bluuebunny/crossref_metadata_2025 huggingface dataset:
Osteosarcoma-Specific Genes as a Diagnostic Tool and Clinical Predictor of Tumor Progression
Authors: Sittiju Pattaralawan , Chaiyawat Parunya , Pruksakorn Dumnoensun , Klangjorhor Jeerawan , Wongrin Weerinrada , Phinyo Phichayut , Kamolphiwong Rawikant , Phanphaisarn Areerak , Teeyakasem Pimpisa , Kongtawelert Prachya , Pothacharoen Peraphan
Published: May 2022

A liquid biopsy is currently an interesting tool for measuring tumor material with the advantage of being non-invasive. The overexpression of vimentin and ezrin genes was associated with epithelial-mesenchymal transition (EMT), a key process in metastasis and progression in osteosarcoma (OS). In this study, we identified other OS-specific genes by calculating differential gene expression using the Gene Expression Omnibus (GEO) database, confirmed by using quantitative reverse transcription-PCR (qRT-PCR) to detect OS-specific genes, including VIM and ezrin in the buffy coat, which were obtained from the whole blood of OS patients and healthy donors. Furthermore, the diagnostic model for OS detection was generated by utilizing binary logistic regression with a multivariable fractional polynomial (MFP) algorithm. The model incorporating VIM, ezrin, and COL5A2 genes exhibited outstanding discriminative ability, as determined by the receiver operating characteristic curve (AUC = 0.9805, 95% CI 0.9603, 1.000). At the probability cut-off value of 0.3366, the sensitivity and the specificity of the model for detecting OS were 98.63% (95% CI 90.5, 99.7) and 94.94% (95% CI 87.5, 98.6), respectively. Bioinformatic analysis and qRT-PCR, in our study, identified three candidate genes that are potential diagnostic and prognostic genes for OS.
Lung Hyaluronasome: Involvement of Low Molecular Weight Ha (Lmw-Ha) in Innate Immunity
Authors: Hoarau Antony , Polette Myriam , Coraux Christelle
Published: May 2022

Hyaluronic acid (HA) is a major component of the extracellular matrix. It is synthesized by hyaluronan synthases (HAS) into high-molecular-weight chains (HMW-HA) that exhibit anti-inflammatory and immunomodulatory functions. In damaged, infected, and/or inflamed tissues, HMW-HA are degraded by hyaluronidases (HYAL) or reactive oxygen species (ROS) to give rise to low-molecular-weight HAs (LMW-HAs) that are potent pro-inflammatory molecules. Therefore, the size of HA regulates the balance of anti- or pro-inflammatory functions. The activities of HA depend also on its interactions with hyaladherins. HA synthesis, degradation, and activities through HA/receptors interactions define the hyaluronasome. In this review, a short overview of the role of high and low-molecular-weight HA polymers in the lungs is provided. The involvement of LMW-HA in pulmonary innate immunity via the activation of neutrophils, macrophages, dendritic cells, and epithelial cells is described to highlight LMW-HA as a therapeutic target in inflammatory respiratory diseases. Finally, the possibilities to counter LMW-HA’s deleterious effects in the lungs are discussed.
Regulation of Δ6Fads2 Gene Involved in LC-PUFA Biosynthesis Subjected to Fatty Acid in Large Yellow Croaker (Larimichthys crocea) and Rainbow Trout (Oncorhynchus mykiss)
Authors: Sun Jie , Li Jingqi , Li Yongnan , Du Jianlong , Zhao Nannan , Mai Kangsen , Ai Qinghui
Published: May 2022

Δ6 fatty acyl desaturase (Δ6Fads2) is regarded as the first rate-limiting desaturase that catalyzes the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFA) from 18-carbon fatty acid in vertebrates, but the underlying regulatory mechanism of fads2 has not been comprehensively understood. This study aimed to investigate the regulation role of fads2 subjected to fatty acid in large yellow croaker and rainbow trout. In vivo, large yellow croaker and rainbow trout were fed a fish oil (FO) diet, a soybean oil (SO) diet or a linseed oil (LO) diet for 10 weeks. The results show that LO and SO can significantly increase fads2 expression (p < 0.05). In vitro experiments were conducted in HEK293T cells or primary hepatocytes to determine the transcriptional regulation of fads2. The results show that CCAAT/enhancer-binding protein α (C/EBPα) can up-regulate fads2 expression. GATA binding protein 3 (GATA3) can up-regulate fads2 expression in rainbow trout but showed opposite effect in large yellow croaker. Furthermore, C/EBPα protein levels were significantly increased by LO and SO (p < 0.05), gata3 expression was increased in rainbow trout by LO but decreased in large yellow croaker by LO and SO. In conclusion, we revealed that FO replaced by LO and SO increased fads2 expression through a C/EBPα and GATA3 dependent mechanism in large yellow croaker and rainbow trout. This study might provide critical insights into the regulatory mechanisms of fads2 expression and LC-PUFA biosynthesis.
Fluid–Structure Interaction Modeling of Ascending Thoracic Aortic Aneurysms in SimVascular
Authors: Valente Rodrigo , Mourato André , Brito Moisés , Xavier José , Tomás António , Avril Stéphane
Published: May 2022

