bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-Biofilm Inhibitory Synergistic Effects of Combinations of Essential Oils and Antibiotics
Authors: Rosato Antonio , Sblano Sabina , Salvagno Lara , Carocci Alessia , Clodoveo Maria Lisa , Corbo Filomena , Fracchiolla Giuseppe
Published: September 2020

In recent years, the increase of bacteria antibiotic- resistance has been a severe problem for public health. A useful solution could be to join some phytochemicals naturally present in essential oils (EOs) to the existing antibiotics, with the aim to increase their efficacy in therapies. According to in vitro studies, EOs and their components could show such effects. Among them, we studied the activity of Cinnammonum zeylanicum, Mentha piperita, Origanum vulgare, and Thymus vulgaris EOs on bacterial biofilm and their synergism when used in association with some common antibiotics such as norfloxacin, oxacillin, and gentamicin. The chemical composition of EOs was determined using gas chromatography (GC) coupled with mass spectrometry (MS) techniques. The EOs drug efficacy was evaluated on four different strains of Gram-positive bacteria forming biofilms. The synergistic effects were tested through the chequerboard microdilution method. The association EOs-antibiotics showed a strong destruction of the biofilm growth of the four bacterial species considered. The interaction of norfloxacin with EOs was the most effective in all the tested combinations against the strains object of this study. These preliminary results suggest the formulation of a new generation of antimicrobial agents based on a combination of antimicrobial compounds with different origin.
The Spec-Radiation Method as a Fast Alternative to the Re-Radiation Method for the Detection of Flaws in Wooden Particleboards
Authors: Schmelt Andreas Sebastian , Twiefel Jens
Published: September 2020

For real-time evaluation of non-destructive air-coupled ultrasonic testing of wood-based materials, efficient and reliable calculation methods from ultrasonic holography are essential. Presented here is the spec-radiation method as a fast alternative to the re-radiation method. The spec-radiation method offers a more accurate and up to 88% faster evaluation than the re-radiation method for the determination of flaws in particleboards. Flaws of sub-wavelength sizes can be identified and their shape and location can be determined with this method. The spec-radiation method produces a better reproduction of the sound field than the re-radiation method, especially in the area of the measuring plane.
MTPR: A Multi-Task Learning Based POI Recommendation Considering Temporal Check-Ins and Geographical Locations
Authors: Xia Bin , Bai Yuxuan , Yin Junjie , Li Qi , Xu Lijie
Published: September 2020

The rapid development of location-based social networks (LBSNs) produces the increasing number of check-in records and corresponding heterogeneous information which bring big challenges of points-of-interest (POIs) recommendation in our daily lives. The emergence of various recommender techniques bridges the gap between the numerous heterogeneous check-ins and the personalized POI recommendation. However, due to the differences between LBSNs and conventional recommendation tasks, besides the user feedback, the spatio-temporal information is also significant to precisely capture the user preferences. In this paper, we propose a multi-task learning model based POI recommender system which exploits a structure of generative adversarial networks (GAN) simultaneously considering temporal check-ins and geographical locations. The GAN-based model is capable of relieving the sparsity of check-in data in POI recommender systems. The temporal check-ins not only present the preference but also show the lifestyle of an individual while the geographical locations describe the active region of users which further filters POIs far from the feasible region. The multi-task learning strategy is capable of combining the information of temporal check-ins and geographical locations to improve the performance of personalized POI recommendation. We conduct the experiments on two real-world LBSNs datasets and the experimental results show the effectiveness of our proposed approach.
Effects of Simultaneous Liquid or Gel Sodium Hypochlorite Irrigation on the Cyclic Fatigue of Two Single-File Nickel-Titanium Instruments
Authors: Pedullà Eugenio , La Rosa Giusy Rita Maria , Albani Marco Sesto , Isola Gaetano , Özyürek Taha , Generali Luigi
Published: September 2020

To evaluate the effect of simultaneous liquid or gel sodium hypochlorite (NaOCl) irrigation on cyclic fatigue of F6 SkyTaper (F6ST) and OneCurve (OC) single files, 180 new 25/0.06 F6ST and OC files were divided into 6 groups (n = 15) for each brand. Groups 1 and 4 included new instruments not exposed to NaOCl at 20 °C and 37 °C, respectively. Groups 2 and 5 included files activated with liquid NaOCl at 20 °C and 37 °C, respectively. Groups 3 and 6 consisted of instruments tested with NaOCl gel at 20 °C and 37 °C, respectively. Instruments were subjected to a fatigue test using a novel customized device. Data were expressed as time to fracture (TtF) and statistically analyzed (p < 0.05) after checking their normality through the Shapiro–Wilk test. Because they were normally distributed, 2-way analyses of variance (ANOVA) and the Tukey multiple comparison post-hoc test were used. Time to fracture of all tested instruments decreased at 37 °C (p < 0.05). At 20 °C, NaOCl improved TtF of F6ST and OC (p < 0.05). NaOCl liquid increased TtF of F6ST (p < 0.05) in comparison with gel, while there was no difference between the two formulations for OC. At 37 °C, both NaOCl formulations had no significant influence on TtF for F6ST, while they increased TtF of OC (p < 0.05). NaOCl improved the cyclic fatigue resistance of OC, independently of the temperature, while for F6ST the negative impact of higher temperature reduced the irrigant benefits.
Experimental and Numerical Study of Orifice Coefficient of Cargo Tank Design of LNG Vessels
Authors: Hwang Se-Yun , Kim Kwang-Sik , Jang Ho-Sang , Lee Jang-Hyun
Published: September 2020

