bluuebunny/crossref_metadata_2025 huggingface dataset:
Розвиток права у Західноукраїнській Народній Республіці (1918–1919 роки)
Authors: ТИЩИК БОРИС
Published: February 2020

У статті проаналізовано становлення у листопаді 1918 р. Західноукраїнської Народної Республіки (ЗУНР), з часу проголошення і діяльності якої у 2018–2019 рр. минуло 100 років.
Мета статті – розглянути історичну долю Галичини перших десятиліть ХХ ст. Значну увагу зосереджено на характеристиці особливостей становлення права ЗУНР (прийняття тимчасової Конституції, конституційних законів про громадянство, про державну мову (українську), про встановлення основних засад виборчого права (його загальність, рівність, таємність), про вибори до Галицького Сейму, серії законів із державного права (про структуру центральних і місцевих органів влади й управління, судоустрій країни, створення правоохоронних орга нів тощо).
Показано, що одним із найважливіших законів, прийнятих Українською Народною Радою (УН Рада), був “Тимчасовий основний закон про державну самостійність українських земель колишньої Австро-Угорської монархії”, який завершив процес конституційного оформлення новоствореної держави. Цей правовий акт забезпечив внутрішню легітимізацію влади та сформулював основні напрями розвитку ЗУНР як суверенної держави. З проголошенням новоствореної держави парламентською республікою було обґрунтовано принципи поділу влади на законодавчу, виконавчу та судову. Територія держави визначалася етнографічними межами проживання українців у складі Австро-Угорської імперії. Засадничими нормами Тимчасової конституції ЗУНР стало гарантування широких політичних і національних прав поляків, євреїв та німців. Тимчасовий характер Конституції обґрунтовувався необхідністю організації роботи Сейму республіки, до першочергових обов’язків якого і входило утвердження Основного закону держави.
УН Радою, урядом, державним секретарствами було прийнято ще чимало нормативно-правових актів із різних галузей державно-політичного, соціально-економічного, культурно-освітнього та інших галузей життя новоствореної української держави на західних землях України. Вживалися енергійні організаційні заходи щодо їх реалізації. Щоправда, довше, ніж вісім місяців, проіснувати, розвинутися, зміцнитися ЗУНР не зуміла: при прямій військовій і дипломатичній підтримці країн Антанти її окупувала Польща. Проте створення її правової основи, як і взагалі розвиток права у ЗУНР, заслуговує на увагу та схвалення навіть сьогодні.
Assessing the evidence of ‘infertile’ sea turtle eggs
Authors: Phillott AD , Godfrey MH
Published: February 2020

There is increasing concern about feminization of sea turtle populations resulting from female-biased production of hatchlings due to climate change and selective loss of males from other anthropogenic drivers. Extreme female-biased breeding populations would reduce the likelihood of successful mating and potentially result in high rates of infertile eggs. Infertile eggs are those in which none of the events between sperm penetration of the ovum and syngamy have occurred. Distinguishing between fertile and infertile eggs is challenging, especially in field conditions, and researchers often have relied on physical evidence gathered from unhatched eggs at the end of the incubation period, which likely have experienced tissue decomposition. We argue that infertility in sea turtle eggs can be demonstrated only by the absence of holes caused by sperm penetration of the inner perivitelline membrane; sperm bound between the inner and outer perivitelline membranes; nuclei in the blastodisc; embryonic tissue or membranes in egg contents; and/or the characteristic white spot on the egg exterior. Unhatched eggs can be examined at the end of the incubation period, but we recommend that studies specifically investigating infertility examine at least 20 oviposited eggs each from clutches laid by at least 20 different turtles at the peak of the nesting season.
PENERIMAAN FINANCIAL TECHNOLOGY BERBASIS TECHNOLOGY ACCEPTANCE MODEL (TAM)
Authors: Sutrisno Sutrisno , FAHLEFI Diva Riza , Sarbullah Sarbullah
Published: February 2020

Tecnology Acceptance Model (TAM) developed by Davis which is a successful and acceptable model in order to predict the acceptance of a new technology. In the last two years, in Indonesia there has emerged a financial technology service that was designed with the open platform principle, OVO. OVO is a service engaged in the field of financial technology, is a smart application designed to make payment services and transactions online, and has penetrated into all business expansion. The purpose of this research is to find out. the effect of perceived ease, perceived risk and attitude of use on the intention of OVO financial technology behavior in Surakarta City.

The population used in this study were all users who intended to use OVO financial technology behavior in Surakarta City amounted to 140. The sample used in this study were 60 people. Data analysis methods used are descriptive statistical analysis, validity test, Classic Assumption Test, multiple regression analysis, t-test statistics and the model feasibility test and the coefficient of determination.

The results of this study indicate that perceptions of ease have a positive and significant influence on the behavioral intention of OVO financial technology in the city of Surakarta with a significance of 0,000 <0.05. perceived risk has a positive and significant effect on the intention of OVO financial technology behavior in Surakarta City with a significance of 0.002 <0.05. usage attitude has a positive and significant influence on the intention of OVO financial technology behavior in Surakarta City with a significance of 0,000 <0.05. This means that all variables affect the intention of OVO financial technology behavior in Surakarta City.

