bluuebunny/crossref_metadata_2025 huggingface dataset:
Determination of Optimum Frequency for Electromagnetic-Assisted Nanofluid Core Flooding
Authors: Wahaab Fatai A. , Yahya Noorhana , Shafie Afza , Soleimani Hassan , Rostami Amir , Ganeson Menaka
Published: October 2019

The coupling of electromagnetic (EM) wave to nanoflooding experiments, termed EM-assisted nanoflooding has gained enormous attention in recent years. This brings about the consideration of transmitter efficiency and the propagation pattern of the ensuing EM wave, both of which depend on reservoir electromagnetic properties. However, this has not been considered in previous works, despite its potential to improve the efficiency of the process through energy maximization. Hence, this study considers the effects of reservoir EM properties on the operation of a transmitter. The EM properties of saturated reservoir rock samples were measured. Afterward, a half-wave dipole antenna was modeled in a cylindrical reservoir based on the measured EM properties. The EM propagation pattern of the antenna was simulated in a frequency range of 100 MHz—2.0 GHz using the finite element method. The antenna was found to display dual resonance (at 800 MHz and 1.3 GHz) for sandstone saturated with oil, brine and nanofluid. Application of the EM wave at resonance frequency can help increase the efficiency of EM-assisted nanoflooding.
Self-Injection Locking of a Distributed Feedback Laser Diode Using a High-Finesse Fabry-Perot Microcavity
Authors: Wei Xing , Xie ZhenDa , Zhu Shi-Ning
Published: October 2019

Optical microcavities have been widely used in nonlinear optics, quantum optics, and laser technologies. Here we demonstrate the self-injection locking of a distributed feedback diode laser using home-made high-finesse Fabry-Perot microcavity. The Fabry-Perot microcavity is fabricated from an x-cut lithium niobate crystal with highly reflective coatings. Frequency pulling effect can be observed for a successful locking, and results in a single-longitudinal mode lasing with narrow linewidth. The lasing wavelength and output power are found robust to the laser-diode current and temperature variations, in comparison to the free-running case. We further characterize the laser linewidth with beat note measurement with a high-performance external cavity diode laser, with beat-note linewidth of 601.85 kHz. This results shows a new method for laser frequency stabilization in a simple setup, and may find applications in telecommunication and spectroscopy.
Improvement Methods for Reduction of the High Stress of Ultra-High Asphalt Concrete Core Dams
Authors: Gao Jun , Dang Faning , Ma Zongyuan , Xue Yi , Ren Jie
Published: October 2019

With the rapid development of asphalt concrete core rockfill dams (ACCRDs), the construction of ultra-high asphalt concrete core rockfill dams (UACCRDs) has been improved significantly. However, the security problems of asphalt concrete core (ACC) become very prominent with the increase of dam height. The shear failure control standard and tensile failure control standard of ACC are suggested. The mechanisms of ACC that generate high shear stress and high tensile stress are investigated. Based on the definition of stress level and the transmission mechanism of arch structures, the improvement methods that reduce the high shear stress and high tensile stress of ultra-high asphalt concrete core (UACC) are proposed and investigated. The results show that the stress level of ACC can be reduced significantly by the increase of the strength parameters of ACC (failure ratio, cohesion, and internal friction angle). The following value ranges of the failure ratio, cohesion, and internal friction angle of ACC for the suitable construction of UACCRDs are recommended: Rf ≥ 0.75, C ≥ 0.30 MPa, and φ ≥ 28.5° (h = 150 m), with the growth gradient adjusted by 5%, 15%, and 5%/25 m. The tensile stress and tensile stress area can be reduced obviously by the new type of dams (curved asphalt concrete core rockfill dams (CACCRDs)). The value ranges of the curvature of CACC (k ≥ 1.0 × 10−3) for the suitable construction of UACCRDs are recommended.
Influence of Gravity on Molten Pool Behavior and Analysis of Microstructure on Various Welding Positions in Pulsed Gas Metal Arc Welding
Authors: Park Jin-Hyeong , Kim Sung-Hwan , Moon Hyeong-Soon , Kim Myung-Hyun
Published: October 2019

This study performed welding on various welding positions in the flat, overhead, and vertical down positions using a pulsed gas metal arc welding (P-GMAW) process. Despite the same amount of heat input on various welding positions, the welding characteristics varied depending on the welding positions. The effect of gravity on the welding process determined the different formation of the weld bead, and the influence of molten pool behavior on various welding positions changed the microstructure in the weld metal. The current and voltage signals were synchronized with a high-speed camera using a data acquisition (DAQ) system. To induce the one pulse one drop (OPOD) process of metal transfer, the shielding gas was used 95% Ar+5% CO2. The microstructure of the weld metal was analyzed in relation to molten pool behavior.
Development of a Novel Variable-Diameter Wheel
Authors: Zeng Wen , Xu Guoyan , Jiang Hui , Gao Feng
Published: October 2019

Variable-diameter wheels balance the high mobility and limited volume of a planetary rover. Moreover, these wheels allow a rover to adjust its body attitude to adapt to rough terrains. These functions are achieved through the expansion–retraction motion of the variable-diameter mechanisms in the wheels. Thus, the traditional wheel design focuses on these mechanisms. To further facilitate its application, we propose a new concept variable-diameter wheel that considers the mechanism characteristics and wheel performances. This new wheel configuration is presented along with the corresponding transmission system, design, and analysis methods. Kinematic equations of the mechanism were established and then applied to synthesize the wheel dimensions. The load–deflection relationship of the wheels was analytically derived by developing a modified pseudo-rigid-body model (PRBM). Finite element analysis (FEA) simulations were performed to validate the design and analysis. In conclusion, the proposed novel wheel is extremely beneficial for rough-terrain locomotion systems. Furthermore, the design and analysis approaches used in this study are applicable for other expandable wheels.
Low-Loss Active Grid Impedance Cancellation in Grid-Connected Inverters with LCL Filter
Authors: Peng Yuqi , He Yuanbin , Hang Lijun
Published: October 2019