Liquid cargo storage tanks of liquefied natural gas (LNG) carriers are designed by strict standards to maintain the cryogenic state (−163 °C). For most LNG cargo storage tanks, it is mandatory to install a system that can safely store leaked fluid for 15 days in the case of leakage of liquid cargo due to crack of the insulation system. To ensure safety, it is necessary to predict the amount of LNG spilling from the cracks in the insulation panels. Although international regulations are provided, they rely on a conservative and consistent coefficient. In this study, experimental and numerical methods were applied to examine the design factor used to predict the flow rate in the tank design process. To check the amount of leakage that occurs under pressure conditions of LNG tanks, an experiment was conducted using crack specimens and pressure containers filled with water. In order to simulate the leakage of LNG, the amount of leakage was predicted using the Computational Fluid Dynamics (CFD) method. The distribution of leakage quantity was investigated according to the shape of the crack through the pressure vessel experiment and the analysis. Through CFD analysis, the leakage rate of LNG was calculated for each operating pressure condition through the crack. Finally, the results of this study examined the need to identify and reconsider the coefficients due to international guidelines and other factors in calculating orifice coefficients applied to the design of LNG tanks.
Brain-to-Brain Neural Synchrony During Social Interactions: A Systematic Review on Hyperscanning Studies
Authors: Nam Chang S. , Choo Sanghyun , Huang Jiali , Park Jiyoung
Published: September 2020

The aim of this study was to conduct a comprehensive review on hyperscanning research (measuring brain activity simultaneously from more than two people interacting) using an explicit systematic method, the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Data were searched from IEEE Xplore, PubMed, Engineering Village, Web of Science and Scopus databases. Inclusion criteria were journal articles written in English from 2000 to 19 June 2019. A total of 126 empirical studies were screened out to address three specific questions regarding the neuroimaging method, the application domain, and the experiment paradigm. Results showed that the most used neuroimaging method with hyperscanning was magnetoencephalography/electroencephalography (MEG/EEG; 47%), and the least used neuroimaging method was hyper-transcranial Alternating Current Stimulation (tACS) (1%). Applications in cognition accounted for almost half the studies (48%), while educational applications accounted for less than 5% of the studies. Applications in decision-making tasks were the second most common (26%), shortly followed by applications in motor synchronization (23%). The findings from this systematic review that were based on documented, transparent and reproducible searches should help build cumulative knowledge and guide future research regarding inter-brain neural synchrony during social interactions, that is, hyperscanning research.
Revealing the True Morphological Structure of Macroporous Soft Hydrogels for Tissue Engineering
Authors: Podhorská Bohumila , Vetrík Miroslav , Chylíková-Krumbholcová Eva , Kománková Lucie , Rashedi Banafshehvaragh Niloufar , Šlouf Miroslav , Dušková-Smrčková Miroslava , Janoušková Olga
Published: September 2020

(1) Background: Macroporous hydrogel scaffolds based on poly [N-(2-hydroxypropyl) methacrylamide] are one of the widely studied biocompatible materials for tissue reparation and regeneration. This study investigated the morphological changes during hydrogel characterization which can significantly influence their future application. (2) Methods: Three types of macroporous soft hydrogels differing in pore size were prepared. The macroporosity was achieved by the addition of sacrificial template particles of sodium chloride of various sizes (0–30, 30–50, and 50–90 µm) to the polymerizing mixture. The 3D structure of the hydrogels was then investigated by scanning electron microscopy (SEM) and laser scanning confocal microscopy (LSCM). The SEM was performed with specimens rapidly frozen to various temperatures, while non-frozen gels were visualized with LSCM. (3 and 4) Results and Conclusion: In comparison to LSCM, the SEM images revealed a significant alteration in the mean pore size and appearance of newly formed multiple connections between the pores, depending on the freezing conditions. Additionally, after freezing for SEM, the gel matrix between the pores and the fine pores collapsed. LSCM visualization aided the understanding of the dynamics of pore generation using sodium chloride, providing the direct observation of hydrogel scaffolds with the growing cells. Moreover, the reconstructed confocal z-stacks were a promising tool to quantify the swollen hydrogel volume reconstruction which is not possible with SEM.
Energy Storage in Earth-Abundant Dolomite Minerals
Authors: Srinivasan Sesha , Dodson Dominic , Charles Mc Ben Joe , Wallen Scott L. , Albarelli Gary , Kaushik Ajeet , Hickman Nicoleta , Chaudhary Ganga Ram , Stefanakos Elias , Dhau Jaspreet
Published: September 2020

Dolomite, a calcium magnesium mineral (CaMg(CO3)2), is considered an undesirable accompanying mineral in the phosphoric acid production process and, as such, large quantities of this mineral are available in Florida. This study is aimed toward the characterization of the high-concentration phosphatic dolomite pebbles (handpicked dolomites) received from the Florida Industrial and Phosphate Research Institute (FIPR) and investigate their feasibility for thermochemical energy storage (TCES). The chemical composition, structural and microstructural characteristics of commercial and handpicked dolomite minerals was studied using a variety of techniques such as X-ray Fluorescence (XRF), Fourier-transform infrared spectroscopy (FTIR), and an automated mineralogy Automated SEM-EDX Mineralogy (or automated scanning electron microscopy) with energy dispersive X-rays spectrometer (SEM-EDX), which confirmed the phosphatic pebbles received contains dolomite (CaMg(CO3)2) phase in a high percentage. Particle size and the surface area were measured using XRD and N2 adsorption, the Brunauer–Emmett–Teller (BET) methods. Thermogravimetric analysis (TGA) was used to determine the activation energy for the calcination and re-carbonation reactions of the dolomite pebbles in nitrogen (N2) and carbon dioxide (CO2) atmospheres at temperatures up to 800 °C. The present results exhibit, for the first time, the potential for using abundant, high phosphatic concentration dolomite possessing long-term cycling behavior for thermochemical energy storage applications in Concentrated Solar Power (CSP) plants.
Contribution of Phoretic and Electrostatic Effects to the Collection Efficiency of Submicron Aerosol Particles by Raindrops
Authors: Lemaitre Pascal , Sow Mamadou , Quérel Arnaud , Dépée Alexis , Monier Marie , Menard Thibaut , Flossmann Andrea
Published: September 2020

