bluuebunny/crossref_metadata_2025 huggingface dataset:
DReAmocracy: A Method to Capitalise on Prior Drug Discovery Efforts to Highlight Candidate Drugs for Repurposing
Authors: Savva Kyriaki , Zachariou Margarita , Bourdakou Marilena M. , Dietis Nikolas , Spyrou George M.
Published: May 2024

In the area of drug research, several computational drug repurposing studies have highlighted candidate repurposed drugs, as well as clinical trial studies that have tested/are testing drugs in different phases. To the best of our knowledge, the aggregation of the proposed lists of drugs by previous studies has not been extensively exploited towards generating a dynamic reference matrix with enhanced resolution. To fill this knowledge gap, we performed weight-modulated majority voting of the modes of action, initial indications and targeted pathways of the drugs in a well-known repository, namely the Drug Repurposing Hub. Our method, DReAmocracy, exploits this pile of information and creates frequency tables and, finally, a disease suitability score for each drug from the selected library. As a testbed, we applied this method to a group of neurodegenerative diseases (Alzheimer’s, Parkinson’s, Huntington’s disease and Multiple Sclerosis). A super-reference table with drug suitability scores has been created for all four neurodegenerative diseases and can be queried for any drug candidate against them. Top-scored drugs for Alzheimer’s Disease include agomelatine, mirtazapine and vortioxetine; for Parkinson’s Disease, they include apomorphine, pramipexole and lisuride; for Huntington’s, they include chlorpromazine, fluphenazine and perphenazine; and for Multiple Sclerosis, they include zonisamide, disopyramide and priralfimide. Overall, DReAmocracy is a methodology that focuses on leveraging the existing drug-related experimental and/or computational knowledge rather than a predictive model for drug repurposing, offering a quantified aggregation of existing drug discovery results to (1) reveal trends in selected tracks of drug discovery research with increased resolution that includes modes of action, targeted pathways and initial indications for the investigated drugs and (2) score new candidate drugs for repurposing against a selected disease.
Endometrial Proliferative Phase-Centered View of Transcriptome Dynamics across the Menstrual Cycle
Authors: Apostolov Apostol , Naydenov Mladen , Kalinina Aive , Nikolova Maria , Saare Merli , Aleksejeva Elina , Milova Nadezhda , Milov Antoan , Salumets Andres , Baev Vesselin , Yahubyan Galina
Published: May 2024

The endometrium, the inner mucosal lining of the uterus, undergoes complex molecular and cellular changes across the menstrual cycle in preparation for embryo implantation. Transcriptome-wide analyses have mainly been utilized to study endometrial receptivity, the prerequisite for successful implantation, with most studies, so far, comparing the endometrial transcriptomes between (i) secretory and proliferative endometrium or (ii) mid-secretory and early secretory endometrium. In the current study, we provide a complete transcriptome description of the endometrium across the entire menstrual cycle and, for the first time, comprehensively characterize the proliferative phase of the endometrium. Our temporal transcriptome analysis includes five time points including the mid-proliferative, late proliferative (peri-ovulatory phase), early secretory, mid-secretory, and late secretory phases. Thus, we unveil exhaustively the transitions between the consecutive proliferative and secretory phases, highlighting their unique gene expression profiles and possible distinct biological functions. The transcriptome analysis reveals many differentially expressed genes (DEGs) across the menstrual cycle, most of which are phase-specific. As an example of coordinated gene activity, the expression profile of histone-encoding genes within the HIST cluster on chromosome 6 shows an increase in cluster activity during the late proliferative and a decline during the mid-secretory phase. Moreover, numerous DEGs are shared among all phases. In conclusion, in the current study, we delineate the endometrial proliferative phase-centered view of transcriptome dynamics across the menstrual cycle. Our data analysis highlights significant transcriptomic and functional changes occurring during the late proliferative phase—an essential transition point from the proliferative phase to the secretory phase. Future studies should explore how the biology of the late proliferative phase endometrium impacts the achievement of mid-secretory endometrial receptivity or contributes to molecular aberrations leading to embryo implantation failure.
An Advanced Human Bone Tissue Culture Model for the Assessment of Implant Osteointegration In Vitro
Authors: Maglio Melania , Fini Milena , Sartori Maria , Codispoti Giorgia , Borsari Veronica , Dallari Dante , Ambretti Simone , Rocchi Martina , Tschon Matilde
Published: May 2024

In the field of biomaterials for prosthetic reconstructive surgery, there is the lack of advanced innovative methods to investigate the potentialities of smart biomaterials before in vivo tests. Despite the complex osteointegration process being difficult to recreate in vitro, this study proposes an advanced in vitro tissue culture model of osteointegration using human bone. Cubic samples of trabecular bone were harvested, as waste material, from hip arthroplasty; inner cylindrical defects were created and assigned to the following groups: (1) empty defects (CTRneg); (2) defects implanted with a cytotoxic copper pin (CTRpos); (3) defects implanted with standard titanium pins (Ti). Tissues were dynamically cultured in mini rotating bioreactors and assessed weekly for viability and sterility. After 8 weeks, immunoenzymatic, microtomographic, histological, and histomorphometric analyses were performed. The model was able to simulate the effects of implantation of the materials, showing a drop in viability in CTR+, while Ti appears to have a trophic effect on bone. MicroCT and a histological analysis supported the results, with signs of matrix and bone deposition at the Ti implant site. Data suggest the reliability of the tested model in recreating the osteointegration process in vitro with the aim of reducing and refining in vivo preclinical models.
Identification of Epigenetic Biomarkers of Adolescent Idiopathic Scoliosis Progression: A Workflow to Assess Local Gene Expression
Authors: Neri Simona , Assirelli Elisa , Manzetti Marco , Viroli Giovanni , Ialuna Marco , Traversari Matteo , Ciaffi Jacopo , Ursini Francesco , Faldini Cesare , Ruffilli Alberto
Published: May 2024

