bluuebunny/crossref_metadata_2025 huggingface dataset:
Fatty Acid Signatures in Different Tissues of Mediterranean Yellowtail, Seriola dumerili (Risso, 1810), Fed Diets Containing Different Levels of Vegetable and Fish Oils
Authors: Bordignon Francesco , Tomás-Vidal Ana , Trocino Angela , Milián Sorribes Maria C. , Jover-Cerdá Miguel , Martínez-Llorens Silvia
Published: January 2020

The study aimed to evaluate how replacing different proportions of fish oil (FO) with vegetable oils (VO) in the diet of Mediterranean yellowtail, Seriola dumerili (Risso, 1810), affects the fatty acids (FA) signature, i.e.; overall FA profile, in different tissues. A total of 225 Mediterranean yellowtail juveniles (initial live weight: 176 ± 3.62 g) were fed for 109 days with one of three diets: A control diet (FO 100), with FO as the only lipid source, or diets with 75% and 100% of FO replaced with a VO mixture. At the end of the feeding trial, the brains, muscles, livers, and visceral fat were sampled in four fish per tank (12 per treatment), and their fat were extracted and used for FA analysis. The FA signatures of red and white muscle, liver, and visceral fat tissues changed when the dietary FA source changed, whereas FA signatures in the brain were rather robust to such dietary changes. These new insights might help evaluate whether key physiological functions are preserved when fish are fed diets with low FO levels, as well as define the dietary FA requirements of Mediterranean yellowtail to improve the sustainability of the production and welfare of the fish.
Glutathione S-Transferases Play a Crucial Role in Mitochondrial Function, Plasma Membrane Stability and Oxidative Regulation of Mammalian Sperm
Authors: Llavanera Marc , Delgado-Bermúdez Ariadna , Olives Samuel , Mateo-Otero Yentel , Recuero Sandra , Bonet Sergi , Fernández-Fuertes Beatriz , Yeste Marc , Barranco Isabel
Published: January 2020

Glutathione S-transferases (GSTs) are essential sperm antioxidant enzymes involved in cell protection against oxidative stress and toxic chemicals, preserving sperm function and fertilising ability. Artificial insemination (AI) in pigs is commonly carried out through the use of liquid-stored semen at 17 °C, which not only reduces sperm metabolic activity but also sperm quality and AI-farrowing rates within the 72 h of storage. While one may reasonably suggest that such enzymes are implicated in the physiology and maintenance of mammalian sperm function during liquid-storage, no previous studies conducted on any species have addressed this hypothesis. Therefore, the objective of the present work was to characterise the presence and function of sperm GSTs in mammalian sperm, using the pig as a model. In this regard, inhibition of such enzymes by ethacrynic acid (EA) during semen storage at 17 °C was performed to evaluate the effects of GSTs in liquid-preserved boar sperm by flow cytometry, immunofluorescence, and immunoblotting analysis. The results of this study have shown, for the first time in mammalian species, that the inhibition of GSTs reduces sperm quality and functionality parameters during their storage at 17 °C. These findings highlight the key role of such enzymes, especially preserving mitochondrial function and maintaining plasma membrane stability. In addition, this study has identified and localised GSTM3 in the tail and equatorial subdomain of the head of boar sperm. Finally, this study has set grounds for future investigations testing supplementation of semen extenders with GSTs, as this may improve fertility outcomes of swine AIs.
Anti-Inflammatory and Antioxidant Activity of Pollen Extract Collected by Scaptotrigona affinis postica: in silico, in vitro, and in vivo Studies
Authors: Lopes Alberto Jorge Oliveira , Vasconcelos Cleydlenne Costa , Garcia João Batista Santos , Pinheiro Myssa Sued Dória , Pereira Francisco Assis Nascimento , Camelo Darleno de Sousa , Morais Sebastião Vieira de , Freitas José Roberto Brito , Rocha Cláudia Quintino da , Ribeiro Maria Nilce de Sousa , Cartágenes Maria do Socorro de Sousa
Published: January 2020

Bees are of great importance for plant diversity for being an important pollinating agents. Stingless bees such as Scaptotrigona affinis postica, is cultivated largely due to the products offered by it. Pollen is one of these products, which has been highlighted for exhibit various therapeutic properties. Considering the bioactivity of this natural product, this study investigated the antioxidant, anti-inflammatory, antinociceptive activities, and elucidated the chemical composition of pollen collected extract by Scaptotrigona affinis postica. Using in vitro assays, the antioxidant potential and inhibitory activity against the COX enzyme from pollen extract was evaluated. Additionally, tests were performed to measure the anti-inflammatory and antinociceptive activities in animal models. In our results, we found that pollen extract showed antioxidant effects and inhibitory activity against the COX enzyme. The in vivo assays showed that the extract acts on the nervous system in local and systemic levels and that the anti-inflammatory activity is due the prostanoids reducing. Chemical analyses recognize 10 molecules in the extract belonging to the polyphenol and flavonoids classes and the computational study suggests that is responsible for the observed results. Thus, it is reported for the first time the biological potential of S. aff. postica pollen extract and we conclude that this bee product can be considered as one source of potential new drugs.
Post-Processing Method for Image Reconstruction Enhancement in Integrating-Bucket-Based Full-Field Optical Coherence Tomography
Authors: Lee Juhyung , Yoon Taeil , Lee Byeong Ha
Published: January 2020

