bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplemental Material: Early Paleozoic crustal anatexis during Wuyi-Yunkai orogenesis: Insights from zircon of Fuhuling migmatites in the Yunkai region, South China
Authors: Zhang Junhao , Huang Qiangtai
Published: June 2023

Table S1: Whole-rock composition of biotite-quartz schist, migmatite, leucosome, melanosome, and migmatitic granite samples from Fuhuling in the Yunkai region. Table S2: Zircon U-Pb data of the metatexite, diatexite, and biotite monzogranite from Fuhuling. Table S3: Zircon trace element data of the metatexite, diatexite, and biotite monzogranite from Fuhuling.
From danger to destination: changes in the language of endemic disease during the COVID-19 pandemic
Authors: Nerlich Brigitte , Jaspal Rusi
Published: June 2023

At the beginning of 2022, the word ‘endemic’ became a buzzword, especially in the UK and the USA, and a kernel for the formation of novel social representations of the COVID-19 pandemic. The word normally refers to a disease which is continuously present, whose incidence is relatively stable and is maintained at a baseline level in any given locality. Over time, ‘endemic’ migrated from scientific discourse into political discourse, where it was mainly used to argue that the pandemic was over and people now had to learn to ‘live with’ the virus. In this article, we examine the emerging meanings, images and social representations of the term ‘endemic’ in English language news between 1 March 2020 and 18 January 2022. We observe a change over time, from the representation of ‘endemic’ as something dangerous and to be avoided to something desirable and to be aspired to. This shift was facilitated by anchoring COVID-19, especially its variant Omicron, to ‘just like the flu’ and by objectifying it through metaphors depicting a path or journey to normality. However, the new language of hope and aspiration did not go entirely unchallenged. Our analysis suggests that two competing polemic social representations emerged: one of endemicity as hope and aspiration and the other focusing on misguided optimism. We discuss these findings in the context of emerging polarisations in beliefs about the pandemic, politics and disease management.
A Glimpse into the Past: What Ancient Viral Genomes Reveal About Human History
Authors: Guzmán-Solís Axel A. , Navarro Miguel Alejandro , Ávila-Arcos María C. , Blanco-Melo Daniel
Published: June 2023

Humans have battled viruses for millennia. However, directly linking the symptomatology of disease outbreaks to specific viral pathogens was not possible until the twentieth century. With the advent of the genomic era and the development of advanced protocols for isolation, sequencing, and analysis of ancient nucleic acids from diverse human remains, the identification and characterization of ancient viruses became feasible. Recent studies have provided invaluable information about past epidemics and made it possible to examine assumptions and inferences on the origin and evolution of certain viral families. In parallel, the study of ancient viruses also uncovered their importance in the evolution of the human lineage and their key roles in shaping major events in human history. In this review, we describe the strategies used for the study of ancient viruses, along with their limitations, and provide a detailed account of what past viral infections have revealed about human history.
Quality Control Strategy and Evaluation Algorithm for Noncontact Instrument Testing
Authors: Jin Xue , Tang Jiayue
Published: June 2023

The test quality of noncontact instruments is an important issue that has aroused social concern at present, which is also widely used in the power quality management of telecommunication systems. The fuzzy logic algorithm can be used in power quality testing to analyze the power quality of electrical equipment. Based on the advantage of the fuzzy logic algorithm, this paper studied the quality control strategy and evaluation algorithm of noncontact instrument testing and drew a conclusion. In terms of the investigation on the safety of power quality measurement, it was concluded that the method of noncontact instrument testing power quality improved the safety of voltage quality, current quality, power supply quality, and power consumption quality. In the investigation of the accuracy of the power quality measurement, it was concluded that the noncontact instrument was used to measure power quality, which greatly improved the accuracy of measurement. In terms of the investigation on the rapidity of the power quality measurement, it was concluded that the use of the noncontact instrument to test power quality could greatly improve the rapidity of current quality measurement and that the rapidity of the power quality measurement could be improved by more than 70%. In the aspect of economic investigation of the power quality measurement, it was concluded that the use of the noncontact instrument to test power quality could greatly improve the economic efficiency of the power quality measurement. In the aspect of fuzzy logic evaluation in power quality management, it was concluded that most of the power quality grades of the selected research objects were excellent. Therefore, the fuzzy logic method was very meaningful for power quality evaluation.
Prevalence of Rape and Its Predictors among Female Students Attending Elementary Schools: In the Case of Kule Refugee Camp, Gambella, Southwest Ethiopia—A Cross-Sectional Study
Authors: Kong Bhan Sudan , Gezimu Wubishet , Demeke Ababo , Duguma Abdissa
Published: June 2023

