bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two and a Half Tales of Europe: How the European Commission Narrates Peoplehood in Migration and Citizenship Policy
Authors: Hase Johanna 
Published: April 2023

AbstractSince 2019, the European Commission has had a vice president for ‘promoting our European way of life’, but whether a European ‘we’ exists at all is disputed. This article investigates whether and how the Commission has constructed this ‘we’ through narratives of peoplehood. Analysing official communications in migration and citizenship policy between 2007 and 2020, it traces three narrative elements: characters, plot and main theme. The article argues, first, that the Commission's narrative of ‘realizing European citizenship’ creates a sense of peoplehood more than its narrative of ‘achieving a comprehensive migration policy’ and, second, that it has largely repeated its citizenship narrative while adapting its migration narrative. The findings suggest that the Commission is a rather subtle narrator of peoplehood and call into question whether it has a clear idea of the ‘we’ whose ‘way of life’ it seeks to promote.
Indeterminate cell histiocytosis: A systematic review of the literature with a comprehensive revision of clinical, histopathological, and molecular features
Authors: Zanella Simone , Berti Emilio , Bonometti Arturo ,   for Associazione Italiana Ricerca Istiocitosi ONLUS
Published: April 2023

AbstractIndeterminate cell histiocytosis (ICH) is a very rare histiocytic disorder, primarily involving the skin. It affects more frequently adults, often presenting with a generalized papular eruption, and needs to be differentiated from other neoplastic, paraneoplastic, and infectious diseases through clinical and histological examination. The knowledge on ICH is limited to case reports and small series. Thus, the lack of larger multicentric studies has prevented recognizing and addressing the specific clinical need of the entity. In this systematic review, we comprehensively analysed the medical literature describing histologically‐confirmed cases of ICH and divided the patients into epidemiologically and clinically different groups. We demonstrate that ICH in adulthood is strongly associated with the development of haematological (and especially myeloid) neoplasms. In this subset of patients, we identify blastic morphology of neoplastic cells as a novel independent prognostic factor and an early histopathological predictor of an associated myeloid neoplasm. Moreover, we highlight that even though ICH may also present in childhood, these patients often show indolent behaviour. Genetically, ICH emerges as a heterogeneous condition. While patients with associated myeloid neoplasms are enriched in pERK pathway gene mutations, in others a specific ETV3::NCOA2 rearrangement is described. We finally reviewe the nosology of ICH since its first description, its possible cell of origin, and summarize the therapeutic options reported for each different clinical subgroup. With this work, we hope to foster studies on rare cutaneous histiocytosis and their comprehensive multidisciplinary characterization.
Abstract 127: Single-cell methylation sequencing data reveals succinct metastatic migration histories and tumor progression models
Authors: Li Xuan C. , Liu Yuelin , Mehrabadi Farid Rashidi , Schäffer Alejandro A. , Pratt Drew , Crawford David R. , Malikić Salem , Molloy Erin K. , Gopalan Vishaka , Mount Stephen M. , Ruppin Eytan , Aldape Kenneth , Sahinalp S. Cenk 
Published: April 2023

