bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of Acute Loud Noise on the Behavior of Laboratory Birds
Authors: Corbani Tayanne L. , Martin Jessica E. , Healy Susan D.
Published: January 2021

Husbandry procedures and facility settings, such as low-frequency fire alarms, can produce noises in a laboratory environment that cause stress to animals used in research. However, most of the data demonstrating harmful effects that have, consequently, led to adaptations to management, have largely come from laboratory rodents with little known of the impacts on avian behavior and physiology. Here we examined whether exposure to a routine laboratory noise, a low-frequency fire alarm test, induced behavioral changes in laboratory zebra finches (Taeniopygia guttata). Twenty-four breeding pairs of zebra finches were randomly selected and exposed to the low-frequency fire alarm (sounding for 10–20 s) or no noise (control) on separate test days. All birds were filmed before and after the alarm sounded and on a control day (without the alarm). The zebra finches decreased their general activity and increased stationary and social behaviors after exposure to the alarm. Brief exposure to a low-frequency alarm disrupted the birds' behavior for at least 15 min. The induction of this behavioral stress response suggests that low-frequency sound alarms in laboratory facilities have the potential to compromise the welfare of laboratory birds.
Circulating Tumor Cells and Bevacizumab Pharmacokinetics during Neoadjuvant Treatment Combining Chemotherapy and Bevacizumab for Early Breast Cancer: Ancillary Analysis of the AVASTEM Trial
Authors: Sabatier Renaud , Pierga Jean-Yves , Curé Hervé , Abulnaja Rakan , Lambaudie Eric , Bidard François-Clément , Extra Jean-Marc , Sfumato Patrick , Gonçalves Anthony
Published: January 2021

The phase II AVASTEM trial explored the impact of chemotherapy-bevacizumab combination on breast cancer stem cells in the neoadjuvant setting. We aimed to identify biological features associated with preoperative chemotherapy efficacy and prognosis by analyses of circulating tumor cells (CTCs) and bevacizumab pharmacokinetics (PK). The main objective was to assess the prognostic (relapse-free survival and overall survival) and predictive (pathological complete response, pCR) values of CTCs (CellSearch technology) and bevacizumab PK (ELISA). Seventy-five patients were included. Out of them 50 received bevacizumab-chemotherapy and 25 received chemotherapy alone. CTC results were available for 60 patients and PK data for 29 patients in the experimental arm. The absence of CTC at inclusion was correlated to better outcome. Five-years overall survival (OS) was 91% for CTC-negative patients vs. 54% for CTC-positive cases (HR = 6.21; 95%CI (1.75–22.06), p = 0.001, log-rank test). Similar results were observed for RFS with 5 y-RFS of 78% vs. 44% (HR = 3.51; 95%CI (1.17–10.52), p = 0.017, log-rank test). However, CTC status at baseline was not predictive of pCR (p = 0.74). CTC status after one cycle was not a significant prognostic factor (HR = 1.56; 95%CI (0.19–12.67); p = 0.68 for OS and HR = 2.76; 95%CI (0.60–12.61); p = 0.17 for RFS, log-rank test). Bevacizumab serum levels could not predict pCR and survival. PK values were not associated with treatment-related toxicities. In conclusion, CTCs detection at baseline is a prognostic marker for breast cancer receiving a neoadjuvant chemotherapy-bevacizumab combination independently of tumor response.
Stromal Protein-Mediated Immune Regulation in Digestive Cancers
Authors: Gamradt Pia , De La Fouchardière Christelle , Hennino Ana
Published: January 2021

The stromal tumor microenvironment (TME) consists of immune cells, vascular and neural structures, cancer-associated fibroblasts (CAFs), as well as extracellular matrix (ECM), and favors immune escape mechanisms promoting the initiation and progression of digestive cancers. Numerous ECM proteins released by stromal and tumor cells are crucial in providing physical rigidity to the TME, though they are also key regulators of the immune response against cancer cells by interacting directly with immune cells or engaging with immune regulatory molecules. Here, we discuss current knowledge of stromal proteins in digestive cancers including pancreatic cancer, colorectal cancer, and gastric cancer, focusing on their functions in inhibiting tumor immunity and enabling drug resistance. Moreover, we will discuss the implication of stromal proteins as therapeutic targets to unleash efficient immunotherapy-based treatments.
Specific and Sensitive Detection of Neuroblastoma mRNA Markers by Multiplex RT-qPCR
Authors: van Zogchel Lieke M. J. , Zappeij-Kannegieter Lily , Javadi Ahmad , Lugtigheid Marjolein , Gelineau Nina U. , Lak Nathalie S. M. , Zwijnenburg Danny A. , Koster Jan , Stutterheim Janine , van der Schoot C. Ellen , Tytgat Godelieve A. M.
Published: January 2021

mRNA RT-qPCR is shown to be a very sensitive technique to detect minimal residual disease (MRD) in patients with neuroblastoma. Multiple mRNA markers are known to detect heterogeneous neuroblastoma cells in bone marrow (BM) or blood from patients. However, the limited volumes of BM and blood available can hamper the detection of multiple markers. To make optimal use of these samples, we developed a multiplex RT-qPCR for the detection of MRD in neuroblastoma. GUSB and PHOX2B were tested as single markers. The adrenergic markers TH, GAP43, CHRNA3 and DBH and mesenchymal markers POSTN, PRRX1 and FMO3 were tested in multiplex. Using control blood and BM, we established new thresholds for positivity. Comparison of multiplex and singleplex RT-qPCR results from 21 blood and 24 BM samples from neuroblastoma patients demonstrated a comparable sensitivity. With this multiplex RT-qPCR, we are able to test seven different neuroblastoma mRNA markers, which overcomes tumor heterogeneity and improves sensitivity of MRD detection, even in those samples of low RNA quantity. With resources and time being saved, reduction in sample volume and consumables can assist in the introduction of MRD by RT-qPCR into clinical practice.
Mechanisms of Resistance to KRASG12C Inhibitors
Authors: Dunnett-Kane Victoria , Nicola Pantelis , Blackhall Fiona , Lindsay Colin
Published: January 2021

KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of “undruggable”. Recent efforts to produce subtype specific inhibitors have been more successful, and several KRASG12C inhibitors have reached clinical trials, including adagrasib and sotorasib, which have shown early evidence of efficacy in patients. Lessons from other inhibitors of the RAS pathway suggest that the effect of these drugs will be limited in vivo by the development of drug resistance, and pre-clinical studies of G12C inhibitors have identified evidence of this. In this review we discuss the current evidence for G12C inhibitors, the mechanisms of resistance to G12C inhibitors and potential approaches to overcome them. We discuss possible targets of combination therapy, including SHP2, receptor tyrosine kinases, downstream effectors and PD1/PDL1, and review the ongoing clinical trials investigating these inhibitors.
Prolonged Diagnostic Intervals as Marker of Missed Diagnostic Opportunities in Bladder and Kidney Cancer Patients with Alarm Features: A Longitudinal Linked Data Study
Authors: Zhou Yin , Walter Fiona M. , Singh Hardeep , Hamilton William , Abel Gary A. , Lyratzopoulos Georgios
Published: January 2021

Background: In England, patients who meet National Institute for Health and Care Excellence (NICE) guideline criteria for suspected cancer should receive a specialist assessment within 14 days. We examined how quickly bladder and kidney cancer patients who met fast-track referral criteria were actually diagnosed. Methods: We used linked primary care and cancer registration data on bladder and kidney cancer patients who met fast-track referral criteria and examined the time from their first presentation with alarm features to diagnosis. Using logistic regression we examined factors most likely to be associated with non-timely diagnosis (defined as intervals exceeding 90 days), adjusting for age, sex and cancer type, positing that such occurrences represent missed opportunity for timely referral, possibly due to sub-optimal guideline adherence. Results: 28%, 42% and 31% of all urological cancer patients reported no, one or two or more relevant symptoms respectively in the year before diagnosis. Of the 2105 patients with alarm features warranting fast-track assessment, 1373 (65%) presented with unexplained haematuria, 382 (18%) with recurrent urinary tract infections (UTIs), 303 (14%) with visible haematuria, and 45 (2%) with an abdominal mass. 27% overall, and 24%, 45%, 18% and 27% of each group respectively, had a non-timely diagnosis. Presentation with recurrent UTI was associated with longest median diagnostic interval (median 83 days, IQR 43–151) and visible haematuria with the shortest (median 50 days, IQR 30–79). After adjustment, presentation with recurrent UTIs, being in the youngest or oldest age group, female sex, and diagnosis of kidney and upper tract urothelial cancer, were associated with greater odds of non-timely diagnosis. Conclusion: More than a quarter of patients presenting with fast-track referral features did not achieve a timely diagnosis, suggesting inadequate guideline adherence for some patients. The findings highlight a substantial number of opportunities for expediting the diagnosis of patients with bladder or kidney cancers.
Development of a Benzalkonium Chloride Based Antibacterial Paper for Health and Food Applications
Authors: Shadman Swarit Ahmed , Sadab Ishmamul Hoque , Noor Mohammed Sakib , Khan Mohidus Samad
Published: January 2021

Pathogenic bacteria and other microorganisms pose a potent threat to humans by causing various infectious diseases. To control the spread of infection, different antibacterial products have been developed. However, most of them are known to be associated with health hazards, environmental pollution, complex fabrication, and/or higher cost. To address these issues, in this study, a low cost, biodegradable and human skin compatible antibacterial paper has been developed. A quaternary ammonium compound, benzalkonium chloride (BKC) has been used for paper surface treatment. The concentration of aqueous solution of BKC coated on paper was varied from 0.1 wt% to 0.2 wt%. No external binder was required for coating BKC onto paper. The efficacy of the coated paper was investigated against Staphylococcus aureus ATCC 6538 and Escherichia coli ATCC 8739 bacterial strains. This antibacterial paper is highly effective against both strains with the concentrations of BKC being within the allowable limit for cytotoxic effects. The optimum concentration of BKC coated on paper can be considered as 0.15 wt%, as nearly 100% inhibition was achieved with it against both strains. The developed antibacterial paper is suitable for being used in the industry for disinfection and food packaging purposes, and also by the public for hand sanitization.
Modeling and Analysis of a Three-Terminal-Memristor-Based Conservative Chaotic System
Authors: Wang Ze , Qi Guoyuan
Published: January 2021

