bluuebunny/crossref_metadata_2025 huggingface dataset:
Olive Mill Wastewater Polyphenol-Enriched Fractions by Integrated Membrane Process: A Promising Source of Antioxidant, Hypolipidemic and Hypoglycaemic Compounds
Authors: Tundis Rosa , Conidi Carmela , Loizzo Monica R. , Sicari Vincenzo , Cassano Alfredo
Published: July 2020

The valorisation of food wastes is a challenging opportunity for the green, sustainable, and competitive development of industry. The recovery of phenols contributes to the sustainability of olive waste sector, reducing its environmental impact and promoting the development of innovative formulations of interest for pharmaceutical, nutraceutical, and cosmeceutical applications. In this work, olive mill wastewater was treated through a combination of microfiltration (MF), nanofiltration (NF), and reverse osmosis (RO) in a sequential design to produce polyphenol-enriched fractions that have been investigated for their chemical profile using ultra-high-performance liquid chromatography (UHPLC), and their potential antioxidant, hypolipidemic, and hypoglycaemic activities. RO retentate exhibited the highest content of hydroxytyrosol, tyrosol, oleuropein, verbascoside, vanillic acid, and luteolin. In particular, a content of hydroxytyrosol of 1522.2 mg/L, about five times higher than the MF feed, was found. RO retentate was the most active extract in all in vitro tests. Interestingly, this fraction showed a 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS) radicals scavenging activity with an IC50 value of 6.9 μg/mL and a potential inhibition of lipid peroxidation evaluated by the β-carotene bleaching test with IC50 values of 25.1 μg/mL after 30 min of incubation. Moreover, RO retentate inhibited α-amylase and α-glucosidase with IC50 values of 65.3 and 66.2 μg/mL, respectively.
The Apoplast: A Key Player in Plant Survival
Authors: Farvardin Atefeh , González-Hernández Ana Isabel , Llorens Eugenio , García-Agustín Pilar , Scalschi Loredana , Vicedo Begonya
Published: July 2020

The apoplast comprises the intercellular space, the cell walls, and the xylem. Important functions for the plant, such as nutrient and water transport, cellulose synthesis, and the synthesis of molecules involved in plant defense against both biotic and abiotic stresses, take place in it. The most important molecules are ROS, antioxidants, proteins, and hormones. Even though only a small quantity of ROS is localized within the apoplast, apoplastic ROS have an important role in plant development and plant responses to various stress conditions. In the apoplast, like in the intracellular cell compartments, a specific set of antioxidants can be found that can detoxify the different types of ROS produced in it. These scavenging ROS components confer stress tolerance and avoid cellular damage. Moreover, the production and accumulation of proteins and peptides in the apoplast take place in response to various stresses. Hormones are also present in the apoplast where they perform important functions. In addition, the apoplast is also the space where microbe-associated molecular Patterns (MAMPs) are secreted by pathogens. In summary, the diversity of molecules found in the apoplast highlights its importance in the survival of plant cells.
Mitochondrial ROS Induce Partial Dedifferentiation of Human Mesothelioma via Upregulation of NANOG
Authors: Sedlic Filip , Seiwerth Fran , Sepac Ana , Sikiric Suncana , Cindric Marina , Milavic Marija , Batelja Vuletic Lovorka , Jakopovic Marko , Seiwerth Sven
Published: July 2020

The expression of pluripotency factors is a key regulator of tumor differentiation status and cancer stem cells. The purpose of this study was to examine the expression of pluripotency factors and differentiation status of human mesothelioma and the role of mitochondria in their regulation. We tested the expression of OCT4/POU5F1, NANOG, SOX2, PI3K-AKT pathway and BCL2 genes and proteins in 65 samples of human mesothelioma and 19 samples of normal mesothelium. Mitochondrial membrane potential, reactive oxygen species (ROS) generation and expression of pluripotency factors were also tested in human mesothelioma cell line. Human mesothelium and mesothelioma expressed SOX2, NANOG, PI3K and AKT genes and proteins and POU5F1 gene, whereby NANOG, SOX2 and phosphorylated (activated) AKT were upregulated in mesothelioma. NANOG protein expression was elevated in less differentiated samples of human mesothelioma. The expression of genes of PI3K-AKT pathway correlated with pluripotency factor genes. Mesothelioma cells had functional, but depolarized mitochondria with large capacity to generate ROS. Mitochondrial ROS upregulated NANOG and mitoTEMPO abrogated it. In conclusion, human mesothelioma displays enhanced expression of NANOG, SOX2 and phosphorylated AKT proteins, while elevated NANOG expression correlates with poor differentiation of human mesothelioma. Mitochondria of mesothelioma cells have a large capacity to form ROS and thereby upregulate NANOG, leading to dedifferentiation of mesothelioma.
ECG Arrhythmia Classification using High Order Spectrum and 2D Graph Fourier Transform
Authors: Liu Shu , Shao Jie , Kong Tianjiao , Malekian Reza
Published: July 2020

