bluuebunny/crossref_metadata_2025 huggingface dataset:
The Simulation of Implications of Sensor Technology on the New Product Development to Solve Lot-Sizing Problems with Fuzzy Approach
Authors: Gaol Ford Lumban , Matsuo Tokuro
Published: August 2020

Implications of sensor technology on new product introduction requires critical decisions on divergent marketing and operational aspects. In this paper, we employed the Bass model for a new product that used the sensor technology diffusion from the perspective of the Wagner-Whitin lot-sizing model which discusses this matter related to suitability of sensor technology on the market and operational dimensions. The objective of this study is to propose an uncertain fuzzy approach to specify the new product that applied the sensor technology introduction’s optimum time, price, production scheduling, and rate simultaneously. This model will be applied to analyze the impact of sensor technology diffusion on the market acceptance and some operational parameters, for instance, total customer population, price elasticities, startup and maintenance costs, the unit’s variable cost and research and development costs on optimized benefit, and the product’s optimized lifespan. In this experiment, we have inspiration from the version of the Sale et al. (2017) model which considers uncertainty by using fuzzy triangular numbers and performing the alpha cut method. Moreover, in this research, variable cost is considered as a Cobb-Douglas function. Initially, in Research Methodology, mathematical modeling is applied, wherein utilizing simulation and the experimental design method, data were generated. Eventually, using LINGO optimization software, the problem was solved, and for further examinations considering the existence of various parameters, design of experiment (DoE) by Design-Expert 8 software and response surface methodology was adopted to analyze and optimize the problem’s parameters. The results indicated that the objective function’s climax occurs when the higher limit of alpha being 0.7 is assumed; hence, the optimum state of demand belongs to this amount of alpha.
Analysis of the Impact of Climate Change on National Vulnerability Based on Fuzzy Comprehensive Evaluation
Authors: Zhu Jia-Ming , Chen Yang , Zhang Su
Published: August 2020

Climate change has become one of the major threats to global security. On the impact of climate change on national vulnerability, the researchers firstly select relevant factors and data and analyze the principal components to determine the weight of climate change on vulnerability so as to analyze the impact of climate change on national vulnerability. Secondly, based on the influencing factors, we obtain the national vulnerability score through the fuzzy comprehensive evaluation method, delineate the impact scope according to the score, and predict climate change by means of regression analysis and time series analysis. Finally, according to the characteristics of cities and continents, the model is revised, a PSR model and a cluster analysis model are established, and the prediction accuracy is improved.
The Emerging Role of PPAR Beta/Delta in Tumor Angiogenesis
Authors: Du Siyue , Wagner Nicole , Wagner Kay-Dietrich
Published: August 2020

PPARs are ligand-activated transcriptional factors that belong to the nuclear receptor superfamily. Among them, PPAR alpha and PPAR gamma are prone to exert an antiangiogenic effect, whereas PPAR beta/delta has an opposite effect in physiological and pathological conditions. Angiogenesis has been known as a hallmark of cancer, and our recent works also demonstrate that vascular-specific PPAR beta/delta overexpression promotes tumor angiogenesis and progression in vivo. In this review, we will mainly focus on the role of PPAR beta/delta in tumor angiogenesis linked to the tumor microenvironment to further facilitate tumor progression and metastasis. Moreover, the crosstalk between PPAR beta/delta and its downstream key signal molecules involved in tumor angiogenesis will also be discussed, and the network of interplay between them will further be established in the review.
Unusual Presentation of Priapism Associated with Acute and Chronic Myeloid Leukemia in Two Patients: Emergency Management
Authors: Gaye Oumar , Thiam Ngor Mack , Cassell Ayun , Gueye Serigne Mourtalla , Sow Yaya , Fall Boubacar , Ndoye Alain Khassim
Published: August 2020

Priapism is a rare urological emergency. It is rarely a telltale sign of myeloid leukemia. We report two cases of acute myeloid leukemia in a child and chronic myeloid leukemia in a young adult presenting with priapism. Puncture irrigation of the corpora cavernosa followed by systemic treatment to lower the hyperviscosity of the blood due to leukemia provided optimal outcome. Prompt emergency management is required to lower the complication of erectile dysfunction.
Adsorption Studies on the Removal of Textile Effluent over Two Natural Eco-Friendly Adsorbents
Authors: Assila Ouissal , Tanji Karim , Zouheir Morad , Arrahli Abdellah , Nahali Loubna , Zerrouq Farid , Kherbeche Abdelhak
Published: August 2020

This study investigates the possibility of applying an adsorption process using two abundant natural minerals M1 and M2. Without pretreatment or activation, the adsorbents were used to treat real textile wastewater samples (collected from Fez city, Morocco). As a cost-effective alternative, these materials were characterized by different analyses, including X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and X-ray fluorescence (XRF). Chemical oxygen demand (COD) and biological oxygen demand (BOD) were used to characterize the textile wastewater. Additionally, the influence of operating conditions (contact time, adsorbent dosages, and pH) was evaluated. Results show that the adsorption process takes place quickly, reaching the equilibrium at 90 and 160 min for M1 (88% COD) and M2 (79% COD). Both materials show a higher affinity to Cr (39%) and lower affinity to Cu (28%). A pseudo-second-order kinetic model provides the best fit to the experimental adsorption data. Germination tests indicate a low toxicity after the adsorption process. Performance of both materials was compared with that of other literature studies.
Integrated Genome-Wide Methylation and Expression Analyses Reveal Key Regulators in Osteosarcoma
Authors: Wang Fei , Qin Guoqing , Liu Junzhi , Wang Xiunan , Ye Baoguo
Published: August 2020