This article presents an experimental study, performed in the BERGAME setup, dedicated to studying the collection of submicron aerosol particles by raindrops. The initial aim was to focus on the influence of the electrical charges of raindrops on the efficiency with which they collect aerosol particles. However, in the relative humidity range considered in this article (26–36%), measurements highlight a first-order role of phoretic effect for submicron aerosol particles. Indeed, measurements highlight a 100% increase in the collection efficiency for each percentage decrease in the atmospheric relative humidity. Phoretic effects are known to play a role in collection by drops; however, none of the models found in the literature predicts the same magnitude as the one presently measured. Characterization of the aerosol trajectories around the drop, accelerated to terminal velocity, seems to show a coupling between phoretic effects and rear capture. This interaction, already suggested by Grover et al., is a line of explanation for such a sharp unpredicted increase of the collection efficiency with moisture decrease.
The Effect of S-15176 Difumarate Salt on Ultrastructure and Functions of Liver Mitochondria of C57BL/6 Mice with Streptozotocin/High-Fat Diet-Induced Type 2 Diabetes
Authors: Belosludtseva Natalia V. , Starinets Vlada S. , Pavlik Lyubov L. , Mikheeva Irina B. , Dubinin Mikhail V. , Belosludtsev Konstantin N.
Published: September 2020

S-15176, a potent derivative of the anti-ischemic agent trimetazidine, was reported to have multiple effects on the metabolism of mitochondria. In the present work, the effect of S-15176 (1.5 mg/kg/day i.p.) on the ultrastructure and functions of liver mitochondria of C57BL/6 mice with type 2 diabetes mellitus (T2DM) induced by a high-fat diet combined with a low-dose streptozotocin injection was examined. An electron microscopy study showed that T2DM induced mitochondrial swelling and a reduction in the number of liver mitochondria. The number of mtDNA copies in the liver in T2DM decreased. The expression of Drp1 slightly increased, and that of Mfn2 and Opa1 somewhat decreased. The treatment of diabetic animals with S-15176 prevented the mitochondrial swelling, normalized the average mitochondrial size, and significantly decreased the content of the key marker of lipid peroxidation malondialdehyde in liver mitochondria. In S-15176-treated T2DM mice, a two-fold increase in the expression of the PGC-1α and a slight decrease in Drp 1 expression in the liver were observed. The respiratory control ratio, the level of mtDNA, and the number of liver mitochondria of S-15176-treated diabetic mice tended to restore. S-15176 did not affect the decrease in expression of Parkin and Opa1 in the liver of diabetic animals, but slightly suppressed the expression of these proteins in the control. The modulatory effect of S-15176 on dysfunction of liver mitochondria in T2DM can be related to the stimulation of mitochondrial biogenesis and the inhibition of lipid peroxidation in the organelles.
Circulating microRNA as a Biomarker for Coronary Artery Disease
Authors: Fazmin Ibrahim T. , Achercouk Zakaria , Edling Charlotte E. , Said Asri , Jeevaratnam Kamalan
Published: September 2020

Coronary artery disease (CAD) is the leading cause of sudden cardiac death in adults, and new methods of predicting disease and risk-stratifying patients will help guide intervention in order to reduce this burden. Current CAD detection involves multiple modalities, but the consideration of other biomarkers will help improve reliability. The aim of this narrative review is to help researchers and clinicians appreciate the growing relevance of miRNA in CAD and its potential as a biomarker, and also to suggest useful miRNA that may be targets for future study. We sourced information from several databases, namely PubMed, Scopus, and Google Scholar, when collating evidentiary information. MicroRNAs (miRNA) are short, noncoding RNAs that are relevant in cardiovascular physiology and pathophysiology, playing roles in cardiac hypertrophy, maintenance of vascular tone, and responses to vascular injury. CAD is associated with changes in miRNA expression profiles, and so are its risk factors, such as abnormal lipid metabolism and inflammation. Thus, they may potentially be biomarkers of CAD. Nevertheless, there are limitations in using miRNA. These include cost and the presence of several confounding factors that may affect miRNA profiles. Furthermore, there is difficulty in the normalisation of miRNA values between published studies, due to pre-analytical variations in samples.
Glutathione-Stabilized Silver Nanoparticles: Antibacterial Activity against Periodontal Bacteria, and Cytotoxicity and Inflammatory Response in Oral Cells
Authors: Zorraquín-Peña Irene , Cueva Carolina , González de Llano Dolores , Bartolomé Begoña , Moreno-Arribas M. Victoria
Published: September 2020