Adolescent idiopathic scoliosis (AIS) is a three-dimensional structural deformity of the spine that affects 2–3% of adolescents under the age of 16. AIS etiopathogenesis is not completely understood; however, the disease phenotype is correlated to multiple genetic loci and results from genetic–environmental interactions. One of the primary, still unresolved issues is the implementation of reliable diagnostic and prognostic markers. For clinical management improvement, predictors of curve progression are particularly needed. Recently, an epigenetic contribution to AIS development and progression was proposed; nevertheless, validation of data obtained in peripheral tissues and identification of the specific mechanisms and genes under epigenetic control remain limited. In this study, we propose a methodological approach for the identification of epigenetic markers of AIS progression through an original workflow based on the preliminary characterization of local expression of candidate genes in tissues directly involved in the pathology. The feasibility of the proposed methodological protocol has been originally tested here in terms of identification of the putative epigenetic markers of AIS progression, collection of the different tissues, retrieval of an appropriate amount and quality of RNA and DNA, and identification of suitable reference genes.
Senescence-Associated Alterations in Matrisome of Mesenchymal Stem Cells
Authors: Matveeva Diana , Kashirina Daria , Ezdakova Mariia , Larina Irina , Buravkova Ludmila , Ratushnyy Andrey
Published: May 2024

The process of aging is intimately linked to alterations at the tissue and cellular levels. Currently, the role of senescent cells in the tissue microenvironment is still being investigated. Despite common characteristics, different cell populations undergo distinctive morphofunctional changes during senescence. Mesenchymal stem cells (MSCs) play a pivotal role in maintaining tissue homeostasis. A multitude of studies have examined alterations in the cytokine profile that determine their regulatory function. The extracellular matrix (ECM) of MSCs is a less studied aspect of their biology. It has been shown to modulate the activity of neighboring cells. Therefore, investigating age-related changes in the MSC matrisome is crucial for understanding the mechanisms of tissue niche ageing. This study conducted a broad proteomic analysis of the matrisome of separated fractions of senescent MSCs, including the ECM, conditioned medium (CM), and cell lysate. This is the first time such an analysis has been conducted. It has been established that there is a shift in production towards regulatory molecules and a significant downregulation of the main structural and adhesion proteins of the ECM, particularly collagens, fibulins, and fibrilins. Additionally, a decrease in the levels of cathepsins, galectins, S100 proteins, and other proteins with cytoprotective, anti-inflammatory, and antifibrotic properties has been observed. However, the level of inflammatory proteins and regulators of profibrotic pathways increases. Additionally, there is an upregulation of proteins that can directly cause prosenescent effects on microenvironmental cells (SERPINE1, THBS1, and GDF15). These changes confirm that senescent MSCs can have a negative impact on other cells in the tissue niche, not only through cytokine signals but also through the remodeled ECM.
Correction: Yagolovich et al. DR5-Selective TRAIL Variant DR5-B Functionalized with Tumor-Penetrating iRGD Peptide for Enhanced Antitumor Activity against Glioblastoma. Int. J. Mol. Sci. 2022, 23, 12687
Authors: Yagolovich Anne V. , Isakova Alina A. , Artykov Artem A. , Vorontsova Yekaterina V. , Mazur Diana V. , Antipova Nadezhda V. , Pavlyukov Marat S. , Shakhparonov Mikhail I. , Gileva Anastasia M. , Markvicheva Elena A. , Plotnikova Ekaterina A. , Pankratov Andrey A. , Kirpichnikov Mikhail P. , Gasparian Marine E. , Dolgikh Dmitry A.
Published: May 2024

In the original publication [...]
Exploring Seaweed and Glycine Betaine Biostimulants for Enhanced Phenolic Content, Antioxidant Properties, and Gene Expression of Vitis vinifera cv. “Touriga Franca” Berries
Authors: Monteiro Eliana , De Lorenzis Gabriella , Ricciardi Valentina , Baltazar Miguel , Pereira Sandra , Correia Sofia , Ferreira Helena , Alves Fernando , Cortez Isabel , Gonçalves Berta , Castro Isaura
Published: May 2024

Climate change will pose a challenge for the winemaking sector worldwide, bringing progressively drier and warmer conditions and increasing the frequency and intensity of weather extremes. The short-term adaptation strategy of applying biostimulants through foliar application serves as a crucial measure in mitigating the detrimental effects of environmental stresses on grapevine yield and berry quality. The aim of this study was to evaluate the effect of foliar application of a seaweed-based biostimulant (A. nodosum—ANE) and glycine betaine (GB) on berry quality, phenolic compounds, and antioxidant activity and to elucidate their action on the secondary metabolism. A trial was installed in a commercial vineyard (cv. “Touriga Franca”) in the Cima Corgo (Upper Corgo) sub-region of the Douro Demarcated Region, Portugal. A total of four foliar sprayings were performed during the growing season: at flowering, pea size, bunch closer, and veraison. There was a positive effect of GB in the berry quality traits. Both ANE and GB increased the synthesis of anthocyanins and other phenolics in berries and influenced the expression of genes related to the synthesis and transport of anthocyanins (CHS, F3H, UFGT, and GST). So, they have the potential to act as elicitors of the secondary metabolism, leading to improved grape quality, and also to set the foundation for sustainable agricultural practices in the long run.
Modulation of Serotonin-Related Genes by Extracellular Vesicles of the Probiotic Escherichia coli Nissle 1917 in the Interleukin-1β-Induced Inflammation Model of Intestinal Epithelial Cells
Authors: Olivo-Martínez Yenifer , Martínez-Ruiz Sergio , Cordero-Alday Cecilia , Bosch Manel , Badia Josefa , Baldoma Laura
Published: May 2024