Osteosarcoma (OS) is one of the most common types of primary bone tumors in early adolescence with unsatisfied prognosis. Aberrant DNA methylation had been demonstrated to be related to tumorigenesis and progression of multiple cancers and could serve as the potential biomarkers for the prognosis of human cancers. In conclusion, this study identified 18 downregulated hypomethylation genes and 52 upregulated hypomethylation genes in OS by integrating the analysis the GSE97529 and GSE42572 datasets. Bioinformatics analysis revealed that OS-specific methylated genes were involved in regulating multiple biological processes, including chemical synaptic transmission, transcription, response to drug, and regulating immune response. KEGG pathway analysis showed that OS-specific methylated genes were associated with the regulation of Hippo, cAMP calcium, MAPK, and Wnt signaling pathways. By analyzing R2 datasets, this study showed that the dysregulation of these OS-specific methylated genes was associated with the metastasis-free survival time in patients with OS, including CBLN4, ANKMY1, BZW1, KRTCAP3, GZMB, KRTDAP, LY9, PFKFB2, PTPN22, and CLDN7. This study provided a better understanding of the molecular mechanisms underlying the progression and OS and novel biomarkers for the prognosis of OS.
Beta-Blockers and Berberine: A Possible Dual Approach to Contrast Neuroblastoma Growth and Progression
Authors: Calvani Maura , Subbiani Angela , Bruno Gennaro , Favre Claudio
Published: August 2020

The use of nutraceuticals during cancer treatment is a long-lasting debate. Berberine (BBR) is an isoquinoline quaternary alkaloid extracted from a variety of medicinal plants. BBR has been shown to have therapeutic effects in different pathologies, particularly in cancer, where it affects pathways involved in tumor progression. In neuroblastoma, the most common extracranial childhood solid tumor, BBR, reduces tumor growth by regulating both stemness and differentiation features and by inducing apoptosis. At the same time, the inhibition of β-adrenergic signaling leads to a reduction in growth and increase of differentiation of neuroblastoma. In this review, we summarize the possible beneficial effects of BBR in counteracting tumor growth and progression in various types of cancer and, in particular, in neuroblastoma. However, BBR administration, besides its numerous beneficial effects, presents a few side effects due to inhibition of MAO A enzyme in neuroblastoma cells. Therefore, herein, we proposed a novel therapeutic strategy to overcome side effects of BBR administration consisting of concomitant administration of BBR together with β-blockers in neuroblastoma.
A Comparative Study on Current- and Voltage-Optimized Circuit Scheme for Multiple-Transmitter and Single-Receiver WPT System
Authors: Zhang Jin , Xu Weiao , Chen Dong , Zhang Chen
Published: August 2020

As an important structural system for effectively improving power delivered to the load (PDL) and power transmission range, multiple-transmitter (TX) and single-receiver (RX) wireless power transfer (WPT) system is gaining more and more attention in both academic circles and the industrial fields. Based on the Lagrange multiplier method, this paper first provides a current- and voltage-optimized circuit scheme to maximize the PDL of the multiple-TX WPT system. Then, for a determined WPT system, the current-optimized circuit scheme is proposed to maximize the PDL effectively with constant source voltages and feeding currents for TXs. While voltage-optimized circuit scheme can effectively adjust the source voltages and feeding currents and maintain the same level of input power and PDL as a current-optimized solution. Through comparative study, the voltage-optimized solution shows its advantages in adjustable source voltage and feeding current without any degradation of PDL. Finally, the theoretical analysis results are confirmed by the results of full-wave electromagnetic simulation.
Evolutionary Dynamics of Interfirm Cooperative System for Radical Innovation from Knowledge Collaboration Perspective
Authors: Li Jinsheng , Shi Yi , Xu Lu
Published: August 2020

Interfirm cooperation can be seen as a significant and effective way for exploring radical innovation. In this article, a framework of interfirm cooperation, with a core manufacture and upstream counterparties in industry, and its evolving mechanism in the reverse-chain radical innovation are established from the perspective of the fundamental role played by knowledge collaboration. Then, an evolution model of interfirm cooperation is constructed on the theory of vibration mechanics, and its evolutionary dynamics is explored through numerical and simulation analysis mainly on the key factors of knowledge potential difference and knowledge rent-seeking behaviour within the firms. The findings show that, if there is no knowledge-based rent-seeking behaviour from the upstream firms, the probable innovative performance from the interfirm cooperation should vary for the knowledge potential difference between the cooperative firms, but can come to a certain equilibrium state. Meanwhile, if the knowledge rent-seeking behaviour does exist, knowledge potential difference would lead the innovative performance evolving ultimately in divergence. What’s more, the negative effect caused by the rent-seeking behaviour could be alleviated or weakened to some extent by the excitation mechanisms presented by the core firms in the cooperation system. Therefore, the drawn conclusions should be useful for the core manufactures’ implementing various strategies to maintain or enhance the cooperation for radical innovation in industry.
Reinforcement Learning-Based Routing Protocol to Minimize Channel Switching and Interference for Cognitive Radio Networks
Authors: Safdar Malik Tauqeer , Hasan Mohd Hilmi
Published: August 2020

