bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional and Structural Leaf Plasticity Determine Photosynthetic Performances during Drought Stress and Recovery in Two Platanus orientalis Populations from Contrasting Habitats
Authors: Velikova Violeta , Arena Carmen , Izzo Luigi Gennaro , Tsonev Tsonko , Koleva Dimitrina , Tattini Massimiliano , Roeva Olympia , De Maio Anna , Loreto Francesco
Published: June 2020

In the context of climatic change, more severe and long-lasting droughts will modify the fitness of plants, with potentially worse consequences on the relict trees. We have investigated the leaf phenotypic (anatomical, physiological and biochemical) plasticity in well-watered, drought-stressed and re-watered plants of two populations of Platanus orientalis, an endangered species in the west of the Mediterranean area. The two populations originated in contrasting climate (drier and warmer, Italy (IT) population; more humid and colder, Bulgaria (BG) population). The IT control plants had thicker leaves, enabling them to maintain higher leaf water content in the dry environment, and more spongy parenchyma, which could improve water conductivity of these plants and may result in easier CO2 diffusion than in BG plants. Control BG plants were also characterized by higher photorespiration and leaf antioxidants compared to IT plants. BG plants responded to drought with greater leaf thickness shrinkage. Drought also caused substantial reduction in photosynthetic parameters of both IT and BG plants. After re-watering, photosynthesis did not fully recover in either of the two populations. However, IT leaves became thicker, while photorespiration in BG plants further increased, perhaps indicating sustained activation of defensive mechanisms. Overall, our hypothesis, that plants with a fragmented habitat (i.e., the IT population) lose phenotypic plasticity but acquire traits allowing better resistance to the climate where they became adapted, remains confirmed.
Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer’s Disease Therapy
Authors: Bautista-Aguilera Óscar M. , Ismaili Lhassane , Chioua Mourad , Andrys Rudolf , Schmidt Monika , Bzonek Petr , Martínez-Grau María Ángeles , Beadle Christopher D. , Vetman Tatiana , López-Muñoz Francisco , Iriepa Isabel , Refouvelet Bernard , Musilek Kamil , Marco-Contelles José
Published: June 2020

In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer’s disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 µM), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.
Impact of the Hereditary P301L Mutation on the Correlated Conformational Dynamics of Human Tau Protein Revealed by the Paramagnetic Relaxation Enhancement NMR Experiments
Authors: Kawasaki Ryosuke , Tate Shin-ichi
Published: June 2020

Tau forms intracellular insoluble aggregates as a neuropathological hallmark of Alzheimer’s disease. Tau is largely unstructured, which complicates the characterization of the tau aggregation process. Recent studies have demonstrated that tau samples two distinct conformational ensembles, each of which contains the soluble and aggregation-prone states of tau. A shift to populate the aggregation-prone ensemble may promote tau fibrillization. However, the mechanism of this ensemble transition remains elusive. In this study, we explored the conformational dynamics of a tau fragment by using paramagnetic relaxation enhancement (PRE) and interference (PRI) NMR experiments. The PRE correlation map showed that tau is composed of segments consisting of residues in correlated motions. Intriguingly, residues forming the β-structures in the heparin-induced tau filament coincide with residues in these segments, suggesting that each segment behaves as a structural unit in fibrillization. PRI data demonstrated that the P301L mutation exclusively alters the transiently formed tau structures by changing the short- and long-range correlated motions among residues. The transient conformations of P301L tau expose the amyloid motif PHF6 to promote tau self-aggregation. We propose the correlated motions among residues within tau determine the population sizes of the conformational ensembles, and perturbing the correlated motions populates the aggregation-prone form.
Norepinephrine Inhibits the Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells via β2-Adrenoceptor-Mediated ERK1/2 and PKA Phosphorylation
Authors: Hedderich Jessica , El Bagdadi Karima , Angele Peter , Grässel Susanne , Meurer Andrea , Straub Rainer H. , Zaucke Frank , Jenei-Lanzl Zsuzsa
Published: June 2020

Bone marrow-derived mesenchymal stem cells (BMSCs) represent an alternative to chondrocytes to support cartilage regeneration in osteoarthritis (OA). The sympathetic neurotransmitter norepinephrine (NE) has been shown to inhibit their chondrogenic potential; however, their proliferation capacity under NE influence has not been studied yet. Therefore, we used BMSCs obtained from trauma and OA donors and compared the expression of adrenergic receptors (AR). Then, BMSCs from both donor groups were treated with NE, as well as with combinations of NE and α1-, α2- or β1/2-AR antagonists (doxazosin, yohimbine or propranolol). Activation of AR-coupled signaling was investigated by analyzing ERK1/2 and protein kinase A (PKA) phosphorylation. A similar but not identical subset of ARs was expressed in trauma (α2B-, α2C- and β2-AR) and OA BMSCs (α2A-, α2B-, and β2-AR). NE in high concentrations inhibited the proliferation of both trauma and OA BMCSs significantly. NE in low concentrations did not influence proliferation. ERK1/2 as well as PKA were activated after NE treatment in both BMSC types. These effects were abolished only by propranolol. Our results demonstrate that NE inhibits the proliferation and accordingly lowers the regenerative capacity of human BMSCs likely via β2-AR-mediated ERK1/2 and PKA phosphorylation. Therefore, targeting β2-AR-signaling might provide novel OA therapeutic options.
Targeting Wnt Signaling for the Treatment of Gastric Cancer
Authors: Koushyar Sarah , Powell Arfon G. , Vincan Elizabeth , Phesse Toby J.
Published: June 2020