Inflammatory bowel disease (IBD) is a chronic inflammatory condition involving dysregulated immune responses and imbalances in the gut microbiota in genetically susceptible individuals. Current therapies for IBD often have significant side-effects and limited success, prompting the search for novel therapeutic strategies. Microbiome-based approaches aim to restore the gut microbiota balance towards anti-inflammatory and mucosa-healing profiles. Extracellular vesicles (EVs) from beneficial gut microbes are emerging as potential postbiotics. Serotonin plays a crucial role in intestinal homeostasis, and its dysregulation is associated with IBD severity. Our study investigated the impact of EVs from the probiotic Nissle 1917 (EcN) and commensal E. coli on intestinal serotonin metabolism under inflammatory conditions using an IL-1β-induced inflammation model in Caco-2 cells. We found strain-specific effects. Specifically, EcN EVs reduced free serotonin levels by upregulating SERT expression through the downregulation of miR-24, miR-200a, TLR4, and NOD1. Additionally, EcN EVs mitigated IL-1β-induced changes in tight junction proteins and oxidative stress markers. These findings underscore the potential of postbiotic interventions as a therapeutic approach for IBD and related pathologies, with EcN EVs exhibiting promise in modulating serotonin metabolism and preserving intestinal barrier integrity. This study is the first to demonstrate the regulation of miR-24 and miR-200a by probiotic-derived EVs.
Proteomic Analysis of Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Systematic Review
Authors: Krishnan Illayaraja , Chan Alvin Man Lung , Law Jia Xian , Ng Min Hwei , Jayapalan Jaime Jacqueline , Lokanathan Yogeswaran
Published: May 2024

Numerous challenges remain within conventional cell-based therapy despite the growing trend of stem cells used to treat various life-debilitating diseases. These limitations include batch-to-batch heterogeneity, induced alloreactivity, cell survival and integration, poor scalability, and high cost of treatment, thus hindering successful translation from lab to bedside. However, recent pioneering technology has enabled the isolation and enrichment of small extracellular vesicles (EVs), canonically known as exosomes. EVs are described as a membrane-enclosed cargo of functional biomolecules not limited to lipids, nucleic acid, and proteins. Interestingly, studies have correlated the biological role of MSC-EVs to the paracrine activity of MSCs. This key evidence has led to rigorous studies on MSC-EVs as an acellular alternative. Using EVs as a therapy was proposed as a model leading to improvements through increased safety; enhanced bioavailability due to size and permeability; reduced heterogeneity by selective and quantifiable properties; and prolonged shelf-life via long-term freezing or lyophilization. Yet, the identity and potency of EVs are still relatively unknown due to various methods of preparation and to qualify the final product. This is reflected by the absence of regulatory strategies overseeing manufacturing, quality control, clinical implementation, and product registration. In this review, the authors review the various production processes and the proteomic profile of MSC-EVs.
Characterisation of Lagovirus europaeus GI–RHDVs (Rabbit Haemorrhagic Disease Viruses) in Terms of Their Pathogenicity and Immunogenicity
Authors: Tokarz-Deptuła Beata , Kulus Jakub , Baraniecki Łukasz , Stosik Michał , Deptuła Wiesław
Published: May 2024

Rabbit haemorrhagic disease viruses (RHDV) belong to the family Caliciviridae, genus Lagovirus europaeus, genogroup GI, comprising four genotypes GI.1–GI.4, of which the genotypes GI.1 and GI.2 are pathogenic RHD viruses, while the genotypes GI.3 and GI.4 are non-pathogenic RCV (Rabbit calicivirus) viruses. Among the pathogenic genotypes GI.1 and GI.2 of RHD viruses, an antigenic variant of RHDV, named RHDVa—now GI.1a–RHDVa, was distinguished in 1996; and in 2010, a variant of RHDV—named RHDVb, later RHDV2 and now GI.2–RHDV2/b—was described; and recombinants of these viruses were registered. Pathogenic viruses of the genotype GI.1 were the cause of a disease described in 1984 in China in domestic (Oryctolagus (O.) cuniculus domesticus) and wild (O. cuniculus) rabbits, characterised by a very rapid course and a mortality rate of 90–100%, which spread in countries all over the world and which has been defined since 1989 as rabbit haemorrhagic disease. It is now accepted that GI.1–RHDV, including GI.1a–RHDVa, cause the predetermined primary haemorrhagic disease in domestic and wild rabbits, while GI.2–RHDV2/b cause it not only in rabbits, including domestic rabbits’ young up to 4 weeks and rabbits immunised with rabbit haemorrhagic disease vaccine, but also in five various species of wild rabbits and seven different species of hares, as well as wild ruminants: mountain muskoxen and European badger. Among these viruses, haemagglutination-positive, doubtful and harmful viruses have been recorded and described and have been shown to form phylogenogroups, immunotypes, haematotypes and pathotypes, which, together with traits that alter and expand their infectious spectrum (rabbit, hare, wild ruminant, badger and various rabbit and hare species), are the determinants of their pathogenicity (infectivity) and immunogenicity and thus shape their virulence. These relationships are the aim of our consideration in this article.
Genome-Wide Identification and Characterization of Homeobox Transcription Factors in Phoma sorghina var. saccharum Causing Sugarcane Twisted Leaf Disease
Authors: Bao Yixue , Deng Jinlan , Akbar Sehrish , Duan Zhenzhen , Zhang Chi , Lin Wenfeng , Wu Suyan , Yue Yabing , Yao Wei , Xu Jianlong , Zhang Muqing
Published: May 2024