Silver nanoparticles (AgNPs) have been proposed as new alternatives to limit bacterial dental plaque because of their antimicrobial activity. Novel glutathione-stabilized silver nanoparticles (GSH-AgNPs) have proven powerful antibacterial properties in food manufacturing processes. Therefore, this study aimed to evaluate the potentiality of GSH-AgNPs for the prevention/treatment of oral infectious diseases. First, the antimicrobial activity of GSH-AgNPs against three oral pathogens (Porphyromonas gingivalis, Fusobacterium nucleatum, and Streptococcus mutans) was evaluated. Results demonstrated the efficiency of GSH-AgNPs in inhibiting the growth of all bacteria, especially S. mutans (IC50 = 23.64 μg/mL, Ag concentration). Second, GSH-AgNPs were assayed for their cytotoxicity (i.e., cell viability) toward a human gingival fibroblast cell line (HGF-1), as an oral epithelial model. Results indicated no toxic effects of GSH-AgNPs at low concentrations (≤6.16 µg/mL, Ag concentration). Higher concentrations resulted in losing cell viability, which followed the Ag accumulation in cells. Finally, the inflammatory response in the HGF-1 cells after their exposure to GSH-AgNPs was measured as the production of immune markers (interleukins 6 and 8 (IL-6 and IL-8) and tumor necrosis factor-alpha (TNF-α)). GSH-AgNPs activates the inflammatory response in human gingival fibroblasts, increasing the production of cytokines. These findings provide new insights for the use of GSH-AgNPs in dental care and encourage further studies for their application.
The Impacts of Antivirals on the Coronavirus Genome Structure and Subsequent Pathogenicity, Virus Fitness and Antiviral Design
Authors: Lin Ching-Hung , Yang Cheng-Yao , Ou Shan-Chia , Wang Meilin , Lo Chen-Yu , Tsai Tsung-Lin , Wu Hung-Yi
Published: September 2020

With the global threat of SARS-CoV-2, much effort has been focused on treatment and disease control. However, how coronaviruses react to the treatments and whether the surviving viruses have altered their characteristics are also unanswered questions with medical importance. To this end, bovine coronavirus (BCoV), which is in the same genus as SARS-CoV-2, was used as a test model and the findings were as follows. With the treatment of antiviral remdesivir, the selected BCoV variant with an altered genome structure developed resistance, but its pathogenicity was not increased in comparison to that of wild type (wt) BCoV. Under the selection pressure of innate immunity, the genome structure was also altered; however, neither resistance developed nor pathogenicity increased for the selected BCoV variant. Furthermore, both selected BCoV variants showed a better efficiency in adapting to alternative host cells than wt BCoV. In addition, the previously unidentified feature that the spike protein was a common target for mutations under different antiviral treatments might pose a problem for vaccine development because spike protein is a common target for antibody and vaccine designs. The findings derived from this fundamental research may contribute to the disease control and treatments against coronaviruses, including SARS-CoV-2.
Acute Effects of Aerobic Exercise on Somatosensory-Evoked Potentials in Patients with Mild Cognitive Impairment
Authors: Amjad Imran , Niazi Imran Khan , Toor Hamza Ghazanfar , Nedergaard Rasmus Bach , Shafique Muhammad , Holt Kelly , Haavik Heidi , Ahmed Touqeer
Published: September 2020

Mild cognitive impairment (MCI) is becoming a serious problem for developing countries as the lifespan of populations increases. Exercise is known to be clinically beneficial for MCI patients. Somatosensory-evoked potentials (SEPs) may be a potential diagnostic and prognostic marker for this population. The objective of this study was to determine the acute effects of aerobic exercise on SEPs in patients with MCI, to test whether SEPs are sensitive enough to detect improvements in early somatosensory processing. The study had a randomized parallel-group design and included 28 MCI subjects (14 in the experimental group and 14 in the control group). The experimental intervention was 20 min of aerobic exercise using a stationary bicycle. The control intervention involved 20 min of movements and stretches. Subjects were assessed before and after a single intervention session. SEPs were recorded by stimulating the median nerve of the dominant hand. Analysis of normalized SEP peak amplitudes showed that a single session of aerobic activity significantly reduced the N30 peak at the F3 channel (p = 0.03). There were no significant effects of aerobic exercise on SEP peak latencies. The results indicate that 20 min of aerobic exercise has a significant effect on the N30 SEP peak amplitude in MCI patients. The results suggest that aerobic exercise is likely to provide sensory-enriching inputs that enhance sensorimotor integration. Future studies should assess the effects of aerobic exercise on somatosensory processing in progressive stages of Alzheimer’s disease, longer exercise durations, and multiple exercise sessions.
Misperception of Visual Verticality in Patients with Primary Headache Disorders: A Systematic Review with Meta-Analysis
Authors: Obrero-Gaitán Esteban , Manrique-Navarro María , Lérida-Ortega Miguel Ángel , Rodríguez-Almagro Daniel , Osuna-Pérez María Catalina , Lomas-Vega Rafael
Published: September 2020

Migraine and tension-type headache (TTH) are the two most prevalent primary headache disorders (PHDs) that may involve visual and vestibular impairments, neck pain, and postural unsteadiness. The perception of visual verticality (VV) has been studied in patients diagnosed with PHD to assess balance disorders showing varying findings. Our study aimed to assess the VV perception in patients diagnosed with PHD in comparison to healthy controls. A systematic review with meta-analysis was carried out in PubMed MEDLINE, Scopus, WOS, CINAHL, and SciELO. The Cohen standardized mean difference (SMD) was used to estimate the differences between exposed and healthy controls. Seven studies with 816 participants were included. The quality of included studies, according to the Newcastle–Ottawa Scale (NOS), was moderate (mean score of 5.2). Patients diagnosed with PHD showed a moderate misperception of VV as assessed with the subjective visual vertical (SVV) test (SMD = 0.530; 95% CI = 0.225, 0.836; p < 0.001). Specifically, a misperception of the SVV was found in patients with migraine (SMD = 0.369; 95% CI = 0.1, 0.638; p = 0.007) and with TTH (SMD = 1.122; 95% CI = 0.540, 1.704; p < 0.001). This review shows a misperception of VV in patients with migraine and TTH when assessed with the SVV test, being higher in patients with TTH, although the THH sample size was low.
BDNF and IL-8, But Not UCHL-1 and IL-11, Are Markers of Brain Injury in Children Caused by Mild Head Trauma
Authors: Tylicka Marzena , Matuszczak Ewa , Hermanowicz Adam , Dębek Wojciech , Karpińska Maria , Kamińska Joanna , Koper-Lenkiewicz Olga Martyna
Published: September 2020

