bluuebunny/crossref_metadata_2025 huggingface dataset:
A Lagrangian Advection Scheme for Solving Cloud Droplet Diffusion Growth
Authors: Wei Lei , Sun Jiming , Lei Hengchi , Dong Li , Hu Wenhao
Published: June 2020

Cloud drop diffusion growth is a fundamental microphysical process in warm clouds. In the present work, a new Lagrangian advection scheme (LAS) is proposed for solving this process. The LAS discretizes cloud drop size distribution (CDSD) with movable bins. Two types of prognostic variable, namely, bin radius and bin width, are included in the LAS. Bin radius is tracked by the well-known cloud drop diffusion growth equation, while bin width is solved by a derived equation. CDSD is then calculated with the information of bin radius, bin width, and prescribed droplet number concentration. The reliability of the new scheme is validated by the reference analytical solutions in a parcel cloud model. Artificial broadening of CDSD, understood as a by-product of numerical diffusion in advection algorithm, is strictly prohibited by the new scheme. The authors further coupled the LAS into a one-and-half dimensional (1.5D) Eulerian cloud model to evaluate its performance. An individual deep cumulus cloud studied in the Cooperative Convective Precipitation Experiment (CCOPE) campaign was simulated with the LAS-coupled 1.5D model and the original 1.5D model. Simulation results of CDSD and microphysical properties were compared with observational data. Improvements, namely, narrower CDSD and accurate reproduction of particle mean diameter, were achieved with the LAS-coupled 1.5D model.
Registration of Atmospheric-Electric Effects from Volcanic Clouds on the Kamchatka Peninsula (Russia)
Authors: Firstov Pavel P. , Malkin Evgeniy I. , Akbashev Rinat R. , Druzhin Gennadiy I. , Cherneva Nina V. , Holzworth Robert H. , Uvarov Vladimir N. , Stasiy Ivan E.
Published: June 2020

The paper is devoted to the description of observations over atmospheric and electric effects from volcanic eruptions on Kamchatka peninsula (Russia) and perspectives of their development. To collect information about atmospheric-electric effects accompanying the eruptions of Kamchatka volcanoes, three sensor networks and a VLF radio direction finding station are used. The World Wide Lightning Location Network (WWLLN) provides information on high-current lightning discharges that occur during the development of an eruptive cloud (EC). Variations in the electric field of the atmosphere (AEF E z ), during the passage of EC, were obtained by a network of electric field mills at the sites for volcanic activity observations. Seismic detector network was used to make precision reference to the eruptions. Based on the data obtained, a description is given of the dynamics of eruptions of the most active volcanoes in Kamchatka and the Northern Kuril Islands (Shiveluch, Bezymianny, Ebeko). The paper presents a simulation of the response of the atmospheric electric field, which showed that the approximation by the field of distributed charges makes it possible to estimate the volume charges of EC. The fact of a multi-stage volcanic thunderstorm is confirmed. The first stage is associated with the formation of an eruptive column, and the second with the emergence, development and transfer of EC. Registration of electrical and electromagnetic processes in eruptive clouds can be one of the components of complex observations of volcanic eruptions in order to assess the ash hazard for air transport.
Positron Scattering from Atoms and Molecules
Authors: Nahar Sultana N. , Antony Bobby
Published: June 2020

A review on the positron scattering from atoms and molecules is presented in this article. The focus on positron scattering studies is on the rise due to their presence in various fields and application of cross section data in such environments. Positron scattering is usually investigated using theoretical approaches that are similar to those for electron scattering, being its anti-particle. However, most experimental or theoretical studies are limited to the investigation of electron and positron scattering from inert gases, single electron systems and simple or symmetric molecules. Optical potential and polarized orbital approaches are the widely used methods for investigating positron scattering from atoms. Close coupling approach has also been used for scattering from atoms, but for lighter targets with low energy projectiles. The theoretical approaches have been quite successful in predicting cross sections and agree reasonably well with experimental measurements. The comparison is generally good for electrons for both elastic and inelastic scatterings cross sections, while spin polarization has been critical due to its sensitive perturbing interaction. Positron scattering cross sections show relatively less features than that of electron scattering. The features of positron impact elastic scattering have been consistent with experiment, while total cross section requires significant improvement. For scattering from molecules, utilization of both spherical complex optical potential and R-matrix methods have proved to be efficient in predicting cross sections in their respective energy ranges. The results obtained shows reasonable comparison with most of the existing data, wherever available. In the present article we illustrate these findings with a list of comprehensive references to data sources, albeit not exhaustive.
Revisiting the Impact of Neurodegenerative Proteins in Epilepsy: Focus on Alpha-Synuclein, Beta-Amyloid, and Tau
Authors: Paudel Yam Nath , Angelopoulou Efthalia , Piperi Christina , Othman Iekhsan , Shaikh Mohd. Farooq
Published: June 2020

Lack of disease-modifying therapy against epileptogenesis reflects the complexity of the disease pathogenesis as well as the high demand to explore novel treatment strategies. In the pursuit of developing new therapeutic strategies against epileptogenesis, neurodegenerative proteins have recently gained increased attention. Owing to the fact that neurodegenerative disease and epileptogenesis possibly share a common underlying mechanism, targeting neurodegenerative proteins against epileptogenesis might represent a promising therapeutic approach. Herein, we review the association of neurodegenerative proteins, such as α-synuclein, amyloid-beta (Aβ), and tau protein, with epilepsy. Providing insight into the α-synuclein, Aβ and tau protein-mediated neurodegeneration mechanisms, and their implication in epileptogenesis will pave the way towards the development of new agents and treatment strategies.
Molecular Aggregation in Immune System Activation Studied by Dynamic Light Scattering
Authors: Velichko Elena , Makarov Sergey , Nepomnyashchaya Elina , Dong Ge
Published: June 2020

