bluuebunny/crossref_metadata_2025 huggingface dataset:
An Energy-Balanced Path Planning Algorithm for Multiple Ferrying UAVs Based on GA
Authors: Wang Lisong , Zhang Xiaoliang , Deng Pingyu , Kang Jiexiang , Gao Zhongjie , Liu Liang
Published: August 2020

When performing a search and rescue mission, unmanned aerial vehicles (UAVs) should continuously search targets above the mission area. In order to transfer the search and rescue information quickly and efficiently, two types of UAVs, the ferrying UAVs and the searching UAVs, are used to complete the mission. Obviously, this application scenario requires an efficient path planning method for ferrying UAVs. The existing path planning methods for ferrying UAVs usually focus on shortening the path length and ignore the different initial energy of ferrying UAVs. However, the following problem does exist: if the ferrying UAV with less initial energy is assigned a longer path, meaning that the ferrying UAV with less initial energy will ferry messages for more searching UAVs. When the lower-initial-energy ferrying UAV is running out of energy, more searching UAVs will no longer deliver messages successfully. Therefore, the mismatch between the planned path length and the initial energy will eventually result in a lower global message delivery ratio. To solve this problem, we propose a new concept energy-factor for a ferrying UAV and use the variance of all ferrying UAVs’ energy-factor to measure the balance between the planned path length and the initial energy. Further, we model the energy-balanced path-planning problem for multiple ferrying UAVs, which actually is a multiobject optimization problem of minimizing the planned path length and minimizing the variance of all ferrying UAVs’ energy-factor. Based on the genetic algorithm, we design and implement an energy-balanced path planning algorithm (EMTSPA) for multiple ferrying UAVs to solve this multiobject optimization problem. Experimental results show that EMTSPA effectively increases the global message delivery ratio and decreases the global message delay.
Analyzing 3D Advection-Diffusion Problems by Using the Improved Element-Free Galerkin Method
Authors: Cheng Heng , Zheng Guodong
Published: August 2020

In this paper, the improved element-free Galerkin (IEFG) method is used for solving 3D advection-diffusion problems. The improved moving least-squares (IMLS) approximation is used to form the trial function, the penalty method is applied to introduce the essential boundary conditions, the Galerkin weak form and the difference method are used to obtain the final discretized equations, and then the formulae of the IEFG method for 3D advection-diffusion problems are presented. The error and the convergence are analyzed by numerical examples, and the numerical results show that the IEFG method not only has a higher computational speed but also can avoid singular matrix of the element-free Galerkin (EFG) method.
Frequency and Factors Associated with Hyperglycaemia First Detected during Pregnancy at Itojo General Hospital, South Western Uganda: A Cross-Sectional Study
Authors: Kiiza Frank , Kayibanda Daniel , Tumushabe Pidson , Kyohairwe Leticia , Atwine Raymond , Kajabwangu Rogers , Kiconco Ritah
Published: August 2020

Background. Hyperglycemia in pregnancy complicates up to 30% of pregnancies in Africa, and this poses a major risk to both the mother and fetus. Although recommended by the World Health Organization (WHO), universal screening for hyperglycaemia in pregnancy is not routinely done in many of the hospital in low- and middle-income countries. This study sought to determine the frequency and factors associated with hyperglycaemia first detected in pregnancy at a general public hospital in South Western Uganda. Methods. We conducted this study at Itojo General Hospital (IGH) in Ntungamo District, South Western Uganda. The study followed a cross-sectional design that employed a systematic random sampling technique to identify potential study participants during the months of October to December 2019. Using a pretested questionnaire, data on sociodemographic and medical characteristics were collected on a sample of 307 pregnant women. Blood samples were collected and analyzed for hyperglycemia using random blood sugar and fasting blood sugar test results. Data generated were analyzed with appropriate statistical tests using the statistical package for social sciences (SPSS) version 26 (SPSS Inc., USA) at P<0.05. Results. The frequency of hyperglycaemia was found to be 15.6% among the study population. Multivariate analysis revealed that the ages of 19-30 years, peasantry, and multiparity with more than 5 live children and second trimester pregnancy were independent risk factors for the observed hyperglycaemia frequency. Conclusion. Our study reports new epidemiological information about the frequency and risk factors of hyperglycaemia in pregnancy from a selected Ugandan population. Our findings suggest an introduction of hyperglycaemia screening in the routine antenatal care package for proper maternal and neonatal health outcomes.
Intelligent Control Using Metaheuristic Optimization for Buck-Boost Converter
Authors: Chanjira P. , Tunyasrirut S.
Published: August 2020

This research aims to introduce an intelligent controlling system of windmill-generated voltage connected to a load of 12 V. As natural wind speed lacks consistency, the resultant irregular voltage can lead to system damage. In the experiment, a buck-boost converter is not only designed to control such voltage but also tuned by intelligent methods. It is very challenging to control the system. PI controller is developed using metaheuristic optimization, an artificial fish-swarm algorithm (AFSA). In testing, the buck-boost converter is controlled by the PI controller at a reference voltage of 14 V and supplied with an input voltage Vin in the range of 5–100V. The result shows that, even with inconstant Vin, the system can effectively control the reference voltage at 14 V.
Overweight and Obesity Coexist with Thinness among Lao’s Urban Area Adolescents
Authors: Ivanovitch Katiya , Keolangsy Sonemany , Homkham Nontiya
Published: August 2020

