bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Alterations Detected by Circulating Tumor DNA in HER2-Low Metastatic Breast Cancer
Authors: Hensing Whitney L. , Gerratana Lorenzo , Clifton Katherine , Medford Arielle J. , Velimirovic Marko , Shah Ami N. , D'Amico Paolo , Reduzzi Carolina , Zhang Qiang , Dai Charles S. , Denault Elyssa N. , Bagegni Nusayba A. , Opyrchal Mateusz , Ademuyiwa Foluso O. , Bose Ron , Behdad Amir , Ma Cynthia X. , Bardia Aditya , Cristofanilli Massimo , Davis Andrew A. 
Published: June 2023

Abstract

Purpose:
About 50% of breast cancers are defined as HER2-low and may benefit from HER2-directed antibody–drug conjugates. While tissue sequencing has evaluated potential differences in genomic profiles for patients with HER2-low breast cancer, genetic alterations in circulating tumor DNA (ctDNA) have not been well described.

Experimental Design:
We retrospectively analyzed 749 patients with metastatic breast cancer (MBC) and ctDNA evaluation by Guardant360 from three academic medical centers. Tumors were classified as HER2-low, HER2-0 (IHC 0) or HER2-positive. Single-nucleotide variants, copy-number variants, and oncogenic pathways were compared across the spectrum of HER2 expression. Overall survival (OS) was evaluated by HER2 status and according to oncogenic pathways.

Results:
Patients with HER2-low had higher rates of PIK3CA mutations [relative risk ratio (RRR), 1.57; P = 0.024] compared with HER2-0 MBC. There were no differences in ERBB2 alterations or oncogenic pathways between HER2-low and HER2-0 MBC. Patients with HER2-positive MBC had more ERBB2 alterations (RRR, 12.43; P = 0.002 for amplification; RRR, 3.22; P = 0.047 for mutations, in the hormone receptor–positive cohort), fewer ERS1 mutations (RRR, 0.458; P = 0.029), and fewer ER pathway alterations (RRR, 0.321; P &lt; 0.001). There was no difference in OS for HER2-low and HER2-0 MBC [HR, 1.01; 95% confidence interval (CI), 0.79–1.29], while OS was improved in HER2-positive MBC (HR, 0.32; 95% CI, 0.21–0.49; P &lt; 0.001).

Conclusions:
We observed a higher rate of PIK3CA mutations, but no significant difference in ERBB2 alterations, oncogenic pathways, or prognosis, between patients with HER2-low and HER2-0 MBC. If validated, our findings support the conclusion that HER2-low MBC does not represent a unique biological subtype.
Abstract A047: Panorama of complex structural variants in primary localized prostate cancer
Authors: Olsen André , Favero Francesco , Li Yilong , Girma Etsehiwot , Feran Breon , Papenfuss Tony , Helin Kristian , Reimand Jüri , Weischenfeldt Joachim 
Published: June 2023

Abstract
Prostate cancer (PCa) is a hormone-driven disease characterized by an abundance of structural variations (SV). Deconvolving the SV patterns can both inform on prior mutational processes leading to cancer, and be leveraged to identify patients with more aggressive disease. Under the auspices of the Pan Prostate Cancer Group (PPCG) consortium, we used whole genome sequencing of 812 treatment naive PCa patients to study both simple and complex SVs. In total, we classified 15,708 simple SVs and 1,448 complex SV events. Complex SVs such as chromothripsis, chromoplexy and templated insertion were found in more than half of the cohort. We also detected tandem duplicator phenotype (TDP) in a subset of the patients associated with CDK12 aberrations. Breakpoint recurrence analysis of driver genes revealed disruption of e.g. PTEN and formation of TMPRSS2-ERG fusion genes frequently coincide with occurrences of specific complex SV types, suggesting specific mutational processes driving these alterations of these cancer genes. Based on the simple and complex SV classifications we extracted six SV signatures, including two TDP-like signatures, distinct deletion-specific SV signatures and a signature characteristic of AR binding sites. We found signatures associated with disease markers, including Gleason score, risk scores, as well as age. Together, these findings provide insights into mechanisms driving SV formation and driver gene alterations in PCa, with potential for identifying markers of aggressive disease.
Citation Format: André Olsen, Francesco Favero, Yilong Li, Etsehiwot Girma, Breon Feran, Tony Papenfuss, Kristian Helin, Jüri Reimand, Joachim Weischenfeldt. Panorama of complex structural variants in primary localized 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 A047.
Abstract A058: Lineage plasticity is associated with an altered MAX cistrome through super-enhancer remodeling
Authors: Kobelev Maxim , Ganguli Dwaipayan , Namekawa Takeshi , Talal Amina , Scurll Joshua , Zoubeidi Amina 
Published: June 2023