Distributed power inverters with inductive capacitive–inductive (LCL) filters have become popular in distributed power generation system. However, due to unknown grid impedance, the inverters are confronted with challenges of local filter resonance, poor power quality, and multiple interactive resonance. This paper proposes a low-loss active compensator that can counteract effects of the grid impedance on the current control performance of single-phase grid-connected inverter with an LCL filter. The compensator utilizes dual unit point-of-common-coupling voltage feedforward control mechanisms (VFFC), in which one is integrated with the inverter controller, and the other is generated through an extra low voltage source converter (LV-VSC) in series with the filter capacitor. The LV-VSC has no additional passive inductive-capacitive filtering elements and provides very low volt-ampere. To confirm its validity, a single-phase inverter testbed integrated with the compensator was built. The experimental results validate the current-controlled performance enhancement of the proposed inverter system operating under different grid conditions.
A Novel Piezoelectric Ceramic Actuator with Scissoring Composite Vibration for Medical Applications
Authors: Yang Jingjing , Zhang Qiang , Xu Taojin
Published: October 2019

This paper presents a novel scissoring composite actuator which can successfully degenerate longitudinal vibration into scissoring vibration at actuator tips for potential medical applications. The proposed actuator consists of back mass, multilayer piezoceramic stack, front mass with netted pre-stress structure and beam. The actuator is driven by only a small axially poled multilayer piezoceramic stack. Moreover, a special symmetrical grooved structure is designed at the beam end to convert longitudinal driving vibration into opposite bending vibrations at the beam tip, resulting in scissoring-type composite vibration. The converted scissoring vibration concentrates on the beam tip without any deflection along other parts, which is highly desirable for narrow-spaced medical operations. The proposed design principle is demonstrated by structural analysis and verified by different types of finite element modeling (FEM) simulations, including Eigen frequency analysis, harmonic analysis, and transient analysis. The results reveal the design effectiveness of the actuator’s structure on scissoring-type mode excitation. Finally, a prototype of the proposed piezoelectric actuator is fabricated and tested, rendering superior performance and highly reliable mode conversion. The proposed actuator exhibits potential for advanced medical applications.
Pre-Inscribed Laser Surface Pattering for Increased Joining Strength in Laser Fusion Bonding of CFRP and Zinc-Coated Steel
Authors: Kam Dong-Hyuck , Jeon Nam-Ki , Jeong Taek-Eon , Kim Jedo
Published: October 2019

In this study, we present improved fusion-bonding strength results between carbon fiber-reinforced polyetheretherketone (CFR-PEEK) and zinc-coated steel through the introduction of pre-inscribed laser surface patterns. Optimized laser welding parameters, including laser power, focal position, pitch, number of passes, and clamping pressure, are presented along with parameters for producing the rectangular laser patterns. It was found that for the optimized parameters, the tensile shear strength of the welded samples is improved by as much as 100% when pre-inscribed laser patterns are present. Detailed SEM images of the fractured fusion welded joint samples after the tensile shear test are presented for analysis. The tight bonding between the polymer matrix and the zinc-coated steel inside the formed grooves is found to be the main reason behind the increased tensile shear strength. A comparison of the tensile shear loads for various joining methods is also presented and discussed.
Study of Persistent Foggy-Hazy Composite Pollution in Winter over Huainan Through Ground-Based and Satellite Measurements
Authors: Fu Songlin , Xie Chenbo , Zhuang Peng , Tian Xiaomin , Zhang Zhanye , Wang Bangxin , Liu Dong
Published: October 2019

Through the observation of ground-based LIDAR and satellite sensors, the weather conditions of continuous foggy-hazy alternations in the Huainan region from 26 December 2016 to 5 January 2017 were analyzed and observed. In this study, the formation and influence of this event were discussed by analyzing pollutant concentrations, meteorological factors and aerosol optical characteristics. The concentrations of PM10 and PM2.5 increased significantly. The maximum value of PM10 was 412 μg/m3, and the maximum value of PM2.5 was 258 μg/m3. The transportation of pollutants and the production of man-made pollutants promote the accumulation of pollutants. In this weather process, meteorological factors such as the surface wind speed, humidity, surface temperature, and inversion also promote the accumulation of pollutants, which is the main reason for the formation of this weather process. Furthermore, the near surface air mass mainly came from the cities near the Huainan region and the heavily polluted areas in the north, while the upper air mass came from Inner Mongolia. In this paper, piecewise inversion was adopted to achieve accurate all-weather extinction coefficient profile inversion by reasonably selecting a cloud LIDAR ratio through a backscatter ratio, and the LIDAR ratio of cloud in this period was 22.57–34.14 Sr. By means of extinction coefficient inversion and correlation analysis, the correlation index of PM2.5 and the aerosol optical depth (AOD) was 0.7368, indicating that there was a positive correlation between PM2.5 and AOD, and AOD can also reflect the pollution condition of this region. The formation process of foggy-hazy weather in the Huainan region studied in this paper can provide a research basis for foggy-hazy pollution in this region.
Measurement of SO2 and NO2 in Ship Plumes Using Rotary Unmanned Aerial System
Authors: Zhou Fan , Gu Jing , Chen Wei , Ni Xunpeng
Published: October 2019

