bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stenopterygiids from the lower Toarcian of Beaujolais and a chemostratigraphic context for ichthyosaur preservation during the Toarcian Oceanic Anoxic Event
Authors: Martin Jeremy E. , Suan Guillaume , Suchéras-Marx Baptiste , Rulleau Louis , Schlögl Jan , Janneau Kevin , Williams Matt , Léna Alex , Grosjean Anne-Sabine , Sarroca Estel , Perrier Vincent , Fernandez Vincent , Charruault Anne-Lise , Maxwell Erin E. , Vincent Peggy 
Published: March 2021

Abstract
We report new ichthyosaur material excavated in lower Toarcian levels of the LafargeHolcim Val d'Azergues quarry in Beaujolais, SE France. A partially articulated skull and a smaller, unprepared but likely subcomplete skeleton preserved in a carbonate concretion are identified as stenopterygiids, a family of wide European distribution during the Early Jurassic. These specimens are among the finest preserved Toarcian exemplars known from Europe and, in one of them, soft tissue preservation is suspected. Their state of preservation is attributed to the combination of prolonged anoxic conditions near the water–sediment interface and early carbonate cementation resulting from the activity of sulfate-reducing bacteria. We also present carbon and strontium isotope values obtained from the study site that allow detailed temporal comparisons with other Toarcian vertebrate-yielding sites and environmental perturbations associated with the Toarcian Oceanic Anoxic Event (T-OAE). These comparisons suggest that the relatively high abundance and good preservation state of Toarcian vertebrates was favoured by a prolonged period of low bottom water oxygenation and accumulation rates. The environmental conditions that prevailed during the T-OAE were probably responsible for the extensive nature of Lagerstätte-type deposits with exceptional preservation of marine organisms. Testing whether the T-OAE had a biological impact on marine vertebrates requires a precise chemostratigraphic context of the fossil record spanning the Pliensbachian–Toarcian interval.
Cancer-Specific Targeting of Taurine-Upregulated Gene 1 Enhances the Effects of Chemotherapy in Pancreatic Cancer
Authors: Tasaki Yoshihiko , Suzuki Miho , Katsushima Keisuke , Shinjo Keiko , Iijima Kenta , Murofushi Yoshiteru , Naiki-Ito Aya , Hayashi Kazuki , Qiu Chenjie , Takahashi Akiko , Tanaka Yoko , Kawaguchi Tokuichi , Sugawara Minoru , Kataoka Tomoya , Naito Mitsuru , Miyata Kanjiro , Kataoka Kazunori , Noda Tetsuo , Gao Wentao , Kataoka Hiromi , Takahashi Satoru , Kimura Kazunori , Kondo Yutaka 
Published: March 2021

Abstract

Overcoming drug resistance is one of the biggest challenges in cancer chemotherapy. In this study, we examine whether targeting the long noncoding RNA taurine upregulated gene 1 (TUG1) could be an effective therapeutic approach to overcome drug resistance in pancreatic ductal adenocarcinoma (PDAC). TUG1 was expressed at significantly higher levels across 197 PDAC tissues compared with normal pancreatic tissues. Overall survival of patients with PDAC who had undergone 5-FU–based chemotherapy was shorter in high TUG1 group than in low TUG1 group. Mechanistically, TUG1 antagonized miR-376b-3p and upregulated dihydropyrimidine dehydrogenase (DPD). TUG1 depletion induced susceptibility to 5-FU in BxPC-3 and PK-9 pancreatic cell lines. Consistently, the cellular concentration of 5-FU was significantly higher under TUG1-depleted conditions. In PDAC xenograft models, intravenous treatment with a cancer-specific drug delivery system (TUG1-DDS) and 5-FU significantly suppressed PDAC tumor growth compared with 5-FU treatment alone. This novel approach using TUG1-DDS in combination with 5-FU may serve as an effective therapeutic option to attenuate DPD activity and meet appropriate 5-FU dosage requirements in targeted PDAC cells, which can reduce the systemic adverse effects of chemotherapy.

Significance:
Targeting TUG1 coupled with a cancer-specific drug delivery system effectively modulates 5-FU catabolism in TUG1-overexpressing PDAC cells, thus contributing to a new combinatorial strategy for cancer treatment.
Shaping Functional Avidity of CAR T Cells: Affinity, Avidity, and Antigen Density That Regulate Response
Authors: Greenman Raanan , Pizem Yoav , Haus-Cohen Maya , Goor Alona , Horev Guy , Denkberg Galit , Sinik Keren , Elbaz Yael , Bronner Vered , Levin Anat Globerson , Horn Galit , Shen-Orr Shai , Reiter Yoram 
Published: March 2021