Background. Tragically, rape victims keep their ailments a secret from the police and their family members or significant others out of concern for societal stigma. The prevalence and severity of rape are highest among minorities, including girls and children who live as refugees. The current study assessed the prevalence of rape and its predictors among female students attending elementary schools in the Kule refugee camp, Gambella, southwest Ethiopia. Methods. An institution-based cross-sectional study was conducted from May 15 to 25, 2022, using an interviewer-administered structured questionnaire. A total of 211 participants were selected using a simple random sampling technique. The collected data were entered into EpiData and then exported to SPSS version 23 for analysis. The descriptive statistics were presented using frequencies, means, and standard deviations. A binary logistic regression model was used to test the association between the outcome and explanatory variables. The multivariable analysis included variables with

p

values of less than 0.25. Finally, statistical significance was declared at a

p

value of less than 0.05. Results. A total of 210 participants were involved in this study, which has a 99.5% response rate. Of these, 73 (34.8%) were subjected to rape. Shockingly, the majority (79.5%) of those who experienced rape reported that their perpetrator did not use a condom. Smoking (AOR: 4.3; 95% CI: 1.61, 10.93), drinking alcohol (AOR: 3.2; 95% CI: 1.43, 7.03), and having a boyfriend (AOR: 2.81; 95% CI: 21, 4.05) were found to be factors associated with rape. Conclusion. This study found a high prevalence of rape in the study area. The study also identified that participants’ behaviors, such as having a boyfriend, smoking, and drinking alcohol, predispose them to rape. Therefore, we recommend that the camp’s administrative bodies and humanitarian service organizations strengthen the preventive measures against rape crime, including the reinforcement of solid laws against perpetrators.
Psychological Care for Children and Adolescents with Diabetes and Patient Outcomes: Results from the International Pediatric Registry SWEET
Authors: Chobot Agata , Eckert Alexander J. , Biester Torben , Corathers Sarah , Covinhas Ana , de Beaufort Carine , Imane Zineb , Kim Jaehyun , Malatynska Anna , Moravej Hossein , Pokhrel Santosh , Skinner Timothy , Study Group SWEET
Published: June 2023

Background. Easy accessibility of psychosocial care is recommended for children and adolescents with type 1 diabetes (T1D) and their families. Objective. The study aimed to evaluate the availability of psychological care and its associations with glycemic control in centers from the multinational SWEET (Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference) registry. Subjects. Centers participating in SWEET (n = 112) were invited to complete a structured online survey, designed for the study, regarding their psychology service. Methods. Linear/logistic regression models adjusted for several confounders were used to determine the patient’s HbA1c (mmol/mol) and odds ratios (ORs) for diabetic ketoacidosis (DKA) and severe hypoglycemia (SH) related to survey responses. Results. 76 (68%) centers with relevant data in the SWEET database responded to the survey. Psychological services were provided in 89% of the centers. The availability of psychological service in centers was associated with a slightly lower HbA1c of the patients (72 (62–82) vs. 67 (57–78) mmol/mol,

p
=
0.004

) and significantly lower odds for DKA (1.8 (1.1–2.9),

p
=
0.027

). Conclusions. Most centers from the SWEET registry offered some form of structured psychological care, consistent with the recommendations of easy access to psychosocial care for children and adolescents with T1D and their families. The main benefit of this psychological care appears to be in the incidence of DKA between centers. The study data also continues to emphasize the importance of treatment targets in shaping the outcomes of pediatric diabetes care. These findings should inform health-service planners and the diabetes community of the importance of mental healthcare in multidisciplinary diabetes teams.
Preservative Potential of Biobased Oils on the Physiochemical Quality of Orange Fruits during Storage
Authors: Abdul-Rahaman Adams , Irtwange Simon V. , Aloho Kortse P.
Published: June 2023

In recent times, there is an increasing global interest in the consumption of safe, healthy fruits and juices without synthetic materials and preservatives. The objective of the study was to evaluate the physiochemical quality of Valencia, Ibadan sweet, and Washington varieties of sweet orange (Citrus sinensis L. Osbeck) fruits in response to eucalyptus leaves, orange peels, and their combination during 30 days of storage at ambient 25°C and 80-85% relative humidity. The experimental design was a

4
×
3

factorial design in a completely randomized design. The results showed that orange fruits coated with the combined oils of eucalyptus leaves and orange peels significantly (

P
≤
0.05

) delayed weight changes, firmness, titratable acidity, total soluble solids concentration, vitamin C content, and higher acceptability with extended shelf life compared to uncoated control fruits. Valencia (V1) exhibited a significant beneficial effect of the biobased oils treatment on weight, firmness, and vitamin C content. In Ibadan sweet (V2) fruits, biobased oils enhanced titratable acidity with relatively better total soluble solids and marketability. Biobased oils are known to reduce fruit weight loss by limiting respiration rate. It was concluded that the combined biobased oil had the best effect on keeping citrus fresh. These findings provide a practical basis for the application of combined biobased oil as an effective preservative to improve the storage quality of citrus fruits.
LXR Signaling-Mediated Cholesterol Metabolism Reprogramming Regulates Cancer Cell Metastasis
Authors: Singh Pankaj K. , Mehla Kamiya
Published: June 2023

Metastasis is a key contributor to mortality in patients with cancer. While many regulators of metastasis have been identified, critical targets to prevent and inhibit metastatic tumor growth remain elusive. A recent study in this issue of Cancer Research by Deng and colleagues compared gene expression signatures between primary esophageal squamous cell carcinoma tumors and metastatic tumors and combined the analysis with genes induced in metastatic cancer cell lines, which identified anoctamin 1 (ANO1) as a key driver of metastasis. ANO1 caused cholesterol accumulation by inhibiting LXR signaling and decreased cholesterol hydroxylation by downregulating the expression of cholesterol hydroxylase CYP27A1. ANO1 also regulated tumor cell–fibroblast cross-talk that contributed to inflammatory cytokine signaling (IL1β) and metastasis. Through in silico analysis, the study identified a novel small-molecule inhibitor of ANO1 that decreased tumor burden at a metastatic site. These studies provide novel insights into the role of ANO1 in cellular cholesterol metabolism and associated signaling in mediating metastasis.