A key research problem in the field of ship emissions is how to perform efficient, accurate, and timely measurements of pollutant gases in a ship’s plume. To address this, we have designed and implemented an unmanned aerial system (UAS) that consists of a rotary unmanned aerial vehicle (UAV), a lightweight pod for exhaust monitoring, and a mobile control terminal. The UAV carries the pod and a camera and can fly into a plume at close range. The pod is equipped with a gas acquisition module, SO2 and NO2 sensors, and communication modules to measure the gases in real time. The mobile control terminal is convenient for operators and receives real-time video and measured gas concentrations. We measured SO2 and NO2 in six ship plumes in 2018 to verify the effectiveness and accuracy of the UAS. The SO2/NO2 ratios in high-sulfur fuel were significantly higher than of those in low-sulfur fuel and can thus be used for distinguishing the sulfur content of ship fuel. In comparison to land-based and airborne-based measurements, we conclude that the UAS provides an active, close-range, low-cost, and accurate measurement approach for monitoring ship emissions in real time.
The Effect of Clouds as an Additional Opacity Source on the Inferred Metallicity of Giant Exoplanets
Authors: Poser Anna Julia , Nettelmann Nadine , Redmer Ronald
Published: October 2019

Atmospheres regulate the planetary heat loss and therefore influence planetary thermal evolution. Uncertainty in a giant planet’s thermal state contributes to the uncertainty in the inferred abundance of heavy elements it contains. Within an analytic atmosphere model, we here investigate the influence that different cloud opacities and cloud depths can have on the metallicity of irradiated extrasolar gas giants, which is inferred from interior models. In this work, the link between inferred metallicity and assumed cloud properties is the thermal profile of atmosphere and interior. Therefore, we perform coupled atmosphere, interior, and evolution calculations. The atmosphere model includes clouds in a much simplified manner; it includes long-wave absorption but neglects shortwave scattering. Within that model, we show that optically thick, high clouds have negligible influence, whereas deep-seated, optically very thick clouds can lead to warmer deep tropospheres and therefore higher bulk heavy element mass estimates. For the young hot Jupiter WASP-10b, we find a possible enhancement in inferred metallicity of up to 10% due to possible silicate clouds at ∼0.3 bar. For WASP-39b, whose observationally derived metallicity is higher than predicted by cloudless models, we find an enhancement by at most 50%. However, further work on cloud properties and their self-consistent coupling to the atmospheric structure is needed in order to reduce uncertainties in the choice of model parameter values, in particular of cloud opacities.
Genome-Wide Identification and Functional Characterization of the Phosphate Transporter Gene Family in Sorghum
Authors: Wang Jiahui , Yang Yang , Liao Lingzi , Xu Jiawei , Liang Xiao , Liu Wen
Published: October 2019

The phosphate transporter (PHT) family mediates the uptake and translocation of the essential macronutrient phosphorus (P) in plants. In this study, 27 PHT proteins in Sorghum were identified via bioinformatics tools. Phylogenetic analysis of their protein sequences in comparison with those family proteins from Arabidopsis and rice indicated that these proteins could be clustered into five typical subfamilies. There are 12 SbPHT1 members, one SbPHT2, six SbPHT3s, six SbPHT4s, and two SbPHOs in Sorghum. Further analysis of the gene structure, conserved motifs, subcellular localization, and transmembrane domains suggested that these features are relatively conserved within each subfamily. Meanwhile, the qRT-PCR assay implied that SbPHT1;2, SbPHT1;11, and SbPHT4;6 were significantly upregulated in roots when exposed to low-phosphate conditions, suggesting that these genes might be involved in P uptake in low-phosphate conditions. Our study will increase our understanding of the roles of phosphate transporters in Sorghum.
Biochemical Characterization of a Novel α/β-Hydrolase/FSH from the White Shrimp Litopenaeus vannamei
Authors: Garcia-Orozco Karina D. , Cinco-Moroyoqui Francisco , Angulo-Sanchez Lucía T. , Marquez-Rios Enrique , Burgos-Hernandez Armando , Cardenas-Lopez Jose L. , Gomez-Aguilar Carolina , Corona-Martinez David O. , Saab-Rincon Gloria , Sotelo-Mundo Rogerio R.
Published: October 2019

(1) Background: Lipases and esterases are important enzymes that share the α/β hydrolase fold. The activity and cellular localization are important characteristics to understand the role of such enzymes in an organism. (2) Methods: Bioinformatic and biochemical tools were used to describe a new α/β hydrolase from a Litopenaeus vannamei transcriptome (LvFHS for Family Serine Hydrolase). (3) Results: The enzyme was obtained by heterologous overexpression in Escherichia coli and showed hydrolytic activity towards short-chain lipid substrates and high affinity to long-chain lipid substrates. Anti-LvFHS antibodies were produced in rabbit that immunodetected the LvFSH enzyme in several shrimp tissues. (4) Conclusions: The protein obtained and analyzed was an α/β hydrolase with esterase and lipase-type activity towards long-chain substrates up to 12 carbons; its immunodetection in shrimp tissues suggests that it has an intracellular localization, and predicted roles in energy mobilization and signal transduction.
Clinical Role of Aspirin in Mood Disorders: A Systematic Review
Authors: Ng Qin Xiang , Ramamoorthy Krishnapriya , Loke Wayren , Lee Matthew Wei Liang , Yeo Wee Song , Lim Donovan Yutong , Sivalingam Vivekanandan
Published: October 2019

