bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations of serum soluble Fas and Fas ligand (FasL) with outcomes in systemic lupus erythematosus
Authors: Vincent Fabien B , Kandane-Rathnayake Rangi , Koelmeyer Rachel , Harris James , Hoi Alberta Y , Mackay Fabienne , Morand Eric F
Published: June 2020

Objective

Fas/Fas ligand (FasL) and B cell-activating factor (BAFF) signalling have pivotal roles in SLE pathogenesis. We investigated the clinical associations of serum concentrations of soluble Fas (sFas) and soluble FasL (sFasL) in SLE and their relationship with BAFF.

Methods

Serum sFas and sFasL were quantified by multiplex assay, and BAFF by ELISA, in 118 patients with SLE and 17 healthy controls (HC). SLE disease activity and organ damage were assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics Damage Index.

Results

sFas, sFasL and BAFF were detectable in all samples. Serum sFas and sFasL were significantly higher in SLE compared with HC. In univariable regression analyses, patients with active renal disease and those with flare had significantly higher levels of sFas compared with those without. High serum BAFF in patients with SLE was associated with increased sFas but not sFasL. The association between sFas and renal disease remained significant after adjusting for BAFF, but the association with flare attenuated. High sFas levels were associated with increased time-adjusted mean SLEDAI-2K, even after adjusting for BAFF, and with higher odds of flare over time. In contrast, high sFasL was associated with reduced organ damage over time. Serum sFasL/sFas ratio was negatively associated with active overall disease, flare and organ damage.

Conclusions

Serum sFas is associated with active renal SLE, and active disease and flare over time, while sFasL/sFas ratio is negatively associated with disease activity and organ damage accrual. Treatments correcting abnormal levels of sFas/FasL may be worthy of evaluation in SLE.
Triage of critical care resources in COVID-19: a stronger role for justice
Authors: Reid Lynette
Published: June 2020

Some ethicists assert that there is a consensus that maximising medical outcomes takes precedence as a principle of resource allocation in emergency triage of absolutely scarce resources. But the nature of the current severe acute respiratory syndrome-related coronavirus 2 pandemic and the history of debate about balancing equity and efficiency in resource allocation do not support this assertion. I distinguish a number of concerns with justice and balancing considerations that should play a role in critical care triage policy, focusing on discrimination and on fundamental egalitarian and social justice concerns.
Mesenchymal stromal/stem cells modulate response to experimental sepsis-induced lung injury via regulation of miR-27a-5p in recipient mice
Authors: Younes Nadim , Zhou Louis , Amatullah Hajera , Mei Shirley H J , Herrero Raquel , Lorente Jose Angel , Stewart Duncan J , Marsden Philip , Liles W Conrad , Hu Pingzhao , dos Santos Claudia C
Published: June 2020

Introduction

Mesenchymal stromal cell (MSC) therapy mitigates lung injury and improves survival in murine models of sepsis. Precise mechanisms of therapeutic benefit remain poorly understood.

Objectives

To identify host-derived regulatory elements that may contribute to the therapeutic effects of MSCs, we profiled the microRNAome (miRNAome) and transcriptome of lungs from mice randomised to experimental polymicrobial sepsis-induced lung injury treated with either placebo or MSCs.

Methods and results

A total of 11 997 genes and 357 microRNAs (miRNAs) expressed in lungs were used to generate a statistical estimate of association between miRNAs and their putative mRNA targets; 1395 miRNA:mRNA significant association pairs were found to be differentially expressed (false discovery rate ≤0.05). MSC administration resulted in the downregulation of miR-27a-5p and upregulation of its putative target gene VAV3 (adjusted p=1.272E-161) in septic lungs. In human pulmonary microvascular endothelial cells, miR-27a-5p expression levels were increased while VAV3 was decreased following lipopolysaccharide (LPS) or tumour necrosis factor (TNF) stimulation. Transfection of miR-27a-5p mimic or inhibitor resulted in increased or decreased VAV3 message, respectively. Luciferase reporter assay demonstrated specific binding of miR-27a-5p to the 3′UTR of VAV3. miR27a-5p inhibition mitigated TNF-induced (1) delayed wound closure, increased (2) adhesion and (3) transendothelial migration but did not alter permeability. In vivo, cell infiltration was attenuated by intratracheal coinstillation of the miR-27a-5p inhibitor, but this did not protect against endotoxin-induced oedema formation.

Conclusions

Our data support involvement of miR-27a-5p and VAV3 in cellular adhesion and infiltration during acute lung injury and a potential role for miR-27a-based therapeutics for acute respiratory distress syndrome.
Cyclicity of all anti-NMHV and $$\hbox {N}^{2}{\mathrm{MHV}}$$ tree amplitudes in $$\mathcal {N}=4$$ SYM
Authors: Rao Junjie
Published: June 2020

This article proves the cyclicity of anti-NMHV and $$\hbox {N}^{2}{\mathrm{MHV}}$$N2MHV tree amplitudes in planar $$\mathcal {N}=4$$N=4 SYM up to any number of external particles as an interesting application of positive Grassmannian geometry. In this proof the two-fold simplex-like structures of tree amplitudes introduced in 1609.08627 play a key role, as the cyclicity of amplitudes will induce similar simplex-like structures for the boundary generators of homological identities. For this purpose, we only need a part of all distinct boundary generators, and the relevant identities only involve BCFW-like cells. The manifest cyclic invariance in this geometric representation reflects one of the invariant characteristics of amplitudes, though they are obtained by the scheme-dependent BCFW recursion relation.
Alternative to the application of PDG scale factors
Authors: Erler Jens , Ferro-Hernández Rodolfo
Published: June 2020

