bluuebunny/crossref_metadata_2025 huggingface dataset:
STAT3 Differentially Regulates TLR4-Mediated Inflammatory Responses in Early or Late Phases
Authors: Ahuja Akash , Kim Eunji , Sung Gi-Ho , Cho Jae Youl
Published: October 2020

Toll-like receptor 4 (TLR4) signaling is an important therapeutic target to manage lipopolysaccharide (LPS)-induced inflammation. The transcription factor signal transducer and activator of transcription 3 (STAT3) has been identified as an important regulator of various immune-related diseases and has generated interest as a therapeutic target. Here, we investigated the time-dependent roles of STAT3 in LPS-stimulated RAW264.7 macrophages. STAT3 inhibition induced expression of the pro-inflammatory genes iNOS and COX-2 at early time points. STAT3 depletion resulted in regulation of nuclear translocation of nuclear factor (NF)-κB subunits p50 and p65 and IκBα/Akt/PI3K signaling. Moreover, we found that one Src family kinase, Lyn kinase, was phosphorylated in STAT3 knockout macrophages. In addition to using pharmacological inhibition of NF-κB, we found out that STAT3KO activation of NF-κB subunit p50 and p65 and expression of iNOS was significantly inhibited; furthermore, Akt tyrosine kinase inhibitors also inhibited iNOS and COX-2 gene expression during early time points of LPS stimulation, demonstrating an NF-κB- Akt-dependent mechanism. On the other hand, iNOS expression was downregulated after prolonged treatment with LPS. Activation of NF-κB signaling was also suppressed, and consequently, nitric oxide (NO) production and cell invasion were repressed. Overall, our data indicate that STAT3 differentially regulates early- and late-phase TLR4-mediated inflammatory responses.
Sodium-Glucose Co-Transporter 2 Inhibitors Correct Metabolic Maladaptation of Proximal Tubular Epithelial Cells in High-Glucose Conditions
Authors: Shirakawa Kohsuke , Sano Motoaki
Published: October 2020

Glucose filtered in the glomerulus is actively reabsorbed by sodium-glucose co-transporter 2 (SGLT2) in proximal tubular epithelial cells (PTEC) and passively returned to the blood via glucose transporter 2 (GLUT2). Healthy PTEC rely primarily on fatty acid beta-oxidation (FAO) for energy. In phase III trials, SGLT2 inhibitors improved outcomes in diabetic kidney disease (DKD). Tubulointerstitial renal fibrosis due to altered metabolic reprogramming of PTEC might be at the root of the pathogenesis of DKD. Here, we investigated the molecular mechanism of SGLT2 inhibitors’ renoprotective effect by examining transcriptional activity of Spp1, which encodes osteopontin, a key mediator of tubulointerstitial renal fibrosis. With primary cultured PTEC from Spp1-enhanced green fluorescent protein knock-in mice, we proved that in high-glucose conditions, increased SGLT2- and GLUT-mediated glucose uptake is causatively involved in aberrant activation of the glycolytic pathway in PTEC, thereby increasing mitochondrial reactive oxygen species (ROS) formation and transcriptional activation of Spp1. FAO activation did not play a direct role in these processes, but elevated expression of a tubular-specific enzyme, myo-inositol oxygenase, was at least partly involved. Notably, canagliflozin blocked overexpression of myo-inositol oxygenase. In conclusion, SGLT2 inhibitors exerted renoprotective effects by inhibiting aberrant glycolytic metabolism and mitochondrial ROS formation in PTEC in high-glucose conditions.
Binding Mode Exploration of B1 Receptor Antagonists’ by the Use of Molecular Dynamics and Docking Simulation—How Different Target Engagement Can Determine Different Biological Effects
Authors: Gemei Marica , Talarico Carmine , Brandolini Laura , Manelfi Candida , Za Lorena , Bovolenta Silvia , Liberati Chiara , Del Vecchio Luigi , Russo Roberto , Cerchia Carmen , Allegretti Marcello , Beccari Andrea Rosario
Published: October 2020

The kinin B1 receptor plays a critical role in the chronic phase of pain and inflammation. The development of B1 antagonists peaked in recent years but almost all promising molecules failed in clinical trials. Little is known about these molecules’ mechanisms of action and additional information will be necessary to exploit the potential of the B1 receptor. With the aim of contributing to the available knowledge of the pharmacology of B1 receptors, we designed and characterized a novel class of allosteric non-peptidic inhibitors with peculiar binding characteristics. Here, we report the binding mode analysis and pharmacological characterization of a new allosteric B1 antagonist, DFL20656. We analyzed the binding of DFL20656 by single point mutagenesis and radioligand binding assays and we further characterized its pharmacology in terms of IC50, B1 receptor internalization and in vivo activity in comparison with different known B1 antagonists. We highlighted how different binding modes of DFL20656 and a Merck compound (compound 14) within the same molecular pocket can affect the biological and pharmacological properties of B1 inhibitors. DFL20656, by its peculiar binding mode, involving tight interactions with N114, efficiently induced B1 receptor internalization and evoked a long-lasting effect in an in vivo model of neuropathic pain. The pharmacological characterization of different B1 antagonists highlighted the effects of their binding modes on activity, receptor occupancy and internalization. Our results suggest that part of the failure of most B1 inhibitors could be ascribed to a lack of knowledge about target function and engagement.
The Role of Inflammation and Myeloperoxidase-Related Oxidative Stress in the Pathogenesis of Genetically Triggered Thoracic Aortic Aneurysms
Authors: Malecki Cassandra , Hambly Brett D. , Jeremy Richmond W. , Robertson Elizabeth N.
Published: October 2020