Determination of the concentration and size of the circulating immune complexes in the blood is an essential part of diagnostics of immune diseases. In this work, we suggest using the dynamic light scattering method to determine the sizes of circulating immune complexes in blood serum. By the dynamic light scattering spectrometer, we found that for healthy and sick donors, the size and concentration of circulating immune complexes differed significantly. The dynamics of formation of these complexes were also examined in this work. It was shown that the formation of immune complexes in the blood of healthy donors is faster than the same reactions in the blood serum of donors with diseases. The results can be used in the diagnostics of the immune status and detection of chronic inflammation. We can recommend the dynamic light scattering method for implementation in biomedical diagnostics.
Lymphoid Tissue in Teleost Gills: Variations on a Theme
Authors: Rességuier Julien , Dalum Alf S. , Du Pasquier Louis , Zhang Yaqing , Koppang Erling Olaf , Boudinot Pierre , Wiegertjes Geert F.
Published: June 2020

In bony fish, the gill filaments are essential for gas exchanges, but also are vulnerable to infection by water-borne microorganisms. Omnipresent across fish, gill-associated lymphoid tissues (GIALT) regulate interactions with local microbiota and halt infection by pathogens. A special GIALT structure has recently been found in Salmonids, the interbranchial lymphoid tissue (ILT). However, the structural variation of GIALT across bony fish remains largely unknown. Here, we show how this critical zone of interaction evolved across fishes. By labeling a conserved T-cell epitope on tissue sections, we find that several basal groups of teleosts possess typical ILT, while modern teleosts have lymphoepithelium of different shape and size at the base of primary gill filaments. Within Cypriniformes, neither body size variation between two related species, zebrafish and common carp, nor morphotype variation, did have a drastic effect on the structure of ILT. Thereby this study is the first to describe the presence of ILT in zebrafish. The ILT variability across fish orders seems to represent different evolutionary solutions to balancing trade-offs between multiple adaptations of jaws and pharyngeal region, and immune responses. Our data point to a wide structural variation in gill immunity between basal groups and modern teleosts.
Jaw Periosteal Cells Seeded in Beta-Tricalcium Phosphate Inhibit Dendritic Cell Maturation
Authors: Dai Jingtao , Umrath Felix , Reinert Siegmar , Alexander Dorothea
Published: June 2020

Mesenchymal stem cells (MSCs) have gained attraction not only in the field of regenerative medicine but also in the field of autoimmune disease therapies or organ transplantation due to their immunoregulatory and/or immunosuppressive features. Dendritic cells (DCs) play a crucial role in initiating and regulating immune reactions by promoting antigen-specific T cell activation. In this study, we investigated the effect of human jaw periosteal progenitor cells (JPCs) seeded in beta-tricalcium phosphate (β-TCP) scaffolds on monocyte-derived DC differentiation. Significantly lower numbers of differentiated DCs were observed in the presence of normal (Co) and osteogenically induced (Ob) JPCs-seeded β-TCP constructs. Gene expression analysis revealed significantly lower interleukin-12 subunit p35 (IL-12p35) and interleukin-12 receptor beta 2 (IL-12Rβ2) and pro-inflammatory cytokine interferon-gamma (IFN-γ) levels in DCs under Ob conditions, while interleukin-8 (IL-8) gene levels were significantly increased. Furthermore, in the presence of JPCs-seeded β-TCP constructs, interleukin-10 (IL-10) gene expression was significantly induced in DCs, particularly under Ob conditions. Analysis of DC protein levels shows that granulocyte-colony stimulating factor (G-CSF) was significantly upregulated in coculture groups. Our results indicate that undifferentiated and osteogenically induced JPCs-seeded β-TCP constructs have an overall inhibitory effect on monocyte-derived DC maturation.
Bakkenolides and Caffeoylquinic Acids from the Aerial Portion of Petasites japonicus and Their Bacterial Neuraminidase Inhibition Ability
Authors: Woo Hyun Sim , Shin Kyung-Chul , Kim Jeong Yoon , Kim Yeong-Su , Ban Young Jun , Oh Yu Jin , Cho Hae Jin , Oh Deok-Kun , Kim Dae Wook
Published: June 2020

Petasites japonicus have been used since a long time in folk medicine to treat diseases including plague, pestilential fever, allergy, and inflammation in East Asia and European countries. Bioactive compounds that may prevent and treat infectious diseases are identified based on their ability to inhibit bacterial neuraminidase (NA). We aimed to isolate and identify bioactive compounds from leaves and stems of P. japonicas (PJA) and elucidate their mechanisms of NA inhibition. Key bioactive compounds of PJA responsible for NA inhibition were isolated using column chromatography, their chemical structures revealed using 1 H NMR, 13 C NMR, DEPT, and HMBC, and identified to be bakkenolide B (1), bakkenolide D (2), 1,5-di-O-caffeoylquinic acid (3), and 5-O-caffeoylquinic acid (4). Of these, 3 exhibited the most potent NA inhibitory activity (IC50 = 2.3 ± 0.4 μM). Enzyme kinetic studies revealed that 3 and 4 were competitive inhibitors, whereas 2 exhibited non-competitive inhibition. Furthermore, a molecular docking simulation revealed the binding affinity of these compounds to NA and their mechanism of inhibition. Negative-binding energies indicated high proximity of these compounds to the active site and allosteric sites of NA. Therefore, PJA has the potential to be further developed as an antibacterial agent for use against diseases associated with NA.
Cigarette Smoking during Pregnancy: Effects on Antioxidant Enzymes, Metallothionein and Trace Elements in Mother-Newborn Pairs
Authors: Pizent Alica , Lazarus Maja , Kovačić Jelena , Tariba Lovaković Blanka , Brčić Karačonji Irena , Živković Semren Tanja , Sekovanić Ankica , Orct Tatjana , Branović-Čakanić Karmen , Brajenović Nataša , Jurič Andreja , Miškulin Iva , Škrgatić Lana , Stasenko Sandra , Mioč Tatjana , Jurasović Jasna , Piasek Martina
Published: June 2020