The Particle Data Group recommends a set of procedures to be applied when discrepant data are to be combined. We introduce an alternative method based on a more general and solid statistical framework, providing a robust way to include possible unknown systematic effects interfering with experimental measurements or their theoretical interpretation. The limit of large data sets and practical cases of interest are discussed in detail.
Photoelectron holography of the H2+ molecule
Authors: Kiss Gellért Zsolt , Borbély Sándor , Tóth Attila , Nagy Ladislau
Published: June 2020

We investigate the photoelectron spectrum of the H2+ target induced by few-cycle XUV laser pulses using first principle calculations. In the photoelectron spectrum, by performing calculations for different internuclear separations, we investigate how the structure of the target is influencing the spatial interference pattern. This interference pattern is created by the coherent superposition of electronic wave packets emitted at the same time, but following different paths. We find that the location of the interference minima in the spectra is dominantly determined by the target’s ionization energy, however, by comparing the H2+ results with model calculations with spherically symmetric potentials, clear differences were observed for the molecular potential relative to the central potentials. Next to the main feature (spatial interference) we have also identified the traces of the two-center interference in the photoelectron spectrum, however, these were mainly washed out due to the complex electronic wave packet dynamics that occurs during the interaction with the considered laser field.

Graphical abstract
IDIOSYNCRATIC RISK AND ACYCLICALLY INCREASING PUBLIC DEBT
Authors: LEE INSOOK
Published: June 2020

Observed public debt of developed economies is not only countercyclical but also acyclically increasing for fairly long peacetime. This paper proposes a politico-economic theory of public debt which coherently rationalizes both acyclical and countercyclical behaviors of public debt. An office-seeking policymaker decides fiscal policies to win over finitely-lived voters who face uninsurable idiosyncratic risk on their disposable incomes. The equilibrium public debt is (i) acyclically increasing, or (ii) countercyclical, or (iii) acyclically decreasing. An increase in the idiosyncratic risk can change public debt behavior to acyclically increasing from countercyclical, entailing rises in public debt.
MODELING ARTERIES AS A MULTILAYERS DILATATION ELASTICITY MEDIUM: A NUMERICAL INVESTIGATION
Authors: VOIGNIER ARNAUD , NJIWA RICHARD KOUITAT
Published: June 2020

Understanding the deformation of arterial walls under loading is essential for the definition of some new therapeutic protocols. This requires the modeling of the mechanical behavior of the artery wall. In this work, in order to account for the microstructure, each of the conventional three layers of the artery is assumed to behave like a dilatation elastic solid. The resulting compound is then submitted to various loads and the response analyzed in order to highlight the contribution of the microstructure. Finally, the impact of a localized zone of microstructure modification on the overall deformation is investigated.
U.S. VETERANS AS EMERGING ENTREPRENEURS: SELF-EFFICACY, INTENTIONS AND CHALLENGES
Authors: CATER JOHN JAMES , YOUNG MARILYN
Published: June 2020

Veterans may acquire technical skills and leadership ability from their military service but have little information concerning specific entrepreneurial tasks, such as developing a business plan. This descriptive survey study examines avenues for veterans to find assistance to acquire needed skills, adding to their entrepreneurial self-efficacy. We surveyed 68 U.S. veterans who were emerging entrepreneurs, either owning their own business or indicating they intended to start their own company. Veterans’ personal attitudes and beliefs, including entrepreneurial self-efficacy, risk propensity and tolerance of ambiguity, may increase their entrepreneurial intentions. A model of veterans as emerging entrepreneurs and five propositions are offered.
Some remarks on the Fourier coefficients of cusp forms
Authors: Kumar Balesh , Mehta Jay , Viswanadham G. K.
Published: June 2020

In this paper, we consider the angular changes of Fourier coefficients of half integral weight cusp forms and sign changes of [Formula: see text]-exponents of generalized modular functions.
Sparse Graph Connectivity for Image Segmentation
Authors: Zhu Xiaofeng , Zhang Shichao , Zhang Jilian , Li Yonggang , Lu Guangquan , Yang Yang
Published: June 2020

It has been demonstrated that the segmentation performance is highly dependent on both subspace preservation and graph connectivity. In the literature, the full connectivity method linearly represents each data point (
e.g., 
a pixel in one image) by all data points for achieving subspace preservation, while the sparse connectivity method was designed to linearly represent each data point by a set of data points for achieving graph connectivity. However, previous methods only focused on either subspace preservation or graph connectivity. In this article, we propose a Sparse Graph Connectivity (SGC) method for image segmentation to automatically learn the affinity matrix from the low-dimensional space of original data, which aims at simultaneously achieving subspace preservation and graph connectivity. To do this, the proposed SGC simultaneously learns a self-representation affinity matrix for subspace preservation and a sparse affinity matrix for graph connectivity, from the intrinsic low-dimensional feature space of high-dimensional original data. Meanwhile, the self-representation affinity matrix is pushed to be similar to the sparse affinity as well as be the final segmentation results. Experimental result on synthetic and real-image datasets showed that our SGC method achieved the best segmentation performance, compared to state-of-the-art segmentation methods.
SIGACT News Complexity Theory Column 105
Authors: Hemaspaandra Lane A.
Published: June 2020