The Wnt signaling pathway is evolutionarily conserved, regulating both embryonic development and maintaining adult tissue homeostasis. Wnt signaling controls several fundamental cell functions, including proliferation, differentiation, migration, and stemness. It therefore plays an important role in the epithelial homeostasis and regeneration of the gastrointestinal tract. Often, both hypo- or hyper-activation of the pathway due to genetic, epigenetic, or receptor/ligand alterations are seen in many solid cancers, such as breast, colorectal, gastric, and prostate. Gastric cancer (GC) is the fourth commonest cause of cancer worldwide and is the second leading cause of cancer-related death annually. Although the number of new diagnoses has declined over recent decades, prognosis remains poor, with only 15% surviving to five years. Geographical differences in clinicopathological features are also apparent, with epidemiological and genetic studies revealing GC to be a highly heterogeneous disease with phenotypic diversity as a result of etiological factors. The molecular heterogeneity associated with GC dictates that a single ‘one size fits all’ approach to management is unlikely to be successful. Wnt pathway dysregulation has been observed in approximately 50% of GC tumors and may offer a novel therapeutic target for patients who would otherwise have a poor outcome. This mini review will highlight some recent discoveries involving Wnt signaling in GC.
Mitochondria: A Galaxy in the Hematopoietic and Leukemic Stem Cell Universe
Authors: Panuzzo Cristina , Jovanovski Aleksandar , Pergolizzi Barbara , Pironi Lucrezia , Stanga Serena , Fava Carmen , Cilloni Daniela
Published: June 2020

Mitochondria are the main fascinating energetic source into the cells. Their number, shape, and dynamism are controlled by the cell’s type and current behavior. The perturbation of the mitochondrial inward system via stress response and/or oncogenic insults could activate several trafficking molecular mechanisms with the intention to solve the problem. In this review, we aimed to clarify the crucial pathways in the mitochondrial system, dissecting the different metabolic defects, with a special emphasis on hematological malignancies. We investigated the pivotal role of mitochondria in the maintenance of hematopoietic stem cells (HSCs) and their main alterations that could induce malignant transformation, culminating in the generation of leukemic stem cells (LSCs). In addition, we presented an overview of LSCs mitochondrial dysregulated mechanisms in terms of (1) increasing in oxidative phosphorylation program (OXPHOS), as a crucial process for survival and self-renewal of LSCs,(2) low levels of reactive oxygen species (ROS), and (3) aberrant expression of B-cell lymphoma 2 (Bcl-2) with sustained mitophagy. Furthermore, these peculiarities may represent attractive new “hot spots” for mitochondrial-targeted therapy. Finally, we remark the potential of the LCS metabolic effectors to be exploited as novel therapeutic targets.
Role of GRK6 in the Regulation of Platelet Activation through Selective G Protein-Coupled Receptor (GPCR) Desensitization
Authors: Chaudhary Preeti Kumari , Kim Sanggu , Jee Youngheun , Lee Seung-Hun , Park Kyung-Mee , Kim Soochong
Published: June 2020

Platelet G protein-coupled receptors (GPCRs) regulate platelet function by mediating the response to various agonists, including adenosine diphosphate (ADP), thromboxane A2, and thrombin. Although GPCR kinases (GRKs) are considered to have the crucial roles in most GPCR functions, little is known regarding the regulation of GPCR signaling and mechanisms of GPCR desensitization by GRKs in platelets. In this study, we investigated the functional role of GRK6 and the molecular basis for regulation of specific GPCR desensitization by GRK6 in platelets. We used GRK6 knockout mice to evaluate the functional role of GRK6 in platelet activation. Platelet aggregation, dense- and α-granule secretion, and fibrinogen receptor activation induced by 2-MeSADP, U46619, thrombin, and AYPGKF were significantly potentiated in GRK6−/− platelets compared to the wild-type (WT) platelets. However, collagen-related peptide (CRP)-induced platelet aggregation and secretion were not affected in GRK6−/− platelets. Interestingly, platelet aggregation induced by co-stimulation of serotonin and epinephrine which activate Gq-coupled 5HT2A and Gz-coupled α2A adrenergic receptors, respectively, was not affected in GRK6−/− platelets, suggesting that GRK6 was involved in specific GPCR regulation. In addition, platelet aggregation in response to the second challenge of ADP and AYPGKF was restored in GRK6−/− platelets whereas re-stimulation of the agonist failed to induce aggregation in WT platelets, indicating that GRK6 contributed to P2Y1, P2Y12, and PAR4 receptor desensitization. Furthermore, 2-MeSADP-induced Akt phosphorylation and AYPGKF-induced Akt, extracellular signal-related kinase (ERK), and protein kinase Cδ (PKCδ) phosphorylation were significantly potentiated in GRK6−/− platelets. Finally, GRK6−/− mice exhibited an enhanced and stable thrombus formation after FeCl3 injury to the carotid artery and shorter tail bleeding times, indicating that GRK6−/− mice were more susceptible to thrombosis and hemostasis. We conclude that GRK6 plays an important role in regulating platelet functional responses and thrombus formation through selective GPCR desensitization.
Current Approaches and Applications in Avian Genome Editing
Authors: Lee Joonbum , Kim Dong-Hwan , Lee Kichoon
Published: June 2020

