bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a Chitooligosaccharide Mechanism against Bacterial Leaf Blight on Rice by In Vitro and In Silico Studies
Authors: Siriwong Supatcharee , Thepbandit Wannaporn , Hoang Nguyen Huy , Papathoti Narendra Kumar , Teeranitayatarn Karsidete , Saardngen Tippawun , Thumanu Kanjana , Bhavaniramya Sundaresan , Baskaralingam Vaseeharan , Le Thanh Toan , Phansak Piyaporn , Buensanteai Natthiya
Published: July 2021

This study focuses on a commercial plant elicitor based on chitooligosaccharides (BIG®), which aids in rice plant growth and disease resistance to bacterial leaf blight (BLB). When the pathogen (Xoo) vigorously attacks rice that has suffered yield losses, it can cause damage in up to 20% of the plant. Furthermore, Xoo is a seed-borne pathogen that can survive in rice seeds for an extended period. In this study, when rice seeds were soaked and sprayed with BIG®, there was a significant increase in shoot and root length, as well as plant biomass. Furthermore, BIG®-treated rice plants showed a significant reduction in BLB severity of more than 33%. Synchrotron radiation-based Fourier transform infrared (SR-FTIR) analysis was used to characterize BIG®’s mechanism in the chemical structure of rice leaves. The SR-FTIR results at 1650, 1735, and 1114 cm−1 indicated changes in biochemical components such as pectins, lignins, proteins, and celluloses. These findings demonstrated that commercial BIG® not only increased rice growth but also induced resistance to BLB. The drug’s target enzyme, Xoo 1075 from Xanthomonas oryzae (PDB ID: 5CY8), was analyzed for its interactions with polymer ingredients, specifically chitooligosaccharides, to gain molecular insights down to the atomic level. The results are intriguing, with a strong binding of the chitooligosaccharide polymer with the drug target, revealing 10 hydrogen bonds between the protein and polymer. Overall, the computational analysis supported the experimentally demonstrated strong binding of chitooligosaccharides to the drug target.
Targeting the Highly Expressed microRNA miR-146b with CRISPR/Cas9n Gene Editing System in Thyroid Cancer
Authors: Santa-Inez Daniel Casartelli de , Fuziwara Cesar Seigi , Saito Kelly Cristina , Kimura Edna Teruko
Published: July 2021

Thyroid cancer is the most common endocrine malignancy, and the characterization of the genetic alterations in coding-genes that drive thyroid cancer are well consolidated in MAPK signaling. In the context of non-coding RNAs, microRNAs (miRNAs) are small non-coding RNAs that, when deregulated, cooperate to promote tumorigenesis by targeting mRNAs, many of which are proto-oncogenes and tumor suppressors. In thyroid cancer, miR-146b-5p is the most overexpressed miRNA associated with tumor aggressiveness and progression, while the antisense blocking of miR-146b-5p results in anti-tumoral effect. Therefore, inactivating miR-146b has been considered as a promising strategy in thyroid cancer therapy. Here, we applied the CRISPR/Cas9n editing system to target the MIR146B gene in an aggressive anaplastic thyroid cancer (ATC) cell line. For that, we designed two single-guide RNAs cloned into plasmids to direct Cas9 nickase (Cas9n) to the genomic region of the pre-mir-146b structure to target miR-146b-5p and miR-146b-3p sequences. In this plasmidial strategy, we cotransfected pSp-Cas9n-miR-146b-GuideA-puromycin and pSp-Cas9n-miR-146b-GuideB-GFP plasmids in KTC2 cells and selected the puromycin resistant + GFP positive clones (KTC2-Cl). As a result, we observed that the ATC cell line KTC2-Cl1 showed a 60% decrease in the expression of miR-146b-5p compared to the control, also showing reduced cell viability, migration, colony formation, and blockage of tumor development in immunocompromised mice. The analysis of the MIR146B edited sequence shows a 5 nt deletion in the miR-146b-5p region and a 1 nt deletion in the miR-146b-3p region in KTC2-Cl1. Thus, we developed an effective CRISPR/Cas9n system to edit the MIR146B miRNA gene and reduce miR-146b-5p expression which constitutes a potential molecular tool for the investigation of miRNAs function in thyroid cancer.
Risk Factors for Retinal Ganglion Cell Distress in Glaucoma and Neuroprotective Potential Intervention
Authors: Vernazza Stefania , Oddone Francesco , Tirendi Sara , Bassi Anna Maria
Published: July 2021

Retinal ganglion cells (RGCs) are a population of neurons of the central nervous system (CNS) extending with their soma to the inner retina and with their axons to the optic nerve. Glaucoma represents a group of neurodegenerative diseases where the slow progressive death of RGCs results in a permanent loss of vision. To date, although Intra Ocular Pressure (IOP) is considered the main therapeutic target, the precise mechanisms by which RGCs die in glaucoma have not yet been clarified. In fact, Primary Open Angle Glaucoma (POAG), which is the most common glaucoma form, also occurs without elevated IOP. This present review provides a summary of some pathological conditions, i.e., axonal transport blockade, glutamate excitotoxicity and changes in pro-inflammatory cytokines along the RGC projection, all involved in the glaucoma cascade. Moreover, neuro-protective therapeutic approaches, which aim to improve RGC degeneration, have also been taken into consideration.
Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes
Authors: Lewicky Jordan D. , Fraleigh Nya L. , Martel Alexandrine L. , Nguyen Thi M.-D. , Schiller Peter W. , Mousavifar Leila , Roy René , Le Anh Dzung , Funk Douglas , Le Hoang-Thanh
Published: July 2021