This is being written during the COVID-19 pandemic, and no one knows what things will be like even when Eshan's article reaches you (psst: please skip this introduction and go right to Eshan's great article now!), much less this coming fall semester, which as this is being written seems likely to be at least in part still shaped by the COVID-19 crisis.
60 Years of Mastering Concurrent Computing through Sequential Thinking
Authors: Rajsbaum Sergio , Raynal Michel
Published: June 2020

Modern computing systems are highly concurrent. Threads run concurrently in shared-memory multi-core systems, and programs run in different servers communicating by sending messages to each other. Concurrent programming is hard because it requires to cope with many possible, unpredictable behaviors of the processes, and the communication media. The article argues that right from the start in 1960's, the main way of dealing with concurrency has been by reduction to sequential reasoning. It traces this history, and illustrates it through several examples, from early ideas based on mutual exclusion (which was initially introduced to access shared physical resources), passing through consensus and concurrent objects (which are immaterial data), until today distributed ledgers. A discussion is also presented, which addresses the limits that this approach encounters, related to fault-tolerance, performance, and inherently concurrent problems.
Experimental Study on the Unsteady Characteristics and the Impact Performance of a High-Pressure Submerged Cavitation Jet
Authors: Yang Yongfei , Li Wei , Shi Weidong , Zhou Ling , Zhang Wenquan
Published: June 2020

High-pressure submerged cavitation jet is widely used in the fields of material peening, petroleum drilling, and ocean engineering. The impact performance of the jet with intensive cavitation is related to the factors such as working condition and the nozzle geometry. To reveal the relationship between the nozzle divergent angle and the jet pressure on the unsteady characteristics of the jet, high-speed photography with frame rate of 20000 fps is used to record the image of the cavitation clouds. Grayscale analysis algorithm developed in MATLAB is used to study the effects of injecting condition on the special structure, unsteady characteristics, and shedding frequency of the cavitation bubbles. The impact load characteristics of the cavitation jet with different cavitation numbers and stand-off distances are recorded using a high-response pressure transducer. It is found that the cavitation number is the main factor affecting the cavitation morphology of the submerged jet. The lower the cavitation number is, the more intense the cavitation occurs. The outlet divergent angle of the convergent-divergent nozzle also has a significant influence on the development of the cavitation clouds. In the three nozzles with the outlet divergent angles of 40°, 80°, and 120°, the highest bubble concentration is formed usinga nozzle with a divergent angle of 40°, but the high-concentration cavitating bubbles are only distributed in a very small range of the nozzle outlet. The cavities generated by using the nozzle with a divergent angle of 80° can achieve good results in terms of concentration and distribution range, while the nozzle with divergent angle of 120° has lower cavitation performance due to the lack of the constraint at the outlet which intensifies the shear stress of the jet. According to the result of frame difference method (FDM) analysis, the jet cavitation is mainly formed in the vortex structure generated by the shearing layer at the nozzle exit, and the most severe region in the collapse stage is the rear end of the downstream segment after the bubble cloud sheds off. The impact load of the cavitation jet is mainly affected by the stand-off distance of the nozzle from the impinged target, while the nozzle outlet geometry also has an effect on the impact performance. Optimizing the stand-off distance and the outlet geometry of the nozzles is found to be a good way to improve the performance of the cavitation jet.
Two Cases of Ectopic Pregnancy Mimicking Gestational Trophoblastic Disease
Authors: Suzuki Haruka , Chigusa Yoshitsugu , Hamanishi Junzo , Mandai Masaki , Kondoh Eiji
Published: June 2020

A well-known typical feature of ectopic pregnancy is an evident gestational sac structure outside of the uterus. However, some cases show atypical appearance that is described as a heterogeneous hypervascular mass. We report two cases of ectopic pregnancy that presented heterogeneous findings mimicking gestational trophoblastic diseases but were correctly diagnosed as ectopic pregnancies on MRI. The first case was an interstitial pregnancy in which the patient underwent surgical treatment. The second case was a cesarean scar pregnancy that was treated conservatively but showed spurious enlargement of pregnancy-related lesions after the treatment. Both cases lacked myometrial invasion on MRI, and the patients were diagnosed with ectopic pregnancies. Invasive findings on MRI may discriminate ectopic pregnancy from trophoblastic tumors and avoid unnecessary hysterectomy.
Research on the Dynamics Game Model in a Green Supply Chain: Government Subsidy Strategies under the Retailer’s Selling Effort Level
Authors: Yuan Xigang , Zhang Xiaoqing , Zhang Dalin
Published: June 2020

Based on dynamic game theory and the principal-agent theory, this paper examined different government subsidy strategies in green supply chain management. Assuming that the retailer’s level of selling effort involved asymmetric information, this study analyzed the impact of different government subsidy strategies on the wholesale price, the product greenness level, retail price, the level of selling effort, the manufacturer’s profit, and the retailer’s profit. The results showed that (1) the government’s subsidy strategy can effectively not only improve the product greenness level but also increase the profits of an enterprise in a green supply chain, which helps the retailer to enhance their selling effort; (2) regardless of whether the retailer’s level of selling effort was high or low, as the government’s subsidy coefficient increased, the wholesale price continued to decrease, and the product greenness level and retailer’s selling effort level also increased.
Yield Management by Reconstruction of Cargo Contribution for Container Shipping
Authors: Lin Yisong , Wang Xuefeng , Jin Jian Gang
Published: June 2020

