bluuebunny/crossref_metadata_2025 huggingface dataset:
Establishment of 3D Neuro-Organoids Derived from Pig Embryonic Stem-Like Cells
Authors: Hwang Seon-Ung , Eun Kiyoung , Kim Mirae , Yoon Junchul David , Cai Lian , Choi Hyerin , Oh Dongjin , Lee Gabsang , Kim Hyunggee , Kim Eunhye , Hyun Sang-Hwan
Published: March 2021

Although the human brain would be an ideal model for studying human neuropathology, it is difficult to perform in vitro culture of human brain cells from genetically engineered healthy or diseased brain tissue. Therefore, a suitable model for studying the molecular mechanisms responsible for neurological diseases that can appropriately mimic the human brain is needed. Somatic cell nuclear transfer (SCNT) was performed using an established porcine Yucatan EGFP cell line and whole seeding was performed using SCNT blastocysts. Two Yucatan EGFP porcine embryonic stem-like cell (pESLC) lines were established. These pESLC lines were then used to establish an in vitro neuro-organoids. Aggregates were cultured in vitro until 61 or 102 days after neural induction, neural patterning, and neural expansion. The neuro-organoids were sampled at each step and the expression of the dopaminergic neuronal marker (TH) and mature neuronal marker (MAP2) was confirmed by reverse transcription-PCR. Expression of the neural stem cell marker (PAX6), neural precursor markers (S100 and SOX2), and early neural markers (MAP2 and Nestin) were confirmed by immunofluorescence staining. In conclusion, we successfully established neuro-organoids derived from pESLCs in vitro. This protocol can be used as a tool to develop in vitro models for drug development, patient-specific chemotherapy, and human central nervous system disease studies.
An Overview of the Molecular Mechanisms Contributing to Musculoskeletal Disorders in Chronic Liver Disease: Osteoporosis, Sarcopenia, and Osteoporotic Sarcopenia
Authors: Yang Young Joo , Kim Dong Joon
Published: March 2021

The prevalence of osteoporosis and sarcopenia is significantly higher in patients with liver disease than in those without liver disease and osteoporosis and sarcopenia negatively influence morbidity and mortality in liver disease, yet these musculoskeletal disorders are frequently overlooked in clinical practice for patients with chronic liver disease. The objective of this review is to provide a comprehensive understanding of the molecular mechanisms of musculoskeletal disorders accompanying the pathogenesis of liver disease. The increased bone resorption through the receptor activator of nuclear factor kappa (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) system and upregulation of inflammatory cytokines and decreased bone formation through increased bilirubin and sclerostin and lower insulin-like growth factor-1 are important mechanisms for osteoporosis in patients with liver disease. Sarcopenia is associated with insulin resistance and obesity in non-alcoholic fatty liver disease, whereas hyperammonemia, low amount of branched chain amino acids, and hypogonadism contributes to sarcopenia in liver cirrhosis. The bidirectional crosstalk between muscle and bone through myostatin, irisin, β-aminoisobutyric acid (BAIBA), osteocalcin, as well as the activation of the RANK and the Wnt/β-catenin pathways are associated with osteosarcopenia. The increased understandings for these musculoskeletal disorders would be contributes to the development of effective therapies targeting the pathophysiological mechanism involved.
Mechanisms by Which Probiotic Bacteria Attenuate the Risk of Hepatocellular Carcinoma
Authors: Thilakarathna Wasitha P.D. Wass , Rupasinghe H.P. Vasantha , Ridgway Neale D.
Published: March 2021

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second leading cause of cancer-related deaths worldwide. Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) are the major extrinsic risk factors of HCC development. Genetic background is pivotal in HCC pathogenesis, and both germline mutations and single nucleotide polymorphism (SNP) are intrinsic risk factors of HCC. These HCC risk factors predispose to hepatic injury and subsequent activation of fibrogenesis that progresses into cirrhosis and HCC. Probiotic bacteria can mitigate HCC risk by modulating host gut microbiota (GM) to promote growth of beneficial microbes and inhibit HCC-associated dysbiosis, thus preventing pathogen-associated molecular patterns (PAMPs)-mediated hepatic inflammation. Probiotics have antiviral activities against HBV and HCV infections, ameliorate obesity and risk of NAFLD/NASH, and their antioxidant, anti-proliferative, anti-angiogenic, and anti-metastatic effects can prevent the HCC pathogenesis. Probiotics also upregulate the expression of tumor suppressor genes and downregulate oncogene expression. Moreover, metabolites generated by probiotics through degradation of dietary phytochemicals may mitigate the risk of HCC development. These multiple anticancer mechanisms illustrate the potential of probiotics as an adjuvant strategy for HCC risk management and treatment.
Allele-Specific Knockout by CRISPR/Cas to Treat Autosomal Dominant Retinitis Pigmentosa Caused by the G56R Mutation in NR2E3
Authors: Diakatou Michalitsa , Dubois Gregor , Erkilic Nejla , Sanjurjo-Soriano Carla , Meunier Isabelle , Kalatzis Vasiliki
Published: March 2021