The effect of maternal smoking as a source of exposure to toxic metals Cd and Pb on superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity, metallothionein (MT), Cd, Pb, Cu, Fe, Mn, Se and Zn concentrations were assessed in maternal and umbilical cord blood and placenta in 74 healthy mother-newborn pairs after term delivery. Sparse discriminant analysis (SDA) was used to identify elements with the strongest impact on the SOD, GPx and MT in the measured compartments, which was then quantified by multiple regression analysis. SOD activity was lower in maternal and cord plasma, and higher in the placenta of smokers compared to non-smokers, whereas GPx activity and MT concentration did not differ between the groups. Although active smoking during pregnancy contributed to higher maternal Cd and Pb concentrations, its contribution to the variability of SOD, GPx or MT after control for other elements identified by SDA was not significant. However, an impaired balance in the antioxidant defence observed in the conditions of relatively low-to-moderate exposure levels to Cd and Pb could contribute to an increased susceptibility of offspring to oxidative stress and risk of disease development later in life. Further study on a larger number of subjects will help to better understand complex interactions between exposure to toxic elements and oxidative stress related to maternal cigarette smoking.
EGFP Reporters for Direct and Sensitive Detection of Mutagenic Bypass of DNA Lesions
Authors: Rodriguez-Alvarez Marta , Kim Daria , Khobta Andriy
Published: June 2020

The sustainment of replication and transcription of damaged DNA is essential for cell survival under genotoxic stress; however, the damage tolerance of these key cellular functions comes at the expense of fidelity. Thus, translesion DNA synthesis (TLS) over damaged nucleotides is a major source of point mutations found in cancers; whereas erroneous bypass of damage by RNA polymerases may contribute to cancer and other diseases by driving accumulation of proteins with aberrant structure and function in a process termed “transcriptional mutagenesis” (TM). Here, we aimed at the generation of reporters suited for direct detection of miscoding capacities of defined types of DNA modifications during translesion DNA or RNA synthesis in human cells. We performed a systematic phenotypic screen of 25 non-synonymous base substitutions in a DNA sequence encoding a functionally important region of the enhanced green fluorescent protein (EGFP). This led to the identification of four loss-of-fluorescence mutants, in which any ulterior base substitution at the nucleotide affected by the primary mutation leads to the reversal to a functional EGFP. Finally, we incorporated highly mutagenic abasic DNA lesions at the positions of primary mutations and demonstrated a high sensitivity of detection of the mutagenic DNA TLS and TM in this system.
NRF2 Regulation Processes as a Source of Potential Drug Targets against Neurodegenerative Diseases
Authors: Cores Ángel , Piquero Marta , Villacampa Mercedes , León Rafael , Menéndez J. Carlos
Published: June 2020

NRF2 acts by controlling gene expression, being the master regulator of the Phase II antioxidant response, and also being key to the control of neuroinflammation. NRF2 activity is regulated at several levels, including protein degradation by the proteasome, transcription, and post-transcription. The purpose of this review is to offer a concise and critical overview of the main mechanisms of NRF2 regulation and their actual or potential use as targets for the treatment of neurodegenerative diseases.
Transcriptome Comparison Reveals Key Components of Nuptial Plumage Coloration in Crested Ibis
Authors: Sun Li , Zhou Tong , Wan Qiu-Hong , Fang Sheng-Guo
Published: June 2020

Nuptial plumage coloration is critical in the mating choice of the crested ibis. This species has a characteristic nuptial plumage that develops from the application of a black sticky substance, secreted by a patch of skin in the throat and neck region. We aimed to identify the genes regulating its coloring, by comparing skin transcriptomes between ibises during the breeding and nonbreeding seasons. In breeding season skins, key eumelanin synthesis genes, TYR, DCT, and TYRP1 were upregulated. Tyrosine metabolism, which is closely related to melanin synthesis, was also upregulated, as were transporter proteins belonging to multiple SLC families, which might act during melanosome transportation to keratinocytes. These results indicate that eumelanin is likely an important component of the black substance. In addition, we observed upregulation in lipid metabolism in breeding season skins. We suggest that the lipids contribute to an oil base, which imbues the black substance with water insolubility and enhances its adhesion to feather surfaces. In nonbreeding season skins, we observed upregulation in cell adhesion molecules, which play critical roles in cell interactions. A number of molecules involved in innervation and angiogenesis were upregulated, indicating an ongoing expansion of nerves and blood vessels in sampled skins. Feather β keratin, a basic component of avian feather filament, was also upregulated. These results are consistent with feather regeneration in the black skin of nonbreeding season ibises. Our results provide the first molecular evidence indicating that eumelanin is the key component of ibis coloration.
Multimarker Approach to Identify Patients with Coronary Artery Disease at High Risk for Subsequent Cardiac Adverse Events: The Multi-Biomarker Study
Authors: Giurgea Georgiana-Aura , Zlabinger Katrin , Gugerell Alfred , Lukovic Dominika , Syeda Bonni , Mandic Ljubica , Pavo Noemi , Mester-Tonczar Julia , Traxler-Weidenauer Denise , Spannbauer Andreas , Kastner Nina , Müller Claudia , Anvari Anahit , Bergler-Klein Jutta , Gyöngyösi Mariann
Published: June 2020