Heart diseases are in the front rank among several kinds of life threats, due to its high incidence and mortality. Regarded as a powerful tool in the diagnosis of the cardiac disorder and arrhythmia detection, analysis of electrocardiogram (ECG) signals has become the focus of numerous researches. In this study, a feature extraction method based on the bispectrum and 2D graph Fourier transform (GFT) was developed. High-order matrix founded on bispectrum are extended into structured datasets and transformed into the eigenvalue spectrum domain by GFT, so that features can be extracted from statistical quantities of eigenvalues. Spectral features have been computed to construct the feature vector. Support vector machine based on the radial basis function kernel (SVM-RBF) was used to classify different arrhythmia heartbeats downloaded from the Massachusetts Institute of Technology - Beth Israel Hospital (MIT-BIH) Arrhythmia Database, according to the Association for the Advancement of Medical Instrumentation (AAMI) standard. Based on the cross-validation method, the experimental results depicted that our proposed model, the combination of bispectrum and 2D-GFT, achieved a high classification accuracy of 96.2%.
Train Speed Estimation from Track Structure Vibration Measurements
Authors: Wang Xinyue , Shi Xianfeng , Wang Jialiang , Yu Xun , Han Baoguo
Published: July 2020

This paper proposes a new method for train speed estimation from track structure vibration measurements for field track structural health monitoring. This method employed image treatment techniques, wavelet transform, and short-time Fourier transform into the signal processing. Afterward, the train speed was estimated by the combination of the extracted features and the geometrical parameters of the passing trains. A total of 240 measurements, gotten from 20 trains measured by 12 sensors, were implemented to verify the effectiveness and practicability of the proposed method. The results showed that the average differences of the train speed calculating by phase differences and the proposed method were 0.61% for slab displacement measurements, 1.39% for rail acceleration measurements, and 2.97% for slab acceleration measurements, respectively. Furthermore, the proposed method was proved to be effective in different test locations and track structure state. Therefore, it is concluded that the proposed method can estimate train speed from the vibration measurements automatically, reliably, and in real time with no need for additional speed measurement modules, which meets the requirement of speed estimation in the short-term, multi-location, and tough environment of structural health monitoring.
Assessing SMEs’ Internationalisation Strategies in Action
Authors: Castagna Francesco , Centobelli Piera , Cerchione Roberto , Oropallo Eugenio , Shashi  , Strazzullo Serena
Published: July 2020

In this paper, a structured review was conducted to investigate the internationalisation process of small and medium enterprises (SMEs) to define barriers and enablers and identify research gaps in this relevant field. Data were collected from two databases of scientific peer-reviewed articles (i.e., Scopus and Web of Science). After the selection process, 161 papers focusing on SMEs’ internalisation were analysed using both descriptive and content analysis. The analysis of the results highlights that SMEs’ internalisation is a growing research field, but different research gaps remain to be filled. These gaps concern barriers, impact on performance, models, and theories related to the different phases of the internationalisation process (e.g., start-up, early entrance, international growth). The future research directions identified interesting suggestions and guidelines for future researchers in the field of SMEs internationalisation.
A Deep Learning-Based Fragment Detection Approach for the Arena Fragmentation Test
Authors: Lee Hyukzae , Kim Jonghee , Jung Chanho , Park Yongchan , Park Woong , Son Jihong
Published: July 2020

The arena fragmentation test (AFT) is one of the tests used to design an effective warhead. Conventionally, complex and expensive measuring equipment is used for testing a warhead and measuring important factors such as the size, velocity, and the spatial distribution of fragments where the fragments penetrate steel target plates. In this paper, instead of using specific sensors and equipment, we proposed the use of a deep learning-based object detection algorithm to detect fragments in the AFT. To this end, we acquired many high-speed videos and built an AFT image dataset with bounding boxes of warhead fragments. Our method fine-tuned an existing object detection network named the Faster R-convolutional neural network (CNN) on this dataset with modification of the network’s anchor boxes. We also employed a novel temporal filtering method, which was demonstrated as an effective non-fragment filtering scheme in our recent previous image processing-based fragment detection approach, to capture only the first penetrating fragments from all detected fragments. We showed that the performance of the proposed method was comparable to that of a sensor-based system under the same experimental conditions. We also demonstrated that the use of deep learning technologies in the task of AFT significantly enhanced the performance via a quantitative comparison between our proposed method and our recent previous image processing-based method. In other words, our proposed method outperformed the previous image processing-based method. The proposed method produced outstanding results in terms of finding the exact fragment positions.
The Effect of Irradiation on the Quality Properties of Tarhana
Authors: Taşoğulları Nermin , Şimşek Ömer
Published: July 2020

Tarhana is a traditional food produced by the fermentation, drying and grinding of dough prepared with wheat flour, yoghurt, various vegetables and spices. Microbiological risks and pest formation are the major problems encountered during the storage of tarhana. In this study, the effect of irradiation was determined in order to eliminate microbiological risks and pest formation while preserving the quality features during the storage of tarhana. Depending on the irradiation dose, microbial inhibition occurred in tarhana samples, and the maximum protection was achieved with 10 kGy. Nevertheless, doses of 2.5 and 5 kGy inhibited the growth of Bacillus cereus. Additionally, all irradiation doses prevented pest formation. The consistency coefficient of soups prepared with irradiated tarhana samples decreased depending on the irradiation doses. There was no difference in 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity and total phenol content in the control with irradiated tarhana samples. However, the 10 kGy irradiated tarhana sample included higher thiobarbituric acid reactive substances. In conclusion, irradiation was applied for the first time to preserve tarhana by reducing the microbiological risk and preventing pest formation. Accordingly, a 5 kGy irradiation dose was recommended, with which the tarhana rheology was affected slightly.
Comparing Semantic Differential Methods in Affective Engineering Processes: A Case Study on Vehicle Instrument Panels
Authors: Shin Gee Won , Park Sunghwan , Kim Yong Min , Lee Yushin , Yun Myung Hwan
Published: July 2020