Retinitis pigmentosa (RP) is an inherited retinal dystrophy that causes progressive vision loss. The G56R mutation in NR2E3 is the second most common mutation causing autosomal dominant (ad) RP, a transcription factor that is essential for photoreceptor development and maintenance. The G56R variant is exclusively responsible for all cases of NR2E3-associated adRP. Currently, there is no treatment for NR2E3-related or, other, adRP, but genome editing holds promise. A pertinent approach would be to specifically knockout the dominant mutant allele, so that the wild type allele can perform unhindered. In this study, we developed a CRISPR/Cas strategy to specifically knockout the mutant G56R allele of NR2E3 and performed a proof-of-concept study in induced pluripotent stem cells (iPSCs) of an adRP patient. We demonstrate allele-specific knockout of the mutant G56R allele in the absence of off-target events. Furthermore, we validated this knockout strategy in an exogenous overexpression system. Accordingly, the mutant G56R-CRISPR protein was truncated and mis-localized to the cytosol in contrast to the (peri)nuclear localizations of wild type or G56R NR2E3 proteins. Finally, we show, for the first time, that G56R iPSCs, as well as G56R-CRISPR iPSCs, can differentiate into NR2E3-expressing retinal organoids. Overall, we demonstrate that G56R allele-specific knockout by CRISPR/Cas could be a clinically relevant approach to treat NR2E3-associated adRP.
Clinical Potential of Kinase Inhibitors in Combination with Immune Checkpoint Inhibitors for the Treatment of Solid Tumors
Authors: Ahn Ryuhjin , Ursini-Siegel Josie
Published: March 2021

Oncogenic kinases contribute to immunosuppression and modulate the tumor microenvironment in solid tumors. Increasing evidence supports the fundamental role of oncogenic kinase signaling networks in coordinating immunosuppressive tumor microenvironments. This has led to numerous studies examining the efficacy of kinase inhibitors in inducing anti-tumor immune responses by increasing tumor immunogenicity. Kinase inhibitors are the second most common FDA-approved group of drugs that are deployed for cancer treatment. With few exceptions, they inevitably lead to intrinsic and/or acquired resistance, particularly in patients with metastatic disease when used as a monotherapy. On the other hand, cancer immunotherapies, including immune checkpoint inhibitors, have revolutionized cancer treatment for malignancies such as melanoma and lung cancer. However, key hurdles remain to successfully incorporate such therapies in the treatment of other solid cancers. Here, we review the recent literature on oncogenic kinases that regulate tumor immunogenicity, immune suppression, and anti-tumor immunity. Furthermore, we discuss current efforts in clinical trials that combine kinase inhibitors and immune checkpoint inhibitors to treat breast cancer and other solid tumors.
The Amniotic Fluid Cell-Free Transcriptome Provides Novel Information about Fetal Development and Placental Cellular Dynamics
Authors: Park Hee Jin , Cho Hee Young , Cha Dong Hyun
Published: March 2021

The amniotic fluid (AF) is a complex biofluid that reflects fetal well-being during development. AF con be divided into two fractions, the supernatant and amniocytes. The supernatant contains cell-free components, including placenta-derived microparticles, protein, cell-free fetal DNA, and cell-free fetal RNA from the fetus. Cell-free mRNA (cfRNA) analysis holds a special position among high-throughput analyses, such as transcriptomics, proteomics, and metabolomics, owing to its ease of profiling. The AF cell-free transcriptome differs from the amniocyte transcriptome and alters with the progression of pregnancy and is often associated with the development of various organ systems including the fetal lung, skin, brain, pancreas, adrenal gland, gastrointestinal system, etc. The AF cell-free transcriptome is affected not only by normal physiologies, such as fetal sex, gestational age, and fetal maturity, but also by pathologic mechanisms such as maternal obesity, and genetic syndromes (Down, Edward, Turner, etc.), as well as pregnancy complications (preeclampsia, intrauterine growth restriction, preterm birth, etc.). cfRNA in the amniotic fluid originates from the placenta and fetal organs directly contacting the amniotic fluid as well as from the fetal plasma across the placenta. The AF transcriptome may reflect the fetal and placental development and therefore aid in the monitoring of normal and abnormal development.
Dispirooxindoles Based on 2-Selenoxo-Imidazolidin-4-Ones: Synthesis, Cytotoxicity and ROS Generation Ability
Authors: Novotortsev Vladimir K. , Kukushkin Maxim E. , Tafeenko Viktor A. , Skvortsov Dmitry A. , Kalinina Marina A. , Timoshenko Roman V. , Chmelyuk Nelly S. , Vasilyeva Liliya A. , Tarasevich Boris N. , Gorelkin Petr V. , Erofeev Alexander S. , Majouga Alexander G. , Zyk Nikolai V. , Beloglazkina Elena K.
Published: March 2021

A regio- and diastereoselective synthesis of two types of dispiro derivatives of 2-selenoxoimidazolidin-4-ones, differing in the position of the nitrogen atom in the central pyrrolidine ring of the spiro-fused system—namely, 2-selenoxodispiro[imidazolidine-4,3′-pyrrolidine-2′,3″-indoline]-2″,5-diones (5a-h) and 2-senenoxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-diones (6a-m)—were developed based on a 1,3-dipolar cycloaddition of azomethine ylides generated from isatin and sarcosine or formaldehyde and sarcosine to 5-arylidene or 5-indolidene-2-selenoxo-tetrahydro-4H-imidazole-4-ones. Selenium-containing dispiro indolinones generally exhibit cytotoxic activity near to the activity of the corresponding oxygen and sulfur-containing derivatives. Compounds 5b, 5c, and 5e demonstrated considerable in vitro cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) test (concentration of compounds that caused 50% death of cells (CC50) 7.6–8.7 μM) against the A549 cancer cell line with the VA13/A549 selectivity index 5.2–6.9; some compounds (5 and 6) increased the level of intracellular reactive oxygen species (ROS) in the experiment on A549 and PC3 cells using platinized carbon nanoelectrode. The tests for p53 activation for compounds 5 and 6 on the transcriptional reporter suggest that the investigated compounds can only have an indirect p53-dependent mechanism of action. For the compounds 5b, 6b, and 6l, the ROS generation may be one of the significant mechanisms of their cytotoxic action.
The Complex and Critical Role of Glycine 12 (G12) in Beta-Connexins of Human Skin
Authors: Bailey Rasheed A. , Beahm Derek L. , Skerrett I. Martha
Published: March 2021