This study provides a cargo contribution yield management model to solve the ship capacity control problem for the container liner shipping industry. We propose a new objective to optimize cargo contribution to replace the focus on total revenue or average revenue in the current research. We reflect the special characteristics of yield management in container liner shipping, and all cost items were identified and calculated to develop a new cargo contribution evaluating system. We propose a mathematical model for service route segments’ allocation distribution based on cargo contribution. We use a genetic algorithm to solve the model further with comparative analysis with actual practice. The study cultivates new ground in the current literature with a wide range of innovative applications at a practical level.
Upper and Lower Bounds for the Kirchhoff Index of the n-Dimensional Hypercube Network
Authors: Liu Jia-Bao , Zhao Jing , Shi Zhi-Yu , Cao Jinde , Alsaadi Fuad E.
Published: June 2020

The hypercube Qn is one of the most admirable and efficient interconnection network due to its excellent performance for some practical applications. The Kirchhoff index KfG is equal to the sum of resistance distances between any pairs of vertices in networks. In this paper, we deduce some bounds with respect to Kirchhoff index of hypercube network Qn.
Correction of Diastasis Rectus Abdominis with Tacking the Rectus Sheath and Resection of Excess Skin for Cosmesis
Authors: Takaya Kento , Aramaki-Hattori Noriko , Yabuki Hanayo , Wada Norihito , Sakai Shigeki , Okabe Keisuke , Kishi Kazuo
Published: June 2020

Introduction. We report a case of diastasis rectus abdominis (DRA), in which the improvement of the appearance was obtained by performing extra skin resection. Case Report. A 30-year-old woman presented persistent abdominal bulging after her second delivery. She was diagnosed as DRA by computed tomography. We underwent a surgery that tacking the anterior layer of the rectus sheath and resecting excess skin. Results. There has been no clinical evidence of recurrence, and the patient satisfies her abdominal appearance. Conclusion. Because DRA is not a true hernia, surgery for DRA should be performed in understanding how patients want to improve their aesthetic appearance.
A Case of Drug-Induced Liver Injury Secondary to Natalizumab
Authors: Santoiemma Phillip P. , Maddur Haripriya , Moore Christopher M.
Published: June 2020

A 33-year-old Caucasian female with relapsing-remitting multiple sclerosis presented with abdominal pain, nausea, and vomiting and was found to have acute liver injury. After thorough investigation, she was diagnosed with drug-induced liver injury (DILI) thought secondary to redosing of Natalizumab therapy.
Improvement of the Safety Profile of Canaloplasty and Phacocanaloplasty: A Review of Complications and Their Management
Authors: Konopińska Joanna , Mariak Zofia , Rękas Marek
Published: June 2020

Research on the methods used to achieve persistent and safe control of intraocular pressure resulted in the implementation of novel surgical procedures, such as canaloplasty and phacocanaloplasty. Herein, we review the literature focused on the safety profile of canaloplasty and phacocanaloplasty and the management of related complications. The aim of canaloplasty is to restore the natural aqueous outflow. This goal is achieved via a surgical procedure that involves viscocanalostomy with catheterisation of Schlemm’s canal (360°) and placement of a circumferential suture that tensions the canal walls. This improves Schlemm’s canal drainage, choroidoscleral flow, and subconjunctival filtration. The efficacy of canaloplasty for reducing the intraocular pressure is similar to those of trabeculectomy with mitomycin C and deep sclerectomy augmented with an implant and mitomycin C. However, canaloplasty is associated with a lower complication rate than those conventional techniques. Novel microsurgical techniques for the treatment of glaucoma are unlikely to replace the conventional methods. However, these new techniques offer alternatives, especially for patients who have an early indication for surgical intervention. Nevertheless, canaloplasty is associated with the expectations of efficient, safe, and modern surgical treatment.
Maternal-Fetal Perinatal Transmission of Staphylococcal Infections: A Report of Two Neonates
Authors: Thadchanamoorthy V. , Dayasiri Kavinda
Published: June 2020

Staphylococcal infection in terms of fetus is rare and is associated with either maternal staphylococcal sepsis or colonization that leads to vertical transmission. Antenatal invasive procedures are a recognized risk factor. Most reported newborns with fetal-onset staphylococcal infections have had a worse outcome. We report the story of two newborns who had pustular-bullous skin lesions at birth and responded successfully to antistaphylococcal antibiotics. Both neonates made complete recovery. It is important to suspect clinically the staphylococcal infections when bullous skin lesions are present in the newborn.
Biomedical Relation Extraction Using Distant Supervision
Authors: Boudjellal Nada , Zhang Huaping , Khan Asif , Ahmad Arshad
Published: June 2020

With the accelerating growth of big data, especially in the healthcare area, information extraction is more needed currently than ever, for it can convey unstructured information into an easily interpretable structured data. Relation extraction is the second of the two important tasks of relation extraction. This study presents an overview of relation extraction using distant supervision, providing a generalized architecture of this task based on the state-of-the-art work that proposed this method. Besides, it surveys the methods used in the literature targeting this topic with a description of different knowledge bases used in the process along with the corpora, which can be helpful for beginner practitioners seeking knowledge on this subject. Moreover, the limitations of the proposed approaches and future challenges were highlighted, and possible solutions were proposed.
Proportion of Immediate Postpartum Anaemia and Associated Factors among Postnatal Mothers in Northwest Ethiopia: A Cross-Sectional Study
Authors: Abebaw Asenake , Gudayu Temesgen Worku , Kelkay Bayew
Published: June 2020