An integrating-bucket method is widely used as a reconstruction tool for full-field optical coherence tomography (FF-OCT). However, it requires high-precision adjustments of the phase modulation parameters. If the parameters are not optimal, the reconstructed tomogram will incur severe artifacts. We propose a post-processing method for removing or reducing such artifacts by utilizing a correction factor extracted from a pre-reconstructed tomogram. FF-OCT imaging created using a coin verifies the effectiveness of the method not only for a single en face image but also for an entire 3-D image. It is expected that the proposed method will expand the application of FF-OCT from biomedical imaging to semiconductor wafers or display panel inspections.
Multi-Task Topic Analysis Framework for Hallmarks of Cancer with Weak Supervision
Authors: Batbaatar Erdenebileg , Pham Van-Huy , Ryu Keun Ho
Published: January 2020

The hallmarks of cancer represent an essential concept for discovering novel knowledge about cancer and for extracting the complexity of cancer. Due to the lack of topic analysis frameworks optimized specifically for cancer data, the studies on topic modeling in cancer research still have a strong challenge. Recently, deep learning (DL) based approaches were successfully employed to learn semantic and contextual information from scientific documents using word embeddings according to the hallmarks of cancer (HoC). However, those are only applicable to labeled data. There is a comparatively small number of documents that are labeled by experts. In the real world, there is a massive number of unlabeled documents that are available online. In this paper, we present a multi-task topic analysis (MTTA) framework to analyze cancer hallmark-specific topics from documents. The MTTA framework consists of three main subtasks: (1) cancer hallmark learning (CHL)—used to learn cancer hallmarks on existing labeled documents; (2) weak label propagation (WLP)—used to classify a large number of unlabeled documents with the pre-trained model in the CHL task; and (3) topic modeling (ToM)—used to discover topics for each hallmark category. In the CHL task, we employed a convolutional neural network (CNN) with pre-trained word embedding that represents semantic meanings obtained from an unlabeled large corpus. In the ToM task, we employed a latent topic model such as latent Dirichlet allocation (LDA) and probabilistic latent semantic analysis (PLSA) model to catch the semantic information learned by the CNN model for topic analysis. To evaluate the MTTA framework, we collected a large number of documents related to lung cancer in a case study. We also conducted a comprehensive performance evaluation for the MTTA framework, comparing it with several approaches.
An Advanced Reversible Data Hiding Algorithm Using Local Similarity, Curved Surface Characteristics, and Edge Characteristics in Images
Authors: Jung Soo-Mok , On Byung-Won
Published: January 2020

In this paper, we proposed methods to accurately predict pixel values by effectively using local similarity, curved surface characteristics, and edge characteristics present in an image. Furthermore, to hide more confidential data in a cover image using the prediction image composed of precisely predicted pixel values, we proposed an effective data hiding technique that applied the prediction image to the conventional reversible data hiding technique. Precise prediction of pixel values greatly increases the frequency at the peak point in the histogram of the difference sequence generated using the cover and prediction images. This considerably increases the amount of confidential data that can be hidden in the cover image. The proposed reversible data hiding algorithm (ARDHA) can hide up to 24.5% more confidential data than the existing algorithm. Moreover, it is not possible to determine the presence of hidden confidential data in stego-images, as they possess excellent visual quality. The confidential data can be extracted from the stego-image without loss, and the original cover image can be restored from the stego-image without distortion. Therefore, the proposed algorithm can be effectively used in digital image watermarking, military, and medical applications.
Special Issue on Cutting-Edge Technologies for Renewable Energy Production and Storage
Authors: Prussi Matteo
Published: January 2020

Anthropogenic greenhouse gas emissions are dramatically influencing the environment, and research is strongly committed in proposing alternatives, mainly based on renewable energy sources [...]
Stability of Traveling Waves Based upon the Evans Function and Legendre Polynomials
Authors: Srivastava H. M. , Abdel-Gawad H. I. , Saad Khaled M.
Published: January 2020

One of the tools and techniques concerned with the stability of nonlinear waves is the Evans function which is an analytic function whose zeros give the eigenvalues of the linearized operator. Here, in this paper, we propose a direct approach, which is based essentially upon constructing the eigenfunction solution of the perturbed equation based upon the topological invariance in conjunction with usage of the Legendre polynomials, which have presumably not considered in the literature thus far. The associated Legendre eigenvalue problem arising from the stability analysis of traveling waves solutions is systematically studied here. The present work is of considerable interest in the engineering sciences as well as the mathematical and physical sciences. For example, in chemical industry, the objective is to achieve a great yield of a given product. This can be controlled by depicting the initial concentration of the reactant, which is determined by its value at the bifurcation point. This analysis leads to the point separating stable and unstable solutions. As far as chemical reactions are described by reaction-diffusion equations, this specific concentration can be found mathematically. On the other hand, the study of stability analysis of solutions may depict whether or not a soliton pulse is well-propagated in fiber optics. This can, and should, be carried out by finding the solutions of the coupled nonlinear Schrödinger equations and by analyzing the stability of these solutions.
Rician Beamforming: Despeckle Method via Coarray Projection Stochastic Analysis
Authors: Yagüe-Jiménez Virginia , Ibáñez Rodríguez Alberto , Parrilla Romero Montserrat , Martínez-Graullera Oscar
Published: January 2020

