bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic awareness in advanced cancer: an integrative literature review
Authors: Mone Sara , Kerr Helen
Published: September 2020

Individuals with advanced cancer who have accurate prognostic awareness are reported to make more informed decisions about their plan of care. Despite this, it is reported that individuals do not always have accurate prognostic awareness with the rationale for this discordance unclear. The primary aim of the integrative literature review was to identify if there is concordance between actual prognosis and accurate prognostic awareness in individuals with advanced cancer. The secondary aim was to identify the rationale for any discordance between actual prognosis and prognostic awareness in individuals with advanced cancer. This is an integrative literature review using a systematic approach. Literature searches were undertaken in March 2018 in four databases; CINAHL, MEDLINE, PsycINFO and Cochrane Library. Searches were limited to between 2008 and 2018 and those written in the English language. Database searches were supplemented with papers from reference lists of included papers and grey literature. Two reviewers independently completed the literature search and independently reviewed the papers. Fourteen eligible research papers were identified. The majority of individuals with advanced cancer in the included studies did not have accurate prognostic awareness. When identified, the rationale for discordance relates to the individual not being communicated accurate prognostic information, not being able to recall prognostic conversations or prognosis being discussed in vague terms. As individuals with advanced cancer with accurate prognostic awareness make more informed decisions at a crucial time in their life trajectory, it is imperative that healthcare professionals are equipped to effectively deliver accurate prognostic information, ensuring understanding is assessed.
Development and validation of a model to predict survival in colorectal cancer using a gradient-boosted machine
Authors: Bibault Jean-Emmanuel , Chang Daniel T , Xing Lei
Published: September 2020

Objective

The success of treatment planning relies critically on our ability to predict the potential benefit of a therapy. In colorectal cancer (CRC), several nomograms are available to predict different outcomes based on the use of tumour specific features. Our objective is to provide an accurate and explainable prediction of the risk to die within 10 years after CRC diagnosis, by incorporating the tumour features and the patient medical and demographic information.

Design

In the prostate, lung, colorectal and ovarian cancer screening (PLCO) Trial, participants (n=154 900) were randomised to screening with flexible sigmoidoscopy, with a repeat screening at 3 or 5 years, or to usual care. We selected patients who were diagnosed with CRC during the follow-up to train a gradient-boosted model to predict the risk to die within 10 years after CRC diagnosis. Using Shapley values, we determined the 20 most relevant features and provided explanation to prediction.

Results

During the follow-up, 2359 patients were diagnosed with CRC. Median follow-up was 16.8 years (14.4–18.9) for mortality. In total, 686 patients (29%) died from CRC during the follow-up. The dataset was randomly split into a training (n=1887) and a testing (n=472) dataset. The area under the receiver operating characteristic was 0.84 (±0.04) and accuracy was 0.83 (±0.04) with a 0.5 classification threshold. The model is available online for research use.

Conclusions

We trained and validated a model with prospective data from a large multicentre cohort of patients. The model has high predictive performances at the individual scale. It could be used to discuss treatment strategies.
Are pet parasite products harming the environment more than we think?
Authors: Perkins Rosemary
Published: September 2020

Rosemary Perkins argues that the environmental impact of veterinary parasiticide products is cause for concern and that more research needs to be done to fully appreciate their environmental effects.
Review and recommendations for structural testing of buried gravity storm drain pipes and culverts
Authors: Darabnoush Tehrani Amin , Kohankar Kouchesfehani Zahra , Najafi Mohammad
Published: September 2020

Buried pipes are important components of the underground infrastructure. Structural failure of these pipes is costly, socially and environmentally disruptive. To prevent such incidents, a deep understanding of the soil–pipe interaction system behavior is needed. Currently, two common standard methods are available for the structural testing of pipes: parallel-plate loading test and three-edge bearing test, in which the effects of surrounding soil and distributed load on the pipe sample are ignored. However, in the available design methodologies the effect of bedding and load distribution is considered though empirical factors. As of today, there is no standard test method available for structural testing of pipes considering the effect of soil–pipe interaction system. Therefore, the objectives of this paper are to present a literature review of full-scale structural testing methods of relatively large diameter gravity pipes ranging from 36 in (90 cm) and larger, and suggest a general soil–pipe test procedure for structural evaluation of large diameter gravity pipes, such as culverts. Discussions are made for selection of a soil–pipe structural testing condition, loading method, loading rate, loading configurations, and required instrumentations for capturing and recording test results.
The non-minimal coupling constant and the primordial de Sitter state
Authors: Hrycyna Orest
Published: September 2020

Dynamical systems methods are used to investigate dynamics of a flat Friedmann–Robertson–Walker cosmological model with the non-minimally coupled scalar field and a potential function. Performed analysis distinguishes the value of non-minimal coupling constant parameter $$\xi =\frac{3}{16}$$