Genetically triggered thoracic aortic aneurysms (TAAs) are usually considered to exhibit minimal levels of inflammation. However, emerging data demonstrate that specific features of an inflammatory response can be observed in TAA, and that the extent of the inflammatory response can be correlated with the severity, in both mouse models and in human studies. Myeloperoxidase (MPO) is a key mediator of the inflammatory response, via production of specific oxidative species, e.g., the hypohalous acids. Specific tissue modifications, mediated by hypohalous acids, have been documented in multiple cardiovascular pathologies, including atherosclerosis associated with coronary artery disease, abdominal aortic, and cerebral aneurysms. Similarly, data are now emerging that show the capacity of MPO-derived oxidative species to regulate mechanisms important in TAA pathogenesis, including alterations in extracellular matrix homeostasis, activation of matrix metalloproteinases, induction of endothelial dysfunction and vascular smooth muscle cell phenotypic switching, and activation of ERK1/2 signaling. The weight of evidence supports a role for inflammation in exacerbating the severity of TAA progression, expanding our understanding of the pathogenesis of TAA, identifying potential biomarkers for early detection of TAA, monitoring severity and progression, and for defining potential novel therapeutic targets.
Prostaglandin E2 Pathway Is Dysregulated in Gastric Adenocarcinoma in a Caucasian Population
Authors: Lopes Catarina , Pereira Carina , Farinha Mónica , Medeiros Rui , Dinis-Ribeiro Mário
Published: October 2020

Gastric cancer (GC) represents the third leading cause of cancer-related deaths worldwide. The levels of prostaglandin E2, a key player in the hallmarks of cancer, are mainly regulated by prostaglandin-endoperoxide synthase 2 (PTGS2) and ATP-binding cassette subfamily C member 4 (ABCC4), involved in its synthesis and exportation, respectively, and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and solute carrier organic anion transporter family member 2A1 (SLCO2A1), responsible for its inactivation. Even though there are distinct molecular signatures across ethnic populations, most published studies focus on Asian populations. Our main aim was to explore the genetic expression of the aforementioned molecules in a Caucasian population. 94 “Normal” and 89 tumoral formalin-fixed paraffin-embedded (FFPE) samples from GC patients were used to assess the mRNA expression of PTGS2, ABCC4, hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD), SLCO2A1 by Real-Time PCR. We found an upregulation for the PTGS2 gene mean factor of 2.51 and a downregulation for the HPGD and SLCO2A1 genes (mean factor of 0.10 and 0.37, respectively) in tumorous mucosa in a gender-independent manner. In females, we observed an ABCC4 downregulation and a PTGS2 mRNA upregulation compared to males in tumoral mucosa (mean factor of 0.61 and 1.64, respectively). We reported dysregulation of the inflammation triggered PGE2 pathway in a Caucasian population with an intermediate risk for GC, which might highlight the applicability of aspirin in the treatment of GC patients.
Modification of Serine 1040 of SIBRI1 Increases Fruit Yield by Enhancing Tolerance to Heat Stress in Tomato
Authors: Wang Shufen , Hu Tixu , Tian Aijuan , Luo Bote , Du Chenxi , Zhang Siwei , Huang Shuhua , Zhang Fei , Wang Xiaofeng
Published: October 2020

High temperature is a major environmental factor that adversely affects plant growth and production. SlBRI1 is a critical receptor in brassinosteroid signalling, and its phosphorylation sites have differential functions in plant growth and development. However, the roles of the phosphorylation sites of SIBRI1 in stress tolerance are unknown. In this study, we investigated the biological functions of the phosphorylation site serine 1040 (Ser-1040) of SlBRI1 in tomato. Phenotype analysis indicated that transgenic tomato harbouring SlBRI1 dephosphorylated at Ser-1040 showed increased tolerance to heat stress, exhibiting better plant growth and plant yield under high temperature than transgenic lines expressing SlBRI1 or SlBRI1 phosphorylated at Ser-1040. Biochemical and physiological analyses further showed that antioxidant activity, cell membrane integrity, osmo-protectant accumulation, photosynthesis and transcript levels of heat stress defence genes were all elevated in tomato plants harbouring SlBRI1 dephosphorylated at Ser-1040, and the autophosphorylation level of SlBRI1 was inhibited when SlBRI1 dephosphorylated at Ser-1040. Taken together, our results demonstrate that the phosphorylation site Ser-1040 of SlBRI1 affects heat tolerance, leading to improved plant growth and yield under high-temperature conditions. Our results also indicate the promise of phosphorylation site modification as an approach for protecting crop yields from high-temperature stress.
Hydroxylation of Antitubercular Drug Candidate, SQ109, by Mycobacterial Cytochrome P450
Authors: Bukhdruker Sergey , Varaksa Tatsiana , Grabovec Irina , Marin Egor , Shabunya Polina , Kadukova Maria , Grudinin Sergei , Kavaleuski Anton , Gusach Anastasiia , Gilep Andrei , Borshchevskiy Valentin , Strushkevich Natallia
Published: October 2020

Spreading of the multidrug-resistant (MDR) strains of the one of the most harmful pathogen Mycobacterium tuberculosis (Mtb) generates the need for new effective drugs. SQ109 showed activity against resistant Mtb and already advanced to Phase II/III clinical trials. Fast SQ109 degradation is attributed to the human liver Cytochrome P450s (CYPs). However, no information is available about interactions of the drug with Mtb CYPs. Here, we show that Mtb CYP124, previously assigned as a methyl-branched lipid monooxygenase, binds and hydroxylates SQ109 in vitro. A 1.25 Å-resolution crystal structure of the CYP124–SQ109 complex unambiguously shows two conformations of the drug, both positioned for hydroxylation of the ω-methyl group in the trans position. The hydroxylated SQ109 presumably forms stabilizing H-bonds with its target, Mycobacterial membrane protein Large 3 (MmpL3). We anticipate that Mtb CYPs could function as analogs of drug-metabolizing human CYPs affecting pharmacokinetics and pharmacodynamics of antitubercular (anti-TB) drugs.
Facts and Challenges in Immunotherapy for T-Cell Acute Lymphoblastic Leukemia
Authors: Bayón-Calderón Fátima , Toribio María L. , González-García Sara
Published: October 2020