Abstract
Background: Roughly 20% of late stage prostate cancer patients display a lineage conversion from typical androgen receptor (AR) driven castrate resistant prostate cancer (CRPC) to a particularly lethal neuroendocrine prostate cancer (NEPC) phenotype as a result of AR pathway inhibition (ARPI). Notably, the mutational landscape of CRPC and NEPC is quite similar, suggesting that epigenetic changes may guide this lineage conversion. Our objective was to explore changes in active epigenetic marks with a particular focus on super-enhancers (SEs) and identify factors that regulate these active regions during lineage plasticity. Methods: We performed ChIP-seq for H3K27ac, H3K4me3 and various TFs in our CRPC and ENZ resistant (ENZR) NEPC-like cell models. We leveraged publicly available H3K27ac data in cell lines as well as PDX models to validate our findings. RNA-seq was integrated with our ChIP-seq results to create a signature which we applied to patient data sets. GIGGLE analysis was used to identify candidate factors at SEs. Results: CRPC and NEPC showed similar active marks at promoters however, enhancer elements were significantly remodeled. We observed extensive remodeling of SEs in our ENZR model compared to CRPC and these unique regions showed greater H3K27ac signals in other ENZR models such as NCI-H660. SE linked genes are associated with stemness pathways and are strongly upregulated as a result of ARPI in vitro, and in vivo. Factor enrichment analysis of these regions showed enrichment for MAX and MYC family binding similar to small cell lung cancer cell lines. ChIPseq for MYC and MAX in our cell models revealed an expansion of MAX binding and contraction of MYC binding in our ENZR model compared to CRPC. In particular, we saw increased binding of MAX at plasticity SEs without MYC suggesting an interaction with MYCL or other factors since MYCN is not expressed in our models. Conclusions: This work improves our understanding of the epigenetic changes that occur during lineage plasticity and ARPI resistance. SE analysis in our models suggests that MAX may be activating these regions with MYCL or independently of the MYC family. MYCL expression is upregulated in NEPC and has higher expression than MYCN suggesting a potential role during lineage plasticity.
Citation Format: Maxim Kobelev, Dwaipayan Ganguli, Takeshi Namekawa, Amina Talal, Joshua Scurll, Amina Zoubeidi. Lineage plasticity is associated with an altered MAX cistrome through super-enhancer remodeling [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 A058.
Abstract B002: Lactate metabolism regulates chromatin accessibility and prostate luminal differentiation
Authors: Goldstein Andrew S. , Giafaglione Jenna M. , Crowell Preston D. 
Published: June 2023