In our prospective non-randomized, single-center cohort study (n = 161), we have evaluated a multimarker approach including S100 calcium binding protein A12 (S100A1), interleukin 1 like-receptor-4 (IL1R4), adrenomedullin, copeptin, neutrophil gelatinase-associated lipocalin (NGAL), soluble urokinase plasminogen activator receptor (suPAR), and ischemia modified albumin (IMA) in prediction of subsequent cardiac adverse events (AE) during 1-year follow-up in patients with coronary artery disease. The primary endpoint was to assess the combined discriminatory predictive value of the selected 7 biomarkers in prediction of AE (myocardial infarction, coronary revascularization, death, stroke, and hospitalization) by canonical discriminant function analysis. The main secondary endpoints were the levels of the 7 biomarkers in the groups with/without AE; comparison of the calculated discriminant score of the biomarkers with traditional logistic regression and C-statistics. The canonical correlation coefficient was 0.642, with a Wilk’s lambda value of 0.78 and p < 0.001. By using the calculated discriminant equation with the weighted mean discriminant score (centroid), the sensitivity and specificity of our model were 79.4% and 74.3% in prediction of AE. These values were higher than that of the calculated C-statistics if traditional risk factors with/without biomarkers were used for AE prediction. In conclusion, canonical discriminant analysis of the multimarker approach is able to define the risk threshold at the individual patient level for personalized medicine.
Image Analysis of 3D Conjunctival Melanoma Cell Cultures Following Electrochemotherapy
Authors: Fiorentzis Miltiadis , Katopodis Periklis , Kalirai Helen , Seitz Berthold , Viestenz Arne , Coupland Sarah E.
Published: June 2020

Three-dimensional (3D) cell cultures represent small avascular tumors in vitro and simulate some of the biological characteristics of solid tumors, enhancing the evaluation of anticancer drug efficacy. Automated image analysis can be used for the assessment of tumor growth and documentation of changes in the size parameters of 3D tumor spheroids following anticancer treatments such as electrochemotherapy. The objective of this article is to assess the effect of various electroporation (EP) conditions (500–750 Volts/cm, 8–20 pulses, 100 µs pulse duration, 5 Hz repetition rate) combined with different bleomycin concentrations (1–2.5 ug/mL) on normal epithelial (HCjE-Gi) and conjunctival melanoma (CRMM1, CRMM2) 3D-cell cultures, through an automated image analysis and a comparison with standard histological assays. A reduction in tumor mass with loss of cell definition was observed after ECT (750 Volts/cm with eight pulses and 500 Volts/cm with 20 pulses) with bleomycin (1 μg/mL and 2.5 μg/mL) in the histological and immunohistochemical analyses of 3D CRMM1 and CRMM2 spheroids, whereas an increase in volume and a decrease in sphericity was documented in the automated image analysis and 3D visualization of both melanoma cell lines. For all other treatment conditions and for the HCjE-Gi cell line, no significant changes to their morphological features were observed. Image analysis with integrated software tools provides an accessible and comprehensive platform for the preliminary selection of homogenous spheroids and for the monitoring of drug efficacy, implementing the traditional screening methods.
Leucine Potentiates Glucose-mediated 18F-FDG Uptake in Brown Adipose Tissue via β-Adrenergic Activation
Authors: Huska Brenda , Niccoli Sarah , Phenix Christopher P. , Lees Simon J.
Published: June 2020

Significant depots of brown adipose tissue (BAT) have been identified in many adult humans through positron emission tomography (PET), with the amount of BAT being inversely correlated with obesity. As dietary activation of BAT has implications for whole body glucose metabolism, leucine was used in the present study to determine its ability to promote BAT activation resulting in increased glucose uptake. In order to assess this, 2-deoxy-2-(fluorine-18)fluoro-d-glucose (18F-FDG) uptake was measured in C57BL/6 mice using microPET after treatment with leucine, glucose, or both in interscapular BAT (IBAT). Pretreatment with propranolol (PRP) was used to determine the role of β-adrenergic activation in glucose and leucine-mediated 18F-FDG uptake. Analysis of maximum standardized uptake values (SUVMAX) determined that glucose administration increased 18F-FDG uptake in IBAT by 25.3%. While leucine did not promote 18F-FDG uptake alone, it did potentiate glucose-mediated 18F-FDG uptake, increasing 18F-FDG uptake in IBAT by 22.5%, compared to glucose alone. Pretreatment with PRP prevented the increase in IBAT 18F-FDG uptake following the combination of glucose and leucine administration. These data suggest that leucine is effective in promoting BAT 18F-FDG uptake through β-adrenergic activation in combination with glucose.
17β-Estradiol Promotes Proinflammatory and Procoagulatory Phenotype of Innate Immune Cells in the Presence of Antiphospholipid Antibodies
Authors: Manukyan Gayane , Martirosyan Anush , Slavik Ludek , Ulehlova Jana , Dihel Martin , Papajik Tomas , Kriegova Eva
Published: June 2020