The aim of the study was to check whether the plasma levels of brain-derived neurotrophic factor (BDNF), interleukin-8 (IL-8), interleukin-11 (IL-11) and ubiquitin C-terminal hydrolase L1 (UCHL-1) change in children with mild head trauma (N = 29) compared to controls (N = 13). Protein concentration in children with mild head trauma (12 children with mild concussion without loss of consciousness and 17 children with severe concussion and loss of consciousness) and the control group were measured by means of the Enzyme-Linked Immunosorbent Assay (ELISA) method. IL-8 and BDNF concentration was statistically higher in the group of children with mild head trauma (9.89 pg/mL and 2798.00 pg/mL, respectively) compared to the control group (7.52 pg/mL and 1163.20 pg/mL, respectively). BDNF concentration was significantly higher in children with severe concussion and loss of consciousness (3826.00 pg/mL) than in the control group. None of the tested proteins differed significantly between children with mild concussion without loss of consciousness and children with severe concussion and loss of consciousness. BDNF and IL-8 may be sensitive markers of brain response to mild head trauma in children. The lack of statistical differences for BDNF and IL-8 between children with mild or severe concussion could indicate that their elevated levels may not result from significant structural brain damage but rather reflect a functional disturbance.
The Unique Pharmacometrics of Small Molecule Therapeutic Drug Tracer Imaging for Clinical Oncology
Authors: Dunphy Mark P. S. , Pillarsetty Nagavarakishore
Published: September 2020

Translational development of radiolabeled analogues or isotopologues of small molecule therapeutic drugs as clinical imaging biomarkers for optimizing patient outcomes in targeted cancer therapy aims to address an urgent and recurring clinical need in therapeutic cancer drug development: drug- and target-specific biomarker assays that can optimize patient selection, dosing strategy, and response assessment. Imaging the in vivo tumor pharmacokinetics and biomolecular pharmacodynamics of small molecule cancer drugs offers patient- and tumor-specific data which are not available from other pharmacometric modalities. This review article examines clinical research with a growing pharmacopoeia of investigational small molecule cancer drug tracers.
Promising Applications of Tumor Spheroids and Organoids for Personalized Medicine
Authors: Gilazieva Zarema , Ponomarev Aleksei , Rutland Catrin , Rizvanov Albert , Solovyeva Valeriya
Published: September 2020

One of the promising directions in personalized medicine is the use of three-dimensional (3D) tumor models such as spheroids and organoids. Spheroids and organoids are three-dimensional cultures of tumor cells that can be obtained from patient tissue and, using high-throughput personalized medicine methods, provide a suitable therapy for that patient. These 3D models can be obtained from most types of tumors, which provides opportunities for the creation of biobanks with appropriate patient materials that can be used to screen drugs and facilitate the development of therapeutic agents. It should be noted that the use of spheroids and organoids would expand the understanding of tumor biology and its microenvironment, help develop new in vitro platforms for drug testing and create new therapeutic strategies. In this review, we discuss 3D tumor spheroid and organoid models, their advantages and disadvantages, and evaluate their promising use in personalized medicine.
Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment
Authors: Martínez-Chantar Maria L. , Avila Matias A. , Lu Shelly C.
Published: September 2020

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and the second most common cause of cancer mortality worldwide [...]
Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes
Authors: Tanaka Takako , Okada Reona , Hozaka Yuto , Wada Masumi , Moriya Shogo , Satake Souichi , Idichi Tetsuya , Kurahara Hiroshi , Ohtsuka Takao , Seki Naohiko
Published: September 2020

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer, and its prognosis is abysmal; only 25% of patients survive one year, and 5% live for five years. MicroRNA (miRNA) signature analysis of PDAC revealed that both strands of pre-miR-30c (miR-30c-5p, guide strand; miR-30c-2-3p, passenger strand) were significantly downregulated, suggesting they function as tumor-suppressors in PDAC cells. Ectopic expression assays demonstrated that these miRNAs attenuated the aggressiveness of PDAC cells, e.g., cell proliferation, migration, and invasiveness. Through a combination of in silico analyses and gene expression data, we identified 216 genes as putative oncogenic targets of miR-30c-5p and miR-30c-2-3p regulation in PDAC cells. Among these, the expression of 18 genes significantly predicted the 5-year survival rates of PDAC patients (p < 0.01). Importantly, the expression levels of 10 genes (YWHAZ, F3, TMOD3, NFE2L3, ENDOD1, ITGA3, RRAS, PRSS23, TOP2A, and LRRFIP1) were found to be independent prognostic factors for patient survival (p < 0.01). We focused on TOP2A (DNA Topoisomerase II Alpha) and investigated its potential as a therapeutic target for PDAC. The overexpression of TOP2A and its transcriptional activators (SP1 and HMGB2) was detected in PDAC clinical specimens. Moreover, the knockdown of TOP2A enhanced the sensitivity of PDAC cells to anticancer drugs. Our analyses of the PDAC miRNA signature and tumor-suppressive miRNAs provide important insights into the molecular pathogenesis of PDAC.
HDAC9 Is Preferentially Expressed in Dedifferentiated Hepatocellular Carcinoma Cells and Is Involved in an Anchorage-Independent Growth
Authors: Kanki Keita , Watanabe Ryota , Nguyen Thai Le , Zhao Chun-Hao , Naito Kyoko
Published: September 2020