Background. Anaemia is a major global health problem, especially in developing countries. Postpartum anaemia hurts both maternal and newborn baby health. Anaemia in pregnancy is sufficiently emphasized; however, very little attention has been paid to postpartum anaemia in Ethiopia. Therefore, this study aimed to investigate the proportion of immediate postpartum anaemia and associated factors among postpartum mothers in Debre Markos Referral Hospital. Methods. Institutional-based cross-sectional study was conducted among 424 study participants from August 1st to October 30th, 2019. A systematic random sampling technique was employed to select the study participants. Data were collected through both face-to-face interview and maternal chart review by using a pretested questionnaire. Data were cleaned, coded, and entered using Epi Data version 4.6.0.0 and then exported to SPSS version 24 for analysis. First, binary logistic regression was applied to identify candidate variables for multivariable regression. Then, variables at p value <0.2 were entered into a multivariable logistic regression to control possible confounders. Finally, variables at p value <0.05 were considered as statistically significant. Results. The proportion of immediate postpartum anaemia was 24.3%. Frequency of antenatal care (ANC) visits <4 times [AOR = 2.40; 95% CI (1.29, 4.43)], antepartum haemorrhage (APH) [AOR = 5.08; 95% CI (1.91, 13.55)], postpartum haemorrhage (PPH) [AOR = 4.47; 95% CI (2.25, 8.88)], giving birth assisted by instruments (vacuum or forceps) [AOR = 3.99; 95% CI (1.42, 11.23)], poor adherence to iron and folic acid (IFA) [AOR = 2.52; 95% CI (1.06, 6.04)], and midupper arm circumference (MUAC) <23 cm [AOR = 3.25; 95% CI (1.87, 5.65)] were the predictors. Conclusion. The proportion of immediate postpartum anaemia was a moderate public health concern. ANC, APH, PPH, mode of delivery, adherence to IFA supplementation, and MUAC measurement were the factors affecting the magnitude of anaemia. Therefore, interventions that would address the above mentioned factors need to be implemented.
Patient Selection Strategies to Maximize Therapeutic Index of Antibody–Drug Conjugates: Prior Approaches and Future Directions
Authors: Williams Marna , Spreafico Anna , Vashisht Kapil , Hinrichs Mary Jane
Published: June 2020

Antibody–drug conjugates (ADC) are targeted agents that have shown promise in treating cancer. A central challenge in development of ADCs is the relatively narrow therapeutic index observed in clinical studies. Patient selection strategies based on expression of the target in tumors have the potential to maximize benefit and provide the best chance of clinical success; however, implementation of biomarker-driven trials can be difficult both practically and scientifically. We conducted a survey of recent clinical experience from early-phase ADC trials completed between 2000 and 2019 to evaluate the different approaches to patient selection currently being used and assess whether there is evidence that target expression is associated with clinical activity. Our analysis of patient selection strategies indicates that optimal trial design for early-stage trials should be based on multiple factors, including prevalence and heterogeneity of target expression among intent-to-treat patients, as well as biological factors influencing expression of cell surface and soluble target. To ensure a high probability of success, early implementation of patient selection strategies centered around target expression are pivotal to development of ADCs. In this review, we propose a strategic approach that can be applied for optimization of trial design.
Abstract A10: Glioma cell-free DNA methylation marker for diagnosis and monitoring
Authors: Sabedot Thais , Malta Tathiane , Snyder James , Nelson Kevin , Wells Michael , deCarvalho Ana , Mukherjee Abir , Chitale Dhan , Mosella Maritza , Asmaro Karam , Robin Adam , Rosenblum Mark , Mikkelsen Tom , Rock Jack , Poisson Laila , Lee Ian , Walbert Tobias , Kalkanis Steven , Castro Ana Valeria , Noushmehr Houtan
Published: June 2020

Genome-wide DNA-methylation profiling has shown that epigenetic abnormalities are biologically and clinically important signs in glioma and can be used to classify these tumors into distinct prognostic groups. Thus far, DNA methylation profiling of gliomas has required surgically resected tissue. Because gliomas release tumoral material into biofluids, such as blood, we developed a method using a liquid biopsy (LB) for minimally invasive surveillance of the tumor. We performed a genome-wide CpG methylation profile of cell-free DNA extracted from serum of patients with primary glioma (N=48) and during clinical follow-up (N=33). We used a supervised machine learning (ML) approach to identify glioma-specific epigenetic signatures in the LB (eLB) (N=1000, false-discovery rate < 0.003) to distinguish patients with glioma from those without glioma. The epigenetic profiles of matched tumor tissue showed that there was 67% concordance between the eLB signatures of the glioma in serum and tissue. Using these signatures as input for ML, we derived the glioma epigenetic liquid biopsy (GeLB) score. An independent validation study (68 gliomas and 65 nongliomas) showed that a GeLB score ≥ 50% could predict with 96% accuracy (sensitivity = 97.1% and specificity = 95.9%) whether a patient had glioma or not. Changes in GeLB score also reflected clinicopathologic changes observed during surveillance (e.g., progression, pseudoprogression, or response to a clinical trial drug). Our results suggest that the GeLB score could be used as a complementary approach to diagnose glioma and follow up patients postsurgically. Finally, we provide an online tool for predicting glioma based on the cell-free DNA methylome (hbtc.shinyapps.io/GeLB/).