Antiphospholipid syndrome (APS) is the most common cause of acquired thrombophilia and recurrent spontaneous miscarriages associated with extended persistence of antiphospholipid antibodies (aPL). How circulating aPL and high-17β-estradiol (E2) environment contribute to the pregnancy complications in APS is poorly defined. Therefore, we aimed to analyse whether E2 could be responsible for the immune cell hyperactivation in aPL- positive (lupus anticoagulant, anti-cardiolipin, anti-β2-glycoprotein) in women. For this, peripheral blood mononuclear cells (PBMCs) from 14 aPL- positive and 13 aPL- negative women were cultured in the presence or absence of E2, LPS or E2+LPS and cell immunophenotype and cytokine release were analysed. In the aPL+ group, E2 presence markedly increased the percentage of NK cells positive for CD69 (p < 0.05), monocytes positive for tissue factor (TF, CD142) (p < 0.05), and B cells expressing PD-L1 (p < 0.05), as well as the elevated production of IL-1β comparing to aPL- women (p < 0.01). Regardless of aPL positivity, E2 augmented the procoagulatory response elicited by LPS in monocytes. Our findings show the ability of E2 to promote proinflammatory and procoagulatory phenotype of innate immune cells in individuals with aPL positivity. Our data highlights the significant impact of female hormones on the activation of immune cells in the presence of aPL.
Pectobacterium atrosepticum Biosensor for Monitoring Blackleg and Soft Rot Disease of Potato
Authors: Hashemi Tameh Mahdis , Primiceri Elisabetta , Chiriacò Maria Serena , Poltronieri Palmiro , Bahar Masoud , Maruccio Giuseppe
Published: June 2020

Pectobacterium atrosepticum (Pba) is a quarantine and threatening phytopathogen known as the causal agent of blackleg and soft rot disease of potatoes in many areas. Its early detection is then important to have healthy potato tubers and reduce economic losses. Today, conventional methods such as enzyme-linked immunosorbent-assay (ELISA) and polymerase chain reaction (PCR) are typically used for Pba detection, but they are expensive and time-consuming. Here we report on the optimization of an alternative approach based on an electrochemical impedance immunosensor combining a microfluidic module and a microelectrodes array, and having advantages in terms of low cost, ease of use and portability. For validation and for assessing its performance, the lab-on-chip platform has been compared with two standard methods (ELISA and PCR).
Variations in Values of State, Response Entropy and Haemodynamic Parameters Associated with Development of Different Epileptiform Patterns during Volatile Induction of General Anaesthesia with Two Different Anaesthetic Regimens Using Sevoflurane in Comparison with Intravenous Induct: A Comparative Study
Authors: Stasiowski Michał , Duława Anna , Szumera Izabela , Marciniak Radosław , Niewiadomska Ewa , Kaspera Wojciech , Krawczyk Lech , Ładziński Piotr , Grabarek Beniamin , Jałowiecki Przemysław
Published: June 2020

Background and Objectives: Raw electroencephalographic (EEG) signals are rarely used to monitor the depth of volatile induction of general anaesthesia (VIGA) with sevoflurane, even though EEG-based indices may show aberrant values. We aimed to identify whether response (RE) and state entropy (SE) variations reliably reflect the actual depth of general anaesthesia in the presence of different types of epileptiform patterns (EPs) in EEGs during induction of general anaesthesia. Materials and Methods: A randomized, prospective clinical study was performed with 60 patients receiving VIGA using sevoflurane with the increasing concentrations (group VIMA) or the vital capacity (group VCRII) technique or an intravenous single dose of propofol (group PROP). Facial electromyography (fEMG), fraction of inspired sevoflurane (FiAA), fraction of expired sevoflurane (FeAA), minimal alveolar concentration (MAC) of sevoflurane, RE and SE, and standard electroencephalographic evaluations were performed in these patients. Results: In contrast to periodic epileptiform discharges, erroneous SE and RE values in the patients’ EEGs were associated with the presence of polyspikes (PS) and rhythmic polyspikes (PSR), which were more likely to indicate toxic depth rather than false emergence from anaesthesia with no changes in the FiAA, FeAA, and MAC of sevoflurane. Conclusion: Calculated RE and SE values may be misleading during VIGA when EPs are present in patients’ EEGs. During VIGA with sevoflurane, we recommend monitoring raw EEG data in scientific studies to correlate it with potentially erroneous RE and SE values and the end-tidal concentration of sevoflurane in everyday clinical practice, when monitoring raw EEG is not available, because they can mislead anaesthesiologists to reduce sevoflurane levels in the ventilation gas and result in unintentional true emergence from anaesthesia. Further studies are required to investigate the behaviour of EEG-based indices during rapid changes in sevoflurane concentrations at different stages of VIGA and the influence of polyspikes and rhythmic polyspikes on the transformation of EEG signals into a digital form.
Familial Hemiplegic Migraine with an ATP1A4 Mutation: Clinical Spectrum and Carbamazepine Efficacy
Authors: Coppola Giangennaro , Pastorino Grazia Maria Giovanna , Vetri Luigi , D’Onofrio Floriana , Operto Francesca Felicia
Published: June 2020

An Italian family with familial hemiplegic migraine (FHM) with the absence of mutations in the known genes associated with this disorder, namely ATP1A2, ATP1A3, CACNA1A, and SCN1A, has recently been reported. Soon afterward, whole exome sequencing allowed the identification of the carrier status of a heterozygous ATP1A4 mutation c.1798 C >T, in four affected members of this family. Here we compare the clinical symptoms of the affected family members with those from the other FHM families linked to mutations in the known genes associated with this disorder. A further two-year follow-up, including clinical response to carbamazepine administered to the proband and the maternal grandmother due to a worsening of the migraine symptoms, is reported. The clinical condition of the proband’s brother, carrying the same mutation and suffering from congenital ventricular and supraventricular extrasystoles, isdiscussed as well.
The Clinicopathological Features and Genetic Alterations in Epstein–Barr Virus-Associated Gastric Cancer Patients after Curative Surgery
Authors: Fang Wen-Liang , Chen Ming-Huang , Huang Kuo-Hung , Lin Chien-Hsing , Chao Yee , Lo Su-Shun , Li Anna Fen-Yau , Wu Chew-Wun , Shyr Yi-Ming
Published: June 2020