In this paper, a three-terminal memristor is constructed and studied through changing dual-port output instead of one-port. A new conservative memristor-based chaotic system is built by embedding this three-terminal memristor into a newly proposed four-dimensional (4D) Euler equation. The generalized Hamiltonian energy function has been given, and it is composed of conservative and non-conservative parts of the Hamiltonian. The Hamiltonian of the Euler equation remains constant, while the three-terminal memristor’s Hamiltonian is mutative, causing non-conservation in energy. Through proof, only centers or saddles equilibria exist, which meets the definition of the conservative system. A non-Hamiltonian conservative chaotic system is proposed. The Hamiltonian of the conservative part determines whether the system can produce chaos or not. The non-conservative part affects the dynamic of the system based on the conservative part. The chaotic and quasiperiodic orbits are generated when the system has different Hamiltonian levels. Lyapunov exponent (LE), Poincaré map, bifurcation and Hamiltonian diagrams are used to analyze the dynamical behavior of the non-Hamiltonian conservative chaotic system. The frequency and initial values of the system have an extensive variable range. Through the mechanism adjustment, instead of trial-and-error, the maximum LE of the system can even reach an incredible value of 963. An analog circuit is implemented to verify the existence of the non-Hamiltonian conservative chaotic system, which overcomes the challenge that a little bias will lead to the disappearance of conservative chaos.
Off-Grid DoA Estimation via Two-Stage Cascaded Neural Network
Authors: Chung Hyeonjin , Seo Hyeongwook , Joo Jeungmin , Lee Dongkeun , Kim Sunwoo
Published: January 2021

This paper introduces an off-grid DoA estimation via two-stage cascaded network which can resolve a mismatch between true direction-of-arrival (DoA) and discrete angular grid. In the first-stage network, the initial DoAs are estimated with a convolutional neural network (CNN), where initial DoAs are mapped on the discrete angular grid. To deal with the mismatch between initially estimated DoAs and true DoAs, the second-stage network estimates a tuning vector which represents the difference between true DoAs and nearest discrete angles. By using tuning vector, the final DoAs are estimated by moving initially estimated DoAs as much as the difference between true DoAs and nearest discrete angles. The limitation on estimation accuracy induced by the discrete angular grid can be resolved with the proposed two-stage network so that the estimation accuracy can be further enhanced. Simulation results show that adding the second-stage network after the first-stage network helps improve the estimation accuracy by resolving mismatch induced by the discretized grid. In the aspect of the implementation of machine learning, results also show that using CNN and using PReLU as the activation function is the best option for accurate estimation.
Reducing the Decarbonisation Cost Burden for EU Energy-Intensive Industries
Authors: Fragkos Panagiotis , Fragkiadakis Kostas , Paroussos Leonidas
Published: January 2021

Carbon leakage features prominently in the climate policy debate in economies implementing climate policies, especially in the EU. The imposition of carbon pricing impacts negatively the competitiveness of energy-intensive industries, inducing their relocation to countries with weaker environmental regulation. Unilateral climate policy may complement domestic emissions pricing with border carbon adjustment to reduce leakage and protect the competitiveness of domestic manufacturing. Here, we use an enhanced version of GEM-E3-FIT model to assess the macro-economic impacts when the EU unilaterally implements the EU Green Deal goals, leading to a leakage of 25% over 2020–2050. The size and composition, in terms of GHG and energy intensities, of the countries undertaking emission reductions matter for carbon leakage, which is significantly reduced when China joins the mitigation effort, as a result of its large market size and the high carbon intensity of its production. Chemicals and metals face the stronger risks for relocation to non-abating countries. The Border Carbon Adjustment can largely reduce leakage and the negative activity impacts on energy-intensive and trade-exposed industries of regulating countries, by shifting the emission reduction to non-abating countries through implicit changes in product prices.
Addressing the Effects of Climate Change on Modeling Future Hydroelectric Energy Production in Chile
Authors: Gil Esteban , Morales Yerel , Ochoa Tomás
Published: January 2021

Despite the growing scientific evidence, the electricity market models used in Chile do not consider the effects of climate change on hydroelectric energy production. Based on a statistical analysis of the historical hydro-energy inflow dataset and a revision of the scientific literature, we suggest a set of technical and statistical criteria to determine an alternative representation of the hydro-energy uncertainty in the Chilean electricity market. Based on these criteria, we then propose an alternative range of historical hydrological data, which is built by shedding the first 35 years of the historical dataset (out of 59 years) and using only a reduced subset of 24 years. Additionally, we propose to capture the potential impacts of even more prolonged droughts on the Chilean electricity system by repeating the last nine years of data at the end of the 24 year-long series. The resulting extended subset of 33 hydro-years is approximately 10% drier on average than the original dataset of 59 years. The proposed range of hydrological data captures some of the anticipated effects of climate change on Chilean hydro-uncertainty reported in the literature and also preserves most of the intra-annual and spatial diversity of the original data.
Use of Gas Desorption Effect in Injection Systems of Diesel Engines
Authors: Bajerlein Maciej , Karpiuk Wojciech , Smolec Rafał
Published: January 2021

