bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic Diseases and Down Syndrome: How Are They Linked Together?
Authors: Moreau Manon , Benhaddou Soukaina , Dard Rodolphe , Tolu Stefania , Hamzé Rim , Vialard François , Movassat Jamileh , Janel Nathalie
Published: February 2021

Down syndrome is a genetic disorder caused by the presence of a third copy of chromosome 21, associated with intellectual disabilities. Down syndrome is associated with anomalies of both the nervous and endocrine systems. Over the past decades, dramatic advances in Down syndrome research and treatment have helped to extend the life expectancy of these patients. Improved life expectancy is obviously a positive outcome, but it is accompanied with the need to address previously overlooked complications and comorbidities of Down syndrome, including obesity and diabetes, in order to improve the quality of life of Down syndrome patients. In this focused review, we describe the associations between Down syndrome and comorbidities, obesity and diabetes, and we discuss the understanding of proposed mechanisms for the association of Down syndrome with metabolic disorders. Drawing molecular mechanisms through which Type 1 diabetes and Type 2 diabetes could be linked to Down syndrome could allow identification of novel drug targets and provide therapeutic solutions to limit the development of metabolic and cognitive disorders.
Neuropeptide Substance P Enhances Skin Wound Healing In Vitro and In Vivo under Hypoxia
Authors: Kumar Suneel , Tan Yuying , Berthiaume Francois
Published: February 2021

Pressure ulcers (PUs) or sores are a secondary complication of diabetic neuropathy and traumatic spinal cord injury (SCI). PUs tend to occur in soft tissues located around bony prominences and may heal slowly or not at all. A common mechanism underlying impaired healing of PUs may be dysfunction of the local neurovascular system including deficiency of essential neuropeptides, such as substance P (SP). Previous studies indicate that disturbance in cutaneous sensory innervation leads to a defect in all stages of wound healing, as is the case after SCI. It is hypothesized that nerve fibers enhance wound healing by promoting initial inflammation via the releasing of neuropeptides such as SP. Therefore, we investigated whether exogenous SP improves skin wound healing using in vitro and in vivo models. For in vitro studies, the effects of SP on keratinocyte proliferation and wound closure after a scratch injury were studied under normoxia (pO2 ~21%) or hypoxia (pO2 ~1%) and in presence of normal serum (10% v/v) or low serum (1% v/v) concentrations. Hypoxia and low serum both significantly slowed cell proliferation and wound closure. Under combined low serum and hypoxia, used to mimic the nutrient- and oxygen-poor environment of chronic wounds, SP (10−7 M) significantly enhanced cell proliferation and wound closure rate. For in vivo studies, two full-thickness excisional wounds were created with a 5 mm biopsy punch on the dorsum on either side of the midline of 15-week-old C57BL/6J male and female mice. Immediately, wounds were treated topically with one dose of 0.5 μg SP or PBS vehicle. The data suggest a beneficial role in wound closure and reepithelization, and thus enhanced wound healing, in male and female mice. Taken together, exogenously applied neuropeptide SP enhanced wound healing via cell proliferation and migration in vitro and in vivo. Thus, exogenous SP may be a useful strategy to explore further for treating PUs in SCI and diabetic patients.
Are Sarcopenia and Cognitive Dysfunction Comorbid after Stroke in the Context of Brain–Muscle Crosstalk?
Authors: Sui Sophia X. , Hordacre Brenton , Pasco Julie A.
Published: February 2021

Stroke is a leading cause of death and disability and is responsible for a significant economic burden. Sarcopenia and cognitive dysfunction are common consequences of stroke, but there is less awareness of the concurrency of these conditions. In addition, few reviews are available to guide clinicians and researchers on how to approach sarcopenia and cognitive dysfunction as comorbidities after stroke, including how to assess and manage them and implement interventions to improve health outcomes. This review synthesises current knowledge about the relationship between post-stroke sarcopenia and cognitive dysfunction, including the physiological pathways, assessment tools, and interventions involved.
Energy, Entropy and Quantum Tunneling of Protons and Electrons in Brain Mitochondria: Relation to Mitochondrial Impairment in Aging-Related Human Brain Diseases and Therapeutic Measures
Authors: Bennett James P. , Onyango Isaac G.
Published: February 2021

Adult human brains consume a disproportionate amount of energy substrates (2–3% of body weight; 20–25% of total glucose and oxygen). Adenosine triphosphate (ATP) is a universal energy currency in brains and is produced by oxidative phosphorylation (OXPHOS) using ATP synthase, a nano-rotor powered by the proton gradient generated from proton-coupled electron transfer (PCET) in the multi-complex electron transport chain (ETC). ETC catalysis rates are reduced in brains from humans with neurodegenerative diseases (NDDs). Declines of ETC function in NDDs may result from combinations of nitrative stress (NS)–oxidative stress (OS) damage; mitochondrial and/or nuclear genomic mutations of ETC/OXPHOS genes; epigenetic modifications of ETC/OXPHOS genes; or defects in importation or assembly of ETC/OXPHOS proteins or complexes, respectively; or alterations in mitochondrial dynamics (fusion, fission, mitophagy). Substantial free energy is gained by direct O2-mediated oxidation of NADH. Traditional ETC mechanisms require separation between O2 and electrons flowing from NADH/FADH2 through the ETC. Quantum tunneling of electrons and much larger protons may facilitate this separation. Neuronal death may be viewed as a local increase in entropy requiring constant energy input to avoid. The ATP requirement of the brain may partially be used for avoidance of local entropy increase. Mitochondrial therapeutics seeks to correct deficiencies in ETC and OXPHOS.
Is There a Relationship between the Elasticity of Brain Tumors, Changes in Diffusion Tensor Imaging, and Histological Findings? A Pilot Study Using Intraoperative Ultrasound Elastography
Authors: Cepeda Santiago , García-García Sergio , Velasco-Casares María , Fernández-Pérez Gabriel , Zamora Tomás , Arrese Ignacio , Sarabia Rosario
Published: February 2021