Ascending Thoracic Aortic Aneurysm (ATAA) is a permanent dilatation of the aorta which is usually related to tissue degeneration, hemodynamic conditions, lifestyle, environmental and genetic factors. As the mechanical conditions can become critical in a dilated aorta, a patient-specific computational model can be very useful to assist clinical decisions in the management of ATAAs. In this article, we model the biomechanical conditions of ATAA by performing Fluid–Structure Interaction (FSI) simulations in the SimVascular open-source software package. The patient-specific geometric model is reconstructed from Computed Tomography scan (CT). The numerical implementation takes into account patient-specific outlet conditions and a temporal flow variation at the model inlet. We performed a mesh convergence analysis on a new mesh reconstruction method in SimVascular and showed that it can significantly reduce the computational cost without impacting the accuracy.
Targeting TKI-Activated NFKB2-MIF/CXCLs-CXCR2 Signaling Pathways in FLT3 Mutated Acute Myeloid Leukemia Reduced Blast Viability
Authors: Cao Huynh , Tadros Verena , Hiramoto Benjamin , Leeper Kevin , Hino Christopher , Xiao Jeffrey , Pham Bryan , Kim Do Hyun , Reeves Mark E. , Chen Chien-Shing , Zhong Jiang F. , Zhang Ke K. , Xie Linglin , Wasnik Samiksha , Baylink David J. , Xu Yi
Published: May 2022

Disease relapse is a common cause of treatment failure in FMS-like tyrosine kinase 3 (FLT3) mutated acute myeloid leukemia (AML). In this study, to identify therapeutic targets responsible for the survival and proliferation of leukemic cells (blasts) with FLT3 mutations after gilteritinib (GILT, a 2nd generation tyrosine kinase inhibitor (TKI)) treatment, we performed proteomic screening of cytokine release and in vitro/ex vivo studies to investigate their associated signaling pathways and transcriptional regulation. Here, we report that macrophage migration inhibition factor (MIF) was significantly increased in the supernatant of GILT-treated blasts when compared to untreated controls. Additionally, the GILT-treated blasts that survived were found to exhibit higher expressions of the CXCR2 gene and protein, a common receptor for MIF and pro-inflammatory cytokines. The supplementation of exogenous MIF to GILT-treated blasts revealed a group of CD44High+ cells that might be responsible for the relapse. Furthermore, we identified the highly activated non-classical NFKB2 pathway after GILT-treatment. The siRNA transient knockdown of NFKB2 significantly reduced the gene expressions of MIF, CXCR2, and CXCL5. Finally, treatments of AML patient samples ex vivo demonstrated that the combination of a pharmaceutical inhibitor of the NFKB family and GILT can effectively suppress primary blasts’ secretion of tumor-promoting cytokines, such as CXCL1/5/8. In summary, we provide the first evidence that targeting treatment-activated compensatory pathways, such as the NFKB2-MIF/CXCLs-CXCR2 axis could be a novel therapeutic strategy to overcome TKI-resistance and effectively treat AML patients with FLT3 mutations.
In Vivo Validation of Diffuse Optical Imaging with a Dual-Direction Measuring Module of Parallel-Plate Architecture for Breast Tumor Detection
Authors: Yu Jhao-Ming , Chen Liang-Yu , Pan Min-Cheng , Hsu Ya-Fen , Pan Min-Chun , Lin Yi-Ling , Sun Sheng-Yih , Chou Chia-Cheng
Published: May 2022

We demonstrate a working prototype of an optical breast imaging system involving parallel-plate architecture and a dual-direction scanning scheme designed in combination with a mammography machine; this system was validated in a pilot study to demonstrate its application in imaging healthy and malignant breasts in a clinical environment. The components and modules of the self-developed imaging system are demonstrated and explained, including its measuring architecture, scanning mechanism, and system calibration, and the reconstruction algorithm is presented. Additionally, the evaluation of feature indices that succinctly demonstrate the corresponding transmission measurements may provide insight into the existence of malignant tissue. Moreover, five cases are presented including one subject without disease (a control measure), one benign case, one suspected case, one invasive ductal carcinoma, and one positive case without follow-up treatment. A region-of-interest analysis demonstrated significant differences in absorption between healthy and malignant breasts, revealing the average contrast between the abnormalities and background tissue to exceed 1.4. Except for ringing artifacts, the average scattering property of the structure densities was 0.65–0.85 mm−1.
Antibiotic Treatment during Pregnancy Alters Offspring Gut Microbiota in a Sex-Dependent Manner
Authors: Madany Abdullah M. , Hughes Heather K. , Ashwood Paul
Published: May 2022

This study investigated the effect of antibiotics administered to pregnant dams on offspring gut microbiome composition and metabolic capabilities, and how these changes in the microbiota may influence their immune responses in both the periphery and the brain. We orally administered a broad-spectrum antibiotic (ABX) cocktail consisting of vancomycin 0.5 mg/mL, ampicillin 1 mg/mL, and neomycin 1 mg/mL to pregnant dams during late gestation through birth. Bacterial DNA was extracted from offspring fecal samples, and 16S ribosomal RNA gene was sequenced by Illumina, followed by analysis of gut microbiota composition and PICRUSt prediction. Serum and brain tissue cytokine levels were analyzed by Luminex. Our results indicate that the ABX-cocktail led to significant diversity and taxonomic changes to the offspring’s gut microbiome. In addition, the predicted KEGG and MetaCyc pathways were significantly altered in the offspring. Finally, there were decreased innate inflammatory cytokines and chemokines and interleukin (IL)-17 seen in the brains of ABX-cocktail offspring in response to lipopolysaccharide (LPS) immune challenge. Our results suggest that maternal ABX can produce long-lasting effects on the gut microbiome and neuroimmune responses of offspring. These findings support the role of the early microbiome in the development of offspring gastrointestinal and immune systems.
Identification of sSIGLEC5 and sLAG3 as New Relapse Predictors in Lung Cancer
Authors: Montalbán-Hernández Karla , Casalvilla-Dueñas José Carlos , Cruz-Castellanos Patricia , Gutierrez-Sainz Laura , Lozano-Rodríguez Roberto , Avendaño-Ortiz José , del Fresno Carlos , de Castro-Carpeño Javier , López-Collazo Eduardo
Published: May 2022