When developing a user-oriented product, it is crucial to consider users’ affective needs. Various semantic differential (SD) methods have been used to identify affect regarding materials, and this is the most important property in products. This study aims to determine which of the three conventional SD methods (absolute evaluation 1 [AE 1], absolute evaluation 2 [AE 2], or relative evaluation [RE]) is most effective for affective evaluation. Affective evaluation was performed for vehicle instrument panels by each of these three SD methods. Two quantitative analysis methods (correlation analysis and repeated-measures ANOVA) were used to examine the performance (sample distinguishability) of each evaluation method, and it was found that both AE 2 and RE produced better results than AE 1. The correlation coefficients and p-values in correlation analysis were slightly better for RE than for AE 2. In conclusion, an affective evaluation produced better results when pairwise samples (especially one sample pair) were presented, indicating that maintaining distinct samples is very important. The clearer the difference in comparison targets is, the more accurate the evaluation results.
Changes in CO2 Soil Degassing Style as a Possible Precursor to Volcanic Activity: The 2019 Case of Stromboli Paroxysmal Eruptions
Authors: Inguaggiato Salvatore , Vita Fabio , Cangemi Marianna , Calderone Lorenzo
Published: July 2020

Paroxysmal explosions are some of the most spectacular evidence of volcanism on Earth and are triggered by the rapid ascent of volatile-rich magma. These explosions often occur in persistently erupting basaltic volcanoes located in subduction zones and represent a major hazard due to the sudden occurrence and wide impact on the neighboring populations. However, the recognition of signals that forecast these blasts remains challenging even in the best-monitored volcanoes. Here, we present the results of the regular monitoring of soil CO2 flux from a fumarole field at the summit of Stromboli (Italy), highlighting that the 2016–2019 period was characterized by two important phases of strong increases of volatile output rate degassing (24 g m2 d−2 and 32 g m2 d−2, respectively) and moreover by significant changes in the degassing style few months before the last paroxysmal explosions occurred in the summer 2019 (3 July and 28 August). Establish that the deep portions of a volcano plumbing system are refilled by new volatiles-rich magma intruding from the mantle is therefore a key factor for forecasting eruptions and helping in recognizing possible precursors of paroxysmal explosions and could be highlighted by the monitoring of soil CO2 flux. The abrupt increase of degassing rate coupled with the strong increase of fluctuating signal (daily natural deviation) recorded during 2019 at Stromboli could be the key to predicting the occurrence of paroxysmal events.
Providing a Visual Understanding of Holography Through Phase Space Representations
Authors: Birnbaum Tobias , Kozacki Tomasz , Schelkens Peter
Published: July 2020

Digital holograms are a prime example for signals, which are best understood in phase space—the joint space of spatial coordinates and spatial frequencies. Many characteristics, as well as optical operations can be visualized therein with so called phase space representations (PSRs). However, literature relies often only on symbolic PSRs or on, in practice, visually insufficient PSRs like the Wigner–Ville representation. In this tutorial-style paper, we will showcase the S-method, which is both a PSR that can be calculated directly from any given signal, and that allows for a clear visual interpretation. We will highlight the power of space-frequency analysis in digital holography, explain why this specific PSR is recommended, discuss a broad range of basic operations, and briefly overview several interesting practical questions in digital holography.
Air Quality Modeling Study on the Controlling Factors of Fine Particulate Matter (PM2.5) in Hanoi: A Case Study in December 2010
Authors: Nguyen Thanh Hung , Nagashima Tatsuya , Doan Quang-Van
Published: July 2020

Meteorology and emission sources are the two main factors determining concentrations of air pollutants, including fine particulate matter. A regional air quality modeling system was used to analyze the sources of fine-particulate air pollution in Hanoi, Vietnam, in December 2010. The impacts of precipitation and winds on PM2.5 concentrations was investigated. Precipitation was negatively correlated with PM2.5 concentrations. However, winds showed both positive and negative correlations with PM2.5 concentrations, depending on wind direction (WD) and the level of upwind concentrations. Sensitivity simulations were conducted to investigate the contribution of local and non-local emissions sources on total PM2.5 by perturbing the emission inputs of the model. Overall, local and non-local sources contributed equally to the total PM2.5 in Hanoi. Local emission sources comprised 57% of the total PM2.5 concentrations for the high PM2.5 pollution levels, while only comprising 42% of the total PM2.5 for low levels of PM2.5 concentrations. In Hanoi’s urban areas, local sources contributed more to the total PM2.5 than non-local sources. In contrast, non-local sources were the main contributors to the PM2.5 in Hanoi’s rural areas. Additional sensitivity simulations were conducted to identify the main local emission sources of PM2.5 concentrations in December 2010. The industrial and residential sectors collectively comprised 79% of the total PM2.5 concentrations while the transport and power sectors comprised only 2% and 3%, respectively. This is the first case study which used a regional air quality modeling system to provide new and informative insights into PM2.5 air pollution in Hanoi by estimating the contributions of local and non-local emissions sources, as well as the contribution of local emission sectors to PM2.5 concentrations in Hanoi.
Dopamine D3 Receptor Heteromerization: Implications for Neuroplasticity and Neuroprotection
Authors: Bono Federica , Mutti Veronica , Fiorentini Chiara , Missale Cristina
Published: July 2020

