bluuebunny/crossref_metadata_2025_split huggingface dataset:
Growth, condition, and swimming performance of juvenile Pacific herring with winter feeding rations
Authors: Sewall Fletcher , Norcross Brenda , Heintz Ron 
Published: February 2021

Juvenile fish winter mortality, whether through starvation, predation, or disease, depends in part on feeding history. Assessing mortality risk thus requires metrics that can distinguish well-fed from poorly fed individuals. To investigate the effects of winter feeding and spring re-feeding after winter fasting on young-of-the-year Pacific herring (Clupea pallasii), captive herring were maintained on different feeding rations for 20 weeks under ambient winter and spring conditions and evaluated for differences in size, gut mass, RNA/DNA ratio, body composition, and swimming performance. Lipid and moisture levels were inversely related indicators of feeding history, differing most between full-ration and fasted herring. Fasted herring that were re-fed in spring had evidence of compensatory growth without impacting swimming performance. Minimal growth and reduced gut mass observed even among fully fed herring suggest limits to winter feeding benefits. Metabolically processing stored fat rather than foraging and incurring greater predation risk may thus be an advantageous strategy regardless of winter food availability. Mortalities due to starvation and possibly disease were highest among small herring across rations, supporting the importance of size-dependent winter mortality.
Multi-lepton signatures of vector-like leptons with flavor
Authors: Bißmann Stefan , Hiller Gudrun , Hormigos-Feliu Clara , Litim Daniel F. 
Published: February 2021

AbstractWe investigate collider signatures of standard model extensions featuring vector-like leptons and a flavorful scalar sector. Such a framework arises naturally within asymptotically safe model building, which tames the UV behavior of the standard model towards the Planck scale and beyond. We focus on values of Yukawa couplings and masses which allow to explain the present data on the muon and electron anomalous magnetic moments. Using a CMS search based on $$77.4 \, \text {fb}^{-1}$$

77.4

fb

-
1

at the $$\sqrt{s}=13$$

s

=
13

TeV LHC we find that flavorful vector-like leptons are excluded for masses below around 300 GeV if they are singlets under $$SU(2)_L$$

S
U

(
2
)

L

, and around 800 GeV if they are doublets. Exploiting the flavor-violating-like decays of the scalars, we design novel null test observables based on opposite sign opposite flavor invariant masses. These multi-lepton distributions allow to signal new physics and to extract mass hierarchies in reach of near-future searches at the LHC and the HL-LHC.
Relativistic Landau levels for a fermion-antifermion pair interacting through Dirac oscillator interaction
Authors: Guvendi Abdullah 
Published: February 2021

AbstractWe introduce a unique model for a fermion-antifermion pair interacting via Dirac oscillator coupling in the presence of an external uniform magnetic field. This model is based on an exact solution of the corresponding form of a fully-covariant two-body Dirac equation (one-time). The dynamic symmetry of the system allows to study in $$2+1$$

2
+
1

dimensions and we choose the interaction of the particles with the external uniform magnetic field in the symmetric gauge. The corresponding equation leads $$4\times 4$$

4
×
4

dimensional matrix equation for such a static composite system. For spin antisymmetric state of the fermion-antifermion pair, we perform an exact solution of the matrix equation and obtain relativistic Landau levels of a fermion-antifermion pair interacting via Dirac oscillator coupling. The results show that such a composite system behaves like a single relativistic quantum oscillator carrying total rest mass of the particles. We discuss several interesting features of this system and show that the obtained energy spectrum agrees well with the previously announced results for one-body systems. We think that the introduced model in this manuscript has a great potential for many theoretical and experimental applications.
Targeting Pan-ETS Factors Inhibits Melanoma Progression
Authors: Huang Lee , Zhai Yougang , La Jennifer , Lui Jason W. , Moore Stephen P.G. , Little Elizabeth C. , Xiao Sixia , Haresi Adil J. , Brem Candice , Bhawan Jag , Lang Deborah 
Published: February 2021