Background: Epstein–Barr virus (EBV)-associated gastric cancer (GC) is one of four major gastric cancer types and is traditionally considered to be related to lymphoepithelioma-like GC. Few studies have investigated the clinical significance of EBV infection in intestinal/solid type, diffuse (poorly cohesive) type, and lymphoepithelioma-like GC. Methods: A total of 460 GC patients receiving curative surgery were enrolled. The clinicopathological features, genetic alterations and prognoses were compared between patients with and without EBV infection. Results: EBV-positive GC patients (n = 43) had more tumors located in the upper and middle stomach, more common in lymphoepithelioma-like carcinoma, more lymphoid stroma, fewer Helicobacter pylori infections, and higher programmed death-ligand 1 (PD-L1) expression than EBV-negative GC patients. For intestinal/solid type GC, EBV-positive tumors were more likely to be located in the upper and middle stomach, have more lymphoid stroma, fewer Helicobacter pylori infections, higher PD-L1 expression, and more liver metastases than EBV-negative tumors. For diffuse (poorly cohesive) type GC, EBV-positive tumors were more likely to be located in the upper stomach, and have more lymphoid stroma than EBV-negative tumors. For lymphoepithelioma-like GC, EBV-positive tumors had more PI3K/AKT pathway mutations than EBV-negative tumors. Conclusions: Intestinal/solid type GC patients with EBV-positive tumors were associated with higher PD-L1 expression and more liver metastases, while lymphoepithelioma-like GC patients with EBV-positive tumors had more PI3K/AKT pathway mutations. Immunotherapy and targeted therapy may be beneficial for these groups of patients. Routine EBV survey is recommended in GC.
DUBs Activating the Hedgehog Signaling Pathway: A Promising Therapeutic Target in Cancer
Authors: Bufalieri Francesca , Lospinoso Severini Ludovica , Caimano Miriam , Infante Paola , Di Marcotullio Lucia
Published: June 2020

The Hedgehog (HH) pathway governs cell proliferation and patterning during embryonic development and is involved in regeneration, homeostasis and stem cell maintenance in adult tissues. The activity of this signaling is finely modulated at multiple levels and its dysregulation contributes to the onset of several human cancers. Ubiquitylation is a coordinated post-translational modification that controls a wide range of cellular functions and signaling transduction pathways. It is mediated by a sequential enzymatic network, in which ubiquitin ligases (E3) and deubiquitylase (DUBs) proteins are the main actors. The dynamic balance of the activity of these enzymes dictates the abundance and the fate of cellular proteins, thus affecting both physiological and pathological processes. Several E3 ligases regulating the stability and activity of the key components of the HH pathway have been identified. Further, DUBs have emerged as novel players in HH signaling transduction, resulting as attractive and promising drug targets. Here, we review the HH-associated DUBs, discussing the consequences of deubiquitylation on the maintenance of the HH pathway activity and its implication in tumorigenesis. We also report the recent progress in the development of selective inhibitors for the DUBs here reviewed, with potential applications for the treatment of HH-related tumors.
Update on GNA Alterations in Cancer: Implications for Uveal Melanoma Treatment
Authors: Larribère Lionel , Utikal Jochen
Published: June 2020

Tumorigenesis is correlated with abnormal expression and activity of G protein-coupled receptors (GPCRs) and associated G proteins. Oncogenic mutations in both GPCRs and G proteins (GNAS, GNAQ or GNA11) encoding genes have been identified in a significant number of tumors. Interestingly, uveal melanoma driver mutations in GNAQ/GNA11 were identified for a decade, but their discovery did not lead to mutation-specific drug development, unlike it the case for BRAF mutations in cutaneous melanoma which saw enormous success. Moreover, new immunotherapies strategies such as immune checkpoint inhibitors have given underwhelming results. In this review, we summarize the current knowledge on cancer-associated alterations of GPCRs and G proteins and we focus on the case of uveal melanoma. Finally, we discuss the possibilities that this signaling might represent in regard to novel drug development for cancer prevention and treatment.
TP53-Deficient Angiosarcoma Expression Profiling in Rat Model
Authors: Smyczyńska Urszula , Strzemecki Damian , Czarnecka Anna M. , Fendler Wojciech , Fiedorowicz Michał , Wełniak-Kamińska Marlena , Guzowska Magdalena , Synoradzki Kamil , Cheda Łukasz , Rogulski Zbigniew , Grieb Paweł
Published: June 2020