Intraoperative ultrasound elastography (IOUS-E) is a novel image modality applied in brain tumor assessment. However, the potential links between elastographic findings and other histological and neuroimaging features are unknown. This study aims to find associations between brain tumor elasticity, diffusion tensor imaging (DTI) metrics, and cell proliferation. A retrospective study was conducted to analyze consecutively admitted patients who underwent craniotomy for supratentorial brain tumors between March 2018 and February 2020. Patients evaluated by IOUS-E and preoperative DTI were included. A semi-quantitative analysis was performed to calculate the mean tissue elasticity (MTE). Diffusion coefficients and the tumor proliferation index by Ki-67 were registered. Relationships between the continuous variables were determined using the Spearman ρ test. A predictive model was developed based on non-linear regression using the MTE as the dependent variable. Forty patients were evaluated. The pathologic diagnoses were as follows: 21 high-grade gliomas (HGG); 9 low-grade gliomas (LGG); and 10 meningiomas. Cases with a proliferation index of less than 10% had significantly higher medians of MTE (110.34 vs. 79.99, p < 0.001) and fractional anisotropy (FA) (0.24 vs. 0.19, p = 0.020). We found a strong positive correlation between MTE and FA (rs (38) = 0.91, p < 0.001). A cubic spline non-linear regression model was obtained to predict tumoral MTE from FA (R2 = 0.78, p < 0.001). According to our results, tumor elasticity is associated with histopathological and DTI-derived metrics. These findings support the usefulness of IOUS-E as a complementary tool in brain tumor surgery.
Self-Reported Nonadherence to Medication Is Not Associated with Health-Related Quality of Life in Parkinson’s Disease
Authors: Zipprich Hannah M. , Mendorf Sarah , Lehmann Thomas , Prell Tino
Published: February 2021

Nonadherence is a growing issue in the treatment of Parkinson’s disease (PD). Many factors are known to influence nonadherence, but little is known about the influence of quality of life (QoL). Detailed clinical data were obtained from 164 patients with PD using the Parkinson’s Disease Questionnaire-39 (PDQ-39) and the German Stendal Adherence with Medication Score (SAMS). Descriptive statistics were used to identify reasons for nonadherence, and multivariable linear models were used to study associations between QoL and clinical parameters as well as nonadherence. Multivariate analysis of variance (MANOVA) and multivariate analysis of covariance (MANCOVA) were used to study the effect of the SAMS on PDQ domains and other medical covariates. The results showed that 10.4% (n = 17) of patients were fully adherent, 66.4% (n = 109) were moderately nonadherent, and 23.2% (n = 38) were nonadherent. Nonadherence was associated with male gender, lower Montreal Cognitive Assessment (MoCA) score, higher non-motor symptoms questionnaire (NMS-Quest) score, greater number of medications per day (an indicator of comorbidity), and higher Beck Depression Inventory (BDI) score. QoL was correlated with male gender, lower MoCA score, higher NMS-Quest score, more comorbidities, and higher BDI score, but was not correlated with nonadherence.
Effect of Frequency Characteristics of Ground Motion on Response of Tuned Mass Damper Controlled Inelastic Concrete Frame
Authors: Rahman Md , Nahar Tahmina , Kim Dookie
Published: February 2021

This paper investigates the performance of tuned mass damper (TMD) and dynamic behavior of TMD-controlled concrete structure considering the ground motion (GM) characteristics based on frequency content. The effectiveness of TMD in reducing the structural response and probability of collapse of the building frames are affected by the frequency characteristics of GMs. To attenuate the seismic vibration of the buildings, the TMD controlled building has been designed based on the modal analysis (modal frequencies and modal mass participation ratio). In this study, to investigate the performance of TMD, four different heights (i.e., 3, 5, 10, 20 stories) inelastic concrete moment-resisting frames equipped with TMDs are developed using an open-source finite element software. A series of numerical analyses have been conducted using sixty earthquakes classified into three categories corresponding to low, medium, and high-frequency characteristics of GMs. To evaluate the proposed strategy, peak lateral displacements, inter-story drift, and the probability of collapse using fragility analysis have been investigated through the structures equipped with and without TMD. The results appraise the effect of TMD and compare the seismic responses of earthquake frequency contents and the vibration control system of the inelastic building frames.
Shikonin Reduces Growth of Docetaxel-Resistant Prostate Cancer Cells Mainly through Necroptosis
Authors: Markowitsch Sascha D. , Juetter Kira M. , Schupp Patricia , Hauschulte Kristine , Vakhrusheva Olesya , Slade Kimberly Sue , Thomas Anita , Tsaur Igor , Cinatl Jindrich , Michaelis Martin , Efferth Thomas , Haferkamp Axel , Juengel Eva
Published: February 2021