A homeobox transcription factor is a conserved transcription factor, ubiquitous in eukaryotes, that regulates the tissue formation of structure, cell differentiation, proliferation, and cancer. This study identified the homeobox transcription factor family and its distribution in Phoma sorghina var. saccharum at the whole genome level. It elucidated the gene structures and evolutionary characteristics of this family. Additionally, knockout experiments were carried out and the preliminary function of these transcription factors was studied. Through bioinformatics approaches, nine homeobox transcription factors (PsHOX1–PsHOX9) were identified in P. sorghina var. saccharum, and these contained HOX-conserved domains and helix–turn–helix secondary structures. Nine homeobox gene deletion mutants were obtained using the homologous recombinant gene knockout technique. Protoplast transformation was mediated by polyethylene glycol (PEG) and the transformants were identified using PCR. The knockouts of PsHOX1, PsHOX2, PsHOX3, PsHOX4, PsHOX6, PsHOX8, and PsHOX9 genes resulted in a smaller growth diameter in P. sorghina var. saccharum. In contrast, the knockouts of the PsHOX3, PsHOX6, and PsHOX9 genes inhibited the formation of conidia and led to a significant decrease in the pathogenicity. This study’s results will provide insights for understanding the growth and development of P. sorghina var. saccharum. The pathogenic mechanism of the affected sugarcane will provide an essential theoretical basis for preventing and controlling sugarcane twisted leaf disease.
Fullerene C60 Conjugate with Folic Acid and Polyvinylpyrrolidone for Targeted Delivery to Tumor Cells
Authors: Borisenkova Alina A. , Bolshakova Olga I. , Titova Anna V. , Ryabokon Irina S. , Markova Maria A. , Lyutova Zhanna B. , Sedov Victor P. , Varfolomeeva Elena Yu. , Bakhmetyev Vadim V. , Arutyunyan Alexandr V. , Burdakov Vladimir S. , Sarantseva Svetlana V.
Published: May 2024

The use of targeted drug delivery systems, including those based on selective absorption by certain receptors on the surface of the target cell, can lead to a decrease in the minimum effective dose and the accompanying toxicity of the drug, as well as an increase in therapeutic efficacy. A fullerene C60 conjugate (FA-PVP-C60) with polyvinylpyrrolidone (PVP) as a biocompatible spacer and folic acid (FA) as a targeting ligand for tumor cells with increased expression of folate receptors (FR) was obtained. Using 13C NMR spectroscopy, FT-IR, UV-Vis spectrometry, fluorometry and thermal analysis, the formation of the conjugate was confirmed and the nature of the binding of its components was established. The average particle sizes of the conjugate in aqueous solutions and cell culture medium were determined using dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA). The FA-PVP-C60 showed antiradical activity against •DPPH, •OH and O2•−, but at the same time, it was shown to generate 1O2. It was found that the conjugate in the studied concentration range (up to 200 μg/mL) is non-toxic in vitro and does not affect the cell cycle. To confirm the ability of the conjugate to selectively accumulate through folate-mediated endocytosis, its uptake into cells was analyzed by flow cytometry and confocal microscopy. It was shown that the conjugate is less absorbed by A549 cells with low FR expression than by HeLa, which has a high level of expression of this receptor.
Human and Murine Toll-like Receptor-Driven Disease in Systemic Lupus Erythematosus
Authors: von Hofsten Susannah , Fenton Kristin Andreassen , Pedersen Hege Lynum
Published: May 2024

The pathogenesis of systemic lupus erythematosus (SLE) is linked to the differential roles of toll-like receptors (TLRs), particularly TLR7, TLR8, and TLR9. TLR7 overexpression or gene duplication, as seen with the Y-linked autoimmune accelerator (Yaa) locus or TLR7 agonist imiquimod, correlates with increased SLE severity, and specific TLR7 polymorphisms and gain-of-function variants are associated with enhanced SLE susceptibility and severity. In addition, the X-chromosome location of TLR7 and its escape from X-chromosome inactivation provide a genetic basis for female predominance in SLE. The absence of TLR8 and TLR9 have been shown to exacerbate the detrimental effects of TLR7, leading to upregulated TLR7 activity and increased disease severity in mouse models of SLE. The regulatory functions of TLR8 and TLR9 have been proposed to involve competition for the endosomal trafficking chaperone UNC93B1. However, recent evidence implies more direct, regulatory functions of TLR9 on TLR7 activity. The association between age-associated B cells (ABCs) and autoantibody production positions these cells as potential targets for treatment in SLE, but the lack of specific markers necessitates further research for precise therapeutic intervention. Therapeutically, targeting TLRs is a promising strategy for SLE treatment, with drugs like hydroxychloroquine already in clinical use.
High-Risk HPV CISH Detection in Cervical Biopsies with Weak and/or Focal p16 Immunohistochemical Positivity
Authors: Cabibi Daniela , Giannone Antonino Giulio , Quattrocchi Alberto , Lo Coco Roberta , Formisano Eleonora , Porcasi Rossana , Benfante Viviana , Comelli Albert , Capra Giuseppina
Published: May 2024