Peptide therapeutics offer numerous advantages in the treatment of diseases and disorders of the central nervous system (CNS). However, they are not without limitations, especially in terms of their pharmacokinetics where their metabolic lability and low blood–brain barrier penetration hinder their application. Targeted nanoparticle delivery systems are being tapped for their ability to improve the delivery of therapeutics into the brain non-invasively. We have developed a family of mannosylated glycoliposome delivery systems for targeted drug delivery applications. Herein, we demonstrate via in vivo distribution studies the potential of these glycoliposomes to improve the utility of CNS active therapeutics using dynantin, a potent and selective dynorphin peptide analogue antagonist of the kappa opioid receptor (KOR). Glycoliposomal entrapment protected dynantin against known rapid metabolic degradation and ultimately improved brain levels of the peptide by approximately 3–3.5-fold. Moreover, we linked this improved brain delivery with improved KOR antagonist activity by way of an approximately 30–40% positive modulation of striatal dopamine levels 20 min after intranasal administration. Overall, the results clearly highlight the potential of our glycoliposomes as a targeted delivery system for therapeutic agents of the CNS.
Structure-Activity Relationships of the Imidazolium Compounds as Antibacterials of Staphylococcus aureus and Pseudomonas aeruginosa
Authors: Pałkowski Łukasz , Karolak Maciej , Błaszczyński Jerzy , Krysiński Jerzy , Słowiński Roman
Published: July 2021

This paper presents the results of structure–activity relationship (SAR) studies of 140 3,3’-(α,ω-dioxaalkan)bis(1-alkylimidazolium) chlorides. In the SAR analysis, the dominance-based rough set approach (DRSA) was used. For analyzed compounds, minimum inhibitory concentration (MIC) against strains of Staphylococcus aureus and Pseudomonas aeruginosa was determined. In order to perform the SAR analysis, a tabular information system was formed, in which tested compounds were described by means of condition attributes, characterizing the structure (substructure parameters and molecular descriptors) and their surface properties, and a decision attribute, classifying compounds with respect to values of MIC. DRSA allows to induce decision rules from data describing the compounds in terms of condition and decision attributes, and to rank condition attributes with respect to relevance using a Bayesian confirmation measure. Decision rules present the most important relationships between structure and surface properties of the compounds on one hand, and their antibacterial activity on the other hand. They also indicate directions of synthesizing more efficient antibacterial compounds. Moreover, the analysis showed differences in the application of various parameters for Gram-positive and Gram-negative strains, respectively.
SERR Spectroelectrochemistry as a Guide for Rational Design of DyP-Based Bioelectronics Devices
Authors: Zuccarello Lidia , Barbosa Catarina , Galdino Edilson , Lončar Nikola , Silveira Célia M. , Fraaije Marco W. , Todorovic Smilja
Published: July 2021

Immobilised dye-decolorizing peroxidases (DyPs) are promising biocatalysts for the development of biotechnological devices such as biosensors for the detection of H2O2. To this end, these enzymes have to preserve native, solution properties upon immobilisation on the electrode surface. In this work, DyPs from Cellulomonas bogoriensis (CboDyP), Streptomyces coelicolor (ScoDyP) and Thermobifida fusca (TfuDyP) are immobilised on biocompatible silver electrodes functionalized with alkanethiols. Their structural, redox and catalytic properties upon immobilisation are evaluated by surface-enhanced resonance Raman (SERR) spectroelectrochemistry and cyclic voltammetry. Among the studied electrode/DyP constructs, only CboDyP shows preserved native structure upon attachment to the electrode. However, a comparison of the redox potentials of the enzyme in solution and immobilised states reveals a large discrepancy, and the enzyme shows no electrocatalytic activity in the presence of H2O2. While some immobilised DyPs outperform existing peroxidase-based biosensors, others fail to fulfil the essential requirements that guarantee their applicability in the immobilised state. The capacity of SERR spectroelectrochemistry for fast screening of the performance of immobilised heme enzymes places it in the front-line of experimental approaches that can advance the search for promising DyP candidates.
Intrauterine Nitric Oxide Deficiency Weakens Differentiation of Vascular Smooth Muscle in Newborn Rats
Authors: Shvetsova Anastasia A. , Borzykh Anna A. , Selivanova Ekaterina K. , Kiryukhina Oxana O. , Gaynullina Dina K. , Tarasova Olga S.
Published: July 2021

Nitric oxide (NO) deficiency during pregnancy is a key reason for preeclampsia development. Besides its important vasomotor role, NO is shown to regulate the cell transcriptome. However, the role of NO in transcriptional regulation of developing smooth muscle has never been studied before. We hypothesized that in early ontogeny, NO is important for the regulation of arterial smooth muscle-specific genes expression. Pregnant rats consumed NO-synthase inhibitor L-NAME (500 mg/L in drinking water) from gestational day 10 till delivery, which led to an increase in blood pressure, a key manifestation of preeclampsia. L-NAME reduced blood concentrations of NO metabolites in dams and their newborn pups, as well as relaxations of pup aortic rings to acetylcholine. Using qPCR, we demonstrated reduced abundances of the smooth muscle-specific myosin heavy chain isoform, α-actin, SM22α, and L-type Ca2+-channel mRNAs in the aorta of newborn pups from the L-NAME group compared to control pups. To conclude, the intrauterine NO deficiency weakens gene expression specific for a contractile phenotype of arterial smooth muscle in newborn offspring.
Anti-Inflammatory Therapeutic Approaches to Prevent or Delay Post-Traumatic Osteoarthritis (PTOA) of the Knee Joint with a Focus on Sustained Delivery Approaches
Authors: Khella Christine M. , Horvath Judith M. , Asgarian Rojiar , Rolauffs Bernd , Hart Melanie L.
Published: July 2021