The prognosis for advanced prostate carcinoma (PCa) remains poor due to development of therapy resistance, and new treatment options are needed. Shikonin (SHI) from Traditional Chinese Medicine has induced antitumor effects in diverse tumor entities, but data related to PCa are scarce. Therefore, the parental (=sensitive) and docetaxel (DX)-resistant PCa cell lines, PC3, DU145, LNCaP, and 22Rv1 were exposed to SHI [0.1–1.5 μM], and tumor cell growth, proliferation, cell cycling, cell death (apoptosis, necrosis, and necroptosis), and metabolic activity were evaluated. Correspondingly, the expression of regulating proteins was assessed. Exposure to SHI time- and dose-dependently inhibited tumor cell growth and proliferation in parental and DX-resistant PCa cells, accompanied by cell cycle arrest in the G2/M or S phase and modulation of cell cycle regulating proteins. SHI induced apoptosis and more dominantly necroptosis in both parental and DX-resistant PCa cells. This was shown by enhanced pRIP1 and pRIP3 expression and returned growth if applying the necroptosis inhibitor necrostatin-1. No SHI-induced alteration in metabolic activity of the PCa cells was detected. The significant antitumor effects induced by SHI to parental and DX-resistant PCa cells make the addition of SHI to standard therapy a promising treatment strategy for patients with advanced PCa.
Facilitating Drug Discovery in Breast Cancer by Virtually Screening Patients Using In Vitro Drug Response Modeling
Authors: Gruener Robert F. , Ling Alexander , Chang Ya-Fang , Morrison Gladys , Geeleher Paul , Greene Geoffrey L. , Huang R. Stephanie
Published: February 2021

(1) Background: Drug imputation methods often aim to translate in vitro drug response to in vivo drug efficacy predictions. While commonly used in retrospective analyses, our aim is to investigate the use of drug prediction methods for the generation of novel drug discovery hypotheses. Triple-negative breast cancer (TNBC) is a severe clinical challenge in need of new therapies. (2) Methods: We used an established machine learning approach to build models of drug response based on cell line transcriptome data, which we then applied to patient tumor data to obtain predicted sensitivity scores for hundreds of drugs in over 1000 breast cancer patients. We then examined the relationships between predicted drug response and patient clinical features. (3) Results: Our analysis recapitulated several suspected vulnerabilities in TNBC and identified a number of compounds-of-interest. AZD-1775, a Wee1 inhibitor, was predicted to have preferential activity in TNBC (p < 2.2 × 10−16) and its efficacy was highly associated with TP53 mutations (p = 1.2 × 10−46). We validated these findings using independent cell line screening data and pathway analysis. Additionally, co-administration of AZD-1775 with standard-of-care paclitaxel was able to inhibit tumor growth (p < 0.05) and increase survival (p < 0.01) in a xenograft mouse model of TNBC. (4) Conclusions: Overall, this study provides a framework to turn any cancer transcriptomic dataset into a dataset for drug discovery. Using this framework, one can quickly generate meaningful drug discovery hypotheses for a cancer population of interest.
Genetic Profiles of Aggressive Variants of Papillary Thyroid Carcinomas
Authors: Jin Meihua , Song Dong Eun , Ahn Jonghwa , Song Eyun , Lee Yu-Mi , Sung Tae-Yon , Kim Tae Yong , Kim Won Bae , Shong Young Kee , Jeon Min Ji , Kim Won Gu
Published: February 2021

Aggressive variants of papillary thyroid carcinoma (PTC) have been described with increasing frequency and are associated with unfavorable clinical outcomes. However, limited data exist on the comprehensive genetic profile of these variants. We performed targeted next-generation sequencing in 36 patients with aggressive variants of PTC and compared it to PTC from The Cancer Genome Atlas (TCGA) project and poorly differentiated thyroid cancers (PDTCs)/anaplastic thyroid cancers (ATCs) from the Memorial Sloan Kettering Cancer Center (MSKCC). BRAF mutation was the most prevalent (89%) in aggressive variants of PTC compared to that in other thyroid cancers. RAS mutation was identified in one patient (3%), which was less frequent than in others. TERT promoter mutation (17%) ranged between that of PTCs (9%) and PDTCs (40%). Tumor suppressor genes, ZFHX3, TP53, and CHEK2, were mutated in 14%, 3%, and 6% of aggressive variants of PTC, respectively. The mutation rate of TP53 (3%) was significantly higher than that of PTCs (0.7%) and lower than that of ATCs (73%). Mutations in three functional groups, histone methyl transferases, SWI/SNF chromatin remodeling complex, and the PI3K/AKT/mTOR pathway, were present in 11%, 14%, and 11% of samples, respectively. In conclusion, aggressive variants of PTC had higher BRAF and lower NRAS mutation prevalence than other thyroid cancers. The prevalence of mutations in the TERT promoter, TP53, and genes encoding three functional groups ranged between that of PTCs and PDTCs/ATCs.
Fine-Needle Aspiration Cytology and Histological Types of Thyroid Cancer in the Elderly: Evaluation of 9070 Patients from a Single Referral Centre
Authors: Poma Anello Marcello , Macerola Elisabetta , Basolo Alessio , Batini Valerio , Rago Teresa , Santini Ferruccio , Torregrossa Liborio
Published: February 2021