See related article by Deng et al., p. 1851
Abstract A005: Androgen receptor variants mRNA absolute quantification in prostate cancer cell models
Authors: Larson Gabrianne , Sychev Zoi , Plymate Stephen , Corey Eva , Drake Justin M.
Published: June 2023

Background: Patients treated with Androgen Deprivation Therapy (ADT) have been shown to increase the expression of constitutively active Androgen Receptor (AR) splice variants (AR-Vs). These splice variants lack the ligand binding domain at the C-terminus of AR, required for binding to antiandrogen therapies. AR-V7 has also been correlated to the development and progression of castration resistant prostate cancer (CRPC). As not all circulating tumor cells (CTCs) contain AR-V7, we hypothesized that other AR-Vs are involved in the mechanism of resistance to ADT commonly seen in CRPC. To test this, we developed an mRNA quantitative assay targeting AR-Vs and then correlated our results with a targeted mass spectrometry (MS) based protein assay. This work will provide a feasible quantification of AR-V transcripts and that may provide a stratification for predicted responses to ADT treatment in patients that could be useful to clinicians. Methods: The absolute copy number of total AR, AR-V2, AR-V7, AR-V12, and AR-V23 were determined in eight different PCa cell lines and 48 patient derived xenografts (PDXs) using qRT-PCR assays. We performed siRNA targeting of these variants to evaluate primer specificity by evaluating knockdown efficiencies. These results will be correlated to targeted MS quantification of AR-Vs in each cell model. Results: We found that the most highly expressed variants in PCa cell lines were AR-V7 and AR-V12. In the LuCaP PDX model, AR-V12 was shown to have the highest expression of the AR-Vs tested. Specificity of AR-V knockdown was tested using AD-1 (which only expresses the full- length AR transcript) and R1-D567 (which only expresses AR-V567es, an AR-V12-like variant) cell lines. Conclusions: We were able to determine the landscape of AR-V mRNA expression in eight PCa cell lines and in 48 PDX tumor samples. This data will be correlated to protein expression currently being analyzed using a targeted MS method developed in our lab. Our work will be useful to help clinicians stratify PCa patients based on their AR-V expression profiles. This will establish a prognostic biomarker program that measures AR-V proteins in real time from clinical biopsy tissues, circulating tumor cells, or exosomes and informs the clinician on which course of treatment may be effective for each patient. Establishing a CRPC biomarker other than AR-V7 that can help explain the AR-V7 negative CRPC patients could eventually improve clinical application and predictive treatment outcomes.

Citation Format: Gabrianne Larson, Zoi Sychev, Stephen Plymate, Eva Corey, Justin M. Drake. Androgen receptor variants mRNA absolute quantification in prostate cancer cell models [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 A005.
Abstract A012: Adaptive and non-adaptive gene expression responses in prostate cancer during androgen deprivation
Authors: Nätkin Reetta , Pennanen Pasi , Syvälä Heimo , Bläuer Merja , Kesseli Juha , Tammela Teuvo L.J. , Nykter Matti , Murtola Teemu J.
Published: June 2023

Development of novel and efficient treatments for advanced prostate cancer (PCa) requires better understanding of the cellular mechanisms behind the transition to castration resistant prostate cancer (CRPC). We created long-term cell cultures to model the development of castration resistance. Using a low passage VCaP cells as an initial model, we first created a highly testosterone-dependent PCa cell line (VCaP-T) and then a subclone cell line developing the ability to grow at low testosterone concentration (VCaP-CT). Adaptation to low testosterone was solely due to long term culturing and experimental work confirmed for example higher AR expression and antiandrogen resistance in VCaP-CT compared to VCaP-T. With the developed models we aimed to uncover persistent and adaptive responses to testosterone level and to identify genes that potentially contribute to transition and proliferation of the castration resistant cells through androgen receptor (AR) regulation. Expression levels were measured using RNA-seq. We defined AR-associated genes as the ones with changes due to testosterone depletion in VCaP-T (418 genes) and further adaptive genes as the ones that restored expression level in VCaP-CT (134 genes). Interestingly, we identified 151 genes that were non-AR-associated in VCaP-T but gained the association in VCaP-CT cells. Genes gaining the AR-association were also hypothesized to be important for CRPC progression and castration resistant cells. We validated and assessed the clinical significance of the model and the findings using The Cancer Genome Atlas Prostate Adenocarcinoma data and multivariate Cox regression analysis. Expressions of 47 AR-associated or association gaining genes were statistically significant markers for progression-free survival. These included genes related to immune response, adhesion and transport. Genes ABCC5, SPRED3, TMPRSS11F, SPARC, SLC1A1, SATB1, PDGFRB and C1QTNF6 showed strong evidence being associated with tumor stage and aggressiveness in addition to progression-free survival. Taken together, we identified and validated multiple genes being linked with progression of prostate cancer and proposed several novel risk genes. These findings increase knowledge on mechanisms of castration resistance and may open new possibilities for treatments. Identified genes have potential to be used as biomarkers or therapeutic targets after further studies.

