bluuebunny/crossref_metadata_2025 huggingface dataset:
Design and Performance Analysis of a Supercritical Carbon Dioxide Heat Exchanger
Authors: Seo Han , Cha Jae Eun , Kim Jaemin , Sah Injin , Kim Yong-Wan
Published: June 2020

This paper presents a preliminary design and performance analysis of a supercritical CO2 (SCO2) heat exchanger for an SCO2 power generation system. The purpose of designing a SCO2 heat exchanger is to provide a high-temperature and high-pressure heat exchange core technology for advanced SCO2 power generation systems. The target outlet temperature and pressure for the SCO2 heat exchanger were 600 °C and 200 bar, respectively. A tubular type with a staggered tube bundle was selected as the SCO2 heat exchanger, and liquefied petroleum gas (LPG) and air were selected as heat sources. The design of the heat exchanger was based on the material selection and available tube specification. Preliminary performance evaluation of the SCO2 heat exchanger was conducted using an in-house code, and three-dimensional flow and thermal stress analysis were performed to verify the tube’s integrity. The simulation results showed that the tubular type heat exchanger can endure high-temperature and high-pressure conditions under an SCO2 environment.
A Novel High Gain Monopole Antenna Array for 60 GHz Millimeter-Wave Communications
Authors: Mneesy Tarek S. , Hamad Radwa K. , Zaki Amira I. , Ali Wael A. E.
Published: June 2020

This paper presented the design and implementation of a 60 GHz single element monopole antenna as well as a two-element array made of two 60 GHz monopole antennas. The proposed antenna array was used for 5G applications with radiation characteristics that conformed to the requirements of wireless communication systems. The proposed single element was designed and optimized to work at 60 GHz with a bandwidth of 6.6 GHz (57.2–63.8 GHz) and a maximum gain of 11.6 dB. The design was optimized by double T-shaped structures that were added in the rectangular slots, as well as two external stubs in order to achieve a highly directed radiation pattern. Moreover, ring and circular slots were made in the partial ground plane at an optimized distance as a defected ground structure (DGS) to improve the impedance bandwidth in the desired band. The two-element array was fed by a feed network, thus improving both the impedance bandwidth and gain. The single element and array were fabricated, and the measured and simulated results mimicked each other in both return loss and antenna gain.
Critical Perspective on Advanced Treatment Processes for Water and Wastewater: AOPs, ARPs, and AORPs
Authors: Capodaglio Andrea G.
Published: June 2020

Emerging contaminants’ presence in water, wastewater, and aquatic environments has been widely reported. Their environmental and health-related effects, and the increasing tendency towards wastewater reuse require technology that could remove to a greater degree, or even mineralize, all these contaminants. Currently, the most commonly used process technologies for their removal are advanced oxidation processes (AOPs); however, recent advances have highlighted other advanced treatment processes (ATPs) as possible alternatives, such as advanced reduction processes (ARPs) and advanced oxidation-reduction processes (AORPs). Although they are not yet widely diffused, they may remove contaminants that are not readily treatable by AOPs, or offer better performance than the former. This paper presents an overview of some of the most common or promising ATPs for the removal of contaminants from water and wastewater, and their application, with discussion of their limitations and merits. Issues about technologies’ costs and future perspectives in the water sector are discussed.
CFD Analysis of Subcooled Flow Boiling in 4 × 4 Rod Bundle
Authors: Seo Ye-Bon , Paramanantham SalaiSargunan S , Bak Jin-Yeong , Yun Byongjo , Park Warn-Gyu
Published: June 2020

Rod bundle flow is an important research field related to reactor cooling in nuclear power plants. Owing to the rapid development of computerized performance assessments, interest in coolant flow analysis using computational fluid dynamics has garnered research interest. Rod bundle flow research data compared with experimental results under various conditions are thus needed. To address this, a boiling model verification study was conducted with reference to experiments. This study adopts the Reynolds-averaged Navier–Stokes equation, a practical analysis method compared to direct numerical simulation and large eddy simulation, including turbulence modeling, to predict the flow of coolant inside a rod bundle. This study also investigates void behavior in low-pressure subcooled flow boiling using a Eulerian approach (two-fluid model). The rod bundle has a length of 0.59 m and a hydraulic diameter of approximately 14.01 mm. At the cross-section at a height of 0.58 m, near the exit, numerical results were compared with the experimental values of the volume fraction of vapor and interfacial area concentration. The simulation results showed good agreement with the experimental data for six different initial conditions with constant density.
A Study on Identification of Development Status of MASS Technologies and Directions of Improvement
Authors: Chae Chong-Ju , Kim Mingyu , Kim Hyung-Ju
Published: June 2020

The introduction of the maritime autonomous surface ship (MASS) to the maritime industry will open up a new era and bring about a new paradigm shift in terms of cost efficiency, maritime accidents, and human resources. Various studies are currently being conducted to realize the MASS. Understanding the scope and direction of these studies will be of great help for future MASS research. In this study, the current development status of technologies for autonomous ships is identified, and considerations and directions of improvement are suggested for six major research fields that cover all technological issues of MASS. Firstly, the results of the regulatory scoping exercise (RSE) on the International Maritime Organization (IMO) conventions to accept MASSs are identified; in particular, human elements are identified as vital issues to be considered for the design and operation of MASSs. Secondly, various studies on the decision-making system are identified, and the future direction is suggested. Thirdly, in terms of ship design and propulsion system, design changes for autonomous cargo ships are investigated, with their potential impacts to be considered. Fourthly, the communication system will need to be robust and supported by multiple systems to minimize potential risk with third-party infrastructures, and suitable protection of systems, networks, and data will be required as an integral part of the safety system for cybersecurity. Fifthly, issues of maintenance and repair are identified, with a maintenance strategy to be considered. Lastly, hazard analysis of the autonomous ship is explored, and system-theoretic process analysis (STPA) and the functional resonance analysis method (FRAM) are identified as the most representative new methods that can be used for hazard analysis of autonomous ships.
Natural Paracontact Magnetic Trajectories on Unit Tangent Bundles
Authors: Kadaoui Abbassi Mohamed Tahar , Amri Noura
Published: June 2020