In the existing network-layered architectural stack of Cognitive Radio Ad Hoc Network (CRAHN), channel selection is performed at the Medium Access Control (MAC) layer. However, routing is done on the network layer. Due to this limitation, the Secondary/Unlicensed Users (SUs) need to access the channel information from the MAC layer whenever the channel switching event occurred during the data transmission. This issue delayed the channel selection process during the immediate routing decision for the channel switching event to continue the transmission. In this paper, a protocol is proposed to implement the channel selection decisions at the network layer during the routing process. The decision is based on past and expected future routing decisions of Primary Users (PUs). A learning agent operating in the cross-layer mode of the network-layered architectural stack is implemented in the spectrum mobility manager to pass the channel information to the network layer. This information is originated at the MAC layer. The channel selection is performed on the basis of reinforcement learning algorithms such as No-External Regret Learning, Q-Learning, and Learning Automata. This leads to minimizing the channel switching events and user interferences in the Reinforcement Learning- (RL-) based routing protocol. Simulations are conducted using Cognitive Radio Cognitive Network simulator based on Network Simulator (NS-2). The simulation results showed that the proposed routing protocol performed better than all the other comparative routing protocols in terms of number of channel switching events, average data rate, packet collision, packet loss, and end-to-end delay. The proposed routing protocol implies the improved Quality of Service (QoS) of the delay sensitive and real-time networks such as Cellular and Tele Vision (TV) networks.
Hematopoietic Stem Cells and Mesenchymal Stromal Cells in Acute Radiation Syndrome
Authors: Qian Liren , Cen Jian
Published: August 2020

With the extensive utilization of radioactive materials for medical, industrial, agricultural, military, and research purposes, medical researchers are trying to identify new methods to treat acute radiation syndrome (ARS). Radiation may cause injury to different tissues and organs, but no single drug has been proven to be effective in all circumstances. Radioprotective agents are always effective if given before irradiation, but many nuclear accidents are unpredictable. Medical countermeasures that can be beneficial to different organ and tissue injuries caused by radiation are urgently needed. Cellular therapy, especially stem cell therapy, has been a promising approach in ARS. Hematopoietic stem cells (HSCs) and mesenchymal stromal cells (MSCs) are the two main kinds of stem cells which show good efficacy in ARS and have attracted great attention from researchers. There are also some limitations that need to be investigated in future studies. In recent years, there are also some novel methods of stem cells that could possibly be applied on ARS, like “drug” stem cell banks obtained from clinical grade human induced pluripotent stem cells (hiPSCs), MSC-derived products, and infusion of HSCs without preconditioning treatment, which make us confident in the future treatment of ARS. This review focuses on major scientific and clinical advances of hematopoietic stem cells and mesenchymal stromal cells on ARS.
Air Gesture Recognition Using WLAN Physical Layer Information
Authors: Dang Xiaochao , Liu Yang , Hao Zhanjun , Tang Xuhao , Shao Chenguang
Published: August 2020

In recent years, the researchers have witnessed the important role of air gesture recognition in human-computer interactive (HCI), smart home, and virtual reality (VR). The traditional air gesture recognition method mainly depends on external equipment (such as special sensors and cameras) whose costs are high and also with a limited application scene. In this paper, we attempt to utilize channel state information (CSI) derived from a WLAN physical layer, a Wi-Fibased air gesture recognition system, namely, WiNum, which solves the problems of users’ privacy and energy consumption compared with the approaches using wearable sensors and depth cameras. In the process of recognizing the WiNum method, the collected raw data of CSI should be screened, among which can reflect the gesture motion. Meanwhile, the screened data should be preprocessed by noise reduction and linear transformation. After preprocessing, the joint of amplitude information and phase information is extracted, to match and recognize different air gestures by using the S-DTW algorithm which combines dynamic time warping algorithm (DTW) and support vector machine (SVM) properties. Comprehensive experiments demonstrate that under two different indoor scenes, WiNum can achieve higher recognition accuracy for air number gestures; the average recognition accuracy of each motion reached more than 93%, in order to achieve effective recognition of air gestures.
Transient Pulse Test for Non‐Darcy Flow Behaviors and Hydromechanical Coupling Effect of Fractured Limestone
Authors: Cheng JianChao , Zhao YanLin , Li Yang , Tan Tao , Chang Le
Published: August 2020