Abstract
Chimeric antigen receptors (CARs) are immunoreceptors that redirect T cells to selectively kill tumor cells. Given their clinical successes in hematologic malignancies, there is a strong aspiration to advance this immunotherapy for solid cancers; hence, molecular CAR design and careful target choice are crucial for their function. To evaluate the functional significance of the biophysical properties of CAR binding (i.e., affinity, avidity, and antigen density), we generated an experimental system in which these properties are controllable. We constructed and characterized a series of CARs, which target the melanoma tumor–associated antigen Tyr/HLA-A2, and in which the affinity of the single-chain Fv binding domains ranged in KD from 4 to 400 nmol/L. These CARs were transduced into T cells, and each CAR T-cell population was sorted by the level of receptor expression. Finally, the various CAR T cells were encountered with target cells that present different levels of the target antigen. We detected nonmonotonic behaviors of affinity and antigen density, and an interrelation between avidity and antigen density. Antitumor activity measurements in vitro and in vivo corroborated these observations. Our study contributes to the understanding of CAR T-cell function and regulation, having the potential to improve therapies by the rational design of CAR T cells.
See related article on p. 946
The Discovery of a Novel Antimetastatic Bcl3 Inhibitor
Authors: Soukupová Jitka , Bordoni Cinzia , Turnham Daniel J. , Yang William W. , Seaton Gillian , Gruca Aleksandra , French Rhiannon , Lee Kok Yung , Varnava Athina , Piggott Luke , Clarkson Richard W.E. , Westwell Andrew D. , Brancale Andrea 
Published: March 2021

Abstract
The development of antimetastatic drugs is an urgent healthcare priority for patients with cancer, because metastasis is thought to account for around 90% of cancer deaths. Current antimetastatic treatment options are limited and often associated with poor long-term survival and systemic toxicities. Bcl3, a facilitator protein of the NF-κB family, is associated with poor prognosis in a range of tumor types. Bcl3 has been directly implicated in the metastasis of tumor cells, yet is well tolerated when constitutively deleted in murine models, making it a promising therapeutic target. Here, we describe the identification and characterization of the first small-molecule Bcl3 inhibitor, by using a virtual drug design and screening approach against a computational model of the Bcl3-NF-kB1(p50) protein–protein interaction. From selected virtual screening hits, one compound (JS6) showed potent intracellular Bcl3-inhibitory activity. JS6 treatment led to reductions in Bcl3-NF-kB1 binding, tumor colony formation, and cancer cell migration in vitro; and tumor stasis and antimetastatic activity in vivo, while being devoid of overt systemic toxicity. These results represent a successful application of in silico screening in the identification of protein–protein inhibitors for novel intracellular targets, and confirm Bcl3 as a potential antimetastatic target.
Discovery of JNJ-63576253, a Next-Generation Androgen Receptor Antagonist Active Against Wild-Type and Clinically Relevant Ligand Binding Domain Mutations in Metastatic Castration-Resistant Prostate Cancer
Authors: Branch Jonathan R. , Bush Tammy L. , Pande Vineet , Connolly Peter J. , Zhang Zhuming , Hickson Ian , Ondrus Janine , Jaensch Steffen , Bischoff James R. , Habineza Georges , Van Hecke Geert , Meerpoel Lieven , Packman Kathryn , Parrett Christopher J. , Chong Yolanda T. , Gottardis Marco M. , Bignan Gilles 
Published: March 2021

Abstract
Numerous mechanisms of resistance arise in response to treatment with second-generation androgen receptor (AR) pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Among these, point mutations in the ligand binding domain can transform antagonists into agonists, driving the disease through activation of AR signaling. To address this unmet need, we report the discovery of JNJ-63576253, a next-generation AR pathway inhibitor that potently abrogates AR signaling in models of human prostate adenocarcinoma. JNJ-63576253 is advancing as a clinical candidate with potential effectiveness in the subset of patients who do not respond to or are progressing while on second-generation AR-targeted therapeutics.
Abstract LT017: ECM mechanical and metabolic architecture during early ductal invasions: integrating in silico modeling, histology-based machine learning and mechanobiology
Authors: Rejniak Katarzyna A. , Poonja Sharan , Mathur Shreya , Kingsley Jessica , Bui Marilyn 
Published: March 2021