Abstract
Lineage transitions are a central feature of prostate development, tumorigenesis and treatment resistance. While epigenetic changes drive prostate lineage transitions, whether upstream metabolic signaling modulates prostate lineage identity remains unclear. Investigations into prostate metabolism are focused primarily on targeting energy metabolism without considering how altering metabolism may influence epigenetic state or cellular differentiation. To understand the relationship between metabolism and prostate lineage identity, we developed an approach to perform metabolic profiling and nutrient tracing on primary prostate epithelial cells and demonstrated that basal and luminal cells exhibit distinct metabolic features. Furthermore, we show that basal to luminal differentiation in vivo and in three-dimensional ex vivo culture is accompanied by metabolic changes consistent with increased glucose oxidation. Using genetic and pharmacological approaches, we identify the mitochondrial pyruvate carrier (MPC) as a regulator of prostate luminal identity in benign and prostate cancer cells. Low MPC expression is inversely correlated with luminal differentiation and associated with poor response to androgen receptor inhibition in clinical prostate cancer. Mechanistically, our results suggest that MPC inhibition likely impairs luminal differentiation through accumulation of intracellular lactate. Increasing intracellular lactate levels is sufficient to alter chromatin accessibility at lineage-specific genes and impair luminal differentiation in prostate epithelial cells. These findings indicate that upstream metabolism is a regulator of chromatin accessibility and prostate lineage differentiation, suggesting that alterations in tumor metabolism may contribute to lineage plasticity and resistance to androgen receptor blockade in prostate cancer.
Citation Format: Andrew S. Goldstein, Jenna M. Giafaglione, Preston D. Crowell. Lactate metabolism regulates chromatin accessibility and prostate luminal differentiation [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 B002.
Abstract B047: Characterizing the landscape of extracellular vesicles from prostate cancer cell lines
Authors: Ludwig Megan , Sychev Zoi , Day Abderrahman , Bergom Hannah , Hwang Justin , Drake Justin M. 
Published: June 2023

Abstract
Multiple subtypes of prostate cancer can emerge in the advanced stages of disease, such as androgen receptor (AR+), AR indifferent with neuroendocrine features (AR-/NE+), and those without AR or NE features (double negative, DN). These latter variants are particularly aggressive and incredibly lethal. Extracellular vesicles (EVs), also known as exosomes, are small particles that are important mediators of cell-cell communication and have been nominated as potential biomarkers of disease state. We hypothesized that the proteome of extracellular vesicles contains enough information about their originating cell that they can distinguish between prostate cancer subtypes. To address this, we isolated EVs from prostate cancer cell lines of differing subtypes – AR+ (LNCaP, LNCaP95, C4-2, 22RV1), AR-/NE+(NCI-H660, EF1, LASCPC-01), and AR-/NE- (PC3, DU145) – and prepared the EV proteome for quantitative mass spectrometry analysis. This identified 2,000+ proteins in the EVs for each cell line. From our analysis, we found that the EVs from cell lines of similar subtypes clustered together with several hundred proteins statistically different between the three groups. Interestingly, we also found that EVs contained enough protein information to utilize already developed gene signature scores for AR or NE activity. EVs isolated from the AR-/NE+ cell line NCI-H660 scored over 90% with a 121 gene NE signature and included proteins such as SYP, CHGA, and UCHL1. EVs from all the AR+ cell lines displayed &gt;80% AR activity that was driven by high expression of PSA and STEAP1. This supports the idea that we can use the proteome of tumor-derived EVs to identify signature molecular markers that are already known to the field to develop liquid-based biomarker assays. Further work in the clinical setting is needed to evaluate the ability for EVs to be specific, informative biomarkers for prostate cancer disease status.
Citation Format: Megan Ludwig, Zoi Sychev, Abderrahman Day, Hannah Bergom, Justin Hwang, Justin M. Drake. Characterizing the landscape of extracellular vesicles from 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 B047.
Abstract B075: Anti-human LIV-1 antibody drug conjugate for treatment of metastatic prostate cancer
Authors: Zhao Xiaobei , Chen Gang 
Published: June 2023

