bluuebunny/crossref_metadata_2025 huggingface dataset:
Propiedades psicométricas del Interpersonal Reactivity Index (IRI) en mexicanos universitarios
Authors: González Alma Lidia Ahuatzin , Martínez-Velázquez Eduardo Salvador , García-Aguilar Gregorio , Vazquez-Moreno Almitra
Published: April 2020

Objetivo El presente estudio tuvo como propósito analizar las propiedades psicométricas de la versión española del Índice de Reactividad Interpersonal (IRI) (Pérez-Albéniz et al., 2003) en universitarios, para su adaptación al contexto mexicano. Material y Método. El IRI se aplicó a 729 estudiantes de pregrado de diversas facultades de la Benemérita Universidad Autónoma de Puebla. Resultados. Los resultados que indican la adaptación del IRImuestra una adecuada consistencia interna (α = .82), y el análisis confirmatorio corroboró la estructura teórica de cuatro factores, similar a la versión original. Asimismo, se diferencian de género en las dimensiones afectivas, pero no en las cognitivas. Conclusión. El estudio proporciona una adaptación adecuada del IRI para ser utilizado en población mexicana con características similares a los de esta investigación. Sin embargo, se puede ampliar la muestra en otras zonas del país para generalizar su validez en todo el territorio mexicano.
Emocionalidad, conducta, habilidades sociales, y funciones ejecutivas en niños de nivel inicial
Authors: Muchiut Alvaro Federico , Dri Constanza Ayelén , Vaccaro Paola , Pietto Marcos
Published: April 2020

Durante el nivel inicial, los infantes suelen recibir respuestas emocionales y conductuales de manera impulsiva, dado que carecen de la aptitud de abstención de conductas que no son afectadas a la ocasión. En este punto, las Habilidades Sociales (HHSS) y las Funciones Ejecutivas (FE) serán facilitadoras de la interacción asertiva con otros, favoreciendo el control conductual y evitando los Problemas de Conducta (PC). El objetivo de este estudio fue analizar la correlación entre las FE, la percepción parental en relación con las emociones, y la percepción de los docentes respecto de las HHSS y la conducta en niños del nivel inicial de educación; a tal fin se realizó un estudio cuantitativo, transversal, descriptivo-correlacional, en base a un diseño no experimental. La muestra estuvo integrada por 36 niños / as de nivel inicial, a quienes se les administró una batería neuropsicológica, además se incluyeron dos cuestionarios, uno para padres y otro para docentes. Se encontró correlación entre HHSS y PC; entre Planeación y Emociones; y entre Atención y Concentración y Memoria de Trabajo. Se concluye que los niños de nivel inicial tienen una conducta socialmente habilitada, y manejan sus emociones sin dificultad indistintamente del sexo, según la perspectiva parental y docente.
Factores de predisposición genéticos y epigenéticos de los trastornos de ansiedad
Authors: Dueñas Amaya Laura Juliana
Published: April 2020

Los trastornos de ansiedad constituyen un grupo de alteraciones psicológicas y neurológicas que representan varias formas de miedo y ansiedad anormales o patológicas (Orozco & Baldares, 2012). Aun cuando alrededor del 14% de la población del planeta ha sufrido algún trastorno de ansiedad, las causas que desencadenan el mismo no son del todo claras (Posada, 2013). La aproximación clásica de los estudios para la identificación de los factores de predisposición de estos trastornos neuropsiquiátricos se ha orientado a las teorías de la personalidad como la Teoría de Eysenck (Mitchell & Kumari, 2016) y la Teoría Bio-Psicológica de la personalidad (Knyazev, Pylkova, Slobodskoj-Plusnin, Bocharov, & Ushakov, 2015). Sin embargo, a partir de estos estudios, han surgido nuevas propuestas involucrando los aspectos neuroanatómicos y neurofuncionales. La transmisión eléctrica y química de la información y como esta se asocia a distintas conductas demuestran la relevación de la regulación de la producción y recaptación de neurotransmisores en sistema nervioso central (SNC). Aunque esta regulación se encuentra directamente relacionada con la expresión genética, em tanto se han identificado ciertos genes candidatos que aportan un porcentaje a esta predisposición, estos no son totalmente determinantes. Actualmente, dado a este vacío, se ha comenzado a investigar la influencia de factores epigenéticos que en conjunto con los factores genéticos permitirían ampliar la explicación de los factores de predisposición de ciertos trastornos neuropsiquiátricos que anteriormente eran considerados de etiología ambiental.
Genómica Social: Relaciones entre teoría de la mente y cariotipo en mujeres con diagnóstico de Síndrome de Turner
Authors: Aguilar María Jose , López Marcela Carolina , Agulla Lucia , Lopez Morales Hernan , Urquijo Sebastian
Published: April 2020

Introducción: La teoría de la mente refiere a la capacidad cognitiva de atribuir mente a los demás y de predecir y comprender su comportamiento en términos de entidades mentales como creencias, deseos e intenciones. Investigaciones recientes sugieren una distinción entre una teoría de la mente afectiva y una cognitiva, asignándoles un sustrato neuroanatómico específico. El Síndrome de Turner es un trastorno genético determinado por la deleción total o parcial del cromosoma X en el sexo femenino. Dadas las características biológicas, psicológicas y sociales encontradas en estas mujeres, pueden ser consideradas como una población relevante para el estudio de la teoría de la mente según parámetros biológicos como la expresión diferencial de los genes del cromosoma X. Objetivos y métodos: los objetivos de este estudio fueron describir la teoría de la mente cognitiva y afectiva en 22 mujeres con diagnóstico de Síndrome de Turner y determinar si existen perfiles distintivos de teoría de la mente asociados al cariotipo. Resultados y discusión: Los resultados indicaron que las mujeres con diagnóstico de Síndrome de Turner presentan dificultades generales en teoría de la mente, observándose un menor rendimiento en el aspecto cognitivo de esta capacidad. Asimismo, se encontró que un mayor daño genético se encuentra relacionado a mayores dificultades en la teoría de la mente cognitiva, vinculada a zonas corticales de procesamiento no automático.
Developmental and Degenerative Characterization of Porcine Parthenogenetic Fetuses during Early Pregnancy
Authors: Hwang In-Sul , Park Mi-Ryung , Lee Hae-Sun , Kwak Tae-Uk , Son Hwa-Young , Kang Jong-Koo , Lee Jeong-Woong , Lee Kichoon , Park Eung-Woo , Hwang Seongsoo
Published: April 2020