Current computation capabilities normal, Delay and Sum (DAS) and Total Focusing Method (TFM) allow new definitions for beamformers. In this paper, a new beamforming method is proposed. It exploits diversity across pixel data after focusing process. The method is based on statistical analysis and sparse array concept. It avoids common aberrations introduced by beamforming process without loosing the original image texture, producing a better quality image. We evaluate the proposed method through simulation on standard phantoms. Images resulting from our novel method display better quality and provide localised estimations on image noise.
Observations of Atmospheric NO2 Using a New Low-Cost MAX-DOAS System
Authors: Roşu Adrian , Constantin Daniel-Eduard , Voiculescu Mirela , Arseni Maxim , Merlaud Alexis , Van Roozendael Michel , Georgescu Puiu Lucian
Published: January 2020

This article describes the prototype of a new MAX-DOAS (multi-axis differential optical absorption spectroscopy) system built at “Dunarea de Jos” University of Galati (UGAL), Romania, and the first results of its use to observe NO2 content over Galati city (45.42° N, 28.04° E). The new equipment is a ground-based MAX-DOAS system capable of measuring the spatial distribution of DSCD (differential slant column densities) of several trace gases using horizontal and vertical observations. The new optic system, named UGAL-2-DOAS, is an in-house, low-cost, solution in comparison to the existing market of the MAX-DOAS systems. This paper describes the technical design and capabilities of the new MAX-DOAS instrument. The UGAL-2D-DOAS system was tested in April and June 2017 in Galati city. Measurements over three days were selected for the present manuscript. Full azimuthal (0–360°), local celestial meridian observations and other elevation angle sequence measurements (e.g., E–W) were performed. We found that the new MAX-DOAS system is able to detect diurnal variation and the local source emissions of NO2 from the urban environment. Also, we present concomitant zenith-sky car-DOAS observations measurements around the location of the new MAX-DOAS instrument. Comparing the horizontal scanning sequence of the new developed instrument with the mobile DOAS observations, we found that both systems can indicate and detect the same NO2 sources.
Comparison of Methodologies for Assessing Desert Dust Contribution to Regional PM10 and PM2.5 Levels: A One-Year Study Over Portugal
Authors: Gama Carla , Pio Casimiro , Monteiro Alexandra , Russo Michael , Fernandes Ana Patrícia , Borrego Carlos , Baldasano José María , Tchepel Oxana
Published: January 2020

Desert dust outbreaks may affect air quality. This study estimates the importance of African dust contribution to the PM10 and PM2.5 concentrations observed in rural regional background sites in Portugal. Desert dust contribution is evaluated by two different approaches: A measurement-approach methodology based on the monthly moving 40th percentile, and a model-approach methodology based on WRF-CHIMERE simulations, whose performance is also assessed within this work. Several desert dust episodes affected atmospheric aerosols in the planetary boundary layer over Portugal during 2016. Their intensity was variable, with at least two events (21–22 February and 27–28 October) contributing to exceedances to the PM10 daily limit value defined in the European Air Quality Directive. African dust contributions obtained for the year 2016 with the measurement-approach methodology are higher than the ones simulated by WRF-CHIMERE. Contributions to PM10 and to PM2.5 concentrations range from 0 to 90 µg m−3 and from 0 to 30 µg m−3, respectively, in most of the regions and days. Caution must be employed when using measurement-approach methodologies to quantify dust contributions to PM levels when forest fires occur simultaneously with the long-range transport of desert dust, as happened in August 2016.
The Genetics of Thoracic Aortic Aneurysms and Dissection: A Clinical Perspective
Authors: Ostberg Nicolai , Zafar Mohammad , Ziganshin Bulat , Elefteriades John
Published: January 2020

Thoracic aortic aneurysm and dissection (TAAD) affects many patients globally and has high mortality rates if undetected. Once thought to be solely a degenerative disease that afflicted the aorta due to high pressure and biomechanical stress, extensive investigation of the heritability and natural history of TAAD has shown a clear genetic basis for the disease. Here, we review both the cellular mechanisms and clinical manifestations of syndromic and non-syndromic TAAD. We particularly focus on genes that have been linked to dissection at diameters <5.0 cm, the current lower bound for surgical intervention. Genetic screening tests to identify patients with TAAD associated mutations that place them at high risk for dissection are also discussed.
Newly Developed System for Acetamiprid Residue Screening in the Lettuce Samples Based on a Bioelectric Cell Biosensor
Authors: Apostolou Theofylaktos , Loizou Konstantinos , Hadjilouka Agni , Inglezakis Antonios , Kintzios Spyridon
Published: January 2020

Population growth and increased production demands on fruit and vegetables have driven agricultural production to new heights. Nevertheless, agriculture remains one of the least optimized industries, with laboratory tests that take days to provide a clear result on the chemical level of produce. To address this problem, we developed a tailor-made solution for the industry that can allow multiple field tests on key pesticides, based on a bioelectric cell biosensor and the measurement of the cell membrane potential changes, according to the principle of the Bioelectric Recognition Assay (BERA). We developed a fully functional system that operates using a newly developed hardware for multiple data sources and an Android application to provide results within 3 min. The presence of acetamiprid residues caused a cell membrane hyperpolarization, which was distinguishable from the control samples. A database that classified samples Below or Above Maximum Residue Levels (MRL) was then created, based on a newly developed algorithm. Additionally, lettuce samples were analyzed with the conventional and the newly developed method, in parallel, revealing a high correlation on sample classification. Thus, it was demonstrated that the novel biosensor system could be used in the food supply chain to increase the number of tested products before they reach the market.
A Short Empathy Paradigm to Assess Empathic Deficits in Schizophrenia
Authors: Peveretou Foteini , Radke Sina , Derntl Birgit , Habel Ute
Published: January 2020