Aberrant activation of histone deacetylases (HDACs) is one of the causes of tumor cell transformation in many types of cancer, however, the critical HDAC responsible for the malignant transformation remain unclear. To identify the HDAC related to the dedifferentiation of hepatocellular carcinoma (HCC) cells, we investigated the expression profile of HDACs in differentiated and undifferentiated hepatoma cells. We found that HDAC9, a member of the class II HDAC, is preferentially expressed in undifferentiated HCC cells. Analysis of 373 HCC patients in The Cancer Genome Atlas (TCGA) database revealed that the expression of HDAC9 mRNA positively correlated with the markers of mesenchymal phenotype and stemness, and conversely, negatively correlated with hepatic differentiation markers. HDAC9 was transcriptionally upregulated in epithelial–mesenchymal transition (EMT)-induced HCC cells treated with TGF-β. Genetic and pharmacological inhibition of HDAC9 in undifferentiated HCC cells showed decreased sphere-forming activity, which indicates an ability of anchorage-independent cell growth and self-renewal. We also showed that aldehyde dehydrogenase 1A3 (ALDH1A3) was downregulated in HDAC9-suppressing cells, and ALDH inhibitor disulfiram significantly decreased the sphere formation of undifferentiated HCC cells. Together, our data provide useful information for the development of HDAC9-specific inhibitors for the treatment of HCC progression.
Nanoparticles in 472 Human Cerebrospinal Fluid: Changes in Extracellular Vesicle Concentration and miR-21 Expression as a Biomarker for Leptomeningeal Metastasis
Authors: Lee Kyue-Yim , Im Ji Hye , Lin Weiwei , Gwak Ho-Shin , Kim Jong Heon , Yoo Byong Chul , Kim Tae Hoon , Park Jong Bae , Park Hyeon Jin , Kim Ho-Jin , Kwon Ji-Woong , Shin Sang Hoon , Yoo Heon , Lee Changjin
Published: September 2020

Leptomeningeal metastasis (LM) has a poor prognosis and is difficult to diagnose and predict the response of treatment. In this study, we suggested that the monitoring of changes in the concentration of extracellular vesicles in cerebrospinal fluid could help diagnose or predict outcomes for LM. We measured nanoparticles in 472 human cerebrospinal fluid (CSF) from patients including LM with both Dynamic Light Scattering (DLS) and Nanoparticle Tracking Analysis (NTA) after two-step centrifugations. NTA revealed that the concentration of CSF nanoparticles was significantly increased in LM compared to other groups (2.80 × 108 /mL vs. 1.49 × 108 /mL, p < 0.01). Changes in NTA-measured nanoparticles concentration after intra-CSF chemotherapy were further examined in 33 non-small cell lung cancer patients with LM. Overall survival was longer for patients with increased EV than the others (442 vs. 165 days, p < 0.001). Markers of extracellular vesicles (CD9/CD63/CD81) significantly decreased in the EV-decreased group. MicroRNA-21 expression decreased in this favorable prognostic group, whereas it increased in the EV-decreased group. In conclusion, the elevated concentration of extracellular vesicles in cerebrospinal fluid in patients with LM may be a predictive marker for survival duration. Moreover, EV changes combined with microRNA-21 might be a biomarker for monitoring the efficacy of intracranial chemotherapy of LM in non-small cell lung cancer patients.
HSPA2 Chaperone Contributes to the Maintenance of Epithelial Phenotype of Human Bronchial Epithelial Cells but Has Non-Essential Role in Supporting Malignant Features of Non-Small Cell Lung Carcinoma, MCF7, and HeLa Cancer Cells
Authors: Sojka Damian Robert , Gogler-Pigłowska Agnieszka , Klarzyńska Katarzyna , Klimczak Marta , Zylicz Alicja , Głowala-Kosińska Magdalena , Krawczyk Zdzisław , Scieglinska Dorota
Published: September 2020

Heat Shock Protein A2 (HSPA2) is a member of the HSPA (HSP70) chaperone family and has a critical role for male fertility. HSPA2 is present in a number of somatic organs. Limited evidence suggests that HSPA2 may be involved in regulating epithelial cell differentiation. HSPA2 also emerged as a cancer-related chaperone; however, no consensus on its functional significance has been reached so far. In this study, we compared the phenotypic effects of HSPA2 deficit in non-transformed human bronchial epithelial cells (HBEC), and in lung, breast, and cervical cancer cells. We used various techniques to inhibit the HSPA2 gene expression in order to examine the impact of HSPA2 deficiency on cell growth, migration, adhesion, and invasion. Our results show that HBEC but not cancer cells are sensitive to HSPA2 deficit. HSPA2 knockdown in HBEC cells impaired their clone-forming ability and adhesiveness. Thus, our results indicate that epithelial cells can rely on a specific activity of HSPA2, but such dependence can be lost in epithelial cells that have undergone malignant transformation.
Pancreatic Ductal Adenocarcinoma (PDAC) Organoids: The Shining Light at the End of the Tunnel for Drug Response Prediction and Personalized Medicine
Authors: Frappart Pierre-Olivier , Hofmann Thomas G.
Published: September 2020

