bluuebunny/crossref_metadata_2025 huggingface dataset:
H∞ Control for the Nonlinear Markov Networked Control System in the Presence of Data Packet Loss and DoS Attacks via Observer
Authors: Wang Yanfeng , Sun Xiaoyue , Tang Youliang , Hou Yuqin , Lin Fanjun , Wang Peiliang , Chen Linfeng
Published: June 2023

The H∞ control issue for nonlinear Markov networked control systems in the presence of data packet loss and periodic denial‐of‐service (DoS) attacks is researched in this paper. First, two Bernoulli random variables are used to describe the packet loss between sensor to controller and controller to actuator. Considering the impact of DoS attacks, the probability of packet loss is set to be different during the attack sleeping interval and the attack active interval. Secondly, an observer is constructed on the controller side, and a comprehensive mathematical model including packet loss and DoS attacks is established. The sufficient conditions for the stochastic stability of the system are derived by the Lyapunov theory, and the design method of the controller and the minimum disturbance suppression performance index are also provided. Finally, a numerical example is utilized to reveal the applicability of the approach.
Efficacy and Feasibility of Remote Cognitive Remediation Therapy in Parkinson’s Disease: A Randomized Controlled Trial
Authors: Hoffman Lisa , Burt Nicholas D. , Piniella Nicholas R. , Baker Madison , Volino Nicole , Yasin Saeed , Jung Min-Kyung , Leder Adena , Sousa Amber
Published: June 2023

Background. Non-motor symptoms of Parkinson’s disease (PD) such as cognitive impairment are common and decrease patient quality of life and daily functioning. While no pharmacological treatments have effectively alleviated these symptoms to date, non-pharmacological approaches such as cognitive remediation therapy (CRT) and physical exercise have both been shown to improve cognitive function and quality of life in people with PD. Objective. This study aims to determine the feasibility and impact of remote CRT on cognitive function and quality of life in patients with PD participating in an organized group exercise program. Methods. Twenty-four subjects with PD recruited from Rock Steady Boxing (RSB), a non-contact group exercise program, were evaluated using standard neuropsychological and quality of life measures and randomized to the control or intervention group. The intervention group attended online CRT sessions for one hour, twice a week for 10 weeks, engaging in multi-domain cognitive exercises and group discussion. Results. Twenty-one subjects completed the study and were reevaluated. Comparing groups over time, the control group (n = 10) saw a decline in overall cognitive performance that trended towards significance (

p
=
0.05

) and a statistically significant decrease in delayed memory (

p
=
0.010

) and self-reported cognition (

p
=
0.011

). Neither of these findings were seen in the intervention group (n = 11), which overwhelmingly enjoyed the CRT sessions and attested to subjective improvements in their daily lives. Conclusions. This randomized controlled pilot study suggests that remote CRT for PD patients is feasible, enjoyable, and may help slow the progression of cognitive decline. Further trials are warranted to determine the longitudinal effects of such a program.
Investigating the Dimensional, Mechanical, and Morphological Properties of Composites Reinforced with Sisal Fibers and Polylactic Acid in Response to Water Absorption
Authors: Kassegn Eshetie , Sirhabizu Belete , Berhanu Temesgen , Buffel Bart , Desplentere Frederik
Published: June 2023

Biocomposites are promising candidates for some engineering applications owing to the growing environmental and economic challenges to replace petrochemical-based polymers with biodegradable polymers. Herein, sisal fiber reinforced polylactic acid (PLA) composite specimens were fabricated using an injection molding machine with and without plasticizer. The weight percentage (wt%) of the sisal fiber varied between 5% and 20%. The effect of the sisal fiber wt% on water absorption resistance and mechanical properties was investigated experimentally using water ageing, mechanical, and morphological studies. The results revealed that tensile and flexural specimens after water ageing exhibited lower tensile and flexural strengths with higher water absorption behavior at 20 wt% sisal fiber than 5 wt% sisal fiber, while the impact strength increased after water ageing. In addition, the sisal fiber/PLA composites exhibited higher water absorption behavior and lower strength and modulus at 20 wt% sisal fiber after water ageing. Moreover, the water absorption decreased with the incorporation of the plasticizer.
Folic Acid‐Functionalized Albumin/Graphene Oxide Nanocomposite to Simultaneously Deliver Curcumin and 5‐Fluorouracil into Human Colorectal Cancer Cells: An In Vitro Study
Authors: Bardania Hassan , Jafari Farajollah , Baneshi Marzieh , Mahmoudi Reza , Ardakani Maryam Tajali , Safari Farshad , Barmak Mehrzad Jafari
Published: June 2023

Background. Nowadays, due to various inherent properties, graphene‐based nanoparticles are widely used in drug delivery research. On the other hand, folate receptors are highly expressed on the surface of human tumor cells. In this work, to enhance the 5‐fluorouracil (5FU) and curcumin (Cur) effects on colon cancer, we constructed a folic acid‐ (FA‐) modified codelivery carrier based on graphene nanoparticles (GO‐Alb‐Cur‐FA‐5FU). Materials and Methods. The HUVEC and HT‐29 were selected for evaluating the antitumor effect of the prepared nanocarriers. The structure of nanocarriers was characterized by FTIR spectroscopy, X‐ray diffraction analysis, TEM microscopy, and a DLS analyzer. The efficiency of the prepared carrier was evaluated by fluorescence microscopy using Annexin V and the PI kit. The cytotoxicity of the carrier’s component individually and the efficacy of the drug carrier GO‐Alb‐Cur‐FA‐5FU were assessed by MTT. Results. The results of the pharmacological tests indicated that the new nanoparticles cause increased apparent toxicity in HT‐29 cells. The apoptosis rate of the HT‐29 and HUVEC cells treated with IC50 values of GO‐Alb‐Cur‐FA‐5FU for 48 h was higher than the cells treated with IC50 values of 5FU and Cur individually, which indicated the greater inhibitory efficacy of GO‐Alb‐Cur‐FA‐5FU than free drugs. Conclusion. The designed GO‐Alb‐CUR‐FA‐5FU delivery system can be applied for targeting colon cancer cells and can be severe as a potential candidate for future drug development.
Nutritional and Phytochemical Composition of Bambara Groundnut (Vigna subterranea [L.] Verdc) Landraces in Kenya
Authors: Chelangat Mercy , Muturi Phyllis , Gichimu Bernard , Gitari Josiah , Mukono Simon
Published: June 2023