Introduction. In recent decades, the developing countries of Southeast Asia, including the Lao People’s Democratic Republic (Lao PDR), have experienced a rapid growth of their urban population. Partly as a result of that, issues of undernutrition and overnutrition became a significant public health problem. Objective. To examine the prevalence of overweight and obesity and their related factors, among the school-attending adolescents in the Lao capital of Vientiane. Methods. A cross-sectional data on 300 adolescents aged 15–19 were collected during the months of March, April, and May 2018 by means of a self-administrated questionnaire. Anthropometric measurements were used to obtain data on height and weight. Pearson’s chi-squared test, Fisher exact tests, and univariable and multivariable logistic regressions were applied in the course of the statistical analysis. Results. The study found a high prevalence of overweight/obesity (23.3%) and thinness (10.3%). Poor eating habits were noted in 67.0% of adolescents, even though 78.0% of them had a good knowledge of nutrition. Factors significantly associated with the overweight/obesity were low physical activities (aOR = 18.3; 95% CI: 5.51–60.66) and adolescents living with their guardians (aOR = 0.25; 95% CI: 0.08–0.79). Results also indicated that, in 47.3% of the cases, teachers, acting as a source of health and nutrition information, can prevent the risk of adolescents’ overweight/obesity (aOR = 2.05, 95% CI = 1.11–3.80) but not their thinness (aOR = 0.4, 95% CI = 0.17–0.88). Conclusions. Laotian adolescents are facing the spectrum of malnutrition in urban areas. To improve adolescents’ nutritional status, there is a need for a collaborative approach of public health agencies that would address the issues of an effective food and nutrition policy. The school curricula should also include programs on nutrition and physical education.
Robustness Analysis of Urban Road Networks from Topological and Operational Perspectives
Authors: Shang Wen-Long , Chen Yanyan , Song Chengcheng , Ochieng Washington Y.
Published: August 2020

This study comprehensively analyses the robustness of urban road networks through topological indices based on the complex network theory and operational indices based on traffic assignment theory: User Equilibrium (UE), System Optimum (SO), and Price of Anarchy (POA). Analysing topological indices may pin down the most important nodes for URNs from the perspective of connectivity, while more sophisticated operational indices are helpful to examine the importance of nodes for URNs by taking into account link capacity, travel demand, and drivers’ behaviour. The previous way is calculated in a static way, which reduces the computation times and increases the efficiency for quick assessment of the robustness of URNs, while the latter is in a dynamic way, namely, calculating is based on removal of individual nodes, although this way is more likely to capture realistic meanings but consumes huge amount of time. The efforts made in this study try to find the relationship between topological and operational indices so as to assist the assessment of robustness of URNs to local disruptions. Seven realistic urban road networks such as Sioux Falls and Anaheim are used as network examples, and results show that different indices reflect robustness characteristics of urban road networks from different ways, and rank correlations between any two indices are poor although small network such as Sioux Falls have better correlations than others.
Prediction Model of HBsAg Seroclearance in Patients with Chronic HBV Infection
Authors: Cao Jing , Gong Jiao , Tsia Hin Fong Christ-Jonathan , Xiao Cuicui , Lin Guoli , Li Xiangyong , Jie Yusheng , Chong Yutian
Published: August 2020

Background. Prediction of HBsAg seroclearance, defined as the loss of circulating HBsAg with or without development of antibodies for HBsAg in patients with chronic hepatitis B (CHB), is highly difficult and challenging due to its low incidence. This study is aimed at developing and validating a nomogram for prediction of HBsAg loss in CHB patients. Methods. We analyzed a total of 1398 patients with CHB. Two‐thirds of the patients were randomly assigned to the training set (n = 918), and one‐third were assigned to the validation set (n = 480). Univariate and multivariate analysis by Cox regression analysis was performed using the training set, and the nomogram was constructed. Discrimination and calibration were performed using the training set and validation set. Results. On multivariate analysis of the training set, independent factors for HBsAg loss including BMI, HBeAg status, HBsAg titer (quantitative HBsAg), and baseline hepatitis B virus (HBV) DNA level were incorporated into the nomogram. The HBsAg seroclearance calibration curve showed an optimal agreement between predictions by the nomogram and actual observation. The concordance index (C‐index) of nomogram was 0.913, with confirmation in the validation set where the C‐index was 0.886. Conclusions. We established and validated a novel nomogram that can individually predict HBsAg seroclearance and non‐seroclearance for CHB patients, which is clinically unprecedented. This practical prognostic model may help clinicians in decision‐making and design of clinical studies.
Impinging Performance of High-Pressure Water Jets Emitting from Different Nozzle Orifice Shapes
Authors: Huang Fei , Mi Jianyu , Li Dan , Wang Rongrong
Published: August 2020

The impinging pressure of a water jet is a key factor in engineering applications, and the jet shape has a great influence on this pressure. In this paper, five different nozzle shapes were designed, and impacting tests were conducted based on a self-designed experimental platform using a PVDF piezoelectric film sensor and a high-speed camera to record the impacting data. Additionally, the computational fluid dynamics (CFD) method was also applied to study the velocity distribution. The results show that the pressure profiles of different water jet shapes impacting onto a solid surface present a consistent pattern, namely, an initial transient and enormous peak pressure and then a longer and smaller stagnation pressure. Although the stagnation pressure in this paper is not sufficiently obvious, the peak pressures of the five water jet shapes are much different from one another. Under the same inlet pressure, the peak pressure of the circular water jet is the largest, and those of the square, triangular, cross-shaped, and elliptical water jets decrease in turn. The flowing regimes captured by the high-speed camera together with the CFD simulation results indicate that the discrepancy in the peak pressure may be a combined action of the liquid velocities and jet head shapes.
ST Elevations in the Era of COVID-19
Authors: Sang Charlie Joseph , Heindl Brittain , Von Mering Gregory , Brott Brigitta , Kopf Robert S. , Rajapreyar Indranee
Published: August 2020