Glycine is an amino acid with unique properties because its side chain is composed of a single hydrogen atom. It confers conformational flexibility to proteins and conserved glycines are often indicative of protein domains involving tight turns or bends. All six beta-type connexins expressed in human epidermis (Cx26, Cx30, Cx30.3, Cx31, Cx31.1 and Cx32) contain a glycine at position 12 (G12). G12 is located about halfway through the cytoplasmic amino terminus and substitutions alter connexin function in a variety of ways, in some cases altering protein interactions and leading to cell death. There is also evidence that alteration of G12 changes the structure of the amino terminus in connexin- and amino acid- specific ways. This review integrates structural, functional and physiological information about the role of G12 in connexins, focusing on beta-connexins expressed in human epidermis. The importance of G12 substitutions in these beta-connexins is revealed in two hereditary skin disorders, keratitis ichthyosis and erythrokeratodermia variabilis, both of which result from missense mutations affecting G12.
Immunological Properties of Atopic Dermatitis-Associated Alopecia Areata
Authors: Kageyama Reiko , Ito Taisuke , Hanai Shiho , Morishita Naomi , Nakazawa Shinsuke , Fujiyama Toshiharu , Honda Tetsuya , Tokura Yoshiki
Published: March 2021

Alopecia areata (AA) is regarded as a tissue-specific and cell-mediated autoimmune disorder. Regarding the cytokine balance, AA has been considered a type 1 inflammatory disease. On the other hand, AA often complicates atopic dermatitis (AD) and AD is regarded as type 2 inflammatory disease. However, the immunological aspects of AA in relation to AD are still poorly understood. Therefore, we aim to clarify the immunological properties of AD-associated AA. In this study, we performed comparative analysis of the expression of intracytoplasmic cytokines (IFN-γ, IL-4, and IL-13), chemokine receptors (CXCR3 and CCR4) in peripheral blood which were taken from healthy controls, non-atopic AA patients, AA patients with extrinsic AD, and AA patients with intrinsic AD by flowcytometric analysis. We also compared the scalp skin samples taken from AA patients with extrinsic AD before and after treatment with dupilumab. In non-atopic AA patients, the ratios of CD4+IFN-γ+ cells to CD4+IL-4+ cells and CD4+IFN-γ+ cells to CD4+IL-13+ cells were higher than those in AA patients with extrinsic AD. Meanwhile, the ratio of CD8+IFN-γ+ cells to CD8+IL-13+ cells was significantly higher in the non-atopic AA than in the healthy controls. In AA patients with extrinsic AD, the skin AA lesion showed dense infiltration of not only CXCR3+ cells but also CCR4+ cells around hair bulb before dupilumab treatment. However, after the treatment, the number of CXCR3+ cells had no remarkable change while the number of CCR4+ cells significantly decreased. These results indicate that the immunological condition of AA may be different between atopic and non-atopic patients and between extrinsic and intrinsic AD patients. Our study provides an important notion that type 2 immunity may participate in the development of AA in extrinsic AD patients. It may be considered that the immunological state of non-atopic AA is different from that of atopic AA.
Ca2+-ATPase Molecules as a Calcium-Sensitive Membrane-Endoskeleton of Sarcoplasmic Reticulum
Authors: Nakamura Jun , Maruyama Yuusuke , Tajima Genichi , Komeiji Yuto , Suwa Makiko , Sato Chikara
Published: March 2021

The Ca2+-transport ATPase of sarcoplasmic reticulum (SR) is an integral, transmembrane protein. It sequesters cytoplasmic calcium ions released from SR during muscle contraction, and causes muscle relaxation. Based on negative staining and transmission electron microscopy of SR vesicles isolated from rabbit skeletal muscle, we propose that the ATPase molecules might also be a calcium-sensitive membrane-endoskeleton. Under conditions when the ATPase molecules scarcely transport Ca2+, i.e., in the presence of ATP and ≤ 0.9 nM Ca2+, some of the ATPase particles on the SR vesicle surface gathered to form tetramers. The tetramers crystallized into a cylindrical helical array in some vesicles and probably resulted in the elongated protrusion that extended from some round SRs. As the Ca2+ concentration increased to 0.2 µM, i.e., under conditions when the transporter molecules fully carry out their activities, the ATPase crystal arrays disappeared, but the SR protrusions remained. In the absence of ATP, almost all of the SR vesicles were round and no crystal arrays were evident, independent of the calcium concentration. This suggests that ATP induced crystallization at low Ca2+ concentrations. From the observed morphological changes, the role of the proposed ATPase membrane-endoskeleton is discussed in the context of calcium regulation during muscle contraction.
Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer
Authors: Rebuzzi Sara Elena , Zullo Lodovica , Rossi Giovanni , Grassi Massimiliano , Murianni Veronica , Tagliamento Marco , Prelaj Arsela , Coco Simona , Longo Luca , Dal Bello Maria Giovanna , Alama Angela , Dellepiane Chiara , Bennicelli Elisa , Malapelle Umberto , Genova Carlo
Published: March 2021