Bambara groundnut (Vigna subterranea) is a highly nutritious legume with good drought tolerance attributes and is therefore a suitable candidate for food and nutritional security especially in drought prone areas. This study was conducted to determine the nutritional and phytochemical composition of seventeen Bambara groundnut landraces that were collected from Vihiga, Kakamega, Bungoma, Busia, and Kisumu Counties in Kenya. Prior to characterization, a field experiment was set up in Ishiara Ward in Mbeere North Sub-County in Embu County for two cropping seasons to standardize and multiply the seeds. The experiment was laid out in a Randomized Complete Block Design with three replicates. The harvested seeds were analyzed for their proximate, nutritional, and phytochemical composition using standard procedures. The moisture content ranged from 3.47 to 6.24%, total ash from 3.17 to 4.69%, crude protein from 21.18 to 26.00%, and fats from 4.56 to 7.02%. Iron levels ranged from 4.07 to 5.13 mg/100 g, sodium from 25.14 to 129.66 mg/100 g, potassium from 819.34 to 1,131.80 mg/100 g, and zinc from 0.06 to 0.42 mg/100 g. The tannin levels ranged from 0.01 to 0.04 mg/g, saponins from 0.82 to 1.06 mg/100 g, alkaloids from 0.01 to 0.12 mg/100 g, and flavonoids from 4.07 to 8.45 mg/100 g. The landraces BG-125, BS-148, and BS-145 with relatively higher nutrients composition and those with high levels of phytochemicals such as BS-104 and MU-137 are recommended to plant breeders for further selection and production of certified seeds. These selections will also be promoted to the farmers for production through various extension programs.
Supplementary Figures from Extrachromosomal Amplification of Human Papillomavirus Episomes Is a Mechanism of Cervical Carcinogenesis
Authors: Rossi Nicole M. , Dai Jieqiong , Xie Yi , Wangsa Darawalee , Heselmeyer-Haddad Kerstin , Lou Hong , Boland Joseph F. , Yeager Meredith , Orozco Roberto , Freites Enrique Alvirez , Mirabello Lisa , Gharzouzi Eduardo , Dean Michael
Published: June 2023

Supplementary figures
Supplementary Data from Extrachromosomal Amplification of Human Papillomavirus Episomes Is a Mechanism of Cervical Carcinogenesis
Authors: Rossi Nicole M. , Dai Jieqiong , Xie Yi , Wangsa Darawalee , Heselmeyer-Haddad Kerstin , Lou Hong , Boland Joseph F. , Yeager Meredith , Orozco Roberto , Freites Enrique Alvirez , Mirabello Lisa , Gharzouzi Eduardo , Dean Michael
Published: June 2023

Supplemental tables
Supplementary Table 6 from ANO1 Reprograms Cholesterol Metabolism and the Tumor Microenvironment to Promote Cancer Metastasis
Authors: Deng Chun-Miao , Zhang Guo-Geng , Liu Qin-Wen , Xu Jiao-Jiao , Liu Zhi-Chao , Yang Jing , Xu Tao-Yang , Li Zhi-Gang , Zhang Fan , Li Bin
Published: June 2023

Supplementary Table 6 shows DEGs of EC9706 overexpressing ANO1 and control cells
Data from Extrachromosomal Amplification of Human Papillomavirus Episomes Is a Mechanism of Cervical Carcinogenesis
Authors: Rossi Nicole M. , Dai Jieqiong , Xie Yi , Wangsa Darawalee , Heselmeyer-Haddad Kerstin , Lou Hong , Boland Joseph F. , Yeager Meredith , Orozco Roberto , Freites Enrique Alvirez , Mirabello Lisa , Gharzouzi Eduardo , Dean Michael
Published: June 2023

Abstract
HPV16 is the most oncogenic type of human papillomaviruses (HPV). Integration of HPV into the human genome is an important mechanism of carcinogenesis but is absent in at least 30% of HPV16+ tumors. We applied long-read whole-genome sequencing (WGS) to cervical cancer cell lines and tumors to characterize HPV16 carcinogenesis in the absence of integration. Large tandem arrays of full-length and unique truncated viral genomes integrated into multiple chromosomes were identified in two HPV16+ cell lines. The dispersion of characteristic viral variants to multiple integration sites indicates that viral deletions formed as extrachromosomal DNA (a phenomenon we term HPV superspreading). In addition, we identified an HPV16+ cell line with unintegrated (episomal) DNA that has tandem arrays of full-length, truncated, and rearranged HPV16 genomes (multimer episomes). Cytogenetic analysis of this cell line shows intense extrachromosomal HPV staining, including structures resembling double-minute chromosomes. WGS of HPV16+ cervical tumor samples from Latin America revealed that 11 of 20 tumors with only episomal HPV (EP) had intact monomer episomes. The remaining nine EP tumors had multimer and rearranged HPV genomes. The majority (80%) of HPV rearrangements and deletions disrupted the E1 and E2 genes, and EP tumors overexpressed the E6 and E7 viral oncogenes, a similar profile to tumors with HPV integration. Tumors with putative multimer HPV integrations display HPV multimers and concatemers of human and viral sequences. Our data uncovered a novel mechanism for HPV16 to cause cancer without integration through aberrant episomal replication, forming rearranged, mutated, and multimer episomes.
Significance:
Multimers of the HPV genome are generated in cervical tumors replicating as extrachromosomal episomes, which is associated with deletion and rearrangement of the HPV genome and provides a mechanism for oncogenesis without integration.
Data from CellMinerCDB: NCATS is a Web-Based Portal Integrating Public Cancer Cell Line Databases for Pharmacogenomic Explorations
Authors: Reinhold William C. , Wilson Kelli , Elloumi Fathi , Bradwell Katie R. , Ceribelli Michele , Varma Sudhir , Wang Yanghsin , Duveau Damien , Menon Nikhil , Trepel Jane , Zhang Xiaohu , Klumpp-Thomas Carleen , Michael Samuel , Shinn Paul , Luna Augustin , Thomas Craig , Pommier Yves
Published: June 2023