In cervical biopsies, for diagnosis of Human Papilloma Virus (HPV) related conditions, the immunohistochemical staining for p16 has a diagnostic value only if diffusely and strongly positive, pattern named “block-like”. “Weak and/or focal (w/f) p16 expression” is commonly considered nonspecific. In our previous study, we demonstrated the presence of high-risk HPV (hrHPV) DNA by LiPa method in biopsies showing w/f p16 positivity. The aim of the present study was to investigate the presence of hrHPV-DNA by CISH in the areas showing w/f p16 expression. We assessed the presence of hrHPV16, 18, 31, 33, 51 by CISH in a group of 20 cervical biopsies showing w/f p16 expression, some with increased Ki67, and in 10 cases of block-like expression, employed as control. The immunohistochemical p16 expression was also assessed by digital pathology. hrHPV-CISH nuclear positivity was encountered in 12/20 cases of w/f p16 expression (60%). Different patterns of nuclear positivity were identified, classified as punctate, diffuse and mixed, with different epithelial distributions. Our results, albeit in a limited casuistry, show the presence of HPV in an integrated status highlighted by CISH in w/f p16 positive cases. This could suggest the necessity of a careful follow-up of the patients with “weak” and/or “focal” immunohistochemical patterns of p16, mainly in cases of increased Ki67 cell proliferation index, supplemented with molecular biology examinations.
Mesothelioma-Associated Fibroblasts Modulate the Response of Mesothelioma Patient-Derived Organoids to Chemotherapy via Interleukin-6
Authors: Cioce Mario , Gatti Veronica , Napolitano Fabiana , Giorgiano Noemi Maria , Marra Andrea , Portella Giuseppe , Fiorelli Alfonso , Pentimalli Francesca , Fazio Vito Michele
Published: May 2024

Malignant pleural mesothelioma (MPM) remains an incurable disease. This is partly due to the lack of experimental models that fully recapitulate the complexity and heterogeneity of MPM, a major challenge for therapeutic management of the disease. In addition, the contribution of the MPM microenvironment is relevant for the adaptive response to therapy. We established mesothelioma patient-derived organoid (mPDO) cultures from MPM pleural effusions and tested their response to pemetrexed and cisplatin. We aimed to evaluate the contribution of mesothelioma-associated fibroblasts (MAFs) to the response to pemetrexed and cisplatin (P+C). Organoid cultures were obtained from eight MPM patients using specific growth media and conditions to expand pleural effusion-derived cells. Flow cytometry was used to verify the similarity of the organoid cultures to the original samples. MAFs were isolated and co-cultured with mPDOs, and the addition of MAFs reduced the sensitivity of mPDOs to P+C. Organoid formation and expression of cancer stem cell markers such as ABCG2, NANOG, and CD44 were altered by conditioned media from treated MAFs. We identified IL-6 as the major contributor to the attenuated response to chemotherapy. IL-6 secretion by MAFs is correlated with increased resistance of mPDOs to pemetrexed and cisplatin.
Gene Expression and Metabolome Analysis Reveals Anti-Inflammatory Impacts of 11,17diHDoPE on PM10-Induced Mouse Lung Inflammation
Authors: Kim Uijin , Kim Dong-Hyuk , Oh Deok-Kun , Shin Ha Youn , Lee Choong Hwan
Published: May 2024

Oxylipins, the metabolites of polyunsaturated fatty acids, are vital in regulating cell proliferation and inflammation. Among these oxylipins, specialized pro-resolving mediators notably contribute to inflammation resolution. Previously, we showed that the specialized pro-resolving mediators isomer 11,17dihydroxy docosapentaenoic acid (11,17diHDoPE) can be synthesized in bacterial cells and exhibits anti-inflammatory effects in mammalian cells. This study investigates the in vivo impact of 11,17diHDoPE in mice exposed to particulate matter 10 (PM10). Our results indicate that 11,17diHDoPE significantly mitigates PM10-induced lung inflammation in mice, as evidenced by reduced pro-inflammatory cytokines and pulmonary inflammation-related gene expression. Metabolomic analysis reveals that 11,17diHDoPE modulates inflammation-related metabolites such as threonine, 2-keto gluconic acid, butanoic acid, and methyl oleate in lung tissues. In addition, 11,17diHDoPE upregulates the LA-derived oxylipin pathway and downregulates arachidonic acid- and docosahexaenoic acid-derived oxylipin pathways in serum. Correlation analyses between gene expression and metabolite changes suggest that 11,17diHDoPE alleviates inflammation by interfering with macrophage differentiation. These findings underscore the in vivo role of 11,17diHDoPE in reducing pulmonary inflammation, highlighting its potential as a therapeutic agent for respiratory diseases.
Current Advancements in Anti-Cancer Chimeric Antigen Receptor T Cell Immunotherapy and How Nanotechnology May Change the Game
Authors: Ku Kimberly S. , Tang Jie , Chen Yuan , Shi Yihui
Published: May 2024