Lung cancer (LC) continues to be the leading cause of cancer-related deaths in both men and women worldwide. After complete tumour resection, around half of the patients suffer from disease relapse, emphasising the critical need for robust relapse predictors in this disease. In search of such biomarkers, 83 patients with non-microcytic lung cancer and 67 healthy volunteers were studied. Pre-operative levels of sSIGLEC5 along with other soluble immune-checkpoints were measured and correlated with their clinical outcome. Soluble SIGLEC5 (sSIGLEC5) levels were higher in plasma from patients with LC compared with healthy volunteers. Looking into those patients who suffered relapse, sSIGLEC5 and sLAG3 were found to be strong relapse predictors. Following a binary logistic regression model, a sSIGLEC5 + sLAG3 score was established for disease relapse prediction (area under the curve 0.8803, 95% confidence intervals 0.7955–0.9652, cut-off > 2.782) in these patients. Based on score cut-off, a Kaplan–Meier analysis showed that patients with high sSIGLEC5 + sLAG3 score had significantly shorter relapse-free survival (p ≤ 0.0001) than those with low sSIGLEC5 + sLAG3 score.Our study suggests that pre-operative sSIGLEC5 + sLAG3 score is a robust relapse predictor in LC patients.
Effect of Vitamin K on Bone Mineral Density and Fracture Risk in Adults: Systematic Review and Meta-Analysis
Authors: Salma  , Ahmad Syed Sufian , Karim Shahid , Ibrahim Ibrahim M. , Alkreathy Huda M. , Alsieni Mohammed , Khan Mohammad Ahmed
Published: May 2022

Summary: Recent studies have proposed that adequate intake of Vitamin K (VK) is associated with a low risk of fracture and high bone mineral density (BMD) to improve skeletal health in adults. This systematic review was designed to summarize the most relevant and updated evidence discussing the relationship between VK and bone. It explores the effect of VK deficiency and its supplementation on various bone parameters. Methods: The distinct databases such as PubMed, the Cochrane Library, Google Scholar, National Clinical Trials, Current Controlled Trials, and Clinical Trials were searched up to Jan 2020 to identify eligible trials. All relevant randomized controlled trial studies with any oral dosage form of VK supplement administered for at least six months and assessing BMD or fracture in adults were extracted. Finally, two independent reviewers identified 20 relevant citations for the systematic review and extracted data in tabular form. Results: The meta-analysis was performed with all studies, including postmenopausal and osteoporotic females, for both total clinical and vertebral fracture outcomes. The quantitative analysis showed that the odds ratios (OR) of any fracture were lower for VK as compared to control [OR 0.42 (95% CI 0.27 to 0.66)] for vertebral fractures and OR of 0.44 (95% CI 0.23 to 0.88) for clinical fracture. For the BMD, a meta-analysis of the pooled effect of interventional studies suggested a non-significant association between the use of VK and improvement in femoral BMD (CI 95%, p = 0.08 [−0.03–0.20]). Conclusion: VK decreases general fracture risk, and it can be an option to counter bone loss disorders. However, insufficient evidence is available regarding the significant impact of VK on femoral neck BMD. Therefore, further studies are required to establish the therapeutic value of VK as a treatment for osteoporosis.
Model-Based Control Strategies to Enhance Energy Flexibility in Electrically Heated School Buildings
Authors: Morovat Navid , Athienitis Andreas K. , Candanedo José Agustín , Delcroix Benoit
Published: May 2022

This paper presents a general methodology to model and activate the energy flexibility of electrically heated school buildings. The proposed methodology is based on the use of archetypes of resistance–capacitance thermal networks for representative thermal zones calibrated with measured data. Using these models, predictive control strategies are investigated with the aim of reducing peak demand in response to grid requirements and incentives. A key aim is to evaluate the potential of shifting electricity use in different archetype zones from on-peak hours to off-peak grid periods. Key performance indicators are applied to quantify the energy flexibility at the zone level and the school building level. The proposed methodology has been implemented in an electrically heated school building located in Québec, Canada. This school has several features (geothermal heat pumps, hydronic radiant floors, and energy storage) that make it ideal for the purpose of this study. The study shows that with proper control strategies through a rule-based approach with near-optimal setpoint profiles, the building’s average power demand can be reduced by 40% to 65% during on-peak hours compared to a typical profile.
Timber Semirigid Frame Connection with Improved Deformation Capacity and Ductility
Authors: Johanides Marek , Lokaj Antonin , Mikolasek David , Mynarcik Petr , Dobes Pavel , Sucharda Oldrich
Published: May 2022

The present study deals with the innovation and the possibilities of improving the design solution of a frame connection for two selected types of fasteners. All specimens were made of glued laminated timber. Dowel-type mechanical fasteners, a combination of bolts and dowels, and full-threaded screws were used for the connection. The main goal of this research was to replace the typical solution (common dowel-type fasteners) with a more modern, faster, and easier solution in order to improve the load-carrying capacity, ductility, and deformation capacity of this type of frame connection. This article also aimed to provide a detailed evaluation of the mechanical properties of the used glued laminated timber and fasteners in order to comprehensively evaluate the research task. For the design solution, a frame connection created from a system of two struts and a partition was chosen as the basis of the experimental program. Dowel-type mechanical fasteners, as well as combinations of bolts and dowels, were used for the connection; however, in addition to these standardly used mechanical fasteners, full-threaded screws were used. The article describes the use of static destructive testing to determine the ductility of the connection, considering different variations in the strengthening of the individual segments of the mentioned connection means. In the first variation, the individual components of the frame were not reinforced in any way. In the second, the crossbar was reinforced with two full-threaded bolts. In the third, the webs and the crossbar were reinforced with two full-threaded bolts. In the article, these ductility values were compared with each other and the procedure was set by the currently valid standard.
Failure Modes of Reinforced Concrete Beams Strengthened in Flexure with Externally Bonded Aramid Fiber-Reinforced Polymer Sheets under Impact Loading
Authors: Sinh Le Huy , Komuro Masato , Kawarai Tomoki , Kishi Norimitsu
Published: May 2022