The difference between early pregnancy and delivery rate is quite large in assisted reproduction techniques (ARTs), including animal cloning. However, it is not clear why the implanted fetuses aborted after the early pregnancy stage. In the present study, we tried to evaluate the developmental and morphological characteristics of porcine parthenogenetically activated (PA) embryos or fetuses by electric stimulation during the early pregnancy period. The implanted PA and artificially inseminated (AI) embryos and fetuses were collected at day 26 and 35 after embryo transfer, respectively. The developmental and morphological parameters in the PA embryos at day 26 were similar to the AI embryos. The size, weight, formation of major organs, and apoptotic cells were not statistically different in both embryos at day 26. However, the PA fetuses at day 35 showed ceased fetal development and degenerated with abnormal morphologies in their organs. The day 35 PA fetuses showed significantly higher apoptotic cells and lower methylation status in three differentially methylated regions of the H19 gene compared to their comparators. Therefore, the normal development of PA embryos and fetuses during early gestation could lead to these pregnancies being misinterpreted as normal and become one of the main reasons for the gap between early pregnancy and delivery rate.
Identification of Differentially Expressed MicroRNAs and Their Potential Target Genes in Adipose Tissue from Pigs with Highly Divergent Backfat Thickness
Authors: Xing Kai , Zhao Xitong , Liu Yibing , Zhang Fengxia , Tan Zhen , Qi Xiaolong , Wang Xiangguo , Ni Hemin , Guo Yong , Sheng Xihui , Wang Chuduan
Published: April 2020

Fatty traits are very important in pig production. However, the role of microRNAs (miRNAs) in fat deposition is not clearly understood. In this study, we compared adipose miRNAs from three full-sibling pairs of female Landrace pigs, with high and low backfat thickness, to investigate the associated regulatory network. We obtained an average of 17.29 million raw reads from six libraries, 62.27% of which mapped to the pig reference genome. A total of 318 pig miRNAs were detected among the samples. Among them, 18 miRNAs were differentially expressed (p-value < 0.05, |log2fold change| ≥ 1) between the high and low backfat groups; 6 were up-regulated and 12 were down-regulated. Functional enrichment of the predicted target genes of the differentially expressed miRNAs, indicated that these miRNAs were involved mainly in lipid and carbohydrate metabolism, and glycan biosynthesis and metabolism. Comprehensive analysis of the mRNA and miRNA transcriptomes revealed possible regulatory relationships for fat deposition. Negatively correlated mRNA–miRNA pairs included miR-137–PPARGC1A, miR-141–FASN, and miR-122-5p–PKM, indicating these interactions may be key regulators of fat deposition. Our findings provide important insights into miRNA expression patterns in the backfat tissue of pig and new insights into the regulatory mechanisms of fat deposition in pig.
Moringa Oleifera Leaf Extract Repairs the Oxidative Misbalance following Sub-Chronic Exposure to Sodium Fluoride in Nile Tilapia Oreochromis niloticus
Authors: Ahmed Nirmen F. , Sadek Kadry M. , Soliman Magdy Kh. , Khalil Reyad H. , Khafaga Asmaa F. , Ajarem Jamaan S. , Maodaa Saleh N. , Allam Ahmed A.
Published: April 2020

The potential antioxidant property of Moringa oleifera (MO) has been the recent focus of an increased number of studies. However few studies investigated its antioxidative ability against sodium fluoride-induced redox balance breakdown in Oreochromis niloticus. Thus, this study evaluates the effects of MO against the oxidative stress induced by sub-chronic exposure to sodium fluoride (NaF). A total of 264 fish (40 ± 3 g BW) were used to calculate the 96 hr-LC50 of NaF and perform the sub-chronic exposure study. 96 hr-LC50 of NaF was calculated as (61 mg/L). The 1/10 dose of the calculated 96 hr-LC50 (6.1 mg/L) was used to complete the sub chronic exposure for eight weeks. Fish were divided into four groups (n = 51; three replicates each); control, non-treated group; NaF group (exposed to NaF 6.1 mg/L); MO group (treated with 1% MO of diet); and NaF+MO (exposed to NaF 6.1 mg/L and treated with 1% MO of diet). The results revealed that the sub-chronic exposure to NaF (6.1 mg/L) was substantially increased malondialdehyde (MDA) and decrease the activities of superoxide dismutase (SOD), catalase (CAT), glutathione reduced (GSH), glutathione peroxidase (GPx), and total antioxidant capacity (TAC) in the gills, liver, kidney, and muscle tissue in a time-dependent manner. In addition, a significant reduction in mRNA expression of GST in the liver was reported following NaF exposure. On the contrary, dietary supplementation of MO to NaF-exposed fish resulted in a significant reduction in MDA levels, and a significant elevation of SOD, CAT, GSH, GPx, and TAC activities in a time-dependent manner, in addition to significant elevation of GST mRNA expression in liver tissue. It could be concluded that a 1% MO (w/w) ration is a promising antioxidant plant that may successfully use to interfere with the oxidation processes induced by NaF in various tissues of Oreochromis niloticus.
Impact of the Timing of Spay-Neuter Related to Transport on Disease Rates in Relocated Dogs
Authors: Doyle Erin , Gupta Maya , Spindel Miranda , Dolan Emily D. , Slater Margaret R. , Janeczko Stephanie
Published: April 2020