Seeing the results of the research conclusions, that Behavioral Intetion of the users stated that those interested in using OVO financial technology applications with the advantages offered such as free transfers
PENGARUH FIRM SIZE, SALES GROWTH, STRUKTUR ASET, DAN PROFITABILITAS TERHADAP NILAI PERUSAHAAN DENGAN STRUKTUR MODAL SEBAGAI VARIABEL INTERVENING (Studi Empiris Pada Perusahaan Manufaktur yang Terdaftar di Bursa Efek Indonesia (BEI) Periode 2012 – 2017)
Authors: Atiningsih Suci , Wahyuni Asri Nur
Published: February 2020

The purpose of this study is to examine the effect of firm size, sales growth, asset structure, and profitability on firm value with capital structure as an intervening variable. The population are all companies listed on the Indonesia Stock Exchange. While the sample in this study were all manufacturing companies listed on the Indonesia Stock Exchange Period 2012 - 2017. Sampling using purposive sampling and data analysis methods using multiple linear regression and path analysis. The results of this study are firm size and asset structure have a positive effect on capital structure. Sales growth and profitability have a negative effect on capital structure. Capital structure, sales growth, and asset structure have a negative effect on firm value. Firm size has a positive effect on company value. Capital structure cannot mediate the influence of firm size and profitability on firm value. Capital structure can mediate the effect of sales growth and asset structure on firm value.
Domestic Foal Weaning: Need for Re-Thinking Breeding Practices?
Authors: Henry Séverine , Sigurjónsdóttir Hrefna , Klapper Aziliz , Joubert Julie , Montier Gabrielle , Hausberger Martine
Published: February 2020

Artificial weaning is a standard practice known to be one of the most stressful events in a domestic foal’s life. Research has mainly focused on ways to alleviate weaning stress. However, there is still a need for more detailed research on what should constitute best practices with respect to animal welfare. The aim of this review is to address this issue by examining the natural weaning process. We first provide an overview of the scientific literature on the natural temporal dynamics of the dam-offspring bond in horses: it is to be noted that the natural process of weaning is little documented, individual variations have been poorly investigated and immediate effects of weaning on the mare–foal relationship remain unexplored. To partly address these gaps, we performed a study around the weaning period on 16 mare–foal pairs kept with minimal human interference. Most foals were weaned spontaneously when 9-10 months old, with individual variations mainly due to the conception rate of mares. Natural weaning induced no stress response in either partner and was performed without clear signs of rejection by the dams either just before or after. We lastly open up the discussion on the need for rethinking weaning practices under domestic conditions.
Critical Parameters for the Development of Novel Therapies for Severe and Resistant Infections—A Case Study on CAL02, a Non-Traditional Broad-Spectrum Anti-Virulence Drug
Authors: Azeredo da Silveira Samareh , Shorr Andrew F.
Published: February 2020

Background: Poor outcomes in severe and resistant infections, together with the economic struggles of companies active in the field of anti-infective development, call for new solutions and front runners with novel approaches. Among “non-traditional” approaches, blocking virulence could be a game changer. Objectives: This review offers a perspective on parameters that have determined the development path of CAL02, a novel anti-virulence agent, with a view to steering clear of the obstacles and limitations that impede market sustainability for new anti-infective drugs. Conclusions and implications of key findings: This case study highlights four pillars that may support the development of other non-traditional drugs and, concurrently, provide a new model that could reshape the field. Therapeutic triggers, study designs, and economic parameters are discussed.
Collagen Hydrolysates for Skin Protection: Oral Administration and Topical Formulation
Authors: Aguirre-Cruz Gabriel , León-López Arely , Cruz-Gómez Verónica , Jiménez-Alvarado Rubén , Aguirre-Álvarez Gabriel
Published: February 2020

Antioxidants are molecules that delay or inhibit the oxidation of other molecules. Its use significantly increased in recent years in the diet of people. Natural antioxidants are replacing the use of synthetic antioxidant ingredients due to their safety, nutritional, and therapeutic values. Hydrolyzed collagen (HC) is a popular ingredient considered to be an antioxidant. This low molecular weight protein has been widely utilized due to its excellent biocompatibility, easy biodegradability, and weak antigenicity. It is a safe cosmetic biomaterial with good moisturizing properties on the skin. The antioxidant properties of HC are conditioned to the size of the molecule: the lower the molecular weight of peptides, the greater the ability to donate an electron or hydrogen to stabilize radicals. The antioxidant capacity of HC is mostly due to the presence of hydrophobic amino acids in the peptide. The exact mechanism of peptides acting as antioxidants is not clearly known but some aromatic amino acids and histidine are reported to play an important role in the antioxidant activity. Oral ingestion of HC increases the levels of collagen-derived peptides in the blood torrent and improves the skin properties such as elasticity, skin moisture, and transepidermal water loss. Additionally, daily intakes of HC protect the skin against UV melasma, enhances the fibroblast production and extracellular matrix of the skin. HC has been identified as a safe cosmetic ingredient for topical formulations with good moisturizing properties at the stratum corneum layer of the skin. It reduces the effects of skin aging (dryness, laxity, and wrinkles). The use of HC as a principal ingredient in safe formulations for skin protection was reviewed and compared when it is used by topical and/or oral administration.
Contribution of Flavonoids and Iridoids to the Hypoglycaemic, Antioxidant, and Nitric Oxide (NO) Inhibitory Activities of Arbutus unedo L.
Authors: Tenuta Maria Concetta , Deguin Brigitte , Loizzo Monica Rosa , Dugay Annabelle , Acquaviva Rosaria , Malfa Giuseppe Antonio , Bonesi Marco , Bouzidi Chouaha , Tundis Rosa
Published: February 2020