Empathy is important for successful social interaction and maintaining relationships. Several studies detected impairments in empathic abilities in schizophrenia, with some even indicating a broader deficit in several components, including emotion recognition, perspective taking, and affective responsiveness. The aim of our study was to validate a short version of the previous empathy paradigm as a reliable and easily applicable method to assess empathic deficits in patients with schizophrenia potentially within clinical routine. To do so, we applied the short version to 30 patients (14 females) diagnosed with schizophrenia meeting the DSM-5 criteria and 30 well-matched healthy controls (14 females). The data analysis indicates a significant empathic deficit in patients due to worse performance in all three domains. We managed to replicate most of the findings of our previous study. In contrary to the previous study, significant correlations between performance in the empathy tasks and psychopathology occurred: the severity of negative symptoms was negatively associated with performance in the emotion recognition task and the affective responsiveness task. Gender did not significantly affect performance in the empathy tasks. Regarding the results, our short empathy paradigm appears to be a valid method in assessing empathic impairments in schizophrenia that may be useful in clinical routine.
Rapid Assessment of Functional Avidity of Tumor-Specific T Cell Receptors Using an Antigen-Presenting Tumor Cell Line Electroporated with Full-Length Tumor Antigen mRNA
Authors: Campillo-Davo Diana , Versteven Maarten , Roex Gils , De Reu Hans , van der Heijden Sanne , Anguille Sébastien , Berneman Zwi N. , Van Tendeloo Viggo F. I. , Lion Eva
Published: January 2020

The functional avidity of T-cell receptor (TCR)-engineered T cells towards their cognate epitope plays a crucial role in successfully targeting and killing tumor cells expressing the tumor-associated antigen (TAA). When evaluating in vitro functional T-cell avidity, an important aspect that is often neglected is the antigen-presenting cell (APC) used in the assay. Cell-based models for antigen-presentation, such as tumor cell lines, represent a valid alternative to autologous APCs due to their availability, off-the-shelf capabilities, and the broad range of possibilities for modification via DNA or messenger RNA (mRNA) transfection. To find a valuable model APC for in vitro validation of TAA Wilms’ tumor 1 (WT1)-specific TCRs, we tested four different WT1 peptide-pulsed HLA-A2+ tumor cell lines commonly used in T-cell stimulation assays. We found the multiple myeloma cell line U266 to be a suitable model APC to evaluate differences in mean functional avidity (EC50) values of transgenic TCRs following transfection in 2D3 Jurkat T cells. Next, to assess the dose-dependent antigen-specific responsiveness of WT1 TCR-engineered 2D3 T cells to endogenously processed epitopes, we electroporated U266 cells with different amounts of full-length antigen WT1 mRNA. Finally, we analyzed the functional avidity of WT1 TCR-transfected primary CD8 T cells towards WT1 mRNA-electroporated U266 cells. In this study, we demonstrate that both the APC and the antigen loading method (peptide pulsing versus full-length mRNA transfection) to analyze T-cell functional avidity have a significant impact on the EC50 values of a given TCR. For rapid assessment of the functional avidity of a cloned TCR towards its endogenously processed MHC I-restricted epitope, we showcase that the TAA mRNA-transfected U266 cell line is a suitable and versatile model APC.
Outcomes for Elderly Patients Aged 70 to 80 Years or Older with Locally Advanced Oral Cavity Squamous Cell Carcinoma: A Propensity Score–Matched, Nationwide, Oldest Old Patient–Based Cohort Study
Authors: Shia Ben-Chang , Qin Lei , Lin Kuan-Chou , Fang Chih-Yuan , Tsai Lo-Lin , Kao Yi-Wei , Wu Szu-Yuan
Published: January 2020

Purpose: Although clinicians encounter patients aged ≥70 years with locally advanced oral cavity squamous cell carcinoma (LA-OCSCC), no evidence is available to facilitate decision making regarding treatment for this elderly population. Methods: We selected elderly (≥70 years) patients from the Taiwan Cancer Registry database who had received a diagnosis of LA-OCSCC. Propensity score matching was performed. Cox proportional hazards model curves were used to analyze all-cause mortality in patients in different age groups receiving different treatments. Results: The matching process yielded a final cohort of 976 patients in concurrent chemoradiotherapy (CCRT), non-treatment, radiotherapy (RT) alone, and surgery cohorts who were eligible for further analysis. After stratified analysis, the adjusted hazard ratios (aHRs) (95% confidence intervals [CIs]) derived for surgery, RT alone, and non-treatment compared with CCRT were 0.66 (0.52 to 0.83), 1.02 (0.81 to 1.28), and 1.52 (1.21 to 1.91), respectively, in patients aged 70 to 80 years. In the oldest patients (aged >80 years), multivariate analysis indicated that the results of surgery or RT alone were nonsignificant compared with those of CCRT. The aHR (95% CI) derived for the highest mortality was 1.81 (1.11 to 2.40) for non-treatment compared with CCRT. Conclusions: Surgery for elderly patients with LA-OCSCC is associated with a significant survival benefit, but the association is nonsignificant in the oldest elderly patients. No survival differences were observed between RT alone and CCRT in these elderly patients. Non-treatment should not be an option for these patients.
Rab GTPases: Emerging Oncogenes and Tumor Suppressive Regulators for the Editing of Survival Pathways in Cancer
Authors: Gopal Krishnan Priya D. , Golden Emily , Woodward Eleanor A. , Pavlos Nathan J. , Blancafort Pilar
Published: January 2020