Advances in genome-editing technologies and sequencing of animal genomes enable researchers to generate genome-edited (GE) livestock as valuable animal models that benefit biological researches and biomedical and agricultural industries. As birds are an important species in biology and agriculture, their genome editing has gained significant interest and is mainly performed by using a primordial germ cell (PGC)-mediated method because pronuclear injection is not practical in the avian species. In this method, PGCs can be isolated, cultured, genetically edited in vitro, and injected into a recipient embryo to produce GE offspring. Recently, a couple of GE quail have been generated by using the newly developed adenovirus-mediated method. Without technically required in vitro procedures of the PGC-mediated method, direct injection of adenovirus into the avian blastoderm in the freshly laid eggs resulted in the production of germ-line chimera and GE offspring. As more approaches are available in avian genome editing, avian research in various fields will progress rapidly. In this review, we describe the development of avian genome editing and scientific and industrial applications of GE avian species.
NF-κB and Its Role in Checkpoint Control
Authors: Betzler Annika C. , Theodoraki Marie-Nicole , Schuler Patrick J. , Döscher Johannes , Laban Simon , Hoffmann Thomas K. , Brunner Cornelia
Published: June 2020

Nuclear factor-κB (NF-κB) has been described as one of the most important molecules linking inflammation to cancer. More recently, it has become clear that NF-κB is also involved in the regulation of immune checkpoint expression. Therapeutic approaches targeting immune checkpoint molecules, enabling the immune system to initiate immune responses against tumor cells, constitute a key breakthrough in cancer treatment. This review discusses recent evidence for an association of NF-κB and immune checkpoint expression and examines the therapeutic potential of inhibitors targeting either NF-κB directly or molecules involved in NF-κB regulation in combination with immune checkpoint blockade.
Oxytocin Controls Chondrogenesis and Correlates with Osteoarthritis
Authors: Roux Christian H. , Pisani Didier F. , Gillet Pierre , Fontas Eric , Yahia Hédi Ben , Djedaini Mansour , Ambrosetti Damien , Michiels Jean-François , Panaia-Ferrari Patricia , Breuil Véronique , Pinzano Astrid , Amri Ez-Zoubir
Published: June 2020

This study investigated the relationship of oxytocin (OT) to chondrogenesis and osteoarthritis (OA). Human bone marrow and multipotent adipose-derived stem cells were cultured in vitro in the absence or presence of OT and assayed for mRNA transcript expression along with histological and immunohistochemical analyses. To study the effects of OT in OA in vivo, a rat model and a human cohort of 63 men and 19 women with hand OA and healthy controls, respectively, were used. The baseline circulating OT, interleukin-6, leptin, and oestradiol levels were measured, and hand X-ray examinations were performed for each subject. OT induced increased aggrecan, collagen (Col) X, and cartilage oligomeric matrix protein mRNA transcript levels in vitro, and the immunolabelling experiments revealed a normalization of Sox9 and Col II protein expression levels. No histological differences in lesion severity were observed between rat OA groups. In the clinical study, a multivariate analysis adjusted for age, body mass index, and leptin levels revealed a significant association between OA and lower levels of OT (odds ratio = 0.77; p = 0.012). Serum OT levels are reduced in patients with hand OA, and OT showed a stimulatory effect on chondrogenesis. Thus, OT may contribute to the pathophysiology of OA.
SMARCB1 Acts as a Quiescent Gatekeeper for Cell Cycle and Immune Response in Human Cells
Authors: Choi Sung Kyung , Kim Myoung Jun , You Jueng Soo
Published: June 2020

Switch/sucrose non-fermentable (SWI/SNF)-related matrix-associated actin-dependent regulator of chromatin (SMARC) subfamily B member 1 (SMARCB1) is a core subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, one of the adenosine triphosphate (ATP)-dependent chromatin remodeler complexes. The unique role of SMARCB1 has been reported in various cellular contexts. Here, we focused on the general role of the ubiquitous expression of SMARCB1 in a normal cell state. We selected ARPE19 (human primary retinal pigment epithelium) and IMR90 (from human fetal lung fibroblasts) cell lines as they have completely different contexts. Furthermore, although these cell lines have been immortalized, they are relatively close to normal human cells. The loss of SMARCB1 in ARPE19 and IMR90 cells reduced cell cycle progression via the upregulation of P21. Transcriptome analysis followed by SMARCB1 knockdown in both cell lines revealed that SMARCB1 was not only involved in cell maintenance but also conferred immunomodulation. Of note, SMARCB1 bound to interleukin (IL) 6 promoter in a steady state and dissociated in an active immune response state, suggesting that SMARCB1 was a direct repressor of IL6, which was further confirmed via loss- and gain-of-function studies. Taken together, we demonstrated that SMARCB1 is a critical gatekeeper molecule of the cell cycle and immune response.
The ENDpoiNTs Project: Novel Testing Strategies for Endocrine Disruptors Linked to Developmental Neurotoxicity
Authors: Lupu Diana , Andersson Patrik , Bornehag Carl-Gustaf , Demeneix Barbara , Fritsche Ellen , Gennings Chris , Lichtensteiger Walter , Leist Marcel , Leonards Pim E. G. , Ponsonby Anne-Louise , Scholze Martin , Testa Giuseppe , Tresguerres Jesus A. F. , Westerink Remco H. S. , Zalc Bernard , Rüegg Joëlle
Published: June 2020