In this paper, we study natural paracontact magnetic trajectories in the unit tangent bundle, i.e., those that are associated to g-natural paracontact metric structures. We characterize slant natural paracontact magnetic trajectories as those satisfying a certain conservation law. Restricting to two-dimensional base manifolds of constant Gaussian curvature and to Kaluza–Klein type metrics on their unit tangent bundles, we give a full classification of natural paracontact slant magnetic trajectories (and geodesics).
Approximating Functions of Positive Compact Operators by Using Bell Polynomials
Authors: Caratelli Diego , Natalini Pierpaolo , Ricci Paolo Emilio
Published: June 2020

After recalling the most important properties of the Bell polynomials, we show how to approximate a positive compact operator by a suitable matrix. Then, we derive a representation formula for functions of the obtained matrix, which can be considered as an approximate value for the functions of the corresponding operator.
Co-Delivery of Imiquimod and Curcumin by Nanoemugel for Improved Topical Delivery and Reduced Psoriasis-Like Skin Lesions
Authors: Algahtani Mohammed S. , Ahmad Mohammad Zaki , Nourein Ihab Hamed , Ahmad Javed
Published: June 2020

The current investigation aimed to improve the topical efficacy of imiquimod in combination with curcumin using the nanoemulsion-based delivery system through a combinatorial approach. Co-delivery of curcumin acts as an adjuvant therapeutic and to minimize the adverse skin reactions that are frequently associated with the topical therapy of imiquimod for the treatment of cutaneous infections and basal cell carcinomas. The low-energy emulsification method was used for the nano-encapsulation of imiquimod and curcumin in the nanodroplet oil phase, which was stabilized using Tween 20 in an aqueous dispersion system. The weak base property of imiquimod helped to increase its solubility in oleic acid compared with ethyl oleate, which indicates that fatty acids should be preferred as the oil phase for the design of imiquimod-loaded topical nanoemulsion compared with fatty acid esters. The phase diagram method was used to optimize the percentage composition of the nanoemulsion formulation. The mean droplet size of the optimized nanoemulsion was 76.93 nm, with a polydispersity index (PdI) value of 0.121 and zeta potential value of −20.5 mV. The optimized imiquimod-loaded nanoemulsion was uniformly dispersed in carbopol 934 hydrogel to develop into a nanoemulgel delivery system. The imiquimod nanoemulgel exhibited significant improvement (p < 0.05) in skin permeability and deposition profile after topical application. The in vivo effectiveness of the combination of imiquimod and curcumin nanoemulgel was compared to the imiquimod nanoemulgel and imiquimod gel formulation through topical application for ten days in BALB/c mice. The combination of curcumin with imiquimod in the nanoemulgel system prevented the appearance of psoriasis-like symptoms compared with the imiquimod nanoemulgel and imiquimod gel formulation entirely. Further, the imiquimod nanoemulgel as a mono-preparation slowed and reduced the psoriasis-like skin reaction when compared with the conventional imiquimod gel, and that was contributed to by the control release property of the nano-encapsulation approach.
Reduced Reelin Expression in the Hippocampus after Traumatic Brain Injury
Authors: Dal Pozzo Valentina , Crowell Beth , Briski Nicholas , Crockett David P. , D’Arcangelo Gabriella
Published: June 2020

Traumatic brain injury (TBI) is a relatively common occurrence following accidents or violence, and often results in long-term cognitive or motor disability. Despite the high health cost associated with this type of injury, presently there are no effective treatments for many neurological symptoms resulting from TBI. This is due in part to our limited understanding of the mechanisms underlying brain dysfunction after injury. In this study, we used the mouse controlled cortical impact (CCI) model to investigate the effects of TBI, and focused on Reelin, an extracellular protein that critically regulates brain development and modulates synaptic activity in the adult brain. We found that Reelin expression decreases in forebrain regions after TBI, and that the number of Reelin-expressing cells decrease specifically in the hippocampus, an area of the brain that plays an important role in learning and memory. We also conducted in vitro experiments using mouse neuronal cultures and discovered that Reelin protects hippocampal neuronal cells from glutamate-induced neurotoxicity, a well-known secondary effect of TBI. Together our findings suggest that the loss of Reelin expression may contribute to neuronal death in the hippocampus after TBI, and raise the possibility that increasing Reelin levels or signaling activity may promote functional recovery.
Survey and Validation of tRNA Modifications and Their Corresponding Genes in Bacillus subtilis sp Subtilis Strain 168
Authors: de Crécy-Lagard Valérie , Ross Robert , Jaroch Marshall , Marchand Virginie , Eisenhart Christina , Brégeon Damien , Motorin Yuri , Limbach Patrick
Published: June 2020