The Rab GTPase family of proteins are mediators of membrane trafficking, conferring identity to the cell membranes. Recently, Rab and Rab-associated factors have been recognized as major regulators of the intracellular positioning and activity of signaling pathways regulating cell growth, survival and programmed cell death or apoptosis. Membrane trafficking mediated by Rab proteins is controlled by intracellular localization of Rab proteins, Rab-membrane interactions and GTP-activation processes. Aberrant expression of Rab proteins has been reported in multiple cancers such as lung, brain and breast malignancies. Mutations in Rab-coding genes and/or post-translational modifications in their protein products disrupt the cellular vesicle trafficking network modulating tumorigenic potential, cellular migration and metastatic behavior. Conversely, Rabs also act as tumor suppressive factors inducing apoptosis and inhibiting angiogenesis. Deconstructing the signaling mechanisms modulated by Rab proteins during apoptosis could unveil underlying molecular mechanisms that may be exploited therapeutically to selectively target malignant cells.
Extracellular Vesicles, A Possible Theranostic Platform Strategy for Hepatocellular Carcinoma—An Overview
Authors: D’Agnano Igea , Berardi Anna Concetta
Published: January 2020

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third highest cause of mortality from cancer, largely because of delays in diagnosis. There is currently no effective therapy for advanced stage HCC, although sorafenib, the standard treatment for HCC, systemic therapy (including tyrosine kinase inhibitors and anti-angiogenesis agents), and more recently, immunotherapy, have demonstrated some survival benefit. The measurement and modification of extracellular vesicle (EVs) cargoes—composed of nucleic acids, including miRNAs, proteins, and lipids—holds great promise for future HCC diagnosis, prognosis, and treatment. This review will provide an overview of the most recent findings regarding EVs in HCC, and the possible future use of EVs as “liquid biopsy”-based biomarkers for early diagnosis and as a vehicle for targeted drug-delivery.
Gastric Cancer in History: A Perspective Interdisciplinary Study
Authors: Topi Skender , Santacroce Luigi , Bottalico Lucrezia , Ballini Andrea , Inchingolo Alessio Danilo , Dipalma Gianna , Charitos Ioannis Alexandros , Inchingolo Francesco
Published: January 2020

Background: Gastric adenocarcinoma is the fourth most common type of cancer and the second leading cause of cancer death in the world. Despite abundant traces of an ancient history, the comprehension of its pathogenic mechanisms is rather recent and continuously updated. Methods: We investigated about how the ancient civilizations tried to understand the exactly physiopathology of gastric cancer, from the time when they could not examine deeply the histological and pathophysiologic aspects of the disease, but they just based their knowledge on a visual analysis of the signs and consequences of such disease. We examined the historical evolving knowledge of the disease along the centuries on the gastroenterological, pharmacological, and surgical fields, defining how gastric cancer became an increasingly curable disease. Results: Cancer was known in the ancient world. Ancient people did not know exactly the causes but the climatic, hygienic, and food conditions were the first to be considered over time, also taking into consideration supernatural negative influences. During the Renaissance, a tumultuous time of scientific discoveries started, thanks to an increasing number of autopsies made on cadavers and to the progressions in visual analysis of the stomach mucosa throughout endoscopy. From the first gastric surgery in 1879, many steps forward have been made and, today, gastric cancer is regarded as a more curable disease; one important discovery in this field has been the revelation of the role of Helicobacter pylori in the peptic ulcer disease (PUD) and in some forms of gastric lymphoma. Conclusions: Gastric cancer has the fourth highest incidence of various cancers worldwide and is ranked second as a cause of cancer-related death. It exists from the antiquity and a lot of hypotheses have been developed about its etiology during the centuries, influencing its therapy. During the 20th century, thanks to the scientific and technological progresses the causes of the cancer have been discovered and the role of the bacterium Helicobacter pylori has been demonstrated, and new perspective research are currently trying to investigate the role of other microorganisms in gastric physiopathology, as well as its possible modulation by probiotics.
Trans-Mucosal Efficacy of Non-Thermal Plasma Treatment on Cervical Cancer Tissue and Human Cervix Uteri by a Next Generation Electrosurgical Argon Plasma Device
Authors: Wenzel Thomas , Carvajal Berrio Daniel A. , Reisenauer Christl , Layland Shannon , Koch André , Wallwiener Diethelm , Brucker Sara Y. , Schenke-Layland Katja , Brauchle Eva-Maria , Weiss Martin
Published: January 2020