The article presents a concept of improving operation of the engine with the effect of gas desorption from a solution with nucleation of gas bubbles. This concept consists in dissolving gas in diesel fuel until the solution is in equilibrium. At a later stage, the phenomenon is reversed, and the gas is released from the solution during its injection into the combustion chamber. The purpose of the study is to present the idea of the desorption effect along with a thermodynamic analysis of the process and to study its impact on the operation of a diesel engine. The article also describes the most important features of the injection pump adapted to employ the desorption effect, which is a proprietary, patented solution. The conducted engine preliminary tests concerned the most important parameters of the engine’s operation (indicated pressure course, pressure growth rate, heat release rate, etc.) and the emission of harmful compounds (PM—particulate matter, CO, HC, and NOx—nitrogen oxides). A significant reduction of PM, CO, and HC, with a simultaneous increase in NOx emissions obtained in tests, confirmed that the desorption effect facilitated engine operation.
Improvement of Position Estimation of PMSMs Using an Iterative Vector Decoupling Algorithm
Authors: Fabbri Stefano , Schuhmacher Klaus , Nienhaus Matthias , Grasso Emanuele
Published: January 2021

This paper presents an improvement of sensorless techniques based on anisotropy for the estimation of the electrical angular position of synchronous machines by means of an iterative algorithm. The presented method reduces the effect of the fourth saliency harmonics on the measured signals avoiding the use of an observer or filter, thus, no additional dynamics are introduced on the system. Instead, a static algorithm based on iterative steps is proposed, minimizing the angular position error. The algorithm is presented and applied using the DFC (Direct Flux Control) technique but it is not limited to this choice. The advantages and limitations of this method are presented within this paper. The proof of the algorithm convergence is given. Simulations and experimental tests are performed in order to prove the effectiveness of the proposed algorithm.
Estimating Energy Forecasting Uncertainty for Reliable AI Autonomous Smart Grid Design
Authors: Selim Maher , Zhou Ryan , Feng Wenying , Quinsey Peter
Published: January 2021

Building safe, reliable, fully automated energy smart grid systems requires a trustworthy electric load forecasting system. Recent work has shown the efficacy of Long Short-Term Memory neural networks in energy load forecasting. However, such predictions do not come with an estimate of uncertainty, which can be dangerous when critical decisions are being made autonomously in energy production and distribution. In this paper, we present methods for evaluating the uncertainty in short-term electrical load predictions for both deep learning and gradient tree boosting. We train Bayesian deep learning and gradient boosting models with real electric load data and show that an uncertainty estimate may be obtained alongside the prediction itself with minimal loss of accuracy. We find that the uncertainty estimates obtained are robust to changes in the input features. This result is an important step in building reliable autonomous smart grids.
Living with Family Is Directly Associated with Regular Dental Checkup and Indirectly Associated with Gingival Status among Japanese University Students: A 3-Year Cohort Study
Authors: Nakahara Momoko , Ekuni Daisuke , Kataoka Kota , Yokoi Aya , Uchida-Fukuhara Yoko , Fukuhara Daiki , Kobayashi Terumasa , Toyama Naoki , Saho Hikari , Islam Md Monirul , Iwasaki Yoshiaki , Morita Manabu
Published: January 2021

Although some studies showed that lifestyle was associated with oral health behavior, few studies investigated the association between household type and oral health behavior. The aim of this prospective cohort study was to investigate the association between household type, oral health behavior, and periodontal status among Japanese university students. Data were obtained from 377 students who received oral examinations and self-questionnaires in 2016 and 2019. We assessed periodontal status using the percentage of bleeding on probing (%BOP), probing pocket depth, oral hygiene status, oral health behaviors, and related factors. We used structural equation modeling to determine the association between household type, oral health behaviors, gingivitis, and periodontitis. At follow-up, 252 students did not live with their families. The mean ± standard deviation of %BOP was 35.5 ± 24.7 at baseline and 32.1 ± 25.3 at follow-up. In the final model, students living with their families were significantly more likely to receive regular dental checkup than those living alone. Regular checkup affected the decrease in calculus. The decrease in calculus affected the decrease in %BOP over 3 years. Living with family was directly associated with regular dental checkups and indirectly contributed to gingival status among Japanese university students.
Postponed Dental Appointments Due to Costs Are Associated with Increased Loneliness—Evidence from the Survey of Health, Ageing and Retirement in Europe
Authors: Walther Carolin , Aarabi Ghazal , Valdez Richelle , Spinler Kristin , Heydecke Guido , Buczak-Stec Elzbieta , König Hans-Helmut , Hajek André
Published: January 2021

As is already well known, demographic changes will presumably lead to a rising number of old aged individuals and loneliness is a tremendous concern in aging populations. Poor health can be a potential consequence of loneliness, as well as a determining factor. Thus, the objective of the current study was to determine whether postponed dental appointments due to costs affect loneliness longitudinally. Focusing on Germany, data from two waves (waves 5 and 6) of the “Survey of Health Ageing, and Retirement in Europe” (SHARE) were analyzed (n = 7703). The three-item loneliness scale (modified version of the revised UCLA Loneliness scale) was used to quantify loneliness. The presence of postponed dental appointments due to costs in the past 12 months (no; yes) served as a key independent variable. Socioeconomic factors as well as health-related factors were adjusted in the longitudinal regression analysis. After adjusting for confounding variables, regression analyses revealed that loneliness increased with decreases in self-rated health among men. Among women, loneliness increased when self-rated health decreased, when fewer chronic diseases and postponed dental appointments due to costs were reported. Among older women, postponed dental appointments due to costs are associated with feelings of loneliness. The study results add evidence that proper dental care (i.e., regular and appropriate visits to the dentist) is vital not only to one’s oral health, but also plays a role in one’s physical and emotional health.
Inhibition of RANKL-Induced Osteoclastogenesis by Novel Mutant RANKL
Authors: Jang Yuria , Sohn Hong Moon , Ko Young Jong , Hyun Hoon , Lim Wonbong
Published: January 2021