Worldwide, depression and bipolar disorder affect a large and growing number of people. However, current pharmacotherapy options remain limited. Despite adequate treatment, many patients continue to have subsyndromal symptoms, which predict relapse in bipolar illness and often result in functional impairments. Aspirin, a common nonsteroidal anti-inflammatory drug (NSAID), has purported beneficial effects on mood symptoms, showing protective effects against depression in early cohort studies. This systematic review thus aimed to investigate the role of aspirin in mood disorders. Using the keywords (aspirin or acetylsalicy* or asa) and (mood or depress* or bipolar or mania or suicid*), a comprehensive search of PubMed, EMBASE, Medline, PsycINFO, Clinical Trials Register of the Cochrane Collaboration Depression, Anxiety and Neurosis Group (CCDANTR), Clinicaltrials.gov and Google Scholar databases found 13,952 papers published in English between 1 January 1988 and 1 May 2019. A total of six clinical studies were reviewed. There were two randomized, placebo-controlled, double-blind trials and populations drawn from two main cohort studies (i.e., the Geelong Osteoporosis Study and the Osteoarthritis Initiative study). Using a random-effects model, the pooled hazard ratio of the three cohort studies was 0.624 (95% confidence interval: 0.0503 to 1.198, p = 0.033), supporting a reduced risk of depression with aspirin exposure. Overall, the dropout rates were low, and aspirin appears to be well-tolerated with minimal risk of affective switch. In terms of methodological quality, most studies had a generally low risk of bias. Low-dose aspirin (80 to 100 mg/day) is safe, well-tolerated and potentially efficacious for improving depressive symptoms in both unipolar and bipolar depression. Due to its ability to modulate neuroinflammation and central nervous system processes, aspirin may also have valuable neuroprotective and pro-cognitive effects that deserve further exploration. Further randomized, controlled trials involving the adjunctive use of aspirin should be encouraged to confirm its therapeutic benefits.
Autoimmune Encephalitis and CSF Anti-GluR3 Antibodies in an MS Patient after Alemtuzumab Treatment
Authors: Buscarinu Maria Chiara , Fornasiero Arianna , Pellicciari Giulia , Reniè Roberta , Landi Anna Chiara , Bozzao Alessandro , Cappelletti Cristina , Bernasconi Pia , Ristori Giovanni , Salvetti Marco
Published: October 2019

A 45-year-old Italian woman, affected by relapsing–remitting multiple sclerosis (RR-MS) starting from 2011, started treatment with alemtuzumab in July 2016. Nine months after the second infusion, she had an immune thrombocytopenic purpura (ITP) with complete recovery after steroid treatment. Three months after the ITP, the patient presented with transient aphasia, cognitive deficits, and focal epilepsy. Serial brain magnetic resonance imaging showed a pattern compatible with encephalitis. Autoantibodies to glutamate receptor 3 peptide A and B were detected in cerebrospinal fluid and serum, in the absence of any other diagnostic cues. After three courses of intravenous immunoglobulin (0.4 mg/kg/day for 5 days, 1 month apart), followed by boosters (0.4 mg/kg/day) every 4–6 weeks, her neurological status improved and is currently comparable with that preceding the encephalitis. Autoimmune complications of the central nervous system during alemtuzumab therapy are relatively rare: only one previous case of autoimmune encephalitis following alemtuzumab treatment has been reported to date.
Models for Understanding Resistance to Chemotherapy in Liver Cancer
Authors: Marin Jose J. G. , Herraez Elisa , Lozano Elisa , Macias Rocio I. R. , Briz Oscar
Published: October 2019

The lack of response to pharmacological treatment constitutes a substantial limitation in the handling of patients with primary liver cancers (PLCs). The existence of active mechanisms of chemoresistance (MOCs) in hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma hampers the usefulness of chemotherapy. A better understanding of MOCs is needed to develop strategies able to overcome drug refractoriness in PLCs. With this aim, several experimental models are commonly used. These include in vitro cell-free assays using subcellular systems; studies with primary cell cultures; cancer cell lines or heterologous expression systems; multicellular models, such as spheroids and organoids; and a variety of in vivo models in rodents, such as subcutaneous and orthotopic tumor xenografts or chemically or genetically induced liver carcinogenesis. Novel methods to perform programmed genomic edition and more efficient techniques to isolate circulating microvesicles offer new opportunities for establishing useful experimental tools for understanding the resistance to chemotherapy in PLCs. In the present review, using three criteria for information organization: (1) level of research; (2) type of MOC; and (3) type of PLC, we have summarized the advantages and limitations of the armamentarium available in the field of pharmacological investigation of PLC chemoresistance.
The Metabolic Inhibitor CPI-613 Negates Treatment Enrichment of Ovarian Cancer Stem Cells
Authors: Bellio Chiara , DiGloria Celeste , Spriggs David R. , Foster Rosemary , Growdon Whitfield B. , Rueda Bo R.
Published: October 2019