Abstract
Major advances have been made in the field of precision medicine for treating cancer. However, many open questions remain that need to be answered to realize the goal of matching every cancer patient to the most efficacious therapy. To facilitate these efforts, we have developed CellMinerCDB:NCATS (https://discover.nci.nih.gov/rsconnect/cellminercdb_ncats/), which makes available activity information for 2,675 drugs and compounds, including multiple non-oncology drugs and 1,866 drugs and compounds unique to the National Center for Advancing Translational Sciences (NCATS). CellMinerCDB:NCATS comprises 183 cancer cell lines with 72 unique to NCATS including some from previously understudied tissues of origin. Multiple forms of data from different institutes are integrated, including single and combination drug activity, DNA copy number, methylation and mutation, transcriptome, protein levels, histone acetylation and methylation, metabolites, CRISPR and miscellaneous signatures. Curation of cell lines and drug names enables cross-database (CDB) analyses. Comparison of the datasets is made possible by the overlap between cell lines and drugs across databases. Multiple univariate and multivariate analysis tools are built-in, including linear regression and LASSO. Examples have been presented here for the clinical topoisomerase I (TOP1) inhibitors topotecan and irinotecan/SN-38. This web-application provides both substantial new data and significant pharmacogenomic integration allowing exploration of interrelationships.
Comparative Genomic Analysis of Pancreatic Acinar Cell Carcinoma (PACC) and Pancreatic Ductal Adenocarcinoma (PDAC) Unveils New Actionable Genomic Aberrations in PACC
Authors: Florou Vaia , Elliott Andrew , Bailey Matthew H. , Stone David , Affolter Kajsa , Soares Heloisa P. , Nevala-Plagemann Chris , Scaife Courtney , Walker Phillip , Korn W. Michael , Lou Emil , Shroff Rachna T. , Hosein Peter J. , Garrido-Laguna Ignacio
Published: June 2023

Purpose:

Pure pancreatic acinar cell carcinomas (PACC) are rare malignancies with no established treatment. PACC demonstrates significant genetic intertumoral heterogeneity with multiple pathways involved, suggesting using targeted cancer therapeutics to treat this disease. We aggregated one of the largest datasets of pure PACC to examine the genomic variability and explore patient-specific therapeutic targets.

Experimental Design:

PACC specimens (n = 51) underwent next-generation sequencing of DNA (n = 29) or whole exome (n = 22) and RNA (whole transcriptome, n = 29) at a commercial laboratory. We performed comparative analyses of a genomic cohort of pancreatic ductal adenocarcinomas (PDAC; n = 4,205). In parallel, we conducted a retrospective review of patients with PACC treated at Huntsman Cancer Institute (HCI).

Results:

The real-world dataset included samples from 51 patients with PACC. We found key molecular differences between pure PACC and PDAC, highlighting the unique characteristics of pure PACC. Major differences in PACC include lower MAPK signaling and less stromal cell abundance compared with PDAC. Pure PACC showed genomic loss-of-heterozygosity to largely coincide with mutations in BRCA1, BRCA2, and PALB2. Of the 7 patients treated at HCI, one had a tumor that harbored a BRAF-V600E mutation. Leveraging precision oncology, this patient is being treated with encorafenib plus binimetinib, achieving an exceptionally durable and ongoing complete response of more than 3 years.

Conclusions:

There are major differences between PACC and PDAC, including downregulation of the MAPK signaling pathway, and less stromal cell abundance. In addition, genomic characterization of pure PACC revealed frequent targetable alterations, which can guide patient treatment.
Preclinical Characterization and Phase I Trial Results of INBRX-109, A Third-Generation, Recombinant, Humanized, Death Receptor 5 Agonist Antibody, in Chondrosarcoma
Authors: Subbiah Vivek , Chawla Sant P. , Conley Anthony P. , Wilky Breelyn A. , Tolcher Anthony , Lakhani Nehal J. , Berz David , Andrianov Vasily , Crago William , Holcomb Monica , Hussain Abrahim , Veldstra Carson , Kalabus James , O’Neill Brianne , Senne Lane , Rowell Emily , Heidt Analeah B. , Willis Katelyn M. , Eckelman Brendan P.
Published: June 2023

Purpose:

Patients with unresectable/metastatic chondrosarcoma have poor prognoses; conventional chondrosarcoma is associated with a median progression-free survival (PFS) of <4 months after first-line chemotherapy. No standard targeted therapies are available. We present the preclinical characterization of INBRX-109, a third-generation death receptor 5 (DR5) agonist, and clinical findings from a phase I trial of INBRX-109 in unresectable/metastatic chondrosarcoma (NCT03715933).

Patients and Methods:

INBRX-109 was first characterized preclinically as a DR5 agonist, with binding specificity and hepatotoxicity evaluated in vitro and antitumor activity evaluated both in vitro and in vivo. INBRX-109 (3 mg/kg every 3 weeks) was then evaluated in a phase I study of solid tumors, which included a cohort with any subtype of chondrosarcoma and a cohort with IDH1/IDH2-mutant conventional chondrosarcoma. The primary endpoint was safety. Efficacy was an exploratory endpoint, with measures including objective response, disease control rate, and PFS.