This study aims at investigating the contribution of two classes of compounds, flavonoids and iridoids, to the bioactivity of Arbutus unedo L. leaves and fruits. The impact of different extraction procedures on phytochemicals content and hypoglycemic, antioxidant, and nitric oxide (NO) inhibitory activities of A. unedo fresh and dried plant materials was investigated. Ellagic acid 4-O-β-D-glucopyranoside, kaempferol 3-O-glucoside, and norbergenin were identified for the first time in this genus by using liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry (LC-ESI-QTOF-MS). Three iridoids (gardenoside, geniposide, unedoside) are specifically identified in the leaves. Interestingly, asperuloside was extracted only from dried fruits by ethanol with Soxhlet apparatus. Extracts were screened for their potential antioxidant activities by using the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), Ferric Reducing Activity Power (FRAP), and β-carotene bleaching tests. Based on the Global Antioxidant Score (GAS) calculation, the most promising antioxidant extract was obtained by hydroalcoholic maceration of dried leaves that showed half maximal inhibitory concentration (IC50) of 0.42 and 0.98 μg/mL in ABTS and DPPH assays, respectively. The hypoglycaemic activity was investigated by α-amylase and α-glucosidase inhibition tests. Extracts obtained by ethanol ultrasound extraction of fresh leaves and hydroalcoholic maceration of fresh fruits (IC50 of 19.56 and 28.42 μg/mL, respectively) are more active against α-glucosidase than the positive control acarbose (IC50 of 35.50 μg/mL). Fruit extracts exhibited the highest anti-inflammatory activity.
Effect of Mass-Center Position of Spinal Segment on Dynamic Performances of Quadruped Bounding with a Flexible-Articulated Spine
Authors: Zeng Shun , Tan Yuegang , Li Zhang , Wu Ping , Li Tianliang , Li Junfeng , Yin Haibin
Published: February 2020

Driven by the layout design of devices arranged on the spine of quadruped robot which has a symmetry spine with a flexible joint, we explore the effect of mass-center position of spinal segment (MCPSS) on dynamic performances of quadruped bounding. A simplified model is introduced with MCPSS set as an independent parameter. Periodically quadruped bounding motions are generated to calculate different dynamic performances related to different MCPSS at the low, medium, and high horizontal speeds, respectively. The results indicate MCPSS corresponding to the optimal or suboptimal dynamic performances mainly gather at two positions: the hip joint and the geometric center of spinal segment. MCPSS near the hip joint leads to the largest stride period, stride length, and spinal oscillation-margin at all speeds. The smallest duty factor can also be obtained at the medium and high speeds. These improved inherent characteristics offer advantages in leg-orientation control and fast movement effectively. MCPSS near the geometric center of spinal segment brings the best self-stability, the smallest mass-center vertical fluctuation, and the smallest maximum foot-end force at all speeds, which should greatly enhance resistances to vertical jitters and reduce torque-demands of joint-drivers. This study should give useful suggestions to robot designs in reality.
New Technologies in Orthodontics: A Digital Workflow to Enhance Treatment Plan and Photobiomodulation to Expedite Clinical Outcomes
Authors: Quinzi Vincenzo , Ronsivalle Vincenzo , Campanella Vincenzo , Mancini Leonardo , Torrisi Salvatore , Lo Giudice Antonino
Published: February 2020

Background: The transversal maxillary deficiency represents one of the most frequent skeletal discrepancies of the craniofacial region. The analysis of morphological characteristics of the maxilla can be detrimental for a correct diagnosis and treatment plan. Methods: This paper shows a user-friendly digital workflow involving mirroring, superimposition, and the deviation analysis of 3D models of the maxilla in order to identify the presence of symmetry/asymmetry of the palatal vault. Such information can be helpful to clinicians in order to design an appropriate orthodontic appliance for the treatment of transversal maxillary deficiency. We also describe a case report of a seven-year-old female affected by mild transversal maxillary deficiency associated with anterior openbite. The appliance is designed after a comprehensive evaluation of the morphology of the maxilla performed by using the presented diagnostic digital workflow. Additionally, the orthodontic treatment is assisted by photobiomodulation sessions that expedite the achievement of clinical outcomes.
Special Issue on Indoor Air Quality
Authors: Saraga Dikaia E.
Published: February 2020

It is a fact that people in developed countries spend almost 90% of their time indoors, where they experience their greatest exposures [...]
High-Strain-Rate Compressive Behavior of UHMWPE Fiber Laminate
Authors: Zhu Yihui , Zhang Xiaoyun , Xue Benyuan , Liu Hengsha , Wen Yaoke , Xu Cheng
Published: February 2020

Ultra-high-molecular-weight polyethylene (UHMWPE) fiber laminate is currently widely used in ballistic protection for its exceptional physical and mechanical properties. However, the dynamic compressive mechanism of UHMWPE laminate remains poorly understood. Therefore, the stress–strain relationship, the influence of different thickness, area, and shape, and the maximum stress and fracture stress are studied in both out-of-plane and in-plane directions under quasi-static and dynamic loading using a universal test machine, Split Hopkinson pressure bar (SHPB), and high-speed camera. Furthermore, numerical models with cohesive elements are developed. The results indicate a dependency on strain rate and loading direction. Firstly, the stress–strain curve of dynamic testing can be divided into different zones according to different loading directions and strain rates. Secondly, with the increase of the strain rate in the dynamic testing, the maximum stress and fracture stress increase as well; relatively speaking, the fracture stress in the out-of-plane direction is greater than the fracture stress in the in-plane direction. Thirdly, both experiment and simulation indicate that the thickness does not influence the modulus clearly the in out-of-plane direction but influences the modulus in the in-plane direction. Fourthly, the fracture stress of dynamic testing is higher than the fracture stress of quasi-static testing in both directions. Finally, the numerical results show good agreement with the experiment in terms of the maximum stress and failure form.
Recommending Cryptocurrency Trading Points with Deep Reinforcement Learning Approach
Authors: Sattarov Otabek , Muminov Azamjon , Lee Cheol Won , Kang Hyun Kyu , Oh Ryumduck , Ahn Junho , Oh Hyung Jun , Jeon Heung Seok
Published: February 2020