This paper focuses on the aramid fiber-reinforced polymer (AFRP) sheet bonding method to investigate the influences of the sheet volume and input impact energy on the failure modes of strengthened RC beams. The drop-weight impact loading tests were conducted on RC beams strengthened with AFRP sheets. The sheet volume was investigated, varying from 415 to 1660 g/m2. The impact force was generated by dropping a 300 kg steel weight onto the midspan of the beams from different heights (0.5, 1.0, 2.0, 2.5, 3.0, and 3.5 m), and the weight’s drop height was raised until the sheets were debonded or ruptured. As a reference beam, nonstrengthened beams were also evaluated. The following are the findings of this research. (1) In the event of impact loading, the impact resistance capacity of strengthened beams can be enhanced by up to 85% by applying the AFRP sheet bonding method; however, (2) in the case of relatively large impact energy, the impact resistance capacity may not always be remarkable. (3) Depending on the sheet volume, the failure mechanism of the AFRP-strengthened beams was classified into two types: sheet debonding and sheet rupturing. Furthermore, (4) increasing the sheet volume may not improve the debonding of the AFRP sheet of the strengthened beams.
EGFR-Mutant Non-Small-Cell Lung Cancer at Surgical Stages: What Is the Place for Tyrosine Kinase Inhibitors?
Authors: Cansouline Xavier , Lipan Béatrice , Sizaret Damien , Tallet Anne , Vandier Christophe , Carmier Delphine , Legras Antoine
Published: May 2022

The ADAURA trial has been significant for the perception of EGFR tyrosine kinase inhibitors (TKIs) as a tool for early stage non-small-cell lung cancer (NSCLC). It produced such great insight that the main TKI, Osimertinib, was rapidly integrated into international guidelines for adjuvant use. However, EGFR-mutant NSCLC is a complex entity and has various targeting drugs, and the benefits for patients might not be as clear as they seem. We reviewed trials and meta-analyses considering TKI adjuvant and neoadjuvant use. We also explored the influence of mutation variability and financial evaluations. We found that TKIs often show disease-free survival (DFS) benefits, yet studies have struggled to improve the overall survival (OS); however, the results from the literature might be confusing because of variability in the stages and mutations. The safety profiles and adverse events are acceptable, but costs remain high and accessibility might not be optimal. TKIs are promising drugs that could allow for tailored treatment designs.
Setting Up an Ultra-Fast Next-Generation Sequencing Approach as Reflex Testing at Diagnosis of Non-Squamous Non-Small Cell Lung Cancer; Experience of a Single Center (LPCE, Nice, France)
Authors: Ilié Marius , Hofman Véronique , Bontoux Christophe , Heeke Simon , Lespinet-Fabre Virginie , Bordone Olivier , Lassalle Sandra , Lalvée Salomé , Tanga Virginie , Allegra Maryline , Salah Myriam , Bohly Doriane , Benzaquen Jonathan , Marquette Charles-Hugo , Long-Mira Elodie , Hofman Paul
Published: May 2022

The number of genomic alterations required for targeted therapy of non-squamous non-small cell lung cancer (NS-NSCLC) patients has increased and become more complex these last few years. These molecular abnormalities lead to treatment that provides improvement in overall survival for certain patients. However, these treated tumors inexorably develop mechanisms of resistance, some of which can be targeted with new therapies. The characterization of the genomic alterations needs to be performed in a short turnaround time (TAT), as indicated by the international guidelines. The origin of the tissue biopsies used for the analyses is diverse, but their size is progressively decreasing due to the development of less invasive methods. In this respect, the pathologists are facing a number of different challenges requiring them to set up efficient molecular technologies while maintaining a strategy that allows rapid diagnosis. We report here our experience concerning the development of an optimal workflow for genomic alteration assessment as reflex testing in routine clinical practice at diagnosis for NS-NSCLC patients by using an ultra-fast-next generation sequencing approach (Ion Torrent Genexus Sequencer, Thermo Fisher Scientific). We show that the molecular targets currently available to personalized medicine in thoracic oncology can be identified using this system in an appropriate TAT, notably when only a small amount of nucleic acids is available. We discuss the new challenges and the perspectives of using such an ultra-fast NGS in daily practice.
HLA-DR Presentation of the Tumor Antigen MSLN Associates with Clinical Outcome of Ovarian Cancer Patients
Authors: Tegeler Christian M. , Scheid Jonas , Rammensee Hans-Georg , Salih Helmut R. , Walz Juliane S. , Heitmann Jonas S. , Nelde Annika
Published: May 2022