Companion animal relocation programs are an important method to address geographic and resource disparities in pet overpopulation through transport from areas with high homeless pet populations to areas with high adopter demand. Despite mitigation by following best practices, a potential risk of animal relocation is increased disease incidence related to infectious disease spread and the effects of stress during transport. Surgical sterilization may compound disease risk due to the impact of surgical stress on disease susceptibility and the potential for disease exposure from other patients. Our study aimed to provide information about disease and surgical complication incidence as relates to the timing of surgical sterilization in relocated dogs. A population of 431 dogs relocated to a shelter in Washington State was monitored for disease while at the destination shelter and immediately post-adoption. No increased disease incidence was identified for dogs altered within two weeks of transport at the destination shelter compared with those altered within two weeks prior to transport at the source shelter. Because of disparities addressed by relocation programs, surgical sterilization of relocated companion animals is typically best performed at the destination shelter. Our study indicates that disease incidence is not increased by spay-neuter at the destination shelter.
Dietary Puerarin Supplementation Alleviates Oxidative Stress in the Small Intestines of Diquat-Challenged Piglets
Authors: Li Meng , Yuan Daixu , Liu Yanhong , Jin Hui , Tan Bie
Published: April 2020

This study was conducted to demonstrate that dietary puerarin supplementation alleviates oxidative stress in the small intestine of diquat-challenged piglets. The results showed that puerarin administration markedly alleviated diquat-induced intestinal injury, which was indicated by the improvement of intestinal morphology, cell proliferation and barrier function. One of the potential mechanisms responsible for this was the decrease in oxidative stress, as evidenced by the increase in activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC) in the small intestine. Puerarin increased the protein expression levels of NF-E2-related factor 2 (Nrf2) and its downstream enzymes, including heme oxygenase 1 (HO-1), glutamate–cysteine ligase catalytic and its modifier subunit (GCLc and GCLm) in the jejunal mucosa of diquat-induced piglets. Puerarin administration improved intestinal morphology, cell proliferation, and barrier function, and increased Nrf2 and its downstream enzymes. These findings indicate that the dietary supplementation of puerarin attenuates the oxidative stress involving Nrf2 signaling pathways in diquat-challenged piglets.
Comprehensive Transcriptome Analysis Reveals Insights into Phylogeny and Positively Selected Genes of Sillago Species
Authors: Lou Fangrui , Zhang Yuan , Song Na , Ji Dongping , Gao Tianxiang
Published: April 2020

Sillago species lives in the demersal environments and face multiple stressors, such as localized oxygen depletion, sulfide accumulation, and high turbidity. In this study, we performed transcriptome analyses of seven Sillago species to provide insights into the phylogeny and positively selected genes of this species. After de novo assembly, 82,024, 58,102, 63,807, 85,990, 102,185, 69,748, and 102,903 unigenes were generated from S. japonica, S. aeolus, S. sp.1, S. sihama, S. sp.2, S. parvisquamis, and S. sinica, respectively. Furthermore, 140 shared orthologous exon markers were identified and then applied to reconstruct the phylogenetic relationships of the seven Sillago species. The reconstructed phylogenetic structure was significantly congruent with the prevailing morphological and molecular biological view of Sillago species relationships. In addition, a total of 44 genes were identified to be positively selected, and these genes were potential participants in the stress response, material (carbohydrate, amino acid and lipid) and energy metabolism, growth and differentiation, embryogenesis, visual sense, and other biological processes. We suspected that these genes possibly allowed Sillago species to increase their ecological adaptation to multiple environmental stressors.
Metabolomic Study to Evaluate the Transformations of Extra-Virgin Olive Oil’s Antioxidant Phytochemicals during In Vitro Gastrointestinal Digestion
Authors: Rocchetti Gabriele , Senizza Biancamaria , Giuberti Gianluca , Montesano Domenico , Trevisan Marco , Lucini Luigi
Published: April 2020

In this work, different commercial extra-virgin olive oils (EVOO) were subjected to in vitro gastrointestinal digestion and the changes in bioactive compounds were evaluated by ultra-high-pressure liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry, using untargeted metabolomics. As expected, raw EVOO samples were abundant in total sterols (on average: 3007.4 mg equivalents/kg) and tyrosol equivalents (on average: 334.1 mg equivalents/kg). However, the UHPLC-QTOF screening allowed us to annotate 309 compounds, with a large abundance of sterols (219 compounds), followed by polyphenols (67 compounds) and terpenoids. The in vitro gastrointestinal digestion was found to affect the phytochemical composition of the different EVOO samples. In particular, both unsupervised and supervised statistics depicted the modifications of the bioactive profile following gastric and pancreatic phases. Overall, the compounds which resulted as the most affected by the in vitro digestion were flavonoids (cyanidin and luteolin equivalents), whilst relatively high % bioaccessibility values were recorded for tyrosol equivalents during the pancreatic phase (on average, 66%). In this regard, oleuropein-aglycone (i.e., the major phenolic compound in EVOO) was converted to hydroxytyrosol, moving from an average value of 1.3 (prior to the in vitro digestion) up to 9.7 mg equivalents/kg during the pancreatic step. As proposed in the literature, the increase in hydroxytyrosol might be the result of the combined effect of lipase(s) activity and acidic conditions. Taken together, the present findings corroborate the suitability of untargeted metabolomics coupled to in vitro digestion methods to investigate the bioaccessibility of phenolic compounds. In this regard, a significant impact of in vitro gastrointestinal digestion on polyphenolic profiles has been detected, thus suggesting the need to account for actual bioaccessibility values rather than just considering the amounts in the raw commodity.
Experimental Investigations of the Strengthening Effects of CFRP for Thin-Walled Storage Tanks under Dynamic Loads
Authors: Phan Viet Nhut , Kitano Yukio , Matsumoto Yukihiro
Published: April 2020