Inflammation plays a central role in the pathogenesis of knee PTOA after knee trauma. While a comprehensive therapy capable of preventing or delaying post-traumatic osteoarthritis (PTOA) progression after knee joint injury does not yet clinically exist, current literature suggests that certain aspects of early post-traumatic pathology of the knee joint may be prevented or delayed by anti-inflammatory therapeutic interventions. We discuss multifaceted therapeutic approaches that may be capable of effectively reducing the continuous cycle of inflammation and concomitant processes that lead to cartilage degradation as well as those that can simultaneously promote intrinsic repair processes. Within this context, we focus on early disease prevention, the optimal timeframe of treatment and possible long-lasting sustained delivery local modes of treatments that could prevent knee joint-associated PTOA symptoms. Specifically, we identify anti-inflammatory candidates that are not only anti-inflammatory but also anti-degenerative, anti-apoptotic and pro-regenerative.
Biomarkers and Mechanisms of Oxidative Stress—Last 20 Years of Research with an Emphasis on Kidney Damage and Renal Transplantation
Authors: Tejchman Karol , Kotfis Katarzyna , Sieńko Jerzy
Published: July 2021

Oxidative stress is an imbalance between pro- and antioxidants that adversely influences the organism in various mechanisms and on many levels. Oxidative damage occurring concomitantly in many cellular structures may cause a deterioration of function, including apoptosis and necrosis. The damage leaves a molecular “footprint”, which can be detected by specific methodology, using certain oxidative stress biomarkers. There is an intimate relationship between oxidative stress, inflammation, and functional impairment, resulting in various diseases affecting the entire human body. In the current narrative review, we strengthen the connection between oxidative stress mechanisms and their active compounds, emphasizing kidney damage and renal transplantation. An analysis of reactive oxygen species (ROS), antioxidants, products of peroxidation, and finally signaling pathways gives a lot of promising data that potentially will modify cell responses on many levels, including gene expression. Oxidative damage, stress, and ROS are still intensively exploited research subjects. We discuss compounds mentioned earlier as biomarkers of oxidative stress and present their role documented during the last 20 years of research. The following keywords and MeSH terms were used in the search: oxidative stress, kidney, transplantation, ischemia-reperfusion injury, IRI, biomarkers, peroxidation, and treatment.
Role of Immune Cells in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma
Authors: Cho Hyo-Jung , Cheong Jae-Youn
Published: July 2021

Hepatocellular carcinoma (HCC) develops almost entirely in the presence of chronic inflammation. Chronic hepatitis B virus (HBV) infection with recurrent immune-mediated liver damage ultimately leads to cirrhosis and HCC. It is widely accepted that HBV infection induces the dysfunction of the innate and adaptive immune responses that engage various immune cells. Natural killer (NK) cells are associated with early antiviral and antitumor properties. On the other hand, inflammatory cells release various cytokines and chemokines that may promote HCC tumorigenesis. Moreover, immunosuppressive cells such as regulatory T cells (Treg) and myeloid-derived suppressive cells play a critical role in hepatocarcinogenesis. HBV-specific CD8+ T cells have been identified as pivotal players in antiviral responses, whilst extremely activated CD8+ T cells induce enormous inflammatory responses, and chronic inflammation can facilitate hepatocarcinogenesis. Controlling and maintaining the balance in the immune system is an important aspect in the management of HBV-related HCC. We conducted a review of the current knowledge on the immunopathogenesis of HBV-induced inflammation and the role of such immune activation in the tumorigenesis of HCC based on the recent studies on innate and adaptive immune cell dysfunction in HBV-related HCC.
Detecting and Profiling Endogenous RNA G-Quadruplexes in the Human Transcriptome
Authors: Zhang Rongxin , Liu Yajun , Zhang Xingxing , Xiao Ke , Hou Yue , Liu Hongde , Sun Xiao
Published: July 2021

G-quadruplexes are the non-canonical nucleic acid structures that are preferentially formed in G-rich regions. This structure has been shown to be associated with many biological functions. Regardless of the broad efforts on DNA G-quadruplexes, we still have limited knowledge on RNA G-quadruplexes, especially in a transcriptome-wide manner. Herein, by integrating the DMS-seq and the bioinformatics pipeline, we profiled and depicted the RNA G-quadruplexes in the human transcriptome. The genes that contain RNA G-quadruplexes in their specific regions are significantly related to immune pathways and the COVID-19-related gene sets. Bioinformatics analysis reveals the potential regulatory functions of G-quadruplexes on miRNA targeting at the scale of the whole transcriptome. In addition, the G-quadruplexes are depleted in the putative, not the real, PAS-strong poly(A) sites, which may weaken the possibility of such sites being the real cleaved sites. In brief, our study provides insight into the potential function of RNA G-quadruplexes in post-transcription.
Distinct Immune Signatures Indicative of Treatment Response and Immune-Related Adverse Events in Melanoma Patients under Immune Checkpoint Inhibitor Therapy
Authors: Reschke Robin , Gussek Philipp , Boldt Andreas , Sack Ulrich , Köhl Ulrike , Lordick Florian , Gora Thomas , Kreuz Markus , Reiche Kristin , Simon Jan-Christoph , Ziemer Mirjana , Kunz Manfred
Published: July 2021