T-cell recognition of HLA-presented antigens is central for the immunological surveillance of malignant disease and key for the development of novel T-cell-based immunotherapy approaches. In recent years, large-scale immunopeptidome studies identified naturally presented tumor-associated antigens for several malignancies. Regarding ovarian carcinoma (OvCa), Mucin-16 (MUC16) and Mesothelin (MSLN) were recently described as the top HLA class I- and HLA class II-presented tumor antigens, respectively. Here, we investigate the role and impact of immunopeptidome-presented tumor antigens on the clinical outcomes of 39 OvCa patients with a follow-up time of up to 50 months after surgery. Patients with a HLA-restricted presentation of high numbers of different MSLN-derived peptides on their tumors exhibited significantly prolonged progression-free (PFS) and overall survival (OS), whereas the presentation of MUC16-derived HLA class I-restricted peptides had no impact. Furthermore, a high HLA-DRB gene expression was associated with increased PFS and OS. In line, in silico prediction revealed that MSLN-derived HLA class II-presented peptides are predominantly presented on HLA-DR allotypes. In conclusion, the correlation of MSLN tumor antigen presentation and HLA-DRB gene expression with prolonged survival indicates a central role of CD4+ T-cell responses for tumor immune surveillance in OvCa, and highlights the importance of immunopeptidome-guided tumor antigen discovery.
Space- and Time-Resolved Metabolomics of a High-Grade Serous Ovarian Cancer Mouse Model
Authors: Sah Samyukta , Ma Xin , Botros Andro , Gaul David A. , Yun Sylvia R. , Park Eun Young , Kim Olga , Moore Samuel G. , Kim Jaeyeon , Fernández Facundo M.
Published: May 2022

The dismally low survival rate of ovarian cancer patients diagnosed with high-grade serous carcinoma (HGSC) emphasizes the lack of effective screening strategies. One major obstacle is the limited knowledge of the underlying mechanisms of HGSC pathogenesis at very early stages. Here, we present the first 10-month time-resolved serum metabolic profile of a triple mutant (TKO) HGSC mouse model, along with the spatial lipidome profile of its entire reproductive system. A high-coverage liquid chromatography mass spectrometry-based metabolomics approach was applied to longitudinally collected serum samples from both TKO (n = 15) and TKO control mice (n = 15), tracking metabolome and lipidome changes from premalignant stages to tumor initiation, early stages, and advanced stages until mouse death. Time-resolved analysis showed specific temporal trends for 17 lipid classes, amino acids, and TCA cycle metabolites, associated with HGSC progression. Spatial lipid distributions within the reproductive system were also mapped via ultrahigh-resolution matrix-assisted laser desorption/ionization (MALDI) mass spectrometry and compared with serum lipid profiles for various lipid classes. Altogether, our results show that the remodeling of lipid and fatty acid metabolism, amino acid biosynthesis, TCA cycle and ovarian steroidogenesis are critical components of HGSC onset and development. These metabolic alterations are accompanied by changes in energy metabolism, mitochondrial and peroxisomal function, redox homeostasis, and inflammatory response, collectively supporting tumorigenesis.
Development and Characterization of MYB-NFIB Fusion Expression in Adenoid Cystic Carcinoma
Authors: Humtsoe Joseph O. , Kim Hyun-Su , Jones Leilani , Cevallos James , Boileau Philippe , Kuo Fengshen , Morris Luc G. T. , Ha Patrick
Published: May 2022

Adenoid cystic carcinoma (ACC) is the second most common cancer type arising from the salivary gland. The frequent occurrence of chromosome t(6;9) translocation leading to the fusion of MYB and NFIB transcription factor genes is considered a genetic hallmark of ACC. This inter-chromosomal rearrangement may encode multiple variants of functional MYB-NFIB fusion in ACC. However, the lack of an ACC model that harbors the t(6;9) translocation has limited studies on defining the potential function and implication of chimeric MYB-NFIB protein in ACC. This report aims to establish a MYB-NFIB fusion protein expressing system in ACC cells for in vitro and in vivo studies. RNA-seq data from MYB-NFIB translocation positive ACC patients’ tumors and MYB-NFIB fusion transcript in ACC patient-derived xenografts (ACCX) was analyzed to identify MYB breakpoints and their frequency of occurrence. Based on the MYB breakpoint identified, variants of MYB-NFIB fusion expression system were developed in a MYB-NFIB deficient ACC cell lines. Analysis confirmed MYB-NFIB fusion protein expression in ACC cells and ACCXs. Furthermore, recombinant MYB-NFIB fusion displayed sustained protein stability and impacted transcriptional activities of interferon-associated genes set as compared to a wild type MYB. In vivo tumor formation analysis indicated the capacity of MYB-NFIB fusion cells to grow as implanted tumors, although there were no fusion-mediated growth advantages. This expression system may be useful not only in studies to determine the functional aspects of MYB-NFIB fusion but also in evaluating effective drug response in vitro and in vivo settings.
Estrogens, Cancer and Immunity
Authors: Orzołek Izabela , Sobieraj Jan , Domagała-Kulawik Joanna
Published: May 2022

Sex hormones are included in many physiological and pathological pathways. Estrogens belong to steroid hormones active in female sex. Estradiol (E2) is the strongest female sex hormone and, with its receptors, contributes to oncogenesis, cancer progression and response to treatment. In recent years, a role of immunosurveillance and suppression of immune response in malignancy has been well defined, forming the basis for cancer immunotherapy. The interplay of sex hormones with cancer immunity, as well as the response to immune checkpoint inhibitors, is of interest. In this review, we investigate the impact of sex hormones on natural immune response with respect to main active elements in anticancer immune surveillance: dendritic cells, macrophages, lymphocytes and checkpoint molecules. We describe the main sex-dependent tumors and the contribution of estrogen in their progression, response to treatment and especially modulation of anticancer immune response.
High-Performance Ligand-Protected Metal Nanocluster Catalysts for CO2 Conversion through the Exposure of Undercoordinated Sites
Authors: Alfonso Dominic
Published: May 2022