Abstract
In the worldwide male population, prostate cancer has the most frequent malignancy; out of all the cancer-related causes of deaths, it is also one of the most common. With the advance of new therapies of androgen receptor pathway inhibitors, patient survival rates have improved significantly. There are still tremendous unmet needs, however, for the patients with treat-refractory metastatic castration-resistant prostate cancer (mCRPC). LIV-1, also known as SLC39A6 or ZIP6, is a member of the zinc transporter family and was first identified as an estrogen-inducible gene in breast cancer. Previous studies with immunohistochemical (IHC) analysis showed that LIV-1 is expressed by estrogen receptor-positive (ER+), hormone-treated tumors (both primary and metastatic sites) and ER-/PR-/Her2- (triple-negative) breast cancers. These studies also showed that in healthy human tissues, LIV-1 expression is limited to hormonally-regulated organs (prostate, uterus, and breast). The broad expression of LIV-1 in prostate and breast cancer tumors in combination with the limited expression in vital organs makes LIV-1 an excellent target for an antibody-drug conjugate (ADC). We generated an ADC, BRY812, consisting of a humanized anti-LIV-1 mAb conjugated to monomethyl auristatin E (MMAE), via a novel conjugation method that prevents MMAE from coming off of the antibody during the circulation. The PK studies in rat and monkey showed that the free MMAE released from ADC is 1 to 2 log lower compared with approved ADCs prepared by the standard conjugation method. Low free MMAE concentration significantly lowers the risk of off target toxicity by the ADC. In vitro and in vivo studies demonstrated the antitumor activity of BRY812 for the treatment of prostate and ER+ and triple-negative breast cancers with a better safety profile and a larger therapeutic window. The humanized LIV-1 ADC, BRY812 is currently in preclinical toxicity studies and will advance to First-in-Human trials in April, 2023.
Citation Format: Xiaobei Zhao, Gang Chen. Anti-human LIV-1 antibody drug conjugate for treatment of metastatic prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B075.
Abstract PR001: An endogenous molecular brake preventing APOBEC-driven tumor mutational burden, heterogeneity and AR therapy resistance
Authors: Mu Ping , Li Xiaoling , Wang Yunguan 
Published: June 2023

Abstract
Tumor mutational burden and heterogeneity fuel resistance to many targeted therapies, which inevitably limits the clinical outcome of patients. The cytosine deaminase APOBEC proteins are major drivers of mutagenesis in human cancer, with over 70% of tumors exhibiting a mutational signature that is impacted by APOBEC activity. Nevertheless, the mechanisms through which tumor cells hijack the powerful APOBEC mutagenesis machinery to promote heterogeneity and therapy resistance remain largely unknown. Through a multi-disciplinary approach integrating bulk and single cell RNA-Seq (scRNA-Seq), whole-genome exome-sequencing (WES), and CRISPR library screening, we identified a long sought-after cell-intrinsic mechanism that prevents APOBEC-driven mutagenesis in non-malignant cells. The loss of this “molecular brake” unleashes APOBEC3B-driven mutagenesis in malignant cells, which then becomes a key mutator and represents the long sought-after molecular source of driver mutations in some frequently mutated genes in cancers, including FOXA1, EP300, and AR. Functional screening identified eight crucial drivers for Androgen Receptor (AR)-targeted therapy resistance in prostate cancer that are mutated by APOBEC3B: BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3, and AR. Finally, contrary to conventional understanding, our study reveals that driver mutations in FOXA1 induced by APOBEC3B, not mutations in AR, evolutionarily outcompete other driver mutations and eventually dominate the resistant tumors. Collectively, these results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring targeted therapy resistance and could be the potential therapeutic targets to overcome resistance.
Citation Format: Ping Mu, Xiaoling Li, Yunguan Wang. An endogenous molecular brake preventing APOBEC-driven tumor mutational burden, heterogeneity and AR therapy resistance [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 PR001.
Unique Issues Facing Sexual and Gender Minorities in Cancer
Authors: Scout NFN 
Published: June 2023

Summary:
There are few resources available that help providers understand unique issues sexual and gender minority (SGM) people face related to cancer screening and care. This article helps fill the gap by providing some of the top-line issues providers and policymakers should know, as assembled by one of the leading experts in this field, the executive director of the National LGBT Cancer Network. The sexual and gender minority (SGM) cancer field has matured significantly in recent years, providing greater insight into the barriers and challenges experienced by this population. Not only are risks of cancer for the population higher, but SGM people also experience low access to tailored resources and ultimately lower satisfaction with care after treatment. This article will lay out key issues related to cancer and this population, including changing demographics, no presumption of care, other access to care barriers, systematic data suppression, and then the lack of population-specific cancer research. It will also review the first step in building a more welcoming clinical practice and give resources for additional steps.
Stroke-Induced Respiratory Dysfunction Is Associated With Cognitive Decline
Authors: Patrizz Anthony , El Hamamy Ahmad , Maniskas Michael , Munshi Yashasvee , Atadja Louise , Ahnstedt Hilda , Howe Matthew , Bu Fan , Mulkey Daniel K. , McCullough Louise D. , Li Jun 
Published: June 2023

BACKGROUND:
Respiratory dysfunction is a common complication of stroke, with an incidence of over 60%. Despite the high prevalence of stroke-induced respiratory dysfunction, how disordered breathing influences recovery and cognitive outcomes after ischemic stroke is unknown. We hypothesized that stroke induces chronic respiratory dysfunction, breathing instability, and apnea in mice, which would contribute to higher mortality and greater poststroke cognitive deficits.