Ubiquitous exposure to endocrine-disrupting chemicals (EDCs) has caused serious concerns about the ability of these chemicals to affect neurodevelopment, among others. Since endocrine disruption (ED)-induced developmental neurotoxicity (DNT) is hardly covered by the chemical testing tools that are currently in regulatory use, the Horizon 2020 research and innovation action ENDpoiNTs has been launched to fill the scientific and methodological gaps related to the assessment of this type of chemical toxicity. The ENDpoiNTs project will generate new knowledge about ED-induced DNT and aims to develop and improve in vitro, in vivo, and in silico models pertaining to ED-linked DNT outcomes for chemical testing. This will be achieved by establishing correlative and causal links between known and novel neurodevelopmental endpoints and endocrine pathways through integration of molecular, cellular, and organismal data from in vitro and in vivo models. Based on this knowledge, the project aims to provide adverse outcome pathways (AOPs) for ED-induced DNT and to develop and integrate new testing tools with high relevance for human health into European and international regulatory frameworks.
Galectin-3 as the Prognostic Factor of Adverse Cardiovascular Events in Long-Term Follow up in Patients after Myocardial Infarction—A Pilot Study
Authors: Święcki Przemysław , Sawicki Robert , Knapp Małgorzata , Kamiński Karol Adam , Ptaszyńska-Kopczyńska Katarzyna , Sobkowicz Bożena , Lisowska Anna
Published: June 2020

Galectin-3 (Gal-3) is a new independent risk factor in the development and severity of coronary artery disease (CAD). The aim of the study was to evaluate whether Gal-3 concentration has prognostic value and if it reflects the progression of atherosclerosis in carotid arteries in patients with CAD after acute myocardial infarction (AMI). The analysis included 110 patients who were hospitalized due to AMI, treated with primary coronary intervention (PCI) and further attended a follow-up visit, and 100 healthy volunteers. The Gal-3 concentration and carotid ultrasound were evaluated at baseline and on a follow-up visit. We found that the Gal-3 concentration in the group with hyperlipidemia decreased during the observation (10.7 vs. 7.9 ng/mL, p = 0.00003). Patients rehospitalized during follow up had higher concentration of Gal-3 in the acute phase of myocardial infarction (MI) (10.7 vs. 7.2 ng/mL, p = 0.02; 10.1 vs. 8.0 ng/mL, p = 0.002, respectively). In the group of patients who had none of the following endpoints: subsequent MI, PCI, coronary artery bypass grafting (CABG) or stroke, there was a decrease in Gal-3 concentration at the follow-up visit. Parameters affecting the frequency of a composite endpoint occurrence are: the presence of atheromatous plaque in the carotid artery (p = 0.017), Gal-3 (p = 0.004) and haemoglobin (p = 0.03) concentration. In multivariate analysis, only Gal-3 concentration higher than 9.2 ng/mL at discharge was associated with a nine-fold increase of risk of composite endpoint occurrence (p = 0.0005, OR = 9.47, 95% CI 2.60–34.45). A significant decrease in Gal-3 concentration was observed in the group of patients after AMI without the endpoint occurrence during observation.
Short-Term Effects of PENS versus Dry Needling in Subjects with Unilateral Mechanical Neck Pain and Active Myofascial Trigger Points in Levator Scapulae Muscle: A Randomized Controlled Trial
Authors: Garcia-de-Miguel Santiago , Pecos-Martin Daniel , Larroca-Sanz Tamara , Sanz-de-Vicente Beatriz , Garcia-Montes Laura , Fernandez-Matias Ruben , Gallego-Izquierdo Tomas
Published: June 2020

Procedures such as dry needling (DN) or percutaneous electrical nerve stimulation (PENS) are commonly proposed for the treatment of myofascial trigger points (MTrP). The aim of the present study is to investigate if PENS is more effective than DN in the short term in subjects with mechanical neck pain. This was an evaluator-blinded randomized controlled trial. Subjects were recruited through announcements and randomly allocated into DN or PENS groups. Pain intensity, disability, pressure pain threshold (PPT), range of motion (ROM), and side-bending strength were measured. The analyses included mixed-model analyses of variance and pairwise comparisons with Bonferroni correction. The final sample was composed of 44 subjects (22 per group). Both groups showed improvements in pain intensity (ηp2 = 0.62; p < 0.01), disability (ηp2 = 0.74; p < 0.01), PPT (ηp2 = 0.79; p < 0.01), and strength (ηp2 = 0.37; p < 0.01). The PENS group showed greater improvements in disability (mean difference, 3.27; 95% CI, 0.27–6.27) and PPT (mean difference, 0.88–1.35; p < 0.01). Mixed results were obtained for ROM. PENS seems to produce greater improvements in PPT and disability in the short term.
EUS-Guided Versus Percutaneous Celiac Neurolysis for the Management of Intractable Pain Due to Unresectable Pancreatic Cancer: A Randomized Clinical Trial
Authors: Yoon Won Jae , Oh Yul , Yoo Changhoon , Jang Sunguk , Cho Seong-Sik , Suh Jeong-Hun , Choi Seong-Soo , Park Do Hyun
Published: June 2020