Myocardial injury, represented by elevated cardiac enzymes, has been associated with increased morbidity and mortality in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections. Coronavirus disease 2019 (COVID-19) has created unique challenges in approaching patients with acute ST-segment changes. We describe two distinct cases of ST elevation on electrocardiogram occurring in patients with COVID-19 and review important diagnostic and management considerations for the front-line clinician.
Antihyperglycemic, Vasodilator, and Diuretic Activities of Microencapsulated Bioactive Product from Moringa stenopetala Leaves Extract
Authors: Dadi Debebe Worku , Emire Shimelis Admassu , Hagos Asfaw Debella , Teka Frehiwot , Woldekidan Samuel , Abebe Abiy , Sileshi Meron
Published: August 2020

Moringa stenopetala has nutritional and medicinal values, which is widely used by the local communities. The study aimed to evaluate the antihyperglycemic, vasodilator, and diuretic activities of the microencapsulated bioactive product from M. stenopetala leaves extract. Microencapsulation of the extract was done by spray drying technique using maltodextrin and pectin as coating materials with the core: coating ratio of 1 : 6. Then, the antihyperglycemic, diuretic, and vasodilator activities were evaluated after the product was administered to experimental animals at different doses and compared with the control groups. There were no observed physical, behavioral, and physiological changes on the mice during the acute toxicity test. The results also indicated no toxicity signs and death occurrence in the experimental animals up to 5000 mg/kg administered dose. Therefore, microencapsulated M. stenopetala leaves extract does not produce adverse effects in experimental mice. The study also showed that the microencapsulated bioactive product exhibited significant antihyperglycemic, vasodilator, and diuretic activities as the doses increase. Therefore, the study showed that microencapsulated bioactive product has significant medicinal values. Further detailed studies are recommended on chronic toxicity tests and to understand the possible mechanism of actions on the antihyperglycemic, vasodilator, and diuretic activities of the microencapsulated product.
Overburden Damage Degree-Based Optimization of High-Intensity Mining Parameters and Engineering Practices in China’s Western Mining Area
Authors: He Xiang , Zhang Cun , Han Penghua
Published: August 2020

China’s western mining area is an arid and semiarid area with a fragile ecological environment, and the high-intensity mining activities aggravate ecological damage. Reasonable choice of the mining parameters (i.e., mining height, panel width, and advancing speed) can not only improve the mining efficiency but also weaken the mining-induced deformation and failures of the overburden and surface. The statistical analysis of the relationship between the mining parameters and periodic weighting interval (PWI) proves that mining parameters have significant influence on overburden failure. In this study, the damage constitutive equation was derived, and the overburden damage degree was defined to quantitatively characterize mining-induced stratum damage in a three-dimensional space. FLAC3D numerical models embedded with a damage constitutive equation were built to compare the panel width effect and advancing speed effect between the overburden damage degree and the water-conducted fracture zone (WCFZ). The reasonable range for mining parameters of the panel 12401 was provided based on the fitting function of the overburden damage degree versus mining parameters. The field measurements were carried out on panel 12401 of the Shangwan coal mine, including the advancing speed, PWI, and ground crack development. The results show that, under constant engineering and geological conditions, the damage degree of overburden will be weakened by increasing the advancing speed, reducing the mining height, or shortening the panel width. The overburden damage degree is more accurate than the height of the water-conducted fractured zone. The reasonable mining parameters of the panel 12401 are 8.8 m in mining height, 300 m in panel width, and 13.47 to 20.58 m/d in advancing speed, respectively. The field measurement results of the PWI and ground cracks have verified the validity using the overburden damage degree to determine high-intensity mining parameters.
Model Contrast of Autonomous Vehicle Impacts on Traffic
Authors: Hungness Derek , Bridgelall Raj
Published: August 2020

The adoption of connected and autonomous vehicles (CAVs) is in its infancy. Therefore, very little is known about their potential impacts on traffic. Meanwhile, researchers and market analysts predict a wide range of possibilities about their potential benefits and the timing of their deployments. Planners traditionally use various types of travel demand models to forecast future traffic conditions. However, such models do not yet integrate any expected impacts from CAV deployments. Consequently, many long-range transportation plans do not yet account for their eventual deployment. To address some of these uncertainties, this work modified an existing model for Madison, Wisconsin. To compare outcomes, the authors used identical parameter changes and simulation scenarios for a model of Gainesville, Florida. Both models show that with increasing levels of CAV deployment, both the vehicle miles traveled and the average congestion speed will increase. However, there are some important exceptions due to differences in the road network layout, geospatial features, sociodemographic factors, land-use, and access to transit.
A New Class of Difference Methods with Intrinsic Parallelism for Burgers–Fisher Equation
Authors: Pan Yueyue , Wu Lifei , Yang Xiaozhong
Published: August 2020