Background: Recently, it was reported that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL and was shown to compete with RANK to bind RANKL and suppress canonical RANK signaling during osteoclast differentiation. The critical role of the protein triad RANK–RANKL in osteoclastogenesis has made their binding an important target for the development of drugs against osteoporosis. In this study, point-mutations were introduced in the RANKL protein based on the crystal structure of the RANKL complex and its counterpart receptor RANK, and we investigated whether LGR4 signaling in the absence of the RANK signal could lead to the inhibition of osteoclastogenesis.; Methods: The effects of point-mutated RANKL (mRANKL-MT) on osteoclastogenesis were assessed by tartrate-resistant acid phosphatase (TRAP), resorption pit formation, quantitative real-time polymerase chain reaction (qPCR), western blot, NFATc1 nuclear translocation, micro-CT and histomorphological assay in wild type RANKL (mRANKL-WT)-induced in vitro and in vivo experimental mice model. Results: As a proof of concept, treatment with the mutant RANKL led to the stimulation of GSK-3β phosphorylation, as well as the inhibition of NFATc1 translocation, mRNA expression of TRAP and OSCAR, TRAP activity, and bone resorption, in RANKL-induced mouse models; and Conclusions: The results of our study demonstrate that the mutant RANKL can be used as a therapeutic agent for osteoporosis by inhibiting RANKL-induced osteoclastogenesis via comparative inhibition of RANKL. Moreover, the mutant RANKL was found to lack the toxic side effects of most osteoporosis treatments.
Energy Metabolism and Ketogenic Diets: What about the Skeletal Health? A Narrative Review and a Prospective Vision for Planning Clinical Trials on this Issue
Authors: Merlotti Daniela , Cosso Roberta , Eller-Vainicher Cristina , Vescini Fabio , Chiodini Iacopo , Gennari Luigi , Falchetti Alberto
Published: January 2021

The existence of a common mesenchymal cell progenitor shared by bone, skeletal muscle, and adipocytes cell progenitors, makes the role of the skeleton in energy metabolism no longer surprising. Thus, bone fragility could also be seen as a consequence of a “poor” quality in nutrition. Ketogenic diet was originally proven to be effective in epilepsy, and long-term follow-up studies on epileptic children undergoing a ketogenic diet reported an increased incidence of bone fractures and decreased bone mineral density. However, the causes of such negative impacts on bone health have to be better defined. In these subjects, the concomitant use of antiepileptic drugs and the reduced mobilization may partly explain the negative effects on bone health, but little is known about the effects of diet itself, and/or generic alterations in vitamin D and/or impaired growth factor production. Despite these remarks, clinical studies were adequately designed to investigate bone health are scarce and bone health related aspects are not included among the various metabolic pathologies positively influenced by ketogenic diets. Here, we provide not only a narrative review on this issue, but also practical advice to design and implement clinical studies on ketogenic nutritional regimens and bone health outcomes. Perspectives on ketogenic regimens, microbiota, microRNAs, and bone health are also included.
Melatonin as an Oncostatic Molecule Based on Its Anti-Aromatase Role in Breast Cancer
Authors: Jin Yunho , Choi Yoo Jin , Heo Kyu , Park Seong Joon
Published: January 2021

Breast cancer is the most common type of cancer. In the developmental stages of breast cancer, estrogens are strongly involved. As estrogen synthesis is regulated by the enzyme aromatase, targeting the activity of this enzyme represents a therapeutic option. The pineal hormone melatonin may exert a suppressive role on aromatase activity, leading to reduced estrogen biosynthesis. A melatonin-mediated decrease in the expression of aromatase promoters and associated genes would provide suitable evidence of this molecule’s efficacy as an aromatase inhibitor. Furthermore, melatonin intensifies radiation-induced anti-aromatase effects and counteracts the unwanted disadvantages of chemotherapeutic agents. In this manner, this review summarizes the inhibitory role of melatonin in aromatase action, suggesting its role as a possible oncostatic molecule in breast cancer.
Polyamines Influence Mouse Sperm Channels Activity
Authors: Rodríguez-Páez Lorena , Aguirre-Alvarado Charmina , Oviedo Norma , Alcántara-Farfán Verónica , Lara-Ramírez Edgar E. , Jimenez-Gutierrez Guadalupe Elizabeth , Cordero-Martínez Joaquín
Published: January 2021

Polyamines are ubiquitous polycationic compounds that are highly charged at physiological pH. While passing through the epididymis, sperm lose their capacity to synthesize the polyamines and, upon ejaculation, again come into contact with the polyamines contained in the seminal fluid, unleashing physiological events that improve sperm motility and capacitation. In the present work, we hypothesize about the influence of polyamines, namely, spermine, spermidine, and putrescine, on the activity of sperm channels, evaluating the intracellular concentrations of chloride [Cl−]i, calcium [Ca2+]i, sodium [Na+]i, potassium [K+]i, the membrane Vm, and pHi. The aim of this is to identify the possible regulatory mechanisms mediated by the polyamines on sperm-specific channels under capacitation and non-capacitation conditions. The results showed that the presence of polyamines did not directly influence the activity of calcium and chloride channels. However, the results suggested an interaction of polyamines with sodium and potassium channels, which may contribute to the membrane Vm during capacitation. In addition, alkalization of the pHi revealed the possible activation of sperm-specific Na+/H+ exchangers (NHEs) by the increased levels of cyclic AMP (cAMP), which were produced by soluble adenylate cyclase (sAC) and interact with the polyamines, evidence that is supported by in silico analysis.
Cardioprotective Role of Heat Shock Proteins in Atrial Fibrillation: From Mechanism of Action to Therapeutic and Diagnostic Target
Authors: van Wijk Stan W. , Ramos Kennedy S. , Brundel Bianca J. J. M.
Published: January 2021

Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia worldwide and is associated with ischemic stroke, heart failure, and substantial morbidity and mortality. Unfortunately, current AF therapy is only moderately effective and does not prevent AF progression from recurrent intermittent episodes (paroxysmal) to persistent and finally permanent AF. It has been recognized that AF persistence is related to the presence of electropathology. Electropathology is defined as structural damage, including degradation of sarcomere structures, in the atrial tissue which, in turn, impairs electrical conduction and subsequently the contractile function of atrial cardiomyocytes. Recent research findings indicate that derailed proteostasis underlies structural damage and, consequently, electrical conduction impairment. A healthy proteostasis is of vital importance for proper function of cells, including cardiomyocytes. Cells respond to a loss of proteostatic control by inducing a heat shock response (HSR), which results in heat shock protein (HSP) expression. Emerging clinical evidence indicates that AF-induced proteostasis derailment is rooted in exhaustion of HSPs. Cardiomyocytes lose defense against structural damage-inducing pathways, which drives progression of AF and induction of HSP expression. In particular, small HSPB1 conserves sarcomere structures by preventing their degradation by proteases, and overexpression of HSPB1 accelerates recovery from structural damage in experimental AF model systems. In this review, we provide an overview of the mechanisms of action of HSPs in preventing AF and discuss the therapeutic potential of HSP-inducing compounds in clinical AF, as well as the potential of HSPs as biomarkers to discriminate between the various stages of AF and recurrence of AF after treatment.
Temporomandibular Joint Osteoarthritis: Regenerative Treatment by a Stem Cell Containing Advanced Therapy Medicinal Product (ATMP)—An In Vivo Animal Trial
Authors: Köhnke Robert , Ahlers Marcus Oliver , Birkelbach Moritz Alexander , Ewald Florian , Krueger Michael , Fiedler Imke , Busse Björn , Heiland Max , Vollkommer Tobias , Gosau Martin , Smeets Ralf , Rutkowski Rico
Published: January 2021

Temporomandibular joint osteoarthritis (TMJ-OA) is a chronic degenerative disease that is often characterized by progressive impairment of the temporomandibular functional unit. The aim of this randomized controlled animal trial was a comparative analysis regarding the chondroregenerative potency of intra-articular stem/stromal cell therapy. Four weeks after combined mechanical and biochemical osteoarthritis induction in 28 rabbits, therapy was initiated by a single intra-articular injection, randomized into the following groups: Group 1: AB Serum (ABS); Group 2: Hyaluronic acid (HA); Group 3: Mesenchymal stromal cells (STx.); Group 4: Mesenchymal stromal cells in hyaluronic acid (HA + STx.). After another 4 weeks, the animals were euthanized, followed by histological examination of the removed joints. The histological analysis showed a significant increase in cartilage thickness in the stromal cell treated groups (HA + STx. vs. ABS, p = 0.028; HA + ST.x vs. HA, p = 0.042; STx. vs. ABS, p = 0.036). Scanning electron microscopy detected a similar heterogeneity of mineralization and tissue porosity in the subchondral zone in all groups. The single intra-articular injection of a stem cell containing, GMP-compliant advanced therapy medicinal product for the treatment of iatrogen induced osteoarthritis of the temporomandibular joint shows a chondroregenerative effect.
CHID1 Is a Novel Prognostic Marker of Non-Small Cell Lung Cancer
Authors: Kovaleva Olga V. , Rashidova Madina A. , Samoilova Daria V. , Podlesnaya Polina A. , Tabiev Rasul M. , Mochalnikova Valeria V. , Gratchev Alexei
Published: January 2021

There is an urgent need for identification of new prognostic markers and therapeutic targets for non-small cell lung cancer (NSCLC). In this study, we evaluated immune cells markers in 100 NSCLC specimens. Immunohistochemical analysis revealed no prognostic value for the markers studied, except CD163 and CD206. At the same time, macrophage markers iNOS and CHID1 were found to be expressed in tumor cells and associated with prognosis. We showed that high iNOS expression is a marker of favorable prognosis for squamous cell lung carcinoma (SCC), and NSCLC in general. Similarly, high CHID1 expression is a marker of good prognosis in adenocarcinoma and in NSCLC in general. Analysis of prognostic significance of a high CHID1/iNOS expression combination showed favorable prognosis with 20 months overall survival of patients from the low CHID1/iNOS expression group. For the first time, we demonstrated that CHID1 can be expressed by NSCLC cells and its high expression is a marker of good prognosis for adenocarcinoma and NSCLC in general. At the same time, high expression of iNOS in tumor cells is a marker of good prognosis in SCC. When used in combination, CHID1 and iNOS show a very good prognostic capacity for NSCLC. We suggest that in the case of lung cancer, tumor-associated macrophages are likely ineffective as a therapeutic target. At the same time, macrophage markers expressed by tumor cells may be considered as targets for anti-tumor therapy or, as in the case of CHID1, as potential anti-tumor agents.
Emerging Options for the Diagnosis of Bacterial Infections and the Characterization of Antimicrobial Resistance
Authors: Rentschler Simone , Kaiser Lars , Deigner Hans-Peter
Published: January 2021