METHODS:
Mice were subjected to a 60-minute transient middle cerebral artery occlusion or permanent distal middle cerebral artery occlusion. Whole body plethysmography was performed on C57BL/6 young (2–3 months) and aged (20 months) male and female mice. Animals were exposed to a variety of gas conditions to assess the contribution of peripheral and central chemoreceptors. A battery of cognitive tests was performed to examine behavioral function.

RESULTS:
Middle cerebral artery occlusion led to disordered breathing characterized by hypoventilation and apneas. Cognitive decline correlated with the severity of disordered breathing. Distal permanent middle cerebral artery occlusion, which produces a smaller cortical infarct, also produced breathing disorders and cognitive impairment but only in aged mice.

CONCLUSIONS:
Our data suggest that poststroke apnea is associated with cognitive decline and highlights the influence of aging on breathing disorders after stroke. Therefore, the treatment of respiratory instability may be a viable approach to improving cognitive outcomes after stroke.
“Eastern Literature” as Happenstance?
Authors: Jia Yan 
Published: June 2023

Abstract
This essay examines how “Eastern literature” was perceived and presented in the making of world literature in 1980s China, an era of political and cultural opening-up, through the lens of Indian literature included in the magazine Shijie Wenxue. Although the magazine’s editors discursively championed the idea of geographic all-inclusiveness, the larger conjuncture brought “Western literature” to the forefront of attention. “Eastern” authors and texts, in contrast, were confined to a state of “happenstance,” due to the occasional manner of their presentation. However, by re-reading Shijie Wenxue on three levels, I argue that the magazine managed to produce a relatively eclectic and “thick” knowledge of Indian literature, which would have otherwise been neglected because of its tokenistic appearance and low visibility. Adopting a more creative and critical mode of reading, one can turn the seemingly Western-centric project of Shijie Wenxue into a useful archive for readers with a special interest in “Eastern literature.”
National Dreams, Worldly Visions
Authors: Novillo-Corvalán Patricia 
Published: June 2023

Abstract
This essay explores the intertwined trajectories of a cluster of Argentine magazines, leftist and avant-garde: Proa, Martín Fierro, Insurrexit, and Revista de Oriente which, in their own peculiar ways, rocked and transformed the Buenos Aires cultural scene. It charts the magazines’ fleeting – though momentous – life-spans and existences at a time of revolution, when small collectives of writers and students spread radical and reformist ideas, formal experimentation, and a vernacular revival. While the nagging question of national identity underpinned the magazines’ literary aesthetics, the essay shows that, from the start, those at the editorial helm increasingly steered them towards the wider waters of world literature. Inasmuch as they realised that the conundrum of how to invent a modern Argentine literature could only be resolved dialectically, facing both inwards and outwards, nationally and transnationally, through the relationship between Argentina, Latin America, and the world at large.
Finding Jesus in the Psalter
Authors: Goswell Gregory 
Published: June 2023

Abstract
A Christological reading of the Psalter in which individual psalms are viewed as primarily the prayers of Jesus is evaluated. This recent evangelical tradition of interpretation goes as far as to assert that the Psalms are only secondarily our prayers. However, while the portrait of David the chief psalmist anticipates Jesus Christ as the ideal Davidic king, this does not require that everything in every psalm be applied to Jesus. When David confesses his sins and failings, these words cannot be placed on the lips of Jesus. It remains nonetheless legitimate for believers to make use of the Psalms and apply much of their content to themselves, for, especially in Books IV and V of the Psalter, David sets an example of devotion to God which others are meant to emulate. As well, a Christian rereading of the Psalter sees the God of the psalmist as the Trinity, so that what is said about God can be applied to Jesus Christ.