This paper proposes a new class of difference methods with intrinsic parallelism for solving the Burgers–Fisher equation. A new class of parallel difference schemes of pure alternating segment explicit-implicit (PASE-I) and pure alternating segment implicit-explicit (PASI-E) are constructed by taking simple classical explicit and implicit schemes, combined with the alternating segment technique. The existence, uniqueness, linear absolute stability, and convergence for the solutions of PASE-I and PASI-E schemes are well illustrated. Both theoretical analysis and numerical experiments show that PASE-I and PASI-E schemes are linearly absolute stable, with 2-order time accuracy and 2-order spatial accuracy. Compared with the implicit scheme and the Crank–Nicolson (C-N) scheme, the computational efficiency of the PASE-I (PASI-E) scheme is greatly improved. The PASE-I and PASI-E schemes have obvious parallel computing properties, which show that the difference methods with intrinsic parallelism in this paper are feasible to solve the Burgers–Fisher equation.
A Division of Labor between YAP and TAZ in Non–Small Cell Lung Cancer
Authors: Shreberk-Shaked Michal , Dassa Bareket , Sinha Sanju , Di Agostino Silvia , Azuri Ido , Mukherjee Saptaparna , Aylon Yael , Blandino Giovanni , Ruppin Eytan , Oren Moshe
Published: August 2020

Lung cancer is the leading cause of cancer-related deaths worldwide. The paralogous transcriptional cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ, also called WWTR1), the main downstream effectors of the Hippo signal transduction pathway, are emerging as pivotal determinants of malignancy in lung cancer. Traditionally, studies have tended to consider YAP and TAZ as functionally redundant transcriptional cofactors with similar biological impact. However, there is growing evidence that each of them also possesses distinct attributes. Here we sought to systematically characterize the division of labor between YAP and TAZ in non–small cell lung cancer (NSCLC), the most common histological subtype of lung cancer. Representative NSCLC cell lines as well as patient-derived data showed that the two paralogs orchestrated nonoverlapping transcriptional programs in this cancer type. YAP preferentially regulated gene sets associated with cell division and cell-cycle progression, whereas TAZ preferentially regulated genes associated with extracellular matrix organization. Depletion of YAP resulted in growth arrest, whereas its overexpression promoted cell proliferation. Likewise, depletion of TAZ compromised cell migration, whereas its overexpression enhanced migration. The differential effects of YAP and TAZ on key cellular processes were also associated with differential response to anticancer therapies. Uncovering the different activities and downstream effects of YAP and TAZ may thus facilitate better stratification of patients with lung cancer for anticancer therapies.

Significance:

Thease findings show that oncogenic paralogs YAP and TAZ have distinct roles in NSCLC and are associated with differential response to anticancer drugs, knowledge that may assist lung cancer therapy decisions.
A DNA Hypomethylating Drug Alters the Tumor Microenvironment and Improves the Effectiveness of Immune Checkpoint Inhibitors in a Mouse Model of Pancreatic Cancer
Authors: Gonda Tamas A. , Fang Jarwei , Salas Martha , Do Catherine , Hsu Emily , Zhukovskaya Anna , Siegel Ariel , Takahashi Ryota , Lopez-Bujanda Zoila A. , Drake Charles G. , Manji Gulam A. , Wang Timothy C. , Olive Kenneth P. , Tycko Benjamin
Published: August 2020

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer that has proven refractory to immunotherapy. Previously, treatment with the DNA hypomethylating drug decitabine (5-aza-dC; DAC) extended survival in the KPC-Brca1 mouse model of PDAC. Here we investigated the effects of DAC in the original KPC model and tested combination therapy with DAC followed by immune checkpoint inhibitors (ICI). Four protocols were tested: PBS vehicle, DAC, ICI (anti-PD-1 or anti-VISTA), and DAC followed by ICI. For each single-agent and combination treatment, tumor growth was measured by serial ultrasound, tumor-infiltrating lymphoid and myeloid cells were characterized, and overall survival was assessed. Single-agent DAC led to increased CD4+ and CD8+ tumor-infiltrating lymphocytes (TIL), PD1 expression, and tumor necrosis while slowing tumor growth and modestly increasing mouse survival without systemic toxicity. RNA-sequencing of DAC-treated tumors revealed increased expression of Chi3l3 (Ym1), reflecting an increase in a subset of tumor-infiltrating M2-polarized macrophages. While ICI alone had modest effects, DAC followed by either of ICI therapies additively inhibited tumor growth and prolonged mouse survival. The best results were obtained using DAC followed by anti-PD-1, which extended mean survival from 26 to 54 days (P < 0.0001). In summary, low-dose DAC inhibits tumor growth and increases both TILs and a subset of tumor-infiltrating M2-polarized macrophages in the KPC model of PDAC, and DAC followed by anti-PD-1 substantially prolongs survival. Because M2-polarized macrophages are predicted to antagonize antitumor effects, targeting these cells may be important to enhance the efficacy of combination therapy with DAC plus ICI.

Significance:

In a pancreatic cancer model, a DNA hypomethylating drug increases tumor-infiltrating effector T cells, increases a subset of M2 macrophages, and significantly prolongs survival in combination with immune checkpoint inhibitors.