Extensive knowledge of both the nature and position of tRNA modifications in all cellular tRNAs has been limited to two bacteria, Escherichia coli and Mycoplasma capricolum. Bacillus subtilis sp subtilis strain 168 is the model Gram-positive bacteria and the list of the genes involved in tRNA modifications in this organism is far from complete. Mass spectrometry analysis of bulk tRNA extracted from B. subtilis, combined with next generation sequencing technologies and comparative genomic analyses, led to the identification of 41 tRNA modification genes with associated confidence scores. Many differences were found in this model Gram-positive bacteria when compared to E. coli. In general, B. subtilis tRNAs are less modified than those in E. coli, even if some modifications, such as m1A22 or ms2t6A, are only found in the model Gram-positive bacteria. Many examples of non-orthologous displacements and of variations in the most complex pathways are described. Paralog issues make uncertain direct annotation transfer from E. coli to B. subtilis based on homology only without further experimental validation. This difficulty was shown with the identification of the B. subtilis enzyme that introduces ψ at positions 31/32 of the tRNAs. This work presents the most up to date list of tRNA modification genes in B. subtilis, identifies the gaps in knowledge, and lays the foundation for further work to decipher the physiological role of tRNA modifications in this important model organism and other bacteria.
Natural Ergot Alkaloids in Ocular Pharmacotherapy: Known Molecules for Novel Nanoparticle-Based Delivery Systems
Authors: Baldim Iara , Oliveira Wanderley P. , Kadian Varsha , Rao Rekha , Yadav Nitesh , Mahant Sheefali , Lucarini Massimo , Durazzo Alessandra , Da Ana Raquel , Capasso Raffaele , Souto Selma B. , Santini Antonello , Souto Eliana B.
Published: June 2020

Several pharmacological properties are attributed to ergot alkaloids as a result of their antibacterial, antiproliferative, and antioxidant effects. Although known for their biomedical applications (e.g., for the treatment of glaucoma), most ergot alkaloids exhibit high toxicological risk and may even be lethal to humans and animals. Their pharmacological profile results from the structural similarity between lysergic acid-derived compounds and noradrenalin, dopamine, and serotonin neurotransmitters. To reduce their toxicological risk, while increasing their bioavailability, improved delivery systems were proposed. This review discusses the safety aspects of using ergot alkaloids in ocular pharmacology and proposes the development of lipid and polymeric nanoparticles for the topical administration of these drugs to enhance their therapeutic efficacy for the treatment of glaucoma.
Tumoricidal and Bactericidal Properties of ZnONPs Synthesized Using Cassia auriculata Leaf Extract
Authors: Prasad Kollur Shiva , Prasad Shashanka K. , Ansari Mohammad Azam , Alzohairy Mohammad A. , Alomary Mohammad N. , AlYahya Sami , Srinivasa Chandrashekar , Murali Mahadevamurthy , Ankegowda Veena Malligere , Shivamallu Chandan
Published: June 2020

In this work, we aimed to synthesize zinc oxide nanoparticles (ZnONPs) using an aqueous extract of Cassia auriculata leaves (CAE) at room temperature without the provision of additional surfactants or capping agents. The formation of as-obtained ZnONPs was analyzed by UV–visible (ultraviolet) absorption and emission spectroscopy, X-ray photoemission spectroscopy (XPS), X-ray diffraction analysis (XRD), energy dispersive X-ray diffraction (EDX), thermogravimetric analysis/differential thermal analysis (TGA-DTA), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), and selected area electron diffraction (SAED). The XRD results reflect the wurtzite structure of as-prepared ZnONPs, which produced diffraction patterns showing hexagonal phases. The SEM images indicate that the morphology of as-prepared ZnONPs is composed of hexagonal nanostructures with an average diameter of 20 nm. The HR-TEM result shows that the inter-planar distance between two lattice fringes is 0.260 nm, which coincides with the distance between the adjacent (d-spacing) of the (002) lattice plane of ZnO. The fluorescence emission spectrum of ZnONPs dispersed in ethanol shows an emission maximum at 569 nm, revealing the semiconductor nature of ZnO. As-obtained ZnONPs enhanced the tumoricidal property of CAE in MCF-7 breast cancer cells without significant inhibition of normal human breast cells, MCF-12A. Furthermore, we have studied the antibacterial effects of ZnONPs, which showed direct cell surface contact, resulting in the disturbance of bacterial cell integrity.
Evidence-Based Physical Therapy for Individuals with Rett Syndrome: A Systematic Review
Authors: Fonzo Marta , Sirico Felice , Corrado Bruno
Published: June 2020

Rett syndrome is a rare genetic disorder that affects brain development and causes severe mental and physical disability. This systematic review analyzes the most recent evidence concerning the role of physical therapy in the management of individuals with Rett syndrome. The review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A total of 17319 studies were found in the main scientific databases. Applying the inclusion/exclusion criteria, 22 studies were admitted to the final phase of the review. Level of evidence of the included studies was assessed using the Oxford Centre for Evidence-Based Medicine—Levels of Evidence guide. Nine approaches to physical therapy for patients with Rett syndrome were identified: applied behavior analysis, conductive education, environmental enrichment, traditional physiotherapy with or without aids, hydrotherapy, treadmill, music therapy, computerized systems, and sensory-based treatment. It has been reported that patients had clinically benefited from the analysed approaches despite the fact that they did not have strong research evidence. According to the results, a multimodal individualized physical therapy program should be regularly recommended to patients with Rett syndrome in order to preserve autonomy and to improve quality of life. However, more high-quality studies are needed to confirm these findings.
The Value of Laboratory Parameters for Anemia, Renal Function, Systemic Inflammation and Nutritional Status as Predictors for Outcome in Elderly Patients with Head-and-Neck Cancers
Authors: Rühle Alexander , Haehl Erik , David Hélène , Kalckreuth Tobias , Sprave Tanja , Stoian Raluca , Zamboglou Constantinos , Gkika Eleni , Knopf Andreas , Grosu Anca-Ligia , Nicolay Nils Henrik
Published: June 2020