Abstract
Recent studies exploring the impact of methylation in tumor evolution suggest that while the methylation status of many of the CpG sites are preserved across distinct lineages, others are altered as the cancer progresses. Since changes in methylation status of a CpG site may be retained in mitosis, they could be used to infer the progression history of a tumor via single-cell lineage tree reconstruction. In this work, we introduce the first principled distance-based computational method, Sgootr, for inferring a tumor's single-cell methylation lineage tree and jointly identifying lineage-informative CpG sites which harbor changes in methylation status that are retained along the lineage. We apply Sgootr on the single-cell bisulfite-treated whole genome sequencing data of multiregionally-sampled tumor cells from 9 metastatic colorectal cancer patients made available by Bian et al., as well as multiregionally-sampled single-cell reduced-representation bisulfite sequencing data from a glioblastoma patient made available by Chaligne et al. We demonstrate that the tumor lineages constructed reveal a simple model underlying colorectal tumor progression and metastatic seeding. A comparison of Sgootr against alternative approaches shows that Sgootr can construct lineage trees with fewer migration events and more in concordance with the sequential-progression model of tumor evolution, in time a fraction of that used in prior studies. Interestingly, lineage-informative CpG sites identified by Sgootr are in inter-CpG island (CGI) regions, as opposed to CGI's, which have been the main regions of interest in genomic methylation-related analyses. Sgootr is implemented as a Snakemake workflow, available at https://github.com/liuy0421/Sgootr.
Citation Format: Xuan C. Li, Yuelin Liu, Farid Rashidi Mehrabadi, Alejandro A. Schäffer, Drew Pratt, David R. Crawford, Salem Malikić, Erin K. Molloy, Vishaka Gopalan, Stephen M. Mount, Eytan Ruppin, Kenneth Aldape, S. Cenk Sahinalp. Single-cell methylation sequencing data reveals succinct metastatic migration histories and tumor progression models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 127.
Abstract 1274: Extrinsic photoaging vs intrinsic aging in dermal fibroblasts: Its impact on the microenvironment and melanoma progression
Authors: Wang Vania , Chhabra Yash , Hueser Laura , Pramod Sneha , Carey Alexis , Weeraratna Ashani 
Published: April 2023

Abstract
Melanoma is the deadliest form of skin cancer, with its incidence rising disproportionally to other cancers. Chronological aging is a major risk factor in all types of cancer as it has been shown to drive changes in noncancerous cells (stromal and immune) of the tumor microenvironment (TME) to promote tumor initiation and progression. Ultraviolet radiation (UVR) exposure, which is a major risk factor for melanoma, also can cause a physical premature aging phenotype, known as photoaging. Photoaging of the skin often occurs in tandem with chronological aging, and contributes to the physical features of aging through similar alterations in normal skin structure (eg. collagen degradation). However, the molecular mechanisms of how photoaging compares to chronological aging in changing the TME and on tumor progression is still lacking.Preliminary data have indicated that photoaging of young dermal fibroblasts induce some similar signature changes to that of intrinsically aged. We have shown in-vitro that UVA exposure in young fibroblasts cause upregulation in MMP-1, a matrix remodeling protein, and downregulation in β-catenin, the cell adhesion transcription regulator. These same changes were also shown in chronologically aged fibroblasts. In addition, both photoaging and chronological aging decreases ECM structural integrity, with increased collagen fragmentation and a reduction in the renewal of cross-linking proteins. To investigate how photoaging contributes to the pro-tumorigenic microenvironment of the aged dermis, we are using biochemical and phenotypic assays to study how chronic UVA exposure induces an intrinsically aged-like fibroblast behavior and secretome. We also hypothesize that photoaged fibroblasts reprogram the TME to become more permissible for the growth of tumor cells, and will test changes in invasion and metastasis or melanoma both in-vitro and in-vivo.Studying the impact of photoaging on aging in the skin microenvironment will help identify therapeutic targets and have direct clinical applications for cancer patients.
Citation Format: Vania Wang, Yash Chhabra, Laura Hueser, Sneha Pramod, Alexis Carey, Ashani Weeraratna. Extrinsic photoaging vs intrinsic aging in dermal fibroblasts: Its impact on the microenvironment and melanoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1274.
Abstract 1364: Profiling tumor microenvironment for therapeutic intervention to soft-tissue sarcomas
Authors: Xiao Jin-Fen , Broz Marina , Piras Roberta , Ishaya Kristin , Ko Emily , Guarnerio Jlenia 
Published: April 2023