T-cell acute lymphoblastic leukemia (T-ALL), a T-cell malignant disease that mainly affects children, is still a medical challenge, especially for refractory patients for whom therapeutic options are scarce. Recent advances in immunotherapy for B-cell malignancies based on increasingly efficacious monoclonal antibodies (mAbs) and chimeric antigen receptors (CARs) have been encouraging for non-responding or relapsing patients suffering from other aggressive cancers like T-ALL. However, secondary life-threatening T-cell immunodeficiency due to shared expression of targeted antigens by healthy and malignant T cells is a main drawback of mAb—or CAR-based immunotherapies for T-ALL and other T-cell malignancies. This review provides a comprehensive update on the different immunotherapeutic strategies that are being currently applied to T-ALL. We highlight recent progress on the identification of new potential targets showing promising preclinical results and discuss current challenges and opportunities for developing novel safe and efficacious immunotherapies for T-ALL.
Calcium Ionophore-Induced Extracellular Vesicles Mediate Cytoprotection against Simulated Ischemia/Reperfusion Injury in Cardiomyocyte-Derived Cell Lines by Inducing Heme Oxygenase 1
Authors: Pečan Peter , Hambalkó Szabolcs , Ha Van Thai , Nagy Csilla T. , Pelyhe Csilla , Lainšček Duško , Kenyeres Bence , Brenner Gábor B. , Görbe Anikó , Kittel Ágnes , Barteková Monika , Ferdinandy Péter , Manček-Keber Mateja , Giricz Zoltán
Published: October 2020

Cardioprotection against ischemia/reperfusion injury is still an unmet clinical need. The transient activation of Toll-like receptors (TLRs) has been implicated in cardioprotection, which may be achieved by treatment with blood-derived extracellular vesicles (EVs). However, since the isolation of EVs from blood takes considerable effort, the aim of our study was to establish a cellular model from which cardioprotective EVs can be isolated in a well-reproducible manner. EV release was induced in HEK293 cells with calcium ionophore A23187. EVs were characterized and cytoprotection was assessed in H9c2 and AC16 cell lines. Cardioprotection afforded by EVs and its mechanism were investigated after 16 h simulated ischemia and 2 h reperfusion. The induction of HEK293 cells by calcium ionophore resulted in the release of heterogenous populations of EVs. In H9c2 and AC16 cells, stressEVs induced the downstream signaling of TLR4 and heme oxygenase 1 (HO-1) expression in H9c2 cells. StressEVs decreased necrosis due to simulated ischemia/reperfusion injury in H9c2 and AC16 cells, which was independent of TLR4 induction, but not that of HO-1. Calcium ionophore-induced EVs exert cytoprotection by inducing HO-1 in a TLR4-independent manner.
miRNA Expression Profiles in Luminal A Breast Cancer—Implications in Biology, Prognosis, and Prediction of Response to Hormonal Treatment
Authors: Kudela Erik , Samec Marek , Koklesova Lenka , Liskova Alena , Kubatka Peter , Kozubik Erik , Rokos Tomas , Pribulova Terezia , Gabonova Eva , Smolar Marek , Biringer Kamil
Published: October 2020

Breast cancer, which is the most common malignancy in women, does not form a uniform nosological unit but represents a group of malignant diseases with specific clinical, histopathological, and molecular characteristics. The increasing knowledge of the complex pathophysiological web of processes connected with breast cancercarcinogenesis allows the development of predictive and prognostic gene expressionand molecular classification systems with improved risk assessment, which could be used for individualized treatment. In our review article, we present the up-to-date knowledge about the role of miRNAs and their prognostic and predictive value in luminal A breast cancer. Indeed, an altered expression profile of miRNAs can distinguish not only between cancer and healthy samples, but they can classify specific molecular subtypes of breast cancer including HER2, Luminal A, Luminal B, and TNBC. Early identification and classification of breast cancer subtypes using miRNA expression profilescharacterize a promising approach in the field of personalized medicine. A detection of sensitive and specific biomarkers to distinguish between healthy and early breast cancer patients can be achieved by an evaluation of the different expression of several miRNAs. Consequently, miRNAs represent a potential as good diagnostic, prognostic, predictive, and therapeutic biomarkers for patients with luminal A in the early stage of BC.
18F- based Quantification of the Osteogenic Potential of hMSCs
Authors: Grossner Tobias , Haberkorn Uwe , Gotterbarm Tobias
Published: October 2020