In this study, the strengthening effects of different lamination conditions on carbon fiber reinforced polymers (CFRPs) for thin-walled storage tanks (TSTs) subjected to internal pressure under dynamic loads were experimentally investigated. A total of three small-scale models of TSTs were used for the investigation, including non-strengthened specimens, specimens strengthened with 0° CFRP layers, and specimens strengthened with 0°/90° CFRP layers. There were two types of tests for every specimen: the static and dynamic tests. A new experimental method using small steel balls was applied to create internal pressure in the TSTs. The results show that small steel balls could be used to increase the internal pressure compared to a normal liquid. Furthermore, the similarity rules for small-scale TSTs with small steel balls inside were also studied to consider the applicability of the models. The experimental results indicated that the CFRP layer could effectively restrain both static and dynamic hoop strains in the TSTs. Moreover, the CFRP layer could also remarkably reduce the impact of sloshing on the TST shells. The 0° CFRP layer proved to have better effects than the 0°/90° CFRP layers on the strengthening of the TSTs against dynamic loads.
Health State Classification of a Spherical Tank Using a Hybrid Bag of Features and K-Nearest Neighbor
Authors: Hasan Md Junayed , Kim Jaeyoung , Kim Cheol Hong , Kim Jong-Myon
Published: April 2020

Feature analysis puts a great impact in determining the various health conditions of mechanical vessels. To achieve balance between traditional feature extraction and the automated feature selection process, a hybrid bag of features (HBoF) is designed for multiclass health state classification of spherical tanks in this paper. The proposed HBoF is composed of (a) the acoustic emission (AE) features and (b) the time and frequency based statistical features. A wrapper-based feature chooser algorithm, Boruta, is utilized to extract the most intrinsic feature set from HBoF. The selective feature matrix is passed to the multi-class k-nearest neighbor (k-NN) algorithm to differentiate among normal condition (NC) and two faulty conditions (FC1 and FC2). Experimental results demonstrate that the proposed methodology generates an average 99.7% accuracy for all working conditions. Moreover, it outperforms the existing state-of-art works by achieving at least 19.4%.
Springback Prediction in Sheet Metal Forming, Based on Finite Element Analysis and Artificial Neural Network Approach
Authors: Spathopoulos Stefanos C. , Stavroulakis Georgios E.
Published: April 2020

Sheet metal forming is one of the most important manufacturing processes applied in many industrial sectors, with the most prevalent being the automotive and aerospace industries. The main purpose of that operation is to produce a desired formed shape blank, without any material failures, which should lie well within the acceptable tolerance limits. Springback is affected by factors such as material properties, sheet thickness, forming tools geometry, contact and friction, etc. The present paper proposes a novel neural network system for the prediction of springback in sheet metal forming processes. It is based on Bayesian regularized backpropagation networks, which have not been tested in the literature, according to the authors’ best knowledge. For the creation of training examples a carefully prepared Finite Element model has been created and validated for a test case used in similar industrial studies.
Domain Heterogeneity in Radiofrequency Therapies for Pain Relief: A Computational Study with Coupled Models
Authors: Singh Sundeep , Melnik Roderick
Published: April 2020

The objective of the current research work is to study the differences between the predicted ablation volume in homogeneous and heterogeneous models of typical radiofrequency (RF) procedures for pain relief. A three-dimensional computational domain comprising of the realistic anatomy of the target tissue was considered in the present study. A comparative analysis was conducted for three different scenarios: (a) a completely homogeneous domain comprising of only muscle tissue, (b) a heterogeneous domain comprising of nerve and muscle tissues, and (c) a heterogeneous domain comprising of bone, nerve and muscle tissues. Finite-element-based simulations were performed to compute the temperature and electrical field distribution during conventional RF procedures for treating pain, and exemplified here for the continuous case. The predicted results reveal that the consideration of heterogeneity within the computational domain results in distorted electric field distribution and leads to a significant reduction in the attained ablation volume during the continuous RF application for pain relief. The findings of this study could provide first-hand quantitative information to clinical practitioners about the impact of such heterogeneities on the efficacy of RF procedures, thereby assisting them in developing standardized optimal protocols for different cases of interest.
Grape-Leaf Extract Attenuates Alcohol-Induced Liver Injury via Interference with NF-κB Signaling Pathway
Authors: Amen Yhiya , Sherif Asmaa E. , Shawky Noha M. , Abdelrahman Rehab S. , Wink Michael , Sobeh Mansour
Published: April 2020