The purpose of this study was to evaluate the value of routine blood markers regarding their predictive potential for treatment outcomes of elderly head-and-neck squamous cell carcinoma (HNSCC) patients. In total, 246 elderly HNSCC patients (≥65 years) undergoing (chemo)radiotherapy from 2010 to 2018 were analyzed for treatment outcomes, depending on their hemoglobin, glomerular filtration rate (GFR), C-reactive protein (CRP) and albumin values, representing anemia, kidney function, inflammation and nutrition status, respectively. Local/locoregional control, progression-free and overall survival (OS) were calculated using the Kaplan–Meier method. Cox analyses were performed to examine the influence of blood parameters on oncological outcomes. In the univariate Cox regression analysis, hemoglobin ≤ 12 g/dL (HR = 1.536, p < 0.05), a GFR ≤ 60 mL/min/1.73 m2 (HR = 1.537, p < 0.05), a CRP concentration > 5 mg/L (HR = 1.991, p < 0.001) and albumin levels ≤ 4.2 g/dL (HR = 2.916, p < 0.001) were significant risk factors for OS. In the multivariate analysis including clinical risk factors, only performance status (HR = 2.460, p < 0.05) and baseline albumin (HR = 2.305, p < 0.05) remained significant prognosticators. Additionally, baseline anemia correlated with the prevalence of higher-grade chronic toxicities. We could show for the first time that laboratory parameters for anemia (and at least partly, tumor oxygenation), decreased renal function, inflammation and reduced nutrition status are associated with impaired survival in elderly HNSCC patients undergoing (chemo)radiotherapy.
Vitamin A Rich Diet Diminishes Early Urothelial Carcinogenesis by Altering Retinoic Acid Signaling
Authors: Zupančič Daša , Korać-Prlić Jelena , Kreft Mateja Erdani , Franković Lucija , Vilović Katarina , Jeruc Jera , Romih Rok , Terzić Janoš
Published: June 2020

Urinary bladder cancer is one of the leading malignancies worldwide, with the highest recurrence rates. A diet rich in vitamin A has proven to lower the risk of cancer, yet the molecular mechanisms underlying this effect are unknown. We found that vitamin A decreased urothelial atypia and apoptosis during early bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Vitamin A did not alter urothelial cell desquamation, differentiation, or proliferation rate. Genes like Wnt5a, involved in retinoic acid signaling, and transcription factors Pparg, Ppara, Rxra, and Hoxa5 were downregulated, while Sox9 and Stra6 were upregulated in early urothelial carcinogenesis. When a vitamin A rich diet was provided during BBN treatment, none of these genes was up- or downregulated; only Lrat and Neurod1 were upregulated. The lecithin retinol acyltransferase (LRAT) enzyme that produces all-trans retinyl esters was translocated from the cytoplasm to the nuclei in urothelial cells as a consequence of BBN treatment regardless of vitamin A rich diet. A vitamin A-rich diet altered retinoic acid signaling, decreased atypia and apoptosis of urothelial cells, and consequently diminished early urothelial carcinogenesis.
The Intermediate Filament Synemin Regulates Non-Homologous End Joining in an ATM-Dependent Manner
Authors: Deville Sara Sofia , Vehlow Anne , Förster Sarah , Dickreuter Ellen , Borgmann Kerstin , Cordes Nils
Published: June 2020

The treatment resistance of cancer cells is a multifaceted process in which DNA repair emerged as a potential therapeutic target. DNA repair is predominantly conducted by nuclear events; yet, how extra-nuclear cues impact the DNA damage response is largely unknown. Here, using a high-throughput RNAi-based screen in three-dimensionally-grown cell cultures of head and neck squamous cell carcinoma (HNSCC), we identified novel focal adhesion proteins controlling DNA repair, including the intermediate filament protein, synemin. We demonstrate that synemin critically regulates the DNA damage response by non-homologous end joining repair. Mechanistically, synemin forms a protein complex with DNA-PKcs through its C-terminal tail domain for determining DNA repair processes upstream of this enzyme in an ATM-dependent manner. Our study discovers a critical function of the intermediate filament protein, synemin in the DNA damage response, fundamentally supporting the concept of cytoarchitectural elements as co-regulators of nuclear events.
PTEN Protein Loss and Loss-of-Function Mutations in Gastric Cancers: The Relationship with Microsatellite Instability, EBV, HER2, and PD-L1 Expression
Authors: Kim Binnari , Kang So Young , Kim Deokgeun , Heo You Jeong , Kim Kyoung-Mee
Published: June 2020