ξ
=

3
16

, which is the conformal coupling in five dimensional theory of gravity. It is shown that for a monomial potential functions at infinite values of the scalar field there exist generic de Sitter and Einstein–de Sitter states. The de Sitter state is unstable with respect to expansion of the Universe for potential functions which do not change faster than linearly. This leads to a generic cosmological evolution without the initial singularity.
The order analysis for the two loop corrections to lepton MDM
Authors: Zhao Shu-Min , Dong Xing-Xing , Su Lu-Hao , Zhang Hai-Bin
Published: September 2020

The experimental data of the magnetic dipole moment(MDM) of lepton(e, $$\mu $$
μ
) is very exact. The deviation between the experimental data and the standard model prediction maybe come from new physics contribution. In the supersymmetric models, there are very many two loop diagrams contributing to the lepton MDM. In supersymmetric models, we suppose two mass scales $$M_{SH}$$

M

SH

and M with $$M_{SH}\gg M$$

M

SH

≫
M

for supersymmetric particles. Squarks belong to $$M_{SH}$$

M

SH

and the other supersymmetric particles belong to M. We analyze the order of the contributions from the two loop diagrams. The two loop triangle diagrams corresponding to the two loop self-energy diagram satisfy Ward-identity, and their contributions possess particular factors. This work can help to distinguish the important two loop diagrams giving corrections to lepton MDM.
Zygarde
Authors: Islam Bashima , Nirjon Shahriar
Published: September 2020

We propose Zygarde --- which is an energy- and accuracy-aware soft real-time task scheduling framework for batteryless systems that flexibly execute deep learning tasks1 that are suitable for running on microcontrollers. The sporadic nature of harvested energy, resource constraints of the embedded platform, and the computational demand of deep neural networks (DNNs) pose a unique and challenging real-time scheduling problem for which no solutions have been proposed in the literature. We empirically study the problem and model the energy harvesting pattern as well as the trade-off between the accuracy and execution of a DNN. We develop an imprecise computing-based scheduling algorithm that improves the timeliness of DNN tasks on intermittently powered systems. We evaluate Zygarde using four standard datasets as well as by deploying it in six real-life applications involving audio and camera sensor systems. Results show that Zygarde decreases the execution time by up to 26% and schedules 9% -- 34% more tasks with up to 21% higher inference accuracy, compared to traditional schedulers such as the earliest deadline first (EDF).
OptoSense
Authors: Zhang Dingtian , Park Jung Wook , Zhang Yang , Zhao Yuhui , Wang Yiyang , Li Yunzhi , Bhagwat Tanvi , Chou Wen-Fang , Jia Xiaojia , Kippelen Bernard , Fuentes-Hernandez Canek , Starner Thad , Abowd Gregory D.
Published: September 2020

Ubiquitous computing requires robust and sustainable sensing techniques to detect users for explicit and implicit inputs. Existing solutions with cameras can be privacy-invasive. Battery-powered sensors require user maintenance, preventing practical ubiquitous sensor deployment. We present OptoSense, a general-purpose self-powered sensing system which senses ambient light at the surface level of everyday objects as a high-fidelity signal to infer user activities and interactions. To situate the novelty of OptoSense among prior work and highlight the generalizability of the approach, we propose a design framework of ambient light sensing surfaces, enabling implicit activity sensing and explicit interactions in a wide range of use cases with varying sensing dimensions (0D, 1D, 2D), fields of view (wide, narrow), and perspectives (egocentric, allocentric). OptoSense supports this framework through example applications ranging from object use and indoor traffic detection, to liquid sensing and multitouch input. Additionally, the system can achieve high detection accuracy while being self-powered by ambient light. On-going improvements that replace Optosense's silicon-based sensors with organic semiconductors (OSCs) enable devices that are ultra-thin, flexible, and cost effective to scale.
What If Conversational Agents Became Invisible?
Authors: Lee Sunok , Cho Minji , Lee Sangsu
Published: September 2020

The popularity of conversational agents (CAs) in the form of AI speakers that support ubiquitous smart homes has increased because of their seamless interaction. However, recent studies have revealed that the use of AI speakers decreases over time, which shows that current agents do not fully support smart homes. Because of this problem, the possibility of unobtrusive, invisible intelligence without a physical device has been suggested. To explore CA design direction that enhances the user experience in smart homes, we aimed to understand each feature by comparing an invisible agent with visible ones embedded in stand-alone AI speakers. We conducted a drawing study to examine users' mental models formed through communicating with two different physical entities (i.e., visible and invisible CAs). From the drawings, interviews, and surveys, we identified how users' mental models and interactions differed depending on the presence of a physical entity. We found that a physical entity affected users' perceptions, expectations, and interactions toward the agent.
Detecting Job Promotion in Information Workers Using Mobile Sensing
Authors: Nepal Subigya , Mirjafari Shayan , Martinez Gonzalo J. , Audia Pino , Striegel Aaron , Campbell Andrew T.
Published: September 2020