Previous experimental breakthroughs reveal the potential to create novel heterogeneous catalysts for the electroreduction of CO2 to a high-value product CO using ligand-protected Au-based nanoclusters. Since the chemical composition and geometric structures have been precisely defined, it is possible to adopt robust design guidelines for the development of practical catalysts and to fundamentally elucidate the underlying reaction mechanism. In this short review, the computational progress made to understand the experimentally observed reduction process on the following subset of materials—Au25(SR)18−, Au24Pd(SR)18, Au23(SR)16− and Au21Cd2(SR)16−—is described. A significant finding from our first-principles mechanistic studies is that CO2 conversion on the fully ligand protected nanoclusters is thermodynamically unfavorable due to the very weak binding of intermediates on the surface region. However, the reaction becomes feasible when either Au or S sites are exposed through the removal of a ligand. The results particularly point to the role of undercoordinated S sites in the creation of highly functional heterogeneous catalysts that are both active and selective for the CO2 conversion process. The incorporation of dopants could significantly influence the catalytic reactivity of the nanoclusters. As demonstrated in the case of the monopalladium substitution in Au25(SR)18−, the presence of the foreign atom leads to an enhancement of CO production selectivity due to the greater stabilization of the intermediates. With the Cd substitution doping of Au23(SR)16−, the improvement in performance is also attributed to the enhanced binding strength of the intermediates on the geometrically modified surface of the nanocluster.
Partial Hydrogenation of Soybean and Waste Cooking Oil Biodiesel over Recyclable-Polymer-Supported Pd and Ni Nanoparticles
Authors: Fiore Ambra Maria , Romanazzi Giuseppe , Leonelli Cristina , Mastrorilli Piero , Dell’Anna Maria Michela
Published: May 2022

Biodiesel obtained through the transesterification in methanol of vegetable oils, such as soybean oil (SO) and waste cooking oil (WCO), cannot be used as a biofuel for automotive applications due to the presence of polyunsaturated fatty esters, which have a detrimental effect on oxidation stability (OS). A method of upgrading this material is the catalytic partial hydrogenation of the fatty acid methyl ester (FAME) mixture. The target molecule of the partial hydrogenation reaction is monounsaturated methyl oleate (C18:1), which represents a good compromise between OS and the cold filter plugging point (CFPP) value, which becomes too high if the biodiesel consists of unsaturated fatty esters only. In the present work, polymer-supported palladium (Pd-pol) and nickel (Ni-pol) nanoparticles were separately tested as catalysts for upgrading SO and WCO biodiesels under mild conditions (room temperature for Pd-pol and T = 100 °C for Ni-pol) using dihydrogen (p = 10 bar) as the reductant. Both catalysts were obtained through co-polymerization of the metal containing monomer M(AAEMA)2 (M = Pd, Ni; AEEMA− = deprotonated form of 2-(acetoacetoxy)ethyl methacrylate)) with co-monomers (ethyl methacrylate for Pd and N,N-dimethylacrilamide for Ni) and cross-linkers (ethylene glycol dimethacrylate for Pd and N,N’-methylene bis-acrylamide for Ni), followed by reduction. The Pd-pol system became very active in the hydrogenation of C=C double bonds, but poorly selective towards the desirable C18:1 product. The Ni-pol catalyst was less active than Pd-pol, but very selective towards the mono-unsaturated product. Recyclability tests demonstrated that the Ni-based system retained its activity and selectivity with both the SO and WCO substrates for at least five subsequent runs, thus representing an opportunity for waste biomass valorization.
MicroRNA-145 Impairs Classical Non-Homologous End-Joining in Response to Ionizing Radiation-Induced DNA Double-Strand Breaks via Targeting DNA-PKcs
Authors: Sudhanva Muddenahalli Srinivasa , Hariharasudhan Gurusamy , Jun Semo , Seo Gwanwoo , Kamalakannan Radhakrishnan , Kim Hyun Hee , Lee Jung-Hee
Published: May 2022

DNA double-strand breaks (DSBs) are one of the most lethal types of DNA damage due to the fact that unrepaired or mis-repaired DSBs lead to genomic instability or chromosomal aberrations, thereby causing cell death or tumorigenesis. The classical non-homologous end-joining pathway (c-NHEJ) is the major repair mechanism for rejoining DSBs, and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is a critical factor in this pathway; however, regulation of DNA-PKcs expression remains unknown. In this study, we demonstrate that miR-145 directly suppresses DNA-PKcs by binding to the 3′-UTR and inhibiting translation, thereby causing an accumulation of DNA damage, impairing c-NHEJ, and rendering cells hypersensitive to ionizing radiation (IR). Of note, miR-145-mediated suppression of DNA damage repair and enhanced IR sensitivity were both reversed by either inhibiting miR-145 or overexpressing DNA-PKcs. In addition, we show that the levels of Akt1 phosphorylation in cancer cells are correlated with miR-145 suppression and DNA-PKcs upregulation. Furthermore, the overexpression of miR-145 in Akt1-suppressed cells inhibited c-NHEJ by downregulating DNA-PKcs. These results reveal a novel miRNA-mediated regulation of DNA repair and identify miR-145 as an important regulator of c-NHEJ.
Effects of One-Day Application of Levodopa/Carbidopa/Entacapone versus Levodopa/Carbidopa/Opicapone in Parkinson’s Disease Patients
Authors: Müller Thomas , Schlegel Eugen , Zingler Stephanie , Thiede Hans Michael
Published: May 2022