Inactivation of phosphatase and tensin homolog (PTEN) is caused by multiple mechanisms, and loss of PTEN activity is related to the progression of various cancers. In gastric cancer (GC), the relationship between the loss of PTEN protein expression and various genetic alterations remains unclear. The effects of microsatellite instability (MSI), Epstein–Barr virus (EBV), HER2 overexpression, and PD-L1 expression on PTEN mutation have not been fully explored. We performed comprehensive cancer panel tests with a cohort of 322 tumor samples from patients with advanced GC. Immunohistochemistry for PTEN protein was performed in all cases, and the loss of protein expression was defined as a complete absence of nuclear staining. In total, 34 cases (10.6%) had pathogenic PTEN mutations, of which 19 (55.9%) showed PTEN protein loss. The most common PTEN variants associated with protein loss were p.R130 (n = 4) followed by p.R335, p.L265fs, and deletions (n = 2). All the ten nonsense mutations identified in the samples resulted in PTEN inactivation. In the remaining 288 GC cases with wild-type PTEN, protein loss was found in 35 cases (12.2%). Thus, PTEN mutations were significantly associated with PTEN protein loss (p = 5.232 × 10−10), high MSI (p = 3.936 × 10−8), and EBV-positivity (p = 0.0071). In conclusion, our results demonstrate that loss-of-function mutations in PTEN are a frequent genetic mechanism of PTEN inactivation in GC.
Basics and Frontiers on Pancreatic Cancer for Radiation Oncology: Target Delineation, SBRT, SIB Technique, MRgRT, Particle Therapy, Immunotherapy and Clinical Guidelines
Authors: Cellini Francesco , Arcelli Alessandra , Simoni Nicola , Caravatta Luciana , Buwenge Milly , Calabrese Angela , Brunetti Oronzo , Genovesi Domenico , Mazzarotto Renzo , Deodato Francesco , Mattiucci Gian Carlo , Silvestris Nicola , Valentini Vincenzo , Morganti Alessio Giuseppe
Published: June 2020

Pancreatic cancer represents a modern oncological urgency. Its management is aimed to both distal and local disease control. Resectability is the cornerstone of treatment aim. It influences the clinical presentation’s definitions as up-front resectable, borderline resectable and locally advanced (unresectable). The main treatment categories are neoadjuvant (preoperative), definitive and adjuvant (postoperative). This review will focus on (i) the current indications by the available national and international guidelines; (ii) the current standard indications for target volume delineation in radiotherapy (RT); (iii) the emerging modern technologies (including particle therapy and Magnetic Resonance [MR]-guided-RT); (iv) stereotactic body radiotherapy (SBRT), as the most promising technical delivery application of RT in this framework; (v) a particularly promising dose delivery technique called simultaneous integrated boost (SIB); and (vi) a multimodal integration opportunity: the combination of RT with immunotherapy.
RORα Regulates Cholesterol Metabolism of CD8+ T Cells for Anticancer Immunity
Authors: Lee In Kyu , Song Hyerin , Kim Hyerim , Kim Ik Soo , Tran Na Ly , Kim Sang-Heon , Oh Seung Ja , Lee Ji Min
Published: June 2020

Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, inflammation, cancer, and lipid metabolism. Here, we demonstrate that RORα is crucial for maintaining cholesterol homeostasis in CD8+ T cells by attenuating NF-κB transcriptional activity. Cholesterol sulfate, the established natural agonist of RORα, exhibits cellular cytotoxicity on, and increased effector responses in, CD8+ T cells. Transcript analysis reveals that the suppression of RORα leads to the upregulation of NF-κB target genes in T cells. Chromatin immunoprecipitation analysis was used to determine the corecruitment of RORα and histone deacetylase (HDAC) on NF-κB target promoters and the subsequent dismissal of coactivators for transcriptional repression. We demonstrate that RORα/HDAC-mediated attenuation of NF-κB signaling controls the balance of cholesterol metabolism in CD8+ T cells, and that therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of solid tumors including colon cancers.
CXCR4 Inhibition Enhances Efficacy of FLT3 Inhibitors in FLT3-Mutated AML Augmented by Suppressed TGF-β Signaling
Authors: Kim Bo-Reum , Jung Seung-Hyun , Han A-Reum , Park Gyeongsin , Kim Hee-Je , Yuan Bin , Battula Venkata Lokesh , Andreeff Michael , Konopleva Marina , Chung Yeun-Jun , Cho Byung-Sik
Published: June 2020

Given the proven importance of the CXCL12/CXCR4 axis in the stroma–acute myeloid leukemia (AML) interactions and the rapid emergence of resistance to FLT3 inhibitors, we investigated the efficacy and safety of a novel CXCR4 inhibitor, LY2510924, in combination with FLT3 inhibitors in preclinical models of AML with FLT3-ITD mutations (FLT3-ITD-AML). Quizartinib, a potent FLT3 inhibitor, induced apoptosis in FLT3-ITD-AML, while LY2510924 blocked surface CXCR4 without inducing apoptosis. LY2510924 significantly reversed stroma-mediated resistance against quizartinib mainly through the MAPK pathway. In mice with established FLT3-ITD-AML, LY2510924 induced durable mobilization and differentiation of leukemia cells, resulting in enhanced anti-leukemia effects when combined with quizartinib, whereas transient effects were seen on non-leukemic blood cells in immune-competent mice. Sequencing of the transcriptome of the leukemic cells surviving in vivo treatment with quizartinib and LY2510924 revealed that genes related to TGF-β signaling may confer resistance against the drug combination. In co-culture experiments of FLT3-ITD-AML and stromal cells, both silencing of TGF-β in stromal cells or TGF-β-receptor kinase inhibitor enhanced apoptosis by combined treatment. Disruption of the CXCL12/CXCR4 axis in FLT3-ITD-AML by LY2510924 and its negligible effects on normal immunocytes could safely enhance the potency of quizartinib, which may be further improved by blockade of TGF-β signaling.
Plasma Level of Circular RNA hsa_circ_0000190 Correlates with Tumor Progression and Poor Treatment Response in Advanced Lung Cancers
Authors: Luo Yung-Hung , Yang Yi-Ping , Chien Chian-Shiu , Yarmishyn Aliaksandr A. , Ishola Afeez Adekunle , Chien Yueh , Chen Yuh-Min , Huang Tsai-Wang , Lee Kang-Yun , Huang Wen-Chien , Tsai Ping-Hsing , Lin Tzu-Wei , Chiou Shih-Hwa , Liu Chao-Yu , Chang Cheng-Chang , Chen Ming-Teh , Wang Mong-Lien
Published: June 2020