Citation Format: Thais Sabedot, Tathiane Malta, James Snyder, Kevin Nelson, Michael Wells, Ana deCarvalho, Abir Mukherjee, Dhan Chitale, Maritza Mosella, Karam Asmaro, Adam Robin, Mark Rosenblum, Tom Mikkelsen, Jack Rock, Laila Poisson, Ian Lee, Tobias Walbert, Steven Kalkanis, Ana Valeria Castro, Houtan Noushmehr. Glioma cell-free DNA methylation marker for diagnosis and monitoring [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A10.
Abstract A22: Simultaneous multiparametric profiling of cell-free RNA (cfRNA) and cell-free tumor DNA (ctDNA) in advanced-stage colorectal cancer
Authors: Feng Zheng , Wang Danyi , Merkle Dennis , Yu Jianjun , Jia Shidong , Scheuenpflug Juergen
Published: June 2020

Background: It has been recognized that intratumoral heterogeneity together with therapeutic intervention-associated multiple genomic alterations added complexity for precision therapy in late-stage colorectal cancer (CRC). The clinical utility/validity of ctDNA assays have been systematically analyzed and proved under clinical settings in select cancer types with demonstrated specificity and sensitivity. Notably, cfRNA sequencing confirmed and enhanced detection sensitivity for variants with low allele frequency. In this study, plasma-based ctDNA mutation and cfRNA gene expression in patients with advanced CRC were simultaneously tested using NGS liquid biopsy panels.

Methods: ctDNA and cfRNA were extracted from plasma of 25 treatment-naive patients with advanced CRC (stage III/IV), then were tested using the 600-gene PredicineATLAS ctDNA NGS assay and 180-gene PredicinePLUS cfRNA NGS assay, respectively. Various genomic alterations including single-nucleotide variation (SNV), Indel, copy number variation (CNV) and genome rearrangement are detected, along with tumor mutation burdens (TMB) evaluation/measurement. RNA-based variants and gene expression are also analyzed.

Results: At ctDNA level, 96% (24/25) ctDNA samples were detected with at least 1 genomic alteration and total 265 SNV/Indels and 27 CNVs were identified across samples, including 180 genes with reported SNVs/indels and 23 genes with CNV. 20% (5/25) of the patients with RAS somatic mutations, 32% (8/25) with TP53 mutations, 8% (2/25) with APC mutations, and 8% (2/25) with PIK3CA mutations. TPM3-NTRK1 fusion was also detected in one patient. A subset of these variants detected at ctDNA level were also confirmed by cfRNA sequencing.

Conclusions: Our results demonstrated the clinical utility/feasibility of simultaneous multiparametric profiling of ctDNA and cfRNA for comprehensive molecular insight/characterization in advanced-stage cancer. cfRNA-derived variant detection confirms the variants originally detected in ctDNA test and further validates the high-specificity results for report interpretation. Further investigation of exploring concordance between temporally matched tissue and plasma samples is ongoing. The ctDNA and cfRNA-based combined liquid biopsy solution provides holistic molecular overview for detecting driver mutations, monitoring efficacy/disease burden, and identifying subclonal alterations that may related to drug resistance and tumor heterogeneity.

Citation Format: Zheng Feng, Danyi Wang, Dennis Merkle, Jianjun Yu, Shidong Jia, Juergen Scheuenpflug. Simultaneous multiparametric profiling of cell-free RNA (cfRNA) and cell-free tumor DNA (ctDNA) in advanced-stage colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A22.
Abstract A23: Ultrasensitive mutation detection in FFPE tissues and circulating tumor DNA using SiMSen-Seq
Authors: Filges Stefan , Andersson Daniel , Kristiansson Helena , Vannas Christoffer , Johansson Gustav , Li Junrui , Godfrey Tony E. , Levin Max , Linderholm Barbro , Ståhlberg Anders
Published: June 2020

Novel diagnostic tools in oncology, prenatal diagnostics, and transplantation medicine depend on the detection of ultrarare variants. The analysis of cell-free DNA has the potential to revolutionize diagnosis, treatment monitoring, and recurrence and resistance of cancer. Yet these analysis remains challenging due to limited amounts of material and low allele frequencies of targeted variants. Simple, Multiplexed, PCR-based barcoding of DNA for Sensitive mutation detection using Sequencing (SiMSen-Seq) enables easy generation of libraries containing unique molecular identifiers (UMI) with minimal DNA input across several kilobases of DNA using two rounds of PCR and allows the detection of rare variants below 0.1% allele frequency. Clinical applications of ctDNA require highly optimized workflows to ensure high sensitivity and reproducibility. Here we present our state-of-the-art liquid biopsy workflow using SiMSen-Seq and simple quality control steps, applicable to almost any liquid biopsy protocol. In a series of case studies with melanoma patients we find that ctDNA mirrors the time-course of established protein markers such as S-100 and in some cases detects minimal residual months in advance of standard clinical diagnostics. SiMSen-Seq efficiently determined even rare mutations across multiple tumor forms in challenging sample types, such as FFPE tissue or cfDNA. We identified mutations in highly degraded FFPE tissue using a 60-plex SiMSen-Seq panel and then analyzed longitudinal cfDNA samples using patient-specific panels in a cohort of metastatic breast cancer patients. Our data indicate that ctDNA might be used as a biomarker for early detection of recurrence in these patients. We were able to detect treatment resistance variants as well as observe tumor recurrence well in advance of the onset of clinical symptoms. Thus, SiMSen-Seq offers an affordable, minimally invasive method for monitoring treatment efficiency and determination of drug resistance development in cancer.