In the scenario of systemic treatment for advanced non-small cell lung cancer (NSCLC) patients, one of the most relevant breakthroughs is represented by targeted therapies. Throughout the last years, inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-Ros oncogene 1 (ROS1), and V-raf murine sarcoma viral oncogene homolog B (BRAF) have been approved and are currently used in clinical practice. However, other promising molecular drivers are rapidly emerging as therapeutic targets. This review aims to cover the molecular alterations with a potential clinical impact in NSCLC, including amplifications or mutations of the mesenchymal–epithelial transition factor (MET), fusions of rearranged during transfection (RET), rearrangements of the neurotrophic tyrosine kinase (NTRK) genes, mutations of the Kirsten rat sarcoma viral oncogene (KRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), as well as amplifications or mutations of human epidermal growth factor receptor 2 (HER2). Additionally, we summarized the current status of targeted agents under investigation for such alterations. This revision of the current literature on emerging molecular targets is needed as the evolving knowledge on novel actionable oncogenic drivers and targeted agents is expected to increase the proportion of patients who will benefit from tailored therapeutic approaches.
Physcomitrium patens: A Single Model to Study Oriented Cell Divisions in 1D to 3D Patterning
Authors: de Keijzer Jeroen , Freire Rios Alejandra , Willemsen Viola
Published: March 2021

Development in multicellular organisms relies on cell proliferation and specialization. In plants, both these processes critically depend on the spatial organization of cells within a tissue. Owing to an absence of significant cellular migration, the relative position of plant cells is virtually made permanent at the moment of division. Therefore, in numerous plant developmental contexts, the (divergent) developmental trajectories of daughter cells are dependent on division plane positioning in the parental cell. Prior to and throughout division, specific cellular processes inform, establish and execute division plane control. For studying these facets of division plane control, the moss Physcomitrium (Physcomitrella) patens has emerged as a suitable model system. Developmental progression in this organism starts out simple and transitions towards a body plan with a three-dimensional structure. The transition is accompanied by a series of divisions where cell fate transitions and division plane positioning go hand in hand. These divisions are experimentally highly tractable and accessible. In this review, we will highlight recently uncovered mechanisms, including polarity protein complexes and cytoskeletal structures, and transcriptional regulators, that are required for 1D to 3D body plan formation.
Multifunctional Role of Chitosan Edible Coatings on Antioxidant Systems in Fruit Crops: A Review
Authors: Adiletta Giuseppina , Di Matteo Marisa , Petriccione Milena
Published: March 2021

Chitosan-based edible coatings represent an eco-friendly and biologically safe preservative tool to reduce qualitative decay of fresh and ready-to-eat fruits during post-harvest life due to their lack of toxicity, biodegradability, film-forming properties, and antimicrobial actions. Chitosan-based coatings modulate or control oxidative stress maintaining in different manner the appropriate balance of reactive oxygen species (ROS) in fruit cells, by the interplay of pathways and enzymes involved in ROS production and the scavenging mechanisms which essentially constitute the basic ROS cycle. This review is carried out with the aim to provide comprehensive and updated over-view of the state of the art related to the effects of chitosan-based edible coatings on anti-oxidant systems, enzymatic and non-enzymatic, evaluating the induced oxidative damages during storage in whole and ready-to-eat fruits. All these aspects are broadly reviewed in this review, with particular emphasis on the literature published during the last five years.
The CXCL2/IL8/CXCR2 Pathway Is Relevant for Brain Tumor Malignancy and Endothelial Cell Function
Authors: Urbantat Ruth , Blank Anne , Kremenetskaia Irina , Vajkoczy Peter , Acker Güliz , Brandenburg Susan
Published: March 2021

We aimed to evaluate the angiogenic capacity of CXCL2 and IL8 affecting human endothelial cells to clarify their potential role in glioblastoma (GBM) angiogenesis. Human GBM samples and controls were stained for proangiogenic factors. Survival curves and molecule correlations were obtained from the TCGA (The Cancer Genome Atlas) database. Moreover, proliferative, migratory and angiogenic activity of peripheral (HUVEC) and brain specific (HBMEC) primary human endothelial cells were investigated including blockage of CXCR2 signaling with SB225502. Gene expression analyses of angiogenic molecules from endothelial cells were performed. Overexpression of VEGF and CXCL2 was observed in GBM patients and associated with a survival disadvantage. Molecules of the VEGF pathway correlated but no relation for CXCR1/2 and CXCL2/IL8 was found. Interestingly, receptors of endothelial cells were not induced by addition of proangiogenic factors in vitro. Proliferation and migration of HUVEC were increased by VEGF, CXCL2 as well as IL8. Their sprouting was enhanced through VEGF and CXCL2, while IL8 showed no effect. In contrast, brain endothelial cells reacted to all proangiogenic molecules. Additionally, treatment with a CXCR2 antagonist led to reduced chemokinesis and sprouting of endothelial cells. We demonstrate the impact of CXCR2 signaling on endothelial cells supporting an impact of this pathway in angiogenesis of glioblastoma.
Impact of Different Physical Exercises on the Expression of Autophagy Markers in Mice
Authors: Pinto Ana P. , da Rocha Alisson L. , Marafon Bruno B. , Rovina Rafael L. , Muñoz Vitor R. , da Silva Lilian E. C. M. , Pauli José R. , de Moura Leandro P. , Cintra Dennys E. , Ropelle Eduardo R. , da Silva Adelino S. R.
Published: March 2021