See related commentary by Nephew, p. 4610
Metastasis-Associated Protein 2 Represses NF-κB to Reduce Lung Tumor Growth and Inflammation
Authors: El-Nikhely Nefertiti , Karger Annika , Sarode Poonam , Singh Indrabahadur , Weigert Andreas , Wietelmann Astrid , Stiewe Thorsten , Dammann Reinhard , Fink Ludger , Grimminger Friedrich , Barreto Guillermo , Seeger Werner , Pullamsetti Soni S. , Rapp Ulf R. , Savai Rajkumar
Published: August 2020

Although NF-κB is known to play a pivotal role in lung cancer, contributing to tumor growth, microenvironmental changes, and metastasis, the epigenetic regulation of NF-κB in tumor context is largely unknown. Here we report that the IKK2/NF-κB signaling pathway modulates metastasis-associated protein 2 (MTA2), a component of the nucleosome remodeling and deacetylase complex (NuRD). In triple transgenic mice, downregulation of IKK2 (Sftpc-cRaf-IKK2DN) in cRaf-induced tumors in alveolar epithelial type II cells restricted tumor formation, whereas activation of IKK2 (Sftpc-cRaf-IKK2CA) supported tumor growth; both effects were accompanied by altered expression of MTA2. Further studies employing genetic inhibition of MTA2 suggested that in primary tumor growth, independent of IKK2, MTA2/NuRD corepressor complex negatively regulates NF-κB signaling and tumor growth, whereas later dissociation of MTA2/NuRD complex from the promoter of NF-κB target genes and IKK2-dependent positive regulation of MTA2 leads to activation of NF-κB signaling, epithelial–mesenchymal transition, and lung tumor metastasis. These findings reveal a previously unrecognized biphasic role of MTA2 in IKK2/NF-κB-driven primary-to-metastatic lung tumor progression. Addressing the interaction between MTA2 and NF-κB would provide potential targets for intervention of tumor growth and metastasis.

Significance:

These findings strongly suggest a prominent role of MTA2 in primary tumor growth, lung metastasis, and NF-κB signaling modulatory functions.
Junctional Adhesion Molecules in Cancer: A Paradigm for the Diverse Functions of Cell–Cell Interactions in Tumor Progression
Authors: Lauko Adam , Mu Zhaomei , Gutmann David H. , Naik Ulhas P. , Lathia Justin D.
Published: August 2020

Tight junction (TJ) proteins are essential for mediating interactions between adjacent cells and coordinating cellular and organ responses. Initial investigations into TJ proteins and junctional adhesion molecules (JAM) in cancer suggested a tumor-suppressive role where decreased expression led to increased metastasis. However, recent studies of the JAM family members JAM-A and JAM-C have expanded the roles of these proteins to include protumorigenic functions, including inhibition of apoptosis and promotion of proliferation, cancer stem cell biology, and epithelial-to-mesenchymal transition. JAM function by interacting with other proteins through three distinct molecular mechanisms: direct cell–cell interaction on adjacent cells, stabilization of adjacent cell surface receptors on the same cell, and interactions between JAM and cell surface receptors expressed on adjacent cells. Collectively, these diverse interactions contribute to both the pro- and antitumorigenic functions of JAM. In this review, we discuss these context-dependent functions of JAM in a variety of cancers and highlight key areas that remain poorly understood, including their potentially diverse intracellular signaling networks, their roles in the tumor microenvironment, and the consequences of posttranslational modifications on their function. These studies have implications in furthering our understanding of JAM in cancer and provide a paradigm for exploring additional roles of TJ proteins.
Anarchy or Respect the Hierarchy? The Complexity of Glioblastoma
Authors: Koncar Robert F. , Agnihotri Sameer
Published: August 2020

Glioma stem-like cells (GSC) in glioblastoma (GBM) structure tumor cells into a hierarchical organization and are postulated to be recalcitrant to conventional treatments, resulting in fatal relapse of the disease. A better understanding of these cells would be essential for meaningful and lasting treatments. In this issue of Cancer Research, Virolle and colleagues report a fascinating phenotype whereby the extracellular signal-regulated kinase (ERK) pathway regulates a mechanism of dedifferentiation of GBM cells into a stem-like state expressing markers of pluripotency through an EGFR-ERK-EGR1–dependent axis. This aptly termed “toggle switch” may contribute to maintenance of GSCs, promote intratumor heterogeneity, and potentially provide innovative treatment options.

See related article by Almairac et al., p. 3236
Safety and Clinical Activity of MEDI0562, a Humanized OX40 Agonist Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors
Authors: Glisson Bonnie S. , Leidner Rom S. , Ferris Robert L. , Powderly John , Rizvi Naiyer A. , Keam Bhumsuk , Schneider Reva , Goel Sanjay , Ohr James P. , Burton Jennifer , Zheng Yanan , Eck Steven , Gribbin Matthew , Streicher Katie , Townsley Danielle M. , Patel Sandip Pravin
Published: August 2020

Purpose:

Immune checkpoint blockade has demonstrated clinical benefits across multiple solid tumor types; however, resistance and relapse often occur. New immunomodulatory targets, which are highly expressed in activated immune cells, are needed. MEDI0562, an agonistic humanized mAb, specifically binds to the costimulatory molecule OX40. This first-in-human study evaluated MEDI0562 in adults with advanced solid tumors.

Patients and Methods:

In this phase I, multicenter, open-label, single-arm, dose-escalation (3+3 design) study, patients received 0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg MEDI0562 through intravenous infusion every 2 weeks, until confirmed disease progression or unacceptable toxicity. The primary objective evaluated safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.

Results:

In total, 55 patients received ≥1 dose of MEDI0562 and were included in the analysis. The most common tumor type was squamous cell carcinoma of the head and neck (47%). Median duration of treatment was 10 weeks (range, 2–48 weeks). Treatment-related adverse events (TRAEs) occurred in 67% of patients, most commonly fatigue (31%) and infusion-related reactions (14%). Grade 3 TRAEs occurred in 14% of patients with no apparent dose relationship; no TRAEs resulted in death. Two patients had immune-related partial responses per protocol and 44% had stable disease. MEDI0562 induced increased Ki67+ CD4+ and CD8+ memory T-cell proliferation in the periphery and decreased intratumoral OX40+ FOXP3+ cells.