Lung cancer (LC) causes the majority of cancer-related deaths. Circular RNAs (circRNAs) were reported to play roles in cancers by targeting pro- and anti-oncogenic miRNAs. However, the mechanisms of circRNAs in LC progression and their prognostic value of treatment response remain unclear. By using next generation sequencing (NGS) of LC cell lines’ transcriptomes, we identified highly overexpressed hsa_circ_0000190 and hsa_circ_000164 as potential biomarkers. By using the highly sensitive RT-ddPCR method, these circRNAs were shown to be secreted by cell lines and were detected in human blood. Clinical validation by RT-ddPCR was carried out on 272 (231 LC patients and 41 controls) blood samples. Higher hsa_circ_0000190 levels were associated with larger tumor size (p < 0.0001), worse histological type of adenocarcinoma (p = 0.0028), later stage (p < 0.0001), more distant metastatic organs (p = 0.0039), extrathoracic metastasis (p = 0.0004), and poor survival (p = 0.047) and prognosis. Using liquid biopsy-based RT-ddPCR, we discovered the correlation between increased hsa_circ_0000190 plasma level (p < 0.0001) and higher programmed death-ligand 1 (PD-L1) level in tumor (p = 0.0283). Notably, long-term follow-up of the immunotherapy treated cases showed that upregulated plasma hsa_circ_0000190 level correlated with poor response to systemic therapy and immunotherapy (p = 0.0002, 0.0058, respectively). Secretory circRNAs are detectable in blood by LB-based RT-ddPCR and may serve as blood-based biomarkers to monitor disease progression and treatment efficacy.
The NLRP3 Inflammasome as a Critical Actor in the Inflammaging Process
Authors: Sebastian-Valverde Maria , Pasinetti Giulio M.
Published: June 2020

As a consequence of the considerable increase in the human lifespan over the last century, we are experiencing the appearance and impact of new age-related diseases. The causal relationships between aging and an enhanced susceptibility of suffering from a broad spectrum of diseases need to be better understood. However, one specific shared feature seems to be of capital relevance for most of these conditions: the low-grade chronic inflammatory state inherently associated with aging, i.e., inflammaging. Here, we review the molecular and cellular mechanisms that link aging and inflammaging, focusing on the role of the innate immunity and more concretely on the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, as well as how the chronic activation of this inflammasome has a detrimental effect on different age-related disorders.
Immunotherapy in Myeloproliferative Diseases
Authors: Braun Lukas M. , Zeiser Robert
Published: June 2020

Myeloproliferative diseases, including myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS), are driven by genetic abnormalities and increased inflammatory signaling and are at high risk to transform into acute myeloid leukemia (AML). Myeloid-derived suppressor cells were reported to enhance leukemia immune escape by suppressing an effective anti-tumor immune response. MPNs are a potentially immunogenic disease as shown by their response to interferon-α treatment and allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Novel immunotherapeutic approaches such as immune checkpoint inhibition, tumor vaccination, or cellular therapies using target-specific lymphocytes have so far not shown strong therapeutic efficacy. Potential reasons could be the pro-inflammatory and immunosuppressive microenvironment in the bone marrow of patients with MPN, driving tumor immune escape. In this review, we discuss the biology of MPNs with respect to the pro-inflammatory milieu in the bone marrow (BM) and potential immunotherapeutic approaches.
Characterization of Hspb8 in Zebrafish
Authors: Dubińska-Magiera Magda , Niedbalska-Tarnowska Joanna , Migocka-Patrzałek Marta , Posyniak Ewelina , Daczewska Małgorzata
Published: June 2020

Hspb8 is a member of the small heat shock protein (sHSP) family. Its expression is known to be upregulated under heat shock. This protein interacts with different partners and can, therefore, be involved in various processes relevant to tissue integrity and functioning. In humans, mutations in the gene encoding Hspb8 can lead to the development of various diseases such as myopathies and neuropathies. In our study, we aimed to perform an in-depth characterization of zebrafish Hspb8 during zebrafish development. We applied techniques such as RT-qPCR, Western blot, immunofluorescence, co-immunoprecipitation, LC-MS, and morpholino-mediated knockdown. We broadened the knowledge regarding zebrafish hspb8 expression during development under normal and heat shock conditions as well as its tissue- and subcellular-specific localization. A co-IP analysis allowed us to conclude that zebrafish Hspb8 can interact with proteins such as Bag3 and Hsc70, which are crucial for formation of an autophagy-inducing complex. We also demonstrated that hspb8 morpholino-mediated knockdown has an impact on zebrafish embryos’ morphology, muscle ultrastructure, and motility behavior. Our research provides a valuable resource for the potential use of the zebrafish as a model for studying pathological conditions associated with hspb8 disorders.
Role of Cyclin-Dependent Kinase 1 in Translational Regulation in the M-Phase
Authors: Kalous Jaroslav , Jansová Denisa , Šušor Andrej
Published: June 2020