To identify potential early biomarkers of treatment response and immune-related adverse events (irAE), a pilot immune monitoring study was performed in stage IV melanoma patients by flow cytometric analysis of peripheral blood mononuclear cells (PBMC). Overall, 17 patients were treated with either nivolumab or pembrolizumab alone, or with a combination of nivolumab and ipilimumab every three weeks. Of 15 patients for which complete response assessment was available, treatment responders (n = 10) as compared to non-responders (n = 5) were characterized by enhanced PD-1 expression on CD8+ T cells immediately before treatment (median ± median absolute deviation/MAD 26.7 ± 10.4% vs. 17.2 ± 5.3%). Responders showed a higher T cell responsiveness after T cell receptor ex vivo stimulation as determined by measurement of programmed cell death 1 (PD-1) expression on CD3+ T cells before the second cycle of treatment. The percentage of CD8+ effector memory (CD8+CD45RA−CD45RO+CCR7−) T cells was higher in responders compared to non-responders before and immediately after the first cycle of treatment (median ± MAD 39.2 ± 7.3% vs. 30.5 ± 4.1% and 37.7 ± 4.6 vs. 24.0 ± 6.4). Immune-related adverse events (irAE) were accompanied by a higher percentage of activated CD4+ (CD4+CD38+HLADR+) T cells before the second treatment cycle (median ± MAD 14.9 ± 3.9% vs. 5.3 ± 0.4%). In summary, PBMC immune monitoring of immune-checkpoint inhibition (ICI) treatment in melanoma appears to be a promising approach to identify early markers of treatment response and irAEs.
Occurrence of Calcium Oscillations in Human Spermatozoa Is Based on Spatial Signaling Enzymes Distribution
Authors: Korobkin Julia , Balabin Fedor A. , Yakovenko Sergey A. , Simonenko Ekaterina Yu. , Sveshnikova Anastasia N.
Published: July 2021

In human spermatozoa, calcium dynamics control most of fertilization events. Progesterone, present in the female reproductive system, can trigger several types of calcium responses, such as low-frequency oscillations. Here we aimed to identify the mechanisms of progesterone-induced calcium signaling in human spermatozoa. Progesterone-induced activation of fluorophore-loaded spermatozoa was studied by fluorescent microscopy. Two computational models were developed to describe the spermatozoa calcium responses: a homogeneous one based on a system of ordinary differential equations and a three-dimensional one with added space dimensions and diffusion for the cytosolic species. In response to progesterone, three types of calcium responses were observed in human spermatozoa: a single transient rise of calcium concentration in cytosol, a steady elevation, or low-frequency oscillations. The homogenous model provided qualitative description of the oscillatory and the single spike responses, while the three-dimensional model captured the calcium peak shape and the frequency of calcium oscillations. The model analysis demonstrated that an increase in the calcium diffusion coefficient resulted in the disappearance of the calcium oscillations. Additionally, in silico analysis suggested that the spatial distribution of calcium signaling enzymes governs the appearance of calcium oscillations in progesterone-activated human spermatozoa.
Parkinson’s Disease: A Prionopathy?
Authors: Vascellari Sarah , Manzin Aldo
Published: July 2021

The principal pathogenic event in Parkinson’s disease is characterized by the conformational change of α-synuclein, which form pathological aggregates of misfolded proteins, and then accumulate in intraneuronal inclusions causing dopaminergic neuronal loss in specific brain regions. Over the last few years, a revolutionary theory has correlated Parkinson’s disease and other neurological disorders with a shared mechanism, which determines α-synuclein aggregates and progresses in the host in a prion-like manner. In this review, the main characteristics shared between α-synuclein and prion protein are compared and the cofactors that influence the remodeling of native protein structures and pathogenetic mechanisms underlying neurodegeneration are discussed.
A Positive Regulatory Feedback Loop between EKLF/KLF1 and TAL1/SCL Sustaining the Erythropoiesis
Authors: Hung Chun-Hao , Lee Tung-Liang , Huang Anna Yu-Szu , Yang Kang-Chung , Shyu Yu-Chiau , Wen Shau-Ching , Lu Mu-Jie , Yuan Shinsheng , Shen Che-Kun James
Published: July 2021

The erythroid Krüppel-like factor EKLF/KLF1 is a hematopoietic transcription factor binding to the CACCC DNA motif and participating in the regulation of erythroid differentiation. With combined use of microarray-based gene expression profiling and the promoter-based ChIP-chip assay of E14.5 fetal liver cells from wild type (WT) and EKLF-knockout (Eklf−/−) mouse embryos, we identified the pathways and direct target genes activated or repressed by EKLF. This genome-wide study together with the molecular/cellular analysis of the mouse erythroleukemic cells (MEL) indicate that among the downstream direct target genes of EKLF is Tal1/Scl. Tal1/Scl encodes another DNA-binding hematopoietic transcription factor TAL1/SCL, known to be an Eklf activator and essential for definitive erythroid differentiation. Further identification of the authentic Tal gene promoter in combination with the in vivo genomic footprinting approach and DNA reporter assay demonstrate that EKLF activates the Tal gene through binding to a specific CACCC motif located in its promoter. These data establish the existence of a previously unknow positive regulatory feedback loop between two DNA-binding hematopoietic transcription factors, which sustains mammalian erythropoiesis.
PON-Sol2: Prediction of Effects of Variants on Protein Solubility
Authors: Yang Yang , Zeng Lianjie , Vihinen Mauno
Published: July 2021

Genetic variations have a multitude of effects on proteins. A substantial number of variations affect protein–solvent interactions, either aggregation or solubility. Aggregation is often related to structural alterations, whereas solubilizable proteins in the solid phase can be made again soluble by dilution. Solubility is a central protein property and when reduced can lead to diseases. We developed a prediction method, PON-Sol2, to identify amino acid substitutions that increase, decrease, or have no effect on the protein solubility. The method is a machine learning tool utilizing gradient boosting algorithm and was trained on a large dataset of variants with different outcomes after the selection of features among a large number of tested properties. The method is fast and has high performance. The normalized correct prediction rate for three states is 0.656, and the normalized GC2 score is 0.312 in 10-fold cross-validation. The corresponding numbers in the blind test were 0.545 and 0.157. The performance was superior in comparison to previous methods. The PON-Sol2 predictor is freely available. It can be used to predict the solubility effects of variants for any organism, even in large-scale projects.
Ligand-Dependent and Ligand-Independent Effects of Ephrin-B2–EphB4 Signaling in Melanoma Metastatic Spine Disease
Authors: Piffko Andras , Broggini Thomas , Harms Christoph , Adams Ralf Heinrich , Vajkoczy Peter , Czabanka Marcus
Published: July 2021

