bluuebunny/crossref_metadata_2025 huggingface dataset:
Panton-Valentine Leukocidin Staphylococcus Aureus (PVL-SA) – an uninvited stowaway aboard a Royal Navy submarine
Authors: Bourn SJN , Evans G , O’Shea MK
Published: February 2021

The toxin Panton-Valentine Leukocidin (PVL) is a virulence factor produced by some strains of Staphylococcus aureus (S. aureus, SA) that destroys leucocytes. PVL-SA predominantly results in skin and soft tissue infections (SSTIs) but may also cause invasive disease, including necrotising pneumonia, which may affect healthy young individuals and has a high mortality. We describe a case of PVL-SA in a submariner who presented at sea and which resulted in a requirement to both alter the submarine’s programme and undertake population screening. The case highlights many important issues pertinent to military populations including clinical and public health considerations.
Anterior chamber gas bubbles in open globe injury
Authors: Barnard EBG , Baxter D , Blanch R
Published: February 2021

We present a case of a 40-year-old soldier who was in close proximity to the detonation of an improvised explosive device (IED). Bubbles of gas were visible within the anterior chamber of his left eye. The authors propose that intraocular gas, present acutely after trauma, is diagnostic of open globe injury and is of particular importance in remote military environments.
Culture obtained from urethral swab of asymptomatic men who screen positive forNeisseria gonorrhoeaeby urine nucleic acid amplification testing
Authors: Ratnappuli Ayoma , Bissessor Melanie , Arumugam Shehara , Williamson Deborah A , Chow Eric P F , Fairley Christopher K , Ong Jason J , De Petra Vesna , Chen Marcus Y
Published: February 2021

Background

In a previous study of men attending Melbourne Sexual Health Centre who hadNeisseria gonorrhoeaedetected by urine Aptima Combo 2 (AC2) testing, 11% were asymptomatic. This study aimed to determine whetherN. gonorrhoeaecan be cultured from asymptomatic men screening positive forN. gonorrhoeaeby nucleic acid amplification testing (NAAT) of urine.

Methods

Between 1 July 2017 and 31 March 2019, all men attending Melbourne Sexual Health Centre were tested forN. gonorrhoeaeby AC2 testing of urine whether urethral symptoms were reported or not. NAAT-positive men were recalled and a urethral swab performed for gonococcal culture using modified Thayer-Martin media with determination of minimum inhibitory concentrations (MICs) by agar dilution.

Results

There were 1001 cases (860 individuals) positive forN. gonorrhoeaeby urine AC2: 892 (89%) reported urethral symptoms; 109 (11%) did not. Twenty-five asymptomatic cases were excluded because of antibiotic use at or following screening. Of the remaining 84 asymptomatic men, 41 (49%) had a urethral swab performed a median of 5 days after screening. Twenty-one men had urethral discharge at the return visit, 11 of whom reported the discharge at the return visit. Of the 41 men who were swabbed, 31 (76%; 95% CI 60% to 88%) were culture positive forN. gonorrhoeae. Among the 21 men who subsequently developed discharge, 19 (90%; 95% CI 70% to 99%) were culture positive. Among the 20 men who remained asymptomatic, 12 (60%; 95% CI 36% to 81%) were culture positive. MIC profiles were obtained from all isolates.

Conclusions

Gonorrhoea was isolated in most but not all asymptomatic men screening positive forN. gonorrhoeaeby urine NAAT. Clinicians should consider performing urethral culture in such men to ensure optimal surveillance for antimicrobial resistance. Isolation ofN. gonorrhoeaeby culture in men without discharge indicates these are true infections with viable organisms.
Development of a large animal model of lethal polytrauma and intra-abdominal sepsis with bacteremia
Authors: O'Connell Rachel L , Wakam Glenn K , Siddiqui Ali , Williams Aaron M , Graham Nathan , Kemp Michael T , Chtraklin Kiril , Bhatti Umar F , Shamshad Alizeh , Li Yongqing , Alam Hasan B , Biesterveld Ben E
Published: February 2021

Background

Trauma and sepsis are individually two of the leading causes of death worldwide. When combined, the mortality is greater than 50%. Thus, it is imperative to have a reproducible and reliable animal model to study the effects of polytrauma and sepsis and test novel treatment options. Porcine models are more translatable to humans than rodent models due to the similarities in anatomy and physiological response. We embarked on a study to develop a reproducible model of lethal polytrauma and intra-abdominal sepsis, which was lethal, though potentially salvageable with treatment.