Citation Format: Stefan Filges, Daniel Andersson, Helena Kristiansson, Christoffer Vannas, Gustav Johansson, Junrui Li, Tony E. Godfrey, Max Levin, Barbro Linderholm, Anders Ståhlberg. Ultrasensitive mutation detection in FFPE tissues and circulating tumor DNA using SiMSen-Seq [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A23.
Abstract A31: Tracking the evolution of soft tissue sarcoma and GIST using liquid biopsies
Authors: Namløs Heidi M. , Boye Kjetil , Moosavi Seyed H , Vodak Daniel , Sharma Nitin , Lorenz Susanne , Bjerkehagen Bodil , Næss Stine , Hovig Eivind , Jebsen Nina , Ståhlberg Anders , Myklebost Ola , Meza-Zepeda Leonardo A.
Published: June 2020

Molecular analysis of circulating tumor DNA (ctDNA) has a large potential for clinical application by capturing mutations and heterogeneity through noninvasive sampling. The CircSarc studies aims to provide new insights into the clinical utility of liquid biopsies in soft tissue sarcomas (CircSarc STS) and gastrointestinal stromal tumors (CircSarc GIST). In CircSarc STS, we have enrolled 35 high-grade soft-tissue sarcoma patients with localized disease. Plasma from each patient has been collected longitudinally throughout the course of their disease, with a follow-up of up to 5 years. To identify patient-specific somatic mutations, the patients’ tumor and germline DNA have been exome sequenced. Somatic mutations in cfDNA are being identified using ultra-low-pass WGS or targeted NGS. At time of surgery and/or progression, we detect ctDNA in 30% of the first soft-tissue sarcoma samples with higher levels in larger or metastatic tumors. In a proof-of-concept study, we have shown that that levels of tumor-specific mutations in plasma correlated to clinical manifestation of metastatic disease. In CircSarc GIST, plasma has been collected for a cohort of 30 metastatic GISTs and at time of diagnosis for 50 GISTs. Somatic mutations in the tumor have been determined by targeted sequencing or whole-exome sequencing. Somatic mutations in ctDNA are identified using targeted NGS. The levels of somatic mutations in ctDNA are being correlated with clinicopathologic features. ctDNA was detected in 36% of treatment-naïve GIST patients, including all patients with metastatic disease, and the tumor burden was the most important detection determinant. Analysis of metastatic GISTs is ongoing, but repeated plasma samples in a progressing patient have demonstrated that clonal evolution can be monitored over time. ctDNA analysis of the patient revealed multiple resistance mutations, and these were spatially distributed in the primary tumor. Our work shows that detection of mutations in plasma is particularly feasible for patients with high tumor burden. Mutational analysis by use of liquid biopsies can capture the molecular heterogeneity of the tumor and guide treatment decisions during progression.

Citation Format: Heidi M. Namløs, Kjetil Boye, Seyed H Moosavi, Daniel Vodak, Nitin Sharma, Susanne Lorenz, Bodil Bjerkehagen, Stine Næss, Eivind Hovig, Nina Jebsen, Anders Ståhlberg, Ola Myklebost, Leonardo A. Meza-Zepeda. Tracking the evolution of soft tissue sarcoma and GIST using liquid biopsies [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A31.
Abstract A33: Impact of tumor-derived exosomes on CD28 expression in T cells
Authors: Schulte Ashley J. , Mills Lauren J. , Makielski Kelly M. , DePauw Taylor A. , Modiano Jaime F.
Published: June 2020

Osteosarcoma is a rare disease with a disproportionate impact, as it is seen mostly in children and adolescents. Despite aggressive treatment, more than 50% of patients succumb to their disease within 10 years of diagnosis, making safe and effective treatments a huge unmet need. Immunotherapy, including immune checkpoint blockade, is drastically changing cancer treatment by increasing the antitumor immune response. Mechanisms of resistance to immune checkpoint blockade are incompletely understood; therefore, there is currently no available method to specifically identify patients who will respond favorably to immunotherapy. Exosomes are extracellular vesicles that can carry proteins, lipids, mRNA, microRNA, and DNA and play a role in extracellular communication. Exosomes can be found in circulation, making them an attractive tool for diagnostic testing. One potential mechanism of immunotherapy resistance could be destabilization of the CD28 coreceptor in T cells by microRNAs secreted in tumor-derived exosomes. Utilizing next-generation RNA-sequencing, we previously identified 2 microRNAs in dogs and 2 microRNAs in humans that were inversely correlated with CD28 expression in 44 human and 39 canine osteosarcoma tissues. Current work entails isolating exosomes from canine and human osteosarcoma tumor cell lines. Using a species mismatched approach, we can identify canine microRNAs in human T cells that were treated with canine exosomes, and vice versa, to verify delivery of microRNAs to T cells via tumor-derived exosomes. We are also using the CRISPR-Cas system to genetically engineer a human osteosarcoma cell line (HOS) that expresses the exosome marker CD63 linked to GFP so we can track exosome uptake by T cells by flow cytometry and determine the effect on CD28 expression levels. Identifying mechanisms of resistance will lead to improved patient selection and identification of therapeutic targets to combat this resistance.