Precise and rapid identification and characterization of pathogens and antimicrobial resistance patterns are critical for the adequate treatment of infections, which represent an increasing problem in intensive care medicine. The current situation remains far from satisfactory in terms of turnaround times and overall efficacy. Application of an ineffective antimicrobial agent or the unnecessary use of broad-spectrum antibiotics worsens the patient prognosis and further accelerates the generation of resistant mutants. Here, we provide an overview that includes an evaluation and comparison of existing tools used to diagnose bacterial infections, together with a consideration of the underlying molecular principles and technologies. Special emphasis is placed on emerging developments that may lead to significant improvements in point of care detection and diagnosis of multi-resistant pathogens, and new directions that may be used to guide antibiotic therapy.
Increasing Oxygen Partial Pressures Induce a Distinct Transcriptional Response in Human PBMC: A Pilot Study on the “Normobaric Oxygen Paradox”
Authors: Fratantonio Deborah , Virgili Fabio , Zucchi Alessandro , Lambrechts Kate , Latronico Tiziana , Lafère Pierre , Germonpré Peter , Balestra Costantino
Published: January 2021

The term “normobaric oxygen paradox” (NOP), describes the response to the return to normoxia after a hyperoxic event, sensed by tissues as oxygen shortage, and resulting in up-regulation of the Hypoxia-inducible factor 1α (HIF-1α) transcription factor activity. The molecular characteristics of this response have not been yet fully characterized. Herein, we report the activation time trend of oxygen-sensitive transcription factors in human peripheral blood mononuclear cells (PBMCs) obtained from healthy subjects after one hour of exposure to mild (MH), high (HH) and very high (VHH) hyperoxia, corresponding to 30%, 100%, 140% O2, respectively. Our observations confirm that MH is perceived as a hypoxic stress, characterized by the activation of HIF-1α and Nuclear factor (erythroid-derived 2)-like 2 (NRF2), but not Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB). Conversely, HH is associated to a progressive loss of NOP response and to an increase in oxidative stress leading to NRF2 and NF-kB activation, accompanied by the synthesis of glutathione (GSH). After VHH, HIF-1α activation is totally absent and oxidative stress response, accompanied by NF-κB activation, is prevalent. Intracellular GSH and Matrix metallopeptidase 9 (MMP-9) plasma levels parallel the transcription factors activation pattern and remain elevated throughout the observation time. In conclusion, our study confirms that, in vivo, the return to normoxia after MH is sensed as a hypoxic trigger characterized by HIF-1α activation. On the contrary, HH and VHH induce a shift toward an oxidative stress response, characterized by NRF2 and NF-κB activation in the first 24 h post exposure.
Characterization of Urine Stem Cell-Derived Extracellular Vesicles Reveals B Cell Stimulating Cargo
Authors: Zidan Asmaa A. , Al-Hawwas Mohammed , Perkins Griffith B. , Mourad Ghada M. , Stapledon Catherine J. M. , Bobrovskaya Larisa , Zhou Xin-Fu , Hurtado Plinio R.
Published: January 2021

Elucidation of the biological functions of extracellular vesicles (EVs) and their potential roles in physiological and pathological processes is an expanding field of research. In this study, we characterized USC–derived EVs and studied their capacity to modulate the human immune response in vitro. We found that the USC–derived EVs are a heterogeneous population, ranging in size from that of micro–vesicles (150 nm–1 μm) down to that of exosomes (60–150 nm). Regarding their immunomodulatory functions, we found that upon isolation, the EVs (60–150 nm) induced B cell proliferation and IgM antibody secretion. Analysis of the EV contents unexpectedly revealed the presence of BAFF, APRIL, IL–6, and CD40L, all known to play a central role in B cell stimulation, differentiation, and humoral immunity. In regard to their effect on T cell functions, they resembled the function of mesenchymal stem cell (MSC)–derived EVs previously described, suppressing T cell response to activation. The finding that USC–derived EVs transport a potent bioactive cargo opens the door to a novel therapeutic avenue for boosting B cell responses in immunodeficiency or cancer.
STAT3 Is an Upstream Regulator of Granzyme G in the Maternal-To-Zygotic Transition of Mouse Embryos
Authors: Ou-Yang Huan , Wu Shinn-Chih , Sung Li-Ying , Yang Shiao-Hsuan , Yang Shang-Hsun , Chong Kowit-Yu , Chen Chuan-Mu
Published: January 2021