Most people desire promotions in the workplace. Typically, rising through the ranks comes with increased demands, better salary and higher status among peers. However, promoted workers have to deal with new challenges, such as, adjusting to new roles and responsibilities, which can in turn impact their physical and mental wellbeing. In this year long study, we use mobile sensing to track physiological and behavioral patterns of N=141 information workers who are promoted. We show that the workers experience a change in their physiological and behavioral patterns after promotion captured by passive sensing from phones, wearables and Bluetooth beacons. Furthermore, we use a random convolutions based approach to extract patterns from multivariate time series signals and evaluate the performance of different models to classify a worker's mobile sensing data as belonging to a promoted or non-promoted period with an AUC of 0.72. As a result, we report for the first time that mobile sensing can detect job promotion events by modeling physiological and behavioral changes of information workers in an objective manner.
Declarative Recursive Computation on an RDBMS
Authors: Jankov Dimitrije , Luo Shangyu , Yuan Binhang , Cai Zhuhua , Zou Jia , Jermaine Chris , Gao Zekai J.
Published: September 2020

We explore the close relationship between the tensor-based computations performed during modern machine learning, and relational database computations. We consider how to make a very small set of changes to a modern RDBMS to make it suitable for distributed learning computations. Changes include adding better support for recursion, and optimization and execution of very large compute plans. We also show that there are key advantages to using an RDBMS as a machine learning platform. In particular, DBMSbased learning allows for trivial scaling to large data sets and especially large models, where different computational units operate on different parts of a model that may be too large to fit into RAM.
Msp1/ATAD1 in Protein Quality Control and Regulation of Synaptic Activities
Authors: Wang Lan , Walter Peter
Published: September 2020

Mitochondrial function depends on the efficient import of proteins synthesized in the cytosol. When cells experience stress, the efficiency and faithfulness of the mitochondrial protein import machinery are compromised, leading to homeostatic imbalances and damage to the organelle. Yeast Msp1 (mitochondrial sorting of proteins 1) and mammalian ATAD1 (ATPase family AAA domain–containing 1) are orthologous AAA proteins that, fueled by ATP hydrolysis, recognize and extract mislocalized membrane proteins from the outer mitochondrial membrane. Msp1 also extracts proteins that have become stuck in the import channel. The extracted proteins are targeted for proteasome-dependent degradation or, in the case of mistargeted tail-anchored proteins, are given another chance to be routed correctly. In addition, ATAD1 is implicated in the regulation of synaptic plasticity, mediating the release of neurotransmitter receptors from postsynaptic scaffolds to allow their trafficking. Here we discuss how structural and functional specialization imparts the unique properties that allow Msp1/ATAD1 ATPases to fulfill these diverse functions and also highlight outstanding questions in the field.
Climate Disruption of Plant-Microbe Interactions
Authors: Rudgers Jennifer A. , Afkhami Michelle E. , Bell-Dereske Lukas , Chung Y. Anny , Crawford Kerri M. , Kivlin Stephanie N. , Mann Michael A. , Nuñez Martin A.
Published: September 2020

Interactions between plants and microbes have important influences on evolutionary processes, population dynamics, community structure, and ecosystem function. We review the literature to document how climate change may disrupt these ecological interactions and develop a conceptual framework to integrate the pathways of plant-microbe responses to climate over different scales in space and time. We then create a blueprint to aid generalization that categorizes climate effects into changes in the context dependency of plant-microbe pairs, temporal mismatches and altered feedbacks over time, or spatial mismatches that accompany species range shifts. We pair a new graphical model of how plant-microbe interactions influence resistance to climate change with a statistical approach to predictthe consequences of increasing variability in climate. Finally, we suggest pathways through which plant-microbe interactions can affect resilience during recovery from climate disruption. Throughout, we take a forward-looking perspective, highlighting knowledge gaps and directions for future research.
Pioneer Transcription Factors Initiating Gene Network Changes
Authors: Zaret Kenneth S.
Published: September 2020

Pioneer transcription factors have the intrinsic biochemical ability to scan partial DNA sequence motifs that are exposed on the surface of a nucleosome and thus access silent genes that are inaccessible to other transcription factors. Pioneer factors subsequently enable other transcription factors, nucleosome remodeling complexes, and histone modifiers to engage chromatin, thereby initiating the formation of an activating or repressive regulatory sequence. Thus, pioneer factors endow the competence for fate changes in embryonic development, are essential for cellular reprogramming, and rewire gene networks in cancer cells. Recent studies with reconstituted nucleosomes in vitro and chromatin binding in vivo reveal that pioneer factors can directly perturb nucleosome structure and chromatin accessibility in different ways. This review focuses on our current understanding of the mechanisms by which pioneer factors initiate gene network changes and will ultimately contribute to our ability to control cell fates at will.
Transposon Insertion Sequencing, a Global Measure of Gene Function
Authors: van Opijnen Tim , Levin Henry L.
Published: September 2020