Grape (Vitis vinifera) leaf extracts (GLEs) are known to be rich in phenolic compounds that exert potent antioxidant effects. Given the vulnerability of the liver to oxidative damage, antioxidants have been proposed as therapeutic agents and coadjuvant drugs to ameliorate liver pathologies. The current study was designed to characterize secondary metabolites and investigate the hepatoprotective effects of GLE and its underlying mechanisms. The secondary metabolites were profiled using HPLC–PDA–ESI-MS, and forty-five compounds were tentatively identified. In experimental in vivo design, liver injury was induced by oral administration of high doses of ethanol (EtOH) for 12 days to male Sprague Dawley rats that were split into five different groups. Blood samples and livers were then collected, and used for various biochemical, immunohistochemical, and histopathological analyses. Results showed that GLE-attenuated liver injury and promoted marked hepatic antioxidant effects, in addition to suppressing the increased heat-shock protein-70 expression. Moreover, GLE suppressed EtOH-induced expression of nuclear factor-κB (NF-κB) p65 subunit and proinflammatory cytokine tumor necrosis factor-α. Caspase-3 and survivin were enhanced by EtOH intake and suppressed by GLE intake. Finally, EtOH-induced histopathological changes in liver sections were markedly normalized by GLE. In conclusion, our results suggested that GLE interferes with NF-κB signaling and induces antioxidant effects, which both play a role in attenuating apoptosis and associated liver injury in a model of EtOH-induced liver damage in rats.
Variation in ω-3 and ω-6 Polyunsaturated Fatty Acids Produced by Different Phytoplankton Taxa at Early and Late Growth Phase
Authors: Taipale Sami , Peltomaa Elina , Salmi Pauliina
Published: April 2020

Phytoplankton synthesizes essential ω-3 and ω-6 polyunsaturated fatty acids (PUFA) for consumers in the aquatic food webs. Only certain phytoplankton taxa can synthesize eicosapentaenoic (EPA; 20:5ω3) and docosahexaenoic acid (DHA; 22:6ω3), whereas all phytoplankton taxa can synthesize shorter-chain ω-3 and ω-6 PUFA. Here, we experimentally studied how the proportion, concentration (per DW and cell-specific), and production (µg FA L−1 day−1) of ω-3 and ω-6 PUFA varied among six different phytoplankton main groups (16 freshwater strains) and between exponential and stationary growth phase. EPA and DHA concentrations, as dry weight, were similar among cryptophytes and diatoms. However, Cryptomonas erosa had two–27 times higher EPA and DHA content per cell than the other tested cryptophytes, diatoms, or golden algae. The growth was fastest with diatoms, green algae, and cyanobacteria, resulting in high production of medium chain ω-3 and ω-6 PUFA. Even though the dinoflagellate Peridinium cinctum grew slowly, the content of EPA and DHA per cell was high, resulting in a three- and 40-times higher production rate of EPA and DHA than in cryptophytes or diatoms. However, the production of EPA and DHA was 40 and three times higher in cryptophytes and diatoms than in golden algae (chrysophytes and synyrophytes), respectively. Our results show that phytoplankton taxon explains 56–84% and growth phase explains ~1% of variation in the cell-specific concentration and production of ω-3 and ω-6 PUFA, supporting understanding that certain phytoplankton taxa play major roles in the synthesis of essential fatty acids. Based on the average proportion of PUFA of dry weight during growth, we extrapolated the seasonal availability of PUFA during phytoplankton succession in a clear water lake. This extrapolation demonstrated notable seasonal and interannual variation, the availability of EPA and DHA being prominent in early and late summer, when dinoflagellates or diatoms increased.
Glutamatergic Activation of Neuronostatin Neurons in the Periventricular Nucleus of the Hypothalamus
Authors: Serter Kocoglu Sema , Gok Yurtseven Duygu , Cakir Cihan , Minbay Zehra , Eyigor Ozhan
Published: April 2020

Neuronostatin, a newly identified anorexigenic peptide, is present in the central nervous system. We tested the hypothesis that neuronostatin neurons are activated by feeding as a peripheral factor and that the glutamatergic system has regulatory influences on neuronostatin neurons. The first set of experiments analyzed the activation of neuronostatin neurons by refeeding as a physiological stimulus and the effectiveness of the glutamatergic system on this physiological stimulation. The subjects were randomly divided into three groups: the fasting group, refeeding group, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)+refeeding group. We found that refeeding increased the phosphorylated signal transducers and transcription activator-5 (pSTAT5) expression in neuronostatin-positive neurons and that the CNQX injection significantly suppressed the number of pSTAT5-expressing neuronostatin neurons. The second set of experiments analyzed the activation pathways of neuronostatin neurons and the regulating effects of the glutamatergic system on neuronostatin neurons. The animals received intraperitoneal injections of glutamate receptor agonists (kainic acid, α-amino-3-hydroxy-5methyl-4-isoazepropionic acid (AMPA), and N-methyl-D-aspartate (NMDA)) or 0.9% NaCl. The number of c-Fos-expressing neuronostatin neurons significantly increased following the AMPA and NMDA injections. In conclusion, we found that the neuronostatin neurons were activated by peripheral or central signals, including food intake and/or glutamatergic innervation, and that the glutamate receptors played an important role in this activation.
Prognostic Impact of PD-L1 Expression in Malignant Salivary Gland Tumors as Assessed by Established Scoring Criteria: Tumor Proportion Score (TPS), Combined Positivity Score (CPS), and Immune Cell (IC) Infiltrate
Authors: Witte Hanno M. , Gebauer Niklas , Lappöhn Daniela , Umathum Vincent G. , Riecke Armin , Arndt Annette , Steinestel Konrad
Published: April 2020