Citation Format: Reetta Nätkin, Pasi Pennanen, Heimo Syvälä, Merja Bläuer, Juha Kesseli, Teuvo L.J. Tammela, Matti Nykter, Teemu J. Murtola. Adaptive and non-adaptive gene expression responses in prostate cancer during androgen deprivation [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 A012.
Abstract A022: Alternative polyadenylation as a therapeutic vulnerability in prostate cancer
Authors: Tietz Kiel T. , McClukey Braedan M. , Munro Sarah A. , Miller Conor R. , Dehm Scott M.
Published: June 2023

Prostate cancer is the second leading cause of male cancer death in the United States. While localized disease can be cured by radiation or surgery, metastatic prostate cancer presents a clinical challenge. Metastatic prostate cancer can initially be controlled by endocrine therapies that target the androgen receptor (AR), however, these tumors will inevitably develop resistance. This stage of the disease, termed castration-resistant prostate cancer (CRPC), is responsible for the majority of prostate cancer-specific deaths. Current treatment options for CRPC patients are not curable and highlight the need to develop novel therapeutic options that will more effectively treat the disease. Spliced mRNA molecules undergo cleavage and polyadenylation ~25 base pair downstream from a canonical 5’AAUAAA poly(A) site located within the 3’ untranslated region (UTR). Shortening of mRNA 3’UTRs through alternative polyadenylation has been found in numerous cancers leading to downregulation of tumor suppressor genes and upregulation of oncogenes. To investigate the function of alternative polyadenylation in CRPC, we conducted a loss-of-function screen of mRNA polyadenylation factors in hormone-sensitive LNCaP cells and hormone-insensitive LNCaP95 and 22Rv1 cells. We found that knockdown of the cleavage and polyadenylation specificity factor (CPSF) component, CPSF1, inhibited growth of all cell lines. To define pathways that are regulated by CPSF1 in prostate cancer, we identified CPSF1-dependent gene expression using RNA-seq and CPSF1-dependent poly(A) sites using poly(A)-ClickSeq (PAC-Seq). Gene set enrichment analysis of RNA-seq data revealed the Glycolysis Hallmark and Hypoxia Hallmark gene sets were positively regulated by CPSF1. Analysis of PAC-seq data revealed global induction of poly(A) sites distal to 3’ UTRs upon CPSF1 knockdown. By integrating these RNA-seq and PAC-seq datasets, we have identified AR-independent pathways that may be attractive for therapeutic targeting in prostate cancer. This study has revealed post-transcriptional gene regulation by CPSF1 as an important pathway used in CRPC.

Citation Format: Kiel T. Tietz, Braedan M. McClukey, Sarah A. Munro, Conor R. Miller, Scott M. Dehm. Alternative polyadenylation as a therapeutic vulnerability 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 A022.
Abstract A023: RNF185 modulates prostate cancer metastatic potential through regulation of epithelial-mesenchymal transition
Authors: Van Espen Benjamin , Fazli Ladan , Oo Htoo Z. , Murad Rabi , Gleave Martin , Ronai Ze'ev A.
Published: June 2023

RNF185 is a RING finger domain-containing ubiquitin ligase which is anchored to the ER and resemble RNF5, a ubiquitin ligase implicated in ER associated degradation. In prostate cancer, deregulation of the expression or activity of several ubiquitin ligases has been shown to contribute to disease progression (e.g., Siah2, SPOP, RNF6). Analysis of prostate tumor patient data revealed a negative correlation between RNF185 expression and prostate adenocarcinoma progression and metastasis. Supporting these observations, several prostate cancer cell lines exhibited greater migration and invasion capabilities upon RNF185 depletion, in vitro. Subcutaneous inoculation of mouse prostate cancer MPC3 cells, stably expressing shRNA against RNF185, resulted in larger tumors and more frequent lung metastases in NSG mice. These results suggest that the increased metastatic potential associated with lower RNF185 levels may depend on molecular changes intrinsic to the tumors cells. RNA-sequencing and Ingenuity Pathway Analysis of RNF185-depleted compared to control MPC3 cells identified wound healing and cellular movement among the most significantly upregulated pathways in RNF185-depleted cells. Transcription regulators of Epithelial-Mesenchymal Transition (EMT) Snai2 and Zeb1 were among the most upregulated genes that were predicted to be activated based on the expression of their target genes. Comparison between differentially expressed genes in patients with low RNF185 expression, and RNF185-depleted cell lines (from mouse and human prostate tumors) confirmed deregulation of genes implicated in EMT. Taken together, our results identify RNF185 as gatekeeper of prostate cancer metastasis, via its control of EMT genes implicated in cell motility and metastasis.