Results:

In preclinical studies, INBRX-109 led to antitumor activity in vitro and in patient-derived xenograft models, with minimal hepatotoxicity. In the phase I study, INBRX-109 was well tolerated and demonstrated antitumor activity in unresectable/metastatic chondrosarcoma. INBRX-109 led to a disease control rate of 87.1% [27/31; durable clinical benefit, 40.7% (11/27)], including two partial responses, and median PFS of 7.6 months. Most treatment-related adverse events, including liver-related events, were low grade (grade ≥3 events in chondrosarcoma cohorts, 5.7%).

Conclusions:

INBRX-109 demonstrated encouraging antitumor activity with a favorable safety profile in patients with unresectable/metastatic chondrosarcoma. A randomized, placebo-controlled, phase II trial (ChonDRAgon, NCT04950075) will further evaluate INBRX-109 in conventional chondrosarcoma.
Abstract A072: Unique mouse models of high-risk prostate cancer adequate for targeted interception
Authors: Levenson Anait S.
Published: June 2023

Metastasis-associate protein 1 (MTA1), a master transcriptional co-regulator and chromatin modifier, is strongly associated with clinically aggressive prostate cancer. The loss of MTA1 reduces the aggressiveness and metastatic potential of prostate cancer cells. Preclinical studies with subcutaneous and orthotopic MTA1 knockdown xenograft models have shown the tumor promoting role of MTA1 and associated survival pathways in prostate cancer. However, the exact role of MTA1 in the pathobiology of prostate cancer is unknown. We first generated a conditional mouse with human MTA1 transgene knocked into the mouse Rosa26 locus (R26MTA1; Cre+ ). By crossing a R26MTA1 mouse with a Pten “floxed” mouse, we have created unique high-risk high-grade PIN-prone R26MTA1; Ptenf/+; Cre+ mice and a high-risk R26MTA1; Ptenf/f; Cre+ cohort of mice with characteristics of a castrate-resistant neuroendocrine subtype suitable for early chemoprevention/interception and novel effective therapies, respectively. I will discuss the potent MTA1-targeted anticancer effects of natural stilbenes (resveratrol, pterostilbene, and Gnetin C) observed in the preclinical R26MTA1; Ptenf/+; Cre+ model mimicking high-risk premalignant tumors with overexpressed MTA1. Further, evidence will be provided on the role of MTA1 in castrate resistance and on the neuroendocrine features defining the potential of the R26MTA1; Ptenf/f; Cre+ model in discovering novel chemoimmunotherapies. Our studies demonstrate progress towards successful targeted interception strategies for prostate cancer with an implication for precision medicine. Supported by the NCI/NIH R15CA216070 Award.

Citation Format: Anait S. Levenson. Unique mouse models of high-risk prostate cancer adequate for targeted interception [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 A072.
Abstract B006: Identifying the molecular signature of bi-potent prostate epithelial cells through scRNA-seq
Authors: Khawaja Hunain , Miranti Cynthia
Published: June 2023

Introduction: Recent studies have shown that cells undergoing oncogenic processes usurp normal developmental pathways to escape regulators of unsolicited growth. Basal to luminal differentiation in the prostate serves as another cellular process that can go awry, the dysregulation of which can enable oncogenesis in the prostate. Studies have found bi-potent cells in prostate epithelium and speculate those to be cells of origin in prostate cancer. Methods and Results: Through single-cell RNA sequencing we investigated basal to luminal differentiation of normal human prostate epithelial cells across timepoints Days 0, 4, 8, 12, 16, and 20 by stimulating with FGF-7 (20ng/mL) and R1881 (10nM) and explored the data to identify unique populations present in the differentiation process. Our results show spatial separation at various timepoints with distinct transcriptomics profile at Day 0, Day 16, and Day 20. As expected, populations present at Day 0 are also present across all timepoint, though enrichment of various distinct populations emerged throughout the differentiation process. Using trajectory analysis (Monocle3) and the Cell Surface Protein Atlas, we profiled surface proteins for each cluster at Day 0 and identified a set of unique surface markers (SLC3A, LYPD3, TACSTD2, DSC2) from undifferentiated basal cells that express both basal (TP63+, K14+) and luminal markers (K8+, K18+), potentially serving as a bi-potent prostate epithelial cells. Conclusion: Our data have identified unique populations present in our prostate differentiation model expressing both luminal and basal signatures which can be isolated using identified surface markers to investigate the role of bi-potent cells in prostate differentiation and oncogenesis.

Citation Format: Hunain Khawaja, Cynthia Miranti. Identifying the molecular signature of bi-potent prostate epithelial cells through scRNA-seq [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 B006.
Abstract B014: ONECUT2 activates diverse drug-resistant phenotypes in prostate cancer
Authors: Qian Chen , Yang Qian , Kim HyoYoung , Yan Yiwu , Mostaghel Elahe , Ellis Leigh , Knudsen Beatrice , Kaochar Salma , Ye Huihui , Garraway Isla , You Sungyong , Freeman Michael
Published: June 2023