Abstract

The failure of once promising target-specific therapeutic strategies often arises from redundancies in gene expression pathways. Even with new melanoma treatments, many patients are not responsive or develop resistance, leading to disease progression in terms of growth and metastasis. We previously discovered that the transcription factors ETS1 and PAX3 drive melanoma growth and metastasis by promoting the expression of the MET receptor. Here, we find that there are multiple ETS family members expressed in melanoma and that these factors have redundant functions. The small molecule YK-4-279, initially developed to target the ETS gene–containing translocation product EWS-FLI1, significantly inhibited cellular growth, invasion, and ETS factor function in melanoma cell lines and a clinically relevant transgenic mouse model, BrafCA;Tyr-CreERT2;Ptenf/f. One of the antitumor effects of YK-4-279 in melanoma is achieved via interference of multiple ETS family members with PAX3 and the expression of the PAX3-ETS downstream gene MET. Expression of exogenous MET provided partial rescue of the effects of YK-4-279, further supporting that MET loss is a significant contributor to the antitumor effects of the drug. This is the first study identifying multiple overlapping functions of the ETS family promoting melanoma. In addition, targeting all factors, rather than individual members, demonstrated impactful deleterious consequences in melanoma progression. Given that multiple ETS factors are known to have oncogenic functions in other malignancies, these findings have a high therapeutic impact.

Significance:
These findings identify YK-4-279 as a promising therapeutic agent against melanoma by targeting multiple ETS family members and blocking their ability to act as transcription factors.
SCIRT lncRNA Blocks the Shot of Breast Cancer Cells Self-Renewal Mechanism
Authors: Pardini Barbara , Dragomir Mihnea P. 
Published: February 2021

Abstract
The study by Zagorac and colleagues represents an important step forward in the field of breast cancer, explaining a novel molecular mechanism of transition from slowly multiplying tumor-initiating cells (TIC) into their more differentiated version characterized by high proliferation. The mechanism involves the transcription factors SOX2 and EZH2, which directly repress transcription of cell-cycle genes and activate self-renewal genes in breast cancer cells. This mechanism is further controlled by a negative feedback loop mediated by a long noncoding RNA, SCIRT, not described previously, which is upregulated in tumorspheres and inhibits SOX2 and EZH2. SCIRT is an atypical tumor suppressor in breast cancer, being upregulated in cancer cells, but counteracting their aggressive phenotype. At the molecular level, by direct interaction with EZH2, SCIRT inhibits the transcriptional activity of EZH2 and “blocks the shot” of cancer cells' self-renewal. From a translational perspective, activating SCIRT or induction of SCIRT mimetics in breast cancer cells may lead to the dedifferentiation of TICs toward a less protumorigenic phenotype and a therapy-fragile state that could open new therapeutic avenues.
See related article by Zagorac et al., p. 580
Abstract IA010: Immunology of endometrial cancers: Tumor genetics, immune recognition, and immunotherapy response
Authors: Zamarin Dmitriy 
Published: February 2021

Abstract
Immune checkpoint blockade therapy targeting the T cell immune inhibitory receptors (e.g. PD1 and CTLA4) has reinvigorated the field of cancer immunotherapy and demonstrated the power of harnessing the adaptive immune system to fight cancers. However, fundamental challenges and questions remain. Endometrial cancers specifically, are largely resistant to immune checkpoint blockade, while the underlying mechanisms of why T cell-mediated tumor elimination largely fails in EC are not well understood. Endometrial cancer encompasses a number of genetically-distinct diseases characterized by recurrent molecular alterations driving each disease subtype. Specifically, four major molecular subtypes have been identified, including POLE-ultramutated, MSI-high, and microsatellite stable copy-number high (serous-like) and copy number-low (endometrioid) cancers. In MSI-H endometrial cancers specifically, response rates of over 50% to single agent PD-1/PD-L1 blockade have been reported across a number of studies. Unfortunately, in non-MSI-H tumors, responses to immune checkpoint inhibitors have been rather limited, calling for novel combinations. Importantly, a trial of combination of multi-targeted tyrosine kinase inhibitor (TKI) lenvatinib with pembrolizumab (anti-PD1) demonstrated response rates of close to 40% irrespective of MMR status, which established this combination as a new standard of care treatment in metastatic endometrial cancer. Nevertheless, even with these promising findings: 1) A large proportion of patients does not benefit; 2) Predictive biomarkers and mechanisms defining immunotherapy response or resistance remain unknown; and 3) Insights into the mechanistic basis underlying the TKI/anti-PD-1 synergy are desperately needed. There is a growing appreciation that intrinsic tumor genomic features are critical in shaping the composition and phenotype of the immune microenvironment, including the recruitment, infiltration, phenotypes and functional states of tumor infiltrating lymphocytes. Understanding how these features predict response to immune checkpoint blockade will be key to development of novel biomarkers and therapeutic combinations.
Citation Format: Dmitriy Zamarin. Immunology of endometrial cancers: Tumor genetics, immune recognition, and immunotherapy response [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA010.
Abstract IA011: Coordinated T and B cell responses exert immune pressure against malignant progression
Authors: Conejo-Garcia Jose R. 
Published: February 2021