Methods

Our laboratory has a well-established porcine model that was used as the foundation. Animals were subjected to a rectus crush injury, long bone fracture, liver and spleen laceration, traumatic brain injury and hemorrhage that was used as a foundation. We tested various colon injuries to create intra-abdominal sepsis. All animals underwent injuries followed by a period of shock, then subsequent resuscitation.

Results

All animals had blood culture-proven sepsis. Attempts at long-term survival of animals after injury were ceased because of poor appetite and energy. We shifted to an 8-hour endpoint. The polytrauma injury pattern remained constant and the colon injury pattern changed with the intention of creating a model that was ultimately lethal but potentially salvageable with a therapeutic drug. An uncontrolled cecal injury (n=4) group resulted in very early deaths. A controlled cecal injury (CCI; n=4) group had prolonged time prior to mortality with one surviving to the endpoint. The sigmoid injury (n=5) produced a similar survival curve to CCI but no animals surviving to the endpoint.

Conclusion

We have described a porcine model of polytrauma and sepsis that is reproducible and may be used to investigate novel treatments for trauma and sepsis.

Level of evidence

Not applicable. Animal study.
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

We 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

We 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.
Challenging Practices of Algebraic Battery Life Models through Statistical Validation and Model Identification via Machine-Learning
Authors: Gasper Paul , Gering Kevin , Dufek Eric , Smith Kandler
Published: February 2021

Various modeling techniques are used to predict the capacity fade of Li-ion batteries. Algebraic reduced-order models, which are inherently interpretable and computationally fast, are ideal for use in battery controllers, technoeconomic models, and multi-objective optimizations. For Li-ion batteries with graphite anodes, solid-electrolyte-interphase (SEI) growth on the graphite surface dominates fade. This fade is often modeled using physically informed equations, such as square-root of time for predicting solvent-diffusion limited SEI growth, and Arrhenius and Tafel-like equations predicting the temperature and state-of-charge rate dependencies. In some cases, completely empirical relationships are proposed. However, statistical validation is rarely conducted to evaluate model optimality, and only a handful of possible models are usually investigated. This article demonstrates a novel procedure for automatically identifying reduced-order degradation models from millions of algorithmically generated equations via bi-level optimization and symbolic regression. Identified models are statistically validated using cross-validation, sensitivity analysis, and uncertainty quantification via bootstrapping. On a LiFePO4/Graphite cell calendar aging data set, automatically identified models utilizing square-root, power law, stretched exponential, and sigmoidal functions result in greater accuracy and lower uncertainty than models identified by human experts, and demonstrate that previously known physical relationships can be empirically “rediscovered” using machine learning.
100th anniversary of the discovery of insulin perspective: insulin and adipose tissue fatty acid metabolism
Authors: Carpentier André C.
Published: February 2021

Insulin inhibits systemic nonesterified fatty acid (NEFA) flux to a greater degree than glucose or any other metabolite. This remarkable effect is mainly due to insulin-mediated inhibition of intracellular triglyceride (TG) lipolysis in adipose tissues and is essential to prevent diabetic ketoacidosis, but also to limit the potential lipotoxic effects of NEFA in lean tissues that contribute to the development of diabetes complications. Insulin also regulates adipose tissue fatty acid esterification, glycerol and TG synthesis, lipogenesis, and possibly oxidation, contributing to the trapping of dietary fatty acids in the postprandial state. Excess NEFA flux at a given insulin level has been used to define in vivo adipose tissue insulin resistance. Adipose tissue insulin resistance defined in this fashion has been associated with several dysmetabolic features and complications of diabetes, but the mechanistic significance of this concept is not fully understood. This review focusses on the in vivo regulation of adipose tissue fatty acid metabolism by insulin and the mechanistic significance of the current definition of adipose tissue insulin resistance. One hundred years after the discovery of insulin and despite decades of investigations, much is still to be understood about the multifaceted in vivo actions of this hormone on adipose tissue fatty acid metabolism.
Epigenetic regulation of arginine vasopressin receptor 2 expression by PAX2 and Pax transcription interacting protein
Authors: Abraham Saji , Paknikar Raghavendra , Bhumbra Samina , Luan Danny , Venkatareddy Madhusudan , O’Connor Christopher , Bitzer Markus , Fenton Robert A. , Hurd Toby , Garg Puneet , Patel Sanjeevkumar R.
Published: February 2021