The goal of genomics and systems biology is to understand how complex systems of factors assemble into pathways and structures that combine to form living organisms. Great advances in understanding biological processes result from determining the function of individual genes, a process that has classically relied on characterizing single mutations. Advances in DNA sequencing has made available the complete set of genetic instructions for an astonishing and growing number of species. To understand the function of this ever-increasing number of genes, a high-throughput method was developed that in a single experiment can measure the function of genes across the genome of an organism. This occurred approximately 10 years ago, when high-throughput DNA sequencing was combined with advances in transposon-mediated mutagenesis in a method termed transposon insertion sequencing (TIS). In the subsequent years, TIS succeeded in addressing fundamental questions regarding the genes of bacteria, many of which have been shown to play central roles in bacterial infections that result in major human diseases. The field of TIS has matured and resulted in studies of hundreds of species that include significant innovations with a number of transposons. Here, we summarize a number of TIS experiments to provide an understanding of the method and explanation of approaches that are instructive when designing a study. Importantly, we emphasize critical aspects of a TIS experiment and highlight the extension and applicability of TIS into nonbacterial species such as yeast.
Moral Judgments
Authors: Malle Bertram F.
Published: September 2020

Research on morality has increased rapidly over the past 10 years. At the center of this research are moral judgments—evaluative judgments that a perceiver makes in response to a moral norm violation. But there is substantial diversity in what has been called moral judgment. This article offers a framework that distinguishes, theoretically and empirically, four classes of moral judgment: evaluations, norm judgments, moral wrongness judgments, and blame judgments. These judgments differ in their typical objects, the information they process, their speed, and their social functions. The framework presented here organizes the extensive literature and provides fresh perspectives on measurement, the nature of moral intuitions, the status of moral dumbfounding, and the prospects of dual-process models of moral judgment. It also identifies omitted questions and sets the stage for a broader theory of moral judgment, which the coming decades may bring forth.
Interference Minimization Resource Allocation for V2X Communication Underlaying 5G Cellular Networks
Authors: Song Xiaoqin , Wang Kuiyu , Lei Lei , Zhao Liping , Li Yong , Wang Jiankang
Published: September 2020

In this paper, the resource allocation for vehicle-to-everything (V2X) underlaying 5G cellular mobile communication networks is considered. The optimization problem is modeled as a mixed binary integer nonlinear programming (MBINP), which minimizes the interference to 5G cellular users (CUs) subject to the quality of service (QoS), the total available power, the interference threshold, and the minimal transmission rate. To achieve that, the original MBINP is decomposed into three steps: transmission power initialization, subchannel assignment, and power allocation. Firstly, the minimum transmission power required by the V2X users (VUs) is set as the initial power value. Secondly, the Hungarian algorithm is used to obtain the appropriate subchannel. Finally, an optimization mechanism is proposed to the power allocation. Simulation results show that the proposed algorithm can not only ensure the minimal transmission rate of VUs but also further improve the CUs’ channel capacity under the premise of guaranteeing the QoS of the CUs.
Parametric Nonlinear Model Reduction Using K-Means Clustering for Miscible Flow Simulation
Authors: Sukuntee Norapon , Chaturantabut Saifon
Published: September 2020

This work considers the model order reduction approach for parametrized viscous fingering in a horizontal flow through a 2D porous media domain. A technique for constructing an optimal low-dimensional basis for a multidimensional parameter domain is introduced by combining K-means clustering with proper orthogonal decomposition (POD). In particular, we first randomly generate parameter vectors in multidimensional parameter domain of interest. Next, we perform the K-means clustering algorithm on these parameter vectors to find the centroids. POD basis is then generated from the solutions of the parametrized systems corresponding to these parameter centroids. The resulting POD basis is then used with Galerkin projection to construct reduced-order systems for various parameter vectors in the given domain together with applying the discrete empirical interpolation method (DEIM) to further reduce the computational complexity in nonlinear terms of the miscible flow model. The numerical results with varying different parameters are demonstrated to be efficient in decreasing simulation time while maintaining accuracy compared to the full-order model for various parameter values.
Nonlinear Dynamics and Power Generation on a New Bistable Piezoelectric-Electromagnetic Energy Harvester
Authors: Yao Minghui , Liu Pengfei , Wang Hongbo
Published: September 2020

This paper focuses power generation and nonlinear dynamic behaviors on a new bistable piezoelectric-electromagnetic energy harvester. Three different kinds of piezoelectric cantilever beam structures, which include the monostable piezoelectric cantilever beam, the bistable piezoelectric cantilever beam with spring and magnet, and the bistable piezoelectric cantilever beam with spring, magnet, and coil, are designed. The power generation efficiency and dynamic behaviors for each structure are experimentally studied, respectively. Due to the spring introduced, the system easily goes through the potential barrier. Experimental results show that the power generation structure of the bistable piezoelectric-electromagnetic harvester can vibrate between two steady states in a wider range of the frequency. Therefore, the effective frequency bandwidth is broadened about 2 Hz when the spring is introduced under the condition of the suitable magnetic distance. Comparing with the power generation efficiency for three different kinds of structures, it is found that the bistable piezoelectric-electromagnetic harvester has the optimum characteristics, which include the optimal magnetic distance of 15 mm, the optimal load of 8 MΩ, and the parameters variation law of coils. For this structure, the influences of the external excitation and the magnetic distance on the output voltage and dynamic behaviors of the system are examined.
Molecular and Immunological Diagnostic Techniques of Medical Viruses
Authors: Reta Daniel Hussien , Tessema Tesfaye Sisay , Ashenef Addis Simachew , Desta Adey Feleke , Labisso Wajana Lako , Gizaw Solomon Tebeje , Abay Solomon Mequanente , Melka Daniel Seifu , Reta Fisseha Alemu
Published: September 2020