Although physical exercise-induced autophagy activation has been considered a therapeutic target to enhance tissue health and extend lifespan, the effects of different exercise models on autophagy in specific metabolic tissues are not completely understood. This descriptive investigation compared the acute effects of endurance (END), exhaustive (ET), strength (ST), and concurrent (CC) physical exercise protocols on markers of autophagy, genes, and proteins in the gastrocnemius muscle, heart, and liver of mice. The animals were euthanized immediately (0 h) and six hours (6 h) after the acute exercise for the measurement of glycogen levels, mRNA expression of Prkaa1, Ppargc1a, Mtor, Ulk1, Becn1, Atg5, Map1lc3b, Sqstm1, and protein levels of Beclin 1 and ATG5. The markers of autophagy were measured by quantifying the protein levels of LC3II and Sqstm1/p62 in response to three consecutive days of intraperitoneal injections of colchicine. In summary, for gastrocnemius muscle samples, the main alterations in mRNA expressions were observed after 6 h and for the ST group, and the markers of autophagy for the CC group were increased (i.e., LC3II and Sqstm1/p62). In the heart, the Beclin 1 and ATG5 levels were downregulated for the ET group. Regarding the markers of autophagy, the Sqstm1/p62 in the heart tissue was upregulated for the END and ST groups, highlighting the beneficial effects of these exercise models. The liver protein levels of ATG5 were downregulated for the ET group. After the colchicine treatment, the liver protein levels of Sqstm1/p62 were decreased for the END and ET groups compared to the CT, ST, and CC groups. These results could be related to diabetes and obesity development or liver dysfunction improvement, demanding further investigations.
Manganese Ferrite Nanoparticles Enhance the Sensitivity of Hepa1-6 Hepatocellular Carcinoma to Radiation by Remodeling Tumor Microenvironments
Authors: Shin Sung-Won , Yang Kyungmi , Lee Miso , Moon Jiyoung , Son Arang , Kim Yeeun , Choi Suha , Kim Do-hyung , Choi Changhoon , Lee Nohyun , Park Hee Chul
Published: March 2021

We evaluated the effect of manganese ferrite nanoparticles (MFN) on radiosensitization and immunologic responses using the murine hepatoma cell line Hepa1-6 and the syngeneic mouse model. The clonogenic survival of Hepa1-6 cells was increased by hypoxia, while being restricted by ionizing radiation (IR) and/or MFN. Although MFN suppressed HIF-1α under hypoxia, the combination of IR and MFN enhanced apoptosis and DNA damage in Hepa1-6 cells. In the Hepa1-6 syngeneic mouse model, the combination of IR and MFN notably limited the tumor growth compared to the single treatment with IR or MFN, and also triggered more frequent apoptosis in tumor tissues than that observed under other conditions. Increased expression of PD-L1 after IR was not observed with MFN alone or the combination of IR and MFN in vitro and in vivo, and the percentage of tumor-infiltrating T cells and cytotoxic T cells increased with MFN, regardless of IR, in the Hepa1-6 syngeneic mouse model, while IR alone led to T cell depletion. MFN might have the potential to overcome radioresistance by alleviating hypoxia and strengthening antitumor immunity in the tumor microenvironment.
An IT Service Management Literature Review: Challenges, Benefits, Opportunities and Implementation Practices
Authors: Serrano João , Faustino João , Adriano Daniel , Pereira Rúben , da Silva Miguel
Published: March 2021

Information technology (IT) service management is considered a collection of frameworks that support organizations managing services. The implementation of these kinds of frameworks is constantly increasing in the IT service provider domain. The main objective is to define and manage IT services through its life cycle. However, from observing the literature, scarcely any research exists describing the main concepts of ITSM. Many organizations still struggle in several contexts in this domain, mainly during implementation. This research aims to develop a reference study detailing the main concepts related with ITSM. Thus, a systematic literature review is performed. In total, 47 articles were selected from top journals and conferences. The benefits, challenges, opportunities, and practices for ITSM implementation were extracted, critically analysed, and then discussed.
Arginase 1 (Arg1) as an Up-Regulated Gene in COVID-19 Patients: A Promising Marker in COVID-19 Immunopathy
Authors: Derakhshani Afshin , Hemmat Nima , Asadzadeh Zahra , Ghaseminia Moslem , Shadbad Mahdi Abdoli , Jadideslam Golamreza , Silvestris Nicola , Racanelli Vito , Baradaran Behzad
Published: March 2021

Background: The coronavirus disease 2019 (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic. It is well-established that SARS-CoV-2 infection can lead to dysregulated immune responses. Arginase-1 (Arg1), which has a pivotal role in immune cells, can be expressed in most of the myeloid cells, e.g., neutrophils and macrophages. Arg1 has been associated with the suppression of antiviral immune responses. Methods: Whole blood was taken from 21 COVID-19 patients and 21 healthy individuals, and after RNA extraction and complementary DNA (cDNA) synthesis, gene expression of Arg1 was measured by real-time PCR. Results: The qPCR results showed that the expression of Arg1 was significantly increased in COVID-19 patients compared to healthy individuals (p < 0.01). The relative expression analysis demonstrated there were approximately 2.3 times increased Arg1 expression in the whole blood of COVID-19 patients. Furthermore, the receiver operating characteristic (ROC) analysis showed a considerable diagnostic value for Arg1 expression in COVID-19 (p = 0.0002 and AUC = 0.8401). Conclusion: Arg1 might be a promising marker in the pathogenesis of the disease, and it could be a valuable diagnostic tool.
SARS-CoV-2 Infection: Modulator of Pulmonary Embolism Paradigm
Authors: Akhter Mohammad Suhail , Hamali Hassan A. , Mobarki Abdullah A. , Rashid Hina , Oldenburg Johannes , Biswas Arijit
Published: March 2021