Citation Format: Benjamin Van Espen, Ladan Fazli, Htoo Z. Oo, Rabi Murad, Martin Gleave, Ze'ev A. Ronai. RNF185 modulates prostate cancer metastatic potential through regulation of epithelial-mesenchymal transition [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 A023.
Abstract A027: Identification and characterization of PLUTO-201, a novel lncRNA associated with prostate cancer metastasis
Authors: Li Haolong , Younger Noah , Shin Hyun Jin , Malik Bhavna , Zhao Shuang G. , Pitchiaya Sethuramasundaram , Calvert Marsha , Zhang Meng , Chang Laura , Chesner Lisa , Hua Junjie , Li Kathy , Kothari Vishal , Egusa Emily , Chou Jonathan , Das Rajdeep , Burlingame Alma , Chinnaiyan Arul M. , Li Hui , Feng Felix Y.
Published: June 2023

Prostate cancer is the most common non-cutaneous malignancy in men, accounting for approximately 268,000 cases and 35,000 deaths in the United States each year. This disease is a heterogeneous entity with a wide spectrum of clinical behaviors and outcomes - while a majority of men will be cured of early-stage prostate cancer, approximately 20% will develop metastatic disease, which is incurable and ultimately fatal. Despite extensive investigation, the factors promoting aggressive prostate cancer are incompletely understood. Using recently reported microarray data representing a comprehensive analysis of lncRNA prevalence across thousands of patients with prostate cancer, we now report the identification of a novel lncRNA, Prostate Locus of Uncharacterized Transcript Outlier 201 (PLUTO-201), which is strongly associated with metastasis and poor overall survival in men with prostate cancer. We find that in vitro manipulation of PLUTO-201 expression levels in prostate cancer cell lines modulates proliferation rates and markers of aggressive phenotype. Further investigation shows that PLUTO-201 localizes to the nucleus and regulates transcription of multiple genes including those responsible for steroid biosynthesis and the MHC class 1 complex, driving increased growth in androgen-depleted conditions and decreased susceptibility to T cell-mediated cytotoxicity. Overall, our findings nominate PLUTO-201 as a driver of aggressive prostate cancer phenotypes and poor clinical outcomes and suggest possible mechanisms accounting for this activity.

Citation Format: Haolong Li, Noah Younger, Hyun Jin Shin, Bhavna Malik, Shuang G. Zhao, Sethuramasundaram Pitchiaya, Marsha Calvert, Meng Zhang, Laura Chang, Lisa Chesner, Junjie Hua, Kathy Li, Vishal Kothari, Emily Egusa, Jonathan Chou, Rajdeep Das, Alma Burlingame, Arul M. Chinnaiyan, Hui Li, Felix Y. Feng. Identification and characterization of PLUTO-201, a novel lncRNA associated with prostate cancer metastasis [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 A027.
Abstract A033: Exploring synthetic lethality of targeting miR346-unfolded protein response dependent DNA damage response mechanisms in treatment-resistant prostate cancer
Authors: Doultsinos Dimitrios , Mills Ian , Fletcher Claire
Published: June 2023

Background: The Unfolded Protein Response (UPR) is a key homeostatic mechanism that is activated during endoplasmic reticulum (ER) stress caused by both intrinsic (genomic instability, metabolic demand) and extrinsic (chemo/radiotherapy, nutrient deprivation, hypoxia) factors. IRE1 is the main UPR transducer, signalling the transcription factor XBP1, and IRE1 Regulated Dependent Decay (RIDD) to resolve ER stress by controlling the expression of mRNA and miRNAs. IRE1 also regulates aspects of the DNA damage response (DDR) and IRE1-binding drugs have clinical effects as monotherapies or as adjuvants to chemotherapeutics. One miRNA involved in both the DDR and IRE1 biology is miR-346, which we have shown to cause widespread DNA damage in prostate cancer (PCa), sensitising PCa to DNA damaging drugs and associating with improved PCa outcomes. Rationale: In RNAseq data datasets we have shown that miR-346 causes a widespread transcriptional downregulation of DDR markers whilst we observed the opposite in IRE1-CRISPR-KO PCa cells. We have also developed novel IRE1 modulators that sensitise cancers to chemotherapy in vivo. These findings offer a strong rationale to explore co-targeting of miR-346 and IRE1 in the presence of DNA damaging agents to treat aggressive forms of PCa. Consequently, we want to elucidate the exact biology underpinning the miR346-IRE1/XBP1/RIDD-DDR axis to prognosticate treatment groups with gene signatures as proxies of PARPi/chemotherapeutic susceptibility. Impact: If miR-346 is a downstream effector of IRE1 activity, then an IRE1 prognostic signature can act as proxy for stratification and selection of patients for miR-346 treatment as sensitiser to DNA damaging agents whilst if miR-346 and IRE1 work in parallel, we could achieve clinically significant results by exploiting synthetic lethality. By stratifying large cohorts through IRE1/miR-346/DDR signatures (personalised precision medicine) we can increase the pool of patients for whom DNA damaging agents are effective by inducing a BRCAness phenotype, improving treatment responses and quality of life.