The net profit of investors can rapidly increase if they correctly decide to take one of these three actions: buying, selling, or holding the stocks. The right action is related to massive stock market measurements. Therefore, defining the right action requires specific knowledge from investors. The economy scientists, following their research, have suggested several strategies and indicating factors that serve to find the best option for trading in a stock market. However, several investors’ capital decreased when they tried to trade the basis of the recommendation of these strategies. That means the stock market needs more satisfactory research, which can give more guarantee of success for investors. To address this challenge, we tried to apply one of the machine learning algorithms, which is called deep reinforcement learning (DRL) on the stock market. As a result, we developed an application that observes historical price movements and takes action on real-time prices. We tested our proposal algorithm with three—Bitcoin (BTC), Litecoin (LTC), and Ethereum (ETH)—crypto coins’ historical data. The experiment on Bitcoin via DRL application shows that the investor got 14.4% net profits within one month. Similarly, tests on Litecoin and Ethereum also finished with 74% and 41% profit, respectively.
A Study on the Fused Deposition Modeling Process of Graphene/Nano-Fe3O4 Composite Absorber and its Absorbing Properties of Electromagnetic Microwave
Authors: Wu Haihua , Xing Lei , Cai Yu , Liu Li , He Enyi , Li Bo , Tian Xiaoyong
Published: February 2020

Graphene/polylactic acid; nano-Fe3O4/polylactic acid; and graphene/nano-Fe3O4/polylactic acid composite absorbers are independently produced by fused deposition modeling technology. The effects of the content of graphene and nano-Fe3O4 on absorbing properties are investigated. After measuring the electromagnetic parameters using the waveguide method, the absorbing property is characterized according to the transmission line theory. The distribution of graphene and nano-Fe3O4 in the matrix is observed by scanning electronic microscopy (SEM). The results show that the graphene and nanometer ferroferric oxide multicomponent absorbing agent helps to form a synergistic absorbing effect. In the frequency range 8.2–18.0 GHz; the absorber has the greatest absorbing property when the content of graphene and nanosize Fe3O4 are 5 wt% and 20 wt%, respectively.
Global Spatial-Temporal Graph Convolutional Network for Urban Traffic Speed Prediction
Authors: Ge Liang , Li Siyu , Wang Yaqian , Chang Feng , Wu Kunyan
Published: February 2020

Traffic speed prediction plays a significant role in the intelligent traffic system (ITS). However, due to the complex spatial-temporal correlations of traffic data, it is very challenging to predict traffic speed timely and accurately. The traffic speed renders not only short-term neighboring and multiple long-term periodic dependencies in the temporal dimension but also local and global dependencies in the spatial dimension. To address this problem, we propose a novel deep-learning-based model, Global Spatial-Temporal Graph Convolutional Network (GSTGCN), for urban traffic speed prediction. The model consists of three spatial-temporal components with the same structure and an external component. The three spatial-temporal components are used to model the recent, daily-periodic, and weekly-periodic spatial-temporal correlations of the traffic data, respectively. More specifically, each spatial-temporal component consists of a dynamic temporal module and a global correlated spatial module. The former contains multiple residual blocks which are stacked by dilated casual convolutions, while the latter contains a localized graph convolution and a global correlated mechanism. The external component is used to extract the effect of external factors, such as holidays and weather conditions, on the traffic speed. Experimental results on two real-world traffic datasets have demonstrated that the proposed GSTGCN outperforms the state-of-the-art baselines.
Deep Learning for EEG-Based Preference Classification in Neuromarketing
Authors: Aldayel Mashael , Ykhlef Mourad , Al-Nafjan Abeer
Published: February 2020

The traditional marketing methodologies (e.g., television commercials and newspaper advertisements) may be unsuccessful at selling products because they do not robustly stimulate the consumers to purchase a particular product. Such conventional marketing methods attempt to determine the attitude of the consumers toward a product, which may not represent the real behavior at the point of purchase. It is likely that the marketers misunderstand the consumer behavior because the predicted attitude does not always reflect the real purchasing behaviors of the consumers. This research study was aimed at bridging the gap between traditional market research, which relies on explicit consumer responses, and neuromarketing research, which reflects the implicit consumer responses. The EEG-based preference recognition in neuromarketing was extensively reviewed. Another gap in neuromarketing research is the lack of extensive data-mining approaches for the prediction and classification of the consumer preferences. Therefore, in this work, a deep-learning approach is adopted to detect the consumer preferences by using EEG signals from the DEAP dataset by considering the power spectral density and valence features. The results demonstrated that, although the proposed deep-learning exhibits a higher accuracy, recall, and precision compared with the k-nearest neighbor and support vector machine algorithms, random forest reaches similar results to deep learning on the same dataset.
Consistent Time-to-Failure Tests and Analyses of Adhesive Anchor Systems
Authors: Ninčević Krešimir , Boumakis Ioannis , Meissl Stefan , Wan-Wendner Roman
Published: February 2020