BACKGROUND. Prostate cancer (PC) cells can escape from lineage confinement and be reprogrammed to a drug-resistant, high-plasticity state, however the mechanism underlying this process is not understood. Our group identified the HOX/CUT transcription factor ONECUT2 (OC2) as a mediator of metastatic castration-resistant PC (mCRPC) that can be inhibited with a novel family of small molecules. OC2 was shown to be a lineage plasticity driver that promotes neuroendocrine prostate cancer (NEPC). In this study, we sought to uncover the mechanism whereby OC2 exerts effects on lineage plasticity. METHODS. RNAseq, CUT&RUNseq, scRNAseq, forced expression, shRNA, CRISPR-Cas9, co-precipitation/western blot, PCR, mutagenesis, human PC, PC models, computational modeling. RESULTS. We found that OC2 is capable of activating multiple androgen receptor- (AR)-indifferent, drug-resistant lineages, including programs not associated with NEPC, such as upregulation of the glucocorticoid receptor (GR). Consistent with the GR findings, OC2 regulated genes on the AR cistrome previously shown to be regulated by GR in CRPC, including KLK3/PSA. OC2 activated bivalent promoters of master regulator genes via epigenetic modification, and reprogramed multiple super-enhancers, including those associated with TMPRSS2 and SRRM4. OC2-expressing cells in human CRPC included populations that express AR, NE+/stem-like+, NE-/stem-like+, and “double negative” (NE-/AR-) phenotypes. OC2 also transcriptionally upregulated UDP-glucuronosyltransferase enzymes UGT2B15 and UGT2B17, which inactivate DHT, suggesting that the emergence of phenotypic plasticity also arises from AR suppression by ligand depletion. Consistent with this, low levels of androgen correlated with OC2 activation in human CRPC tumors. Enforced OC2 promoted both enzalutamide and docetaxel resistance in PC models. CONCLUSIONS. These findings identify OC2 as an upstream mediator of many lineage-defining factors that govern drug resistance, including those associated with adenocarcinoma. Because OC2 can be inhibited pharmacologically, these results suggest that suppressing this target may inhibit the emergence of a wide range of drug resistance mechanisms arising from loss of lineage confinement.

Citation Format: Chen Qian, Qian Yang, HyoYoung Kim, Yiwu Yan, Elahe Mostaghel, Leigh Ellis, Beatrice Knudsen, Salma Kaochar, Huihui Ye, Isla Garraway, Sungyong You, Michael Freeman. ONECUT2 activates diverse drug-resistant phenotypes 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 B014.
Abstract B022: Dopamine receptor antagonists sensitize prostate cancer cells to androgen targeted therapy
Authors: Zhang Le , Billet Sandrine , Gonzales Gabrielle , Rohena-Rivera Krizia , Muranaka Hayato , Lee Yeonjoo , You Sungyong , Posadas Edwin M. , Bhowmick Neil A.
Published: June 2023

Prostate cancer (PC) incidence is predicted to reach around 2 million new cases by 2040. High fat diet and obesity are associated with the progression and mortality of PC. Palmitate is a common saturated fatty acid, it induces endoplasmic reticulum (ER) stress that activates the unfolded protein response (UPR). Failure to adapt to ER stress results in apoptosis to eliminate irreversibly damaged cells. Master regulator analysis found that Arid5a was a master regulator of saturated fat-induced cellular responses. We confirmed that exogenous palmitate activated ARID5a/UPR signaling, while further activation could induce apoptosis. In trying to determine the mechanism of ARID5a activation, we found that palmitate promoted the expression of dopamine receptors 2 and 3 (DRD2, DRD3) in prostate cancer cell lines. Since high diets have other deleterious effects, we tested the role of dopamine receptor antagonists (e.g. ONC201, prochlorperazine) and found them to serve as UPR activators, inducing apoptosis in ARCaPM and 22Rv1 cells. As our data showed that ARID5a expression could inhibit prostate-specific membrane antigen (PSMA), we next tested the role of dopamine receptor antagonists in sensitizing castrate resistant cells to androgen targeted therapy. Both castrate resistant cell lines (22Rv1 and ARCaPM) were found to be made sensitive to enzalutamide by dopamine inhibition, inhibiting cell proliferation and promoting apoptosis. These findings are especially compelling since dopamine receptor antagonist, prochlorperazine, is a commonly prescribed anti-nausea drug and ONC201 is currently in clinical trials meeting safety endpoints. Preclinical studies in mouse models of castrate resistant PC support the administration of such dopamine receptor antagonists with androgen targeted therapy to sensitize otherwise refractile tumors by the promotion of ER stress pathway, addressing a common adaptation mechanism employed by cancer cells.

Citation Format: Le Zhang, Sandrine Billet, Gabrielle Gonzales, Krizia Rohena-Rivera, Hayato Muranaka, Yeonjoo Lee, Sungyong You, Edwin M. Posadas, Neil A. Bhowmick. Dopamine receptor antagonists sensitize prostate cancer cells to androgen targeted 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 B022.
Abstract B029: Foxf2 activates antitumor immunity to repress the progression of prostate cancer by repressing Fgl1
Authors: Jia Deyong , Zhou Zhicheng , Kwon OhJoon , Xin Li
Published: June 2023

Targeting immune suppressive mechanisms in the tumor microenvironment has revolutionized cancer treatment. Although immune checkpoint inhibition (ICI) has yielded meaningful responses across many cancer types, the ICI efficacy is still limited for prostate cancer. We generated a mouse model with prostate epithelial specific expression of Foxf2, a Forkhead box transcription factor. Foxf2 overexpression suppressed tumor growth in two mouse models for prostate cancer with prostate specific Pten deletion or TRAMP. Foxf2 expression strongly induced tumor cell-intrinsic immune responses by recruiting and activating CD8+ T cells and switching the polarization of macrophages from an immunosuppressive M2-like phenotype to a more inflammatory M1-like state in both syngeneic and autochthonous mouse prostate cancer models in an immunocompetent context. Furthermore, we showed that overexpression of Foxf2 in mouse and human prostate cells repressed the expression of FGL1, a major ligand of LAG-3 that mediates T cell suppression. In this study, we take a combination of bioinformatic, molecular, cellular, and genetic approaches and reveal that Foxf2 overexpression in prostate cancer suppresses tumor progression by activating antitumor immunity.