Citation Format: Dimitrios Doultsinos, Ian Mills, Claire Fletcher. Exploring synthetic lethality of targeting miR346-unfolded protein response dependent DNA damage response mechanisms in treatment-resistant 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 A033.
Abstract A045: Whole transcriptome analysis of paired African American prostate cancer cell lines
Authors: Lee Kristi Y. , Beatson Erica L. , Chau Cindy H. , Price Douglas K. , Figg William D.
Published: June 2023

Recent investigations on patient race have begun to characterize biological differences in prostate cancer, particularly among patients of African ancestry. Despite clinical trends continuously demonstrating this health disparity, very few African American cell line models exist for downstream molecular investigations, and even fewer have undergone proper characterization of their expression profiles. Here, we characterize the transcriptome of the non-malignant RC-77 N/E and malignant RC-77 T/E prostate epithelial cell lines previously established from prostate specimens from the same African American patient with early-stage primary prostate cancer. Total RNA sequencing was performed on the paired cell lines using Illumina NextSeq 2000 P2 to build transcriptomic profiles that have previously been undetermined. Following data analysis and normalization, we identified 369 genes with significant upregulation in the RC-77 T/E cell line in comparison to its normal counterpart. Among the top 15 upregulated genes, half of them were previously characterized in prostate cancer but not in the context of patient race. We further compared the transcriptome of RC-77 T/E to that of the African American metastatic MDA-PCa-2b. Finally, we analyzed differential gene expression by race among prostate cancer patients in The Cancer Genome Atlas (TCGA) to correlate our transcriptomics findings on the cell line level with that on the population level. These findings may allow for more targeted assessments of genes that are dependent on race as molecular tools are established to narrow the health disparities gap in prostate cancer.

Citation Format: Kristi Y. Lee, Erica L. Beatson, Cindy H. Chau, Douglas K. Price, William D. Figg. Whole transcriptome analysis of paired African American prostate cancer cell lines [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 A045.
Abstract A068: Prostate luminal progenitors as the cell-of-origin for androgen receptor-independent prostate cancer
Authors: Chua Chee Wai
Published: June 2023

In the recent years, we have witnessed the emergence of androgen receptor (AR)-independent prostate cancer (AIPC) with the clinical use of second-generation androgen deprivation therapy, namely Enzalutamide and Abiraterone. Unluckily, treatment options for the end-stage AIPC patients are mainly palliative but not curable. However, the cellular origin and mechanisms involved in the evolution of AIPCs remain unclear. Previously, we have discovered that AR is not required for the survival and maintenance of progenitor property of CA stration- R esistant N kx3.1-expressing cells (CARNs), thus highlighting the AR-independent nature of this luminal progenitor subset. Interestingly, AR-deleted CARNs demonstrate gene expression profile that is highly similar to human neuroendocrine prostate cancer (NEPC), a subtype of AIPC. Moreover, upon Pten deletion and mutated Kras activation, AR-deleted CARNs can generate tumors exhibiting focal neuroendocrine differentiation, indicating the ability of CARNs to serve as a cell-of-origin for NEPC. Based on these observations, we hypothesize that AR-independent prostate luminal progenitor subsets are capable of initiating AIPC upon oncogenic transformation, while the transformed cells represent distinct subsets in AIPC that possess cancer stem cell property. In our latest assessments, we have validated the ability of CARNs to initiate NEPC using a novel genetically-engineered mouse model of prostate cancer. Moreover, we have established tumor organoids from CARNs-initiated AIPC, which are capable of generating allografts in both immunodeficient and immunocompetent mice, implying their immune-evading capability. Lastly, we have performed small molecule library screening on the transformed CARNs-derived tumor organoids to identify effective treatment options for AIPC. Taken together, our study has provided novel insights into the cellular origin of AIPCs. Consequently, targeting these prostate luminal progenitors-initiated tumor cells as well as their molecular property may serve as novel therapeutic strategies to overcome AR independence in prostate cancer.

Citation Format: Chee Wai Chua. Prostate luminal progenitors as the cell-of-origin for androgen receptor-independent 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 A068.
Abstract A074: In vivo modeling of castration-resistant prostate cancer in the immunodeficient SRG OncoRat
Authors: Walton R. Grace , Begemann Diane , Dunn Cynthia , Steffey Valeriya , Ross Abigail , Haque Razoanul , Noto Fallon K.
Published: June 2023