Motivated by tunnel accidents in the recent past, several investigations into the sustained load behavior of adhesive anchors have been initiated. Nevertheless, the reliable lifetime prediction of bonded anchor systems based on a relatively short testing period still represents an unsolved challenge due to the complex nonlinear viscoelastic behavior of concrete and adhesives alike. This contribution summarizes the results of a comprehensive experimental investigation and systematically carried out time-to-failure analysis performed on bonded anchors under sustained tensile load. Two different adhesive materials that find widespread application in the building industry were used, one epoxy and one vinylester based. Performed experiments include full material characterizations of concrete and the adhesives, bonded anchor pull-out tests at different loading rates, and time-to-failure sustained load tests. All anchor tests are performed in a confined configuration with close support. After a thorough review of available experimental data and analysis methods in the literature, the experimental data are presented with the main goal to (i) provide guidance for the analysis of load versus time-to-failure test data, and (ii) to derive a set of recommendations for efficient time-to-failure tests having in mind the needs associated with different analysis techniques. Finally, a new approach based on a sigmoid function, previously used only for concrete, is for the first time applied to bonded anchors systems and compared to the established regression models.
Harmonics Consequences on Drive Systems with Induction Motor
Authors: Beleiu Horia Gheorghe , Maier Virgil , Pavel Sorin Gheorghe , Birou Iulian , Pică Constantin Sorin , Dărab Pompei Cosmin
Published: February 2020

In the case of adjustable drives systems with an induction motor (IM), a harmonic regime is manifested, whose knowledge and analysis are always necessary. However, most studies are focused on specific drive systems, the results of these works being valid only for drive systems of the same type. The objective of the present paper was to determine the harmonics consequences not only on the technical characteristics of the IM but also on the power supply as well as on the mechanical drive system. Thus, by initiating a methodology for estimating the consequences of each voltage harmonic separately, the aim was to substantiate a generally applicable method, which allows the evaluation, for any application, of the overall effects of the harmonics. The main feature of the method used in this paper was the consideration of the presence of voltage harmonics in the stator voltage of the IM, of certain frequencies and with certain levels, and the determination of all the electrical and mechanical consequences on the model of the drive system. It has been found that the harmonics of the IM affects the power quality (PQ) of the power supply, having significant influences also on the mechanical part of the drive system.
Functional and Dysfunctional Neuroplasticity in Learning to Cope with Stress
Authors: Cabib Simona , Campus Paolo , Conversi David , Orsini Cristina , Puglisi-Allegra Stefano
Published: February 2020

In this brief review, we present evidence of the primary role of learning-associated plasticity in the development of either adaptive or maladaptive coping strategies. Successful interactions with novel stressors foster plasticity within the neural circuits supporting acquisition, consolidation, retrieval, and extinction of instrumental learning leading to development of a rich repertoire of flexible and context-specific adaptive coping responses, whereas prolonged or repeated exposure to inescapable/uncontrollable stressors fosters dysfunctional plasticity within the learning circuits leading to perseverant and inflexible maladaptive coping strategies. Finally, the results collected using an animal model of genotype-specific coping styles indicate the engagement of different molecular networks and the opposite direction of stress effects (reduced vs. enhanced gene expression) in stressed animals, as well as different behavioral alterations, in line with differences in the symptoms profile associated with post-traumatic stress disorder.
Mechanisms of the Antitumor Activity of Low Molecular Weight Heparins in Pancreatic Adenocarcinomas
Authors: Bokas Alexandros , Papakotoulas Pavlos , Sarantis Panagiotis , Papadimitropoulou Adriana , Papavassiliou Athanasios G , Karamouzis Michalis V
Published: February 2020

Immune checkpoint inhibitors have revolutionized cancer treatment in the last decade. Despite the progress in immunotherapy, most pancreatic cancer patients still do not derive benefit when receiving immune-based therapies. Recently, resistance mechanisms to immune therapies have been mainly focused on tumor microenvironment properties. Pancreatic cancer is considered one of the most lethal and difficult to treat tumors due to its highly immunosuppressive and desmoplastic microenvironment. Low molecular weight heparins (LMWHs) have been used for the treatment and prevention of thromboembolic disease in these patients. However, many nonanticoagulant properties attributed to LMWHs have been described. Exploiting LMWH properties in a combined treatment modality with immune checkpoint inhibition and chemotherapy could provide a new approach in the management of pancreatic adenocarcinoma patients. The ability of LMWH to interfere with various aspects of the tumor microenvironment could result in both the alleviation of immunosuppression and improvement in drug delivery within the tumor, leading to higher cancer cell destruction rates and more potent immune system activity that would, ultimately, lead to better patient outcomes.
Bone Marrow Stromal Cell-Derived IL-8 Upregulates PVR Expression on Multiple Myeloma Cells via NF-kB Transcription Factor
Authors: Mekhloufi Abdelilah , Kosta Andrea , Stabile Helena , Molfetta Rosa , Zingoni Alessandra , Soriani Alessandra , Cippitelli Marco , Paolini Rossella , Gismondi Angela , Ricciardi Maria Rosaria , Petrucci Maria Teresa , Masuelli Laura , Caracciolo Giulio , Palchetti Sara , Santoni Angela , Fionda Cinzia
Published: February 2020