Viral infections are causing serious problems in human population worldwide. The recent outbreak of coronavirus disease 2019 caused by SARS-CoV-2 is a perfect example how viral infection could pose a great threat to global public health and economic sectors. Therefore, the first step in combating viral pathogens is to get a timely and accurate diagnosis. Early and accurate detection of the viral presence in patient sample is crucial for appropriate treatment, control, and prevention of epidemics. Here, we summarize some of the molecular and immunological diagnostic approaches available for the detection of viral infections of humans. Molecular diagnostic techniques provide rapid viral detection in patient sample. They are also relatively inexpensive and highly sensitive and specific diagnostic methods. Immunological-based techniques have been extensively utilized for the detection and epidemiological studies of human viral infections. They can detect antiviral antibodies or viral antigens in clinical samples. There are several commercially available molecular and immunological diagnostic kits that facilitate the use of these methods in the majority of clinical laboratories worldwide. In developing countries including Ethiopia where most of viral infections are endemic, exposure to improved or new methods is highly limited as these methods are very costly to use and also require technical skills. Since researchers and clinicians in all corners of the globe are working hard, it is hoped that in the near future, they will develop good quality tests that can be accessible in low-income countries.
Acquired Hemophilia A Presenting as Massive Postoperative Bleeding in a Patient with Oral Squamous Cell Carcinoma
Authors: Oba Susumu , Nakahira Mitsuhiko , Kogashiwa Yasunao , Ebihara Yasuhiro , Sugasawa Masashi
Published: September 2020

Acquired hemophilia A (AHA) is an extremely rare and serious bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). Approximately, 10% of patients with AHA have an underlying malignancy. We report on a 46-year-old man with AHA and advanced oral cancer who presented with massive bleeding after surgery. Preoperative blood coagulation tests showed no abnormalities. He underwent radical tumor resection followed by reconstruction using a free rectus abdominal musculocutaneous flap. Massive subcutaneous hemorrhage developed in his neck and abdomen on the first postoperative day. The hemorrhage remained uncontrolled, despite embolization of the responsible vessels. Subsequent laboratory data showed prolonged activated partial thromboplastin time and decreased FVIII levels. On the basis of his clinical course and the presence of the FVIII inhibitor, we speculated that the patient suffered from AHA. We administered recombinant activated factor VII and prednisolone, after which the spontaneous bleeding stopped and the subcutaneous hemorrhage resolved. A review of the literature identified only three previous documented cases of AHA associated with head and neck cancer. This case indicates that AHA should not be ruled out in patients with uncontrolled postoperative bleeding, while attempting to ensure bleeding control and preventing potentially catastrophic fatal consequences.
Abstract 1002: Immune microenvironment features of lung adenomatous premalignancy in a Chinese cohort
Authors: Guo Liting , Shao Weiwei
Published: September 2020

Introduction: The widespread of implementation of computed tomography (CT) has resulted in a drastic increase in the detection of small pulmonary nodules presenting as ground glass opacities (GGOs). Many of these GGOs are atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and sometimes invasive adenocarcinoma (IAC). The concept of a continuum between the precursor lesions AAH and AIS to MIA and frankly invasive IAC is backed by a wealth of recent data showing a gradual decrease in overall survival from 100% for AAH, AIS and MIA to moderately lower rates for IAC. A growing body of evidence suggests that the immune response is a significant determinant of cancer progression. However, little is known about the immune microenvironment features in the early stages of lung carcinogenesis. Methods: A total of 40 tumor tissue samples including 10 AAH, 10 AIS, 10 MIA and 10 early IAC from 40 patients who underwent surgical resection of pulmonary nodules at Yancheng No.1 People's Hospital, China were included. Immunohistochemistry (IHC) staining for the expression of CD3, CD4, CD8 and programmed death ligand 1 (PD-L1) to assess the role of T-cell immune surveillance in these pre- and early lung cancers were performed. Results: We observed CD3, CD4, CD8 and PD-L1 positivity in AAH, AIS, MIA and IAC, suggesting that immunoediting has started before the invasion. Higher expressions of CD3, CD4, CD8 and PD-L1 in IAC implying tumor invasion. Conclusions: Our preliminary results of the immune subgroups provide evidence for immune recognition in pulmonary premalignancy and are critical for understanding tumorigenesis and the development of effective preventive and interception strategies. Associations with genomic landscape is underway.