Chimeric antigen receptor (CAR)-T cell immunotherapy represents a cutting-edge advancement in the landscape of cancer treatment. This innovative therapy has shown exceptional promise in targeting and eradicating malignant tumors, specifically leukemias and lymphomas. However, despite its groundbreaking successes, (CAR)-T cell therapy is not without its challenges. These challenges, particularly pronounced in the treatment of solid tumors, include but are not limited to, the selection of appropriate tumor antigens, managing therapy-related toxicity, overcoming T-cell exhaustion, and addressing the substantial financial costs associated with treatment. Nanomedicine, an interdisciplinary field that merges nanotechnology with medical science, offers novel strategies that could potentially address these limitations. Its application in cancer treatment has already led to significant advancements, including improved specificity in drug targeting, advancements in cancer diagnostics, enhanced imaging techniques, and strategies for long-term cancer prevention. The integration of nanomedicine with (CAR)-T cell therapy could revolutionize the treatment landscape by enhancing the delivery of genes in (CAR)-T cell engineering, reducing systemic toxicity, and alleviating the immunosuppressive effects within the tumor microenvironment. This review aims to explore how far (CAR)-T cell immunotherapy has come alone, and how nanomedicine could strengthen it into the future. Additionally, the review will examine strategies to limit the off-target effects and systemic toxicity associated with (CAR)-T cell therapy, potentially enhancing patient tolerance and treatment outcomes.
Apolipoprotein-CIII O-Glycosylation Is Associated with Micro- and Macrovascular Complications of Type 2 Diabetes
Authors: Naber Annemieke , Demus Daniel , Slieker Roderick C. , Nicolardi Simone , Beulens Joline W. J. , Elders Petra J. M. , Lieverse Aloysius G. , Sijbrands Eric J. G. , ‘t Hart Leen M. , Wuhrer Manfred , van Hoek Mandy
Published: May 2024

Apolipoprotein-CIII (apo-CIII) inhibits the clearance of triglycerides from circulation and is associated with an increased risk of diabetes complications. It exists in four main proteoforms: O-glycosylated variants containing either zero, one, or two sialic acids and a non-glycosylated variant. O-glycosylation may affect the metabolic functions of apo-CIII. We investigated the associations of apo-CIII glycosylation in blood plasma, measured by mass spectrometry of the intact protein, and genetic variants with micro- and macrovascular complications (retinopathy, nephropathy, neuropathy, cardiovascular disease) of type 2 diabetes in a DiaGene study (n = 1571) and the Hoorn DCS cohort (n = 5409). Mono-sialylated apolipoprotein-CIII (apo-CIII1) was associated with a reduced risk of retinopathy (β = −7.215, 95% CI −11.137 to −3.294) whereas disialylated apolipoprotein-CIII (apo-CIII2) was associated with an increased risk (β = 5.309, 95% CI 2.279 to 8.339). A variant of the GALNT2-gene (rs4846913), previously linked to lower apo-CIII0a, was associated with a decreased prevalence of retinopathy (OR = 0.739, 95% CI 0.575 to 0.951). Higher apo-CIII1 levels were associated with neuropathy (β = 7.706, 95% CI 2.317 to 13.095) and lower apo-CIII0a with macrovascular complications (β = −9.195, 95% CI −15.847 to −2.543). In conclusion, apo-CIII glycosylation was associated with the prevalence of micro- and macrovascular complications of diabetes. Moreover, a variant in the GALNT2-gene was associated with apo-CIII glycosylation and retinopathy, suggesting a causal effect. The findings facilitate a molecular understanding of the pathophysiology of diabetes complications and warrant consideration of apo-CIII glycosylation as a potential target in the prevention of diabetes complications.
Multiresistant Kawasaki Disease in a Young Infant with Giant Aneurysms Growing Fast
Authors: Amorim-Figueiredo Rosa , Pereira Lemos Ana , Rito Tiago , Conde Marta , Brito Maria João , Pinto Fátima
Published: May 2024

Background: Kawasaki disease (KD) is a type of vasculitis in which giant coronary artery aneurysms (CAAs) can occur. There are no specific guidelines for managing giant CAAs that develop quickly and are at risk of rupture. Regarding cardiovascular drugs, only beta-blockers are formally recommended in the acute phase of KD. Case presentation: A 6-month-old male patient with multiresistant Kawasaki disease and giant CAAs that continued to enlarge after controlling systemic inflammation was examined. The patient required three doses of intravenous immunoglobulin, methylprednisolone pulses, and anakinra and infliximab to normalize systemic inflammation. Due to the rapid increment of aneurysms’ dimensions and the risk of rupture, we introduced anticoagulant therapy and propranolol plus captopril, and titration doses were introduced according to a tolerated decrease in heart rate and arterial pressure. CAAs increment stabilized and slowly reduced their dimensions. Conclusions: The authors describe an atypical case of multiresistant KD with giant rapidly increasing CAAs even after controlling systemic inflammation. The introduction of a beta-blocker and an angiotensin-converting enzyme (ACE) inhibitor was demonstrated to be useful for stabilizing giant CAAs growth and reducing the potential risk of rupture.
Differences and Similarities in the Feet of Metatarsalgia Patients with and without Rheumatoid Arthritis in Remission
Authors: Bueno Fermoso Rebeca , Morales Lozano Maria Rosario , Nieto Cordero Marta , Martínez Rincón Carmen , García-Fernández Pablo , González Fernández María Luz
Published: May 2024