Bone marrow stromal cells (BMSCs) strongly contribute to multiple myeloma (MM) progression, promoting the survival and growth of malignant plasma cells (PCs). However, the possible impact of these cells on the immune-mediated recognition of MM cells remains largely unknown. DNAM-1 activating receptor plays a prominent role in NK cell anti-MM response engaging the ligands poliovirus receptor (PVR) and nectin-2 on malignant PCs. Here, we analysed the role of MM patient-derived BMSCs in the regulation of PVR expression. We found that BMSCs enhance PVR surface expression on MM cells and promote their NK cell-mediated recognition. PVR upregulation occurs at transcriptional level and involves NF-kB transcription factor activation by BMSC-derived soluble factors. Indeed, overexpression of a dominant-negative mutant of IKBα blocked PVR upregulation. IL-8 plays a prominent role in these mechanisms since blockade of CXCR1/2 receptors as well as depletion of the cytokine via RNA interference prevents the enhancement of PVR expression by BMSC-derived conditioned medium. Interestingly, IL-8 is associated with stromal microvesicles which are also required for PVR upregulation via CXCR1/CXCR2 signaling activation. Our findings identify BMSCs as regulators of NK cell anti-MM response and contribute to define novel molecular pathways involved in the regulation of PVR expression in cancer cells.
Epigenetics of SFRP1: The Dual Roles in Human Cancers
Authors: Baharudin Rashidah , Tieng Francis Yew Fu , Lee Learn-Han , Ab Mutalib Nurul Syakima
Published: February 2020

Secreted frizzled-related protein 1 (SFRP1) is a gene that belongs to the secreted glycoprotein SFRP family. SFRP1 has been classified as a tumor suppressor gene due to the loss of expression in various human cancers, which is mainly attributed by epigenetic inactivation via DNA methylation or transcriptional silencing by microRNAs. Epigenetic silencing of SFRP1 may cause dysregulation of cell proliferation, migration, and invasion, which lead to cancer cells formation, disease progression, poor prognosis, and treatment resistance. Hence, restoration of SFRP1 expression via demethylating drugs or over-expression experiments opens the possibility for new cancer therapy approach. While the role of SFRP1 as a tumor suppressor gene is well-established, some studies also reported the possible oncogenic properties of SFRP1 in cancers. In this review, we discussed in great detail the dual roles of SFRP1 in cancers—as tumor suppressor and tumor promoter. The epigenetic regulation of SFRP1 expression will also be underscored with additional emphasis on the potentials of SFRP1 in modulating responses toward chemotherapeutic and epigenetic-modifying drugs, which may encourage the development of novel drugs for cancer treatment. We also present findings from clinical trials and patents involving SFRP1 to illustrate its clinical utility, extensiveness of each research area, and progression toward commercialization. Lastly, this review provides directions for future research to advance SFRP1 as a promising cancer biomarker.
Novel Quinoline Compounds Active in Cancer Cells through Coupled DNA Methyltransferase Inhibition and Degradation
Authors: Zwergel Clemens , Fioravanti Rossella , Stazi Giulia , Sarno Federica , Battistelli Cecilia , Romanelli Annalisa , Nebbioso Angela , Mendes Eduarda , Paulo Alexandra , Strippoli Raffaele , Tripodi Marco , Pechalrieu Dany , Arimondo Paola , De Luca Teresa , Del Bufalo Donatella , Trisciuoglio Daniela , Altucci Lucia , Valente Sergio , Mai Antonello
Published: February 2020

DNA methyltransferases (DNMTs) play a relevant role in epigenetic control of cancer cell survival and proliferation. Since only two DNMT inhibitors (azacitidine and decitabine) have been approved to date for the treatment of hematological malignancies, the development of novel potent and specific inhibitors is urgent. Here we describe the design, synthesis, and biological evaluation of a new series of compounds acting at the same time as DNMTs (mainly DNMT3A) inhibitors and degraders. Tested against leukemic and solid cancer cell lines, 2a–c and 4a–c (the last only for leukemias) displayed up to submicromolar antiproliferative activities. In HCT116 cells, such compounds induced EGFP gene expression in a promoter demethylation assay, confirming their demethylating activity in cells. In the same cell line, 2b and 4c chosen as representative samples induced DNMT1 and -3A protein degradation, suggesting for these compounds a double mechanism of DNMT3A inhibition and DNMT protein degradation.
Extracellular Vesicle microRNAs Contribute to the Osteogenic Inhibition of Mesenchymal Stem Cells in Multiple Myeloma
Authors: Raimondo Stefania , Urzì Ornella , Conigliaro Alice , Lo Bosco Giosuè , Parisi Sofia , Carlisi Melania , Siragusa Sergio , Raimondi Lavinia , De Luca Angela , Giavaresi Gianluca , Alessandro Riccardo
Published: February 2020