The dopamine (DA) D3 receptor (D3R) plays a pivotal role in the control of several functions, including motor activity, rewarding and motivating behavior and several aspects of cognitive functions. Recently, it has been reported that the D3R is also involved in the regulation of neuronal development, in promoting structural plasticity and in triggering key intracellular events with neuroprotective potential. A new role for D3R-dependent neurotransmission has thus been proposed both in preserving DA neuron homeostasis in physiological conditions and in preventing pathological alterations that may lead to neurodegeneration. Interestingly, there is evidence that nicotinic acetylcholine receptors (nAChR) located on DA neurons also provide neurotrophic support to DA neurons, an effect requiring functional D3R and suggesting the existence of a positive cross-talk between these receptor systems. Increasing evidence suggests that, as with the majority of G protein-coupled receptors (GPCR), the D3R directly interacts with other receptors to form new receptor heteromers with unique functional and pharmacological properties. Among them, we recently identified a receptor heteromer containing the nAChR and the D3R as the molecular effector of nicotine-mediated neurotrophic effects. This review summarizes the functional and pharmacological characteristics of D3R, including the capability to form active heteromers as pharmacological targets for specific neurodegenerative disorders. In particular, the molecular and functional features of the D3R-nAChR heteromer will be especially discussed since it may represent a possible key etiologic effector for DA-related pathologies, such as Parkinson’s disease (PD), and a target for drug design.
Identification of 5-Fluoro-5-Deoxy-Ribulose as a Shunt Fluorometabolite in Streptomyces sp. MA37
Authors: Wu Linrui , Tong Ming Him , Kyeremeh Kwaku , Deng Hai
Published: July 2020

A fluorometabolite, 5-fluoro-5-deoxy-D-ribulose (5-FDRul), from the culture broth of the soil bacterium Streptomyces sp. MA37, was identified through a combination of genetic manipulation, chemo-enzymatic synthesis and NMR comparison. Although 5-FDRul has been chemically synthesized before, it was not an intermediate or a shunt product in previous studies of fluorometalism in S. cattleya. Our study of MA37 demonstrates that 5-FDRul is a naturally occurring fluorometabolite, rendering it a new addition to this rare collection of natural products. The genetic inactivation of key biosynthetic genes involved in the fluorometabolisms in MA37 resulted in the increased accumulation of unidentified fluorometabolites as observed from 19F-NMR spectral comparison among the wild type (WT) of MA37 and the mutated variants, providing evidence of the presence of other new biosynthetic enzymes involved in the fluorometabolite pathway in MA37.
Glucose-Induced Expression of DAPIT in Pancreatic β-Cells
Authors: Leguina-Ruzzi Alberto , Vodičková Anežka , Holendová Blanka , Pavluch Vojtěch , Tauber Jan , Engstová Hana , Dlasková Andrea , Ježek Petr
Published: July 2020

Transcript levels for selected ATP synthase membrane FO-subunits—including DAPIT—in INS-1E cells were found to be sensitive to lowering glucose down from 11 mM, in which these cells are routinely cultured. Depending on conditions, the diminished mRNA levels recovered when glucose was restored to 11 mM; or were elevated during further 120 min incubations with 20-mM glucose. Asking whether DAPIT expression may be elevated by hyperglycemia in vivo, we studied mice with hyaluronic acid implants delivering glucose for up to 14 days. Such continuous two-week glucose stimulations in mice increased DAPIT mRNA by >5-fold in isolated pancreatic islets (ATP synthase F1α mRNA by 1.5-fold). In INS-1E cells, the glucose-induced ATP increment vanished with DAPIT silencing (6% of ATP rise), likewise a portion of the mtDNA-copy number increment. With 20 and 11-mM glucose the phosphorylating/non-phosphorylating respiration rate ratio diminished to ~70% and 96%, respectively, upon DAPIT silencing, whereas net GSIS rates accounted for 80% and 90% in USMG5/DAPIT-deficient cells. Consequently, the sufficient DAPIT expression and complete ATP synthase assembly is required for maximum ATP synthesis and mitochondrial biogenesis, but not for insulin secretion as such. Elevated DAPIT expression at high glucose further increases the ATP synthesis efficiency.
Overview of Recent Advances in the Design of Plasmonic Fiber-Optic Biosensors
Authors: Esfahani Monfared Yashar
Published: July 2020

Plasmonic fiber-optic biosensors combine the flexibility and compactness of optical fibers and high sensitivity of nanomaterials to their surrounding medium, to detect biological species such as cells, proteins, and DNA. Due to their small size, accuracy, low cost, and possibility of remote and distributed sensing, plasmonic fiber-optic biosensors are promising alternatives to traditional methods for biomolecule detection, and can result in significant advances in clinical diagnostics, drug discovery, food process control, disease, and environmental monitoring. In this review article, we overview the key plasmonic fiber-optic biosensing design concepts, including geometries based on conventional optical fibers like unclad, side-polished, tapered, and U-shaped fiber designs, and geometries based on specialty optical fibers, such as photonic crystal fibers and tilted fiber Bragg gratings. The review will be of benefit to both engineers in the field of optical fiber technology and scientists in the fields of biosensing.
Comparison of Different Intervention Options for Massive Seismic Upgrading of Essential Facilities
Authors: Anelli Angelo , Vona Marco , Santa-Cruz Hidalgo Sandra
Published: July 2020