Abstract
Soft-tissue sarcomas (STS) are mesenchymal tumors having remarkably diverse histological features. Genomic studies reported that STS have low frequencies of genetic mutation, but often harboring copy number variations (CNVs). For STS, CNVs frequently happen in essential tumor suppressor genes and oncogenic transcriptional genes, neither of which are easily “druggable” targets. Moreover, in concordance with low tumor mutation burden rate, STS show low immunogenicity with less cytotoxic TIL in the TME and is unfortunately linked to a lower responsive rate to PD1/PD-L1 ICB. Using a syngeneic mouse UPS model, we previously found that tumor-associated macrophages (TAM) in the TME are promoting the growth of sarcoma. We further identified specific tumor microenvironmental elements contributing to the pro-tumorigenicity of TAMs, which represent a promising novel clinical target for myeloid-related intervention. Therefore, we hypothesize that exploration of TME is beneficial to identify clinically promising targets for STS. To study the TME in STS, we performed bulk RNA-seq and scRNA-seq on human sarcoma samples which covered different histological subtypes of STS and compare them to normal samples. Our results show that, unlike carcinomas originating from epithelial cells, extracellular matrix (ECM)-related genes are highly upregulated in both cancer-associated fibroblast (CAF) and sarcoma tumor cells. Further analysis show that upregulation of these ECM genes is associated with a worse survival outcome in sarcoma patients. In order to further explore the STS and TME orchestra, we established several syngeneic mouse models according to the genetic aberrations reported in TCGA data. We are currently characterizing these syngeneic mouse models to find out whether they recapitulate human STS samples. Our goal is to utilize these mouse models to study the relationship of ECM-related genes in both CAF and tumor cells, find out the effect of upregulated ECM-related genes on the immune compartment in TME and search for potential therapeutic interventions.
Citation Format: Jin-Fen Xiao, Marina Broz, Roberta Piras, Kristin Ishaya, Emily Ko, Jlenia Guarnerio. Profiling tumor microenvironment for therapeutic intervention to soft-tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1364.
Abstract 1457: PDEF restricts prostate cancer cellular plasticity in part by modulating YAP1/TAZ-TEAD transcriptional network
Authors: Koul Hari K. , Jaiswal Praveen K. , Mohajan Suman , Vatanmakanian Mousa , Wang Fengtian , Koul Sweaty 
Published: April 2023

Abstract
Background: The Hippo TEAD-transcriptional regulators YAP1 and TAZ play essential role in cancer cell growth and metastasis. However, the function of YAP1 and TAZ in prostate cancer is not well characterized. We discovered that expression of PDEF is decreased during prostate cancer progression and re-expression of PDEF limits prostate cancer metastasis in part by promoting luminal epithelial phenotype, but mechanisms of PDEF action are not completely understood. In the present study, we evaluated the effects of the SPDEF on YAP1/TAZ levels and expression of YAP1/TAZ regulated genes in prostate cancer (PCa) cells. We also evaluated expression of SPDEF, YAP1, TAZ and YAPTAZZ-Tead regulated genes in clinical cohorts of prostate cancer patients.
Material & Method: Prostate cancer (PC3 and DU145) cells were transfected with PDEF or respective vector control. shRNA was used to knock down SPDEF in AR positive and androgen responsive LNCaP cells. Protein levels were analyzed by western blotting. Gene expression was monitored by microarray analysis/RNA seq and confirmed by RTPCR assays. Cell migration and invasion were measured by scratch wound healing and by trans well migration though Matrigel assays respectively. We analyzed publicly available gene expression data in several prostate cancer cohorts.
Results: We observed that the two well-characterized metastatic PCa cells (PC3 and DU145 cells) express both YAP1 and TAZ, but do not express SPDEF. Expression of PDEF in PC3 and DU145 cells resulted in an increased phospho-YAP1 and phospho-TAZ protein levels and inhibition of YAP1/TAZ target genes, as compared to the respective vector control, directly demonstrating that PDEF plays a critical role in modulating YAP1/TAZ-TEAD transcriptional activity, and by extension in the regulation of the Hippo pathway. Analysis of publicly available PCa data sets revealed a significant increase in TAZ mRNA levels in prostate cancer tissues as compared to normal prostate tissues (p=4.95E-08). Furthermore, we also found a significant gradual increase in TAZ mRNA expression and concomitant decrease in YAP1 mRNA during disease progression and metastasis and in neuroendocrine PCa.
Conclusions: Taken together these data suggest that SPDEF limits prostate cancer metastasis in part by targeting YAP1/TAZ driven transcriptional output.
Citation Format: Hari K. Koul, Praveen K. Jaiswal, Suman Mohajan, Mousa Vatanmakanian, Fengtian Wang, Sweaty Koul. PDEF restricts prostate cancer cellular plasticity in part by modulating YAP1/TAZ-TEAD transcriptional network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1457.
Abstract 1529: Characterizing antibody internalization for rational selection of ADC linker design
Authors: Shao Zekun , Panyam Jayanth 
Published: April 2023