Background. The prevalence of thyroid nodules increases with age. Their management takes into account the presence of co-morbidities, which are frequent among the elderly. We sought to highlight the differences between the elderly and the general population in cytological and histological diagnoses. Methods. In this retrospective cohort study, we gathered 13,747 nodule data and compared cytological and histological diagnoses between patients aged over 65 years and a control group. Results. Elderly patients had a higher prevalence of cytologically benign nodules and, consequently, they were less frequently subject to surgery. However, there were no differences in terms of malignancy-risk after surgery. At histology, elderly patients often presented aggressive histology such as medullary thyroid carcinoma, poorly-differentiated and anaplastic cancer, tall cell variant of papillary thyroid carcinoma and Hürthle cell carcinoma. Even in presence of well-differentiated cancer, older patients had higher rates of local invasiveness, lateral lymph node involvement and vascular invasion. Conclusion. Thyroid nodules in elderly patients represent a challenging entity since they are very often benign, but, in case of malignancy, aggressive histotypes and high-risk features are more frequent. Therefore, presurgical characterization of nodules in older patients is crucial and might require strict monitoring.
Picturing Breast Cancer Brain Metastasis Development to Unravel Molecular Players and Cellular Crosstalk
Authors: Figueira Inês , Galego Sofia , Custódio-Santos Tânia , Vicente Raquel , Molnár Kinga , Haskó Janos , Malhó Rui , Videira Mafalda , Wilhelm Imola , Krizbai István , Brito Maria Alexandra
Published: February 2021

With breast cancer (BC) therapy improvements, the appearance of brain metastases has been increasing, representing a life-threatening condition. Brain metastasis formation involves BC cell (BCC) extravasation across the blood–brain barrier (BBB) and brain colonization by unclear mechanisms. We aimed to disclose the actors involved in BC brain metastasis formation, focusing on BCCs’ phenotype, growth factor expression, and signaling pathway activation, correlating with BBB alterations and intercellular communication. Hippocampi of female mice inoculated with 4T1 BCCs were examined over time by hematoxylin-eosin, immunohistochemistry and immunofluorescence. Well-established metastases were observed at seven days, increasing thereafter. BCCs entering brain parenchyma presented mesenchymal, migratory, and proliferative features; however, with time, they increasingly expressed epithelial markers, reflecting a mesenchymal–epithelial transition. BCCs also expressed platelet-derived growth factor-B, β4 integrin, and focal adhesion kinase, suggesting autocrine and/or paracrine regulation with adhesion signaling activation, while balance between Rac1 and RhoA was associated with the motility status. Intercellular communication via gap junctions was clear among BCCs, and between BCCs and endothelial cells. Thrombin accumulation, junctional protein impairment, and vesicular proteins increase reflect BBB alterations related with extravasation. Expression of plasmalemma vesicle-associated protein was increased in BCCs, along with augmented vascularization, whereas pericyte contraction indicated mural cells’ activation. Our results provide further understanding of BC brain metastasis formation, disclosing potential therapeutic targets.
Vaccination against PD-L1 with IO103 a Novel Immune Modulatory Vaccine in Basal Cell Carcinoma: A Phase IIa Study
Authors: Jørgensen Nicolai Grønne , Kaae Jeanette , Grauslund Jacob Handlos , Met Özcan , Nielsen Signe Ledou , Pedersen Ayako Wakatsuki , Svane Inge Marie , Ehrnrooth Eva , Andersen Mads Hald , Zachariae Claus , Skov Lone
Published: February 2021

Antitumor activity of immune checkpoint blocking antibodies against programmed death 1 (PD-1) in basal cell carcinoma (BCC) has been described. IO103 is a peptide vaccine against the major PD-1 ligand PD-L1. A phase IIa study of vaccination with IO103 and Montanide adjuvant was conducted in patients with resectable BCC (NCT03714529). Vaccinations were given six times every 2 weeks (q2w), followed by three vaccines q4w in responders. Primary endpoints were clinical responses of target tumors, change in target tumor size and immune responses to the vaccine. Secondary endpoint was safety. One tumor per patient was designated target tumor and biopsied twice during the course of vaccination. Synchronous non-target BCCs were not biopsied during vaccinations. Ten patients were vaccinated (six patients received six vaccinations and four patients received nine vaccinations). A partial response (PR) was seen in two target tumors. Two complete responses (CR) and one PR were observed in eight non-target tumors in four patients. No tumors progressed. Related adverse events were grade 1 and reversible. Immune responses against IO103 were induced in blood samples from nine of ten and skin-infiltrating lymphocytes from five of the nine patients. The regressions seen in non-target tumors suggest that IO103 may be effective against a subtype of BCC.
Facile Synthesis of COF-Supported Reduced Pd-Based Catalyst for One-Pot Reductive Amination of Aldehydes
Authors: Liu Jianguo , Zhang Mingyue , Ma Longlong
Published: February 2021

Dibenzylamine motifs are an important class of crucial organic compounds and are widely used in fine chemical and pharmaceutical industries. The development of the efficient, economical, and environmentally friendly synthesis of amines using transition metal-based heterogeneous catalysts remains both desirable and challenging. Herein, we prepared the covalent organic framework (COF)-supported heterogeneous reduced COF-supported Pd-based catalyst and used it for the one-pot reductive amination of aldehydes. There are both Pd metallic state and oxidated Pdσ+ in the catalysts. Furthermore, in the presence of the reduced COF-supported Pd-based catalyst, many aromatic, aliphatic, and heterocyclic aldehydes with various functional groups substituted were converted to their corresponding amines products in good to excellent selectivity (up to 91%) under mild reaction conditions (70 °C, 2 h, NH3, 20 bar H2). This work expands the covalent organic frameworks for the material family and its support catalyst, opening up new catalytic applications in the economical, practical, and effective synthesis of secondary amines.
Nanocatalysts for Hydrogen Production
Authors: Roh Hyun-Seog
Published: February 2021