In bone tissue engineering, there is a constant need to design new methods for promoting in vitro osteogenic differentiation. Consequently, there is a strong demand for fast, effective and reliable methods to track and quantify osteogenesis in vitro. In this study, we used the radiopharmacon fluorine-18 (18F) to evaluate the amount of hydroxylapatite produced by mesenchymal stem cells (MSCs) in a monolayer cell culture in vitro. The hydroxylapatite bound tracer was evaluated using µ-positron emission tomography (µ-PET) scanning and activimeter analysis. It was therefore possible to determine the amount of synthesized mineral and thus to conclude the osteogenic potential of the cells. A Student’s t-test revealed a highly significant difference regarding tracer uptake between the osteogenic group and the corresponding control group (µ-PET p = 0.043; activimeter analysis p = 0.012). This tracer uptake showed a highly significant correlation with the gold standard of quantitative Alizarin Red staining (ARS) (r2 = 0.86) as well as with the absolute calcium content detected by inductively coupled plasma mass spectrometry (r2 = 0.81). The results showed that 18F labeling is a novel method to prove and quantify hydroxyapatite content in MSC monolayer cultures. The mineral layer remains intact for further analysis. This non-destructive in vitro method can be used to rapidly investigate bone tissue engineering strategies in terms of hydroxylapatite production, and could therefore accelerate the process of implementing new strategies in clinical practice.
Biodiversity Inventory and Distribution of Metriorrhynchina Net-Winged Beetles (Coleoptera: Lycidae), with the Identification of Generic Ranges
Authors: Bocak Ladislav , Motyka Michal , Kusy Dominik , Bilkova Renata
Published: October 2020

We reviewed the species-level classification of Metriorrhynchina net-winged beetles to make the group accessible for further studies. Altogether, 876 valid species are listed in a checklist along with known synonyms, combinations, and distribution data. The compilation of geographic distribution showed that Metriorrhynchina is distributed mainly in the Australian region with very high diversity in the islands at the northern edge of the Australian craton, i.e., in the Moluccas and New Guinea (54 and 423 spp. respectively). The neighboring northern part of the Australian continent houses a majority of known Australian species (112 spp.) and the diversity of net-winged beetles gradually decreases to the south (43 spp.). The fauna of Sulawesi is highly endemic at the generic level (4 of 10 genera, 67 of 84 spp.). Less Metriorrhynchina occur in the Solomon Islands and Oceania (in total 22 spp.). The Oriental Metriorrhynchina fauna consists of a few genera and a limited number of species, and most of these are known from the Philippines (51 of 94 Oriental spp.). We identified a high species level turn-over between all neighboring landmasses. The genus-level endemism is high in Sulawesi (4 genera) and New Guinea (11 genera), but only a single genus is endemic to Australia. During the compilation of the checklist, we identified some homonyms, and we propose the following replacement names and a new synonym: Metriorrhynchus pseudobasalis, nom. nov. for M. basalis Lea, 1921 nec M. basalis Bourgeois, 1911; Metriorrhynchus pseudofunestus, nom. nov. for M. funestus Lea, 1921 nec M. funestus (Guérin-Méneville, 1838), Trichalus pseudoternatensis, nom. nov. for T. ternatensis Kleine, 1930 nec T. ternatensis Bourgeois, 1900, Procautires subparallelus, nom. nov. for P. parallelus (Pic, 1926) nec P. parallelus (Bourgeois, 1883), and Cautires pseudocorporaali, nom. nov. for C. corporaali (Pic, 1921: 12), (formerly Odontocerus and Cladophorus) nec C. corporaali (Pic, 1921) (formerly Bulenides, later Cautires). Diatrichalus biroi Kleine, 1943, syn. nov. is proposed as a junior subjective synonym of D. subarcuatithorax (Pic, 1926). Altogether, 161 new combinations are proposed, and 47 species earlier placed in Xylobanus Waterhouse, 1879 transferred from Cautirina to Metriorrhynchina incertae sedis. The study clarifies the taxonomy of Metriorrhynchini and should serve as a restarting point for further taxonomic, evolutionary, and biogeographic studies.
Models of Diabrotica Populations: Demography, Population Genetics, Geographic Spread, and Management
Authors: Onstad David W. , Caprio Michael A. , Pan Zaiqi
Published: October 2020

Both Diabrotica virgifera virgifera LeConte and D. barberi Smith and Lawrence are among the most damaging insects impacting corn in North America. D. virgifera virgifera has also invaded Europe and has become an important pest in that region. Computer models have become an important tool for understanding the impact and spread of these important pests. Over the past 30 years, over 40 models have been published related to these pests. The focus of these models range from occupancy models (particularly for Europe), impact of climate change, range expansion, economics of pest management, phenology, to the evolution of resistance to toxins and crop rotation. All of these models share characteristics. We elaborate on the methods in which modelers have incorporated the biology of these pests, including density-dependence, movement, fecundity and overwintering mortality. We discuss the utility of both spatially-explicit, complex models and spatially-implicit, generational models and where each might be appropriate. We review resistance models that either explain past evolution to crop rotation, insecticides or insecticidal traits or attempt to predict the consequences of resistance management strategies.
MiRNAs Regulating Oxidative Stress: A Correlation with Doppler Sonography of Uteroplacental Complex and Clinical State Assessments of Newborns in Fetal Growth Restriction
Authors: Gusar Vladislava , Ganichkina Mariya , Chagovets Vitaliy , Kan Nataliya , Sukhikh Gennadiy
Published: October 2020