Although endoscopic ultrasound-guided celiac neurolysis (EUS-CN) and percutaneous celiac neurolysis (PCN) are utilized to manage intractable pain in pancreatic cancer patients, no direct comparison has been made between the two methods. We compared the efficacy and safety of EUS-CN and PCN in managing intractable pain in such patients. Sixty pancreatic cancer patients with intractable pain were randomly assigned to EUS-CN (n = 30) or PCN (n = 30). The primary outcomes were pain reduction in numerical rating scale (NRS) and opioid requirement reduction. Secondary outcomes were: successful pain response (NRS decrease ≥50% or ≥3-point reduction from baseline); quality of life; patient satisfaction; adverse events; and survival rate at 3 months postintervention. Both groups reported sustained decreases in pain scores up to 3 months postintervention (mean reductions in abdominal pain: 0.9 (95% confidence interval (CI): −0.8 to 4.2) and 1.7 (95% CI: −0.3 to 2.1); back pain: 1.3 (95% CI: −0.9 to 3.4) and 2.5 (95% CI: −0.2 to 5.2) in EUS-CN, and PCN groups, respectively). The differences in mean pain scores between the two groups at baseline and 3 months were −0.5 (p = 0.46) and −1.4 (p = 0.11) for abdominal pain and 0.1 (p = 0.85) and −0.9 (p = 0.31) for back pain in favor of PCN. No significant differences were noted in opioid requirement reduction and other outcomes. EUS-CN and PCN were similarly effective and safe in managing intractable pain in pancreatic cancer patients. Either methods may be used depending on the resources and expertise of each institution.
Severe Traumatic Brain Injury (TBI) Modulates the Kinetic Profile of the Inflammatory Response of Markers for Neuronal Damage
Authors: Schindler Cora Rebecca , Lustenberger Thomas , Woschek Mathias , Störmann Philipp , Henrich Dirk , Radermacher Peter , Marzi Ingo
Published: June 2020

The inflammatory response plays an important role in the pathophysiology of multiple injuries. This study examines the effects of severe trauma and inflammatory response on markers of neuronal damage. A retrospective analysis of prospectively collected data in 445 trauma patients (Injury Severity Score (ISS) ≥ 16) is provided. Levels of neuronal biomarkers (calcium-binding Protein B (S100b), Enolase2 (NSE), glial fibrillary acidic protein (GFAP)) and Interleukins (IL-6, IL-10) in severely injured patients (with polytrauma (PT)) without traumatic brain injury (TBI) or with severe TBI (PT+TBI) and patients with isolated TBI (isTBI) were measured upon arrival until day 5. S100b, NSE, GFAP levels showed a time-dependent decrease in all cohorts. Their expression was higher after multiple injuries (p = 0.038) comparing isTBI. Positive correlation of marker level after concomitant TBI and isTBI (p = 0.001) was noted, while marker expression after PT appears to be independent. Highest levels of IL-6 and -10 were associated to PT und lowest to isTBI (p < 0.001). In all groups pro-inflammatory response (IL-6/-10 ratio) peaked on day 2 and at a lower level on day 4. Severe TBI modulates kinetic profile of inflammatory response by reducing interleukin expression following trauma. Potential markers for neuronal damage have a limited diagnostic value after severe trauma because undifferentiated increase.
Association Analysis of TP53 rs1042522, MDM2 rs2279744, rs3730485, MDM4 rs4245739 Variants and Acute Myeloid Leukemia Susceptibility, Risk Stratification Scores, and Clinical Features: An Exploratory Study
Authors: Tripon Florin , Iancu Mihaela , Trifa Adrian , Crauciuc George Andrei , Boglis Alina , Balla Beata , Cosma Adriana , Dima Delia , Candea Marcela , Lazar Erzsebet , Jimbu Laura , Banescu Claudia
Published: June 2020

This study aimed to explore the associations between the TP53 rs1042522 (TP53 Arg72Pro), MDM2 rs2279744 (MDM2 309T>G), rs3730485 (MDM2 del1518), MDM4 rs4245739 (MDM4 34091 C>A) variants and odds of developing acute myeloid leukemia (AML) in a cohort of 809 adult subjects, consisting of 406 healthy controls and 403 AML patients. Model-based multifactor dimensionality reduction (MB-MDR) framework was used to identify the interactions of the mentioned variants and their association with AML risk. Associations of the mentioned variants with clinical features of AML, somatic mutations, and response to treatment were also evaluated. Significant associations between TP53 rs1042522 and MDM4 rs4245739 variants and AML susceptibility were noticed. MB-MDR and logistic regression analysis revealed an interaction between MDM2 rs2279744 and TP53 rs1042522, between MDM4 rs4245739 and MDM2 rs3730485, as well as significant associations with AML susceptibility. Several associations between the mentioned variants and clinical features of AML and somatic mutations were also noticed. Individually, the variant genotypes of TP53 rs1042522 and MDM4 rs4245739 were associated with AML susceptibility, but their interaction with MDM2 rs2279744 and rs3730485 modulated the risk for AML. The variant genotypes of TP53 rs1042522 were associated with adverse molecular and cytogenetic risk and also with NPM1 mutations.
Diagnostic Biomarkers for Alzheimer’s Disease Using Non-Invasive Specimens
Authors: Paraskevaidi Maria , Allsop David , Karim Salman , Martin Francis L. , Crean StJohn
Published: June 2020