Osteolytic bone disease is the major complication associated with the progression of multiple myeloma (MM). Recently, extracellular vesicles (EVs) have emerged as mediators of MM-associated bone disease by inhibiting the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Here, we investigated a correlation between the EV-mediated osteogenic inhibition and MM vesicle content, focusing on miRNAs. By the use of a MicroRNA Card, we identified a pool of miRNAs, highly expressed in EVs, from MM cell line (MM1.S EVs), expression of which was confirmed in EVs from bone marrow (BM) plasma of patients affected by smoldering myeloma (SMM) and MM. Notably,we found that miR-129-5p, which targets different osteoblast (OBs) differentiation markers, is enriched in MM-EVs compared to SMM-EVs, thus suggesting a selective packaging correlated with pathological grade. We found that miR-129-5p can be transported to hMSCs by MM-EVs and, by the use of miRNA mimics, we investigated its role in recipient cells. Our data demonstrated that the increase of miR-129-5p levels in hMSCs under osteoblastic differentiation stimuli inhibited the expression of the transcription factor Sp1, previously described as a positive modulator of osteoblastic differentiation, and of its target the Alkaline phosphatase (ALPL), thus identifying miR-129-5p among the players of vesicle-mediated bone disease.
Misregulation of ELK1, AP1, and E12 Transcription Factor Networks Is Associated with Melanoma Progression
Authors: Singh Komudi , Baird Michelle , Fischer Robert , Chaitankar Vijender , Seifuddin Fayaz , Chen Yun-Ching , Tunc Ilker , Waterman Clare M. , Pirooznia Mehdi
Published: February 2020

Melanoma is among the most malignant cutaneous cancers and when metastasized results in dramatically high mortality. Despite advances in high-throughput gene expression profiling in cancer transcriptomic studies, our understanding of mechanisms driving melanoma progression is still limited. We present here an in-depth bioinformatic analysis of the melanoma RNAseq, chromatin immunoprecipitation (ChIP)seq, and single-cell (sc)RNA seq data to understand cancer progression. Specifically, we have performed a consensus network analysis of RNA-seq data from clinically re-grouped melanoma samples to identify gene co-expression networks that are conserved in early (stage 1) and late (stage 4/invasive) stage melanoma. Overlaying the fold-change information on co-expression networks revealed several coordinately up or down-regulated subnetworks that may play a critical role in melanoma progression. Furthermore, by incorporating histone lysine-27 acetylation information and highly expressed genes identified from the single-cell RNA data from melanoma patient samples, we present a comprehensive list of pathways, putative protein-protein interactions (PPIs) and transcription factor (TF) networks that are driving cancer progression. From this analysis, we have identified Elk1, AP1 and E12 TF networks that coordinately change expression in late melanoma when compared to early melanoma, implicating these TFs in melanoma progression. Additionally, the sumoylation-associated interactome is upregulated in invasive melanoma. Together, this bioinformatic analysis potentially implicates a combination of TF networks and PPIs in melanoma progression, which if confirmed in the experimental systems, could be used as targets for drug intervention in melanoma.
Decitabine Augments Chemotherapy-Induced PD-L1 Upregulation for PD-L1 Blockade in Colorectal Cancer
Authors: Huang Kevin Chih-Yang , Chiang Shu-Fen , Chen William Tzu-Liang , Chen Tsung-Wei , Hu Ching-Han , Yang Pei-Chen , Ke Tao-Wei , Chao K. S. Clifford
Published: February 2020

Programmed cell death-1 (PD-1) has demonstrated impressive clinical outcomes in several malignancies, but its therapeutic efficacy in the majority of colorectal cancers is still low. Therefore, methods to improve its therapeutic efficacy in colorectal cancer (CRC) patients need further investigation. Here, we demonstrate that immunogenic chemotherapeutic agents trigger the induction of tumor PD-L1 expression in vitro and in vivo, a fact which was validated in metastatic CRC patients who received preoperatively neoadjuvant chemotherapy (neoCT) treatment, suggesting that tumor PD-L1 upregulation by chemotherapeutic regimen is more feasible via PD-1/PD-L1 immunotherapy. However, we found that the epigenetic control of tumor PD-L1 via DNA methyltransferase 1 (DNMT1) significantly influenced the response to chemotherapy. We demonstrate that decitabine (DAC) induces DNA hypomethylation, which not only directly enhances tumor PD-L1 expression but also increases the expression of immune-related genes and intratumoral T cell infiltration in vitro and in vivo. DAC was found to profoundly enhance the therapeutic efficacy of PD-L1 immunotherapy to inhibit tumor growth and prolong survival in vivo. Therefore, it can be seen that DAC remodels the tumor microenvironment to improve the effect of PD-L1 immunotherapy by directly triggering tumor PD-L1 expression and eliciting stronger anti-cancer immune responses, providing potential clinical benefits to CRC patients in the future.
Dual PI3K/mTOR Inhibitor NVP-BEZ235 Enhances Radiosensitivity of Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines Due to Suppressed Double-Strand Break (DSB) Repair by Non-Homologous End Joining
Authors: Schötz Ulrike , Balzer Viola , Brandt Friedrich-Wilhelm , Ziemann Frank , Subtil Florentine S.B. , Rieckmann Thorsten , Köcher Sabrina , Engenhart-Cabillic Rita , Dikomey Ekkehard , Wittig Andrea , Arenz Andrea
Published: February 2020