Citation Format: Liting Guo, Weiwei Shao. Immune microenvironment features of lung adenomatous premalignancy in a Chinese cohort [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1002.
Abstract 1036: Discovery of a highly potent, efficacious and orally active small-molecule inhibitor of embryonic ectoderm development (EED)
Authors: Wang Changwei , Rej Rohan Kalyan , Lu Jianfeng , Wang Mi , Harvey Kaitlin P. , Yang Chao-Yie , Fernandez-Salas Ester , Stuckey Jeanne , Petrunak Elyse , Foster Caroline , Zhou Yunlong , Zhou Rubin , Tang Guozhi , Chen Jianyong , Wang Shaomeng
Published: September 2020

Embryonic ectoderm development (EED) is a key component of the polycomb repressive complex 1 (PRC1) and PRC2 and targeting EED by an allosteric mechanism represents a potentially attractive strategy for the treatment of human cancers. We report herein the discovery of a new class of highly potent and efficacious small-molecule EED inhibitors, as exemplified by UM-EEDi-5285. UM-EEDi-5285 binds to EED protein with a low nanomolar affinity and achieves IC50 values of < 1 nM in inhibition of cell growth in Pfeiffer and Karpas-422 lymphoma cell lines carrying an EZH2 mutation. UM-EEDi-5285 is capable of achieving complete and durable tumor regression in the KARPAS-422 xenograft model in mice at well-tolerated dose-schedules. The co-crystal structure of UM-EEDi-5285 in a complex with EED provides the structural basis for their high-affinity interaction. UM-EEDi-5285 is arguably the most potent and efficacious EED inhibitor reported to date. UM-EEDi-5285 is a promising lead compound for advanced preclinical development studies.

Citation Format: Changwei Wang, Rohan Kalyan Rej, Jianfeng Lu, Mi Wang, Kaitlin P. Harvey, Chao-Yie Yang, Ester Fernandez-Salas, Jeanne Stuckey, Elyse Petrunak, Caroline Foster, Yunlong Zhou, Rubin Zhou, Guozhi Tang, Jianyong Chen, Shaomeng Wang. Discovery of a highly potent, efficacious and orally active small-molecule inhibitor of embryonic ectoderm development (EED) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1036.
Abstract 1047: Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors
Authors: Palmer Adam C. , Sorger Peter K. , Izar Benjamin
Published: September 2020

IMPORTANCE Immune Checkpoint Inhibitors (ICIs), frequently combined with other therapies, have become the standard of care for the treatment of several cancers, and hundreds of clinical trials evaluate the efficacy of novel combinations with ICI. However, it is unclear whether combination therapies truly enhance ICI activity or simply provide multiple “shots on target” for a response to occur.

OBJECTIVE To assess whether ICIs in combination with other therapies result in ‘additive' or ‘synergistic' anti-tumor activity. The null hypothesis is independent drug action, where each patient's response to a combination of therapies is equal to that patient's best single-agent response.

DATA SOURCES We analyzed twelve randomized-controlled clinical trials testing combinations of ICIs with other drug classes in patients with advanced cancers, including melanoma and lung, breast, gastric, kidney, and head and neck cancers. For each analysis, the clinical activity of each constituent therapy of the combination was available in the respective study population.

METHODS We digitized Progression Free Survival curves for combination therapies and their constituents, and computed PFS expected for the null hypothesis of independent action by randomly sampling single-agent PFS durations (with correlation ρ=0.3±0.2 to account for cross-resistance), and assigning each simulated patient the longer of the two sampled PFS values. For each combination therapy, simulated and clinically observed PFS distributions were compared.

RESULTS None of the analyzed clinical trials of ICIs in combination therapies exhibited PFS surpassing the null hypothesis of independent drug action. This suggest that there is no additive or synergistic effect in patients receiving combination therapies with ICIs. Rather, these combinations provided benefits that are largely predictable from the response probabilities of each constituent therapy.

CONCLUSIONS Combining ICIs with other cancer therapies provides predictable and clinically meaningful benefit by bet-hedging: providing patients with more chances of a response to any one therapy. This implies that similar benefits may in principle result from sequential treatments or biomarker-stratified choice of treatment. This insight may be most valuable in cases where toxicity prevents full-dose combinations.

Citation Format: Adam C. Palmer, Peter K. Sorger, Benjamin Izar. Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1047.
Abstract 105: Clobetasol-induced quiescence in the vulvar carcinoma cell line UMSCV-4 can be overcome by repeated removal and re-exposure to this ultrapotent corticosteroid
Authors: Jaramillo Nolberto , Mustico Nina M. , Lewis Jani E.
Published: September 2020

Vulvar cancer is rare, mostly afflicting women aged 60 and older. The cancer is often preceded by a common vulvar rash, Lichen sclerosis, that is usually treated with the ultra-potent corticosteroid, clobetasol propionate. This treatment may, in turn, be associated with vulvar carcinogenesis. We found that clobetasol slows metabolism and proliferation in the vulvar carcinoma cell line, UMSCV-4 as revealed through MTT and BrdU/Ki67 assays. Upon removal from clobetasol, a subpopulation of UMSCV-4 cells had proliferation rates restabilize to baseline levels. The rate of cell death slightly increased in the presence of clobetasol as shown using trypan blue exclusion, but the majority of cells remained viable. RT-qPCR showed that the cell cycle inhibitors, p16 and p21 were upregulated while cyclin D1 was downregulated after 10 days of clobetasol treatment. The subpopulation removed from clobetasol proliferated at normal levels when re-exposed. These studies suggest that UMSCV-4 cells are a good model for studying quiescence. In addition, these studies highlight the potential for vulvar cancer cells to evade cancer treatments in the presence of clobetasol and lead to selection for more aggressive subpopulations.