Overproduction of reactive oxygen species (ROS) and, as a result, uncontrolled oxidative stress (OS) can play a central role in disorders of fetal hemodynamics and subsequent development of adverse perinatal outcomes in newborns with fetal growth restriction (FGR). Given the epigenetic nature of such disorders, the aim of our study was to evaluate the expression of miRNAs associated with OS and endothelial dysfunction (miR-27a-3p, miR-30b-5p, miR-125b-5p, miR-221-3p, miR-451a and miR-574-3p) in umbilical cord blood using real-time quantitative RT-PCR. ΜiRNA expression was evaluated in patients with FGR delivery before (n = 9 pregnant) and after 34 weeks of gestation (n = 13 pregnant), and the control groups corresponding to the main groups by gestational age (13 pregnant women in each group, respectively). A significant increase in miR-451a expression was detected in late-onset FGR and correlations with fetoplacental and cerebral circulation were established (increase of resistance in the umbilical artery (pulsatility index, PI UA (umbilical artery): r = −0.59, p = 0.001) and a decrease in cerebral blood flow (CPR: r = 0.48, p = 0.009)). The change in miR-125b-5p expression in the placenta is associated with reduced Doppler of cerebral hemodynamics (CPR: r = 0.73, p = 0.003; PI MCA (middle cerebral artery): r = 0.79, p = 0.0007), and newborn weight (r = 0.56, p = 0.04) in early-onset FGR. In addition, significant changes in miR-125b-5p and miR-451a expression in umbilical cord blood plasma were found in newborns with neonatal respiratory distress syndrome (NRDS) (in early-onset FGR) and very low birth weight (VLBW) (in late-onset FGR). A number of key signaling pathways have been identified in which the regulation of the studied miRNAs is involved, including angiogenesis, neurotrophin signaling pathway and oxidative stress response. In general, our study showed that changes of the redox homeostasis in the mother-placenta-fetus system in FGR and subsequent perinatal outcomes may be due to differential expression of oxidative stress-associated miRNAs.
Acute Effects of Metformin and Vildagliptin after a Lipid-Rich Meal on Postprandial Microvascular Reactivity in Patients with Type 2 Diabetes and Obesity: A Randomized Trial
Authors: Schiappacassa Alessandra , Maranhão Priscila A. , Souza Maria das Graças Coelho de , Panazzolo Diogo G. , Nogueira Neto José Firmino , Bouskela Eliete , Kraemer-Aguiar Luiz Guilherme
Published: October 2020

Background: Type 2 diabetes mellitus and obesity are both related to endothelial dysfunction. Postprandial lipemia is a cardiovascular risk. Notably, it is known that a high-fat diet may elicit microvascular dysfunction, even in healthy subjects. Since anti-diabetic drugs have different mechanisms of action and also distinct vascular benefits, we aimed to compare the results of two anti-diabetic drugs after the intake of a lipid-rich meal on microcirculation in patients with type 2 diabetes and obesity. In parallel, we also investigated the metabolic profile, oxidative stress, inflammation, plasma viscosity, and some gastrointestinal peptides. Subjects/Methods: We included 38 drug-naïve patients, all women aged between 19 and 50 years, with BMI ≥ 30 kg/m2. We performed endothelial measurements and collected samples before (fasting) and after the intake of a lipid-rich meal at 30, 60, 120, and 180 min. Patients were randomized to metformin or vildagliptin, given orally just before the meal. Endothelial function was assessed by videocapillaroscopy and laser-Doppler flowmetry to investigate microvascular reactivity. Besides, we also investigated plasma viscosity, inflammatory and oxidative stress biomarkers, gastrointestinal peptides, and metabolic profile in all time points. Results: No differences at baseline were noted between groups. Vildagliptin increased glucagon-like peptide-1 compared to metformin. Paired comparisons showed that, during the postprandial period, vildagliptin significantly changed levels of insulin and glucagon-like peptide-1, and also the dipeptidyl peptidase-4 activity, while metformin had effects on plasma glucose solely. Metformin use during the test meal promoted an increase in functional capillary density, while vildagliptin kept non-nutritive microvascular blood flow and vasomotion unchanged. Conclusions: After the intake of a lipid-rich meal, the use of vildagliptin preserved postprandial non-nutritive microflow and vasomotion, while metformin increased capillary recruitment, suggesting protective and different mechanisms of action on microcirculation.
Daratumumab Monotherapy in Severe Patients with AL Amyloidosis and Biopsy-Proven Renal Involvement: A Real Life Experience
Authors: Roccatello Dario , Fenoglio Roberta , Naretto Carla , Baldovino Simone , Sciascia Savino , Ferro Michela , Rossi Daniela
Published: October 2020

Objectives: This paper aims to describe the clinical experience with Daratumumab (DARA), a first-in-class anti-CD38 human monoclonal IgG1κ antibody monotherapy, in severe patients with AL and biopsy-proven renal involvement. Immunoglobulin light chain (AL) amyloidosis with multi-organ involvement is characterized by short survival. Novel powerful drugs are expanding the therapeutic options. Current treatment of AL amyloidosis, which has been adopted from multiple myeloma (MM), is based on chemotherapy targeting the underlying plasma cell clone. DARA is effective in treating MM. The clinical activity and toxicity profile of DARA as a single agent in the treatment of AL amyloidosis is currently under evaluation. Patients and Methods: DARA was administered in a series of patients with severe AL amyloidosis and biopsy-proven renal involvement. Five patients(mean age 64.2 years) were treated. One patient was refractory and one intolerant to conventional bortezomib-based therapy, two were treated with DARA for relapsing disease, and one was treated front-line. Results: Data showed that DARA monotherapy resulted in good clinical results, with the disappearance of M-proteins in four out of five patients and with serum free light chains (sFLC) ratio normalization in three out of four and a remarkable amelioration in the remaining patient. The four patients with still preserved renal function at baseline also showed serum creatinine stabilization or improvement and a decrease in proteinuria. These data were paralleled by the reduction of the N-terminal prohormone of brain natriuretic peptide (NT pro-BNP)values. Conclusions: Our data show that monotherapy with DARA had significant clinical efficacy in pretreated/naïve patients with severe AL amyloidosis and biopsy-proven renal involvement.
Treatment with Intravenous Methylprednisolone in Patients with Graves’ Orbitopathy Significantly Affects Adrenal Function: Assessment of Serum, Salivary Cortisol and Serum Dehydroepiandrosterone Sulfate
Authors: Pelewicz Katarzyna , Szewczyk Sebastian , Miśkiewicz Piotr
Published: October 2020