Non-invasive physical plasma (NIPP) generated by non-thermally operated electrosurgical argon plasma sources is a promising treatment for local chronic inflammatory, precancerous and cancerous diseases. NIPP-enabling plasma sources are highly available and medically approved. The purpose of this study is the investigation of the effects of non-thermal NIPP on cancer cell proliferation, viability and apoptosis and the identification of the underlying biochemical and molecular modes of action. For this, cervical cancer (CC) single cells and healthy human cervical tissue were analyzed by cell counting, caspase activity assays, microscopic and flow-cytometric viability measurements and molecular tissue characterization using Raman imaging. NIPP treatment caused an immediate and persisting decrease in CC cell growth and cell viability associated with significant plasma-dependent effects on lipid structures. These effects could also be identified in primary cells from healthy cervical tissue and could be traced into the basal cell layer of superficially NIPP-treated cervical mucosa. This study shows that NIPP treatment with non-thermally operated electrosurgical argon plasma devices is a promising method for the treatment of human mucosa, inducing specific molecular changes in cells.
Molecular Mechanisms of the Efficacy of Cold Atmospheric Pressure Plasma (CAP) in Cancer Treatment
Authors: Semmler Marie Luise , Bekeschus Sander , Schäfer Mirijam , Bernhardt Thoralf , Fischer Tobias , Witzke Katharina , Seebauer Christian , Rebl Henrike , Grambow Eberhard , Vollmar Brigitte , Nebe J. Barbara , Metelmann Hans-Robert , Woedtke Thomas von , Emmert Steffen , Boeckmann Lars
Published: January 2020

Recently, the potential use of cold atmospheric pressure plasma (CAP) in cancer treatment has gained increasing interest. Especially the enhanced selective killing of tumor cells compared to normal cells has prompted researchers to elucidate the molecular mechanisms for the efficacy of CAP in cancer treatment. This review summarizes the current understanding of how CAP triggers intracellular pathways that induce growth inhibition or cell death. We discuss what factors may contribute to the potential selectivity of CAP towards cancer cells compared to their non-malignant counterparts. Furthermore, the potential of CAP to trigger an immune response is briefly discussed. Finally, this overview demonstrates how these concepts bear first fruits in clinical applications applying CAP treatment in head and neck squamous cell cancer as well as actinic keratosis. Although significant progress towards understanding the underlying mechanisms regarding the efficacy of CAP in cancer treatment has been made, much still needs to be done with respect to different treatment conditions and comparison of malignant and non-malignant cells of the same cell type and same donor. Furthermore, clinical pilot studies and the assessment of systemic effects will be of tremendous importance towards bringing this innovative technology into clinical practice.
Multistate Markov Model to Predict the Prognosis of High-Risk Human Papillomavirus-Related Cervical Lesions
Authors: Taguchi Ayumi , Hara Konan , Tomio Jun , Kawana Kei , Tanaka Tomoki , Baba Satoshi , Kawata Akira , Eguchi Satoko , Tsuruga Tetsushi , Mori Mayuyo , Adachi Katsuyuki , Nagamatsu Takeshi , Oda Katsutoshi , Yasugi Toshiharu , Osuga Yutaka , Fujii Tomoyuki
Published: January 2020

Cervical intraepithelial neoplasia (CIN) has a natural history of bidirectional transition between different states. Therefore, conventional statistical models assuming a unidirectional disease progression may oversimplify CIN fate. We applied a continuous-time multistate Markov model to predict this CIN fate by addressing the probability of transitions between multiple states according to the genotypes of high-risk human papillomavirus (HPV). This retrospective cohort comprised 6022 observations in 737 patients (195 normal, 259 CIN1, and 283 CIN2 patients at the time of entry in the cohort). Patients were followed up or treated at the University of Tokyo Hospital between 2008 and 2015. Our model captured the prevalence trend satisfactory, particularly for up to two years. The estimated probabilities for 2-year transition to CIN3 or more were the highest in HPV 16-positive patients (13%, 30%, and 42% from normal, CIN1, and CIN2, respectively) compared with those in the other genotype-positive patients (3.1–9.6%, 7.6–16%, and 21–32% from normal, CIN1, and CIN2, respectively). Approximately 40% of HPV 52- or 58-related CINs remained at CIN1 and CIN2. The Markov model highlights the differences in transition and progression patterns between high-risk HPV-related CINs. HPV genotype-based management may be desirable for patients with cervical lesions.
Pancreatic Enzyme Replacement Therapy in Pancreatic Cancer
Authors: Pezzilli Raffaele , Caccialanza Riccardo , Capurso Gabriele , Brunetti Oronzo , Milella Michele , Falconi Massimo
Published: January 2020

Pancreatic cancer is an aggressive malignancy and the seventh leading cause of global cancer deaths in industrialised countries. More than 80% of patients suffer from significant weight loss at diagnosis and over time tend to develop severe cachexia. A major cause of weight loss is malnutrition. Patients may experience pancreatic exocrine insufficiency (PEI) before diagnosis, during nonsurgical treatment, and/or following surgery. PEI is difficult to diagnose because testing is cumbersome. Consequently, PEI is often detected clinically, especially in non-specialised centres, and treated empirically. In this position paper, we review the current literature on nutritional support and pancreatic enzyme replacement therapy (PERT) in patients with operable and non-operable pancreatic cancer. To increase awareness on the importance of PERT in pancreatic patients, we provide recommendations based on literature evidence, and when data were lacking, based on our own clinical experience.
Targeting NRF2-Governed Glutathione Synthesis for SDHB-Mutated Pheochromocytoma and Paraganglioma
Authors: Liu Yang , Pang Ying , Caisova Veronika , Ding Jianyi , Yu Di , Zhou Yiqiang , Huynh Thanh-Truc , Ghayee Hans , Pacak Karel , Yang Chunzhang
Published: January 2020