In this paper, the transient pulse test is used to study the permeability and hydromechanical coupling effect of the fractured limestone. The permeability parameters (permeability, β factor of non‐Darcy flow, and acceleration coefficient) of non‐Darcy flow in fractured limestone are obtained by experimental data. The experimental results show that, in the process of transient seepage test of fractured Maokou limestone, the relationship between hydraulic pressure gradient and seepage velocity does not conform to Darcy’s law but meets Forchimer relationship. The relationship between hydraulic pressure difference and time can be fitted by quartic polynomial. The larger the confining pressure is, the more obvious the non‐Darcy seepage effect of fractured rock seepage is. The seepage of rock fracture under high confining pressure is a highly nonlinear time‐varying seepage. The permeability coefficient of rock decreases with the increase of volume stress. Under the action of low volume stress, the relationship between permeability coefficient and stress is more sensitive, while under the action of high volume stress, the relationship between permeability coefficient and volume stress is not significant. In the process of volume stress increasing, the β factor of non‐Darcy flow appears negative. Under the action of low volume stress, the acceleration coefficient and β factor of non‐Darcy flow increase, while under the action of high volume stress, the acceleration coefficient and β factor of non‐Darcy flow decrease.
Study on the Large Deformation Characteristics and Disaster Mechanism of a Thin‐Layer Soft‐Rock Tunnel
Authors: Zhang Xiulian , He Manchao , Wang Fengnian , Li Gan , Xu Shengxin , Tao Zhigang
Published: August 2020

In view of the large deformation of thin‐layer soft rock in the No. 2 inclined shaft of the Muzhailing Tunnel, we performed an experimental investigation on the mineral composition, physical characteristics, and uniaxial compressive strength of the surrounding rock of the tunnel. The characteristics of the large deformation of the surrounding rock of the tunnel were analyzed, and the main factors influencing the deformation of the tunnel were revealed. The influence of various factors on the large deformation of the surrounding rock was analyzed using the 3DEC‐Trigon discrete element numerical simulation method. The results show that (1) the deformation of the surrounding rock of the tunnel has remarkable asymmetry, the deformation of the initial support of the tunnel is significant, and the buried depth of the area where the maximum deformation of the tunnel exceeded 1 m is greater than 500 m; (2) the main factors influencing the deformation of a thin‐layer slate tunnel include joint inclination, buried depth, water absorption, and softening of the surrounding rock; and (3) the maximum deformation of the surrounding rock is observed for a joint angle of 45°, at which the buried depth is directly proportional to the deformation and failure of the tunnel. Furthermore, after the surrounding rock was softened by water absorption, the floor of the tunnel, the left shoulder socket, and the right side of the tunnel are deformed greatly. The results of this study will provide a theoretical basis for the study of similar deformation control methods and supporting measures for tunnels excavated in thin‐layer soft rock.
A Discussion of Reinforcement Timing Optimization for Main Inclined Shaft Roadway with Water Seepage
Authors: Zhang Minglei , Chang Chaoyu , Cao Wen
Published: August 2020

The infiltration and physical and chemical effects of fissure water often have a degrading effect on the strength and bearing capacity of the surrounding rock of the roadway. With the increase of the time of water infiltration, the roadway deformation increases exponentially, resulting in a higher risk of roadway destruction. In this paper, targeting at the supporting and protection issues associated with the main inclined shaft during the water-drenching, a numerical simulation method was established to evaluate the impact of the fissure water on the deformation of the surrounding rock of the roadway, and a solution to control the top water in main inclined shafts by grouting was proposed. Through the numerical simulation method, the effective penetration range of the slurry in the surrounding rock and the variation of the tunnel deformation with the grouting timing were studied. A method of combining numerical simulation with on-site monitoring to determine a reasonable grouting timing was proposed. The field application suggests that grouting at a reasonable timing can effectively control the influence of seepage water from the roof crack of the main inclined shaft on the deformation of the roadway surrounding rock, improve the integrity of the roadway surrounding rock, increase the bearing capacity of the support, and maintain the safety and stability of the roadway surrounding rock of the main inclined shaft. Furthermore, this study can provide insightful references to the grouting reinforcement adopted by similar main inclined shafts.
Energy Dissipation-Based Method for Strength Determination of Rock under Uniaxial Compression
Authors: He M. M. , Pang F. , Wang H. T. , Zhu J. W. , Chen Y. S.
Published: August 2020

The energy conversion in rocks has an important significance for evaluation of the stability and safety of rock engineering. In this paper, some uniaxial compression tests for fifteen different rocks were performed. The evolution characteristics of the total energy, elastic energy, and dissipated energy for the fifteen rocks were studied. The dissipation energy coefficient was introduced to study the evolution characteristics of rock. The evolution of the dissipation energy coefficient for different rocks was investigated. The linear interrelations of the dissipation energy coefficients and the yield strength and peak strength were explored. The method was proposed to determine the strength of rock using the dissipation energy coefficients. The results show that the evolution of the dissipation energy coefficient exhibits significant deformation properties of rock. The dissipation energy coefficients linearly increase with the compaction strength, but decrease with the yield strength and peak strength. Moreover, the dissipation energy coefficient can be used to determine the rock burst proneness and crack propagation in rocks.
Experimental Investigation on Strength and Deformation Characteristics of Red Sandstone at Strain Rates of 10−2∼55 s−1
Authors: Shi Jie , Luo Zongmu , Liu Huachao , Wang Dan , Shen Haipeng , Li Zeng
Published: August 2020