Tumor–endothelial cell interactions represent an essential mechanism in spinal metastasis. Ephrin-B2–EphB4 communication induces tumor cell repulsion from the endothelium in metastatic melanoma, reducing spinal bone metastasis formation. To shed further light on the Ephrin-B2–EphB4 signaling mechanism, we researched the effects of pharmacological EphB4 receptor stimulation and inhibition in a ligand-dependent/independent context. We chose a preventative and a post-diagnostic therapeutic window. EphB4 stimulation during tumor cell seeding led to an increase in spinal metastatic loci and number of disseminated melanoma cells, as well as earlier locomotion deficits in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, reduction of metastatic loci with a later manifestation of locomotion deficits occurred. Thus, EphB4 receptor stimulation affects metastatic dissemination depending on the presence/absence of endothelial Ephrin-B2. After the manifestation of solid metastasis, EphB4 kinase inhibition resulted in significantly earlier manifestation of locomotion deficits in the presence of the ligand. No post-diagnostic treatment effect was found in the absence of endothelial Ephrin-B2. For solid metastasis treatment, EphB4 kinase inhibition induced prometastatic effects in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, both therapies showed no effect on the growth of solid metastasis.
Novel N-Substituted 3-Aryl-4-(diethoxyphosphoryl)azetidin-2-ones as Antibiotic Enhancers and Antiviral Agents in Search for a Successful Treatment of Complex Infections
Authors: Głowacka Iwona E. , Grabkowska-Drużyc Magdalena , Andrei Graciela , Schols Dominique , Snoeck Robert , Witek Karolina , Podlewska Sabina , Handzlik Jadwiga , Piotrowska Dorota G.
Published: July 2021

A novel series of N-substituted cis- and trans-3-aryl-4-(diethoxyphosphoryl)azetidin-2-ones were synthesized by the Kinugasa reaction of N-methyl- or N-benzyl-(diethyoxyphosphoryl)nitrone and selected aryl alkynes. Stereochemistry of diastereoisomeric adducts was established based on vicinal H3–H4 coupling constants in azetidin-2-one ring. All the obtained azetidin-2-ones were evaluated for the antiviral activity against a broad range of DNA and RNA viruses. Azetidin-2-one trans-11f showed moderate inhibitory activity against human coronavirus (229E) with EC50 = 45 µM. The other isomer cis-11f was active against influenza A virus H1N1 subtype (EC50 = 12 µM by visual CPE score; EC50 = 8.3 µM by TMS score; MCC > 100 µM, CC50 = 39.9 µM). Several azetidin-2-ones 10 and 11 were tested for their cytostatic activity toward nine cancerous cell lines and several of them appeared slightly active for Capan-1, Hap1 and HCT-116 cells values of IC50 in the range 14.5–97.9 µM. Compound trans-11f was identified as adjuvant of oxacillin with significant ability to enhance the efficacy of this antibiotic toward the highly resistant S. aureus strain HEMSA 5. Docking and molecular dynamics simulations showed that enantiomer (3R,4S)-11f can be responsible for the promising activity due to the potency in displacing oxacillin at β-lactamase, thus protecting the antibiotic from undesirable biotransformation.
Combining Cancer Vaccines with Immunotherapy: Establishing a New Immunological Approach
Authors: Kim Chang-Gon , Sang Yun-Beom , Lee Ji-Hyun , Chon Hong-Jae
Published: July 2021

Therapeutic cancer vaccines have become increasingly qualified for use in personalized cancer immunotherapy. A deeper understanding of tumor immunology and novel antigen delivery technologies has assisted in optimizing vaccine design. Therapeutic cancer vaccines aim to establish long-lasting immunological memory against tumor cells, thereby leading to effective tumor regression and minimizing non-specific or adverse events. However, due to several resistance mechanisms, significant challenges remain to be solved in order to achieve these goals. In this review, we describe our current understanding with respect to the use of the antigen repertoire in vaccine platform development. We also summarize various intrinsic and extrinsic resistance mechanisms behind the failure of cancer vaccine development in the past. Finally, we suggest a strategy that combines immune checkpoint inhibitors to enhance the efficacy of cancer vaccines.
Diagnostic Performance of Extracellular Volume Quantified by Dual-Layer Dual-Energy CT for Detection of Acute Myocarditis
Authors: Si-Mohamed Salim Aymeric , Restier Lauria Marie , Branchu Arthur , Boccalini Sara , Congi Anaelle , Ziegler Arthur , Tomasevic Danka , Bochaton Thomas , Boussel Loic , Douek Philippe Charles
Published: July 2021