One of the most significant therapeutic challenges in the treatment of ovarian cancer is the development of recurrent platinum-resistant disease. Cancer stem cells (CSCs) are postulated to contribute to recurrent and platinum-resistant ovarian cancer (OvCa). Drugs that selectively target CSCs may augment the standard of care cytotoxics and have the potential to prevent and/or delay recurrence. Increased reliance on metabolic pathway modulation in CSCs relative to non-CSCs offers a possible therapeutic opportunity. We demonstrate that treatment with the metabolic inhibitor CPI-613 (devimistat, an inhibitor of tricarboxylic acid (TCA) cycle) in vitro decreases CD133+ and CD117+ cell frequency relative to untreated OvCa cells, with negligible impact on non-CSC cell viability. Additionally, sphere-forming capacity and tumorigenicity in vivo are reduced in the CPI-613 treated cells. Collectively, these results suggest that treatment with CPI-613 negatively impacts the ovarian CSC population. Furthermore, CPI-613 impeded the unintended enrichment of CSC following olaparib or carboplatin/paclitaxel treatment. Collectively, our results suggest that CPI-613 preferentially targets ovarian CSCs and could be a candidate to augment current treatment strategies to extend either progression-free or overall survival of OvCa.
Size Matters in the Cytotoxicity of Polydopamine Nanoparticles in Different Types of Tumors
Authors: Nieto Celia , Vega Milena A. , Enrique Jesús , Marcelo Gema , Martín del Valle Eva M.
Published: October 2019

Polydopamine has acquired great relevance in the field of nanomedicine due to its physicochemical properties. Previously, it has been reported that nanoparticles synthetized from this polymer are able to decrease the viability of breast and colon tumor cells. In addition, it is well known that the size of therapeutic particles plays an essential role in their effect. As a consequence, the influence of this parameter on the cytotoxicity of polydopamine nanoparticles was studied in this work. For this purpose, polydopamine nanoparticles with three different diameters (115, 200 and 420 nm) were synthetized and characterized. Their effect on the viability of distinct sorts of human carcinomas (breast, colon, liver and lung) and stromal cells was investigated, as well as the possible mechanisms that could be responsible for such cytotoxicity. Moreover, polydopamine nanoparticles were also loaded with doxorubicin and the therapeutic action of the resulting nanosystem was analyzed. As a result, it was demonstrated that a smaller nanoparticle size is related to a more enhanced antiproliferative activity, which may be a consequence of polydopamine’s affinity for iron ions. Smaller nanoparticles would be able to adsorb more lysosomal Fe3+ and, when they are loaded with doxorubicin, a synergistic effect can be achieved.
Intra-Patient Heterogeneity of Circulating Tumor Cells and Circulating Tumor DNA in Blood of Melanoma Patients
Authors: Gorges Katharina , Wiltfang Lisa , Gorges Tobias , Sartori Alexander , Hildebrandt Lina , Keller Laura , Volkmer Beate , Peine Sven , Babayan Anna , Moll Ingrid , Schneider Stefan , Twarock Sören , Mohr Peter , Fischer Jens , Pantel Klaus
Published: October 2019

Despite remarkable progress in melanoma therapy, the exceptional heterogeneity of the disease has prevented the development of reliable companion biomarkers for the prediction or monitoring of therapy responses. Here, we show that difficulties in detecting blood-based markers, like circulating tumor cells (CTC), might arise from the translation of the mutational heterogeneity of melanoma cells towards their surface marker expression. We provide a unique method, which enables the molecular characterization of clinically relevant CTC subsets, as well as circulating tumor DNA (ctDNA), from a single blood sample. The study demonstrates the benefit of a combined analysis of ctDNA and CTC counts in melanoma patients, revealing that CTC subsets and ctDNA provide synergistic real-time information on the mutational status, RNA and protein expression of melanoma cells in individual patients, in relation to clinical outcome.
Protein Kinase A Distribution in Meningioma
Authors: Caretta Antonio , Denaro Luca , D’Avella Domenico , Mucignat-Caretta Carla
Published: October 2019

Deregulation of intracellular signal transduction pathways is a hallmark of cancer cells, clearly differentiating them from healthy cells. Differential intracellular distribution of the cAMP-dependent protein kinases (PKA) was previously detected in cell cultures and in vivo in glioblastoma and medulloblastoma. Our goal is to extend this observation to meningioma, to explore possible differences among tumors of different origins and prospective outcomes. The distribution of regulatory and catalytic subunits of PKA has been examined in tissue specimens obtained during surgery from meningioma patients. PKA RI subunit appeared more evenly distributed throughout the cytoplasm, but it was clearly detectable only in some tumors. RII was present in discrete spots, presumably at high local concentration; these aggregates could also be visualized under equilibrium binding conditions with fluorescent 8-substituted cAMP analogues, at variance with normal brain tissue and other brain tumors. The PKA catalytic subunit showed exactly overlapping pattern to RII and in fixed sections could be visualized by fluorescent cAMP analogues. Gene expression analysis showed that the PKA catalytic subunit revealed a significant correlation pattern with genes involved in meningioma. Hence, meningioma patients show a distinctive distribution pattern of PKA regulatory and catalytic subunits, different from glioblastoma, medulloblastoma, and healthy brain tissue. These observations raise the possibility of exploiting the PKA intracellular pathway as a diagnostic tool and possible therapeutic interventions.
Secondary Somatic Mutations in G-Protein-Related Pathways and Mutation Signatures in Uveal Melanoma
Authors: Piaggio Francesca , Tozzo Veronica , Bernardi Cinzia , Croce Michela , Puzone Roberto , Viaggi Silvia , Patrone Serena , Barla Annalisa , Coviello Domenico , J. Jager Martine , van der Velden Pieter A. , Zeschnigk Michael , Cangelosi Davide , Eva Alessandra , Pfeffer Ulrich , Amaro Adriana
Published: October 2019