Citation Format: Deyong Jia, Zhicheng Zhou, OhJoon Kwon, Li Xin. Foxf2 activates antitumor immunity to repress the progression of prostate cancer by repressing Fgl1 [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 B029.
Abstract B033: Probing the role of hypoxia and the tumor microenvironment at spatially resolved single cell resolution in prostate cancer disease trajectories
Authors: Mikutenaite Migle , Karadoulama Evdoxia , Simon Ronald , Minner Sarah , Bristow Robert , Sauter Guido , Schlomm Thorsten , Weischenfeldt Joachim L.
Published: June 2023

Prostate cancer (PCa) is the second most common cancer in men. Most patients will not develop aggressive disease, and a main challenge is to distinguish those patients that can be put on surveillance strategies from those that require definite treatment. Identifying robust prognostic and predictive biomarkers from tumor biopsies have been challenging due to the intra-tumor heterogeneity (ITH) and long life-history of the disease. Several components of the tumor micro-environment (TME) have been associated with shorter time to biochemical relapse and time to metastasis, but these analyses have mostly been based on single sample analysis, thus neglecting the high degree of ITH in PCa. Here, we performed pathology-guided 3D spatial sampling of PCa, followed by multi-layered genomic and transcriptomic profiling. Using single-cell sequencing from multiple distinct areas from each patient, we find both genomic, transcriptional and cellular ITH. We identify “pockets” of the tumor associated with markers of hypoxia and oxidative phosphorylation, and that these are associated with specific tumor and stromal cell-types. Using copy-number based analysis, our data reveal clonal evolution patterns at the single-cell level, pointing towards the earliest clonal populations, and our data supports an interplay between clonal evolution and tumor-promoting TMEs.

Citation Format: Migle Mikutenaite, Evdoxia Karadoulama, Ronald Simon, Sarah Minner, Robert Bristow, Guido Sauter, Thorsten Schlomm, Joachim L. Weischenfeldt. Probing the role of hypoxia and the tumor microenvironment at spatially resolved single cell resolution in prostate cancer disease trajectories [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 B033.
Abstract IA002: Genomic and epigenomic regulation during prostate cancer progression
Authors: Yu Jindan
Published: June 2023

Prostate cancer (PCa) development and progression are controlled by aberrant expression, mutation, and function of essential transcriptional factors and epigenetic modifiers. Over the years, our work has delineated the molecular mechanisms by which androgen receptor (AR) and Polycomb Repressive Complex 2 (PRC2) protein EZH2 regulate PCa progression in concert with other key transcriptional factors such as TMPRSS2-ERG and FOXA1. We recently found that HOXB13, a homeodomain transcription factor primarily known as a pioneering factor of AR, plays an AR-independent role in inhibiting cancer metabolism and tumor metastasis. An important function that is mediated by its interaction with the HDAC3-NCoR corepressor complex, which is disrupted by the PCa risk-associated HOXB13 G84E mutation. On the other hand, we characterize the unique roles of PALI1, a newly identified PRC2-accessory protein, in mediating molecular crosstalk between PRC2 and G9A proteins to catalyze dual H3K27 and H3K9 methylation at target loci. Thus, PALI1 enforces strong repression of differentiation genes, rendering cell stemness and cancer progression. Our findings laid the foundations for the development of several new therapeutic strategies for the treatment of advanced PCa.

Citation Format: Jindan Yu. Genomic and epigenomic regulation during prostate cancer progression [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 IA002.
Abstract IA007: Science of prostate cancer care and survivorship in black men: Structural, social and biological determinants
Authors: Odedina Folakemi , Dronca Roxana , Ashing Kimlin , Kaninjing Ernest , Rotimi Solomon , Ngufor Che ,   Arnold Merriweather, iCCaRE Consortium
Published: June 2023

Black men are disproportionately affected by prostate cancer (CaP), with limited progress in closing the CaP care and survivorship gaps experienced by Black men compared to other racial/ethnic groups. Unfortunately, there is an uptick in CaP incidence rate in the United States (US) since 2014. As reported by the American Cancer Society, the rising CaP incidence rate indicates a shift towards higher grade and stage during diagnosis. The prostate cancer (CaP) disparities experienced by Black men in the US is a microcosm of the global burden of CaP seen in men of African ancestry. For example, the top ten countries leading CaP mortality in the world are all Black nations in Africa and the Caribbean. The complexity of CaP disparities and the need for a unique approach to better understand and address a complex chronic disease, such as CaP, underscores the need for consortium research that is multilevel, collaborative, translational, and global. Through the Department of Defense funding, we formed an inclusive Cancer Care Research Equity (iCCaRE) for Black Men Consortium to advance health equity and reduce disparities in CaP.

Comprising CaP survivors, advocates, scientists, and clinicians, the iCCaRE for Black Men Consortium addresses structural, social and biological determinants of CaP among ethnically diverse Black men globally, including US Black men, West African immigrant men in the US and indigenous West African men. The overall goal of the iCCaRE consortium is to optimize CaP diagnosis experiences, treatment and survivorship based on the Science of Survivorship (SOS). Our central hypothesis is that improving social-determinants of health (SDOH) factors, CaP care and survivorship (CaPCaS)-related factors and mediating biological factors will lead to an improvement in patient-reported outcomes (PROs). This presentation will highlight the structural inequities, societal injustices and biological determinants found to be associated with CaP care and survivorship among Black men. Additionally, we will present the use of Community Living Lab (CoLLab) Health System approach to address inequity in minoritized and marginalized communities.