Background: Myocardial extracellular volume (ECV) is a marker of the myocarditis inflammation burden and can be used for acute myocarditis diagnosis. Dual-energy computed tomography (DECT) enables its quantification with high concordance with cardiac magnetic resonance (CMR). Purpose: To investigate the diagnostic performance of myocardial ECV quantified on a cardiac dual-layer DECT in a population of patients with suspected myocarditis, in comparison to CMR. Methods: 78 patients were included in this retrospective monocenter study, 60 were diagnosed with acute myocarditis and 18 patients were considered as a control population, based on the 2009 Lake and Louise criteria. All subjects underwent a cardiac DECT in acute phase consisted in an arterial phase followed by a late iodine enhancement phase at 10 min after injection (1.2 mL/kg, iodinated contrast agent). ECV was calculated using the hematocrit level measured the day of DECT examinations. Non-parametric analyses have been used to test the differences between groups and the correlations between the variables. A ROC curve has been used to identify the optimal ECV cut-off discriminating value allowing the detection of acute myocarditis cases. A p value < 0.05 has been considered as significant. Results: The mean ECV was significantly higher (p < 0.001) for the myocarditis group compared to the control (34.18 ± 0.43 vs. 30.04 ± 0.53%). A cut-off value of ECV = 31.60% (ROC AUC = 0.835, p < 0.001) allows to discriminate the myocarditis with a sensitivity of 80% and a specificity of 78% (positive predictive value = 92.3%, negative predictive value = 53.8% and accuracy = 79.5%). Conclusion: Myocardial ECV enabled by DECT allows to diagnose the acute myocarditis with a cut-off at 31.60% for a sensitivity of 80% and specificity of 78%.
Differences in Psychiatric Comorbidities and Gender Distribution among Three Clusters of Personality Disorders: A Nationwide Population-Based Study
Authors: Hsu Chih-Wei , Wang Liang-Jen , Lin Pao-Yen , Hung Chi-Fa , Yang Yao-Hsu , Chen Yu-Ming , Kao Hung-Yu
Published: July 2021

Personality disorders (PDs) are grouped into clusters A, B, and C. However, whether the three clusters of PDs have differences in comorbid mental disorders or gender distribution is still lacking sufficient evidence. We aim to investigate the distribution pattern across the three clusters of PDs with a population-based cohort study. This study used the Taiwan national database between 1995 and 2013 to examine the data of patients with cluster A PDs, cluster B PDs, or cluster C PDs. We compared the differences of psychiatric comorbidities classified in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition across the three clusters of PDs. Moreover, we formed gender subgroups of the three PDs to observe the discrepancy between male and female. Among the 9845 patients, those with cluster A PDs had the highest proportion of neurodevelopmental disorders, schizophrenia and neurocognitive disorders, those with cluster B PDs demonstrated the largest percentage of bipolar disorders, trauma and stressor disorders, feeding and eating disorders, and substance and addictive disorders, and those with cluster C PDs had the greatest proportion of depressive disorders, anxiety disorders, obsessive–compulsive disorders, somatic symptom disorders, and sleep–wake disorders. The gender subgroups revealed significant male predominance in neurodevelopmental disorders and female predominance in sleep–wake disorders across all three clusters of PDs. Our findings support that some psychiatric comorbidities are more prevalent in specified cluster PDs and that gender differences exist across the three clusters of PDs. These results are an important reference for clinicians who are developing services that target real-world patients with PDs.
Current Advances in Spinal Diseases of the Elderly: Introduction to the Special Issue
Authors: Hirai Takashi , Uehara Masashi , Miyagi Masayuki , Takahashi Shinji , Nakashima Hiroaki
Published: July 2021

Spine-related disorders often impair quality of life (QOL) and the ability to perform activities of daily living and are a problem in rapidly aging societies [...]
Ultrawide Field Imaging in Diabetic Retinopathy: Exploring the Role of Quantitative Metrics
Authors: Ashraf Mohamed , Cavallerano Jerry D. , Sun Jennifer K. , Silva Paolo S. , Aiello Lloyd Paul
Published: July 2021

Ultrawide field imaging (UWF) has allowed the visualization of a significantly greater area of the retina than previous standard approaches. In diabetic retinopathy (DR), significantly more lesions are seen on UWF imaging compared to the seven-standard ETDRS fields. In addition, some eyes have lesions that are located predominantly in the peripheral retina that are associated with an increased risk of DR progression. The current DR severity scales are still largely based on clinically visible retinal microvascular lesions and do not incorporate retinal periphery, neuroretinal, or pathophysiologic changes. Thus, current scales are not well suited for documenting progression or regression in eyes with very early or advanced DR, nor in the setting of vascular endothelial growth factor inhibitors (antiVEGF). In addition, the categorical system is highly subjective, and grading is variable between different graders based on experience level and training background. Recently, there have been efforts to quantify DR lesions on UWF imaging in an attempt to generate objective metrics for classification, disease prognostication and prediction of treatment response. The purpose of this review is to examine current quantitative metrics derived from UWF fluorescein angiograms and UWF color imaging to determine their feasibility in any potential future DR classification.
Seasonal Trends of Viral Prevalence and Incidence of Kawasaki Disease: A Korea Public Health Data Analysis
Authors: Lim Jae Hee , Kim Yu Kyeong , Min So Hyeon , Kim Sang Won , Lee Young Hwan , Lee Jae Min
Published: July 2021