Rising concerns about the effects of global warming and climate change have led to a search for environmentally clean and energy efficient technologies. Hydrogen is one of the most popular new types of energy, which is considered as a clean energy carrier for the future. Hydrogen is primarily produced by the steam reforming of natural gas. Other methods have also been developed, such as the gasification of coal/biomass/waste, water splitting by electrolysis, and so on. All the ways are using nanocatalysts to obtain a high efficiency of hydrogen production [...]
Twig and Shoot Dieback of Citrus, a New Disease Caused by Colletotrichum Species
Authors: Riolo Mario , Aloi Francesco , Pane Antonella , Cara Magdalena , Cacciola Santa Olga
Published: February 2021

(1) Background: This study was aimed at identifying the Colletotrichum species associated with twig and shoot dieback of citrus, a new syndrome occurring in the Mediterranean region and also reported as emerging in California. (2) Methods: Overall, 119 Colletotrichum isolates were characterized. They were recovered from symptomatic trees of sweet orange, mandarin and mandarin-like fruits during a survey of citrus groves in Albania and Sicily (southern Italy). (3) Results: The isolates were grouped into two distinct morphotypes. The grouping of isolates was supported by phylogenetic sequence analysis of two genetic markers, the internal transcribed spacer regions of rDNA (ITS) and β-tubulin (TUB2). The groups were identified as Colletotrichum gloeosporioides and C. karstii, respectively. The former accounted for more than 91% of isolates, while the latter was retrieved only occasionally in Sicily. Both species induced symptoms on artificially wound inoculated twigs. C. gloeosporioides was more aggressive than of C. karstii. Winds and prolonged drought were the factor predisposing to Colletotrichum twig and shoot dieback. (4) Conclusions: This is the first report of C. gloeosporioides and C. karstii as causal agents of twig and shoot dieback disease in the Mediterranean region and the first report of C. gloeosporioides as a citrus pathogen in Albania.
A Multi-Omics Study Revealing the Metabolic Effects of Estrogen in Liver Cancer Cells HepG2
Authors: Shen Minqian , Xu Mengyang , Zhong Fanyi , Crist McKenzie C. , Prior Anjali B. , Yang Kundi , Allaire Danielle M. , Choueiry Fouad , Zhu Jiangjiang , Shi Haifei
Published: February 2021

Hepatocellular carcinoma (HCC) that is triggered by metabolic defects is one of the most malignant liver cancers. A much higher incidence of HCC among men than women suggests the protective roles of estrogen in HCC development and progression. To begin to understand the mechanisms involving estrogenic metabolic effects, we compared cell number, viability, cytotoxicity, and apoptosis among HCC-derived HepG2 cells that were treated with different concentrations of 2-deoxy-d-glucose (2-DG) that blocks glucose metabolism, oxamate that inhibits lactate dehydrogenase and glycolysis, or oligomycin that blocks ATP synthesis and mitochondrial oxidative phosphorylation. We confirmed that HepG2 cells primarily utilized glycolysis followed by lactate fermentation, instead of mitochondrial oxidative phosphorylation, for cell growth. We hypothesized that estrogen altered energy metabolism via its receptors to carry out its anticancer effects in HepG2 cells. We treated cells with 17β-estradiol (E2), 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) an estrogen receptor (ER) α (ERα) agonist, or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), an ERβ agonist. We then used transcriptomic and metabolomic analyses and identified differentially expressed genes and unique metabolite fingerprints that are produced by each treatment. We further performed integrated multi-omics analysis, and identified key genes and metabolites in the gene–metabolite interaction contributed by E2 and ER agonists. This integrated transcriptomic and metabolomic study suggested that estrogen acts on estrogen receptors to suppress liver cancer cell growth via altering metabolism. This is the first exploratory study that comprehensively investigated estrogen and its receptors, and their roles in regulating gene expression, metabolites, metabolic pathways, and gene–metabolite interaction in HCC cells using bioinformatic tools. Overall, this study provides potential therapeutic targets for future HCC treatment.
Why Do We Not Assess Sympathetic Nervous System Activity in Heart Failure Management: Might GRK2 Serve as a New Biomarker?
Authors: Bencivenga Leonardo , Palaia Maria Emiliana , Sepe Immacolata , Gambino Giuseppina , Komici Klara , Cannavo Alessandro , Femminella Grazia Daniela , Rengo Giuseppe
Published: February 2021