Abstract
Memory B-cell and plasma cell infiltrates have been associated with better outcome in ovarian cancer, but the nature and functional relevance of these responses in other gynecologic malignancies remains elusive. Using a cohort totaling 107 endometrial cancers of different histological subtypes we show that the density of T cell infiltrates is associated with improved outcome in low-grade endometrial cancer, while better survival is associated with increased B cell and plasma cell infiltrates in high-grade endometrioid tumors. IgA and IgG are similarly abundant in endometrial tumors, but play opposite roles, whereby IgA:tumor cell co-localization is associated with accelerated malignant progression in clear cell and high-grade endometrioid tumors, while binding of IgG is associated with improved outcome in the same histological subtypes. Our data indicate that T cell and B cell responses work in coordination against endometrial cancer, but their role in tumor progression depends on the flavor of these responses and the histological subtype of endometrial cancer.
Citation Format: Jose R. Conejo-Garcia. Coordinated T and B cell responses exert immune pressure against malignant progression [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA011.
Abstract IA013: Endometrial carcinomas with a mutation in DNA polymerase epsilon: A pathologist view
Authors: Bosse Tjalling 
Published: February 2021

Abstract
POLE exonuclease domain mutations (referred to as ‘POLE mutations’) are found in a wide variety of human malignancies, including endometrial cancer (EC). In all tumor types, cancers with POLE mutations are characterized by an exceptionally high mutational burden and a specific mutational signature. Despite their so-called ‘ultramutated’ phenotype, patients with POLE-mutant cancers have significantly better outcomes compared to patients with POLE-wild-type tumors. This prognostic benefit has thus far been shown for early-stage EC and stage II/III colorectal cancers, and has been suggested for glioblastomas. I will discuss the gained insight into somatic POLE mutations, the underlying mechanism(s) by which these POLE mutations contribute to low risk of recurrence and the possible ways for clinical implementation.
Citation Format: Tjalling Bosse. Endometrial carcinomas with a mutation in DNA polymerase epsilon: A pathologist view [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA013.
Abstract IA014: POLE mutations in endometrial cancer: Consequences and mechanisms
Authors: Shcherbakova Polina V. 
Published: February 2021

Abstract
Mutations in the POLE gene encoding DNA polymerase ϵ (Pol ϵ) drive the development of ultramutated endometrial tumors. We aim to understand the mechanisms through which POLE defects cause ultramutation and establish approaches to identify functionally significant variants. Because POLE mutations preferentially affect conserved amino acid residues in the exonuclease domain of Pol ϵ, a concept has initially formed that defective proofreading of replication errors triggers ultramutation. However, genetic and biochemical studies of the most common POLE variants suggested that their pathogenicity is determined by functional alterations other than loss of proofreading. When modeled in yeast, most of the exonuclease domain changes seen in tumors produce mutator effects far exceeding the effect of Polϵ exonuclease deficiency. The magnitude of the mutator effect is allele-specific and does not correlate with the severity of the exonuclease defect. A yeast mimic of the most common variant, P286R, shows greatly increased DNA polymerase activity, in addition to the exonuclease defect, which likely underlies the high mutagenicity. We discuss the implications of POLE status for tumor progression and the design of therapeutic strategies. We also discuss current approaches to assess the functional significance of the multitude of reported POLE mutations and present the most up-to-date list of experimentally confirmed significant variants.
Citation Format: Polina V. Shcherbakova. POLE mutations in endometrial cancer: Consequences and mechanisms [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA014.
Abstract IA018: Breaking the obesity-endometrial cancer link: Lessons from preclinical studies
Authors: Hursting Stephen D. 
Published: February 2021

Abstract
The prevalence of obesity, an established risk factor for endometrial cancer, has increased dramatically over the past 50 years in the US and many other countries. Relative to normoweight cancer patients, obese cancer patients also often have poorer prognoses, resistance to chemotherapies, and are more likely to develop distant metastases. Recent progress on elucidating the mechanisms underlying the obesity-cancer connection suggests that obesity exerts pleomorphic effects on pathways related to tumor development and progression, and thus there are multiple opportunities for primary to tertiary prevention of obesity-related endometrial cancers. We now know that obesity can impact each of the well-established hallmarks of cancer, but obesity-associated perturbations in systemic metabolism and inflammation, and the interactions of these perturbations with cancer cell energetics and immune response, are emerging as the primary drivers of obesity-associated endometrial cancer development and progression. While additional work is needed on the mechanisms underlying the obesity-endometrial cancer link, research is also urgently needed on how to best mitigate the procancer effects of obesity on the endometrium, as well as ways to prevent obesity-associated metastatic progression and therapeutic resistance. We will thus discuss relevant dietary and lifestyle interventions that are being implemented in preclinical and clinical trials, with the ultimate goal of reducing incidence and progression of obesity-associated endometrial cancer.
Citation Format: Stephen D. Hursting. Breaking the obesity-endometrial cancer link: Lessons from preclinical studies [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA018.
Abstract IA019: Organoids to model endometrial cancer subtypes
Authors: Huntsman David G. 
Published: February 2021