Treatment of active, moderate-to-severe Graves’ orbitopathy (GO) is the administration of intravenous methylprednisolone (IVMP). IVMP may be followed by additional therapy with oral prednisone. The aim of this study was to analyze the impact of IVMP on adrenal function by evaluation of serum, salivary cortisol and serum dehydroepiandrosterone sulfate (DHEA-S). Fourteen patients received IVMP treatment (cumulative dose of 4.5 g in 12 weekly infusions) followed by oral prednisone (for three months). All patients showed normal adrenal function before the 12th IVMP pulse and one patient was diagnosed with secondary adrenal insufficiency (AI) after prednisone treatment. DHEA-S was significantly lower before the 12th IVMP pulse and after oral prednisone (p = 0.015 and p = 0.00002, respectively) in comparison to evaluation before therapy. DHEA-S levels were below the reference range in one and three patients before the 12th IVMP pulse and after prednisone therapy, respectively. We observed decreased serum (p = 0.05) and salivary (p = 0.011) cortisol levels after oral prednisone therapy in comparison to evaluation before therapy. Treatment with IVMP in a cumulative dose of 4.5 g affects adrenal function, causing more severe impairment of DHEA-S secretion than that of cortisol but does not cause secondary AI. Additional therapy with oral glucocorticoids after IVMP can cause secondary AI.
CoQ10 Deficient Endothelial Cell Culture Model for the Investigation of CoQ10 Blood–Brain Barrier Transport
Authors: Wainwright Luke , Hargreaves Iain P. , Georgian Ana R. , Turner Charles , Dalton R. Neil , Abbott N. Joan , Heales Simon J. R. , Preston Jane E.
Published: October 2020

Primary coenzyme Q10 (CoQ10) deficiency is unique among mitochondrial respiratory chain disorders in that it is potentially treatable if high-dose CoQ10 supplements are given in the early stages of the disease. While supplements improve peripheral abnormalities, neurological symptoms are only partially or temporarily ameliorated. The reasons for this refractory response to CoQ10 supplementation are unclear, however, a contributory factor may be the poor transfer of CoQ10 across the blood–brain barrier (BBB). The aim of this study was to investigate mechanisms of CoQ10 transport across the BBB, using normal and pathophysiological (CoQ10 deficient) cell culture models. The study identifies lipoprotein-associated CoQ10 transcytosis in both directions across the in vitro BBB. Uptake via SR-B1 (Scavenger Receptor) and RAGE (Receptor for Advanced Glycation Endproducts), is matched by efflux via LDLR (Low Density Lipoprotein Receptor) transporters, resulting in no “net” transport across the BBB. In the CoQ10 deficient model, BBB tight junctions were disrupted and CoQ10 “net” transport to the brain side increased. The addition of anti-oxidants did not improve CoQ10 uptake to the brain side. This study is the first to generate in vitro BBB endothelial cell models of CoQ10 deficiency, and the first to identify lipoprotein-associated uptake and efflux mechanisms regulating CoQ10 distribution across the BBB. The results imply that the uptake of exogenous CoQ10 into the brain might be improved by the administration of LDLR inhibitors, or by interventions to stimulate luminal activity of SR-B1 transporters.
Role of the Cyclooxygenase Pathway in the Association of Obstructive Sleep Apnea and Cancer
Authors: Picado César , Roca-Ferrer Jordi
Published: October 2020

The objective of this review is to examine the findings that link obstructive sleep apnea (OSA) with cancer and the role played by the cyclooxygenase (COX) pathway in this association. Epidemiological studies in humans suggest a link between OSA and increased cancer incidence and mortality. Studies carried out in animal models have shown that intermittent hypoxia (IH) induces changes in several signaling pathways involved in the regulation of host immunological surveillance that results in tumor establishment and invasion. IH induces the expression of cyclooxygenase 2 (COX-2) that results in an increased synthesis of prostaglandin E2 (PGE2). PGE2 modulates the function of multiple cells involved in immune responses including T lymphocytes, NK cells, dendritic cells, macrophages, and myeloid-derived suppressor cells. In a mouse model blockage of COX-2/PGE2 abrogated the pro-oncogenic effects of IH. Despite the fact that aspirin inhibits PGE2 production and prevents the development of cancer, none of the epidemiological studies that investigated the association of OSA and cancer included aspirin use in the analysis. Studies are needed to investigate the regulation of the COX-2/PGE2 pathway and PGE2 production in patients with OSA, to better define the role of this axis in the physiopathology of OSA and the potential role of aspirin in preventing the development of cancer.
A Novel Bioengineered Functional Motor Unit Platform to Study Neuromuscular Interaction
Authors: Saini Jasdeep , Faroni Alessandro , Reid Adam J. , Mamchaoui Kamel , Mouly Vincent , Butler-Browne Gillian , Lightfoot Adam P. , McPhee Jamie S. , Degens Hans , Al-Shanti Nasser
Published: October 2020

Background: In many neurodegenerative and muscular disorders, and loss of innervation in sarcopenia, improper reinnervation of muscle and dysfunction of the motor unit (MU) are key pathogenic features. In vivo studies of MUs are constrained due to difficulties isolating and extracting functional MUs, so there is a need for a simplified and reproducible system of engineered in vitro MUs. Objective: to develop and characterise a functional MU model in vitro, permitting the analysis of MU development and function. Methods: an immortalised human myoblast cell line was co-cultured with rat embryo spinal cord explants in a serum-free/growth fact media. MUs developed and the morphology of their components (neuromuscular junction (NMJ), myotubes and motor neurons) were characterised using immunocytochemistry, phase contrast and confocal microscopy. The function of the MU was evaluated through live observations and videography of spontaneous myotube contractions after challenge with cholinergic antagonists and glutamatergic agonists. Results: blocking acetylcholine receptors with α-bungarotoxin resulted in complete, cessation of myotube contractions, which was reversible with tubocurarine. Furthermore, myotube activity was significantly higher with the application of L-glutamic acid. All these observations indicate the formed MU are functional. Conclusion: a functional nerve-muscle co-culture model was established that has potential for drug screening and pathophysiological studies of neuromuscular interactions.
Incidence and Predictors of Unplanned Hospital Readmission after Percutaneous Coronary Intervention
Authors: Biswas Sinjini , Dinh Diem , Lucas Mark , Duffy Stephen J. , Brennan Angela L. , Liew Danny , Cox Nicholas , Nadurata Voltaire , Reid Christopher M. , Lefkovits Jeffrey , Stub Dion
Published: October 2020