Citation Format: Folakemi Odedina, Roxana Dronca, Kimlin Ashing, Ernest Kaninjing, Solomon Rotimi, Che Ngufor, Arnold Merriweather, iCCaRE Consortium. Science of prostate cancer care and survivorship in black men: Structural, social and biological determinants [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 IA007.
Abstract IA012: Modeling prostate cancer metastasis in genetically engineered mouse models
Authors: Abate-Shen Cory , Giacobbe Arianna , Obradovic Aleksandar , Vasciaveo Alessandro , Picech Florencia , Ronaldson-Bouchard Kacey , Vunjak-Novakovic Gordana , Shen Michael M. , Califano Andrea , Sims Peter
Published: June 2023

My laboratory has a longstanding interest in developing mouse models of prostate cancer that recapitulate the broad spectrum of prostate cancer phenotypes. We have been employing state-of-the-art systems biology approaches to integrate molecular data from our mouse models with comparable data from human prostate cancer, with the ultimate goal of informing patient care. This is exemplified by our recent description of OncoLoop, a transcriptomic framework that can support rapid-turnaround co-clinical studies to identify and validate drugs for individual patients. Our current studies have largely focused on modeling metastatic prostate cancer, particularly metastasis to bone. We have generated genetically engineered mouse models, as well as syngeneic allograft models, that model bone metastasis with high penetrance. In addition, we are employing an “organ-on-a-chip” platform that simulates bone tropism. We are using these models to decipher the molecular mechanisms that drive metastatic dissemination and bone metastasis. My presentation at this AACR conference will focus on how we have been using these various models to study circulating tumor cells (CTCs). In particular, I will describe our recent studies in which we have been using single-cell sequencing of CTCs and have generated CTC-derived organoids to interrogate mechanisms that drive dissemination and metastasis.

Citation Format: Cory Abate-Shen, Arianna Giacobbe, Aleksandar Obradovic, Alessandro Vasciaveo, Florencia Picech, Kacey Ronaldson-Bouchard, Gordana Vunjak-Novakovic, Michael M. Shen, Andrea Califano, Peter Sims. Modeling prostate cancer metastasis in genetically engineered mouse 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 IA012.
Abstract IA020: Senescence in cancer and myeloid cells control prostate cancer progression
Authors: Alimonti Andrea
Published: June 2023

Recent evidence demonstrates that senescence can act as a tumor-suppressive or tumor-promoting mechanism in cancer. Here, I will discuss recent findings demonstrating that cellular senescence can promote metastases formation in prostate cancer and that therapies that eliminate senescent tumor cells (senolytics) or reprogram the SASP (senostatics) can efficiently prevent metastases in different mouse models. Moreover, I will present recent data demonstrating that senescence can occur in tumor-infiltrating myeloid cells (PMN-MDSCs). As previously reported, this population of immune cells can support prostate tumor proliferation through different mechanisms. Senescent-like myeloid cells express TREM2, are more immunosuppressive and tumor-promoting, and have an increased lifespan than canonical PMN-MDSCs. Genetic and pharmacological elimination of senescent-like myeloid cells decreases tumor progression in different mouse models of prostate cancer. These results support the development of senolytics targeting cancer and senescent-like myeloid cells for cancer therapy.

Citation Format: Andrea Alimonti. Senescence in cancer and myeloid cells control prostate cancer progression [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 IA020.
Supplementary Tables from Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Lesions
Authors: Carpenter Eileen S. , Elhossiny Ahmed M. , Kadiyala Padma , Li Jay , McGue Jake , Griffith Brian D. , Zhang Yaqing , Edwards Jacob , Nelson Sarah , Lima Fatima , Donahue Katelyn L. , Du Wenting , Bischoff Allison C. , Alomari Danyah , Watkoske Hannah R. , Mattea Michael , The Stephanie , Espinoza Carlos E. , Barrett Meredith , Sonnenday Christopher J. , Olden Nicholas , Chen Chin-Tung , Peterson Nicole , Gunchick Valerie , Sahai Vaibhav , Rao Arvind , Bednar Filip , Shi Jiaqi , Frankel Timothy L. , Pasca di Magliano Marina
Published: June 2023

Supplemental Table 1: Demographics and clinical data for donor Gife of Life Samples
Supplemental Table 2: Putative Ligand-Receptor pairs comparing all cell types from single cell sequencing of tumor samples compared to healthy samples.
Supplemental Table 3: Differential gene expression using linear mixed model analysis of cell types from spatial transcriptomic ROIs.
Supplemental Table 4: Kras mutational profiling on select donor samples
Supplemental Table 5: Antibodies used for multiplex immunofluoresence.
Supplemental Table 6: Antibodies and RNAScope probe used for co-IF/ISH.
Figure 3 from Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia
Authors: Nowicki-Osuch Karol , Zhuang Lizhe , Cheung Tik Shing , Black Emily L. , Masqué-Soler Neus , Devonshire Ginny , Redmond Aisling M. , Freeman Adam , di Pietro Massimilliano , Pilonis Nastazja , Januszewicz Wladyslaw , O'Donovan Maria , Tavaré Simon , Shields Jacqueline D. , Fitzgerald Rebecca C.
Published: June 2023