Background: Malignant neoplasms of the salivary glands are rare, and therapeutic options are limited. Results from recently published studies indicate a possible use for checkpoint inhibition in a subset of patients, but there are no established criteria for programme cell death ligand 1 (PD-L1) scoring in salivary gland carcinomas (SGCs). Methods: In this retrospective study, we present a cohort of 94 SGC patients with full clinical follow-up. We included 41 adenoid cystic carcinomas (AdCC), 21 mucoepidermoid carcinomas (MEC), 16 acinic cell carcinomas (ACC), 12 adenocarcinomas, not otherwise specified (AC, NOS), 2 epithelial-myoepithelial carcinomas (EMC), one salivary duct carcinoma (SDC), and one carcinoma ex pleomorphic adenoma (CA ex PA). Subsequent histopathological analysis was performed with special emphasis on the composition of the immune cell infiltrate (B-/T-lymphocytes). We assessed PD-L1 (SP263) on full slides by established scoring criteria: tumor proportion score (TPS), combined positivity score (CPS) and immune cell (IC) score. Results: We identified significantly elevated CD3+, TP, CP, and IC scores in AC, NOS compared to AdCC, MEC, and ACC. CPS correlated with node-positive disease. Moreover, AC, NOS displayed IC scores of 2 or 3 in the majority (67%) of cases (p = 0.0031), and was associated with poor prognosis regarding progression-free (PFS) (p < 0.0001) and overall survival (OS) (p < 0.0001). CPS correlated with strong nuclear or null p53 staining in AC, NOS but not in other SGCs. Long-lasting partial remission could be achieved in one AC, NOS patient who received Pembrolizumab as third-line therapy. Conclusions: The current study is the first to investigate the use of established scoring criteria for PD-L1 expression in malignant salivary gland tumors. Our findings identify unique characteristics for AC, NOS among the family of SGCs, as it is associated with poor prognosis and might represent a valuable target for immune checkpoint inhibition.
Biological and Clinical Significance of the CCR5/CCL5 Axis in Hepatocellular Carcinoma
Authors: Singh Santosh K. , Mishra Manoj K. , Rivers Brian M. , Gordetsky Jennifer B. , Bae Sejong , Singh Rajesh
Published: April 2020

Despite the improvement in survival for patients with liver cancer (LCa) in recent decades, only one in five patients survive for 5 years after diagnosis. Thus, there is an urgent need to find new treatment options to improve patient survival. For various cancers, including LCa, the chemokine CCL5 (RANTES) facilitates tumor progression and metastasis. Since the function of the CCR5/CCL5 interaction in LCa cell proliferation and migration is poorly understood, the present study was undertaken to investigate the role of the CCR5/CCL5 axis in these processes. Flow cytometry, RT-PCR, Western blot, and immunofluorescence techniques were used to quantify the expression of CCR5 and CCL5 in LCa cells. To determine the biological significance of CCR5 expressed by LCa cell lines, a tissue microarray of LCas stained for CCR5 and CCL5 was analyzed. The results showed higher expression (p < 0.001) of CCR5 and CCL5 in hepatocellular carcinoma (HCC) tissues compared to non-neoplastic liver tissues. Furthermore, to delineate the role of the CCR5/CCL5 interaction in LCa cell proliferation and migration, various LCa cells were treated with maraviroc, a CCR5 antagonist, in the presence of CCL5. These data demonstrated the biological and clinical significance of the CCR5/CCL5 axis in LCa progression. The targeting of this axis is a promising avenue for the treatment of LCa.
Tumor Ulceration, Reduced Infiltration of CD8-Lymphocytes, High Neutrophil-to-CD8-Lymphocyte Ratio and Absence of MC Virus are Negative Prognostic Markers for Patients with Merkel Cell Carcinoma
Authors: Naseri Simon , Steiniche Torben , Bæhr Georgsen Jeanette , Thomsen Rune , Ladekarl Morten , Heje Martin , Engberg Damsgaard Tine , Bønnelykke-Behrndtz Marie Louise
Published: April 2020

(1) Background: Merkel cell carcinoma (MCC) is caused by the Merkel cell polyomavirus and UV radiation. Understanding of the underlying biology is limited, but identification of prognostic markers may lead to better prognostic stratification for the patients. (2) Methods: Ninety patients diagnosed with MCC (1996–2012) were included. Virus status was estimated by polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Ulceration status, PD-L1, cd66b neutrophils, cd8 lymphocytes and biomarkers of vascularization (cd34 endothelial cells) and migration (e-cadherin) were estimated by IHC and analyzed with digital pathology. (3) Results: Virus was present in 47% of patient samples and correlated with lower E-cadherin expression (p = 0.0005), lower neutrophil-to-CD8 lymphocyte ratio (N:CD8 ratio) (p = 0.02) and increased PD-L1 expression (p = 0.03). Ulceration was associated with absence of virus (p = 0.03), increased neutrophil infiltration (p < 0.0001) and reduced CD8 lymphocyte infiltration (p = 0.04). In multivariate analysis, presence of virus (p = 0.01), ulceration (p = 0.05) and increased CD8 lymphocyte infiltration (p = 0.001) showed independent prognostic impacts on MCC-specific survival. (3) Conclusions: In this study, we found that a high N:CD8 ratio, ulceration, virus-negative status and absence of CD8 lymphocytes are negative prognostic markers. Accurate prognostic stratification of the patients may be important in the clinical setting for determination of adjuvant treatment.
Immunotherapy in Metastatic Colorectal Cancer: Could the Latest Developments Hold the Key to Improving Patient Survival?
Authors: Damilakis Emmanouil , Mavroudis Dimitrios , Sfakianaki Maria , Souglakos John
Published: April 2020

Immunotherapy has considerably increased the number of anticancer agents in many tumor types including metastatic colorectal cancer (mCRC). Anti-PD-1 (programmed death 1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) immune checkpoint inhibitors (ICI) have been shown to benefit the mCRC patients with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H). However, ICI is not effective in mismatch repair proficient (pMMR) colorectal tumors, which constitute a large population of patients. Several clinical trials evaluating the efficacy of immunotherapy combined with chemotherapy, radiation therapy, or other agents are currently ongoing to extend the benefit of immunotherapy to pMMR mCRC cases. In dMMR patients, MSI testing through immunohistochemistry and/or polymerase chain reaction can be used to identify patients that will benefit from immunotherapy. Next-generation sequencing has the ability to detect MSI-H using a low amount of nucleic acids and its application in clinical practice is currently being explored. Preliminary data suggest that radiomics is capable of discriminating MSI from microsatellite stable mCRC and may play a role as an imaging biomarker in the future. Tumor mutational burden, neoantigen burden, tumor-infiltrating lymphocytes, immunoscore, and gastrointestinal microbiome are promising biomarkers that require further investigation and validation.
Targeting the Acidic Tumor Microenvironment: Unexpected Pro-Neoplastic Effects of Oral NaHCO3 Therapy in Murine Breast Tissue
Authors: Voss Ninna C. S. , Dreyer Thomas , Henningsen Mikkel B. , Vahl Pernille , Honoré Bent , Boedtkjer Ebbe
Published: April 2020