Studies in the field of Alzheimer’s disease (AD) have shown the emergence of biomarkers in biologic fluids that hold great promise for the diagnosis of the disease. A diagnosis of AD at a presymptomatic or early stage may be the key for a successful treatment, with clinical trials currently investigating this. It is anticipated that preventative and therapeutic strategies may be stage-dependent, which means that they have a better chance of success at a very early stage—before critical neurons are lost. Several studies have been investigating the use of cerebrospinal fluid (CSF) and blood as clinical samples for the detection of AD with a number of established core markers, such as amyloid beta (Aβ), total tau (T-tau) and phosphorylated tau (P-tau), being at the center of clinical research interest. The use of oral samples—including saliva and buccal mucosal cells—falls under one of the least-investigated areas in AD diagnosis. Such samples have great potential to provide a completely non-invasive alternative to current CSF and blood sampling procedures. The present work is a thorough review of the results and analytical approaches, including proteomics, metabolomics, spectroscopy and microbiome analyses that have been used for the study and detection of AD using salivary samples and buccal cells. With a few exceptions, most of the studies utilizing oral samples were performed in small cohorts, which in combination with the existence of contradictory results render it difficult to come to a definitive conclusion on the value of oral markers. Proteins such as Aβ, T-tau and P-tau, as well as small metabolites, were detected in saliva and have shown some potential as future AD diagnostics. Future large-cohort studies and standardization of sample preparation and (pre-)analytical factors are necessary to determine the use of these non-invasive samples as a diagnostic tool for AD.
Identification of a miRNA Based-Signature Associated with Acute Coronary Syndrome: Evidence from the FLORINF Study
Authors: Elbaz Meyer , Faccini Julien , Laperche Clémence , Grousset Elisa , Roncalli Jérôme , Ruidavets Jean-Bernard , Vindis Cécile
Published: June 2020

Background: The discovery of novel biomarkers that improve risk prediction models of acute coronary syndrome (ACS) is needed to better identify and stratify very high-risk patients. MicroRNAs (miRNAs) are essential non-coding modulators of gene expression. Circulating miRNAs recently emerged as important regulators and fine-tuners of physiological and pathological cardiovascular processes; therefore, specific miRNAs expression profiles may represent new risk biomarkers. The aims of the present study were: (i) to assess the changes in circulating miRNAs levels associated with ACS and (ii) to evaluate the incremental value of adding circulating miRNAs to a clinical predictive risk model. Methods and Results: The study population included ACS patients (n = 99) and control subjects (n = 103) at high to very high cardiovascular risk but without known coronary event. Based on a miRNA profiling in a matched derivation case (n = −6) control (n = 6) cohort, 21 miRNAs were selected for validation. Comparing ACS cases versus controls, seven miRNAs were significantly differentially expressed. Multivariate logistic regression analyses demonstrated that among the seven miRNAs tested, five were independently associated with the occurrence of ACS. A receiver operating characteristic curve analysis revealed that the addition of miR-122 + miR-150 + miR-195 + miR-16 to the clinical model provided the best performance with an increased area under the curve (AUC) from 0.882 to 0.924 (95% CI 0.885–0.933, p = 0.003). Conclusions: Our study identified a powerful signature of circulating miRNAs providing additive value to traditional risk markers for ACS.
Caffeine and Gastric Emptying Time in Very Preterm Neonates
Authors: Gounaris Antonios K. , Grivea Ioanna N. , Baltogianni Maria , Gounari Eleni , Antonogeorgos George , Kokori Fedra , Panagiotounakou Polytimi , Theodoraki Martha , Konstantinidi Aikaterini , Sokou Rozeta
Published: June 2020

Background: Caffeine has been commonly used for prevention and treatment of apnea-related symptoms in premature infants. However, its side effects have not been thoroughly studied. We investigated whether caffeine affects gastric motility in very-preterm (VP) neonates. Methods: The study is a randomized crossover clinical trial. Twenty-two neonates with mean birth weight (BW) (standard deviation—SD) 1077 (229) g and mean gestational age (GA) (SD) 28.6 (2.1) weeks were recruited. Each neonate had its gastric emptying time checked twice with ultrasound assessment of changes in antral cross sectional area (ACSA). All neonates were sequentially allocated to the caffeine group (A) and the control group (B). Complications from the gastrointestinal tract were documented throughout the study. Results: Statistically significant difference was found with regards to the gastric emptying time [median, (range)] between caffeine and control group (p = 0.040). Additionally, in the neonates with BW 1000–1500 g and GA ≥ 28 weeks, the gastric emptying time (minutes) was significantly longer during caffeine treatment [44.5 (36–68.2)] and [40 (34.5–66.5)] respectively, as compared to the gastric emptying time during no caffeine treatment [27 (24.2–30)] (p = 0.002) and [27 (24.5–30)] (p = 0.001). The incidence of gastrointestinal (GI) complications was significantly greater in neonates receiving caffeine [6 (27.%)] as compared with those without caffeine treatment [1 (4.6%)] (p = 0.039). Conclusions: During caffeine treatment, a significantly delayed gastric emptying time was noted in all study neonates, especially in these with BW 1000–1500 g and those with GA ≥ 28 weeks. Further larger studies are necessary in order to confirm this interesting finding.
What Is the Impact of Intraoperative Microscope-Integrated OCT in Ophthalmic Surgery? Relevant Applications and Outcomes. A Systematic Review
Authors: Posarelli Chiara , Sartini Francesco , Casini Giamberto , Passani Andrea , Toro Mario Damiano , Vella Giovanna , Figus Michele
Published: June 2020