Sarcomas are a heterogeneous group of malignant tumors, that develop from mesenchymal cells. Sarcomas are tumors associated with poor prognosis and expected short overall survival. Efforts to improve treatment efficacy and treatment outcomes of advanced and metastatic sarcoma patients have not led to significant improvements in the last decades. In the Tp53C273X/C273X rat model we therefore aimed to characterize specific gene expression pattern of angiosarcomas with a loss of TP53 function. The presence of metabolically active tumors in several locations including the brain, head and neck, extremities and abdomen was confirmed by magnetic resonance imaging (MRI) and positron emission tomography (PET) examinations. Limb angiosarcoma tumors were selected for microarray expression analysis. The most upregulated pathways in angiosarcoma vs all other tissues were related to cell cycle with mitosis and meiosis, chromosome, nucleosome and telomere maintenance as well as DNA replication and recombination. The downregulated genes were responsible for metabolism, including respiratory chain electron transport, tricarboxylic acid (TCA) cycle, fatty acid metabolism and amino-acid catabolism. Our findings demonstrated that the type of developing sarcoma depends on genetic background, underscoring the importance of developing more malignancy susceptibility models in various strains and species to simulate the study of the diverse genetics of human sarcomas.
Prevalence and Type Distribution of High-Risk Human Papillomavirus (HPV) in Breast Cancer: A Qatar Based Study
Authors: Sher Gulab , Salman Nadia Aziz , Kulinski Michal , Fadel Rayyan Abdulaziz , Gupta Vinod Kumar , Anand Ambika , Gehani Salahddin , Abayazeed Sheraz , Al-Yahri Omer , Shahid Fakhar , Alshaibani Salman , Hassan Sara , Chawdhery M. Zafar , Davies Giles , Dermime Said , Uddin Shahab , Ashrafi G. Hossein , Junejo Kulsoom
Published: June 2020

Human papillomavirus (HPV) has been implicated in the etiology of a variety of human cancers. Studies investigating the presence of high-risk (HR) HPV in breast tissue have generated considerable controversy over its role as a potential risk factor for breast cancer (BC). This is the first investigation reporting the prevalence and type distribution of high-risk HPV infection in breast tissue in the population of Qatar. A prospective comparison blind research study herein reconnoitered the presence of twelve HR-HPV types’ DNA using multiplex PCR by screening a total of 150 fresh breast tissue specimens. Data obtained shows that HR-HPV types were found in 10% of subjects with breast cancer; of which the presence of HPV was confirmed in 4/33 (12.12%) of invasive carcinomas. These findings, the first reported from the population of Qatar, suggest that the selective presence of HPV in breast tissue is likely to be a related factor in the progression of certain cases of breast cancer.
Pathophysiology of Bone Loss in Patients with Prostate Cancer Receiving Androgen-Deprivation Therapy and Lifestyle Modifications for the Management of Bone Health: A Comprehensive Review
Authors: Kim Tae Jin , Koo Kyo Chul
Published: June 2020

Androgen-deprivation therapy (ADT) is a systemic therapy administered for the management of advanced prostate cancer (PCa). Although ADT may improve survival, long-term use reduces bone mass density (BMD), posing an increased risk of fracture. Considering the long natural history of PCa, it is essential to preserve bone health and quality-of-life in patients on long-term ADT. As an alternative to pharmacological interventions targeted at preserving BMD, current evidence recommends lifestyle modifications, including individualized exercise and nutritional interventions. Exercise interventions include resistance training, aerobic exercise, and weight-bearing impact exercise, and have shown efficacy in preserving BMD. At the same time, it is important to take into account that PCa is a progressive and debilitating disease in which a substantial proportion of patients on long-term ADT are older individuals who harbor axial bone metastases. Smoking cessation and limited alcohol consumption are commonly recommended lifestyle measures in patients receiving ADT. Contemporary guidelines regarding lifestyle modifications vary by country, organization, and expert opinion. This comprehensive review will provide an evidence-based, updated summary of lifestyle interventions that could be implemented to preserve bone health and maintain quality-of-life throughout the disease course of PCa.
Specific Roles of HSP27 S15 Phosphorylation Augmenting the Nuclear Function of HER2 to Promote Trastuzumab Resistance
Authors: Hwang Soo-Yeon , Choi Seul-Ki , Seo Seung Hee , Jo Hyunji , Shin Jae-Ho , Na Younghwa , Lee Yun-Sil , Kwon Youngjoo
Published: June 2020

Trastuzumab (TZMB) is widely used as first line therapy for breast cancer (BC) patients overexpressing human epidermal growth factor receptor 2 (HER2). Despite its clinical benefits, many patients suffer from primary or secondary resistance to this drug within one year. As diverse molecular mechanisms occur contemporaneously during the resistance development, we focused on elucidating the role of heat shock protein 27 (HSP27) in TZMB-resistance, as this protein simultaneously regulates the function of diverse client molecules that are involved in the resistance mechanism. By extensively utilizing TZMB-refractory breast cancer cell lines transduced with diverse phosphovariants of HSP27, our study newly revealed that specific phosphorylation of HSP27 at S15 promoted its S78 phosphorylation and served as key mediator to promote direct interactions that increase the stability of HER2 and protein kinase B (AKT). This phosphorylation promoted nuclear translocation of HER2, enhancing the distinct nuclear function of HER2 that promoted AKT activation and cyclin D1 expression. Co-administration of TZMB and a functional inhibitor of HSP27, J2, significantly reduced the S15/78 phosphorylation of HSP27, which downregulated HER2 and its downstream signals, sensitizing TZMB-refractory cell, and JIMT1-xenograft mouse models to TZMB. Collectively, p-HSP27S15 could serve as a valuable predictive marker and also a therapeutic target for TZMB-resistance.
Active RAC1 Promotes Tumorigenic Phenotypes and Therapy Resistance in Solid Tumors
Authors: De Pradip , Rozeboom Brett James , Aske Jennifer Carlson , Dey Nandini
Published: June 2020