Abstract
Progression from a ductal carcinoma in situ (DCIS) to an invasive tumor is a major step initiating a devastating and often lethal metastatic cascade. One sentinel event that initiate this process is the development of ductal microinvasions, i.e., small cohorts of tumor cells that breach the basement membrane surrounding the duct and migrate through the extracellular matrix (ECM) leading to irreversible changes in tumor and stromal architecture. We used a combination of advanced image analysis techniques applied to patients’ histology data to extract features which identify specific properties of individual tumor cells inside the duct and on the invasive front. By integrating these histology-based data with a hybrid agent-based mathematical model, we investigated the biomechanical interactions between the cells and the ECM fiber architecture, and microenvironmental physical and metabolic features that define tumor niche prone to microinvasions. The identified physical properties of the matrix elucidate conditions that can facilitate or prevent the progression of such microinvasions. The presented method provides also a tool for quantifying morphological and immunohistochemical properties of individual cells within the mammary ducts and ductal microinvasion, as well as for testing biomechanical hypotheses of tumor cell-tumor matrix interactions. These findings can be compared to the patient histology samples and help define criteria for identification of changes in tumor architecture and future development of new diagnostic methods.
Citation Format: Katarzyna A. Rejniak, Sharan Poonja, Shreya Mathur, Jessica Kingsley, Marilyn Bui. ECM mechanical and metabolic architecture during early ductal invasions: integrating in silico modeling, histology-based machine learning and mechanobiology [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT017.
Abstract PO040: Protease inhibitors of HGF activation prevent HGF-dependent tumor progression and overcome resistance to anti-cancer therapy
Authors: Voss Jorine J.L.P. , Damalanka Vishnu , Mahoney Matthew , Klampfer Lidija , Janetka James W. 
Published: March 2021

Abstract
Overproduction of Hepatocyte Growth Factor (HGF) in the tumor microenvironment by tumor-associated fibroblasts or cancer cells is associated with poor patient outcomes and is a common cause of therapeutic resistance. HGF signals via the MET receptor, which results in the activation of downstream signaling pathways that promote cell survival, proliferation, migration, scattering, and invasion of cancer cells. HGF is secreted as an inactive precursor, pro-HGF, and proteolytic processing into its active form by one of the serine proteases, matriptase, hepsin, or HGF Activator (HGFA), is the rate-limiting step in HGF/MET signaling. The expression of these proteases is upregulated in cancer, whereas the activity of endogenous inhibitors of HGF-activating proteases, HGF-Activation Inhibitors (HAI-1/HAI-2), is reduced in cancer. We have developed small-molecule inhibitors of the three HGF-activating proteases, matriptase, hepsin, and HGFA. We refer to these inhibitors as synthetic HGF-Activation Inhibitors (sHAI), because they mimic the activity of HAI-1/HAI-2. The activity of sHAI was tested in in vitro models of therapeutic resistance and in in vivo models of HGF-driven lung cancer progression. ZFH7116 and VD2173, two lead SHAI compounds, are both potent inhibitors of the HGF-activating proteases and have good drug-like pharmacokinetic (PK) properties. We demonstrated that ZFH7116 and VD2173 inhibit proteolytic activation of pro-HGF to its active form. Both compounds overcome HGF-mediated resistance to EGFR and MET-targeted therapy in lung and colon cancer models of therapeutic resistance. Furthermore, ZFH7116 and VD2173 inhibit HGF-dependent growth of lung cancer cells in mice. Overall, our data demonstrate that inhibitors of HGF activation, such as ZFH7116 and VD2173, prevent HGF-dependent tumor growth, and overcome HGF-mediated resistance to targeted anti-cancer therapy. As such, they represent a unique way of inhibiting oncogenic HGF/MET signaling.
Citation Format: Jorine J.L.P. Voss, Vishnu Damalanka, Matthew Mahoney, Lidija Klampfer, James W. Janetka. Protease inhibitors of HGF activation prevent HGF-dependent tumor progression and overcome resistance to anti-cancer therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO040.
Abstract PO041: Hyaluronan processing and function in the progression of breast cancer
Authors: Witschen Patrice M. , Chaffee Thomas S. , Brady Nicholas J. , Knutson Todd P. , LaRue Rebecca S. , Munro Sarah , Tiegs Lyubov , McCarthy James B. , Nelson Andrew C. , Schwertfeger Kathryn L. 
Published: March 2021