Pulmonary embolism (PE) is a life-threatening complication arising from venous thromboembolism with a difficult diagnosis and treatment and is often associated with increased mortality and morbidity. PE had a significantly low incidence prior to the COVID-19 epidemic. This condition saw a sharp surge during the COVID-19 pandemic, indicating an evident viral influence on PE’s pathophysiology in COVID-19 patients. The hypercoagulable state induced by the viral load seems to be the major contributor, and the classical causative factors seem to play a lesser role. PE in COVID-19 infection has become a mammoth challenge since the diagnosis is quite challenging due to overlapping symptoms, lack of prior-known predisposing risk factors, limited resources, and viral transmittance risk. Numerous factors arising out of the viral load or treatment lead to an increased risk for PE in COVID-19 patients, besides the fact that certain unknown risk factors may also contribute to the incidence of PE in COVID-19 patients. The management of PE in COVID-19 infection mainly comprises thromboprophylaxis and anticoagulant therapy with mechanical ventilation, depending on the risk stratification of the patient, with a post-COVID-19 management that prevents recurrent PE and complications. This review aims to discuss various aspects of COVID-19-infection-associated PE and major differential aspects from non-COVID-19 PE.
Public Interest in Knee Pain and Knee Replacement during the SARS-CoV-2 Pandemic in Western Europe
Authors: Kienzle Arne , Biedermann Lara , Babeyko Evgeniya , Kirschbaum Stephanie , Duda Georg , Perka Carsten , Gwinner Clemens
Published: March 2021

Due to the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic, a large number of elective knee replacement procedures had to be postponed in both early and late 2020 in most western countries including Germany and the UK. It is unknown how public interest and demand for total knee arthroplasties was affected. Public interest in knee pain, knee osteoarthritis and knee arthroplasty in Germany and the UK was investigated using Google Trend Analysis. In addition, we monitored for changes in patient composition in our outpatient department. As of early March in Germany and of late March in the UK, until the lockdown measures, a 50 to 60% decrease in relative search frequency was observed in all categories investigated compared to the beginning of the year. While public interest for knee pain rapidly recovered, decreased interest for knee osteoarthritis and replacement lasted until the easing of measures. Shortly prior to and during the first lockdown mean search frequency for knee replacement was significantly decreased from 39.7% and 36.6 to 26.9% in Germany and from 47.7% and 50.9 to 23.7% in the UK (Germany: p = 0.022 prior to lockdown, p < 0.001 during lockdown; UK: p < 0.0001 prior to and during lockdown). In contrast, mean search frequencies did not differ significantly from each other for any of the investigated time frames during the second half of 2020 in both countries. Similarly, during the first lockdown, the proportion of patients presenting themselves to receive primary knee arthroplasty compared to patients that had already undergone knee replacement declined markedly from 64.7% to 46.9%. In contrast, patient composition changed only marginally during the lockdown measures in late 2020 in both Germany and the UK. We observed a high level of public interest in knee arthroplasty despite the ongoing pandemic. The absence of a lasting decline in interest in primary knee arthroplasty suggests that sufficient symptom reduction cannot be achieved without surgical care for a substantial number of patients.
Diagnosis of Pancreatic Solid Lesions, Subepithelial Lesions, and Lymph Nodes Using Endoscopic Ultrasound
Authors: Fujita Akashi , Ryozawa Shomei , Mizuide Masafumi , Tanisaka Yuki , Ogawa Tomoya , Suzuki Masahiro , Katsuda Hiromune , Saito Yoichi , Tashima Tomoaki , Miyaguchi Kazuya , Arai Eiichi , Kawasaki Tomonori , Mashimo Yumi
Published: March 2021

Currently, endoscopic ultrasound (EUS) has become widely accepted and has considerable advantages over computed tomography (CT) and other imaging modalities, given that it enables echostructure assessment in lesions with <1 cm diameter and permits high resolution imaging. EUS-guided tissue acquisition (EUS-TA) provides consistent results under ultrasound guidance and has been considered more effective compared to CT- or ultrasound-guided lesion biopsy. Moreover, complication rates, including pancreatitis and bleeding, have been extremely low, with <1% morbidity and mortality rates, thereby suggesting the exceptional overall safety of EUS-TA. The aggressive use of EUS for various lesions has been key in facilitating early diagnosis and therapy. This review summarizes the diagnostic ability of EUS for pancreatic solid lesions, subepithelial lesions, and lymph nodes where it is mainly used. EUS has played an important role in diagnosing these lesions and planning treatment strategies. Future developments in EUS imaging technology, such as producing images close to histopathological findings, are expected to further improve its diagnostic ability. Moreover, tissue acquisition via EUS is expected to be used for precision medicine, which facilitates the selection of an appropriate therapeutic agent by increasing the amount of tissue collected and improving genetic analysis.
Lung Ultrasound to Phenotype Chronic Lung Allograft Dysfunction in Lung Transplant Recipients. A Prospective Observational Study
Authors: Davidsen Jesper Rømhild , Laursen Christian B. , Højlund Mikkel , Lund Thomas Kromann , Jeschke Klaus Nielsen , Iversen Martin , Kalhauge Anna , Bendstrup Elisabeth , Carlsen Jørn , Perch Michael , Henriksen Daniel Pilsgaard , Schultz Hans Henrik Lawaetz
Published: March 2021