Abstract
Before the Cancer Genome Atlas and other genomic studies, endometrial cancer had no reproducible biologic or clinical structure. The molecular classification of endometrial cancer is reproducible, potentially clinically useful and, in the same way that recognition of subtypes led to more effective ovarian cancer research, should enable researchers to have greater impact through more focused studies. Some mutations found in endometrial cancer are subtype specific such as MMR mutations in the MRD subtype or PPP2R1a mutations in the tp53 mutation/copy number high subtype while others such as ARID1a are seen in multiple subtypes. Although the frequency of clear cell cancer is much higher in endometriosis associated ovarian cancers that eutopic endometrial cancers, both sites have similar tumors and these are distinct from those that occur from the similar appearing epithelium of the fallopian tube. This points to the importance of interactions between cell context, mutation and also microenvironment in the development of these cancers. To study these processes we have developed an organoid model system using normal endometrial epithelium. In initial experiments we used Notch inhibitors to force ciliated differentiation and single cell RNA seq to compare ciliated to secretory cell expression profiles. From these data novel markers for ciliated differentiation were obtained. When deployed against endometrial carcinoma tissue microarrays these markers revealed that many cancers are replete with ciliated like cells. Perhaps not surprisingly, as this is a form of differentiation, the presence of these cells was associated with an improved survival as did expression of a secretory cell marker MST. To model uterine cancers we have mutated the organoids with commonly found mutations. ARID1a loss in combination with PIK3CA mutation in this model leads to a morphologic shift towards clear cell cancer and consistent expression changes including loss of RBP1. The key experiments to determine how stromal interactions shape the oncogenic impact of these mutations are ongoing.
Citation Format: David G. Huntsman. Organoids to model endometrial cancer subtypes [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA019.
Abstract PO007: Evaluation of crosstalk between estrogen and Wnt signaling in endometrial cancer
Authors: Osby Krystle , Rodriguez Adriana C. , Gertz Jay 
Published: February 2021

Abstract
Estrogen signaling through estrogen receptor alpha (ER) is considered to be a driving oncogenic signal in type 1 endometrial cancer. However, excess estrogen exposure isn’t sufficient to initiate tumorigenesis in mouse models, suggesting additional genomic or epigenomic changes are required for tumor formation. Activating mutations in beta-catenin, a downstream regulator of Wnt signaling, are prevalent in type I endometrial tumors, with almost 40% of cases harboring these mutations. The combination of excess estrogen and Wnt signals appears to drive endometrial cancer formation and growth, but the mechanisms underlying interplay between these pathways is not well understood. Based on previous studies and our preliminary data, we are currently exploring the hypothesis that beta-catenin acts as a cofactor for ER, representing a convergence of these two oncogenic pathways. Using Ishikawa cells, a type 1 endometrial cancer cell line expressing wildtype beta-catenin, we are measuring differences in gene expression and chromatin between cells that have been induced with 17-beta-estradiol (E2), Wnt3a, or the combination. Our findings suggest that a combination induction affects where ER and beta-catenin bind the genome. In the presence of E2 and Wnt3a, ER’s genomic occupancy expanded and revealed Wnt dependent ER sites separate from canonical ER and Wnt binding sites. Analysis of acetylation of lysine 27 on histone H3 (H3K27ac) using ChIP-seq support this pattern, where acetylation is enriched in the combination treatment over an E2 or Wnt3a induction alone. Additionally, we observed unique gene expression patterns with a simultaneous E2 and Wnt3a induction. We are in the process of creating an isogenic Ishikawa cell line that harbors an activating beta-catenin mutation to determine molecular differences between Wnt ligand activation and constitutively active beta-catenin and discover how these forms of Wnt activation relate to estrogen signaling. Overall, we hope our studies deepen our understanding of estrogen driven transcriptional regulation and shed light on the functional consequences of beta-catenin activating mutations in endometrial cancer.
Citation Format: Krystle Osby, Adriana C. Rodriguez, Jay Gertz. Evaluation of crosstalk between estrogen and Wnt signaling in endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO007.