The mechanical properties of rocks under low to intermediate strain rate are of great importance for seismic engineering, rock impact, and blasting excavation. To study the strength and deformation characteristics of sandstone subjected to low‐medium speed impact loading, the complete stress‐strain relationships of uniaxial compression at strain rates of 10−2∼55 s−1 were obtained utilizing MTS and drop weight impact test devices. It is indicated that the dynamic compressive strength of sandstone in the range of intermediate strain rate increases approximately linearly with the strain rate under the quasi‐static loading condition, while increasing nonlinearly under the dynamic loading condition. The deformation and fracture process of sandstone still consists of pore compaction stage, elastic deformation stage, instable microcrack propagation stage, and brittle fracture stage. The peak stress, critical strain, and residual strain increase with an increase in the strain rate, and the corresponding fracture mode changes from shear failure to split failure. The evolution law of total absorbed strain energy with deformation coincides with that of stored elastic strain energy for sandstone at the intermediate strain rate. The effect of the strain rate on elastic strain energy is more significant than that of dissipated strain energy. Furthermore, both the brittleness and fracture degree of sandstone become more remarkable with the strain rate increasing.
Small Extracellular Vesicles from Human Fetal Dermal Cells and Their MicroRNA Cargo: KEGG Signaling Pathways Associated with Angiogenesis and Wound Healing
Authors: Chinnici Cinzia Maria , Amico Giandomenico , Gallo Alessia , Iannolo Gioacchin , Cuscino Nicola , Vella Serena , Carcione Claudia , Nascari David , Conaldi Pier Giulio
Published: August 2020

The use of cell secreted factors in clinical settings could be an alternative to conventional cell therapy, with the advantage of limiting concerns generally associated with traditional cell transplantation, such as tumorigenicity, immunoreactivity, and carrying of infections. Based on our published data, we predict a potential role for extracellular vesicles (EVs) in contributing to the proangiogenic activity of human fetal dermal cell secretome. Depletion of nanosized EVs from secretome significantly impaired its ability to induce formation of mesh-like structures in vitro. The isolated EVs were characterized for size and concentration by nanoparticle tracking analysis, and for protein markers (Rab5+, Alix+, CD63+, and calnexin-). The microRNA profile of EVs revealed 87 microRNAs significantly upregulated (≥15-fold increase) in fetal compared to adult dermal cell-derived EVs. Interestingly, these upregulated microRNAs included microRNAs with a validated role in angiogenesis according to literature. Moreover, the DIANA-TarBase v7.0 analysis confirmed enrichment in the KEGG signaling pathways associated with angiogenesis and wound healing, with the identification of putative target genes including thrombospondin 1. To validate the in silico data, EVs were also characterized for total protein contents. When tested in in vitro angiogenesis, fetal dermal cell-derived EVs were more effective than their adult counterpart in inducing formation of complete mesh-like structures. Furthermore, treatment of fibroblasts with fetal dermal-derived EVs determined a 4-fold increase of thrombospondin 1 protein amounts compared with the untreated fibroblasts. Finally, visualization of CSFE-labeled EVs in the cytosol of target cells suggested a successful uptake of these particles at 4-8 hours of incubation. We conclude that EVs are important contributors of the proangiogenic effect of fetal dermal cell secretome. Hence, EVs could also serve as vehicle for a successful delivery of microRNAs or other molecules of therapeutic interest to target cells.
The Effects of 1 mA tACS and tRNS on Children/Adolescents and Adults: Investigating Age and Sensitivity to Sham Stimulation
Authors: Splittgerber Maike , Suwelack Jan Hendrik , Kadish Navah Ester , Moliadze Vera
Published: August 2020

The aim of this study was to investigate the effect of transcranial random noise (tRNS) and transcranial alternating current (tACS) stimulation on motor cortex excitability in healthy children and adolescents. Additionally, based on our recent results on the individual response to sham in adults, we explored this effect in the pediatric population. We included 15 children and adolescents (10–16 years) and 28 adults (20–30 years). Participants were stimulated four times with 20 Hz and 140 Hz tACS, tRNS, and sham stimulation (1 mA) for 10 minutes over the left M1HAND. Single-pulse MEPs (motor evoked potential), short-interval intracortical inhibition, and facilitation were measured by TMS before and after stimulation (baseline, 0, 30, 60 minutes). We also investigated aspects of tolerability. According to the individual MEPs response immediately after sham stimulation compared to baseline (Wilcoxon signed-rank test), subjects were regarded as responders or nonresponders to sham. We did not find a significant age effect. Regardless of age, 140 Hz tACS led to increased excitability. Incidence and intensity of side effects did not differ between age groups or type of stimulation. Analyses on responders and nonresponders to sham stimulation showed effects of 140 Hz, 20 Hz tACS, and tRNS on single-pulse MEPs only for nonresponders. In this study, children and adolescents responded to 1 mA tRNS and tACS comparably to adults regarding the modulation of motor cortex excitability. This study contributes to the findings that noninvasive brain stimulation is well tolerated in children and adolescents including tACS, which has not been studied before. Finally, our study supports a modulating role of sensitivity to sham stimulation on responsiveness to a broader stimulation and age range.
Some Trapezium-Like Inequalities Involving Functions Having Strongly n-Polynomial Preinvexity Property of Higher Order
Authors: Awan Muhammad Uzair , Talib Sadia , Noor Muhammad Aslam , Chu Yu-Ming , Noor Khalida Inayat
Published: August 2020