Abstract
Hyaluronan (HA) is a large, soluble, glycosaminoglycan of the extracellular matrix that has anti-inflammatory effects under physiologic conditions. However, HA is cleaved into low molecular weight (LMW) fragments under conditions of cellular or organismal stress, acting as a molecular “switch” that promotes inflammation. In breast cancer, a decrease in HA synthesis has been correlated with decreased tumor cell proliferation and migration. However, the roles of HA fragmentation in the progression of breast cancer are unknown. We predict that HA fragmentation increases during this transition, promoting inflammation through LMW HA-CD44 interactions. To test our hypothesis, the presence/absence of HA fragmentation was determined using gel electrophoresis in breast cancer cell lines. Additionally, qRT-PCR was performed to examine gene expression of the three major hyaluronan synthases (Has) 1-3 and the three major hyaluronidases (Hyal) 1, 2, and PH-20. Our data suggest as a cancerous lesion progresses, HMW HA production increases (primarily through Has2), but HA fragmentation does not occur until the tumor acquires a more aggressive phenotype (primarily through Hyal1). Following characterization of HA fragmentation and machinery within our system, we found changes in inflammatory cytokines (such as CCL2) as downstream effects of CD44 and HA synthesis inhibition. We have currently knocked out CD44 in two breast cancer cell lines using the CRISPR/Cas9 method to determine the functional relationship between CD44 and HA using an in vivo mouse model. By targeting HA-CD44 signaling associated with inflammation, new therapeutic approaches can be developed for the treatment of breast cancer.
Citation Format: Patrice M. Witschen, Thomas S. Chaffee, Nicholas J. Brady, Todd P. Knutson, Rebecca S. LaRue, Sarah Munro, Lyubov Tiegs, James B. McCarthy, Andrew C. Nelson, Kathryn L. Schwertfeger. Hyaluronan processing and function in the progression of breast cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO041.
Abstract PO046: Interaction between Desmoglein2 and hypoxia controls breast cancer metastasis
Authors: Hwang-Verslues Wendy W. , Chang Po-Hao 
Published: March 2021

Abstract
Breast cancer is the most common cancer of women worldwide. Although the 5-year survival rate has greatly improved due to early detection and advance in therapeutic strategies, metastasis remains the major cause of breast cancer death. Metastatic cancer cells which formed clusters of circulating tumor cells (CTCs) are particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and CTC clustering remain elusive. We found that Desmoglein2 (DSG2), a cell adhesion molecule involved in desmosome mediated intercellular adhesion, promoted tumor growth, increased the prevalence of CTC clusters and facilitated distant organ colonization. Importantly, regulation of DSG2 by hypoxia was a key to this process. Hypoxia-induced DSG2 downregulation led to elevated epithelial-mesenchymal transition (EMT) gene expression allowing cells to detach from the primary tumor and undergo intravasation. Subsequent reactivation of DSG2 expression after release of hypoxic stress in the circulation allowed CTCs to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1α (HIF1α). In contrast to its more widely observed function to activate expression of hypoxia-inducible genes, HIF1α repressed DSG2 by recruitment of the Polycomb Repressive Complex 2 components, EZH2 and SUZ12, to the DSG2 promoter. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a new mechanism by which hypoxia drives metastasis.
Citation Format: Wendy W. Hwang-Verslues, Po-Hao Chang. Interaction between Desmoglein2 and hypoxia controls breast cancer metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO046.
Abstract PO050: EphA2 signaling segregation and modulation by diverse tumor microenvironment components differentially regulates cancer cell invasion and survival
Authors: Moyano-Galceran Lidia , Turunen Pauliina S. , Sugiyama Nami , von Nandelstadh Pernilla , Gucciardo Erika , Varjosalo Markku , Lehti Kaisa 
Published: March 2021

Abstract
The receptor tyrosine kinase EphA2 is overexpressed in many solid cancers and associated with disease aggressiveness and poor clinical outcome. EphA2 signaling mechanisms are complex, context-dependent and still not completely understood. In several cancers, EphA2-ephrinA1 interaction is associated with cell repulsion and growth suppressive signaling. Yet, this receptor can also be activated in a ligand-independent manner by crosstalk with growth factor receptors and adhesion molecules, and its signaling can be further regulated via proteolytic cleavage by the matrix metalloproteinase MT1-MMP (MMP14). Studying how such proteolytic events, duality in signaling modes and repulsive responses are co-regulated and coexist in cancer could reveal potential therapeutic opportunities. To this goal, we have here used human breast, ovarian and prostate cancer cells grown in 2D and 3D extracellular matrices (ECM), as mono- and co-cultures to mimic the confines provided by the tumor microenvironment. Our results revealed segregation of EphA2 signaling within cancer colonies, including EphA2-MMP14 co-internalization at the cancer cells confronting ephrinA1-expressing cells, in contrast to the stabilization of the receptor and induction of non-canonical signaling in the colonies. This separation of the ligand-mediated and non-canonical EphA2 signaling was dependent on MMP14 and affected platinum chemotherapy-induced apoptosis. By a mass spectroscopy-based screen for EphA2 interacting proteins in the different signaling contexts we identified regulators of proteolysis as well as endocytic pathways with differential interactions upon the ligand-dependent and independent activation states of this receptor. Our studies will help to understand the diverse EphA2 signaling modes and their impact on the regulation of cell-cell and cell-ECM communication affecting cell invasion and survival upon anti-cancer drug treatments.
Citation Format: Lidia Moyano-Galceran, Pauliina S. Turunen, Nami Sugiyama, Pernilla von Nandelstadh, Erika Gucciardo, Markku Varjosalo, Kaisa Lehti. EphA2 signaling segregation and modulation by diverse tumor microenvironment components differentially regulates cancer cell invasion and survival [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO050.