Background: Uveal melanoma (UM), a rare cancer of the eye, is characterized by initiating mutations in the genes G-protein subunit alpha Q (GNAQ), G-protein subunit alpha 11 (GNA11), cysteinyl leukotriene receptor 2 (CYSLTR2), and phospholipase C beta 4 (PLCB4) and by metastasis-promoting mutations in the genes splicing factor 3B1 (SF3B1), serine and arginine rich splicing factor 2 (SRSF2), and BRCA1-associated protein 1 (BAP1). Here, we tested the hypothesis that additional mutations, though occurring in only a few cases (“secondary drivers”), might influence tumor development. Methods: We analyzed all the 4125 mutations detected in exome sequencing datasets, comprising a total of 139 Ums, and tested the enrichment of secondary drivers in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that also contained the initiating mutations. We searched for additional mutations in the putative secondary driver gene protein tyrosine kinase 2 beta (PTK2B) and we developed new mutational signatures that explain the mutational pattern observed in UM. Results: Secondary drivers were significantly enriched in KEGG pathways that also contained GNAQ and GNA11, such as the calcium-signaling pathway. Many of the secondary drivers were known cancer driver genes and were strongly associated with metastasis and survival. We identified additional mutations in PTK2B. Sparse dictionary learning allowed for the identification of mutational signatures specific for UM. Conclusions: A considerable part of rare mutations that occur in addition to known driver mutations are likely to affect tumor development and progression.
Successful Targeting of the Warburg Effect in Prostate Cancer by Glucose-Conjugated 1,4-Naphthoquinones
Authors: Dyshlovoy Sergey A. , Pelageev Dmitry N. , Hauschild Jessica , Borisova Ksenia L. , Kaune Moritz , Krisp Christoph , Venz Simone , Sabutskii Yurii E. , Khmelevskaya Ekaterina A. , Busenbender Tobias , Denisenko Vladimir A. , Pokhilo Natalia D. , Atopkina Lyubov N. , Graefen Markus , Schlüter Hartmut , Stonik Valentin A. , Bokemeyer Carsten , Anufriev Victor Ph. , von Amsberg Gunhild
Published: October 2019

Treatment of castration-resistant prostate cancer (CRPC) remains challenging due to the development of drug resistance. The Warburg effect describes the ability of cancer cells to consume larger amounts of glucose compared to normal tissues. We identified derivatives of natural 1,4-naphthoquinones to be active in CRPC and further synthetically modified them via glucose conjugation to increase selectivity by Warburg effect targeting. Mechanisms of action were examined by quantitative proteomics followed by bioinformatical analysis and target validation. Four synthesized molecules revealed the highest selectivity towards human CRPC cells, which correlated with higher GLUT-1 activity and expression. The compounds were able to induce pro-apoptotic signs and to inhibit the pro-survival processes and mechanisms of drug resistance (i.e., AR-signaling and autophagy). Proteome analysis suggested a disruption of the mitochondria/oxidative phosphorylation, which was validated by further functional analysis: thus, mitochondria depolarization, elevated levels of cytotoxic ROS, an increase of Bax/Bcl-2 ratio as well as release of mitochondrial AIF and cytochrome C to cytoplasm were observed. In conclusion, glucose-conjugated 1,4-naphthoquinones show potent activity and selectivity in human CRPC exerted via mitochondrial targeting. The compounds can overcome drug resistance against current standard therapies and suppress pro-survival mechanisms. This unique combination of properties makes them new promising candidates for the treatment of CRPC.
Deconvolution of the Genomic and Epigenomic Interaction Landscape of Triple-Negative Breast Cancer
Authors: Wu Jiande , Mamidi Tarun Karthik Kumar , Zhang Lu , Hicks Chindo
Published: October 2019

Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer. Emerging evidenced suggests that both genetics and epigenetic factors play a role in the pathogenesis of TNBC. However, oncogenic interactions and cooperation between genomic and epigenomic variation have not been characterized. The objective of this study was to deconvolute the genomic and epigenomic interaction landscape in TNBC using an integrative genomics approach, which integrates information on germline, somatic, epigenomic and gene expression variation. We hypothesized that TNBC originates from a complex interplay between genomic (both germline and somatic variation) and epigenomic variation. We further hypothesized that these complex arrays of interacting genomic and epigenomic factors affect entire molecular networks and signaling pathways which, in turn, drive TNBC. We addressed these hypotheses using germline variation from genome-wide association studies and somatic, epigenomic and gene expression variation from The Cancer Genome Atlas (TCGA). The investigation revealed signatures of functionally related genes containing germline, somatic and epigenetic variations. DNA methylation had an effect on gene expression. Network and pathway analysis revealed molecule networks and signaling pathways enriched for germline, somatic and epigenomic variation, among them: Role of BRCA1 in DNA Damage Response, Hereditary Breast Cancer Signaling, Molecular Mechanisms of Cancer, Estrogen-Dependent Breast Cancer, p53, MYC Mediated Apoptosis, and PTEN Signaling pathways. The investigation revealed that integrative genomics is a powerful approach for deconvoluting the genomic-epigenomic interaction landscape in TNBC. Further studies are needed to understand the biological mechanisms underlying oncogenic interactions between genomic and epigenomic factors in TNBC.
How Do Synchronous Lung Metastases Influence the Surgical Management of Children with Hepatoblastoma? An Update and Systematic Review of the Literature
Authors: Angelico Roberta , Grimaldi Chiara , Gazia Carlo , Saffioti Maria Cristina , Manzia Tommaso Maria , Castellano Aurora , Spada Marco
Published: October 2019