The seismic retrofitting of essential facilities is a typical problem of public administrations. Due to the large amount of existing and/or historic buildings with a high seismic vulnerability and the limited economic resources, it is necessary to provide efficient solutions for the structural reinforcement of these structures on a national, regional, and urban level. This paper proposes an innovative and multidisciplinary framework to choose massive interventions on a large territorial scale according to the potential benefits of the intervention in terms of reduction in expected economic losses associated with retrofitting intervention and other important aspects usually neglected in intervention strategies. The proposed framework is based on Multi-Criteria Decision-Making (MCDM) analysis. It is applied to a very complex urban area: the case study is the school buildings stock (4458 buildings) in the Lima Metropolitan area, Peru. The goal of the study is arisk analysis aimed at selecting the optimal retrofitting strategy in a huge urban area. The results of this work can be considered the base for decision-makers. They could use them as a decision support tool in the seismic risk mitigation on a large territorial scale.
Exosomal MicroRNAs and Organotropism in Breast Cancer Metastasis
Authors: Wong Grace L. , Abu Jalboush Sara , Lo Hui-Wen
Published: July 2020

Breast cancer is the most frequent malignancy for women in which one in eight women will be diagnosed with the disease in their lifetime. Despite advances made in treating primary breast cancer, there is still no effective treatment for metastatic breast cancer. Consequently, metastatic breast cancer is responsible for 90% of breast cancer-related deaths while only accounting for approximately one third of all breast cancer cases. To help develop effective treatments for metastatic breast cancer, it is important to gain a deeper understanding of the mechanisms by which breast cancer metastasizes, particularly, those underlying organotropism towards brain, bone, and lungs. In this review, we will primarily focus on the roles that circulating exosomal microRNAs (miRNAs) play in organotropism of breast cancer metastasis. Exosomes are extracellular vesicles that play critical roles in intercellular communication. MicroRNAs can be encapsulated in exosomes; cargo-loaded exosomes can be secreted by tumor cells into the tumor microenvironment to facilitate tumor–stroma interactions or released to circulation to prime distant organs for subsequent metastasis. Here, we will summarize our current knowledge on the biogenesis of exosomes and miRNAs, mechanisms of cargo sorting into exosomes, the exosomal miRNAs implicated in breast cancer metastasis, and therapeutic exosomal miRNAs.
Harnessing Omics Approaches on Advanced Preclinical Models to Discovery Novel Therapeutic Targets for the Treatment of Metastatic Colorectal Cancer
Authors: Porru Manuela , Zizza Pasquale , Panera Nadia , Alisi Anna , Biroccio Annamaria , Leonetti Carlo
Published: July 2020

Metastatic colorectal cancer (mCRC) remains challenging because of the emergence of resistance mechanisms to anti-epidermal growth factor receptor (EGFR) therapeutics, so more effective strategies to improve the patients’ outcome are needed. During the last decade, the application of a multi-omics approach has contributed to a deeper understanding of the complex molecular landscape of human CRC, identifying a plethora of drug targets for precision medicine. Target validation relies on the use of experimental models that would retain the molecular and clinical features of human colorectal cancer, thus mirroring the clinical characteristics of patients. In particular, organoids and patient-derived-xenografts (PDXs), as well as genetically engineered mouse models (GEMMs) and patient-derived orthotopic xenografts (PDOXs), should be considered for translational purposes. Overall, omics and advanced mouse models of cancer represent a portfolio of sophisticated biological tools that, if optimized for use in concert with accurate data analysis, could accelerate the anticancer discovery process and provide new weapons against cancer. In this review, we highlight success reached following the integration of omics and experimental models; moreover, results produced by our group in the field of mCRC are also presented.
Transitions of Liver and Biliary Enzymes during Proton Beam Therapy for Hepatocellular Carcinoma
Authors: Sumiya Taisuke , Mizumoto Masashi , Oshiro Yoshiko , Baba Keiichiro , Murakami Motohiro , Shimizu Shosei , Nakamura Masatoshi , Hiroshima Yuichi , Ishida Toshiki , Iizumi Takashi , Saito Takashi , Numajiri Haruko , Nakai Kei , Okumura Toshiyuki , Sakurai Hideyuki
Published: July 2020

Proton beam therapy (PBT) is a curative treatment for hepatocellular carcinoma (HCC), because it can preserve liver function due to dose targeting via the Bragg peak. However, the degree of direct liver damage by PBT is unclear. In this study, we retrospectively analyzed liver/biliary enzymes and total bilirubin (T-Bil) as markers of direct liver damage during and early after PBT in 300 patients. The levels of these enzymes and bilirubin were almost stable throughout the treatment period. In patients with normal pretreatment levels, aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), and T-Bil were abnormally elevated in only 2 (1.2%), 1 (0.4%), 0, 2 (1.2%), and 8 (3.5%) patients, respectively, and in 8 of these 13 patients (61.5%) the elevations were temporary. In patients with abnormal pretreatment levels, the levels tended to decrease during PBT. GGT and T-Bil were elevated by 1.62 and 1.57 times in patients who received 66 Gy (RBE) in 10 fractions and 74 Gy (RBE) in 37 fractions, respectively, but again these changes were temporary. These results suggest that direct damage to normal liver caused by PBT is minimal, even if a patient has abnormal pretreatment enzyme levels.
Glutamic-Pyruvic Transaminase 1 Facilitates Alternative Fuels for Hepatocellular Carcinoma Growth—A Small Molecule Inhibitor, Berberine
Authors: Guo Wei , Tan Hor-Yue , Li Sha , Wang Ning , Feng Yibin
Published: July 2020