The main objective of this paper is to introduce a new class of preinvex functions which is called as n-polynomial preinvex functions of a higher order. As applications of this class of functions, we discuss several new variants of trapezium-like inequalities. In order to obtain the main results of the paper, we use the concepts and techniques of k-fractional calculus. We also discuss some special cases of the obtained results which show that the main results of the paper are quite unifying one.
Abstract A02: Photodynamic therapy in combination with immunotherapy enhances the long-term cure of bladder cancer in tumored mice
Authors: Durrani Farukh , Aly Ahmed , Guru Khurshid , Pandey Ravindra
Published: August 2020

Introduction and Objectives: To investigate the utility of combination approach for treating bladder cancer, mice bearing UMUC3 (human transitional cell carcinoma) and T24 (human urinary bladder) tumors were treated with HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a)-PDT alone and in combination with BCG. The HPPH, a multifunctional agent, was selected as a photosensitizer because of its higher tumor avidity, improved fluorescence imaging ability, and limited skin phototoxicity than Photofrin, a current clinical standard.

Methods: Imaging: IVIS/Spectrum: A noninvasive in vivo, continuous wave fluorescence imaging apparatus used to assess the localization and distribution of the PS at variable time points. In vivo efficacy studies using UMUC3 and T24 tumors in SCID mice with PS HPPH in combination with BCG.

Results: Imaging: Tumor uptake in UMUC3 and T24 tumors using IVIS Imaging. PS HPPH showed high tumor uptake and significant difference in their pharmacokinetic profiles in UMUC3 and T24 tumors implanted in SCID mice: The SCID mice bearing either UMUC3 or T24 tumors (4-5 mm size) were injected with the PS HPPH. The tumored mice (3 mice/group) at a dose of 0.47 u-mol/kg) and imaged at variable time points. The uptake of tumor, liver, and skin was measured by IVIS system and interesting pharmacokinetic profiles of the PS were observed. The optimal tumors uptake in UMUC3 and T24 were at 24 hours and 8-12 hours, respectively. In vivo efficacy studies: PS (HPPH) in combination with BCG shows enhanced PDT efficacy CR (Cures) Day 30 = 14/22 = 63.6% and RG (Re-Growth) 6/22 = 36.4% in bladder tumors (UMUC3). To investigate the utility of combination treatment approach for treating bladder cancer, mice bearing UMUC3 tumors were injected intravenously with HPPH (0.47 u-mol/kg) and the tumors were exposed to laser light (135 J/cm2, 75 mW/cm2) at 24 h post-injection. One hour after the PDT treatment, BCG was injected (1-1.5 × 106 CFU), SQ weekly x 3 doses, and at day 30 the results are very encouraging.

Conclusions: The HPPH showed higher in vivo uptake (determined by fluorescence) in UMUC3 and T24 bladder cancer tumors with significant differences in the two tumor types. The treatment of HPPH-PDT in combination with BCG using SCID mice bearing UMUC3 tumors showed enhanced long-term tumor cure. Before initiating this approach to human phase I clinical trial, further studies are under way. Source of funding: Roswell Park Alliance Foundation.

Citation Format: Farukh Durrani, Ahmed Aly, Khurshid Guru, Ravindra Pandey. Photodynamic therapy in combination with immunotherapy enhances the long-term cure of bladder cancer in tumored mice [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A02.
Abstract A04: DNA damage repair gene mutations and associated tumor immune landscape as biomarkers of response to immunotherapy in muscle-invasive urothelial cancer
Authors: Vidotto Thiago , Nersesian Sarah , Graham Charles , Siemens David Robert , Koti Madhuri
Published: August 2020

Molecular subtyping of urothelial cancer (UC) has significantly advanced the understanding of bladder tumor heterogeneity and development of prognostic and predictive biomarkers. Evolving evidence across cancers strongly suggests that tumor immunoediting has a profound impact on the behavior of cancer cells and their adaptation to the coevolving microenvironment and response to treatment. In alignment with this concept, recent immune checkpoint blockade (ICB) therapies in UC have demonstrated the predictive potential of mutations in the DNA damage repair (DDR). A comprehensive understanding of DDR mutation-associated expression of immune regulatory genes could thus aid in expansion of current immunotherapies and predictive biomarkers for the design of patient-tailored combination treatments. We thus investigated the pretreatment tumor transcriptomic profiles of the five recently described molecular subtypes of muscle-invasive urothelial cancer (MIUC; n=408) from the Genomic Data Commons, to determine subtype-specific immune cell abundance, expression of 67 immune regulatory genes, and association with DDR gene mutation profiles. Analysis using CIBERSORT immune cell abundance determination tool showed significant differences in immune cell profiles and abundance between MIUC subtypes. Expression patterns of a selected panel of 67 genes including both immune-stimulatory and -inhibitory genes showed significant associations with subtypes and DDR mutation status. Findings from our study provide compelling evidence for coexpression of multiple immune checkpoint genes including PD-1, PD-L1, IDO1, TIGIT, TIM-3, TGFB1, LAG3, and others, that potentially contribute to compensatory immune evasion in bladder tumors. Our findings also emphasize the urgent need for biomarker discovery approaches that combine molecular subtype, DDR gene mutation status, tumor immune landscape classification, and immune checkpoint gene expression to increase the number of patients responding to immunotherapies.