The transcription factor PAX2 plays an indispensable role in kidney development. In the adult kidney, we identified the first described protein this protein regulates. PAX2 and its interacting partner Pax transcription interacting protein recruit a histone methyltransferase complex to the promoter and epigentically regulate the expression of arginine vasopressin receptor 2, a protein that plays a crucial role in osmoregulation in the distal tubule.
A plasma creatinine- and urea-based equation to estimate glomerular filtration rate in rats
Authors: Besseling Paul J. , Pieters Tobias T. , Nguyen Isabel T. N. , de Bree Petra M. , Willekes Nel , Dijk Adele H. , Bovée Dominique M. , Hoorn Ewout J. , Rookmaaker Maarten B. , Gerritsen Karin G. , Verhaar Marianne C. , Gremmels Hendrik , Joles Jaap A.
Published: February 2021

This is the first equation, that we know of, which estimates glomerular filtration rate in rats based on a single measurement of body weight, plasma creatinine, and plasma urea.
Evaluation of Urinary Tract Infection following Corticosteroid Therapy in Patients with Multiple Sclerosis Exacerbation
Authors: Bazi Aliyeh , Baghbanian Seyed Mohammad , Ghazaeian Monireh , Fallah Sahar , Hendoiee Narjes
Published: February 2021

The first treatment for multiple sclerosis exacerbation is usually short-term intravenous methylprednisolone (IVMP), with or without a regimen of oral prednisone taper (OPT). This study aims to evaluate the effects of IVMP and OPT in comparison with IVMP alone in raising the risk of urinary tract infection (UTI) and posttreatment improvement of urinary tract symptoms in patients with relapsing-remitting multiple sclerosis. This double-blind randomized clinical trial was conducted on 56 people with multiple sclerosis relapse who had undergone methylprednisolone for 5 days. Patients were randomly split into two groups: oral prednisolone and placebo (tapering for 20 days). Demographic data, duration of multiple sclerosis, urinary tract symptoms, the Expanded Disability Status Scale (EDSS) score, and urine data were analyzed. The incidence of UTI in the intervention and control groups did not differ significantly (

p
=
560

). However, the improvement of urinary tract symptoms in the intervention group was significantly more favorable than in the control group (

p
≤
0.001

). Furthermore, administering OPT after IVMP did not increase the risk of UTI occurrence in patients with multiple sclerosis exacerbation. The urine analysis results did not show any differences at baseline and after the corticosteroid tapering regimen. Due to the risk of infection by corticosteroids, it is no longer necessary to do further urinary screening in this group of patients.
On
J
-Cone Metric Spaces over a Banach Algebra and Some Fixed-Point Theorems
Authors: Fernandez Jerolina , Malviya Neeraj , Parvaneh Vahid , Aydi Hassen , Mohammadi Babak
Published: February 2021

In the present paper, we define

J

-cone metric spaces over a Banach algebra which is a generalization of

G

p

b

-metric space (

G

p

b

-MS) and cone metric space (CMS) over a Banach algebra. We give new fixed-point theorems assuring generalized contractive and expansive maps without continuity. Examples and an application are given at the end to support the usability of our results.
Architecture for Resource Allocation in the Internet of Vehicles for Cooperating Driving System
Authors: kalsoom Nafeesa , Ahmad Iftikhar , Alroobaea Roobaea , Raza Muhammad Ahsan , Khalid Samina , Ahmed Zaheed , Ali Ihsan
Published: February 2021

Internet of Vehicles (IoV) is a complex system that consists of resource types such as vehicles, humans, and sensors. Although the Internet of Vehicles is complex, it improvises communication among vehicles on the roads. Quality of service (QoS) enabled the cooperative driving system (CDS) based on 5G technology, enabling vehicles to communicate and cooperate to improve road traffic efficiency. Due to the high vehicle density and limited resources (bandwidth) of current network infrastructure, sometimes a better channel that meets the requirements of cooperative driving is not available that causes network congestion, which directly influences the overall QoS of the CDS. To overcome this, we proposed a 5G network-based architecture for CDS that incorporates a D2D technology-based resource allocation scheme. The proposed network architecture and cooperative behavior-based scheme helps in improving QoS for CDS. We implemented our proposed scheme by incorporating the density-based scattered clustering algorithm with noise for vehicular clustering. The proposed scheme’s performance shows significant improvement in terms of throughput compared with existing D2D approaches.
Study on the Influence of Light Intensity on the Performance of Solar Cell
Authors: Li Zhe , Yang Jian , Dezfuli Pouya Asareh Nejad
Published: February 2021