Approximately 20% of children with hepatoblastoma (HB) have metastatic disease at diagnosis, most frequently in the lungs. In children with HB, lung metastatic disease is associated with poorer prognosis. Its treatment has been approached with a variety of methods that integrate chemotherapy and surgical resection. The timing and feasibility of complete extirpation of lung metastases, by chemotherapy and/or metastasectomy, is crucial for the surgical treatment of the primary liver tumor, which can vary from major hepatic resections to liver transplantation (LT). In children with unresectable HB, which can be surgically treated only by LT, the persistence of unresectable metastases after neoadjuvant chemotherapy excludes the possibility of recurring to LT with consequent negative impact on patients’ outcomes. Due to limited evidence and experience, there is no consensus amongst oncologists and surgeons across institutions regarding the surgical treatment for HB with synchronous metastatic lung disease. This narrative review aimed to update the current management of pulmonary metastasis in children with HB and to define its role in the decision-making strategy for the surgical approach to primary liver tumours.
Role of Sphingosylphosphorylcholine in Tumor and Tumor Microenvironment
Authors: Park Mi Kyung , Lee Chang Hoon
Published: October 2019

Sphingosylphosphorylcholine (SPC) is a unique type of lysosphingolipid found in some diseases, and has been studied in cardiovascular, neurological, and inflammatory phenomena. In particular, SPC's studies on cancer have been conducted mainly in terms of effects on cancer cells, and relatively little consideration has been given to aspects of tumor microenvironment. This review summarizes the effects of SPC on cancer and tumor microenvironment, and presents the results and prospects of modulators that regulate the various actions of SPC.
Peptide–Gold Nanoparticle Conjugates as Artificial Carbonic Anhydrase Mimics
Authors: Mikolajczak Dorian J. , Koksch Beate
Published: October 2019

We herein describe the design and synthesis of a catalytically active peptide–gold nanoparticle conjugate (Pep-Au-NP) that binds Zn(II) within its peptide monolayer and develops carbonic anhydrase activity. Specifically, a modified variant of the β-sheet forming IHIHIQI-peptide (IHQ), which forms an interstrand 3-His Zn(II)-binding site, was used as a ligand for spherical gold nanoparticles (Au-NPs). The resulting immobilized peptide maintains its ability to form β-sheets, as determined by circular dichroism (CD)-spectroscopy and, thus, maintains its ability to form Zn(II)-binding sites. The addition of Zn(II)-ions to the peptide–gold nanoparticle conjugates (Au@IHQ-NP) resulted in significant improvements in rates of ester hydrolysis of 4-nitrophenyl acetate (4-NPA) and the hydration of CO2 compared to the unconjugated peptide variants. Recycling of the catalyst revealed that Au@IHQ-NP remains intact with at least 94% of its initial activity after five rounds of CO2 hydration. The herein reported results reveal that Pep-Au-NPs are able to perform reactions catalyzed by natural metalloenzymes and open up new possibilities for the implementation of these conjugates.
Second-Generation Antipsychotics and Dysregulation of Glucose Metabolism: Beyond Weight Gain
Authors: Grajales Diana , Ferreira Vitor , Valverde Ángela M.
Published: October 2019

Second-generation antipsychotics (SGAs) are the cornerstone of treatment for schizophrenia because of their high clinical efficacy. However, SGA treatment is associated with severe metabolic alterations and body weight gain, which can increase the risk of type 2 diabetes and cardiovascular disease, and greatly accelerate mortality. Several underlying mechanisms have been proposed for antipsychotic-induced weight gain (AIWG), but some studies suggest that metabolic changes in insulin-sensitive tissues can be triggered before the onset of AIWG. In this review, we give an outlook on current research about the metabolic disturbances provoked by SGAs, with a particular focus on whole-body glucose homeostasis disturbances induced independently of AIWG, lipid dysregulation or adipose tissue disturbances. Specifically, we discuss the mechanistic insights gleamed from cellular and preclinical animal studies that have reported on the impact of SGAs on insulin signaling, endogenous glucose production, glucose uptake and insulin secretion in the liver, skeletal muscle and the endocrine pancreas. Finally, we discuss some of the genetic and epigenetic changes that might explain the different susceptibilities of SGA-treated patients to the metabolic side-effects of antipsychotics.
A Low-Therapeutic Dose of Lithium Inhibits GSK3 and Enhances Myoblast Fusion in C2C12 Cells
Authors: Kurgan Nigel , Whitley Kennedy C. , Maddalena Lucas A. , Moradi Fereshteh , Stoikos Joshua , Hamstra Sophie I. , Rubie Elizabeth A. , Kumar Megha , Roy Brian D. , Woodgett James R. , Stuart Jeffrey A. , Fajardo Val A.
Published: October 2019

Glycogen synthase kinase 3 (GSK3) slows myogenic differentiation and myoblast fusion partly by inhibiting the Wnt/β-catenin signaling pathway. Lithium, a common medication for bipolar disorder, inhibits GSK3 via Mg+ competition and increased Ser21 (GSK3α) or Ser9 (GSK3β) phosphorylation, leading to enhanced myoblast fusion and myogenic differentiation. However, previous studies demonstrating the effect of lithium on GSK3 have used concentrations up to 10 mM, which greatly exceeds concentrations measured in the serum of patients being treated for bipolar disorder (0.5–1.2 mM). Here, we determined whether a low-therapeutic (0.5 mM) dose of lithium could promote myoblast fusion and myogenic differentiation in C2C12 cells. C2C12 myotubes differentiated for three days in media containing 0.5 mM lithium chloride (LiCl) had significantly higher GSK3β (ser9) and GSK3α (ser21) phosphorylation compared with control myotubes differentiated in the same media without LiCl (+2–2.5 fold, p < 0.05), a result associated with an increase in total β-catenin. To further demonstrate that 0.5 mM LiCl inhibited GSK3 activity, we also developed a novel GSK3-specific activity assay. Using this enzyme-linked spectrophotometric assay, we showed that 0.5 mM LiCl-treated myotubes had significantly reduced GSK3 activity (−86%, p < 0.001). Correspondingly, 0.5 mM LiCl treated myotubes had a higher myoblast fusion index compared with control (p < 0.001) and significantly higher levels of markers of myogenesis (myogenin, +3-fold, p < 0.001) and myogenic differentiation (myosin heavy chain, +10-fold, p < 0.001). These results indicate that a low-therapeutic dose of LiCl is sufficient to promote myoblast fusion and myogenic differentiation in muscle cells, which has implications for the treatment of several myopathic conditions.
MLL-Rearranged Acute Leukemia with t(4;11)(q21;q23)—Current Treatment Options. Is There a Role for CAR-T Cell Therapy?
Authors: Britten Oliver , Ragusa Denise , Tosi Sabrina , Mostafa Kamel Yasser
Published: October 2019