Citation Format: Ashley J. Schulte, Lauren J. Mills, Kelly M. Makielski, Taylor A. DePauw, Jaime F. Modiano. Impact of tumor-derived exosomes on CD28 expression in T cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A33.
Abstract A35: Cell-free tumor DNA profiling of colon cancer patients: Searching for mechanisms of chemoresistance
Authors: Vymetalkova Veronika , Pardini Barbara , Urbanova Marketa , Cervena Klara , Vodicka Pavel , Naccarati Alessio
Published: June 2020

Colorectal cancer (CRC) is a worldwide health burden, with nearly 1.2 million new cases expected each year. Significant efforts are currently being employed to find patients who will benefit from chemotherapy. In fact, drug resistance is a limiting factor for the efficacy of chemotherapy in CRC treatment. In the present work, we aimed at identifying molecular markers in plasma cell-free DNA that could be associated with good/poor response and chemoresistance, comparing good responders (i.e., benefitting from chemotherapy, not having side effects like toxicity, no relapses, and having a complete response with no residual cancer) from non-/poor responders (patients with chemoresistance and lacking any response, or developing toxicity). Paired plasma samples from 10 colon cancer patients collected before and after adjuvant 5-fluorouracil (5-FU)-based therapy were profiled by a whole-exome sequencing (WES) approach in order to identify mutations associated with therapy response. In concomitance, DNA from tumor tissue from the same patients was also profiled by WES for mutation burden concordance. Analyses were performed on colon cancer patients treated with the same 5-FU-based therapy. The first sampling was performed at the time of the diagnosis (i.e., active disease), and the second after 6-9 months depending on patients’ conditions (i.e., covering the tumor resection, administration of adjuvant chemotherapy, etc.). After follow-up, 3 patients were clinically classified as “good responders” and 7 as “non-/poor responders.” All prepared libraries passed the quality control checkpoints and were sequenced. The number of total reads exceeds 2,57 × 109. Mean read length is about 100 nt. Alignment to human reference genome (hg38) is > 99.8%. The bioinformatics analyses are currently ongoing to profile the two different groups over time. Detailed results of the study will be presented during the meeting. The significance of the project lies in the improvement of the diagnosis and therapy efficacy in colon cancer patients. Supported by grant AZV MZ 17-30920A.

Citation Format: Veronika Vymetalkova, Barbara Pardini, Marketa Urbanova, Klara Cervena, Pavel Vodicka, Alessio Naccarati. Cell-free tumor DNA profiling of colon cancer patients: Searching for mechanisms of chemoresistance [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A35.
Abstract A47: Circulating tumor cell-defined minimal residual disease in locally advanced rectal cancer treated with multimodality therapy
Authors: Lee Lucas , Hall Carol , Lucci Antony , Bednarski Brian , Rodriguez-Bigas Miguel , Chang George , You Y. Nancy
Published: June 2020

Background: Current treatment for locally advanced rectal cancer (LARC) includes multimodality therapy in the neoadjuvant and adjuvant settings. Response to neoadjuvant therapy (NT) is prognostic of long-term outcomes. While long-course chemoradiation (CRT) had been the traditional NT regimen, novel regimens adding systemic therapy and/or eliminating radiation have been introduced. We examined if circulating tumor cells provide prognostic information independent of the specific treatment regimen utilized. Specifically, we aimed to define the significance of CTC-defined minimal residual disease (MRD) in LARC.

Methods: A prospective longitudinal protocol enrolled LARC patients (N=100; clinical stage II=4; stage III=96) undergoing NT. Peripheral blood was collected at baseline (t1, treatment-naive), after NT (t2, intraoperatively before tumor manipulation), after resection (t3, 2-8 weeks postoperatively), and after completion of adjuvant therapy (t4, 2-12 weeks after completion). CTC was enumerated by the CellSearch® platform within 72 hours of collection. Patients were followed for disease-free survival (DFS).

Results: At t1, CTCs were detected in 28/90 (31.1%) patients with available samples with a median CTC count of 1.5 [IQR: 1.0, 2.75]. NT consisted of long-course pelvic CRT (65%), extended NT with systemic chemotherapy and long- or short-course pelvic CRT (22%), and a radiation-sparing regimen with systemic chemotherapy only (13%). At t2, CTCs were detected in 34/75 (45.3%) patients with a median CTC count of 1 [IQR: 1, 1]. Type of NAT did not correlate with CTC positivity (p=0.637). Ten (9.4%) patients declined surgery, while cPR occurred in 12/93 (12.9%) surgical patients. Postoperatively (t3), CTC was detected in 12/47 (25.5%) patients, with a median count of 1.5 (IQR: 1.0-3.0). After completing adjuvant chemotherapy (t4), only 3/29 (10.3%) patients had detectable CTC. With a median follow-up of 47.50 months from diagnosis for the entire cohort, CTC positivity at t4 significantly stratified DFS (p=0.035).

Conclusions: One third of locally advanced RC patients harbored detectable CTCs at baseline. CTC detection after completion of curative-intent multimodality therapy (i.e., MRD) correlated with long-term DFS.

Citation Format: Lucas Lee, Carol Hall, Antony Lucci, Brian Bednarski, Miguel Rodriguez-Bigas, George Chang, Y. Nancy You. Circulating tumor cell-defined minimal residual disease in locally advanced rectal cancer treated with multimodality therapy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A47.