In order to solve the problem that the influence of light intensity on solar cells is easily affected by the complexity of photovoltaic cell parameters in the past, it is proposed based on the influence of light intensity on the power generation performance of solar cells. By analyzing the electrical performance parameters of photovoltaic cell trough solar energy and determining the influencing factors, discarding other weakly related parameters, and designing targeted research programs, according to the study of the impact of light intensity and temperature on the battery temperature changes, the performance of photovoltaic power generation was understood. The output voltage and current of the maximum power point were obtained. By analyzing its relationship with influencing factors, the impact analysis on the power generation performance of photovoltaic cells was realized. The experimental results show that the open circuit voltage, short-circuit current, and maximum output power of solar cells increase with the increase of light intensity. Therefore, it can be known that the greater the light intensity, the better the power generation performance of the solar cell.
Derivations of a Sullivan Model and the Rationalized
G
-Sequence
Authors: Maphane Oteng
Published: February 2021

Let

G

k
,
n

ℂ

for

2
≤
k
<
n

denote the Grassmann manifold of

k

-dimensional vector subspaces of

ℂ

n

. In this paper, we compute, in terms of the Sullivan models, the rational evaluation subgroups and, more generally, the

G

-sequence of the inclusion

G

2
,
n

ℂ

↣

G

2
,
n
+
r

ℂ

for

r
≥
1

.
Study on the Effect of Cu (II) and Zn (II) on the Accumulation of Pb (II) from Soil to the Biomass of Vegetable
Authors: Thanh Tran Le Thi , Luan Le Van , Hieu Tran Quang , Van Tan Le
Published: February 2021

Among soil pollutants, lead (Pb) is one of the toxic metal pollutants widely used in many industrial processes and occurs as a contaminant in environment. In this study, a field experiment was carried out to investigate the accumulation of lead from soil contaminated by this metal ion on the biomass of some vegetables, including spinach, lettuce, carrots, and potatoes. The results showed that lead was cumulative metal. Besides, the level of lead accumulation in soil of the studied vegetables decreased in the order of tubers of carrots, tubers of potato, spinach root, lettuce root, stems and leaves of spinach, stem and leaves of carrot, stems and leaves of potato, and stem and leaves of lettuce, respectively. Our investigations demonstrate the effect of copper and zinc micronutrient elements which play an important role in the growth and development of plants, on the accumulation of lead from contaminated soil of the studied vegetables. The obtained results showed that high concentration of copper and zinc in soil cause competition with lead in the process of absorption and accumulation in the plant. Specifically, copper and zinc showed the inhibition effect on the uptake and accumulation of lead by these plants.
Fast and Universal Inter-Slice Handover Authentication with Privacy Protection in 5G Network
Authors: Ren Zhe , Li Xinghua , Jiang Qi , Cheng Qingfeng , Ma Jianfeng
Published: February 2021

In a 5G network-sliced environment, mobility management introduces a new form of handover called inter-slice handover among network slices. Users can change their slices as their preferences or requirements vary over time. However, existing handover-authentication mechanisms cannot support inter-slice handover because of the fine-grained demand among network slice services, which could cause challenging issues, such as the compromise of service quality, anonymity, and universality. In this paper, we address these issues by introducing a fast and universal inter-slice (FUIS) handover authentication framework based on blockchain, chameleon hash, and ring signature. To address these issues, we introduce an anonymous service-oriented authentication protocol with a key agreement for inter-slice handover by constructing an anonymous ticket with the trapdoor collision property of chameleon hash functions. In order to reduce the computation overhead of the user side in the process of authentication, a privacy-preserving ticket validation with a ring signature is designed to finish in the consensus phase of the blockchain in advance. Thanks to the edge computing capabilities in 5G, distributed edge nodes help to store the anonymous ticket information, which guarantees that the legal users can finish authentication swiftly during handover. Our scheme's performance is evaluated through simulation experiments to testify the efficiency and feasibility in a 5G network-sliced environment. The results show that compared to other authentication schemes of the same type, the overall inter-slice handover delay has been reduced by 97.94%.
Study on the Operation Efficiency of Toll Roads in China from the Perspective of Scale Economy
Authors: Xu Yan , Fan Jianqiang , Xu Haicheng
Published: February 2021