Conclusions:

MEDI0562 was safely administered at doses up to 10 mg/kg in heavily pretreated patients. On-target pharmacodynamic effects were suggested in this setting. Further evaluation with immune checkpoint inhibitors is ongoing.
Coexpression of IL7 and CCL21 Increases Efficacy of CAR-T Cells in Solid Tumors without Requiring Preconditioned Lymphodepletion
Authors: Luo Hong , Su Jingwen , Sun Ruixin , Sun Yansha , Wang Yi , Dong Yiwei , Shi Bizhi , Jiang Hua , Li Zonghai
Published: August 2020

Purpose:

T-cell recruitment, survival, and proliferation are the important limitations to chimeric antigen receptor (CAR) T cells therapy in the treatment of solid tumors. In this study, we engineered CAR-T cells to coexpress cytokines IL7 and CCL21 (7 × 21 CAR-T), a cytokine combination in order to improve proliferation and chemotaxis of CAR-T cells.

Experimental Design:

CLDN18.2-specific second-generation CAR-T cells coexpressing cytokines were prepared using retroviral vector transduction. The proliferation and migration of genetically engineered CAR-T cells were evaluated in vitro. The antitumor activities of genetically engineered CAR-T cells were evaluated against multiple solid tumors in C57BL/6 mice in vivo.

Results:

In vitro, the proliferation and chemotaxis of 7 × 21 CAR-T cells are significantly improved when compared with those of the conventional CAR-T cells. In vivo, 7 × 21 CAR-T cells revealed superior therapeutic effects to either conventional CAR-T cells or 7 × 19 CAR-T cells which coexpress IL7 and CCL19 as previously reported in three different solid tumors without cyclophosphamide precondition. Interestingly, 7 × 21 CAR-T cells could also suppress the tumor growth with heterogeneous antigen expression and even induce tumor complete remission. Mechanistically, IL7 and CCL21 significantly improved survival and infiltration of CAR-T cells and dendritic cells in tumor. In addition, CCL21 also inhibited the tumor angiogenesis as proved by IHC.

Conclusions:

Coexpression of IL7 and CCL21 could boost CAR-T cells' antitumor activity, and 7 × 21 CAR-T cells may be served as a promising therapy strategy for solid tumors.
HLA Genotyping in Synovial Sarcoma: Identifying HLA-A*02 and Its Association with Clinical Outcome
Authors: Rosenbaum Evan , Seier Kenneth , Bandlamudi Chaitanya , Dickson Mark , Gounder Mrinal , Keohan Mary L. , Chi Ping , Kelly Ciara , Movva Sujana , Nacev Benjamin , Simeone Noemi , Donoghue Mark , Slotkin Emily K. , Qin Li-Xuan , Antonescu Cristina R. , Tap William D. , D'Angelo Sandra P.
Published: August 2020

Purpose:

To determine if a targeted exome panel utilizing matched normal DNA can accurately detect germline and somatic HLA genes in patients with synovial sarcoma (SS) and whether select HLA-A*02 genotypes are prognostic or predictive of outcome in metastatic SS.

Experimental Design:

Patients with metastatic SS consented to HLA typing by a Clinical Laboratory Improvement Amendments (CLIA)-certified test to determine eligibility for a clinical trial of NY-ESO-1–specific engineered T cells restricted to carriers of HLA-A*02:01, -A*02:05, or -A*02:06 (HLA-A*02 eligible). HLA genotype was determined from Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets (MSK-IMPACT), where feasible, and somatic loss of heterozygosity (LOH) in HLA alleles was identified. Overall survival (OS) was estimated and stratified by HLA-A*02 eligibility.

Results:

A total of 23 patients had HLA genotyping by a CLIA-certified lab and MSK-IMPACT. Ninety percent (108/110) of the sequenced alleles were concordant between IMPACT and the outside lab. LOH of HLA genes was detected in three tumors, one had loss of HLA-A*02:01. In total, 66 patients were screened for T-cell therapy and 20 (30%) were HLA-A*02 eligible on outside testing. Univariate analysis of OS from the time of metastasis found HLA-A*02 eligibility was marginally associated with shorter OS [HR = 1.95; 95% confidence interval (CI), 0.995–3.813; P = 0.052]. On multivariate analysis, older age and larger tumor size, but not HLA-A*02 eligibility, were significantly associated with decreased OS. HLA-A*02 eligibility did not impact OS after chemotherapy or pazopanib in the metastatic setting.

Conclusions:

Targeted gene panels like MSK-IMPACT may accurately report HLA type and identify loss of somatic HLA alleles. In a multivariable model, HLA-A*02 eligibility was not significantly associated with OS in patients with metastatic SS.
A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination–deficient Pancreatic Cancer
Authors: Wang Yifan , Park Jin Yong Patrick , Pacis Alain , Denroche Robert E. , Jang Gun Ho , Zhang Amy , Cuggia Adeline , Domecq Celine , Monlong Jean , Raitses-Gurevich Maria , Grant Robert C. , Borgida Ayelet , Holter Spring , Stossel Chani , Bu Simeng , Masoomian Mehdi , Lungu Ilinca M. , Bartlett John M.S. , Wilson Julie M. , Gao Zu-Hua , Riazalhosseini Yasser , Asselah Jamil , Bouganim Nathaniel , Cabrera Tatiana , Boucher Louis-Martin , Valenti David , Biagi James , Greenwood Celia M.T. , Polak Paz , Foulkes William D. , Golan Talia , O'Kane Grainne M. , Fischer Sandra E. , Knox Jennifer J. , Gallinger Steven , Zogopoulos George
Published: August 2020

Purpose:

Pancreatic ductal adenocarcinoma (PDAC) arising in patients with a germline BRCA1 or BRCA2 (gBRCA) mutation may be sensitive to platinum and PARP inhibitors (PARPi). However, treatment stratification based on gBRCA mutational status alone is associated with heterogeneous responses.