Kawasaki disease (KD) is a systemic vasculitis that occurs mainly in children under 5 years of age and is often accompanied by coronary artery lesions. The cause of the disease remains undetermined, but it is estimated to result from viral or bacterial infections. Certain studies have shown infection as a leading cause of KD. The purpose of this study was to investigate the relationship between KD incidence and viral infections in different pediatric age groups, using the Health Insurance Review and Assessment (HIRA) Open Access Big Data Platform, to confirm seasonal trends by analyzing monthly patterns. We investigated the HIRA data of KD patients (M30.3) who were treated with intravenous immunoglobulin from 2015 to 2018. Weekly virus positive detection rate data (PDR) for this period was obtained from the Korea Disease Control and Prevention Agency for human adenovirus (HAdV), human parainfluenza virus (HPIV), human respiratory syncytial virus (HRSV), influenza virus (IFV), human coronavirus (HCoV), human rhinovirus (HRV), human bocavirus (HBoV), human metapneumovirus (HMPV), rotavirus, norovirus, and astrovirus. We then analyzed the weekly/monthly virus PDR and its association with KD incidence, including monthly incidence patterns, and seasonal trends. Seasonal trend analysis of the virus PDR was performed using the time series analysis method through ARIMA (Autoregressive Integrated Moving Average). Correlations between KD incidence and PDR at 1- and 2-month intervals were analyzed using the Granger test. A total of 16,740 patients were diagnosed with KD during the study period, mainly young children, with a male-to-female ratio of 1.35. Specifically, 15,635 (93%) patients were under 5 years of age, with an incidence rate of 172.4/100,000 person-years. Annually, the cumulative number of cases per month was the highest in January, with an average of 469 cases, and was the lowest in September, with an average of 291 cases, although most were diagnosed with KD in winter (29.3%). Granger tests showed that PDR for HRSV, rotavirus, and norovirus were related with KD incidence by 1 month, while PDR for HRSV, HRV, rotavirus, and norovirus by 2 months. This study found that detection rates of respiratory and enteric viruses preceded KD by 1–2 months. Further research is needed to confirm the association between these viruses and KD.
One Year after Mild COVID-19: The Majority of Patients Maintain Specific Immunity, But One in Four Still Suffer from Long-Term Symptoms
Authors: Rank Andreas , Tzortzini Athanasia , Kling Elisabeth , Schmid Christoph , Claus Rainer , Löll Eva , Burger Roswitha , Römmele Christoph , Dhillon Christine , Müller Katharina , Girl Philipp , Hoffmann Reinhard , Grützner Stefanie , Dennehy Kevin M.
Published: July 2021

After COVID-19, some patients develop long-term symptoms. Whether such symptoms correlate with immune responses, and how long immunity persists, is not yet clear. This study focused on mild COVID-19 and investigated correlations of immunity with persistent symptoms and immune longevity. Persistent complications, including headache, concentration difficulties and loss of smell/taste, were reported by 51 of 83 (61%) participants and decreased over time to 28% one year after COVID-19. Specific IgA and IgG antibodies were detectable in 78% and 66% of participants, respectively, at a 12-month follow-up. Median antibody levels decreased by approximately 50% within the first 6 months but remained stable up to 12 months. Neutralizing antibodies could be found in 50% of participants; specific INFgamma-producing T-cells were present in two thirds one year after COVID-19. Activation-induced marker assays identified specific T-helper cells and central memory T-cells in 80% of participants at a 12-month follow-up. In correlative analyses, older age and a longer duration of the acute phase of COVID-19 were associated with higher humoral and T-cell responses. A weak correlation between long-term loss of taste/smell and low IgA levels was found at early time points. These data indicate a long-lasting immunological memory against SARS-CoV-2 after mild COVID-19.
Selective Laser Trabeculoplasty in the Treatment of Ocular Hypertension and Open-Angle Glaucoma: Clinical Review
Authors: Zgryźniak Aleksandra , Przeździecka-Dołyk Joanna , Szaliński Marek , Turno-Kręcicka Anna
Published: July 2021

Selective laser trabeculoplasty (SLT) is a glaucoma treatment that reduces intraocular pressure (IOP). Its mechanism is based on the biological effects of the selective application of laser energy to pigmented trabecular meshwork (TM) cells, resulting in increased outflow facility. Herein, we review current publications on SLT and summarize its efficacy and safety for different indications in open-angle glaucoma (OAG) and ocular hypertension (OHT) treatment. SLT effectively reduces IOP when used as a primary treatment. In patients whose IOP is medically controlled, SLT helps to reduce medication use, and when maximally tolerated topical therapy is ineffective, SLT facilitates the realization of the target IOP. SLT is a repeatable procedure for which the vast majority of complications are mild and self-limiting. With effective IOP reduction, low complication rates and the potential to repeat the procedure, SLT offers the possibility of delaying the introduction of medical therapy and other more invasive treatment modalities while simultaneously avoiding the accompanying complications. With this knowledge, we suggest that SLT be considered as an essential primary treatment option in OAG and OHT, switching to other treatment modalities only when laser procedures are insufficient for achieving the required target IOP.
Usefulness of a Hepatitis B Surface Antigen-Based Model for the Prediction of Functional Cure in Patients with Chronic Hepatitis B Virus Infection Treated with Nucleos(t)ide Analogues: A Real-World Study
Authors: Caviglia Gian Paolo , Troshina Yulia , Garro Enrico , Gesualdo Marcantonio , Aneli Serena , Birolo Giovanni , Pittaluga Fabrizia , Cavallo Rossana , Saracco Giorgio Maria , Ciancio Alessia
Published: July 2021

In patients with chronic hepatitis B (CHB) under long-term treatment with nucleso(t)ide analogues (NAs), the loss of hepatitis B surface antigen (HBsAg) is a rare event. A growing body of evidence supports the use of quantitative HBsAg for the prediction of functional cure, although these results are mainly derived from studies performed on Asian patients with hepatitis B e antigen (HBeAg)-positive CHB. Here, we investigated the clinical role of quantitative HBsAg in a real-life cohort of CHB patients under treatment with NAs in a tertiary care center from North-West Italy. A total of 101 CHB patients (HBeAg-negative, n = 86) undergoing NAs treatment were retrospectively enrolled. HBsAg was measured at baseline (T0), 6 months (T1), 12 months (T2) and at the last follow-up (FU). Median FU was 5.5 (3.2–8.3) years; at the end of FU, 11 patients lost the HBsAg (annual incidence rate = 1.8%). Baseline HBsAg levels were significantly different between patients with no HBsAg loss and those achieving a functional cure (3.46, 2.91–3.97 vs. 1.11, 0.45–1.98 Log IU/mL, p < 0.001). Similarly, the HBsAg decline (Δ) from T0 to T2 was significantly different between the two groups of patients (0.05, −0.04–0.13, vs. 0.38, 0.11–0.80 Log IU/mL, p = 0.002). By stratified cross-validation analysis, the combination of baseline HBsAg and ΔHBsAg T0–T2 showed an excellent accuracy for the prediction of HBsAg loss (C statistic = 0.966). These results corroborate the usefulness of quantitative HBsAg in Caucasian CHB patients treated with antivirals for the prediction of HBsAg seroclearance.
Liposomal Inhalation after Tracheostomy—A Randomized Controlled Trial
Authors: Hofauer Benedikt , Straßen Ulrich , Chaker Adam , Schossow Beate , Wirth Magdalena , Wirth Markus , Bas Murat , Knopf Andreas
Published: July 2021