Heart failure (HF) represents the end-stage condition of several structural and functional cardiovascular diseases, characterized by reduced myocardial pump function and increased pressure load. The dysregulation of neurohormonal systems, especially the hyperactivity of the cardiac adrenergic nervous system (ANS), constitutes a hallmark of HF and exerts a pivotal role in its progression. Indeed, it negatively affects patients’ prognosis, being associated with high morbidity and mortality rates, with a tremendous burden on global healthcare systems. To date, all the techniques proposed to assess the cardiac sympathetic nervous system are burdened by intrinsic limits that hinder their implementation in clinical practice. Several biomarkers related to ANS activity, which may potentially support the clinical management of such a complex syndrome, are slow to be implemented in the routine practice for several limitations due to their assessment and clinical impact. Lymphocyte G-protein-coupled Receptor Kinase 2 (GRK2) levels reflect myocardial β-adrenergic receptor function in HF and have been shown to add independent prognostic information related to ANS overdrive. In the present manuscript, we provide an overview of the techniques currently available to evaluate cardiac ANS in HF and future perspectives in this field of relevant scientific and clinical interest.
Ellagic Acid and Schisandrins: Natural Biaryl Polyphenols with Therapeutic Potential to Overcome Multidrug Resistance in Cancer
Authors: Yoganathan Sabesan , Alagaratnam Anushan , Acharekar Nikita , Kong Jing
Published: February 2021

Multidrug resistance (MDR) is one of the major clinical challenges in cancer treatment and compromises the effectiveness of conventional anticancer chemotherapeutics. Among known mechanisms of drug resistance, drug efflux via ATP binding cassette (ABC) transporters, namely P-glycoprotein (P-gp) has been characterized as a major mechanism of MDR. The primary function of ABC transporters is to regulate the transport of endogenous and exogenous small molecules across the membrane barrier in various tissues. P-gp and similar efflux pumps are associated with MDR because of their overexpression in many cancer types. One of the intensively studied approaches to overcome this mode of MDR involves development of small molecules to modulate P-gp activity. This strategy improves the sensitivity of cancer cells to anticancer drugs that are otherwise ineffective. Although multiple generations of P-gp inhibitors have been identified to date, reported compounds have demonstrated low clinical efficacy and adverse effects. More recently, natural polyphenols have emerged as a promising class of compounds to address P-gp linked MDR. This review highlights the chemical structure and anticancer activities of selected members of a structurally unique class of ‘biaryl’ polyphenols. The discussion focuses on the anticancer properties of ellagic acid, ellagic acid derivatives, and schisandrins. Research reports regarding their inherent anticancer activities and their ability to sensitize MDR cell lines towards conventional anticancer drugs are highlighted here. Additionally, a brief discussion about the axial chirality (i.e., atropisomerism) that may be introduced into these natural products for medicinal chemistry studies is also provided.
Chemically Defined Xeno- and Serum-Free Cell Culture Medium to Grow Human Adipose Stem Cells
Authors: Panella Stefano , Muoio Francesco , Jossen Valentin , Harder Yves , Eibl-Schindler Regine , Tallone Tiziano
Published: February 2021

Adipose tissue is an abundant source of stem cells. However, liposuction cannot yield cell quantities sufficient for direct applications in regenerative medicine. Therefore, the development of GMP-compliant ex vivo expansion protocols is required to ensure the production of a “cell drug” that is safe, reproducible, and cost-effective. Thus, we developed our own basal defined xeno- and serum-free cell culture medium (UrSuppe), specifically formulated to grow human adipose stem cells (hASCs). With this medium, we can directly culture the stromal vascular fraction (SVF) cells in defined cell culture conditions to obtain hASCs. Cells proliferate while remaining undifferentiated, as shown by Flow Cytometry (FACS), Quantitative Reverse Transcription PCR (RT-qPCR) assays, and their secretion products. Using the UrSuppe cell culture medium, maximum cell densities between 0.51 and 0.80 × 105 cells/cm2 (=2.55–4.00 × 105 cells/mL) were obtained. As the expansion of hASCs represents only the first step in a cell therapeutic protocol or further basic research studies, we formulated two chemically defined media to differentiate the expanded hASCs in white or beige/brown adipocytes. These new media could help translate research projects into the clinical application of hASCs and study ex vivo the biology in healthy and dysfunctional states of adipocytes and their precursors. Following the cell culture system developers’ practice and obvious reasons related to the formulas’ patentability, the defined media’s composition will not be disclosed in this study.
Identification of Accessible Hepatic Gene Signatures for Interindividual Variations in Nutrigenomic Response to Dietary Supplementation of Omega-3 Fatty Acids
Authors: Shi Yu , Li Ping , Jiang Cheng-fei , Chen Yi , Ma Yonghe , Gupta Nikhil , Ruan Xiangbo , Cao Haiming
Published: February 2021

Dietary supplementation is a widely adapted strategy to maintain nutritional balance for improving health and preventing chronic diseases. Conflicting results in studies of similar design, however, suggest that there is substantial heterogenicity in individuals’ responses to nutrients, and personalized nutrition is required to achieve the maximum benefit of dietary supplementation. In recent years, nutrigenomics studies have been increasingly utilized to characterize the detailed genomic response to a specific nutrient, but it remains a daunting task to define the signatures responsible for interindividual variations to dietary supplements for tissues with limited accessibility. In this work, we used the hepatic response to omega-3 fatty acids as an example to probe such signatures. Through comprehensive analysis of nutrigenomic response to eicosapentaneoid acid (EPA) and/or docosahexaenoic acid (DHA) including both protein coding and long noncoding RNA (lncRNA) genes in human hepatocytes, we defined the EPA- and/or DHA-specific signature genes in hepatocytes. By analyzing gene expression variations in livers of healthy and relevant disease populations, we identified a set of protein coding and lncRNA signature genes whose responses to omega-3 fatty acid exhibit very high interindividual variabilities. The large variabilities of individual responses to omega-3 fatty acids were further validated in human hepatocytes from ten different donors. Finally, we profiled RNAs in exosomes isolated from the circulation of a liver-specific humanized mouse model, in which the humanized liver is the sole source of human RNAs, and confirmed the in vivo detectability of some signature genes, supporting their potential as biomarkers for nutrient response. Taken together, we have developed an efficient and practical procedure to identify nutrient-responsive gene signatures as well as accessible biomarkers for interindividual variations.
Cytochrome c Oxidase at Full Thrust: Regulation and Biological Consequences to Flying Insects
Authors: Mesquita Rafael , Gaviraghi Alessandro , Gonçalves Renata , Vannier-Santos Marcos , Mignaco Julio , Fontes Carlos , Machado Luciana , Oliveira Marcus
Published: February 2021