Background: Optical coherence tomography (OCT) has recently been introduced in the operating theatre. The aim of this review is to present the actual role of microscope-integrated optical coherence tomography (MI-OCT) in ophthalmology. Method: A total of 314 studies were identified, following a literature search adhering to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. After full-text evaluation, 81 studies discussing MI-OCT applications in ophthalmology were included. Results: At present, three microscope-integrated optical coherence tomography systems are commercially available. MI-OCT can help anterior and posterior segment surgeons in the decision-making process, providing direct visualization of anatomic planes before and after surgical manoeuvres, assisting in complex cases, and detecting or confirming intraoperative complications. Applications range from corneal transplant to macular surgery, including cataract surgery, glaucoma surgery, paediatric examination, proliferative diabetic retinopathy surgery, and retinal detachment surgery. Conclusion: The use of MI-OCT in ophthalmic surgery is becoming increasingly prevalent and has been applied in almost all procedures. However, there are still limitations to be overcome and the technology involved remains difficult to access and use.
Acute Coronary Syndromes and Covid-19: Exploring the Uncertainties
Authors: Schiavone Marco , Gobbi Cecilia , Biondi-Zoccai Giuseppe , D’Ascenzo Fabrizio , Palazzuoli Alberto , Gasperetti Alessio , Mitacchione Gianfranco , Viecca Maurizio , Galli Massimo , Fedele Francesco , Mancone Massimo , Forleo Giovanni Battista
Published: June 2020

Since an association between myocardial infarction (MI) and respiratory infections has been described for influenza viruses and other respiratory viral agents, understanding possible physiopathological links between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and acute coronary syndromes (ACS) is of the greatest importance. The initial data suggest an underestimation of ACS cases all over the world, but acute MI still represents a major cause of morbidity and mortality worldwide and should not be overshadowed during the coronavirus disease (Covid-19) pandemic. No common consensus regarding the most adequate healthcare management policy for ACS is currently available. Indeed, important differences have been reported between the measures employed to treat ACS in China during the first disease outbreak and what currently represents clinical practice across Europe and the USA. This review aims to discuss the pathophysiological links between MI, respiratory infections, and Covid-19; epidemiological data related to ACS at the time of the Covid-19 pandemic; and learnings that have emerged so far from several catheterization labs and coronary care units all over the world, in order to shed some light on the current strategies for optimal management of ACS patients with confirmed or suspected SARS-CoV-2 infection.
Relationship between Kidney Stone Disease and Arterial Stiffness in a Taiwanese Population
Authors: Sun Zih-Jie , Hsiao Hsuan-Jung , Cheng Hsiang-Ju , Chou Chieh-Ying , Lu Feng-Hwa , Yang Yi-Ching , Wu Jin-Shang , Chang Chih-Jen
Published: June 2020

Previous studies examining the association between kidney stone disease (KSD) and arterial stiffness have been limited. Both age and gender have been found to have an impact on KSD, but their influence on the relationship between KSD and increased arterial stiffness is unclear. This study included 6694 subjects from October 2006 to August 2009. The diagnosis of kidney stone was based on the results of ultrasonographic examination. Increased arterial stiffness was defined as right-sided brachial-ankle pulse wave velocity (baPWV) ≥ 14 m/s. Associations between KSD and increased arterial stiffness were analyzed using multiple logistic regression models. KSD was positively related to increased arterial stiffness in both male and female groups (males: odds ratio [OR], 1.306; 95% confidence interval [CI], 1.035–1.649; females: OR, 1.585; 95% CI, 1.038–2.419) after adjusting for confounding factors. Subgroup analysis by age group (<50 and ≥50 years) showed a significant positive relationship only in the groups ≥ 50 years for both genders (males: OR, 1.546; 95% CI, 1.111–2.151; females: OR, 1.783; 95% CI, 1.042–3.054), but not in the groups < 50 years. In conclusion, KSD is associated with a higher risk of increased arterial stiffness in individuals aged ≥ 50 years, but not in those aged < 50 years for both genders.
The Effect of Integrated Care Management on Dementia in Atrial Fibrillation
Authors: Yang Pil-Sung , Sung Jung-Hoon , Jang Eunsun , Yu Hee Tae , Kim Tae-Hoon , Uhm Jae-Sun , Kim Jong-Youn , Pak Hui-Nam , Lee Moon-Hyoung , Lip Gregory Y. H. , Joung Boyoung
Published: June 2020

Clinical outcomes of patients with atrial fibrillation (AF) can be improved by an integrated care approach. We analyzed whether adherence with the AF Better Care (ABC) pathway for integrated care management would reduce the risk of dementia in a nationwide AF cohort. Using the National Health Insurance Service database of Korea, 228,026 non-valvular AF patients were retrospectively evaluated between 2005 and 2015. Patients meeting all criteria of the ABC pathway were classified as the “ABC” group and those not classified as the “non-ABC” group. During a median (25th, 75th percentiles) follow-up of 6.0 (3.3, 9.5) years, the ABC group had lower rates and risk of overall dementia (0.17 vs. 1.11 per 100 person-years, p < 0.001; hazard ratio (HR) 0.80; 95% CI 0.73–0.87) and both Alzheimer’s (HR 0.79, 95% CI 0.71–0.88) and vascular dementia (HR 0.76, 95% CI 0.59–0.98) than the non-ABC group. The stratified analysis showed that the ABC pathway reduced the risk of dementia regardless of sex, comorbidities, and in patients with high stroke risk. Adherence with the ABC pathway is associated with a reduced risk of dementia in AF patients. Due to the high medical burden of AF, it is necessary to implement integrated AF management to reduce the risk of dementia.
Towards the Development of a Novel Ex Ovo Model of Infection to Pre-Screen Biomaterials Intended for Treating Chronic Wounds
Authors: García-Gareta Elena , Binkowska Justyna , Kohli Nupur , Sharma Vaibhav
Published: June 2020