Experimental Design:

We performed a seven-arm preclinical trial consisting of 471 mice, representing 12 unique PDAC patient-derived xenografts, of which nine were gBRCA mutated. From 179 patients whose PDAC was whole-genome and transcriptome sequenced, we identified 21 cases with homologous recombination deficiency (HRD), and investigated prognostic biomarkers.

Results:

We found that biallelic inactivation of BRCA1/BRCA2 is associated with genomic hallmarks of HRD and required for cisplatin and talazoparib (PARPi) sensitivity. However, HRD genomic hallmarks persisted in xenografts despite the emergence of therapy resistance, indicating the presence of a genomic scar. We identified tumor polyploidy and a low Ki67 index as predictors of poor cisplatin and talazoparib response. In patients with HRD PDAC, tumor polyploidy and a basal-like transcriptomic subtype were independent predictors of shorter survival. To facilitate clinical assignment of transcriptomic subtype, we developed a novel pragmatic two-marker assay (GATA6:KRT17).

Conclusions:

In summary, we propose a predictive and prognostic model of gBRCA-mutated PDAC on the basis of HRD genomic hallmarks, Ki67 index, tumor ploidy, and transcriptomic subtype.
Integration of Antiangiogenic Therapy with Cisplatin and Gemcitabine Chemotherapy in Patients with Nasopharyngeal Carcinoma
Authors: Chong Wan Qin , Lim Chwee Ming , Sinha Arvind Kumar , Tan Chee Seng , Chan Gloria Hui Jia , Huang Yiqing , Kumarakulasinghe Nesaretnam Barr , Sundar Raghav , Jeyasekharan Anand D. , Loh Woei Shyang , Tay Joshua K. , Yadav Kritika , Wang Lingzhi , Wong Andrea L. , Kong Li Ren , Soo Ross Andrew , Lau Jieying Amelia , Soon Yu Yang , Goh Robby Miguel , Ho Francis Cho Hao , Chong Siew Meng , Lee Soo Chin , Loh Kwok Seng , Tai Bee Choo , Lim Yaw Chyn , Goh Boon Cher
Published: August 2020

Purpose:

Induction cisplatin and gemcitabine chemotherapy is a standard treatment for locally advanced nasopharyngeal carcinoma (NPC). Inhibition of VEGF axis has been shown to promote maturation of microvasculature and improve perfusion. We conducted a four-arm study to assess the effect of two doses of either sunitinib or bevacizumab with chemotherapy in NPC.

Patients and Methods:

Patients with treatment-naïve locally advanced NPC were treated with three cycles of 3-weekly cisplatin and gemcitabine preceded by 1 week of anti-VEGF therapy for each cycle, followed by standard concurrent chemoradiation: arm A patients received 7 days of 12.5 mg/day sunitinib; arm B 7 days of 25 mg/day sunitinib; arm C bevacizumab 7.5 mg/kg infusion; arm D bevacizumab 2.5 mg/kg infusion. Patients with metastatic NPC were treated with up to six cycles of similar treatment without concurrent chemoradiation.

Results:

Complete metabolic response (mCR) by whole body 18FDG PET was highest in arm C (significant difference in four groups Fisher exact test P = 0.001; type 1 error = 0.05), with 42% mCR (95% confidence interval, 18–67) and 3-year relapse-free survival of 88% in patients with locally advanced NPC. Significant increase in pericyte coverage signifying microvascular maturation and increased immune cell infiltration was observed in posttreatment tumor biopsies in Arm C. Myelosuppression was more profound in sunitinib containing arms, and tolerability was established in arm C where hypertension was the most significant toxicity.

Conclusions:

Bevacizumab 7.5 mg/kg with cisplatin and gemcitabine was well tolerated. Promising tumor response was observed and supported mechanistically by positive effects on tumor perfusion and immune cell trafficking into the tumor.
Acute Myeloid Leukemia and Myelodysplastic Syndromes with TP53 Aberrations — A Distinct Stem Cell Disorder
Authors: Sill Heinz , Zebisch Armin , Haase Detlef
Published: August 2020

The tumor suppressor p53 exerts pivotal roles in hematopoietic stem cell (HSC) homeostasis. Mutations of the TP53 gene have recently been described in individuals with clonal hematopoiesis conferring substantial risk of developing blood cancers. In patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), TP53 aberrations—mutations, deletions, and a combination thereof—are encountered at a constant frequency of approximately 10%. These aberrations affect HSCs transforming them into preleukemic stem cells, pinpointing their central role in leukemogenesis. AML and MDS with TP53 aberrations are characterized by complex chromosomal aberrations. Respective patients experience a dismal long-term outcome following treatment with both intensive and nonintensive regimens including novel agents like venetoclax combinations or even allogeneic HSC transplantation. However, according to the 2016 WHO classification, AML and MDS with TP53 aberrations are still regarded as separate disease entities. On the basis of their common biological and clinical features, we propose to classify AML and MDS with TP53 aberrations as a single, distinct stem cell disorder with a unique genetic make-up, comparable with the WHO classification of “AML with recurrent genetic abnormalities.” This approach will have implications for basic and translational research endeavors, aid in harmonization of current treatment strategies, and facilitate the development of master trials targeting a common deleterious driver event.
Moving Beyond BRCA—Incorporating Molecular Assays into Ovarian Cancer Trials
Authors: McMullen Michelle , Karakasis Katherine , Oza Amit M.
Published: August 2020