Objectives: Metatarsalgia continues to be a problem in patients with rheumatoid arthritis (RA) in remission (remRA), as well as in the non-rheumatic population, with a mechanical origin. Identify and compare clinical, morphological, disability, synovitis (ultrasound), and radiological osteoarticular damage characteristics in two groups of patients with lesser-ray metar-tarsalgia, with remRA, and without RA. Methods: Cross-sectional study with 84 patients with remRA (mRA) and 60 patients without RA (nmRA). The study evaluated five clinical variables (pain, Foot Function Index (FFI), joint mobility, digital deformities, and foot type), a radiological variable (osteoarticular damage), and an ultrasound variable (metatarsal synovitis). The data were analysed using descriptive and correlational techniques. Results: There were no significant differences in sex, age, body mass index (BMI), or degree of pain. Both groups showed a high prevalence of limited joint mobility for the ankle and first metatarsal phalanx (DF1st MTPJ) and digital deformities, with no statistically significant differences. Similarly, there were no differences in lesser-ray synovitis. On the other hand, there were differences in mRA with greater disability and activity limitation (FFI), LDD (lesser-ray digital deformities) stiffness, first-ray deformities, radiological damage, synovitis in 1st MTPJ, and positive Doppler (five patients). Conclusions: Metatarsalgia presents similarities in both populations. Biomechanical factors may influence the symptoms and presence of synovitis in patients with RA in remission. Other characteristics are more frequent in mRA, which could be related to the disease; thus, future research should include both biomechanical and ultrasound exploration of the foot in the valuation of patients in remission.
Long-Term Adherence to Continuous Positive Airway Pressure in Patients with Obstructive Sleep Apnoea Set Up in a Complete Remote Pathway: A Single-Centre Service Evaluation Project
Authors: Bikov Andras , Bentley Andrew , Csoma Balazs , Smith Nicola , Morris Bryn , Bokhari Saba
Published: May 2024

Background: Continuous positive airway pressure (CPAP) is the first-line treatment for obstructive sleep apnoea (OSA). Maintaining adherence to CPAP in the long term is a clinical problem, and numerous factors have been identified that impact adherence. Although fully remote diagnostic and CPAP services were frequently utilised during the COVID-19 pandemic for patients with OSA, long-term adherence data have not been published. The aim of this service evaluation project was to describe the long-term adherence to CPAP. We also analysed factors that are associated with it. Methods: two-hundred and eighty patients diagnosed with OSA and set up on CPAP remotely during the first wave of the COVID-19 pandemic as part of routine clinical practice were analysed. Results: One-hundred and seven patients (38%) were fully adherent to CPAP at 24 months, determined by at least 4 h of usage on at least 70% of the days. Of the factors analysed, body mass index, disease severity, driving status and the presence of depression were related to long-term adherence (all p < 0.05). Conclusions: with the likelihood of future pandemics similar to COVID-19, our data provide evidence that fully remote pathways for management of patients with OSA can be designed and be sustainable with good long-term adherence.
Exploring Vaping Patterns and Weight Management-Related Concerns among Adolescents and Young Adults: A Systematic Review
Authors: Mohapatra Srishti , Wisidagama Sharadha , Schifano Fabrizio
Published: May 2024

Background: Electronic cigarettes or vapes are battery-operated devices that heat a liquid, often containing nicotine and flavouring substances, to produce an inhalable aerosol. Despite being used as an alternative to traditional smoking, many studies have reported their health risks and ineffectiveness in smoking cessation. The impact of e-cigarettes on weight control behaviours, a known effect of traditional cigarette smoking, is unclear. Herein, a systematic review was conducted to explore the relationship between e-cigarette use and body weight changes in adolescents and young adults. Methods: The existing literature from databases such as PubMed, Cochrane Library, Embase, Science Direct, Web of Science, Scopus, and Google Scholar until October 2023 was searched and included in the review. The methodological quality of all selected studies was assessed using the Joanna Briggs Institute’s (JBI) Critical Appraisal Checklists for Studies. Results: Out of 5117 citations, 20 publications featuring cross-sectional studies with adolescent participants were qualitatively analysed. The high rates of e-cigarette usage seemed to correlate with increased weight concerns, particularly among females. Regular e-cigarette users who reported being overweight and used calorie restriction for weight reduction were more likely to view vaping as a weight loss or control strategy. Young adults (<24 years) may consume more flavoured e-cigarettes than older users (>25 years). Conclusions: This study revealed a significant use of e-cigarettes among high school students, driven by taste preferences, weight management, and perceived harm reduction. Particularly among girls facing body image pressures, vaping serves as a weight control method. This highlights the need to assess cardiovascular risks and advocate for further research, including longitudinal studies, to inform public health strategies effectively.
Intra-Individual Relationship between Heart Rate Variability and the Underlying Heart Rate in Children and Adolescents
Authors: Šišáková Martina , Helánová Kateřina , Hnatkova Katerina , Andršová Irena , Novotný Tomáš , Malik Marek
Published: May 2024