Citation Format: Nolberto Jaramillo, Nina M. Mustico, Jani E. Lewis. Clobetasol-induced quiescence in the vulvar carcinoma cell line UMSCV-4 can be overcome by repeated removal and re-exposure to this ultrapotent corticosteroid [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 105.
Abstract 1151: Inclusion of cholesterol and A549 lipid extract in CLENs improved cellular uptake in adenocarcinoma non-small cell lung cancer target cells
Authors: Langlois Maxime , Kao Guo-Yun , Lasker Diana
Published: September 2020

Purpose:The purpose of this investigation was to determine the optimal amount of cholesterol and A549-derived lipid extract (LE) included in the initial design and development of A-549-cell membrane lipid extracted nanoliposomes (A549-CLENs) for cell targeting studies.

Methods and Materials:A549 (ATCC® CCL-185™), used as a positive control and NCI-H1703 (ATCC® CRL-5889™), used as a negative control, and respective growth media were purchased from ATCC (Manassas, VA). A549-GFP (green fluorescent protein) cell line was purchased from AntiCancer, Inc. DOPC, DOTAP, cholesterol, and DSPE-PEG5000 were obtained from Avanti Polar Lipids (Alabastar, AL). Cellular membrane lipids of A549 cells were extracted by modified Bligh & Dyer method. CLENs were fluorescently labeled with rhodamine-B. Particle sizes and zeta potentials were performed using ZetaPALS (Brookhaven Instruments Corporation, Holtsville, NY, USA). For cellular uptake studies cells were seeded at 2.0 x 104 cells in a 48-well plate followed by incubation for 24 hours. A fluorescence microplate reader and/or fluorescence microscopy were used to evaluate cellular uptake as a function of relative amount of cholesterol and A549-lipid extract inclusion in CLENs.

Results:In general, an increase in the inclusion of cholesterol reduced the particle size of CLENs. Amount of 10 mol% of cholesterol content in CLENs demonstrated the smallest mean size diameters and a zeta potential value recorded at 243 ± 4.4 nm and 1 ± 2.61 mV, respectively. The finding correlated also with a relatively high degree of cellular uptake of the preparation type for part I of the physicochemical characterization studies. We next maintained 10 mol% cholesterol content consistent in all future preparations and increased the total A-549 lipid extract material at the expense of DOPC. In general, the mean diameter and zeta potential for A549-CLENs were 246 ± 3.8 nm and 20.4 ± 0.84 mV, respectively. Approximately 10-15 mol% of A-549 lipid extract inclusion resulted in a consistently high degree of overall cellular uptake by GFP-A549 and A549 target cells compared to control and the non-target cell population, NCI-H1703.

Conclusion: Preparation of A549-CLENs consisting of DOPC/ DOTAP/ Chol/ LE/PEG (65/10/10/10/5) established the greatest increase in cellular uptake and overall selectivity. Future studies will consider antibody conjugation and development of tumor-specific biomarkers for serodiagnostic detection and lung cancer treatment.

Citation Format: Maxime Langlois, Guo-Yun Kao, Diana Lasker. Inclusion of cholesterol and A549 lipid extract in CLENs improved cellular uptake in adenocarcinoma non-small cell lung cancer target cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1151.
Abstract 1237: Biological effects of a FRα-targeting antibody-drug conjugate, IMGN853 (mirvetuximab soravtansine) in high-grade serous ovarian cancer
Authors: Chelariu-Raicu Anca , Stur Elaine , Ivan Cristina , Coleman Robert L. , Sood Anil K. , Yunfei Wen
Published: September 2020

Objective: Autophagic cell death is an important mechanism induced by blocking folate receptor (FRα) in inhibiting tumor growth. Here, our objective is to examine the biological effects of IMGN853 (mirvetuximab soravtansine) in preclinical models of ovarian cancer and to identify potential combination therapies.

Methods: In vitro, immunoblotting, assays for cell viability, proliferation and cell cycle by fluorescence-activated cell sorting (FACS) were performed in an array of high grade serous carcinoma (HGSC) cell lines. Autophagy flux and activities of autophagy factors were also determined. In vivo, metastasis mouse models were used for testing the therapeutic efficacy of IMGN853 monotherapy or in combination with olaparib or cisplatin. Potential synergy with these drugs was assessed using in vitro assays. The resulting tumors were subjected to immunohistochemistry and reverse phase protein arrays (RPPA).

Results: Data from the Cancer Genome Atlas Data (TCGA) revealed that FRα copy-number alterations was significantly correlated with shorter disease-free survival in patients with HGSC. Autophagy marker LC3 was upregulated following monotherapy with IMGN853 as well as in combination of IMGN853 with olaparib or cisplatin in HGSC cell lines such as OVCA8 and OVCA432, which express high-level of FRα. Experiments using metastatic HGSC models showed that IMGN853 monotherapy reduced tumor growth (30% change); the combination of IMGN853 and olaparib was superior to olaparib monotherapy (24% change; p 0.0033). Integrated analysis on RPPA revealed increased expression of ABL1 and PEA15 in the groups treated with IMGN853 monotherapy or in combination with olaparib. We further found reduced FRα expression and increased caspase 3 expression in IMGN853 groups compared with control.