Prostate cancer is the second most common cause of cancer-related deaths in American men. When locally targeted approaches fail, androgen deprivation therapy is administered to block androgen stimulated prostate cancer growth signals. Most tumors initially exhibit rapid and dramatic regression following androgen deprivation therapy. However, many patients treated with androgen deprivation therapy will have disease recurrence and develop castration-resistant prostate cancer (CRPC), which is highly metastatic with poor survival rates. To improve clinical options for CRPC, pre-clinical animal models that closely recapitulate the human disease course are an essential component of drug development. SRG OncoRats are highly immunocompromised Rag2/Il2rg double knockouts that lack mature B cells, T cells, and circulating NK cells. To establish an in vivo model of CRPC, we inoculated VCaP cells subcutaneously into the hind-flank of SRG OncoRats and monitored tumor growth. On Day 24 rats underwent orchiectomy and tumor growth was further monitored through Day 46. As seen with androgen deprivation therapy in humans, VCaP tumors initially regressed in the SRG OncoRats. However, VCaP tumors resumed growth 14 days after castration, faithfully modeling the progression of CRPC. After tumor regrowth, animals were enrolled into a therapeutic efficacy study that mimics the current clinical challenges in prostate cancer treatment.

Citation Format: R. Grace Walton, Diane Begemann, Cynthia Dunn, Valeriya Steffey, Abigail Ross, Razoanul Haque, Fallon K. Noto. In vivo modeling of castration-resistant prostate cancer in the immunodeficient SRG OncoRat [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 A074.
Abstract B007: New generation mTOR blocker sensitizes prostate cancer models to AR-targeting therapy
Authors: Li Shuang , La Manna Federico , Chouvardas Panagiotis , Thalmann George , Kruithof-de Julio Marianna
Published: June 2023

Advanced stage prostate cancers (PCa) can develop bone metastasis, a lethal feature of castration-resistant prostate cancer (CRPC) for which no curative options are currently available. Androgen deprivation therapy (ADT) is the main therapeutic strategy for treating advanced PCa; patients with bone metastasis, however, are frequently developing resistance to ADT, progressing to CRPC. Dysregulation of the mTOR pathway has been linked with AR reactivation and with progression to CRPC, and mutations in targets of the PI3K/Akt/mTOR pathway are frequently found in CRPC patients. This study investigates the effect of synergistic AR and mTOR pathways blockade on therapy resistance in advanced PCa in vitro and in vivo. LNCaP and LAPC4 cells were treated in vitro with AR blockers (apalutamide, enzalutamide), mTOR blockers (rapamycin, everolimus, MLN0128 or Rapalink-1) or a combination of both blockers. Viability was measured in a timecourse from 1 to 10 days after drug administration using CellTiter Acqueous 96. To mimick ADT in vitro, cells were cultured for 7 days in charcoal-stripped serum in medium without dihydroxytestosterone or phenol red before the drug screening. Two already established PDX models of bone-metastatic PCa, BM18 and LAPC9 respectively androgen-dependent and -independent, were used to assess the effect of combined ADT and mTOR-targeting therapy in vivo. Both LNCaP and LAPC4 models showed a higher sensitivity to MLN0128 and Rapalink-1 compared to rapalogs, LAPC4 cells in particular were more sensitive than LNCaP cells to mTOR inhibitors. AR blockers were moderately effective and only at concentrations between 10 and 100 µM, when used alone. However, treatment with sublethal doses of Rapalink-1 (0.001-0.01 µM) sensitized both cell lines to 2- to 3-log fold lower concentrations of apalutamide. In vivo, treatment with Rapalink-1 alone significantly reduced the growth rate of LAPC9 PDX, while co-treatment with ADT and Rapalink-1 resulted in regression in this CRPC model, a result not achievable by either treatment alone. Treatment with Rapalink-1, while effectively reducing cell viability in vitro already when used alone, could sensitize the tested models to AR blockers, at clinically relevant concentrations. In vivo treatment with Rapalink-1 was well-tolerated and sufficient to control the growth of the BM18 PDX model. When used in combination with ADT, it could induce regression of the CRPC model LAPC9.

Citation Format: Shuang Li, Federico La Manna, Panagiotis Chouvardas, George Thalmann, Marianna Kruithof-de Julio. New generation mTOR blocker sensitizes prostate cancer models to AR-targeting therapy [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 B007.
Abstract B013: KLF5 drives basal cell identity to promote prostate cancer lineage plasticity
Authors: Pitzen Samuel P. , Qiu Yinjie , Munro Sarah , Dehm Scott M.
Published: June 2023

The purpose of this study was to characterize the phenotypes and drivers of therapy-induced lineage plastic castration resistant prostate cancer (CRPC). Since the majority of primary prostate cancer presents with a luminal cell identity, which relies on androgen receptor (AR) signaling for growth and survival, AR-targeted therapies have become an effective method of slowing progression. However, CRPC cells can develop resistance through reduced or lost dependence on AR. These cells can transition their identity to neuroendocrine CRPC (NEPC), which lacks AR and expresses neuroendocrine lineage specific markers like chromogranin A. More frequently, these cells display transition to a cell identity that lacks AR and neuroendocrine markers and has been termed double-negative CRPC (DNPC). Identifying effective therapeutic targets to treat or prevent DNPC remains a significant clinical challenge. By utilizing prostate cancer cell lines, patient derived xenografts (PDX), and publicly available data from clinical CRPC specimens, we have identified an upregulation in basal cell identity in a subset of CRPC in response to AR-targeted therapies. Additionally, we show that the stem cell transcription factor KLF5, which is highly expressed in healthy prostate basal cells, is uniquely upregulated in CRPC subtypes displaying basal cell identity. In a cell line model of DNPC, we found that knockdown of KLF5 decreased the expression of genes that define basal cell identity. From these results, we conclude that AR-targeted therapies, while effective at targeting luminal-like adenocarcinoma, promote upregulation of KLF5 which can drive a basal cell identity and AR independence. These studies nominate KLF5 signaling as a potential therapeutic target to block the emergence of basal identity, inhibit prostate cancer lineage plasticity, and increase the durability of AR-targeted therapies.