Flight dispersal represents a key aspect of the evolutionary and ecological success of insects, allowing escape from predators, mating, and colonization of new niches. The huge energy demand posed by flight activity is essentially met by oxidative phosphorylation (OXPHOS) in flight muscle mitochondria. In insects, mitochondrial ATP supply and oxidant production are regulated by several factors, including the energy demand exerted by changes in adenylate balance. Indeed, adenylate directly regulates OXPHOS by targeting both chemiosmotic ATP production and the activities of specific mitochondrial enzymes. In several organisms, cytochrome c oxidase (COX) is regulated at transcriptional, post-translational, and allosteric levels, impacting mitochondrial energy metabolism, and redox balance. This review will present the concepts on how COX function contributes to flying insect biology, focusing on the existing examples in the literature where its structure and activity are regulated not only by physiological and environmental factors but also how changes in its activity impacts insect biology. We also performed in silico sequence analyses and determined the structure models of three COX subunits (IV, VIa, and VIc) from different insect species to compare with mammalian orthologs. We observed that the sequences and structure models of COXIV, COXVIa, and COXVIc were quite similar to their mammalian counterparts. Remarkably, specific substitutions to phosphomimetic amino acids at critical phosphorylation sites emerge as hallmarks on insect COX sequences, suggesting a new regulatory mechanism of COX activity. Therefore, by providing a physiological and bioenergetic framework of COX regulation in such metabolically extreme models, we hope to expand the knowledge of this critical enzyme complex and the potential consequences for insect dispersal.
Hyperglycemia Potentiates Prothrombotic Effect of Aldosterone in a Rat Arterial Thrombosis Model
Authors: Gromotowicz-Poplawska Anna , Szoka Piotr , Zakrzeska Agnieszka , Kolodziejczyk Patrycjusz , Marcinczyk Natalia , Szemraj Janusz , Tutka Piotr , Chabielska Ewa
Published: February 2021

We investigated the role of aldosterone (ALDO) in the development of arterial thrombosis in streptozotocin-induced diabetic rats. To evaluate the effect of endogenous ALDO, the rats underwent adrenalectomy (ADX). ADX reduced the development of arterial thrombosis. A 1 h infusion of ALDO (30 μg/kg/h) enhanced thrombosis in adrenalectomized rats, while this effect was potentiated in diabetic rats. ALDO shortened bleeding time, increased plasma levels of tissue factor (TF) and plasminogen activator inhibitor, decreased plasma level of nitric oxide (NO) metabolites, and increased oxidative stress. Moreover, 2 h incubation of human umbilical vein endothelial cells (HUVECs) with ALDO (10−7 M) disrupted hemostatic balance in endothelial cells in normoglycemia (glucose 5.5 mM), and this effect was more pronounced in hyperglycemia (glucose 30 mM). We demonstrated that the acute ALDO infusion enhances arterial thrombosis in rats and hyperglycemia potentiates this prothrombotic effect. The mechanism of ALDO action was partially mediated by mineralocorticoid (MR) and glucocorticoid (GR) receptors and related to impact of the hormone on primary hemostasis, TF-dependent coagulation cascade, fibrinolysis, NO bioavailability, and oxidative stress balance. Our in vitro study confirmed that ALDO induces prothrombotic phenotype in the endothelium, particularly under hyperglycemic conditions.
A First Step toward the Clinical Application of Landmark-Based Acoustic Analysis in Child Mandarin
Authors: Liu Chin-Ting
Published: February 2021

As an initial step for the clinical application of landmark-based acoustic analysis in child Mandarin, the study quantified the developmental trajectories of consonants produced by four-to-seven-year-old children who acquired Taiwanese Mandarin as their first language. The results from a total of 80 children (20 in each age group, with gender balanced) indicated that younger age groups produced more +b landmark features than seven-year-olds did, showing that the development of obstruents was not completed by the age of six. A multiple regression showed that the participants’ speech intelligibility scores could be predicted by landmark features. Additionally, the +b landmark feature demonstrated the strongest net effect on speech intelligibility scores. The findings indicated that: (a) the landmark feature +b was an essential indicator of speech development in child Mandarin and; (b) the consonantal development in child Mandarin could be predicted by the physiological complexity of the articulatory gestures. Future studies focusing on a wider range of population (e.g., typically developing adults, aging and other clinical groups) with different language backgrounds are encouraged to apply landmark-based acoustic analysis to trace the linguistic development of a particular group.
Epidemiology and One-Year Follow-Up of Neonates with CDH-Data from Health Insurance Claims in Germany
Authors: Wittekindt Boris , Doberschuetz Nora , Schmedding Andrea , Theilen Till-Martin , Schloesser Rolf , Gfroerer Stefan , Rolle Udo
Published: February 2021