Metabolic reprogramming is an essential hallmark of cancer. Besides the “Warburg effect”, cancer cells also actively reprogram amino acid metabolism to satisfy high nutritional demands in a nutrient-poor environment. In the glucose–alanine cycle, exogenous alanine taken up by hepatocytes is converted to pyruvate via glutamic-pyruvic transaminases (GPTs). However, the precise role of the glucose–alanine cycle in hepatocellular carcinoma (HCC) remains elusive. The current study revealed that alanine, as an alternative energy source, induced the metabolic reprogramming of HCC cells via activation of the downstream glucose–alanine cycle and thus promoted HCC growth in nutrient-depleted conditions. Further overexpression and loss-of-function studies indicated that GPT1 was an essential regulator for alanine-supplemented HCC growth. Combining molecular docking and metabolomics analyses, our study further identified a naturally occurring alkaloid, berberine (BBR), as the GPT1 inhibitor in HCC. Mechanically, BBR-mediated metabolic reprogramming of alanine-supplemented HCC via GPT1 suppression attenuated adenosine triphosphate (ATP) production and thus suppressed HCC growth. In conclusion, our study suggests that GPT1-mediated alanine–glucose conversion may be a potential molecular target for HCC therapy. Further demonstration of BBR-mediated metabolic reprogramming of HCC would contribute to the development of this Chinese medicine-derived compound as an adjuvant therapy for HCC.
Tumor-Associated Neutrophils Dampen Adaptive Immunity and Promote Cutaneous Squamous Cell Carcinoma Development
Authors: Khou Sokchea , Popa Alexandra , Luci Carmelo , Bihl Franck , Meghraoui-Kheddar Aida , Bourdely Pierre , Salavagione Emie , Cosson Estelle , Rubod Alain , Cazareth Julie , Barbry Pascal , Mari Bernard , Rezzonico Roger , Anjuère Fabienne , Braud Veronique M.
Published: July 2020

Cutaneous squamous cell carcinoma (cSCC) development has been linked to immune dysfunctions but the mechanisms are still unclear. Here, we report a progressive infiltration of tumor-associated neutrophils (TANs) in precancerous and established cSCC lesions from chemically induced skin carcinogenesis. Comparative in-depth gene expression analyses identified a predominant protumor gene expression signature of TANs in lesions compared to their respective surrounding skin. In addition, in vivo depletion of neutrophils delayed tumor growth and significantly increased the frequency of proliferating IFN-γ (interferon-γ)-producing CD8+ T cells. Mechanisms that limited antitumor responses involved high arginase activity, production of reactive oxygen species (ROS) and nitrite (NO), and the expression of programmed death-ligand 1 (PD-L1) on TAN, concomitantly with an induction of PD-1 on CD8+ T cells, which correlated with tumor size. Our data highlight the relevance of targeting neutrophils and PD-L1-PD-1 (programmed death-1) interaction in the treatment of cSCC.
Immunotherapy in Hepatocellular Cancer Patients with Mild to Severe Liver Dysfunction: Adjunctive Role of the ALBI Grade
Authors: Pinato David J. , Kaneko Takahiro , Saeed Anwaar , Pressiani Tiziana , Kaseb Ahmed , Wang Yinghong , Szafron David , Jun Tomi , Dharmapuri Sirish , Naqash Abdul Rafeh , Muzaffar Mahvish , Navaid Musharraf , Lee Chieh-Ju , Bulumulle Anushi , Yu Bo , Paul Sonal , Nimkar Neil , Bettinger Dominik , Hildebrand Hannah , Abugabal Yehia I. , Ang Celina , Marron Thomas U. , Khan Uqba , Personeni Nicola , Rimassa Lorenza , Huang Yi-Hsiang
Published: July 2020

Immune checkpoint inhibitors (ICI) have shown positive results in patients with hepatocellular carcinoma (HCC). As liver function contributes to prognosis, its precise assessment is necessary for the safe prescribing and clinical development of ICI in HCC. We tested the accuracy of the albumin-bilirubin (ALBI) grade as an alternative prognostic biomarker to the Child-Turcotte-Pugh (CTP). In a prospectively maintained multi-centre dataset of HCC patients, we assessed safety and efficacy of ICI across varying levels of liver dysfunction described by CTP (A to C) and ALBI grade and evaluated uni- and multi-variable predictors of overall (OS) and post-immunotherapy survival (PIOS). We studied 341 patients treated with programmed-death pathway inhibitors (n = 290, 85%). Pre-treatment ALBI independently predicted for OS, with median OS of 22.5, 9.6, and 4.6 months across grades (p < 0.001). ALBI was superior to CTP in predicting 90-days mortality with area under the curve values of 0.65 (95% CI 0.57–0.74) versus 0.63 (95% CI 0.54–0.72). ALBI grade at ICI cessation independently predicted for PIOS (p < 0.001). Following adjustment for ICI regimen, neither ALBI nor CTP predicted for overall response rates or treatment-emerging adverse events (p > 0.05). ALBI grade identifies a subset of patients with prolonged survival prior to and after ICI therapy, lending itself as an optimal stratifying biomarker to optimise sequencing of systemic therapies in advanced HCC.
The E2F Pathway Score as a Predictive Biomarker of Response to Neoadjuvant Therapy in ER+/HER2− Breast Cancer
Authors: Oshi Masanori , Takahashi Hideo , Tokumaru Yoshihisa , Yan Li , Rashid Omar M. , Nagahashi Masayuki , Matsuyama Ryusei , Endo Itaru , Takabe Kazuaki
Published: July 2020