Abstract
Antibody-drug conjugates (ADC), which target a highly potent cytotoxin to a specific protein overexpressed on tumor cells, are a promising class of anticancer therapeutics. In addition to the antibody characteristics, intracellular reactivity of the antibody-cytotoxin linker (which affects drug release) is a key determinant of ADC efficacy. While many different linkers have been used in approved ADCs, the intracellular trafficking profile of an antibody will likely impact the effectiveness of different linkers differently. Here, we determined the cellular internalization of two antibodies, anti-perlecan antibody (‘AM6’), and anti-EGFR antibody (cetuximab; ‘Ctx’), in MDA-MB-231-LM2 cells (a lung-metastatic TNBC cell line). Using live-cell confocal microscopy, we investigated the effect of endocytosis inhibitors on intracellular trafficking of AM6 and Ctx. While AM6 was internalized quicker compared to Ctx, the internalization of both antibodies was reduced significantly by 5-(N-Ethyl-N-isopropyl)-amiloride, a macropinocytosis inhibitor and, to a lesser extent, by chlorpromazine, an inhibitor of clathrin-mediated-endocytosis. The results suggest both AM6 and Ctx were internalized by both macropinocytosis and clathrin-mediated endocytosis. We then investigated whether acidic pH in the lysosomes and the reductive environment in the endosomal vesicles would facilitate drug release from ADC. We conjugated thiol-reactive doxorubicin to reduced interchain disulfides of Ctx via either the acid and glutathione (GSH)-labile pyridinyldithio-hydrazide linker or the non-cleavable C6-maleimide linker. Intracellular doxorubicin release for the two ADCs was evaluated by live-cell confocal microscopy. Doxorubicin was successfully conjugated to Ctx, with a DAR of 4.8 and 8.6 for the cleavable and non-cleavable linkers, respectively. Conjugation of doxorubicin to the antibody was confirmed by fluorescent gel imaging after SDS-PAGE and by using hydrophobic interaction chromatography. Confocal microscopic studies showed that the ADC with cleavable linker resulted in greater doxorubicin accumulation in the nucleus compared to the ADC with non-cleavable linker, which was predominantly sequestered in the lysosomes. These results suggest that the cleavable linker results in better drug release compared to the non-cleavable linker for the Ctx-doxorubicin ADC. Studies examining the effect of linker chemistry on drug release from the anti-perlecan ADC and on the anticancer efficacy of the two ADCs are ongoing.
Citation Format: Zekun Shao, Jayanth Panyam. Characterizing antibody internalization for rational selection of ADC linker design [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1529.
Abstract 1723: Ferroptosis is a novel therapeutic target for RB1 deficient lethal prostate cancer
Authors: Wang Mu-En , Chen Jiaqi , Lu Yi , Wy Jinjin , Ou Jianhong , Asara John , Armstrong Andrew , Wang Qianben , Li Lei , Wang Yuzhuo , Huang Jiaoti , Chen Ming 
Published: April 2023