Pancreatic ductal adenocarcinoma (PDAC) represents 90% of pancreatic malignancies. In contrast to many other tumor entities, the prognosis of PDAC has not significantly improved during the past thirty years. Patients are often diagnosed too late, leading to an overall five-year survival rate below 10%. More dramatically, PDAC cases are on the rise and it is expected to become the second leading cause of death by cancer in western countries by 2030. Currently, the use of gemcitabine/nab-paclitaxel or FOLFIRINOX remains the standard chemotherapy treatment but still with limited efficiency. There is an urgent need for the development of early diagnostic and therapeutic tools. To this point, in the past 5 years, organoid technology has emerged as a revolution in the field of PDAC personalized medicine. Here, we are reviewing and discussing the current technical and scientific knowledge on PDAC organoids, their future perspectives, and how they can represent a game change in the fight against PDAC by improving both diagnosis and treatment options.
Ammonium Salts Catalyzed Acetalization Reactions in Green Ethereal Solvents
Authors: Azzena Ugo , Carraro Massimo , Corrias Martina , Crisafulli Rosella , De Luca Lidia , Gaspa Silvia , Nuvoli Luca , Pintus Salvatore , Pisano Luisa , Polese Riccardo , Sanna Michela , Satta Giuseppe , Senes Nina , Urtis Luigi , Garroni Sebastiano
Published: September 2020

Cyclopentyl methyl ether and 2-methyltetrahydrofuran, low impact ethereal solvents forming a positive azeotrope with water, were successfully employed as solvents in the synthesis of a variety of acetals carried out under Dean–Stark conditions in the presence of heterogeneous acidic catalysts. Under these conditions, ammonium salts, either as such or supported on SiO2, performed better or equally well than widely employed homogeneous and heterogeneous acidic catalysts such as p-toluenesulfonic acid, Amberlyst 15®, or Montmorillonite K10. Several examples highlight the advantage of tuning the relative acidities of ammonium salts by appropriately selecting the counterion. Within one of these examples, our protocol clearly outweighs the classic p-toluenesulfonic acid/toluene protocol in terms of chemoselectivity. Silica-supported catalysts were characterized by SEM, TEM, and FTIR spectroscopies, as well as by N2 physisorption. Such a characterization reveals an even distribution of ammonium salts on silica, thus confirming the formation of expected catalytic supports.
Neutrophil Extracellular Traps Promote the Development and Growth of Human Salivary Stones
Authors: Schapher Mirco , Koch Michael , Weidner Daniela , Scholz Michael , Wirtz Stefan , Mahajan Aparna , Herrmann Irmgard , Singh Jeeshan , Knopf Jasmin , Leppkes Moritz , Schauer Christine , Grüneboom Anika , Alexiou Christoph , Schett Georg , Iro Heinrich , Muñoz Luis E. , Herrmann Martin
Published: September 2020

Salivary gland stones, or sialoliths, are the most common cause of the obstruction of salivary glands. The mechanism behind the formation of sialoliths has been elusive. Symptomatic sialolithiasis has a prevalence of 0.45% in the general population, is characterized by recurrent painful periprandial swelling of the affected gland, and often results in sialadenitis with the need for surgical intervention. Here, we show by the use of immunohistochemistry, immunofluorescence, computed tomography (CT) scans and reconstructions, special dye techniques, bacterial genotyping, and enzyme activity analyses that neutrophil extracellular traps (NETs) initiate the formation and growth of sialoliths in humans. The deposition of neutrophil granulocyte extracellular DNA around small crystals results in the dense aggregation of the latter, and the subsequent mineralization creates alternating layers of dense mineral, which are predominantly calcium salt deposits and DNA. The further agglomeration and appositional growth of these structures promotes the development of macroscopic sialoliths that finally occlude the efferent ducts of the salivary glands, causing clinical symptoms and salivary gland dysfunction. These findings provide an entirely novel insight into the mechanism of sialolithogenesis, in which an immune system-mediated response essentially participates in the physicochemical process of concrement formation and growth.
The Role of Chaperone-Mediated Autophagy in Cell Cycle Control and Its Implications in Cancer
Authors: Andrade-Tomaz Marina , de Souza Izadora , Rocha Clarissa Ribeiro Reily , Gomes Luciana Rodrigues
Published: September 2020

The cell cycle involves a network of proteins that modulate the sequence and timing of proliferation events. Unregulated proliferation is the most fundamental hallmark of cancer; thus, changes in cell cycle control are at the heart of malignant transformation processes. Several cellular processes can interfere with the cell cycle, including autophagy, the catabolic pathway involved in degradation of intracellular constituents in lysosomes. According to the mechanism used to deliver cargo to the lysosome, autophagy can be classified as macroautophagy (MA), microautophagy (MI), or chaperone-mediated autophagy (CMA). Distinct from other autophagy types, CMA substrates are selectively recognized by a cytosolic chaperone, one-by-one, and then addressed for degradation in lysosomes. The function of MA in cell cycle control, and its influence in cancer progression, are already well-established. However, regulation of the cell cycle by CMA, in the context of tumorigenesis, has not been fully addressed. This review aims to present and debate the molecular mechanisms by which CMA can interfere in the cell cycle, in the context of cancer. Thus, cell cycle modulators, such as MYC, hypoxia-inducible factor-1 subunit alpha (HIF-1α), and checkpoint kinase 1 (CHK1), regulated by CMA activity will be discussed. Finally, the review will focus on how CMA dysfunction may impact the cell cycle, and as consequence promote tumorigenesis.
Human Mesenchymal Stromal Cell Secretome Promotes the Immunoregulatory Phenotype and Phagocytosis Activity in Human Macrophages
Authors: Holopainen Minna , Impola Ulla , Lehenkari Petri , Laitinen Saara , Kerkelä Erja
Published: September 2020