Unplanned readmissions to hospital after percutaneous coronary intervention (PCI) pose a significant burden to the healthcare system and are potentially preventable. In this study, we sought to determine the incidence of, and risk factors for, unplanned hospital readmissions within 30 days following PCI. We prospectively collected data on 28,488 patients undergoing PCI between 2013 and 2019, who were enrolled in the state-wide multi-centre Victorian Cardiac Outcomes Registry. Patients’ data were then linked to data from the Victorian Department of Health administrative database that records statewide hospital admissions. Disease diagnosis codes were used to identify cause of readmission. Patients who had an unplanned readmission were further divided into those who had a cardiac vs. non-cardiac cause for readmission. Overall, 3059 patients (10.7%) had an unplanned hospital readmission within 30 days of PCI, of which 1848 patients (60.4%) were readmitted for primarily cardiac diagnoses. Independent predictors of both 30-day unplanned cardiac and non-cardiac readmissions post-PCI were female sex, having ≥1 admission in the 12 months prior to PCI, acute coronary syndrome presentation, having any in-hospital complication and being discharged on an oral anticoagulant (all p < 0.05). A stepwise increase in readmission risk was observed with increasing number of admissions from 1 to ≥4 admissions in the 12 months prior to PCI. In conclusion, a substantial proportion of patients undergoing PCI have unexpected readmissions to hospital in the 30 days following PCI. Targeted strategies for patients with risk factors for readmission may be useful to reduce this significant burden to the healthcare system.
Elderly or ageless? Physical Activity in the Aged Orthopaedic Patient
Authors: Pigozzi Fabio , Denaro Vincenzo
Published: October 2020

Progression of osteoarthritis in the elderly is often a synonym of impaired function, discontinuation of physical activity and sport participation [...]
Prevalence of Current and Past SARS-CoV-2 Infections among Police Employees in Poland, June–July 2020
Authors: Gujski Mariusz , Jankowski Mateusz , Pinkas Jarosław , Wierzba Waldemar , Samel-Kowalik Piotr , Zaczyński Artur , Jędrusik Piotr , Pańkowski Igor , Juszczyk Grzegorz , Rakocy Kamil , Raciborski Filip
Published: October 2020

Background: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to determine the prevalence of current and past SARS-CoV-2 infections among police employees. Methods: This cross-sectional survey was undertaken among 5082 police employees from Mazowieckie Province, Poland. RT-PCR testing for current SARS-CoV-2 infection and serological tests (ELISA) for the presence of anti-SARS-CoV-2 IgM+IgA and IgG antibodies were performed. Results: All RT-PCR tests were negative. The anti-SARS-CoV-2 IgM+IgA index was positive (>8) in 8.9% of participants, including 11.2% women and 7.7% men (p < 0.001). Equivocal IgM+IgA index (6–8) was found in 9.8% of participants, including 11.9% women and 8.7% men (p < 0.001). The IgG index was positive (>6) in 4.3% and equivocal (4–6) in 13.2% of participants. A higher odds of positive IgM+IgA index was found in women vs. men (OR: 1.742) and police officers vs. civilian employees (OR: 1.411). Participants aged ≥60 years had a higher odds of positive IgG index vs. those aged 20–29 years (OR: 3.309). Daily vaping also increased the odds of positive IgG index (OR: 2.058). Conclusions: The majority of Polish police employees are seronegative for SARS-CoV-2 infection. Vaping and older age (≥60 years) were associated with a higher risk of SARS-CoV-2 infection.
Mindfulness-Based Program Plus Amygdala and Insula Retraining (MAIR) for the Treatment of Women with Fibromyalgia: A Pilot Randomized Controlled Trial
Authors: Sanabria-Mazo Juan P. , Montero-Marin Jesus , Feliu-Soler Albert , Gasión Virginia , Navarro-Gil Mayte , Morillo-Sarto Héctor , Colomer-Carbonell Ariadna , Borràs Xavier , Tops Mattie , Luciano Juan V. , García-Campayo Javier
Published: October 2020

The lack of highly effective treatments for fibromyalgia (FM) represents a great challenge for public health. The objective of this parallel, pilot randomized controlled trial (RCT) was two-fold: (1) to analyze the clinical effects of mindfulness plus amygdala and insula retraining (MAIR) compared to a structurally equivalent active control group of relaxation therapy (RT) in the treatment of FM; and (2) to evaluate its impact on immune-inflammatory markers and brain-derived neurotrophic factor (BDNF) in serum. A total of 41 FM patients were randomized into two study arms: MAIR (intervention group) and RT (active control group), both as add-ons of treatment as usual. MAIR demonstrated significantly greater reductions in functional impairment, anxiety, and depression, as well as higher improvements in mindfulness, and self-compassion at post-treatment and follow-up, with moderate to large effect sizes. Significant decreases in pain catastrophizing and psychological inflexibility and improvements in clinical severity and health-related quality of life were found at follow-up, but not at post-treatment, showing large effect sizes. The number needed to treat was three based on the criteria of ≥50% Fibromyalgia Impact Questionnaire (FIQ) reduction post-treatment. Compared to RT, the MAIR showed significant decreases in BDNF. No effect of MAIR was observed in immune-inflammatory biomarkers (i.e., TNF-α, IL-6, IL-10, and hs-CRP). In conclusion, these results suggest that MAIR, as an adjuvant of treatment-as-usual (TAU), appears to be effective for the management of FM symptoms and for reducing BDNF levels in serum.
Mid-to Long-Term Survival of Total Knee Arthroplasty in Hemophilic Arthropathy
Authors: Bae Jung-Kwon , Kim Kang-Il , Lee Sang-Hak , Yoo Myung-Chul
Published: October 2020