Citation Format: Samuel P. Pitzen, Yinjie Qiu, Sarah Munro, Scott M. Dehm. KLF5 drives basal cell identity to promote prostate cancer lineage plasticity [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 B013.
Abstract B018: Loss of androgen receptor-mediated repression leads to EphA2 overexpression that promotes cellular dedifferentiation and castration resistance of prostate cancer through noncanonical signaling
Authors: Lingerak Ryan , Wang Bingcheng
Published: June 2023

As a member of Eph subfamily receptor tyrosine kinases, EphA2 has been extensively studied in cancer. It is frequently overexpressed in many different types of human cancer, which is often correlated with tumor progression. We reported recently that EphA2 has diametrically opposite roles in regulating PCa cell differentiation, proliferation, migration, and invasion. In the presence of ligands called ephrin-As, EphA2 canonical signaling inhibits Ras/ERK and PI3K/Akt pathways and suppressed cell proliferation and migration. In contrast, in the absence of ligands EphA2 mediates noncanonical signaling, which promotes chemotactic migration and invasion and accentuates the tumor cell stem properties. Interestingly the ligand-independent noncanonical signaling is correlated with phosphorylation of EphA2 on serine 897 (S897). S897A mutation abolished this ligand-independent effect on cell differentiation and migration and suppressed tumor development in PC3 xenograft model. In mouse prostate, EphA2 is expressed in the stem cell niche together with its cognate ephrin-A ligands in the peri-urethra region but is repressed in AR-positive, differentiated prostate epithelial cells. During progression toward CRPC, ephrin-ligand expression is reduced while EphA2 is overexpressed, facilitating ligand-independent noncanonical signaling by EphA2. Consistent with the negative roles of AR in regulating EphA2 expression, treatment with anti-AR enzalutamide promotes EphA2 expression. In contrast, activating AR with DHT strongly suppressed EphA2 expression. Knockout of EphA2 in the AR+ LAPC4 cells, delayed progression towards castration resistance in vivo. Our results unveiled the previously unknown functional crosstalk between AR and EphA2, and the important role of EphA2 in the malignant progression of prostate cancer.

Citation Format: Ryan Lingerak, Bingcheng Wang. Loss of androgen receptor-mediated repression leads to EphA2 overexpression that promotes cellular dedifferentiation and castration resistance of prostate cancer through noncanonical signaling [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 B018.
Abstract B026: PIM kinases regulates tumor associated macrophage survival and inflammatory signaling
Authors: Clements Amber N. , Warfel Noel A.
Published: June 2023

Prostate tumors are highly infiltrated by immunosuppressive tumor associated macrophages (TAMs). TAMs secrete various factors that promote tumor progression and suppress antitumor immunity, making them a promising therapeutic target. PIM kinases are serine/threonine kinases that are overexpressed in several tumor types including prostate cancer. PIM regulates many signaling pathways that promote cell proliferation and cell survival. However, the role of PIM in macrophages is not well understood. Macrophages express NLRP3, a cytosolic innate immune sensor, that forms a complex with ASC and caspase-1 termed the inflammasome. Activation of the inflammasome leads to release of proinflammatory cytokines including IL-1β and induces pyroptotic cell death. We hypothesize that PIM promotes macrophage survival by suppressing inflammasome activation. To test our hypothesis, we treated mouse bone marrow derived macrophages (BMDMs) with PIM447, a pan-PIM kinase inhibitor, and activated the inflammasome via lipopolysaccharide (LPS) and ATP stimulation. Preliminary data demonstrates that PIM inhibition in BMDMs promotes increased inflammasome activation as indicated by increased cleaved caspase-1 and increased IL-1β secretion. Recent studies have demonstrated that PIM kinases promote immune evasion through the modulation of both tumor cells and immune cells within the tumor microenvironment. We hypothesize that PIM kinase promotes TAM survival leading to increased immunosuppression and immunotherapy resistance in prostate cancer. We treated immunocompetent mice injected with MyC-Cap prostate cancer cells with PIM447. PIM inhibition decreased tumor growth and decreased the presence of tumor associated macrophages. In summary, the results of these studies suggest that PIM plays an important role in regulating macrophage survival and inflammatory signaling. Furthermore, PIM may be a potential target to enhance the efficacy of immunotherapies for the treatment of prostate cancer.

Citation Format: Amber N. Clements, Noel A. Warfel. PIM kinases regulates tumor associated macrophage survival and inflammatory signaling [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 B026.