Background/Objective: The relationship between heart rate and heart rate variability (HRV) indices has been repeatedly studied in adults but limited data are available on the relationship in paediatric populations. Methods: Continuous 12-lead electrocardiograms were recorded in 1016 healthy children and adolescents (534 females) aged 4 to 19 years during postural manoeuvres with rapid changes between 10-min positions of supine → sitting → standing → supine → standing → sitting → supine. In each position, the averaged RR interval was measured together with four HRV indices, namely the SDNN, RMSSD, quasi-normalised high-frequency components (qnHF), and the proportions of low- and high-frequency components (LF/HF). In each subject, the slope of the linear regression between the repeated HRV measurements and the corresponding RR interval averages was calculated. Results: The intra-subject regression slopes, including their confidence intervals, were related to the age and sex of the subjects. The SDNN/RR, RMSSD/RR, and qnHF/RR slopes were significantly steeper (p < 0.001) and the (LF/HF)/RR slopes were significantly shallower (p < 0.001) in younger children compared to older children and adolescents. Conclusions: The study suggests that sympathetic and vagal influences on heart rate are present in both younger and older children. With advancing age, the sympatho-vagal balance gradually develops and allows the vagal control to suppress the sympathetic drive towards higher heart rates seen in younger age children.
Effect of Bleaching on Resin-Infiltration-Masked Artificial White Spots In Vitro
Authors: Sinanovic Alan Leon , Messer-Hannemann Philipp , Samadi Mariam , Schwendicke Falk , Effenberger Susanne
Published: May 2024

Resin infiltration is an effective method to mask vestibular white spots. If needed, external bleaching is usually recommended before infiltration, whilst in clinical practice, this sequence may not always be feasible. This in vitro study evaluated the effect of bleaching after resin infiltration regarding surface roughness and color using bovine incisors. Unlike for the untreated specimens (control, n = 25), artificial caries lesions were created within the test group (n = 25) using a demineralization solution at 37 °C for five days (pH = 4.95). The lesions were subsequently infiltrated using a resin infiltrant (Icon, DMG, Hamburg, Germany), followed by polishing. Afterwards, all specimens were bleached with a 10% carbamide peroxide gel (Opalescence, Ultradent, South Jordan, UT, USA) for 8 h/day over a ten-day period. Between bleaching treatments, specimens were stored in an opaque container with moistened paper tissues at 37 °C. Surface roughness was measured using a profilometer, and color in the L*a*b* space was assessed spectrophotometrically before and after bleaching. Bleaching increased the L*-values of both infiltrated (mean ± SD; ΔL* = 3.52 ± 1.98) and untreated (control) specimens (ΔL* = 3.53 ± 2.30) without any significant difference between the groups (p = 0.983). Bleaching also induced a significant increase in the mean surface roughness of both infiltrated (p < 0.001) and untreated (p = 0.0134) teeth. In terms of clinical relevance; it can be concluded that bleaching resin-infiltrated enamel is as effective as bleaching sound enamel.
Semi-Supervised Medical Image Segmentation Based on Deep Consistent Collaborative Learning
Authors: Zhao Xin , Wang Wenqi
Published: May 2024

In the realm of medical image analysis, the cost associated with acquiring accurately labeled data is prohibitively high. To address the issue of label scarcity, semi-supervised learning methods are employed, utilizing unlabeled data alongside a limited set of labeled data. This paper presents a novel semi-supervised medical segmentation framework, DCCLNet (deep consistency collaborative learning UNet), grounded in deep consistent co-learning. The framework synergistically integrates consistency learning from feature and input perturbations, coupled with collaborative training between CNN (convolutional neural networks) and ViT (vision transformer), to capitalize on the learning advantages offered by these two distinct paradigms. Feature perturbation involves the application of auxiliary decoders with varied feature disturbances to the main CNN backbone, enhancing the robustness of the CNN backbone through consistency constraints generated by the auxiliary and main decoders. Input perturbation employs an MT (mean teacher) architecture wherein the main network serves as the student model guided by a teacher model subjected to input perturbations. Collaborative training aims to improve the accuracy of the main networks by encouraging mutual learning between the CNN and ViT. Experiments conducted on publicly available datasets for ACDC (automated cardiac diagnosis challenge) and Prostate datasets yielded Dice coefficients of 0.890 and 0.812, respectively. Additionally, comprehensive ablation studies were performed to demonstrate the effectiveness of each methodological contribution in this study.
Seeing without a Scene: Neurological Observations on the Origin and Function of the Dorsal Visual Stream
Authors: Rafal Robert D.
Published: May 2024

In all vertebrates, visual signals from each visual field project to the opposite midbrain tectum (called the superior colliculus in mammals). The tectum/colliculus computes visual salience to select targets for context-contingent visually guided behavior: a frog will orient toward a small, moving stimulus (insect prey) but away from a large, looming stimulus (a predator). In mammals, visual signals competing for behavioral salience are also transmitted to the visual cortex, where they are integrated with collicular signals and then projected via the dorsal visual stream to the parietal and frontal cortices. To control visually guided behavior, visual signals must be encoded in body-centered (egocentric) coordinates, and so visual signals must be integrated with information encoding eye position in the orbit—where the individual is looking. Eye position information is derived from copies of eye movement signals transmitted from the colliculus to the frontal and parietal cortices. In the intraparietal cortex of the dorsal stream, eye movement signals from the colliculus are used to predict the sensory consequences of action. These eye position signals are integrated with retinotopic visual signals to generate scaffolding for a visual scene that contains goal-relevant objects that are seen to have spatial relationships with each other and with the observer. Patients with degeneration of the superior colliculus, although they can see, behave as though they are blind. Bilateral damage to the intraparietal cortex of the dorsal stream causes the visual scene to disappear, leaving awareness of only one object that is lost in space. This tutorial considers what we have learned from patients with damage to the colliculus, or to the intraparietal cortex, about how the phylogenetically older midbrain and the newer mammalian dorsal cortical visual stream jointly coordinate the experience of a spatially and temporally coherent visual scene.