While satisfactory results have been reported during short-to mid-term follow-up assessments of hemophilic patients who have undergone total knee arthroplasty (TKA), limited literature focusing on long-term survival following TKA exists to date. As part of this investigation, a consecutive series of 78 TKAs in 56 patients with hemophilic arthropathy was reviewed. The mean patient age at the time of operation was 38.7 years old and the mean length of follow up was 10.2 years. Clinical and radiologic outcomes, quality of life, complications, and long-term survivorship of TKA were evaluated. At the latest point of follow up, the average American Knee Society (AKS) knee and function scores had improved from 32.1 to 85.7 points and 41.5 to 83.3 points, respectively. Moreover, the average range of motion (ROM) was significantly increased from 64.2° preoperatively to 84.2° postoperatively. The physical and mental Short Form-36 results were also significantly improved at the latest point of follow up. Postoperative complications appeared in 12 knees (15.4%). The readmission rate in the 30 days after discharge was 6.4%. Revision TKA was performed in three knees for periprosthetic joint infection (n = 2 knees) and tibial component loosening (n = 1 knee). The Kaplan–Meier 10- and 13-year prosthesis survival rates were 97.1% and 93.2%, respectively. The current study suggests that the mid-to long-term results of TKA in patients with hemophilic arthropathy are favorable, with successful long-term prosthesis survival achievable in most cases.
Immune Activation and Anemia Are Associated with Decreased Quality of Life in Patients with Solid Tumors
Authors: Kink Patricia , Egger Eva Maria , Lanser Lukas , Klaunzner Michaela , Holzner Bernhard , Willenbacher Wolfgang , Kasseroler Maria Theresia , Fuchs Dietmar , Weiss Günter , Kurz Katharina
Published: October 2020

Anemia often coincides with depression and impaired quality of life (QoL) in cancer patients. Sustained immune activation can lead to the development of anemia. Furthermore, it also may go along with changes in tryptophan and phenylalanine metabolism. The aim of our pilot study was to study the relationship between anemia, immune-mediated changes in amino acid metabolism, and the QoL and mood of cancer patients. Questionnaires to measure QoL and depression were completed by 152 patients with solid tumors. Hemoglobin, parameters of immune activation as well as tryptophan and phenylalanine metabolism were determined in the patients’ sera. Anemic patients (51.7%) presented with higher inflammatory markers, and a higher tryptophan breakdown with lower tryptophan concentrations. They reported an impaired QoL and had higher depression scores. Patients with an impaired QoL (65.8%) also suffered from more fatigue and impaired physical, emotional, and social functioning. They, furthermore, presented with higher concentrations of inflammatory markers (C-reactive protein (CRP) and neopterin) as well as higher tryptophan degradation (in men) and higher phenylalanine concentrations (in women). Sixty-one patients (40.1%) had (mostly mild) depression. In these patients, a higher degree of Th1 immune activation was found. The results of our study suggest that cancer-related anemia goes along with an impaired QoL, which is also associated with immune-mediated disturbances of tryptophan and phenylalanine metabolism.
Temporomandibular Disorders and Bruxism Outbreak as a Possible Factor of Orofacial Pain Worsening during the COVID-19 Pandemic—Concomitant Research in Two Countries
Authors: Emodi-Perlman Alona , Eli Ilana , Smardz Joanna , Uziel Nir , Wieckiewicz Gniewko , Gilon Efrat , Grychowska Natalia , Wieckiewicz Mieszko
Published: October 2020

Background: In late December 2019, a new pandemic caused by the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection began to spread around the world. The new situation gave rise to severe health threats, economic uncertainty, and social isolation, causing potential deleterious effects on people’s physical and mental health. These effects are capable of influencing oral and maxillofacial conditions, such as temporomandibular disorders (TMD) and bruxism, which could further aggravate the orofacial pain. Two concomitant studies aimed to evaluate the effect of the current pandemic on the possible prevalence and worsening of TMD and bruxism symptoms among subjects selected from two culturally different countries: Israel and Poland. Materials and Methods: Studies were conducted as cross-sectional online surveys using similar anonymous questionnaires during the lockdown practiced in both countries. The authors obtained 700 complete responses from Israel and 1092 from Poland. In the first step, data concerning TMDs and bruxism were compared between the two countries. In the second step, univariate analyses (Chi2) were performed to investigate the effects of anxiety, depression, and personal concerns of the Coronavirus pandemic, on the symptoms of TMD, and bruxism symptoms and their possible aggravation. Finally, multivariate analyses (logistic regression models) were carried out to identify the study variables that had a predictive value on TMD, bruxism, and symptom aggravation in the two countries. Results: The results showed that the Coronavirus pandemic has caused significant adverse effects on the psychoemotional status of both Israeli and Polish populations, resulting in the intensification of their bruxism and TMD symptoms. Conclusions: The aggravation of the psychoemotional status caused by the Coronavirus pandemic can result in bruxism and TMD symptoms intensification and thus lead to increased orofacial pain.