Citation Format: Thiago Vidotto, Sarah Nersesian, Charles Graham, David Robert Siemens, Madhuri Koti. DNA damage repair gene mutations and associated tumor immune landscape as biomarkers of response to immunotherapy in muscle-invasive urothelial cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A04.
Abstract A11: Generation and characterization of immune-competent syngeneic model of muscle-invasive bladder cancer (MIBC)
Authors: Shah Shruti D. , Gillard Bryan , Karasik Ellen , Wrobel Michelle , Moser Michael T. , Foster Barbara A.
Published: August 2020

Immunologically, MIBC tumors can be divided into inflamed and noninflamed phenotype. Inflamed tumors show high immune cell infiltration. In contrast, noninflamed tumors have little to no immune infiltration. Clinical evidence shows that response to therapy, particularly immune therapy, is associated with the immune phenotype of the tumor. In our preliminary analysis of the TCGA tumor expression data, we observed that patients with high CD8 T-cell infiltration expression signature show an improved overall survival irrespective of treatment. To study the molecular and immunologic drivers of CD8+ T-cell tumor infiltration in MIBC, we have generated immune-competent syngeneic models of bladder cancer. The mouse models were generated by inducing invasive disease by treating C57BL/6 mice with carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). The induced tumors were grafted into sex-matched immune-competent syngeneic hosts establishing allograft tumor lines. The models represent different clinical subtypes both molecularly and histologically. Currently we have 8 different models with squamous, sarcamatoid, or a more differentiated phenotype. RNA-seq analysis of the tumor lines was used to classify the models into basal-like and luminal-like tumors using the TCGA classifier system. Using the RNA-seq data, we applied a deconvolution algorithm to identify models that had inflamed or noninflamed immune phenotype. Flow cytometry data indicate that the inflamed tumors have a higher infiltration of the myeloid population. We treated 4/8 models with cisplatin, the current standard of care. The models show variable response to cisplatin, indicating the variability between the different models. In conclusion, we have successfully developed immune-competent syngeneic mouse models of MIBC that can be used to study the molecular and immune-driven processes of the disease.

Citation Format: Shruti D. Shah, Bryan Gillard, Ellen Karasik, Michelle Wrobel, Michael T. Moser, Barbara A. Foster. Generation and characterization of immune-competent syngeneic model of muscle-invasive bladder cancer (MIBC) [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A11.
Abstract A15: Uninflamed immunologic microenvironment of muscle-invasive bladder cancer associates with activating FGFR3 gene alterations
Authors: Weyerer Veronika , Stoehr Robert , Strissel Pamela , Strick Reiner , Bolenz Christian , Hartmann Arndt , Erben Philipp , Eckstein Markus
Published: August 2020

Background and Objective: Muscle-invasive bladder cancer (MIBC) is a complex disease for which perioperative chemotherapy followed by radical cystectomy is a standard treatment. In recent years new therapy options for advanced urothelial tumors have emerged, representing a personalized medicine approach for patients. For example, targeting fibroblast growth factor receptors (FGFR) as well as restoring antitumor activity using PD-1/PD-L1 inhibitors are currently being evaluated in clinical trials and show promising results. Our present goal in this study was to assess the relationship of FGFR3-gene alterations, immune cell types, gene expression of checkpoint inhibitors like PD-L1/PD-1, and immune-related genes in MIBC to gain insight into significant differential expression.

Materials and Methods: We analyzed the TCGA cohort (n=407). Tumors were identified with activating FGFR3-gene alterations (FGFR3-altered: mutation, amplification, fusion, gain). A comparison was performed between tumors with FGFR3-altered or wild-type tumors and tumor mutational burden (TMB), neoantigen load, immune checkpoint, and immune-related gene expression as well as specific immune cell populations using the CIBERSORT-algorithm.

Results: Activating FGFR3-altered tumors showed significantly less TMB and neoantigen load compared to wild-type cases (p=0.037 and p=0.04). Tumors with high expression of PD-1, PD-L1, CTLA4, and IDO1 were predominately not FGFR3-altered (p<0.0001). Additionally, expression of immune-related genes like CD3Z, CD8A, FOXP3 and amounts of specific immune cell populations were significantly inversely associated with an FGFR3-altered status.

Conclusion: Strikingly, our analysis demonstrates that activating FGFR3 gene alterations in MIBC show low immune checkpoint and immune-related gene expression as well as low amounts of immune cells, demonstrating association with an uninflamed tumor microenvironment. Therefore, combination therapies targeting FGFR3 and, e.g., PD-1/PD-L1 might not be effective. It will be essential to validate these results in another MIBC cohort as well as unravel the role of aberrant signaling of FGFR3.