The PI3K/Akt/mTOR pathway is frequently altered in human papillomavirus (HPV)-positive and negative squamous cell carcinoma of the head and neck (HNSCC) and overstimulation is associated with poor prognosis. PI3K drives Akt activation and constitutive signaling acts pro-proliferative, supports cell survival, DNA repair, and contributes to radioresistance. Since the small molecule NVP-BEZ235 (BEZ235) is a potent dual inhibitor of this pathway, we were interested whether BEZ235 could be an efficient radiosensitizer. The 50 nM BEZ235 was found to abrogate endogenous and irradiation-induced phosphorylation of Akt (Ser473). The anti-proliferative capacity of the drug resulted in an increase in G1-phase cells. Repair of radiation-induced DNA double-strand breaks (DSBs) was strongly suppressed. Reduction in DSB repair was only apparent in G1- but not in G2-phase cells, suggesting that BEZ235 primarily affects non-homologous end joining. This finding was confirmed using a DSB repair reporter gene assay and could be attributed to an impaired phosphorylation of DNA-PKcs (S2056). Cellular radiosensitivity increased strongly after BEZ235 addition in all HNSCC cell lines used, especially when irradiated in the G0 or G1 phase. Our data indicate that targeting the PI3K/Akt/mTOR pathway by BEZ235 with concurrent radiotherapy may be considered an effective strategy for the treatment of HNSCC, regardless of the HPV and Akt status.
Predictive Value of Soluble PD-1, PD-L1, VEGFA, CD40 Ligand and CD44 for Nivolumab Therapy in Advanced Non-Small Cell Lung Cancer: A Case-Control Study
Authors: Tiako Meyo Manuela , Jouinot Anne , Giroux-Leprieur Etienne , Fabre Elizabeth , Wislez Marie , Alifano Marco , Leroy Karen , Boudou-Rouquette Pascaline , Tlemsani Camille , Khoudour Nihel , Arrondeau Jennifer , Thomas-Schoemann Audrey , Blons Hélène , Mansuet-Lupo Audrey , Damotte Diane , Vidal Michel , Goldwasser François , Alexandre Jérôme , Blanchet Benoit
Published: February 2020

A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), soluble CD40 ligand (sCD40L) and soluble CD44 (sCD44), with survival in nivolumab-treated metastatic non-small cell lung cancer (NSCLC) patients. Plasma biomarkers were assayed at baseline and after two cycles of nivolumab. A cut-off of positivity for sPD-1, sPD-L1 and sCD40L expressions was defined as a plasma level above the lower limit of quantification. Baseline sPD-1 and sPD-L1 levels were subsequently analyzed in a control group of EGFR-mutated (Epidermal Growth Factor Receptor) NSCLC patients. Association between survival and biomarkers was investigated using Cox proportional hazard regression model. Eighty-seven patients were included (51 nivolumab-treated patients, 36 in EGFR-mutated group). In nivolumab group, baseline sPD-1, sPD-L1 and sCD40L were positive for 15(29.4%), 27(52.9%) and 18(50%) patients, respectively. We defined a composite criteria (sCombo) corresponding to sPD-1 and/or sPD-L1 positivity for each patient. In nivolumab group, baseline sCombo positivity was associated with shorter median progression-free survival (PFS) (78 days 95%CI (55–109) vs. 658 days (222-not reached); HR: 4.12 (1.95–8.71), p = 0.0002) and OS (HR: 3.99(1.63–9.80), p = 0.003). In multivariate analysis, baseline sCombo independently correlated with PFS (HR: 2.66 (1.17–6.08), p = 0.02) but not OS. In EGFR-mutated group, all patients were baseline sCombo positive; therefore this factor was not associated with survival. After two cycles of nivolumab, an increased or stable sPD-1 level independently correlated with longer PFS (HR: 0.49, 95%CI (0.30–0.80), p = 0.004) and OS (HR: 0.39, 95%CI (0.21–0.71), p = 0.002). VEGFA, sCD40L and sCD44 did not correlate with survival. We propose a composite biomarker using sPD-1and sPDL-1 to predict nivolumab efficacy in NSCLC patients. A larger validation study is warranted.
Biological Features and Prognostic Impact of Bone Marrow Infiltration in Patients with Diffuse Large B-cell Lymphoma
Authors: Alonso-Álvarez Sara , Alcoceba Miguel , García-Álvarez María , Blanco Oscar , Rodríguez Marta , Baile Mónica , Caballero Juan Carlos , Dávila Julio , Vidriales María Belén , Esteban Carmen , Arias Piedad , Díaz Luis G. , Tamayo Pilar , Caballero María Dolores , Gutiérrez Norma C. , González Marcos , Martín Alejandro
Published: February 2020

The biology and clinical impact of bone marrow (BM) infiltration in patients with diffuse large B-cell lymphoma (DLBCL) remains unclear in the rituximab era. We retrospectively analyzed 232 patients diagnosed with DLBCL at our center between 1999 and 2014. Concordant-presence of large cells similar to those of the lymph node biopsy- and discordant-infiltration by small cells forming lymphoid aggregates, lacking cytological atypia-BM infiltration was defined by histological criteria and further characterized by flow cytometry (FCM). Cell of origin (COO) was determined using Hans’ algorithm. For the clonal relationship between tumor and discordant BM, the VDJH rearrangement was analyzed. Survival analyses were restricted to 189 patients treated with rituximab and chemotherapy. Thirty-six (16%) had concordant, and 37 (16%) discordant BM infiltration. FCM described different indolent lymphomas among discordant cases, clonally related with DLBCL in 10/13 available samples. Median follow-up was 58 months. 5-year-progression-free survival (PFS) for non-infiltrated, discordant and concordant groups was 68%, 65% and 30%, respectively (p < 0.001). Combining COO and BM infiltration, patients with discordant BM and non-germinal center B-cell COO also had decreased 5-year-PFS (41.9%). In multivariate analysis, concordant BM had an independent effect on PFS (HR 2.5, p = 0.01). Five-year cumulative incidence of central nervous system (CNS) relapse was 21%, 4% and 1% in concordant, discordant and non-infiltrated groups, respectively (p < 0.001). In conclusion, concordant BM infiltration represents a subset with poor prognosis, whereas the prognostic impact of discordant BM infiltration could be limited to non-CGB cases.