Acting as molecular switches, all three members of the Guanosine triphosphate (GTP)-ase-family, Ras-related C3 botulinum toxin substrate (RAC), Rho, and Cdc42 contribute to various processes of oncogenic transformations in several solid tumors. We have reviewed the distribution of patterns regarding the frequency of Ras-related C3 botulinum toxin substrate 1 (RAC1)-alteration(s) and their modes of actions in various cancers. The RAC1 hyperactivation/copy-number gain is one of the frequently observed features in various solid tumors. We argued that RAC1 plays a critical role in the progression of tumors and the development of resistance to various therapeutic modalities applied in the clinic. With this perspective, here we interrogated multiple functions of RAC1 in solid tumors pertaining to the progression of tumors and the development of resistance with a special emphasis on different tumor cell phenotypes, including the inhibition of apoptosis and increase in the proliferation, epithelial-to-mesenchymal transition (EMT), stemness, pro-angiogenic, and metastatic phenotypes. Our review focuses on the role of RAC1 in adult solid-tumors and summarizes the contextual mechanisms of RAC1 involvement in the development of resistance to cancer therapies.
Reciprocal Regulation Between Indoleamine 2,3-Dioxigenase 1 and Notch1 Involved in Radiation Response of Cervical Cancer Stem Cells
Authors: Low Hui-Ying , Lee Yueh-Chun , Lee Yi-Ju , Wang Hui-Lin , Chen Yu-I , Chien Peng-Ju , Li Shao-Ti , Chang Wen-Wei
Published: June 2020

Cervical cancer is the fourth most common cancer in women around the world. Cancer stem cells (CSCs) are responsible for cancer initiation, as well as resistance to radiation therapy, and are considered as the effective target of cancer therapy. Indoleamine 2,3-dioxygenase 1 (IDO1) mediates tryptophan metabolism and T cell suppression, but the immune-independent function of IDO1 in cancer behavior is not fully understood. Using tumorsphere cultivation for enriched CSCs, we firstly found that IDO1 was increased in HeLa and SiHa cervical cancer cells and in these two cell lines after radiation treatment. The radiosensitivity of HeLa and SiHa tumorsphere cells was increased after the inhibition of IDO1 through RNA interference or by the treatment of INCB-024360, an IDO1 inhibitor. With the treatment of kynurenine, the first breakdown product of the IDO1-mediated tryptophan metabolism, the radiosensitivity of HeLa and SiHa cells decreased. The inhibition of Notch1 by shRNA downregulated IDO1 expression in cervical CSCs and the binding of the intracellular domain of Notch (NICD) on the IDO1 promoter was reduced by Ro-4929097, a γ-secretase inhibitor. Moreover, the knockdown of IDO1 also decreased NICD expression in cervical CSCs, which was correlated with the reduced binding of aryl hydrocarbon receptor nuclear translocator to Notch1 promoter. In vivo treatment of INCB-0234360 sensitized SiHa xenograft tumors to radiation treatment in nude mice through increased DNA damage. Furthermore, kynurenine increased the tumorsphere formation capability and the expression of cancer stemness genes including Oct4 and Sox2. Our data provide a reciprocal regulation mechanism between IDO1 and Notch1 expression in cervical cancer cells and suggest that the IDO1 inhibitors may potentially be used as radiosensitizers.
Integrated Analysis of Key Differentially Expressed Genes Identifies DBN1 as a Predictive Marker of Response to Endocrine Therapy in Luminal Breast Cancer
Authors: Alfarsi Lutfi H. , El Ansari Rokaya , Masisi Brendah K. , Parks Ruth , Mohammed Omar J , Ellis Ian O. , Rakha Emad A. , Green Andrew R.
Published: June 2020

Endocrine therapy is the mainstay of adjuvant treatment for patients with luminal breast cancer. Despite ongoing advances in endocrine therapy to date, a proportion of patients ultimately develop endocrine resistance, resulting in failure of therapy and poor prognosis. Therefore, as part of the growing concept of personalised medicine, the need for identification of predictive markers of endocrine therapy response at an early stage, is recognised. The METABRIC series was used to identify differentially expressed genes (DEGs) in term of response to adjuvant endocrine therapy. Drebrin 1 (DBN1) was identified as a key DEG associated with response to hormone treatment. Next, large, well-characterised cohorts of primary luminal breast cancer with long-term follow-up were assessed at the mRNA and protein levels for the value of DBN1 as a prognostic marker in luminal breast cancer, as well as its potential for predicting the benefit of endocrine therapy. DBN1 positivity was associated with aggressive clinicopathological variables and poor patient outcomes. Importantly, high DBN1 expression predicted relapse patients who were subject to adjuvant endocrine treatment. Our results further demonstrate that DBN1 is an independent prognostic marker in luminal breast cancer. Its association with the response to endocrine therapy and outcome provides evidence for DBN1 as a potential biomarker in luminal breast cancer, particularly for the benefit of endocrine treatment. Further functional investigations into the mechanisms underlying sensitivity to endocrine therapy is required.
Tissue-Resident NK Cells: Development, Maturation, and Clinical Relevance
Authors: Hashemi Elaheh , Malarkannan Subramaniam
Published: June 2020

Natural killer (NK) cells belong to type 1 innate lymphoid cells (ILC1) and are essential in killing infected or transformed cells. NK cells mediate their effector functions using non-clonotypic germ-line-encoded activation receptors. The utilization of non-polymorphic and conserved activating receptors promoted the conceptual dogma that NK cells are homogeneous with limited but focused immune functions. However, emerging studies reveal that NK cells are highly heterogeneous with divergent immune functions. A distinct combination of several activation and inhibitory receptors form a diverse array of NK cell subsets in both humans and mice. Importantly, one of the central factors that determine NK cell heterogeneity and their divergent functions is their tissue residency. Decades of studies provided strong support that NK cells develop in the bone marrow. However, evolving evidence supports the notion that NK cells also develop and differentiate in tissues. Here, we summarize the molecular basis, phenotypic signatures, and functions of tissue-resident NK cells and compare them with conventional NK cells.