Columnar cells of the stomach and esophageal IM have mosaic gastric and intestinal phenotypes. A, UMAP of columnar cells isolated from samples of NSCJ, NGC, NGB, ND, ileum, colon, rectum, BE, gastric metaplasia of esophagus, squamocolumnar junction between NE and BE, CIM, GIM, nonchronic atrophic gastritis, and chronic atrophic gastritis with color denoting cell types. The cell types were assigned using cells from normal tissue types. B, Scatter plot of log-normalized expression of intestinal (GPA33) and gastric (MUC5AC) markers in the selected tissue types. C, Coimmunofluorescent staining of the esophagus with BE with BE-IM and GIM shows coexpression of intestinal and gastric markers in both types of IM using lineage markers MUC5AC (gastric) and GPA33 (intestinal), and progenitor markers MUC6 (gastric) and OLFM4 (intestinal). White arrowheads denote selected goblet cells; dashed white lines indicate selected BE-IM and GIM crypts, for GIM samples: 1, a crypt with mixed gastric and intestinal phenotype; 2, a crypt with cells showing mosaic phenotype; 3, a crypt with features of complete IM; scale bar, 100 μm. See supplementary Figs. S8 and S9 for ND and NGC. Images are representative of 12 patients (NGC = 2, ND = 2, BE-IM = 4, and GIM = 4). D, UMAP with MuSiC-derived contribution of gastric and intestinal phenotypes to individual cells of the esophageal IM (top) and stomach IM (bottom). E, Violin plots of squamous, SMG, gastric, or intestinal phenotype contribution to cells from NGC, E-GM, BE-IM, BSCJ, NAG, CAG, GIM, CIM, and ND samples.
Figure 4 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Authors: Spain Lavinia , Coulton Alexander , Lobon Irene , Rowan Andrew , Schnidrig Desiree , Shepherd Scott T.C. , Shum Benjamin , Byrne Fiona , Goicoechea Maria , Piperni Elisa , Au Lewis , Edmonds Kim , Carlyle Eleanor , Hunter Nikki , Renn Alexandra , Messiou Christina , Hughes Peta , Nobbs Jaime , Foijer Floris , van den Bos Hilda , Wardenaar Rene , Spierings Diana C.J. , Spencer Charlotte , Schmitt Andreas M. , Tippu Zayd , Lingard Karla , Grostate Lauren , Peat Kema , Kelly Kayleigh , Sarker Sarah , Vaughan Sarah , Mangwende Mary , Terry Lauren , Kelly Denise , Biano Jennifer , Murra Aida , Korteweg Justine , Lewis Charlotte , O'Flaherty Molly , Cattin Anne-Laure , Emmerich Max , Gerard Camille L. , Pallikonda Husayn Ahmed , Lynch Joanna , Mason Robert , Rogiers Aljosja , Xu Hang , Huebner Ariana , McGranahan Nicholas , Al Bakir Maise , Murai Jun , Naceur-Lombardelli Cristina , Borg Elaine , Mitchison Miriam , Moore David A. , Falzon Mary , Proctor Ian , Stamp Gordon W.H. , Nye Emma L. , Young Kate , Furness Andrew J.S. , Pickering Lisa , Stewart Ruby , Mahadeva Ula , Green Anna , Larkin James , Litchfield Kevin , Swanton Charles , Jamal-Hanjani Mariam , Turajlic Samra
Published: June 2023

Mechanisms of resistance to therapy. A,KIT copy number vs. KIT expression in matching exome and RNA-seq samples. TPM, transcripts per million. B, Hierarchical clustering tree of SCNAs found in the single cells of a representative sample of CRUKP9359. Bars on the right show the copy number of KIT in each cell. C, Diagram of split reads mapping at the edges of the amplified region, from which a circular structure can be inferred. Created with BioRender.com. D, Images showing FISH probes against KIT (red) in individual cells. E, Heat map of alterations in antigen-presentation genes in the exome data. Each column represents a sample. LOH events are shown in red and blue, and nonsynonymous mutations are in red and purple. Bars on the x-axis show the number of genes altered in each sample, whereas y-axis bars show the number of samples altered per gene, colored by the type of event.
Figure 1 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Authors: Spain Lavinia , Coulton Alexander , Lobon Irene , Rowan Andrew , Schnidrig Desiree , Shepherd Scott T.C. , Shum Benjamin , Byrne Fiona , Goicoechea Maria , Piperni Elisa , Au Lewis , Edmonds Kim , Carlyle Eleanor , Hunter Nikki , Renn Alexandra , Messiou Christina , Hughes Peta , Nobbs Jaime , Foijer Floris , van den Bos Hilda , Wardenaar Rene , Spierings Diana C.J. , Spencer Charlotte , Schmitt Andreas M. , Tippu Zayd , Lingard Karla , Grostate Lauren , Peat Kema , Kelly Kayleigh , Sarker Sarah , Vaughan Sarah , Mangwende Mary , Terry Lauren , Kelly Denise , Biano Jennifer , Murra Aida , Korteweg Justine , Lewis Charlotte , O'Flaherty Molly , Cattin Anne-Laure , Emmerich Max , Gerard Camille L. , Pallikonda Husayn Ahmed , Lynch Joanna , Mason Robert , Rogiers Aljosja , Xu Hang , Huebner Ariana , McGranahan Nicholas , Al Bakir Maise , Murai Jun , Naceur-Lombardelli Cristina , Borg Elaine , Mitchison Miriam , Moore David A. , Falzon Mary , Proctor Ian , Stamp Gordon W.H. , Nye Emma L. , Young Kate , Furness Andrew J.S. , Pickering Lisa , Stewart Ruby , Mahadeva Ula , Green Anna , Larkin James , Litchfield Kevin , Swanton Charles , Jamal-Hanjani Mariam , Turajlic Samra
Published: June 2023

Driver mutations and SCNA overview. A, Genomic landscape of the cohort, illustrating mutations in key melanoma driver genes, TMB (total mutations/Mb), ploidy, WGD status, weighted genome instability index (wGII, an SCNA burden metric), and the anatomic site of each sample. “Multi-variant” indicates the presence of more than one variant in the same gene within one sample. Panel and WES samples are included. AD, adrenal; BR, brain; LI, liver; LMS, leptomeninges; LN, lymph node; LU, lung; PE, peritoneum; PR, primary; ST, soft tissue. B, The proportion of the genome altered by copy-number gains and losses per sample in diploid and WGD tumor samples. C, The frequency of copy-number gains and losses along the genome (based on WES data only). Dark red and blue indicate clonal events, and light red and blue indicate subclonal events. Also shown are frequency of clonal and subclonal LOH and AI.