The catechol-O-methyltransferase inhibitors entacapone and opicapone prolong the efficacy of conventional oral levodopa/dopa decarboxylase inhibitor formulations through an increase in levodopa plasma bioavailability. Catechol-O-methyltransferase inhibitors influence the homocysteine metabolism associated with levodopa/dopa decarboxylase application. The objectives of this study were to compare the impact of additional single-day entacapone or opicapone intake on the pharmacokinetic plasma behaviour of levodopa, 3-O-methyldopa and total homocysteine in 15 Parkinson’s disease patients, with concomitant scoring of motor symptoms, under standardized conditions. The patients received opicapone plus two doses of 100 mg levodopa/carbidopa and, one week later, two doses of levodopa/carbidopa/entacapone or vice versa. Levodopa, 3-O-methyldopa and total homocysteine were determined with reversed-phase high-performance liquid chromatography. Levodopa bioavailability and its maximum concentration were higher with opicapone. The computed peak-to-trough difference was lower after the second levodopa administration with entacapone. The fluctuation index of levodopa did not differ between both conditions. 3-O-methyldopa decreased on both days. Homocysteine levels did not significantly vary between both conditions. A significant homocysteine decrease occurred with entacapone, but not with opicapone. Motor behaviour improved with entacapone, but not with opicapone. Opicapone baseline scores were significantly better, and thus the potential for the improvement in motor symptoms was lower compared with the entacapone condition. The higher levodopa bioavailability with opicapone suggests that it is more efficacious than entacapone for the amelioration of “off” phenomena in fluctuating patients when co-administered with a levodopa/dopa decarboxylase inhibitor regimen. Both compounds prevented an increase in homocysteine, which is a metabolic marker for an impaired capacity in the performance of methylation processes.
Alpha-Linolenic Acid Modulates T Cell Incorporation in a 3D Tissue-Engineered Psoriatic Skin Model
Authors: Morin Sophie , Simard Mélissa , Rioux Geneviève , Julien Pierre , Pouliot Roxane
Published: May 2022

Psoriasis is an autoimmune skin disease with an increased number of leukocytes infiltrating the dermal and epidermal compartments compared with normal skin. N-3 polyunsaturated fatty acids (n-3 PUFAs) are frequently used in the clinic in order to attenuate the symptoms of psoriasis. For psoriatic patients, a supplementation of the diet with alpha-linolenic acid (ALA) reduces the activation of T cell signaling pathways, leading to a significant reduction in inflammatory cytokine secretion. However, the precise mechanism of action of n-3 PUFAs in psoriasis is still not understood. In the present study, we elucidated the bioaction of ALA on the adaptive immune component of psoriasis by using a psoriatic skin model produced with the addition of activated T cells. Healthy and psoriatic skin substitutes were produced according to the self-assembly method, using culture media supplemented with 10 μM of ALA. T cells were isolated from blood samples using a negative selection isolation method. ALA supplementation regulated the hyperproliferation and abnormal cell differentiation of psoriatic keratinocytes stimulated by T cells. Additionally, the exogenous ALA was correctly incorporated into the phospholipids of keratinocytes, which resulted in increased levels of ALA, eicosapentaenoic acid (EPA) and n-3 docosapentaenoic acid (n-3 DPA). The infiltration of T cells into the epidermis was reduced when ALA was added to the culture medium, and significant decreases in the levels of inflammatory cytokines and chemokines such as CXCL1, interleukin-6 (IL-6) and interleukin-8 (IL-8) were consequently measured in psoriatic substitutes supplemented with this n-3 PUFA. Altogether, our results showed that in this psoriatic skin model enriched with T cells, ALA exerted its beneficial effect by decreasing the quantities of inflammatory mediators released by T cells.
IFN-γ and TNF Induce Senescence and a Distinct Senescence-Associated Secretory Phenotype in Melanoma
Authors: Homann Lorenzo , Rentschler Maximilian , Brenner Ellen , Böhm Katharina , Röcken Martin , Wieder Thomas
Published: May 2022

Immune checkpoint blockade (ICB) therapy is a central pillar of melanoma treatment leading to durable response rates. Important mechanisms of action of ICB therapy include disinhibition of CD4+ and CD8+ T cells. Stimulated CD4+ T helper 1 cells secrete the effector cytokines interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF), which induce senescence in tumor cells. Besides being growth-arrested, senescent cells are metabolically active and secrete a large spectrum of factors, which are summarized as senescence-associated secretory phenotype (SASP). This secretome affects the tumor growth. Here, we compared the SASP of cytokine-induced senescent (CIS) cells with the SASP of therapy-induced senescent (TIS) cells. Therefore, we established in vitro models for CIS and TIS in melanoma. The human melanoma cell lines SK-MEL-28 and WM115 were treated with the cytokines IFN-γ and TNF as CIS, the chemotherapeutic agent doxorubicin, and the cell cycle inhibitor palbociclib as TIS. Then, we determined several senescence markers, i.e., growth arrest, p21 expression, and senescence-associated β-galactosidase (SA-β-gal) activity. For SASP analyses, we measured the regulation and secretion of several common SASP factors using qPCR arrays, protein arrays, and ELISA. Each treatment initiated a stable growth arrest, enhanced SA-β-gal activity, and—except palbociclib—increased the expression of p21. mRNA and protein analyses revealed that gene expression and secretion of SASP factors were severalfold stronger in CIS than in TIS. Finally, we showed that treatment with the conditioned media (CM) derived from cytokine- and palbociclib-treated cells induced senescence characteristics in melanoma cells. Thus, we conclude that senescence induction via cytokines may lead to self-sustaining senescence surveillance of melanoma.
The Role of E3 Ligase Pirh2 in Disease
Authors: Daks Alexandra , Fedorova Olga , Parfenyev Sergey , Nevzorov Ivan , Shuvalov Oleg , Barlev Nickolai A.
Published: May 2022