This communication reports preliminary data towards the development of a live ex vivo model of persistent infection that is based on the chick embryo chorioallantoic membrane (CAM), which can be used for pre-screening biomaterials with antimicrobial properties for their antimicrobial and angiogenic potential. Our results showed that it was possible to infect chicken embryos with Staphylococcus aureus, one of the main types of bacteria found in the persistent infection associated with chronic wounds, and maintain the embryos’ survival for up to 48 h. Survival of the embryos varied with the dose of bacteria inoculum and with the use and time of streptomycin application after infection. In infected yet viable embryos, the blood vessels network of the CAM was maintained with minimal disruption. Microbiological tests could confirm embryo infection, but quantification was difficult. By publishing these preliminary results, we hope that not only our group but others within the scientific community further this research towards the establishment of biomimetic and reproducible ex vivo models of persistent infection.
Electronic Properties of a Synthetic Single-Crystal Diamond Exposed to High Temperature and High Radiation
Authors: Crnjac Andreo , Skukan Natko , Provatas Georgios , Rodriguez-Ramos Mauricio , Pomorski Michal , Jakšić Milko
Published: June 2020

Diamond, as a wide band-gap semiconductor material, has the potential to be exploited under a wide range of extreme operating conditions, including those used for radiation detectors. The radiation tolerance of a single-crystal chemical vapor deposition (scCVD) diamond detector was therefore investigated while heating the device to elevated temperatures. In this way, operation under both high-temperature and high-radiation conditions could be tested simultaneously. To selectively introduce damage in small areas of the detector material, a 5 MeV scanning proton microbeam was used as damaging radiation. The charge collection efficiency (CCE) in the damaged areas was monitored using 2 MeV protons and the ion beam induced charge (IBIC) technique, indicating that the CCE decreases with increasing temperature. This decreasing trend saturates in the temperature range of approximately 660 K, after which CCE recovery is observed. These results suggest that the radiation hardness of diamond detectors deteriorates at elevated temperatures, despite the annealing effects that are also observed. It should be noted that the diamond detector investigated herein retained its very good spectroscopic properties even at an operation temperature of 725 K (≈2% for 2 MeV protons).
Research of Binary and Ternary Composites Based on Selected Aliphatic or Aliphatic–Aromatic Polymers, 5CB or SWCN toward Biodegradable Electrodes
Authors: Fryń Patryk , Jewłoszewicz Beata , Bogdanowicz Krzysztof Artur , Przybył Wojciech , Gonciarz Agnieszka , Pich Robert , Marzec Monika , Iwan Agnieszka
Published: June 2020

The main goal of this paper was to study the optical, electrical, and thermal properties of hybrid composites based on biodegradable polymers (L,D-poly(lactic acid), polycaprolactone or Ecoflex®), single walled carbon nanotubes (SWCN), and 4′-pentyl-4-biphenylcarbonitrile (5CB). The biodegradable polymers’ binary and ternary compositions were analyzed in detail by ultraviolet and visible (UV–Vis) spectroscopy taking into consideration their chemical structure and interactions with 5CB and SWCN. Differential scanning calorimetry (DSC) studies of the created hybrid layers showed thermal stability and changes in glass transition temperature and melting point in comparison to neat polymers, depending on the chemical structure of the polymer used and the type of composition. Morphology of the created layers were investigated by atomic force and polarizing microscopy. The static contact angle measurements of a water drop showed that all of the neat polymer layers were hydrophobic with angle values ranging from 108° to 115°. In addition, in the case of the Ecoflex® layers, both with and without additives, a rapid sorption of the deposited water drop was observed. Finally, a simple device with poly(ethylene terephthalate) (PET)/indium tin oxide (ITO)/poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS)/poly [[4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b′]dithiophene-2,6-diyl][3-fluoro-2-[(2-ethylhexyl)carbonyl]thieno[3,4-b]thiophenediyl]] (PTB7): [6,6]-phenyl-C71-butyric acid methyl ester (PC70BM)/Ag/biodegradable polymer:SWCN architecture was constructed and tested using an infrared (IR) thermographic camera to investigate the surface defects on the created hybrid layers. Increasing the SWCN admixture from 0.01 to 0.5% significantly improved the conductivity only in the case of L,D-poly(lactic acid):SWCN (10:0.5), for which above 5 V, a current with a resistance of 3030.7 Ω could be measured. In order to use the created layers as flexible electrodes, the first experiments were carried out with an admixture of SWCN and poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) as conductive compounds.
Recent Advances in Applications of Cellulose Derivatives-Based Composite Membranes with Hydroxyapatite
Authors: Oprea Madalina , Voicu Stefan Ioan
Published: June 2020

The development of novel polymeric composites based on cellulose derivatives and hydroxyapatite represents a fascinating and challenging research topic in membranes science and technology. Cellulose-based materials are a viable alternative to synthetic polymers due to their favorable physico-chemical and biological characteristics. They are also an appropriate organic matrix for the incorporation of hydroxyapatite particles, inter and intramolecular hydrogen bonds, as well as electrostatic interactions being formed between the functional groups on the polymeric chains surface and the inorganic filler. The current review presents an overview on the main application fields of cellulose derivatives/hydroxyapatite composite membranes. Considering the versatility of hydroxyapatite particles, the hybrid materials offer favorable prospects for applications in water purification, tissue engineering, drug delivery, and hemodialysis. The preparation technique and the chemical composition have a big influence on the final membrane properties. The well-established membrane fabrication methods such as phase inversion, electrospinning, or gradual electrostatic assembly are discussed, together with the various strategies employed to obtain a homogenous dispersion of the inorganic particles in the polymeric matrix. Finally, the main conclusions and the future directions regarding the preparation and applications of cellulose derivatives/hydroxyapatite composite membranes are presented.