Succinate dehydrogenase subunit B (SDHB) deficiency frequently occurs in cluster I pheochromocytomas and paragangliomas (PCPGs). SDHB-mutated PCPGs are characterized by alterations in the electron transport chain, metabolic reprogramming of the tricarboxylic cycle, and elevated levels of reactive oxygen species (ROS). We discovered that SDHB-deficient PCPG cells exhibit increased oxidative stress burden, which leads to elevated demands for glutathione metabolism. Mechanistically, nuclear factor erythroid 2-related factor 2 (NRF2)-guided glutathione de novo synthesis plays a key role in supporting cellular survival and the proliferation of SDHB-knockdown (SDHBKD) cells. NRF2 blockade not only disrupted ROS homeostasis in SDHB-deficient cells but also caused severe cytotoxicity by the accumulation of DNA oxidative damage. Brusatol, a potent NRF2 inhibitor, showed a promising effect in suppressing SDHBKD metastatic lesions in vivo, with prolonged overall survival in mice bearing PCPG allografts. Our findings highlight a novel therapeutic strategy of targeting the NRF2-driven glutathione metabolic pathway against SDHB-mutated PCPG.
Reply to Comment on “Malfitano, A.M. et al. Virotherapy as a Potential Therapeutic Approach for the Treatment of Aggressive Thyroid Cancer” Cancers 2019, 11, 1532
Authors: Malfitano Anna Maria , Di Somma Sarah , Prevete Nella , Portella Giuseppe
Published: January 2020

Our work is focused on the future clinical use of oncolytic viruses (OVs) for the treatment of aggressive thyroid carcinomas [...]
Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 Antibodies
Authors: Zhang Peng , Xiong Xinxin , Rolfo Christian , Du Xuexiang , Zhang Yan , Yang Han , Russo Alessandro , Devenport Martin , Zhou Penghui , Liu Yang , Zheng Pan
Published: January 2020

Background: CTLA-4 was the first immune checkpoint targeted for cancer therapy and the first target validated by the FDA (Food and Drug Administration) after approval of the anti-CTLA-4 antibody, Ipilimumab. However, clinical response rates to anti-CTLA-4 antibodies are lower while the rates of immunotherapy-related adverse events (irAE) are higher than with anti-PD-1 antibodies. As a result, the effort to target CTLA-4 for cancer immunotherapy has stagnated. To reinvigorate CTLA-4-targeted immunotherapy, we and others have reported that rather than blocking CTLA-4 interaction with its cognate targets, CD80 and CD86, anti-CTLA-4 antibodies achieve their therapeutic responses through selective depletion of regulatory T cells in the tumor microenvironment. Accordingly, we have developed a new generation of anti-CTLA-4 antibodies with reduced irAE and enhanced antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC/ADCP). A major unresolved issue is how to select appropriate cancer types for future clinical development. Methods: We generated a landscape of the immune tumor microenvironment from RNAseq and genomic data of 7279 independent cancer samples belonging to 22 cancer types from The Cancer Genomics Atlas (TCGA) database. Based primarily on genomic and RNAseq data from pre-treatment clinical samples of melanoma patients who were later identified as responders and nonresponders to the anti-CTLA-4 antibody Ipilimumab, we identified 5 ranking components of responsiveness to anti-CTLA-4, including CTLA-4 gene expression, ADCC potential, mutation burden, as well as gene enrichment and cellular composition that favor CTLA-4 responsiveness. The total ranking number was calculated by the sum of 5 independent partitioning values, each comprised of 1–3 components. Results: Our analyses predict metastatic melanoma as the most responsive cancer, as expected. Surprisingly, non-small cell lung carcinoma (NSCLC) is predicted to be highly responsive to anti-CTLA-4 antibodies. Single-cell RNAseq analysis and flow cytometry of human NSCLC-infiltrating T cells supports the potential of anti-CTLA-4 antibodies to selectively deplete intratumoral Treg. Conclusions: Our in silico and experimental analyses suggest that non-small cell lung carcinoma will likely respond to a new generation of anti-CTLA-4 monoclonal antibodies. Our approach provides an objective ranking of the sensitivity of human cancers to anti-CTLA-4 antibodies. The comprehensive ranking of major cancer types provides a roadmap for clinical development of the next generation of anti-CTLA-4 antibodies.
Independent Evaluation of the Respective Predictive Values for High-Grade Prostate Cancer of Clinical Information and RNA Biomarkers after Upfront MRI and Image-Guided Biopsies
Authors: Roumiguié Mathieu , Ploussard Guillaume , Nogueira Léonor , Bruguière Eric , Meyrignac Olivier , Lesourd Marine , Péricart Sarah , Malavaud Bernard
Published: January 2020