Abstract
Background: Although the development of next-generation antiandrogens has significantly extended the survival time of patients with metastatic castration-resistant prostate cancer (mCRPC), drug resistance inevitably developed over time. Therefore, the identification of novel therapeutic strategies targeting mCRPC is urgent. RB1 deficiency is a common genetic event and contributes to the development of therapy resistance and poor prognosis in prostate cancer. However, effective therapies against RB1-deficient lethal prostate cancer remain elusive. Here we determined how RB1 regulates the sensitivity of prostate cancer cells to ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, and whether we can exploit ferroptosis for the treatment of RB1 deficient lethal prostate cancer.
Methods: To determine how RB1 regulates ferroptosis in prostate cancer, we generated RB1 stable knockdown prostate cancer cell lines using lentivirus-delivered shRNAs. We compared cellular sensitivity to ferroptosis and associated lipid peroxidation between control and RB1 stable knockdown prostate cancer cells. Using western blotting, qPCR, and ChIP analyses, we examined the regulation of ferroptosis by RB1. We also evaluated the therapeutic efficacy of ferroptosis inducers in cell-derived xenograft, patient-derived xenograft, and genetically engineered mouse models.
Results: Our studies revealed that RB1 deficiency sensitizes prostate cancer cells to ferroptosis. Mechanistically, we found that the E2F family of transcription factors directly binds and activates the ACSL4 promoter and that RB1 inhibits ferroptosis by suppressing E2F-mediated ACSL4 transcriptional activation. More importantly, our preclinical studies demonstrated that induction of ferroptosis by JKE-1674, a recently discovered ferroptosis inducer, significantly blocks RB1 deficient prostate tumor growth and metastasis, and improves the overall survival of mice in the absence of obvious toxicity.
Conclusions:
Our findings uncover an RB1/E2F/ACSL4 molecular axis that governs ferroptosis and also suggest a new approach to the treatment of RB1-deficient lethal prostate cancer.
Citation Format: Mu-En Wang, Jiaqi Chen, Yi Lu, Jinjin Wy, Jianhong Ou, John Asara, Andrew Armstrong, Qianben Wang, Lei Li, Yuzhuo Wang, Jiaoti Huang, Ming Chen. Ferroptosis is a novel therapeutic target for RB1 deficient lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1723.
Abstract 1920: Association of type 2 diabetes with overall and site-specific cancer among predominantly low-income Black and White Americans
Authors: Pradhan Pranoti , Wen Wanqing , Zheng Wei 
Published: April 2023

Abstract
Background: Black individuals have the highest cancer incidence rate in the United States compared to White and other populations. Additionally, they are also twice as likely to develop type 2 diabetes (T2D) during their lifetime. Specifically considering the association between diabetes and cancer incidence, both diseases share common modifiable and nonmodifiable risk factors such as, aging, obesity, lack of physical activity, unhealthy diet, excessive alcohol consumption, and smoking. This association could vary between cancer types and race is also a factor which could disproportionately affect this relationship. However, studies on these associations are limited and the impact in terms of risk between the Black and White Americans remains unclear.
Objective: We evaluated the association of T2D with risk of total and 26 site-specific cancers in a large cohort study conducted among predominantly low-income Black and White Americans who have a higher risk of T2D than other populations. Given the previous literature on T2D, cancer, and race, we hypothesized that T2D might be associated with varying risk for cancer.
Methods: For this analysis, we used data from the Southern Community Cohort Study, an on-going prospective cohort study. Enrollment began in 2002 and concluded in 2009, with active follow-up until 2020. Study participants were asked whether they were diagnosed with T2D by physicians at the follow-up interviews and T2D was assessed as a time-varying covariate. Ascertainment of incident cancer was carried out via linkage to state cancer registries. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for confounders.
Results: This study included 81,525 participants (30.2 % (N=24,581) White; 65.9% (N=53,711) Black) of whom 36.2% (N=29,487) were diagnosed with diabetes. Among those with diabetes, 10.3% (N=3,024) were diagnosed with cancer. Individuals with T2D had an elevated risk of several cancers, including pancreatic cancer (HR = 1.52, 95% CI: 1.18-1.96); but a reduced risk of esophageal cancer (HR = 0.55, 95% CI: 0.34-0.89). Some racial differences were found regarding the association of T2D with cancer risk.
Conclusion: We found varying risks between T2D and risk of cancer between White and Black individuals. This highlights the importance of T2D prevention practices to help mitigate the risk of cancer and that further research is necessary to understand this association in minority individuals.
Citation Format: Pranoti Pradhan, Wanqing Wen, Wei Zheng. Association of type 2 diabetes with overall and site-specific cancer among predominantly low-income Black and White Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1920.