture of Pythagoras and to elevate his own hagiographic protagonist Antony.
The relationship between temperature, growth rate and body condition of Bufo bufo toadlets prior to their first hibernation
Authors: Reading Christopher , Jofré Gabriela 
Published: June 2023

Abstract
The effect of environmental temperature on the growth and body condition of common toad (Bufo bufo) toadlets was studied during their first terrestrial growth season, following metamorphosis, at a pond in south Dorset, UK, between 2010 and 2021. Toadlet samples were collected annually on the first day of emergence and then approximately once a week until late September/early October. In total, 15-19 samples were collected annually depending on the duration of the toadlet activity season. Toadlet snout-vent length (mm) and body mass (mg) of each captured toadlet was measured and their body condition (Scaled Mass Index: SMI) estimated both annually and for each annual quarter season. Toadlet growth rate and SMI varied between years and were significantly correlated with the duration of their first growth season and its lowest recorded temperature. Growth rate declined as the duration of the growth season increased whilst the reverse was true for SMI. Growth rates also increased as temperatures increased and vice versa for SMI. SMI was inversely correlated to growth rate and suggest that toadlets may enter their first hibernation larger, but in poorer condition, following warm summers than cool summers, and that this may have the potential to reduce their survivorship during a following mild winter. Assuming that similar relationships, between growth rates, body condition and environmental temperatures are not restricted to toadlets during their first terrestrial growth season, then this scenario may also be applicable to subsequent juvenile stages, further increasing the potential consequences for individual survival and fitness.