E2F transcription factors play critical roles in the cell cycle. Therefore, their activity is expected to reflect tumor aggressiveness and responsiveness to therapy. We scored 3905 tumors of nine breast cancer cohorts for this activity based on their gene expression for the Hallmark E2F targets gene set. As expected, tumors with a high score had an increased expression of cell proliferation-related genes. A high score was significantly associated with shorter patient survival, greater MKI67 expression, histological grade, stage, and genomic aberrations. Furthermore, metastatic tumors had higher E2F scores than the primary tumors from which they arose. Although tumors with a high score had greater infiltration by both pro- and anti-cancerous immune cells, they had an increased expression of immune checkpoint genes. Estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative cancer with a high E2F score achieved a significantly higher pathological complete response (pCR) rate to neoadjuvant chemotherapy. The E2F score was significantly associated with the expression of cyclin-dependent kinase (CDK)-related genes and strongly correlated with sensitivity to CDK inhibition in cell lines. In conclusion, the E2F score is a marker of breast cancer aggressiveness and predicts the responsiveness of ER-positive/HER2-negative patients to neoadjuvant chemotherapy and possibly to CDK and immune checkpoint inhibitors.
Immuno-Surgical Management of Pancreatic Cancer with Analysis of Cancer Exosomes
Authors: Takeda Yu , Kobayashi Shogo , Kitakaze Masatoshi , Yamada Daisaku , Akita Hirofumi , Asai Ayumu , Konno Masamitsu , Arai Takahiro , Kitagawa Toru , Ofusa Ken , Yabumoto Masami , Hirotsu Takaaki , Vecchione Andrea , Taniguchi Masateru , Doki Yuichiro , Eguchi Hidetoshi , Ishii Hideshi
Published: July 2020

Exosomes (EXs), a type of extracellular vesicles secreted from various cells and especially cancer cells, mesenchymal cells, macrophages and other cells in the tumor microenvironment (TME), are involved in biologically malignant behaviors of cancers. Recent studies have revealed that EXs contain microRNAs on their inside and express proteins and glycolipids on their outsides, every component of which plays a role in the transmission of genetic and/or epigenetic information in cell-to-cell communications. It is also known that miRNAs are involved in the signal transduction. Thus, EXs may be useful for monitoring the TME of tumor tissues and the invasion and metastasis, processes that are associated with patient survival. Because several solid tumors secrete immune checkpoint proteins, including programmed cell death-ligand 1, the EX-mediated mechanisms are suggested to be potent targets for monitoring patients. Therefore, a companion therapeutic approach against cancer metastasis to distant organs is proposed when surgical removal of the primary tumor is performed. However, EXs and immune checkpoint mechanisms in pancreatic cancer are not fully understood, we provide an update on the recent advances in this field and evidence that EXs will be useful for maximizing patient benefit in precision medicine.
Size-Regulated Symmetry Breaking in Reaction-Diffusion Models of Developmental Transitions
Authors: Cornwall Scoones Jake , Banerjee Deb Sankar , Banerjee Shiladitya
Published: July 2020

The development of multicellular organisms proceeds through a series of morphogenetic and cell-state transitions, transforming homogeneous zygotes into complex adults by a process of self-organisation. Many of these transitions are achieved by spontaneous symmetry breaking mechanisms, allowing cells and tissues to acquire pattern and polarity by virtue of local interactions without an upstream supply of information. The combined work of theory and experiment has elucidated how these systems break symmetry during developmental transitions. Given that such transitions are multiple and their temporal ordering is crucial, an equally important question is how these developmental transitions are coordinated in time. Using a minimal mass-conserved substrate-depletion model for symmetry breaking as our case study, we elucidate mechanisms by which cells and tissues can couple reaction–diffusion-driven symmetry breaking to the timing of developmental transitions, arguing that the dependence of patterning mode on system size may be a generic principle by which developing organisms measure time. By analysing different regimes of our model, simulated on growing domains, we elaborate three distinct behaviours, allowing for clock-, timer- or switch-like dynamics. Relating these behaviours to experimentally documented case studies of developmental timing, we provide a minimal conceptual framework to interrogate how developing organisms coordinate developmental transitions.
CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer
Authors: Olivares-Urbano María Auxiliadora , Griñán-Lisón Carmen , Marchal Juan Antonio , Núñez María Isabel
Published: July 2020