The p53-dependent ubiquitin ligase Pirh2 regulates a number of proteins involved in different cancer-associated processes. Targeting the p53 family proteins, Chk2, p27Kip1, Twist1 and others, Pirh2 participates in such cellular processes as proliferation, cell cycle regulation, apoptosis and cellular migration. Thus, it is not surprising that Pirh2 takes part in the initiation and progression of different diseases and pathologies including but not limited to cancer. In this review, we aimed to summarize the available data on Pirh2 regulation, its protein targets and its role in various diseases and pathological processes, thus making the Pirh2 protein a promising therapeutic target.
Behavioral Studies of p62 KO Animals with Implications of a Modulated Function of the Endocannabinoid System
Authors: Keller Christina , Rading Sebastian , Bindila Laura , Karsak Meliha
Published: May 2022

Elementary emotional states and memory can be regulated by the homeostasis of the endocannabinoid system (ECS). Links between the ECS and the autophagy receptor p62 have been found at the molecular level and in animal studies. This project aimed to validate the anxiety and memory phenotype of p62 knockout (KO) animals and whether the ECS plays a role in this. We examined the behavior of p62 KO animals and analyzed whether endocannabinoid levels are altered in the responsible brain areas. We discovered in age-dependent obese p62 KO mice decreased anandamide levels in the amygdala, a brain structure important for emotional responses. Against our expectation, p62 KO animals did not exhibit an anxiety phenotype, but showed slightly increased exploratory behavior as evidenced in novel object and further tests. In addition, KO animals exhibited decreased freezing responses in the fear conditioning. Administration of the phytocannabinoid delta9-tetrahydrocannabinol (THC) resulted in lesser effects on locomotion but in comparable hypothermic effects in p62 KO compared with WT littermates. Our results do not confirm previously published results, as our mouse line does not exhibit a drastic behavioral phenotype. Moreover, we identified further indications of a connection to the ECS and hence offer new perspectives for future investigations.
SIN-Like Pathway Kinases Regulate the End of Mitosis in the Methylotrophic Yeast Ogataea polymorpha
Authors: Maekawa Hiromi , Jiangyan Shen , Takegawa Kaoru , Pereira Gislene
Published: May 2022

The mitotic exit network (MEN) is a conserved signalling pathway essential for the termination of mitosis in the budding yeast Saccharomyces cerevisiae. All MEN components are highly conserved in the methylotrophic budding yeast Ogataea polymorpha, except for Cdc15 kinase. Instead, we identified two essential kinases OpHcd1 and OpHcd2 (homologue candidate of ScCdc15) that are homologous to SpSid1 and SpCdc7, respectively, components of the septation initiation network (SIN) of the fission yeast Schizosaccharomyces pombe. Conditional mutants for OpHCD1 and OpHCD2 exhibited significant delay in late anaphase and defective cell separation, suggesting that both genes have roles in mitotic exit and cytokinesis. Unlike Cdc15 in S. cerevisiae, the association of OpHcd1 and OpHcd2 with the yeast centrosomes (named spindle pole bodies, SPBs) is restricted to the SPB in the mother cell body. SPB localisation of OpHcd2 is regulated by the status of OpTem1 GTPase, while OpHcd1 requires the polo-like kinase OpCdc5 as well as active Tem1 to ensure the coordination of mitotic exit (ME) signalling and cell cycle progression. Our study suggests that the divergence of molecular mechanisms to control the ME-signalling pathway as well as the loss of Sid1/Hcd1 kinase in the MEN occurred relatively recently during the evolution of budding yeast.
RhoA Signaling in Neurodegenerative Diseases
Authors: Schmidt Sissel Ida , Blaabjerg Morten , Freude Kristine , Meyer Morten
Published: May 2022

Ras homolog gene family member A (RhoA) is a small GTPase of the Rho family involved in regulating multiple signal transduction pathways that influence a diverse range of cellular functions. RhoA and many of its downstream effector proteins are highly expressed in the nervous system, implying an important role for RhoA signaling in neurons and glial cells. Indeed, emerging evidence points toward a role of aberrant RhoA signaling in neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. In this review, we summarize the current knowledge of RhoA regulation and downstream cellular functions with an emphasis on the role of RhoA signaling in neurodegenerative diseases and the therapeutic potential of RhoA inhibition in neurodegeneration.
Moderating Effect of Changes in Perceived Social Support during Pregnancy on the Emotional Health of Mothers and Fathers and on Baby’s Anthropometric Parameters at Birth
Authors: Castelar-Ríos María José , De los Santos-Roig Macarena , Robles-Ortega Humbelina , Díaz-López Miguel Ángel , Maldonado-Lozano José , Bellido-González Mercedes
Published: May 2022

(1) Background: this study is based on a model of how changes in protective factors may affect the emotional health of mothers and fathers and thus influence the development of the baby. Our research goal is to determine whether variations in perceived social support moderate levels of stress and depression during pregnancy and/or the effect of parents’ emotional health on the baby’s anthropometric parameters. (2) Methods: to achieve these aims, a longitudinal study was made of 132 couples and babies, who were evaluated at weeks 12 and 32 of gestation and at birth. Separate analyses were performed for the mothers and fathers, focused on the role of social support in moderating their levels of depression and stress during pregnancy, and the consequent impact on the baby. (3) Results: the results obtained show the moderating effects of changes in social support on maternal and paternal stress and depression. Reduced social support during pregnancy is associated with higher levels of stress and depression in both parents and with a high cephalisation index in their babies. (4) Conclusions: special attention should be paid to social support, which can have a strong impact on the evolution of emotional health during pregnancy and concomitantly on the development of the baby.