The MLL (mixed-lineage leukemia) gene, located on chromosome 11q23, is involved in chromosomal translocations in a subtype of acute leukemia, which represents approximately 10% of acute lymphoblastic leukemia and 2.8% of acute myeloid leukemia cases. These translocations form fusions with various genes, of which more than 80 partner genes for MLL have been identified. The most recurrent fusion partner in MLL rearrangements (MLL-r) is AF4, mapping at chromosome 4q21, accounting for approximately 36% of MLL-r leukemia and particularly prevalent in MLL-r acute lymphoblastic leukemia (ALL) cases (57%). MLL-r leukemia is associated with a sudden onset, aggressive progression, and notoriously poor prognosis in comparison to non-MLL-r leukemias. Despite modern chemotherapeutic interventions and the use of hematopoietic stem cell transplantations, infants, children, and adults with MLL-r leukemia generally have poor prognosis and response to these treatments. Based on the frequency of patients who relapse, do not achieve complete remission, or have brief event-free survival, there is a clear clinical need for a new effective therapy. In this review, we outline the current therapy options for MLL-r patients and the potential application of CAR-T therapy.
Functions and Implications of Autophagy in Colon Cancer
Authors: Devenport Samantha N , Shah Yatrik M
Published: October 2019

Autophagy is an essential function to breakdown cellular proteins and organelles to recycle for new nutrient building blocks. In colorectal cancer, the importance of autophagy is becoming widely recognized as it demonstrates both pro- and anti-tumorigenic functions. In colon cancer, cell autonomous and non-autonomous roles for autophagy are essential in growth and progression. However, the mechanisms downstream of autophagy (to reduce or enhance tumor growth) are not well known. Additionally, the signals that activate and coordinate autophagy for tumor cell growth and survival are not clear. Here, we highlight the context- and cargo-dependent role of autophagy in proliferation, cell death, and cargo breakdown.
Adenosine Depletion as A New Strategy to Decrease Glioblastoma Stem-Like Cells Aggressiveness
Authors: Niechi Ignacio , Uribe-Ojeda Atenea , Erices José Ignacio , Torres Ángelo , Uribe Daniel , Rocha José Dellis , Silva Pamela , Richter Hans G. , San Martín Rody , Quezada Claudia
Published: October 2019

Glioblastoma is the brain tumor with the worst prognosis. This is mainly due to a cell subpopulation with an extremely aggressive potential, called glioblastoma stem-like cells (GSCs). These cells produce high levels of extracellular adenosine, which are increased even more under hypoxic conditions. Under hypoxia, adenosine signaling is related to HIF-2α expression, enhancing cell aggressiveness. Adenosine can be degraded using recombinant adenosine deaminase (ADA) to revert its pathological effects. The aim of this study was to degrade adenosine using ADA in order to decrease malignancy of GSCs. Adenosine depletion was performed using recombinant ADA. Migration and invasion were measured by transwell and matrigel-coated transwell assay, respectively. HIF-2α-dependent cell migration/invasion decreased in GSCs treated with ADA under hypoxia. MRPs-mediated chemoresistance and colony formation decreased in treatment with ADA. In conclusion, adenosine depletion using adenosine deaminase decreases GSCs aggressiveness.
Peripheral Delivery of Neural Precursor Cells Ameliorates Parkinson’s Disease-Associated Pathology
Authors: Edwards George , Gamez Nazaret , Armijo Enrique , Kramm Carlos , Morales Rodrigo , Taylor-Presse Kathleen , Schulz Paul E. , Soto Claudio , Moreno-Gonzalez Ines
Published: October 2019

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of motor control due to a wide loss of dopaminergic neurons along the nigro-striatal pathway. Some of the mechanisms that contribute to this cell death are inflammation, oxidative stress, and misfolded alpha-synuclein-induced toxicity. Current treatments are effective at managing the early motor symptoms of the disease, but they become ineffective over time and lead to adverse effects. Previous research using intracerebral stem cell therapy for treatment of PD has provided promising results; however, this method is very invasive and is often associated with unacceptable side effects. In this study, we used an MPTP-injected mouse model of PD and intravenously administered neural precursors (NPs) obtained from mouse embryonic and mesenchymal stem cells. Clinical signs and neuropathology were assessed. Female mice treated with NPs had improved motor function and reduction in the neuroinflammatory response. In terms of safety, there were no tumorigenic formations or any detectable adverse effect after treatment. Our results suggest that peripheral administration of stem cell-derived NPs may be a promising and safe therapy for the recovery of impaired motor function and amelioration of brain pathology in PD.