Upfront MRI is taking the lead in the diagnosis of clinically significant prostate cancer, while few image-guided biopsies (IGBs) fail to demonstrate clinically significant prostate cancer. The added value of innovative biomarkers is not confirmed in this context. We analysed SelectMDx-v2 (MDx-2) in a cohort of upfront MRI and image-guided biopsy patients. Participants included patients who received a trans-rectal elastic-fusion registration IGB on the basis of DRE, PSA, PCA3, and PCPT-2.0 risk evaluation. Pre-biopsy MRI DICOM archives were reviewed according to PI-RADS-v2. Post-massage first-void urine samples stored in the institutional registered bio-repository were commercially addressed to MDxHealth to obtain MDx-2 scores. Univariate and multivariate analyses were conducted with the detection on IGB of high-grade (ISUP 2 and higher) as the dependent variable. High-grade cancer was demonstrated in 32/117 (27.4%) patients (8/2010–8/2018). Age, prostate volume, biopsy history, MDx-2, and PI-RADS-v2 scores significantly related to the detection of high-grade cancer. MDx-2 scores and the clinical variables embedded into MDx-2 scores were analysed in multivariate analysis to complement PI-RADS-v2 scores. The two combinations outperformed PI-RADS-v2 alone (AUC-ROC 0.67 vs. 0.73 and 0.80, respectively, p < 0.05) and calibration curves confirmed an adequate prediction. Similar discrimination (C-statistics, p = 0.22) was observed in the prediction of high-grade cancer, thereby questioning the respective inputs and added values of biomarkers and clinical predictors in MDx-2 scores. Based on the results of this study, we can conclude that instruments of prediction developed for systematic prostate biopsies, including those that incorporate innovative biomarkers, must be reassessed and eventually confirmed in the context of upfront MRI and IGB.
Synergistic Palladium-Phosphoric Acid Catalysis in (3 + 2) Cycloaddition Reactions between Vinylcyclopropanes and Imines
Authors: Corti Vasco , Marcantonio Enrico , Mamone Martina , Giungi Alessandro , Fochi Mariafrancesca , Bernardi Luca
Published: January 2020

The palladium-catalyzed (3 + 2) cycloaddition reaction between vinylcyclopropanes (VCPs) bearing geminal EWG’s and imines represents a straightforward and flexible entry to polysubstituted pyrrolidine derivatives. In this paper, we demonstrate that using a synergistic catalysis approach, based on the combination of phosphoric acid and palladium catalysts, it is possible to engage for the first time N-aryl and N-benzyl imines in this cycloaddition reaction. A range of polysubstituted pyrrolidines is obtained with moderate to good yields and diastereoselectivities, using a simple palladium species (Pd(PPh3)4) and an archetypical phosphoric acid as catalyst combination. A two-step scheme which exploits the same palladium catalyst for two consecutive and mechanistically distinct reactions (the cycloaddition and a Suzuki–Miyaura cross-coupling) is also presented. This synergistic catalysis approach is well posited for the development of the enantioselective version of this reaction. A screening of common BINOL-derived chiral phosphoric acids as catalyst component identified a species giving the product with moderate, yet promising, enantioselectivity (64% ee).
Dopamine Receptor Activation Modulates the Integrity of the Perisynaptic Extracellular Matrix at Excitatory Synapses
Authors: Mitlöhner Jessica , Kaushik Rahul , Niekisch Hartmut , Blondiaux Armand , Gee Christine E. , Happel Max F. K. , Gundelfinger Eckart , Dityatev Alexander , Frischknecht Renato , Seidenbecher Constanze
Published: January 2020

In the brain, Hebbian-type and homeostatic forms of plasticity are affected by neuromodulators like dopamine (DA). Modifications of the perisynaptic extracellular matrix (ECM), which control the functions and mobility of synaptic receptors as well as the diffusion of transmitters and neuromodulators in the extracellular space, are crucial for the manifestation of plasticity. Mechanistic links between synaptic activation and ECM modifications are largely unknown. Here, we report that neuromodulation via D1-type DA receptors can induce targeted ECM proteolysis specifically at excitatory synapses of rat cortical neurons via proteases ADAMTS-4 and -5. We showed that receptor activation induces increased proteolysis of brevican (BC) and aggrecan, two major constituents of the adult ECM both in vivo and in vitro. ADAMTS immunoreactivity was detected near synapses, and shRNA-mediated knockdown reduced BC cleavage. We have outlined a molecular scenario of how synaptic activity and neuromodulation are linked to ECM rearrangements via increased cAMP levels, NMDA receptor activation, and intracellular calcium signaling.
Towards Age-Related Anti-Inflammatory Therapy: Klotho Suppresses Activation of ER and Golgi Stress Response in Senescent Monocytes
Authors: Mytych Jennifer , Sołek Przemysław , Będzińska Agnieszka , Rusinek Kinga , Warzybok Aleksandra , Tabęcka-Łonczyńska Anna , Koziorowski Marek
Published: January 2020

Immunosenescence in monocytes has been shown to be associated with several biochemical and functional changes, including development of senescence-associated secretory phenotype (SASP), which may be inhibited by klotho protein. To date, it was believed that SASP activation is associated with accumulating DNA damage. However, some literature data suggest that endoplasmic reticulum and Golgi stress pathways may be involved in SASP development. Thus, the aim of this study was to investigate the role of klotho protein in the regulation of immunosenescence-associated Golgi apparatus and ER stress response induced by bacterial antigens in monocytes. We provide evidence that initiation of immunosenescent-like phenotype in monocytes is accompanied by activation of CREB34L and TFE3 Golgi stress response and ATF6 and IRE1 endoplasmic reticulum stress response, while klotho overexpression prevents these changes. Further, these changes are followed by upregulated secretion of proinflammatory cytokines, which final modification takes place exclusively in the Golgi apparatus. In conclusion, we provide for the first time evidence of klotho involvement in the crosstalk on the line ER-Golgi, which may, in turn, affect activation of SASP. This data may be useful for a novel potential target for therapy in age-related and chronic inflammatory conditions.