Background: Tracheostomy is a common procedure in critical care. The aim of this study was to evaluate the application of a liposomal inhalation compared to standard physiologic saline (SPS) inhalation on basis of objective and subjective parameters of airway inflammation. Methods: We evaluated in this two-armed, double-blinded and randomized control group study the effect of liposomal compared with SPS inhalation in newly tracheotomized patients. The primary endpoint was defined as trend of tracheobronchial IL-6 secretion at day 1 compared to day 10. Further objective and subjective parameter were evaluated. Results: Fifty patients were randomized in each arm. Tracheal IL-6 levels decreased significantly only after liposomal inhalation. Both inhalative agents seem to have an effect on the respiratory impairment after tracheostomy. Subjective patient impairment was reduced significantly from day 1 to day 10 after tracheostomy with liposomal inhalation. Conclusions: Liposomal inhalation demonstrated an advantage over SPS inhalation in newly tracheotomized patients.
N-Terminal Pro Brain Natriuretic Peptide, sST2, and Galectin-3 Levels in Breast Cancer Survivors
Authors: Patel Shruti Rajesh , Herrmann Joerg , Vierkant Robert A. , Olson Janet E. , Couch Fergus J. , Hazim Antonious , Sloan Jeff A. , Loprinzi Charles L. , Ruddy Kathryn J.
Published: July 2021

NT-proBNP, soluble ST2 (sST2), and galectin-3 are biomarkers of cardiac dysfunction that have been proposed as identifiers of patients experiencing asymptomatic cardiac dysfunction after anthracycline-based chemotherapy. This study aimed to compare the proportion of breast cancer (BC) survivors with elevated serum levels of these three putative biomarkers by prior receipt of anthracycline (yes vs. no). Five-hundred-eighty survivors of BC who had received anthracycline-based chemotherapy were matched by age and time between diagnosis and serum storage to 580 who had not. Cardiac biomarker levels were analyzed using immunoassays. Analyses were carried out using linear and logistic regression models. Anthracycline recipients had higher values of NT-proBNP than non-recipients (mean 116.0 ng/L vs. 97.0 ng/L, respectively; p < 0.001). Values for ST2 and galectin-3 did not significantly differ by receipt of anthracycline. After further adjustment for age at breast cancer diagnosis, ethnicity, and receipt of trastuzumab, associations between receipt of anthracycline and higher NT-proBNP persisted (p < 0.001), showing that NT-proBNP may be a biomarker of cardiovascular toxicity after receipt of anthracycline-based chemotherapy. Further research to assess the clinical utility of NT-proBNP testing after receipt of anthracycline is recommended. sST2 and galectin-3 do not appear to differentiate between anthracycline recipients and non-recipients amongst breast cancer survivors.
Balloon Enteroscopy-Assisted Endoscopic Retrograde Cholangiopancreatography for the Treatment of Common Bile Duct Stones in Patients with Roux-en-Y Gastrectomy: Outcomes and Factors Affecting Complete Stone Extraction
Authors: Obata Taisuke , Tsutsumi Koichiro , Kato Hironari , Ueki Toru , Miyamoto Kazuya , Yamazaki Tatsuhiro , Matsumi Akihiro , Fujii Yuki , Matsumoto Kazuyuki , Horiguchi Shigeru , Yasugi Kengo , Ogawa Tsuneyoshi , Takenaka Ryuta , Okada Hiroyuki
Published: July 2021

Background: Endoscopic retrograde cholangiopancreatography (ERCP) for extraction of common bile duct (CBD) stones in patients with Roux-en-Y gastrectomy (RYG) remains technically challenging. Methods: Seventy-nine RYG patients (median 79 years old) underwent short-type double-balloon enteroscopy-assisted ERCP (sDBE-ERCP) for CBD stones at three referral hospitals from 2011–2020. We retrospectively investigated the treatment outcomes and potential factors affecting complete stone extraction. Results: The initial success rates of reaching the papilla of Vater, biliary cannulation, and biliary intervention, including complete stone extraction or biliary stent placement, were 92%, 81%, and 78%, respectively. Of 57 patients with attempted stone extraction, complete stone extraction was successful in 74% for the first session and ultimately in 88%. The adverse events rate was 5%. The multivariate analysis indicated that the largest CBD diameter ≥ 14 mm (odds ratio (OR), 0.04; 95% confidence interval (CI), 0.01–0.58; p = 0.018) and retroflex position (OR, 6.43; 95% CI, 1.12–36.81; p = 0.037) were independent predictive factors affecting complete stone extraction achievement. Conclusions: Therapeutic sDBE-ERCP for CBD stones in a relatively elderly RYG cohort, was effective and safe. A larger CBD diameter negatively affected complete stone extraction, but using the retroflex position may be useful for achieving complete stone clearance.