Although China’s toll highways are world-renowned, they suffer from indisputable operational inefficiencies. Operationally, China’s toll highway sector is characterized by an administrative monopoly. In particular, governmental loan-repayment highways have such characteristics as franchising, monopoly, and “one highway by one company.” Hence, this study concentrates on the relationship between economic performance, administrative monopoly, and scale efficiency with respect to toll highways, and explores how the China-specific administrative monopoly affects the transformation of toll highways from scale to efficiency. Using the globally referenced data envelopment analysis- (DEA-) Malmquist Index, this study first measures the operational efficiency of China’s toll highway sector from 2010 to 2017. Based on provincial panel data, this paper then discusses the relationship between toll highway scale and economic performance through system-generalized method of moments estimation and verifies the status quo of the transformation of toll highways from scale to efficiency. From the provincial and industrial perspectives, this study further verifies how an administrative monopoly restricts the transformation from scale to total factor productivity and scale efficiency through the unique operation pattern in the toll highway sector. Finally, this study conducts an extended analysis of the relationship between operational efficiency and debt in the toll highway sector. The administrative monopoly is found to increase the debt burden of the toll highway sector and to have a negative impact on the long-term sustainability of the sector.
Calibration of the EBT3 Gafchromic Film Using HNN Deep Learning
Authors: Chang Liyun , Yeh Shyh-An , Ho Sheng-Yow , Ding Hueisch-Jy , Chen Pang-Yu , Lee Tsair-Fwu
Published: February 2021

To achieve a dose distribution conformal to the target volume while sparing normal tissues, intensity modulation with steep dose gradient is used for treatment planning. To successfully deliver such treatment, high spatial and dosimetric accuracy are crucial and need to be verified. With high 2D dosimetry resolution and a self‐development property, the Ashland Inc. product EBT3 Gafchromic film is a widely used quality assurance tool designed especially for this. However, the film should be recalibrated each quarter due to the “aging effect,” and calibration uncertainties always exist between individual films even in the same lot. Recently, artificial neural networks (ANN) are applied to many fields. If a physicist can collect the calibration data, it could be accumulated to be a substantial ANN data input used for film calibration. We therefore use the Keras functional Application Program Interface to build a hierarchical neural network (HNN), with the inputs of net optical densities, pixel values, and inverse transmittances to reveal the delivered dose and train the neural network with deep learning. For comparison, the film dose calculated using red‐channel net optical density with power function fitting was performed and taken as a conventional method. The results show that the percentage error of the film dose using the HNN method is less than 4% for the aging effect verification test and less than 4.5% for the intralot variation test; in contrast, the conventional method could yield errors higher than 10% and 7%, respectively. This HNN method to calibrate the EBT film could be further improved by adding training data or adjusting the HNN structure. The model could help physicists spend less calibration time and reduce film usage.
Multiobjective Optimization of an Off-Road Vehicle Suspension Parameter through a Genetic Algorithm Based on the Particle Swarm Optimization
Authors: Peng Dengzhi , Tan Gangfeng , Fang Kekui , Chen Li , Agyeman Philip K. , Zhang Yuxiao
Published: February 2021

Ride comfort and handling performances are known conflicts for off-road vehicles. Recent publications focus on passenger vehicles on class B and class C roads, while, for off-road vehicles, they should be able to run on rougher roads: class D, class E, or class F roads. In this paper, a quarter vehicle model with nonlinear damping is established to analyze the suspension performance of a medium off-road vehicle on the class F road. The ride comfort, road holding, and handling performance of the vehicle are indicated by the weighted root mean square (RMS) value of the vertical acceleration of the sprung mass, suspension travel, and tire deflection. To optimize these objectives, the genetic algorithm (GA), particle swarm optimization (PSO), and a genetic algorithm based on the particle swarm optimization (GA-PSO) are initiated. The efficiency and accuracy of these algorithms are compared to find the best suspension parameters. The effect of the optimized method is validated by the field test result. The ride comfort, road holding, and handling performance are improved by approximately 20%.
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

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

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

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

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

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

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

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

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

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.