Congenital diaphragmatic hernia (CDH) is a major congenital malformation with high mortality. Outcome data on larger unselected patient groups in Germany are unavailable as there is no registry for CDH. Therefore, routine data from the largest German health insurance fund were analyzed for the years 2009–2013. Main outcome measures were incidence, survival and length of hospital stay. Follow-up was 12 months. 285 patients were included. The incidence of CDH was 2.73 per 10,000 live births. Overall mortality was 30.2%. A total of 72.1% of the fatalities occurred before surgery. Highest mortality (64%) was noted in patients who were admitted to specialized care later as the first day of life. Patients receiving surgical repair had a better prognosis (mortality: 10.8%). A total of 67 patients (23.5%) were treated with ECMO with a mortality of 41.8%. The median cumulative hospital stay among one-year survivors was 40 days and differed between ECMO- and non-ECMO-treated patients (91 vs. 32.5 days, p < 0.001). This is the largest German cohort study of CDH patients with a one-year follow-up. The ECMO subgroup showed a higher mortality. Another important finding is that delayed treatment in specialized care increases mortality. Prospective clinical registries are needed to elucidate the treatment outcomes in detail.
Physical Activity of Serbian Children in Daycare
Authors: Janković Milenko , Batez Maja , Stupar Dušan , Obradović Jelena , Trajković Nebojša
Published: February 2021

Background: Monitoring of physical activity within the educational institution is of great importance, primarily because of the orientation and content implemented in the daycare. This research aimed to examine the number of steps children took during their stay in daycare with regards to age, gender and the frequency of going out. Methods: The research was conducted in four daycares in the urban environment of Novi Sad (Republic of Serbia), where 231 children, aged 5 to 7, were monitored (129 boys and 102 girls). Data on the number of steps were obtained using the pedometers. Results: The result of the univariate analysis of the variance test confirmed a statistically significant difference in the number of steps in relation to the age of children (p = 0.04). Boys were more active than girls in both age groups (p = 0.001). Children who were going to the daycare yard three to five times a week took drastically more steps than children who went up to twice a week (p = 0.001). Conclusion: The results of the current study show that age, gender, and time spent outdoors are significant determinants of physical activity in preschool age. Therefore, interventions regarding physical activity should be made during early childhood in order to promote health and prevent disease.
Detection of Early Warning Signs in Autism Spectrum Disorders: A Systematic Review
Authors: Salgado-Cacho José María , Moreno-Jiménez María del Pilar , de Diego-Otero Yolanda
Published: February 2021

Due to the exponential increase of autism spectrum disorders’ prevalence in Western countries, it is necessary to improve early detection and intervention to enhance developmental milestones. This systematic review identified the most effective screening instrument, which can be used at an early age and which identifies the maximum number of autism cases. We identified several instruments with adequate predictive properties—the Autism Parent Screen for Infants (APSI), Battelle Development Inventory, second edition (BDI-2); Brief Infant-Toddler Social and Emotional Assessment (BITSEA); First Year Inventory (FYI); Infant-Toddler Checklist/Communication and Symbolic Behavior Scales Developmental Profile (ITC/CSBS-DP); Program of Research and Studies on AUTISM (PREAUT-Grid); Checklist for Early Signs of Developmental Disorders (CESDD); Social Attention and Communication Study (SACS); and the Screening Tool for Autism in Toddlers and Young Children (STAT)—that can be applied from 12 months of age in Western countries. The ITC/CSBS-DP has been proposed for universal screening from 12 months of age onwards, complemented by the Modified Checklist for Autism in Toddlers, Revised/Revised with Follow-Up (M-CHAT-R/F), which can be used from 15 months of age onwards. This strategy could improve early detection in at-risk children within the current health system, thus allowing for early intervention.
The Role of Alexithymia in Social Withdrawal during Adolescence: A Case–Control Study
Authors: Iannattone Sara , Miscioscia Marina , Raffagnato Alessia , Gatta Michela
Published: February 2021

Although social withdrawal is becoming increasingly common among adolescents, there is still no consensus on its definition from the diagnostic and psychopathological standpoints. So far, research has focused mainly on social withdrawal as a symptom of specific diagnostic categories, such as depression, social phobia, or anxiety disorders, or in the setting of dependence or personality disorders. Few studies have dealt with social withdrawal in terms of its syndromic significance, also considering aspects of emotion control, such as alexithymia. The present case-control study aimed to further investigate the issue of social withdrawal, and try to clarify the part played by alexithymia in a sample of Italian adolescents diagnosed with psychological disorders (n = 80; Average Ageg = 15.2 years, SD = 1.49). Our patients with social withdrawal (cases) scored significantly higher than those without this type of behavior (controls) in every domain of alexithymia investigated, using the Toronto Alexithymia Scale (TAS-20) and with the scales in the Youth Self-Report (YSR) regarding internalizing problems, anxiety–depression, social problems, and total problems. Internalizing problems and total levels of alexithymia also emerged as predictors of social withdrawal. These variables may therefore precede and predispose adolescents to social withdrawal, while social problems may develop as a consequence of the latter.