The maternal-to-zygotic transition (MZT), which controls maternal signaling to synthesize zygotic gene products, promotes the preimplantation development of mouse zygotes to the two-cell stage. Our previous study reported that mouse granzyme g (Gzmg), a serine-type protease, is required for the MZT. In this study, we further identified the maternal factors that regulate the Gzmg promoter activity in the zygote to the two-cell stage of mouse embryos. A full-length Gzmg promoter from mouse genomic DNA, FL-pGzmg (−1696~+28 nt), was cloned, and four deletion constructs of this Gzmg promoter, Δ1-pGzmg (−1369~+28 nt), Δ2-pGzmg (−939~+28 nt), Δ3-pGzmg (−711~+28 nt) and Δ4-pGzmg (−417~+28 nt), were subsequently generated. Different-sized Gzmg promoters were used to perform promoter assays of mouse zygotes and two-cell stage embryos. The results showed that Δ4-pGzmg promoted the highest expression level of the enhanced green fluorescent protein (EGFP) reporter in the zygotes and two-cell embryos. The data suggested that time-specific transcription factors upregulated Gzmg by binding cis-elements in the −417~+28-nt Gzmg promoter region. According to the results of the promoter assay, the transcription factor binding sites were predicted and analyzed with the JASPAR database, and two transcription factors, signal transducer and activator of transcription 3 (STAT3) and GA-binding protein alpha (GABPα), were identified. Furthermore, STAT3 and GABPα are expressed and located in zygote pronuclei and two-cell nuclei were confirmed by immunofluorescence staining; however, only STAT3 was recruited to the mouse zygote pronuclei and two-cell nuclei injected with the Δ4-pGzmg reporter construct. These data indicated that STAT3 is a maternal transcription factor and may upregulate Gzmg to promote the MZT. Furthermore, treatment with a STAT3 inhibitor, S3I-201, caused mouse embryonic arrest at the zygote and two-cell stages. These results suggest that STAT3, a maternal protein, is a critical transcription factor and regulates Gzmg transcription activity in preimplantation mouse embryos. It plays an important role in the maternal-to-zygotic transition during early embryonic development.
Intermittent Hypoxic Conditioning Rescues Cognition and Mitochondrial Bioenergetic Profile in the Triple Transgenic Mouse Model of Alzheimer’s Disease
Authors: Correia Sónia C. , Machado Nuno J. , Alves Marco G. , Oliveira Pedro F. , Moreira Paula I.
Published: January 2021

The lack of effective disease-modifying therapeutics to tackle Alzheimer’s disease (AD) is unsettling considering the actual prevalence of this devastating neurodegenerative disorder worldwide. Intermittent hypoxic conditioning (IHC) is a powerful non-pharmacological procedure known to enhance brain resilience. In this context, the aim of the present study was to investigate the potential long-term protective impact of IHC against AD-related phenotype, putting a special focus on cognition and mitochondrial bioenergetics and dynamics. For this purpose, six-month-old male triple transgenic AD mice (3×Tg-AD) were submitted to an IHC protocol for two weeks and the behavioral assessment was performed at 8.5 months of age, while the sacrifice of mice occurred at nine months of age and their brains were removed for the remaining analyses. Interestingly, IHC was able to prevent anxiety-like behavior and memory and learning deficits and significantly reduced brain cortical levels of amyloid-β (Aβ) in 3×Tg-AD mice. Concerning brain energy metabolism, IHC caused a significant increase in brain cortical levels of glucose and a robust improvement of the mitochondrial bioenergetic profile in 3×Tg-AD mice, as mirrored by the significant increase in mitochondrial membrane potential (ΔΨm) and respiratory control ratio (RCR). Notably, the improvement of mitochondrial bioenergetics seems to result from an adaptative coordination of the distinct but intertwined aspects of the mitochondrial quality control axis. Particularly, our results indicate that IHC favors mitochondrial fusion and promotes mitochondrial biogenesis and transport and mitophagy in the brain cortex of 3×Tg-AD mice. Lastly, IHC also induced a marked reduction in synaptosomal-associated protein 25 kDa (SNAP-25) levels and a significant increase in both glutamate and GABA levels in the brain cortex of 3×Tg-AD mice, suggesting a remodeling of the synaptic microenvironment. Overall, these results demonstrate the effectiveness of the IHC paradigm in forestalling the AD-related phenotype in the 3×Tg-AD mouse model, offering new insights to AD therapy and forcing a rethink concerning the potential value of non-pharmacological interventions in clinical practice.
Assessing the Severity of Traumatic Brain Injury—Time for a Change?
Authors: Tenovuo Olli , Diaz-Arrastia Ramon , Goldstein Lee E. , Sharp David J. , van der Naalt Joukje , Zasler Nathan D.
Published: January 2021

Traumatic brain injury (TBI) has been described to be man’s most complex disease, in man’s most complex organ. Despite this vast complexity, variability, and individuality, we still classify the severity of TBI based on non-specific, often unreliable, and pathophysiologically poorly understood measures. Current classifications are primarily based on clinical evaluations, which are non-specific and poorly predictive of long-term disability. Brain imaging results have also been used, yet there are multiple ways of doing brain imaging, at different timepoints in this very dynamic injury. Severity itself is a vague concept. All prediction models based on combining variables that can be assessed during the acute phase have reached only modest predictive values for later outcome. Yet, these early labels of severity often determine how the patient is treated by the healthcare system at large. This opinion paper examines the problems and provides caveats regarding the use of current severity labels and the many practical and scientific issues that arise from doing so. The objective of this paper is to show the causes and consequences of current practice and propose a new approach based on risk classification. A new approach based on multimodal quantifiable data (including imaging and biomarkers) and risk-labels would be of benefit both for the patients and for TBI clinical research and should be a priority for international efforts in the field.