PrOTYPE is a locked down assay validated to Institute of Medicine standards, using NanoString technology to classify high-grade serous ovarian cancer into four defined subgroups. Future directions will include prospective–retrospective analysis and prospective clinical validation to define the predictive role of this assay and its role in influencing treatment decisions.

See related article by Talhouk et al., p. 5411
Pancreatitis and Biliary Obstruction Secondary to Duodenal Metastasis from Rapidly Progressing Lung Adenocarcinoma Treated with Common Bile Duct Stenting
Authors: O’Neill Robert Sean , Duong Tuan , Dionela Welan , Rogge Claudia , Brungs Daniel
Published: August 2020

Non-small cell lung cancer (NSCLC) is characterised by diffuse metastases, with common sites being the brain, liver, bones, and adrenal glands. Small bowel metastasis from NSCLC is a rare phenomenon, particularly in patients with an adenocarcinoma histology. We report the case of a 56-year-old lung adenocarcinoma patient with a duodenal metastasis diagnosed on FDG/PET-CT and confirmed on duodenal biopsy. Although initially asymptomatic, he subsequently presented with obstructive jaundice secondary to rapid local disease progression at the duodenal metastasis, requiring endoscopic intervention for biliary drainage. He was commenced on single agent pembrolizumab, with disease response on subsequent follow-up. This case highlights a rare case of gastrointestinal metastasis from NSCLC requiring endoscopic intervention due to rapid progression of the disease at the site of metastasis.
Diabetes Mellitus Might Not Be Associated with Any Stone Component in a Local District
Authors: Chen Han , Chen Gang , Pan Yang , Zhu Yunxiao , Xiong Chaoyu , Chen Hualin , Yang Ziyi
Published: August 2020

Background: Type II diabetes mellitus (DM) is a risk factor for urinary stones, but the pathogenesis remains unclear. The aim of our study was to present the distribution of stone components between DM and no DM group from a local stone center in China and to help the prevention department in decision-making. Methods: We reviewed the records of patients with upper urinary stones attending our hospital from January 2015 to September 2018. The patients with complete information were divided into 2 groups: type II DM group (DM group) and without DM group (no DM group). The distribution of stone components was analyzed. Results: Two hundred twenty-two patients were complicated with DM, whereas 1,894 (89%) were not. Significant difference was found in the distribution of hypertension and BMI (p = 0, p = 0, respectively). Distribution of sex, age, and stone components did not differ between the 2 groups. By the binary logistic analysis, increasing age and sex seemed to be the main risk factors influencing the stone components. Only the calcium stone seemed to be free of the ­impact from age and sex. Occurrence of hypertension is a single risk factor for calcium stone from our analysis. Presence of diabetes and increasing BMI was not found to be significantly associated with the risk for any stone component. Conclusions: In a local district, DM might not be the main factor associated with an increased risk for uric acid stone formation or any stone component. We should also consider the local characteristics of the stone distribution.
CD8 Treg Cells Inhibit B-Cell Proliferation and Immunoglobulin Production
Authors: Gupta Sudhir , Su Houfen , Agrawal Sudhanshu
Published: August 2020

Aim: The role of CD4+ Treg in immune responses has been well established. More recently, a role of CD8+ T regulatory cells (CD8 Treg) in the regulation of immune responses in health and autoimmune diseases has been investigated. Furthermore, different investigators have used different markers to define CD8 Treg. Finally, regulatory effects of CD8 Treg have been studied against T-cell responses; however, their role in regulating B-cell proliferation and immunoglobulin production has not been evaluated. Therefore, in this study we examined the effect of two types of CD8 Treg on B-cell proliferation and immunoglobulin production. Methods: Purified CD8+ T cells were activated with anti-CD3/CD28 for 48 h and then sorted into two different types of CD8 Treg as defined by two different sets of markers, CD8+CD183+CD197+CD45RA− and CD8+CD183+CD25highCD278+. Purified B cells were cocultured with sorted CD8 Treg at 1:1, 1:1/2, and 1:1/4 ratios and activated with anti-CD40 and CpG. B-cell proliferation was assessed by the CFSE dye dilution assay and immunoglobulin production by the ELISA assay. Results: Our data show CD183+CD197+CD45RA−CD8 Treg significantly inhibited B-cell proliferation and inhibited IgM and IgG production but not IgA production at 1:1 ratio only. However, CD183+CD25highCD278+CD8 Treg inhibited significantly B-cell proliferation at 1:1 and 1:1/2 ratios and IgM, IgG, and IgA production at all ratios. Conclusion: CD8 Treg regulate B-cell responses, and CD183+CD25highCD278+CD8 Treg are more powerful regulators of B-cell proliferation and immunoglobulin production than CD183+CD197+CD45RA−CD8 Treg and, therefore, may be used as preferred markers for CD8 Treg.