The acidic tumor microenvironment modifies malignant cell behavior. Here, we study consequences of the microenvironment in breast carcinomas. Beginning at carcinogen-based breast cancer induction, we supply either regular or NaHCO3-containing drinking water to female C57BL/6j mice. We evaluate urine and blood acid-base status, tumor metabolism (microdialysis sampling), and tumor pH (pH-sensitive microelectrodes) in vivo. Based on freshly isolated epithelial organoids from breast carcinomas and normal breast tissue, we assess protein expression (immunoblotting, mass spectrometry), intracellular pH (fluorescence microscopy), and cell proliferation (bromodeoxyuridine incorporation). Oral NaHCO3 therapy increases breast tumor pH in vivo from 6.68 ± 0.04 to 7.04 ± 0.09 and intracellular pH in breast epithelial organoids by ~0.15. Breast tumors develop with median latency of 85.5 ± 8.2 days in NaHCO3-treated mice vs. 82 ± 7.5 days in control mice. Oral NaHCO3 therapy does not affect tumor growth, histopathology or glycolytic metabolism. The capacity for cellular net acid extrusion is increased in NaHCO3-treated mice and correlates negatively with breast tumor latency. Oral NaHCO3 therapy elevates proliferative activity in organoids from breast carcinomas. Changes in protein expression patterns—observed by high-throughput proteomics analyses—between cancer and normal breast tissue and in response to oral NaHCO3 therapy reveal complex influences on metabolism, cytoskeleton, cell-cell and cell-matrix interaction, and cell signaling pathways. We conclude that oral NaHCO3 therapy neutralizes the microenvironment of breast carcinomas, elevates the cellular net acid extrusion capacity, and accelerates proliferation without net effect on breast cancer development or tumor growth. We demonstrate unexpected pro-neoplastic consequences of oral NaHCO3 therapy that in breast tissue cancel out previously reported anti-neoplastic effects.
Human Peripheral Blood-Derived Endothelial Colony-Forming Cells Are Highly Similar to Mature Vascular Endothelial Cells yet Demonstrate a Transitional Transcriptomic Signature
Authors: Kutikhin Anton G. , Tupikin Alexey E. , Matveeva Vera G. , Shishkova Daria K. , Antonova Larisa V. , Kabilov Marsel R. , Velikanova Elena A.
Published: April 2020

Endothelial colony-forming cells (ECFC) are currently considered as a promising cell population for the pre-endothelialization or pre-vascularization of tissue-engineered constructs, including small-diameter biodegradable vascular grafts. However, the extent of heterogeneity between ECFC and mature vascular endothelial cells (EC) is unclear. Here, we performed a transcriptome-wide study to compare gene expression profiles of ECFC, human coronary artery endothelial cells (HCAEC), and human umbilical vein endothelial cells (HUVEC). Characterization of the abovementioned cell populations was carried out by immunophenotyping, tube formation assay, and evaluation of proliferation capability while global gene expression profiling was conducted by means of RNA-seq. ECFC were similar to HUVEC in terms of immunophenotype (CD31+vWF+KDR+CD146+CD34-CD133-CD45-CD90-) and tube formation activity yet had expectedly higher proliferative potential. HCAEC and HUVEC were generally similar to ECFC with regards to their global gene expression profile; nevertheless, ECFC overexpressed specific markers of all endothelial lineages (NRP2, NOTCH4, LYVE1), in particular lymphatic EC (LYVE1), and had upregulated extracellular matrix and basement membrane genes (COL1A1, COL1A2, COL4A1, COL4A2). Proteomic profiling for endothelial lineage markers and angiogenic molecules generally confirmed RNA-seq results, indicating ECFC as an intermediate population between HCAEC and HUVEC. Therefore, gene expression profile and behavior of ECFC suggest their potential to be applied for a pre-endothelialization of bioartificial vascular grafts, whereas in terms of endothelial hierarchy they differ from HCAEC and HUVEC, having a transitional phenotype.
Nobiletin Promotes Megakaryocytic Differentiation through the MAPK/ERK-Dependent EGR1 Expression and Exerts Anti-Leukemic Effects in Human Chronic Myeloid Leukemia (CML) K562 Cells
Authors: Yen Jui-Hung , Lin Ching-Yen , Chuang Chin-Hsien , Chin Hsien-Kuo , Wu Ming-Jiuan , Chen Pei-Yi
Published: April 2020