Human mesenchymal stromal/stem cells (hMSCs) show great promise in cell therapy due to their immunomodulatory properties. The overall immunomodulatory response of hMSCs resembles the resolution of inflammation, in which lipid mediators and regulatory macrophages (Mregs) play key roles. We investigated the effect of hMSC cell-cell contact and secretome on macrophages polarized and activated toward Mreg phenotype. Moreover, we studied the effect of supplemented polyunsaturated fatty acids (PUFAs): docosahexaenoic acid (DHA) and arachidonic acid, the precursors of lipid mediators, on hMSC immunomodulation. Our results show that unlike hMSC cell-cell contact, the hMSC secretome markedly increased the CD206 expression in both Mreg-polarized and Mreg-activated macrophages. Moreover, the secretome enhanced the expression of programmed death-ligand 1 on Mreg-polarized macrophages and Mer receptor tyrosine kinase on Mreg-activated macrophages. Remarkably, these changes were translated into improved Candida albicans phagocytosis activity of macrophages. Taken together, these results demonstrate that the hMSC secretome promotes the immunoregulatory and proresolving phenotype of Mregs. Intriguingly, DHA supplementation to hMSCs resulted in a more potentiated immunomodulation with increased CD163 expression and decreased gene expression of matrix metalloproteinase 2 in Mreg-polarized macrophages. These findings highlight the potential of PUFA supplementations as an easy and safe method to improve the hMSC therapeutic potential.
Transmembrane BAX Inhibitor-1 Motif Containing Protein 5 (TMBIM5) Sustains Mitochondrial Structure, Shape, and Function by Impacting the Mitochondrial Protein Synthesis Machinery
Authors: Seitaj Bruno , Maull Felicia , Zhang Li , Wüllner Verena , Wolf Christina , Schippers Philipp , La Rovere Rita , Distler Ute , Tenzer Stefan , Parys Jan B. , Bultynck Geert , Methner Axel
Published: September 2020

The Transmembrane Bax Inhibitor-1 motif (TMBIM)-containing protein family is evolutionarily conserved and has been implicated in cell death susceptibility. The only member with a mitochondrial localization is TMBIM5 (also known as GHITM or MICS1), which affects cristae organization and associates with the Parkinson’s disease-associated protein CHCHD2 in the inner mitochondrial membrane. We here used CRISPR-Cas9-mediated knockout HAP1 cells to shed further light on the function of TMBIM5 in physiology and cell death susceptibility. We found that compared to wild type, TMBIM5-knockout cells were smaller and had a slower proliferation rate. In these cells, mitochondria were more fragmented with a vacuolar cristae structure. In addition, the mitochondrial membrane potential was reduced and respiration was attenuated, leading to a reduced mitochondrial ATP generation. TMBIM5 did not associate with Mic10 and Mic60, which are proteins of the mitochondrial contact site and cristae organizing system (MICOS), nor did TMBIM5 knockout affect their expression levels. TMBIM5-knockout cells were more sensitive to apoptosis elicited by staurosporine and BH3 mimetic inhibitors of Bcl-2 and Bcl-XL. An unbiased proteomic comparison identified a dramatic downregulation of proteins involved in the mitochondrial protein synthesis machinery in TMBIM5-knockout cells. We conclude that TMBIM5 is important to maintain the mitochondrial structure and function possibly through the control of mitochondrial biogenesis.
T3 Critically Affects the Mhrt/Brg1 Axis to Regulate the Cardiac MHC Switch: Role of an Epigenetic Cross-Talk
Authors: Forini Francesca , Nicolini Giuseppina , Kusmic Claudia , D’Aurizio Romina , Mercatanti Alberto , Iervasi Giorgio , Pitto Letizia
Published: September 2020

The LncRNA my-heart (Mhrt) and the chromatin remodeler Brg1 inhibit each other to respectively prevent or favor the maladaptive α-myosin-heavy-chain (Myh6) to β-myosin-heavy-chain (Myh7) switch, so their balance crucially guides the outcome of cardiac remodeling under stress conditions. Even though triiodothyronine (T3) has long been recognized as a critical regulator of the cardiac Myh isoform composition, its role as a modulator of the Mhrt/Brg1 axis is still unexplored. Here the effect of T3 on the Mhrt/Brg1 regulatory circuit has been analyzed in relation with chromatin remodeling and previously identified T3-dependent miRNAs. The expression levels of Mhrt, Brg1 and Myh6/Myh7 have been assessed in rat models of hyperthyroidism or acute myocardial ischemia/reperfusion (IR) treated with T3 replacement therapy. To gain mechanistic insights, in silico analyses and site-directed mutagenesis have been adopted in combination with gene reporter assays and loss or gain of function strategies in cultured cardiomyocytes. Our results indicate a pivotal role of Mhrt over-expression in the T3-dependent regulation of Myh switch. Mechanistically, T3 activates the Mhrt promoter at two putative thyroid hormone responsive elements (TRE) located in a crucial region that is necessary for both Mhrt activation and Brg1-dependent Mhrt repression. This newly identified T3 mode of action requires DNA chromatinization and is critically involved in mitigating the repressive function of the Brg1 protein on Mhrt promoter. In addition, T3 is also able to prevent the Brg1 over-expression observed in the post-IR setting through a pathway that might entail the T3-mediated up-regulation of miR-208a. Taken together, our data evidence a novel T3-responsive network of cross-talking epigenetic factors that dictates the cardiac Myh composition and could be of great translational relevance.