Cyclin dependent kinase 1 (CDK1) has been primarily identified as a key cell cycle regulator in both mitosis and meiosis. Recently, an extramitotic function of CDK1 emerged when evidence was found that CDK1 is involved in many cellular events that are essential for cell proliferation and survival. In this review we summarize the involvement of CDK1 in the initiation and elongation steps of protein synthesis in the cell. During its activation, CDK1 influences the initiation of protein synthesis, promotes the activity of specific translational initiation factors and affects the functioning of a subset of elongation factors. Our review provides insights into gene expression regulation during the transcriptionally silent M-phase and describes quantitative and qualitative translational changes based on the extramitotic role of the cell cycle master regulator CDK1 to optimize temporal synthesis of proteins to sustain the division-related processes: mitosis and cytokinesis.
Progressively De-Differentiated Pancreatic Cancer Cells Shift from Glycolysis to Oxidative Metabolism and Gain a Quiescent Stem State
Authors: Ambrosini Giulia , Dalla Pozza Elisa , Fanelli Giuseppina , Di Carlo Claudia , Vettori Andrea , Cannino Giuseppe , Cavallini Chiara , Carmona-Carmona Cristian Andres , Brandi Jessica , Rinalducci Sara , Scupoli Maria Teresa , Rasola Andrea , Cecconi Daniela , Palmieri Marta , Dando Ilaria
Published: June 2020

Pancreatic ductal adenocarcinoma (PDAC) is typically characterized by high chemoresistance and metastatic spread, features mainly attributable to cancer stem cells (CSCs). It is of central interest the characterization of CSCs and, in particular, the study of their metabolic features in order to selectively identify their peculiarities for an efficient therapeutic approach. In this study, CSCs have been obtained by culturing different PDAC cell lines with a specific growth medium. Cells were characterized for the typical stem/mesenchymal properties at short-, medium-, and long-term culture. Metabolomics, proteomics, analysis of oxygen consumption rate in live cells, and the effect of the inhibition of lactate transporter on cell proliferation have been performed to delineate the metabolism of CSCs. We show that gradually de-differentiated pancreatic cancer cells progressively increase the expression of both stem and epithelial-to-mesenchymal transition markers, shift their metabolism from a glycolytic to an oxidative one, and lastly gain a quiescent state. These quiescent stem cells are characterized by high chemo-resistance, clonogenic ability, and metastatic potential. Re-differentiation reverts these features, re-activating their proliferative capacity and glycolytic metabolism, which generally correlates with high aggressiveness. These observations add an important piece of knowledge to the comprehension of the biology of CSCs, whose metabolic plasticity could be exploited for the generation of promising and selective therapeutic approaches for PDAC patients.
Cetuximab and IL-15 Promote NK and Dendritic Cell Activation In Vitro in Triple Negative Breast Cancer
Authors: Juliá Estefanía Paula , Mordoh José , Levy Estrella Mariel
Published: June 2020

Triple Negative Breast Cancer (TNBC) treatment is still challenging, and immunotherapy is a potential approach in this tumor subtype. Cetuximab is an IgG1 monoclonal antibody (mAb) directed against Epidermic Growth Factor Receptor (EGFR), a protein overexpressed in a subgroup of TNBC patients and associated with poor prognosis. Previously, we demonstrated in vitro that Cetuximab triggers Ab-dependent cell cytotoxicity against TNBC cells. In this study, using co-cultures including TNBC cells, and NK and Dendritic Cells (DCs) from healthy donors, we studied the effect of Cetuximab-activated NK cells on DC function. Given that we already demonstrated that TNBC has an immunosuppressive effect on NK cells, we also tested Cetuximab combination with IL-15. We determined that Cetuximab opsonization of TNBC cells increased IFN-γ and TNF-α production by NK cells co-cultured with DCs. Moreover, we showed that NK cells activated by TNBC cells opsonized with Cetuximab promoted tumor material uptake and maturation of DCs, as well as their ability to produce IL-12. Furthermore, the stimulation with IL-15 increased the activation of NK cells and the maturation of DCs. These results suggest that IL-15 may enhance the efficacy of Cetuximab in the treatment of TNBC by promoting activation of both NK cells and DCs.
MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo
Authors: Schober Sebastian J. , Thiede Melanie , Gassmann Hendrik , Prexler Carolin , Xue Busheng , Schirmer David , Wohlleber Dirk , Stein Stefanie , Grünewald Thomas G. P. , Busch Dirk H. , Richter Guenther H. S. , Burdach Stefan E. G. , Thiel Uwe
Published: June 2020

In this study we report the functional comparison of T cell receptor (TCR)-engineered major histocompatibility complex (MHC) class I-restricted CD4+ versus CD8+ T cells targeting a peptide from six transmembrane epithelial antigen of the prostate 1 (STEAP1) in the context of HLA-A*02:01. STEAP1 is a tumor-associated antigen, which is overexpressed in many cancers, including Ewing sarcoma (EwS). Based on previous observations, we postulated strong antitumor potential of tumor-redirected CD4+ T cells transduced with an HLA class I-restricted TCR against a STEAP1-derived peptide. We compared CD4+ T cell populations to their CD8+ counterparts in vitro using impedance-based xCELLigence and cytokine/granzyme release assays. We further compared antitumor activity of STEAP130-TCR transgenic (tg) CD4+ versus CD8+ T cells in tumor-bearing xenografted Rag2−/−γc−/− mice. TCR tgCD4+ T cells showed increased cytotoxic features over time with similar functional avidity compared to tgCD8+ cells after 5–6 weeks of culture. In vivo, local tumor control was equal. Assessing metastatic organotropism of intraveniously (i.v.) injected tumors, only tgCD8+ cells were associated with reduced metastases. In this analysis, EwS-redirected tgCD4+ T cells contribute to local tumor control, but fail to control metastatic outgrowth in a model of xenografted EwS.
Effect of Low-Concentration Rb+ Mixing on Semiconductor Majority Charge Carriers Type of Perovskite Light-Absorption Layer by Using Two-Step Spin-Coating Method
Authors: Liu Baoyu , Zou Xiaoping , Cheng Jin , Ling Tao , Yao Yujun , Chen Dan , Chang Chuangchuang , Yu Xing , Wang Junqi , Zhou Zixiao , Li Guangdong
Published: June 2020