Citation Format: Veronika Weyerer, Robert Stoehr, Pamela Strissel, Reiner Strick, Christian Bolenz, Arndt Hartmann, Philipp Erben, Markus Eckstein. Uninflamed immunologic microenvironment of muscle-invasive bladder cancer associates with activating FGFR3 gene alterations [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A15.
Abstract A16: Characterization of ErbB family expression in intratibial bladder cancer xenografts: Considerations for preclinical modeling
Authors: Broses Luke J. , Day Kathleen C. , Udager Aaron M. , Day Mark L.
Published: August 2020

Background: Approximately 40% of patients with distant metastatic bladder cancer are diagnosed with bone metastases and a dismal 5-year survival rate of less than 10%. The bone has long been thought to act as “soil” for metastatic cells to “seed,” likely due to the favorable, albeit complex microenvironment that comprises various cell types and growth factors. A study by The Cancer Genome Atlas (TCGA) profiling 405 muscle-invasive bladder cancers reported alterations of the receptor tyrosine kinase pathway in 20% of these patients. This included amplification of EGFR in 9% of cases, mutation or amplification of ERBB2 in 9% of cases, and mutation of ERBB3 in 6% of cases. The purpose of this study was to correlate the expression of ErbB family members in human bladder cancer cell lines with their ability to grow as intratibial xenografts in immune-compromised mice.

Methods: We performed intratibial injections with six established human bladder cancer cell lines in 22 NSG mice and we allowed these xenografts to grow for five weeks. Four cell lines expressed luciferase and were measured for bioluminescent signals at multiple time points. The resulting formalin-fixed, paraffin-embedded tibiae were processed for immunohistochemistry (IHC) which utilized human specific antibodies to CK8, EGFR, HER2, Ki-67, and uroplakin.

Results: The four luciferase-expressing cell lines exhibited increasing bioluminescent signal over the duration of the study (n=14). Five cell lines had positive human anti-Ki-67 staining in the tibia, confirming their growth in the bone after the intratibial injection. All five cell lines maintained expression, and in certain cases overexpression, of EGFR and HER2 in the intratibial xenografts. We observed an 87.5% take rate (n=16) in a subset of bladder cell lines (5 out of 6) and only the UM-UC-12 cell line exhibiting a 0% take rate (n=6).

Conclusion: The high take rate of these five cell lines in the tibia exceeded that of previous studies (25-50%), indicating that the take rate is cell line dependent. Characterizing the ErbB expression profile of individual cell lines in the tibia xenograft model is an important consideration before using these xenografts as a preclinical model. Furthermore, ubiquitous expression of ErbB receptors in tibiae xenografts highlights the importance of growth factor signaling in metastatic bladder cancer and the potential for ErbB targeted therapy.

Citation Format: Luke J. Broses, Kathleen C. Day, Aaron M. Udager, Mark L. Day. Characterization of ErbB family expression in intratibial bladder cancer xenografts: Considerations for preclinical modeling [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A16.
Abstract A20: Disruption and restoration of pioneer transcription factor function in bladder cancer
Authors: Schuerger Caroline , Gu Xiaorong , Parker Yvonne , Lindner Daniel , Jha Babal
Published: August 2020

Urothelial bladder cancer (BLCA) is characterized by the failure to complete epithelial-differentiation. The mechanisms underlying this failure are unknown. To address this knowledge gap, we used unbiased analyzes to identify 1,000 genes significantly suppressed in BLCA vs normal bladder (p<0.001, FDR<0.01) (n=426, TCGA RNA-seq). Remarkably, these genes are located in compacted chromatin in embryonic stem cells (ESC) (decreased H3K4me3, increased CpG methylation), while 1,000 genes upregulated in BLCA vs normal bladder are located in open chromatin at this same ultimate baseline. This striking pattern in unbiased analyses suggested pioneer transcription factor (TF) loss of function in BLCA: pioneer TF access compacted chromatin to initiate the remodeling necessary for gene activation. The pioneer TF hub containing FOXA1, GATA4 is highly expressed in normal bladder, and these pioneer TFs are frequently haploinsufficient in BLCA, 32% and 56%, respectively. We pulled down endogenous FOXA1, the most expressed TF, from UM-UC-6 BLCA cells. Proteomic analyzes by mass spectrometry revealed enrichment for corepressors (DNMT1) over coactivators (ARID1A) in this pioneer TF hub. Genetic analyses showed frequent mutation/deletion of the coactivators: 43% bi-allelic ARID1A inactivation, while corepressors, e.g., CHD4 and DNMT1, were amplified or unaltered. Restoration of ARID1A into UM-UC-6 upregulated epithelial genes, downregulated MYC, upregulated CDKN1B, and terminated proliferation. To translate into therapy, we confirmed using immunoprecipitation LCMS/MS that DNMT1-depletion using noncytotoxic concentrations of the clinical drug decitabine (0.2-0.5 μM) shifted hub composition to coactivators, to thereby induce terminal epithelial-differentiation of BLCA cells. This was also seen in vivo in UM-UC-6 xenograft: very low dose non-cytotoxic decitabine (0.1 mg/kg) combined with an inhibitor of its degradation, THU, decreased tumor size more than standard high-dose cytotoxic gemcitabine/cisplatinum. Thus, BLCA suppresses hundreds of epithelial-differentiation genes via corepressor/coactivator imbalance in the bladder pioneer TF hub. Sensitivity of the pioneer TF hub to corepressor/coactivator stoichiometry, however, also enables pharmacologic reduction of corepressors to compensate for genetic reduction of coactivators, to thereby release BLCA cells to destined terminal epithelial fates.

Citation Format: Caroline Schuerger, Xiaorong Gu, Yvonne Parker, Daniel Lindner, Babal Jha. Disruption and restoration of pioneer transcription factor function in bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A20.