Differentiation therapy is an alternative strategy used to induce the differentiation of blast cells toward mature cells and to inhibit tumor cell proliferation for cancer treatment. Nobiletin (NOB), a polymethoxyflavone phytochemical, is present abundantly in citrus peels and has been reported to possess anti-cancer activity. In this study, we investigated the anti-leukemic effects of NOB on cell differentiation and its underlying mechanisms in human chronic myeloid leukemia (CML) K562 cells. NOB (100 μM) treatment for 24 and 48 h significantly decreased viability of K562 cells to 54.4 ± 5.3% and 46.2 ± 9.9%, respectively. NOB (10–100 μM) significantly inhibited cell growth in K562 cells. Flow cytometry analysis and immunoblotting data showed that NOB (40 and 80 μM) could modulate the cell cycle regulators including p21, p27, and cyclin D2, and induce G1 phase arrest. NOB also increased the messenger RNA (mRNA) and protein expression of megakaryocytic differentiation markers, such as CD61, CD41, and CD42 as well as the formation of large cells with multi-lobulated nuclei in K562 cells. These results suggested that NOB facilitated K562 cells toward megakaryocytic differentiation. Furthermore, microarray analysis showed that expression of EGR1, a gene associated with promotion of megakaryocytic differentiation, was markedly elevated in NOB-treated K562 cells. The knockdown of EGR1 expression by small interference RNA (siRNA) could significantly attenuate NOB-mediated cell differentiation. We further elucidated that NOB induced EGR1 expression and CD61 expression through increases in MAPK/ERK phosphorylation in K562 cells. These results indicate that NOB promotes megakaryocytic differentiation through the MAPK/ERK pathway-dependent EGR1 expression in human CML cells. In addition, NOB when combined with imatinib could synergistically reduce the viability of K562 cells. Our findings suggest that NOB may serve as a beneficial anti-leukemic agent for differentiation therapy.
Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1
Authors: Hii Ling-Wei , Chung Felicia Fei-Lei , Mai Chun Wai , Yee Zong Yang , Chan Hong Hao , Raja Vijay Joseph , Dephoure Noah Elias , Pyne Nigel J. , Pyne Susan , Leong Chee-Onn
Published: April 2020

Cancer stem cells (CSCs) represent rare tumor cell populations capable of self-renewal, differentiation, and tumor initiation and are highly resistant to chemotherapy and radiotherapy. Thus, therapeutic approaches that can effectively target CSCs and tumor cells could be the key to efficient tumor treatment. In this study, we explored the function of SPHK1 in breast CSCs and non-CSCs. We showed that RNAi-mediated knockdown of SPHK1 inhibited cell proliferation and induced apoptosis in both breast CSCs and non-CSCs, while ectopic expression of SPHK1 enhanced breast CSC survival and mammosphere forming efficiency. We identified STAT1 and IFN signaling as key regulatory targets of SPHK1 and demonstrated that an important mechanism by which SPHK1 promotes cancer cell survival is through the suppression of STAT1. We further demonstrated that SPHK1 inhibitors, FTY720 and PF543, synergized with doxorubicin in targeting both breast CSCs and non-CSCs. In conclusion, we provide important evidence that SPHK1 is a key regulator of cell survival and proliferation in breast CSCs and non-CSCs and is an attractive target for the design of future therapies.
Development of Mucosal PNAd+ and MAdCAM-1+ Venules during Disease Course in Ulcerative Colitis
Authors: Roosenboom Britt , van Lochem Ellen G. , Meijer Jos , Smids Carolijn , Nierkens Stefan , Brand Eelco C. , van Erp Liselot W. , Kemperman Larissa G.J.M. , Groenen Marcel J.M. , Horjus Talabur Horje Carmen S. , Wahab Peter J.
Published: April 2020

PNAd and MAdCAM-1 addressins on venules are of importance in T-cell homing and potential therapeutic targets in ulcerative colitis (UC). Normally, PNAd+ high endothelial venules (HEVs) are only present in lymphoid organs, whereas small numbers of MAdCAM-1+ venules can be seen in non-lymphoid tissue. We aimed to study their presence in the intestinal mucosa of UC patients at diagnosis and during follow-up, and their correlation with disease activity. Colonic biopsy specimens of 378 UC patients were analyzed by immunohistochemistry for CD3, CD20, ERG, MECA-79 (PNAd) and MECA-376 (MAdCAM-1) and compared to healthy controls (HC). The proportion of PNAd+HEVs in UC at diagnosis was 4.9% (IQR 2.0%–8.3%), while none were detected in HC. During follow-up, PNAd+HEVs completely disappeared in remission (n = 93), whereas the proportion in active disease was similar to baseline (n = 285, p = 0.39). The proportion of MAdCAM-1+venules in UC at baseline was 5.8% (IQR 2.6–10.0). During follow-up, the proportion in remission was comparable to diagnosis, but upregulated (7.5% (IQR 4.4–10.9), p = 0.001) in active disease. In conclusion, PNAd+HEVs appear in UC during active inflammation which could thus serve as a marker for disease activity, whereas MAdCAM-1+venules remain present after inflammation is resolved and increase after subsequent flares, reflecting chronicity and potentially serving as a therapeutic target.
Matrix Mechanosensation in the Erythroid and Megakaryocytic Lineages
Authors: Ward Christina M. , Ravid Katya
Published: April 2020

The biomechanical properties of the bone marrow microenvironment emerge from a combination of interactions between various extracellular matrix (ECM) structural proteins and soluble factors. Matrix stiffness directs stem cell fate, and both bone marrow stromal and hematopoietic cells respond to biophysical cues. Within the bone marrow, the megakaryoblasts and erythroblasts are thought to originate from a common progenitor, giving rise to fully mature magakaryocytes (the platelet precursors) and erythrocytes. Erythroid and megakaryocytic progenitors sense and respond to the ECM through cell surface adhesion receptors such as integrins and mechanosensitive ion channels. While hematopoietic stem progenitor cells remain quiescent on stiffer ECM substrates, the maturation of the erythroid and megakaryocytic lineages occurs on softer ECM substrates. This review surveys the major matrix structural proteins that contribute to the overall biomechanical tone of the bone marrow, as well as key integrins and mechanosensitive ion channels identified as ECM sensors in context of megakaryocytosis or erythropoiesis.