Background: Bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) are two distinct phenotypes of chronic lung allograft dysfunction (CLAD) in lung transplant (LTx) recipients. Contrary to BOS, RAS can radiologically present with a pleuroparenchymal fibroelastosis (PPFE) pattern. This study investigates lung ultrasound (LUS) to identify potential surrogate markers of PPFE in order to distinguish CLAD phenotype RAS from BOS. Methods: A prospective cohort study performed at a National Lung Transplantation Center during June 2016 to December 2017. Patients were examined with LUS and high-resolution computed tomography of the thorax (HRCT). Results: Twenty-five CLAD patients (72% males, median age of 54 years) were included, corresponding to 19/6 BOS/RAS patients. LUS-identified pleural thickening was more pronounced in RAS vs. BOS patients (5.6 vs. 2.9 mm) compatible with PPFE on HRCT. LUS-identified pleural thickening as an indicator of PPFE in RAS patients’ upper lobes showed a sensitivity of 100% (95% CI; 54–100%), specificity of 100% (95% CI; 82–100%), PPV of 100% (95% CI; 54–100%), and NPV of 100% (95% CI; 82–100%). Conclusion: Apical pleural thickening detected by LUS and compatible with PPFE on HRCT separates RAS from BOS in patients with CLAD. We propose LUS as a supplementary tool for initial CLAD phenotyping.
Association of Neutrophil–Lymphocyte and Platelet–Lymphocyte Ratio with Adverse Events in Endovascular Repair for Abdominal Aortic Aneurysm
Authors: Ntalouka Maria P. , Nana Petroula , Kouvelos George N. , Stamoulis Konstantinos , Spanos Konstantinos , Giannoukas Athanasios , Matsagkas Miltiadis , Arnaoutoglou Eleni
Published: March 2021

The association of chronic inflammatory markers with the clinical outcome after endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA) was investigated. We included 230 patients, treated electively with EVAR. The values of neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) were measured pre- and postoperatively. Any major adverse cardiovascular event (MACE) and acute kidney injury (AKI) were recorded. Adverse events occurred in 12 patients (5.2%). Seven patients suffered from MACE and five from AKI. Median NLR and PLR values were significantly increased after the procedure (NLR: from 3.34 to 8.64, p < 0.001 and PLR: from 11.37 to 17.21, p < 0.001). None of the patients or procedure characteristics were associated with the occurrence of either a MACE or AKI. Receiver operating characteristic curve analysis showed that postoperative NLR and PLR were strongly associated with AKI. A threshold postoperative NLR value of 9.9 was associated with the occurrence of AKI, with a sensitivity of 80% and specificity of 81%. A threshold postoperative PLR value of 22.8 was associated with the occurrence of AKI, with a sensitivity of 80% and specificity of 83%. Postoperative NLR and PLR have been associated with the occurrence of AKI after EVAR for AAA.
Overview of Neo-Vascular Lesions after Delivery or Miscarriage
Authors: Shiina Yuji
Published: March 2021

The concept of intrauterine neo-vascular lesions after pregnancy, initially called placental polyps, has changed gradually. Now, based on diagnostic imaging, such lesions are defined as retained products of conception (RPOC) with vascularization. The lesions appear after delivery or miscarriage, and they are accompanied by frequent abundant vascularization in the myometrium attached to the remnant. Many of these vascular lesions have been reported to resolve spontaneously within a few months. Acquired arteriovenous malformations (AVMs) must be considered in the differential diagnosis of RPOC with vascularization. AVMs are errors of morphogenesis. The lesions start to be constructed at the time of placenta formation. These lesions do not show spontaneous regression. Although these two lesions are recognized as neo-vascular lesions, neo-vascular lesions on imaging may represent conditions other than these two lesions (e.g., peritrophoblastic flow, uterine artery pseudoaneurysm, and villous-derived malignancies). Detecting vasculature at the placenta–myometrium interface and classifying vascular diseases according to hemodynamics in the remnant would facilitate the development of specific treatments.
Prediction of Neurologically Intact Survival in Cardiac Arrest Patients without Pre-Hospital Return of Spontaneous Circulation: Machine Learning Approach
Authors: Seo Dong-Woo , Yi Hahn , Bae Hyun-Jin , Kim Youn-Jung , Sohn Chang-Hwan , Ahn Shin , Lim Kyoung-Soo , Kim Namkug , Kim Won-Young
Published: March 2021

Current multimodal approaches for the prognostication of out-of-hospital cardiac arrest (OHCA) are based mainly on the prediction of poor neurological outcomes; however, it is challenging to identify patients expected to have a favorable outcome, especially before the return of spontaneous circulation (ROSC). We developed and validated a machine learning-based system to predict good outcome in OHCA patients before ROSC. This prospective, multicenter, registry-based study analyzed non-traumatic OHCA data collected between October 2015 and June 2017. We used information available before ROSC as predictor variables, and the primary outcome was neurologically intact survival at discharge, defined as cerebral performance category 1 or 2. The developed models’ robustness were evaluated and compared with various score metrics to confirm their performance. The model using a voting classifier had the best performance in predicting good neurological outcome (area under the curve = 0.926). We confirmed that the six top-weighted variables predicting neurological outcomes, such as several duration variables after the instant of OHCA and several electrocardiogram variables in the voting classifier model, showed significant differences between the two neurological outcome groups. These findings demonstrate the potential utility of a machine learning model to predict good neurological outcome of OHCA patients before ROSC.
Treatment Strategy in Human Ocular Toxoplasmosis: Why Antibiotics Have Failed
Authors: Garweg Justus G. , Pleyer Uwe
Published: March 2021