Radiotherapy (RT) is a modality of oncologic treatment that can be used to treat approximately 50% of all cancer patients either alone or in combination with other treatment modalities such as surgery, chemotherapy, immunotherapy, and therapeutic targeting. Despite the technological advances in RT, which allow a more precise delivery of radiation while progressively minimizing the impact on normal tissues, issues like radioresistance and tumor recurrence remain important challenges. Tumor heterogeneity is responsible for the variation in the radiation response of the different tumor subpopulations. A main factor related to radioresistance is the presence of cancer stem cells (CSC) inside tumors, which are responsible for metastases, relapses, RT failure, and a poor prognosis in cancer patients. The plasticity of CSCs, a process highly dependent on the epithelial–mesenchymal transition (EMT) and associated to cell dedifferentiation, complicates the identification and eradication of CSCs and it might be involved in disease relapse and progression after irradiation. The tumor microenvironment and the interactions of CSCs with their niches also play an important role in the response to RT. This review provides a deep insight into the characteristics and radioresistance mechanisms of CSCs and into the role of CSCs and tumor microenvironment in both the primary tumor and metastasis in response to radiation, and the radiobiological principles related to the CSC response to RT. Finally, we summarize the major advances and clinical trials on the development of CSC-based therapies combined with RT to overcome radioresistance. A better understanding of the potential therapeutic targets for CSC radiosensitization will provide safer and more efficient combination strategies, which in turn will improve the live expectancy and curability of cancer patients.
COVID-19, Renin-Angiotensin System and Endothelial Dysfunction
Authors: Amraei Razie , Rahimi Nader
Published: July 2020

The newly emergent novel coronavirus disease 2019 (COVID-19) outbreak, which is caused by SARS-CoV-2 virus, has posed a serious threat to global public health and caused worldwide social and economic breakdown. Angiotensin-converting enzyme 2 (ACE2) is expressed in human vascular endothelium, respiratory epithelium, and other cell types, and is thought to be a primary mechanism of SARS-CoV-2 entry and infection. In physiological condition, ACE2 via its carboxypeptidase activity generates angiotensin fragments (Ang 1–9 and Ang 1–7), and plays an essential role in the renin-angiotensin system (RAS), which is a critical regulator of cardiovascular homeostasis. SARS-CoV-2 via its surface spike glycoprotein interacts with ACE2 and invades the host cells. Once inside the host cells, SARS-CoV-2 induces acute respiratory distress syndrome (ARDS), stimulates immune response (i.e., cytokine storm) and vascular damage. SARS-CoV-2 induced endothelial cell injury could exacerbate endothelial dysfunction, which is a hallmark of aging, hypertension, and obesity, leading to further complications. The pathophysiology of endothelial dysfunction and injury offers insights into COVID-19 associated mortality. Here we reviewed the molecular basis of SARS-CoV-2 infection, the roles of ACE2, RAS signaling, and a possible link between the pre-existing endothelial dysfunction and SARS-CoV-2 induced endothelial injury in COVID-19 associated mortality. We also surveyed the roles of cell adhesion molecules (CAMs), including CD209L/L-SIGN and CD209/DC-SIGN in SARS-CoV-2 infection and other related viruses. Understanding the molecular mechanisms of infection, the vascular damage caused by SARS-CoV-2 and pathways involved in the regulation of endothelial dysfunction could lead to new therapeutic strategies against COVID-19.
Identifying the Structural Adaptations that Drive the Mechanical Load-Induced Growth of Skeletal Muscle: A Scoping Review
Authors: Jorgenson Kent W. , Phillips Stuart M. , Hornberger Troy A.
Published: July 2020

The maintenance of skeletal muscle mass plays a critical role in health and quality of life. One of the most potent regulators of skeletal muscle mass is mechanical loading, and numerous studies have led to a reasonably clear understanding of the macroscopic and microscopic changes that occur when the mechanical environment is altered. For instance, an increase in mechanical loading induces a growth response that is mediated, at least in part, by an increase in the cross-sectional area of the myofibers (i.e., myofiber hypertrophy). However, very little is known about the ultrastructural adaptations that drive this response. Even the most basic questions, such as whether mechanical load-induced myofiber hypertrophy is mediated by an increase in the size of the pre-existing myofibrils and/or an increase in the number myofibrils, have not been resolved. In this review, we thoroughly summarize what is currently known about the macroscopic, microscopic and ultrastructural changes that drive mechanical load-induced growth and highlight the critical gaps in knowledge that need to be filled.
Mechanisms behind the Immunoregulatory Dialogue between Mesenchymal Stem Cells and Th17 Cells
Authors: Terraza-Aguirre Claudia , Campos-Mora Mauricio , Elizondo-Vega Roberto , Contreras-López Rafael A. , Luz-Crawford Patricia , Jorgensen Christian , Djouad Farida
Published: July 2020

Mesenchymal stem cells (MSCs) exhibit potent immunoregulatory abilities by interacting with cells of the adaptive and innate immune system. In vitro, MSCs inhibit the differentiation of T cells into T helper 17 (Th17) cells and repress their proliferation. In vivo, the administration of MSCs to treat various experimental inflammatory and autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, and bowel disease showed promising therapeutic results. These therapeutic properties mediated by MSCs are associated with an attenuated immune response characterized by a reduced frequency of Th17 cells and the generation of regulatory T cells. In this manuscript, we review how MSC and Th17 cells interact, communicate, and exchange information through different ways such as cell-to-cell contact, secretion of soluble factors, and organelle transfer. Moreover, we discuss the consequences of this dynamic dialogue between MSC and Th17 well described by their phenotypic and functional plasticity.