In recent years, perovskite materials have been the subject of great progress in optoelectronic devices. The perovskite layer is the light absorption layer of perovskite solar cells (PSCs), and the majority charge carriers type play a crucial role in the formation of a P–N junction. In this paper, the light absorption layer of PSCs was Rb-mixed at a low concentrations by using a two-step spin-coating method, which could adjust the majority charge carriers type in perovskite films from N-type to P-type, and it has little influence on the crystal structure and light absorption capacity of perovskite. In addition, low concentration Rb-mixing is different from high concentration Rb-mixing. With increasing Rb-mixing concentration, the perovskite grains does not change shape. Although the quality of perovskite films deteriorated and the PL peaks exhibit a slight blue shift after mixing, the efficiency only slightly decreased, indicating that the new P-N hetero-junction was still formed after mixing, which provided a new idea for the future research of homo-junction PSCs.
Oxygen Plasma Improved Shear Strength of Bonding between Zirconia and Composite Resin
Authors: Yan Min , Yang Chun-Chuan , Chen Yi-Hsuan , Ding Shinn-Jyh
Published: June 2020

Improving the strength of the bonding of zirconia to composite resins remains a challenge in dental restorations. The purpose of this study was to evaluate the shear strength of the bonding of zirconia to composite resins, thereby verifying the hypothesis that as the power of the non-thermal oxygen plasma increases, the bonding strength of the plasma-treated zirconia is increased. The effects of the oxygen plasma power (100, 200, and 400 W) on the surface structure, chemical composition, and hydrophilicity of the zirconia and the strength of the bonding between zirconia and composite resin were investigated. As a result, after different plasma power treatments, the surface structure and phase composition of zirconia were not different from those of zirconia without treatment. However, the oxygen plasma treatment not only reduced carbon adsorption but also greatly increased the hydrophilicity of the zirconia surface. More importantly, the strength of the bonding between the plasma-treated zirconia and composite resin was significantly higher than that in the corresponding control group without plasma treatment. Regardless of whether the zirconia was pristine or sandblasted, the higher the plasma power, the greater the bond strength obtained. The conclusion is that the oxygen plasma treatment of zirconia can effectively improve the strength of the bonding between the zirconia and composite resin without damaging the microstructure and phase composition of the zirconia.
Local Vibrational Mode Analysis of π–Hole Interactions between Aryl Donors and Small Molecule Acceptors
Authors: Yannacone Seth , Freindorf Marek , Tao Yunwen , Zou Wenli , Kraka Elfi
Published: June 2020

11 aryl–lone pair and three aryl–anion π –hole interactions are investigated, along with the argon–benzene dimer and water dimer as reference compounds, utilizing the local vibrational mode theory, originally introduced by Konkoli and Cremer, to quantify the strength of the π –hole interaction in terms of a new local vibrational mode stretching force constant between the two engaged monomers, which can be conveniently used to compare different π –hole systems. Several factors have emerged which influence strength of the π –hole interactions, including aryl substituent effects, the chemical nature of atoms composing the aryl rings/ π –hole acceptors, and secondary bonding interactions between donors/acceptors. Substituent effects indirectly affect the π –hole interaction strength, where electronegative aryl-substituents moderately increase π –hole interaction strength. N-aryl members significantly increase π –hole interaction strength, and anion acceptors bind more strongly with the π –hole compared to charge neutral acceptors (lone–pair donors). Secondary bonding interactions between the acceptor and the atoms in the aryl ring can increase π –hole interaction strength, while hydrogen bonding between the π –hole acceptor/donor can significantly increase or decrease strength of the π –hole interaction depending on the directionality of hydrogen bond donation. Work is in progress expanding this research on aryl π –hole interactions to a large number of systems, including halides, CO, and OCH3− as acceptors, in order to derive a general design protocol for new members of this interesting class of compounds.
Is the Distribution of Two Rare Orchis Sister Species Limited by Their Main Mycobiont?
Authors: Calevo Jacopo , Voyron Samuele , Ercole Enrico , Girlanda Mariangela
Published: June 2020

As orchids rely on their mycorrhizal fungi for nutrient supply, their spatial range is dependent on the distribution of orchid mycorrhizal (OM) fungi. We addressed possible correlations between mycorrhizal specificity and the geographic distribution of orchids and OM fungi in three populations of the rare sister species Orchis patens and O. canariensis. Metabarcoding of the fungal ITS2 region indicated that, although adult plants of either species were colonized by several ceratobasidioid, tulasnelloid, sebacinoid and serendipitoid fungi, the mycobiont spectra were dominated by Tulasnella helicospora (which occurred in 100% of examined plants with high read numbers), which is a globally distributed fungus. In vitro assays with a T. helicospora isolate obtained from O. patens indicated the effectiveness of this OM fungus at germinating seeds of its native host. At a local scale, higher read numbers for T. helicospora were found in soil samples collected underneath O. patens roots than at locations unoccupied by the orchid. Although these findings suggest that the geographical pattern of the main fungal symbiont does not limit the distribution of O. patens and O. canariensis at this scale, the actual causal link between orchid and OM fungal occurrence/abundance still needs to be better understood.