Background: There is currently no clear evidence of the effectiveness of antibiotic therapy in acute ocular toxoplasmosis (OT), but its effect as a secondary prophylaxis is undisputed. The majority of uveitis specialists advocate treatment. This meta-analytic review aims to critically analyze determinants of treatment success and to update current treatment strategies for OT in order to explain this discrepancy. Methods: A systematic literature search was performed in NCBI/PubMed, Clinical Trials, Google Scholar and ScienceDirect to retrieve pro- and retrospective studies using the key terms “ocular toxoplasmosis” or “retinochoroiditis” and “immunocompetent” and “treatment” or “therapy” and “human.” Of these, larger case series and prospective clinical studies and cross references identified from meta-analyses were selected by a manual search, and primary and secondary outcome parameters were extracted. Results: Ten case series and clinical trials reported success parameters for treatment outcomes, and four additional for recurrence prophylaxis. Five treatment studies were randomized clinical trials, three comparative and two noncomparative case series. Though several outcome parameters were reported, five of them defined time to healing, four visual gain and one lesion size as primary and secondary outcome parameters, recurrence rate as a secondary outcome parameter was reported once. No conclusive evidence was found for an antibiotic treatment effect. Four prophylaxis studies addressed the prevention of recurrences after treatment. The primary outcome in all studies was the effect of treatment and prophylaxis on recurrences, and all four found a significant effect on the risk of and time to recurrences. Conclusions: Antibiotic treatment of OT aims at controlling parasite proliferation. The absence of an effect on visual acuity and time to healing is thus not surprising. The fact that time to and number of recurrences respond to recurrence of prophylaxis proves the antibiotic effect on parasite activity.
Swept Source Optical Coherence Tomography Analysis of the Selected Eye’s Anterior Segment Parameters
Authors: Dembski Michał , Nowińska Anna , Ulfik-Dembska Klaudia , Wylęgała Edward
Published: March 2021

Background: The present study determined the mean reference values of the anterior segment parameters of the selected eye using swept source optical coherence tomography (SS-OCT) in healthy Caucasian participants. Methods: A total of 166 volunteers (age 54–79 years), women (n = 92) and men (n = 74), were analyzed. One eye of each subject was randomly selected for anterior segment imaging. The anterior segment of the eye was scanned with CASIA2. The analyzed anterior segment parameters were divided into three groups, namely parameters of the cornea, lens, and angle. Results: The OCT (e.g., Ks, Kf, pKf, pKs, and central corneal thickness) and Fourier parameters of the cornea were significantly different between females and males. The iridocorneal angle was the smallest in the upper quadrant for all distance from the apex of the angle (250, 500, and 750 µm). Conclusions: Therefore, SS-OCT enables the analysis of parameters of the cornea, anterior chamber, lens, and iridocorneal angle, highlighting its clinical utility. Sex-specific differences in the analyzed parameters should be taken into account during the diagnosis of corneal diseases. The configuration of the filtration angle is an important marker during glaucoma diagnosis and drainage implant surgery. Measurements with CASIA 2is characterized by very good repeatability.
The Good, the Bad, and the Clever: Faking Ability as a Socio-Emotional Ability?
Authors: Geiger Mattis , Bärwaldt Romy , Wilhelm Oliver
Published: March 2021

Socio-emotional abilities have been proposed as an extension to models of intelligence, but earlier measurement approaches have either not fulfilled criteria of ability measurement or have covered only predominantly receptive abilities. We argue that faking ability—the ability to adjust responses on questionnaires to present oneself in a desired manner—is a socio-emotional ability that can broaden our understanding of these abilities and intelligence in general. To test this theory, we developed new instruments to measure the ability to fake bad (malingering) and administered them jointly with established tests of faking good ability in a general sample of n = 134. Participants also completed multiple tests of emotion perception along with tests of emotion expression posing, pain expression regulation, and working memory capacity. We found that individual differences in faking ability tests are best explained by a general factor that had a large correlation with receptive socio-emotional abilities and had a zero to medium-sized correlation with different productive socio-emotional abilities. All correlations were still small after controlling these effects for shared variance with general mental ability as indicated by tests of working memory capacity. We conclude that faking ability is indeed correlated meaningfully with other socio-emotional abilities and discuss the implications for intelligence research and applied ability assessment.
How Multidimensional Is Emotional Intelligence? Bifactor Modeling of Global and Broad Emotional Abilities of the Geneva Emotional Competence Test
Authors: Simonet Daniel V. , Miller Katherine E. , Askew Kevin L. , Sumner Kenneth E. , Mortillaro Marcello , Schlegel Katja
Published: March 2021

Drawing upon multidimensional theories of intelligence, the current paper evaluates if the Geneva Emotional Competence Test (GECo) fits within a higher-order intelligence space and if emotional intelligence (EI) branches predict distinct criteria related to adjustment and motivation. Using a combination of classical and S-1 bifactor models, we find that (a) a first-order oblique and bifactor model provide excellent and comparably fitting representation of an EI structure with self-regulatory skills operating independent of general ability, (b) residualized EI abilities uniquely predict criteria over general cognitive ability as referenced by fluid intelligence, and (c) emotion recognition and regulation incrementally predict grade point average (GPA) and affective engagement in opposing directions, after controlling for fluid general ability and the Big Five personality traits. Results are qualified by psychometric analyses suggesting only emotion regulation has enough determinacy and reliable variance beyond a general ability factor to be treated as a manifest score in analyses and interpretation. Findings call for renewed, albeit tempered, research on EI as a multidimensional intelligence and highlight the need for refined assessment of emotional perception, understanding, and management to allow focused analyses of different EI abilities.