Conclusion: Our results point to sustained autophagy in FRα positive cells as a mechanism of effect of IMGN853. These findings could have implications for clinical development of anti-FRα therapies, especially in combination with other drugs such as olaparib.

Citation Format: Anca Chelariu-Raicu, Elaine Stur, Cristina Ivan, Robert L. Coleman, Anil K. Sood, Wen Yunfei. Biological effects of a FRα-targeting antibody-drug conjugate, IMGN853 (mirvetuximab soravtansine) in high-grade serous ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1237.
Abstract 124: Recycling endosomes in mature epithelia restrain tumorigenic signaling
Authors: Goswami Sayantani
Published: September 2020

The effects of polarized membrane trafficking in mature epithelial tissue on cell growth and cancer progression have not been fully explored in vivo. A majority of colorectal cancers have reduced and mislocalized Rab11, a small GTPase dedicated to trafficking of recycling endosomes. Patients with low Rab11 protein expression have poor survival rates. Using genetic models across species, we show that intact recycling endosome function restrains aberrant epithelial growth elicited by APC or RAS mutations. Loss of Rab11 protein led to epithelial dysplasia in early animal development and synergized with oncogenic pathways to accelerate tumor progression initiated by carcinogen, genetic mutation, or aging. Transcriptomic analysis uncovered an immediate expansion of the intestinal stem cell pool along with cell-autonomous Yki/Yap activation following disruption of Rab11a-mediated recycling endosomes. Intestinal tumors lacking Rab11a traffic exhibited marked elevation of nuclear Yap, upd3/IL6-Stat3, and amphiregulin-MAPK signaling, while suppression of Yki/Yap or upd3/IL6 reduced gut epithelial dysplasia and hyperplasia. Examination of Rab11a function in enteroids or cultured cell lines suggested that this endosome unit is required for suppression of the Yap pathway by Hippo kinases. Thus, recycling endosomes in mature epithelia constitute key tumor suppressors, loss of which accelerates carcinogenesis. Statement of significance: Recycling endosome traffic in mature epithelia constitutes a novel tumor suppressing mechanism.

Citation Format: Sayantani Goswami. Recycling endosomes in mature epithelia restrain tumorigenic signaling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 124.
Abstract 126: Dasatinib attenuates Src pathway signaling and combined with veliparib and carboplatin potently inhibits tumor growth in PTEN-null TNBC model
Authors: Sun Yuliang , Lin Xiaoqian , Aske Jennifer , Williams Casey , Abramovitz Mark , Leyland-Jones Brian
Published: September 2020

Background: The combination of a poly ADP ribose polymerase (PARP) inhibitor with a DNA-damaging agent has shown promise in treating triple-negative breast cancer (TNBC); but not all patients respond to this combination. The Src protein kinase modulates multiple cancer cell properties and plays a key role in tumorigenic processes. However, Src inhibitors as single agents have shown limited effects in solid tumors. In this study, we examined the antitumor effects of the Src inhibitor dasatinib, the PARP inhibitor veliparib, and the DNA-damaging agent carboplatin in PTEN-null TNBC cells in vitro and tumors in vivo to try to identify the combination with the most clinical potential. Methods: The PTEN-null TNBC cell line, MDA-MB-468, was used in this study. For in vitro studies, proliferation, cellular apoptosis, and 3D on-top clonogenic growth were measured, tube formation assays and western blot analysis were performed. For in vivo studies, a xenograft model was used to examine treatment responses, and immunohistochemical analysis was performed. Results: Interestingly, treatment with the combination of veliparib plus carboplatin led to an increase in Src phosphorylation of MDA-MB-468 cells. Importantly, addition of dasatinib attenuated Src overexpression induced by veliparib plus carboplatin and further increased the activation of caspase 3 and PARP, thereby enhancing the antitumor efficacy of veliparib plus carboplatin. In an MDA-MB-468 xenograft model, the triple combination of dasatinib with veliparib plus carboplatin showed greater tumor growth inhibitory effects compared with single agents or double combinations. No systemic toxicity was observed in mice treated with the triple combination. Conclusion: Here, we provide novel evidence that veliparib combined with carboplatin drives Src activation in the preclinical model tested. Moreover, we provide provocative in vitro and in vivo data highlighting the potential for increasing therapeutic efficacy by combining dasatinib with veliparib and carboplatin in PTEN-null TNBC.

Citation Format: Yuliang Sun, Xiaoqian Lin, Jennifer Aske, Casey Williams, Mark Abramovitz, Brian Leyland-Jones. Dasatinib attenuates Src pathway signaling and combined with veliparib and carboplatin potently inhibits tumor growth in PTEN-null TNBC model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 126.