bluuebunny/crossref_metadata_2025 huggingface dataset:
Mesenchymal Stromal Cells (MSCs) Isolated from Various Tissues of the Human Arthritic Knee Joint Possess Similar Multipotent Differentiation Potential
Authors: Wagenbrenner Mike , Poker Konrad , Heinz Tizian , Herrmann Marietta , Horas Konstantin , Ebert Regina , Mayer-Wagner Susanne , Holzapfel Boris M. , Rudert Maximilian , Steinert Andre F. , Weißenberger Manuel
Published: February 2022

(1) Background: The mesenchymal stromal cells (MSCs) of different tissue origins are applied in cell-based chondrogenic regeneration. However, there is a lack of comparability determining the most suitable cell source for the tissue engineering (TE) of cartilage. The purpose of this study was to compare the in vitro chondrogenic potential of MSC-like cells from different tissue sources (bone marrow, meniscus, anterior cruciate ligament, synovial membrane, and the infrapatellar fat pad removed during total knee arthroplasty (TKA)) and define which cell source is best suited for cartilage regeneration. (2) Methods: MSC-like cells were isolated from five donors and expanded using adherent monolayer cultures. Differentiation was induced by culture media containing specific growth factors. Transforming growth factor (TGF)-ß1 was used as the growth factor for chondrogenic differentiation. Osteogenesis and adipogenesis were induced in monolayer cultures for 27 days, while pellet cell cultures were used for chondrogenesis for 21 days. Control cultures were maintained under the same conditions. After, the differentiation period samples were analyzed, using histological and immunohistochemical staining, as well as molecularbiological analysis by RT-PCR, to assess the expression of specific marker genes. (3) Results: Plastic-adherent growth and in vitro trilineage differentiation capacity of all isolated cells were proven. Flow cytometry revealed the clear co-expression of surface markers CD44, CD73, CD90, and CD105 on all isolated cells. Adipogenesis was validated through the formation of lipid droplets, while osteogenesis was proven by the formation of calcium deposits within differentiated cell cultures. The formation of proteoglycans was observed during chondrogenesis in pellet cultures, with immunohistochemical staining revealing an increased relative gene expression of collagen type II. RT-PCR proved an elevated expression of specific marker genes after successful differentiation, with no significant differences regarding different cell source of native tissue. (4) Conclusions: Irrespective of the cell source of native tissue, all MSC-like cells showed multipotent differentiation potential in vitro. The multipotent differentiation capacity did not differ significantly, and chondrogenic differentiation was proven in all pellet cultures. Therefore, cell suitability for cell-based cartilage therapies and tissue engineering is given for various tissue origins that are routinely removed during total knee arthroplasty (TKA). This study might provide essential information for the clinical tool of cell harvesting, leading to more flexibility in cell availability.
Investigation of the Possibilities for Removal of Phenolic Toxic Compounds from Water by Nanoporous Carbon from Polymer By-Products
Authors: Stoycheva Ivanka , Tsyntsarski Boyko , Petrova Bilyana , Georgiev Georgi , Budinova Temenuzhka , Petrov Nartzislav , Trzebicka Barbara , Pusz Slawomira , Kumanek Bogumila , Szeluga Urszula
Published: February 2022

Nanoporous carbon is synthesized on the base of phenol-formaldehyde resin and polyolefin wax, a by-product from industrial production of polyethylene at low pressure. The adsrption of phenol derivates from aqueous solutions on obtained carbon material was studied. The adsorption capacity of the carbon is related to the surface area and composition of the synthesized material, as well as to the nature of the adsorbent. The obtained adsorbent is characterized by high surface area and porosity, and it demonstrates high adsorption capacity towards aromatic compounds. All studied phenolic compounds show high affinity towards carbon, confirming that the retention mechanism occurs via non-specific interactions between the electronic density of the adsorbent and molecules of aromatic pollutants. Electrostatic interactions may also appear depending on pH of the solution pH and charge distribution of the carbons; and these effects has a strong influence on the final performance of the carbon.
Optimal Assistance Timing to Induce Voluntary Dorsiflexion Movements: A Preliminary Study in Healthy Participants
Authors: Hong Jing-Chen , Yasuda Kazuhiro , Ohashi Hiroki , Iwata Hiroyasu
Published: February 2022

Swing-phase dorsiflexion assistance with robotic ankle–foot orthosis could improve toe clearance and limb shortening such that compensatory movements are suppressed. However, facilitating voluntary effort under assistance remains a challenge. In our previous study, we examined assistance effects of swing-phase dorsiflexion with different delay times after toe-off on a dorsiflexion-restricted gait with a high-dorsiflexion assistive system. Results showed that later dorsiflexion assistance could lead to an increase in the tibialis anterior’s surface electromyography but could also deteriorate compensatory movement. Thus, we concluded that there is a suitable assistance timing to simultaneously achieve voluntary effort and optimal gait. In the present research, we derived a method to identify a suitable dorsiflexion assistance delay time via a multiple linear regression analysis on ankle data of stroke patients with a pathological gait with insufficient dorsiflexion. With the identification method, an experiment was conducted on six healthy participants with restricted dorsiflexion. Results showed that the identified assistance timing improved the amplitude of the tibialis anterior’s surface electromyography while also suppressing limb shortening during circumduction and hip hiking. Although a practical study of stroke survivors is required, observations from this research indicate the potential to successfully induce voluntary efforts with the identified dorsiflexion assistance timing.
Investigation of the Properties of a Five-Phase Induction Motor in the Introduction of New Fault-Tolerant Control
Authors: Kellner Jakub , Kaščák Slavomír , Ferková Želmíra
Published: February 2022

Multiphase electric motors in cooperation with power semiconductor converters belong to the future of electric drives. This is because of their better properties compared to three-phase motors, such as better fault tolerance. How a multiphase motor will behave in a fault state is very important when using such motors in EV and HEV. This is the basis of the research in this article; we investigate the options for operating a five-phase motor in a fault condition in order to improve the drive qualities during fault operation. The complete mathematical expressions of the five-phase induction motor model in the normal operation as well as in fault operation and also the control modification to improve the properties of the drive are presented. The new five-phase field-oriented control is next described, which improves the drive qualities in four-phase operation and is the first fundamental aspect of the study. Another important aspect of the project is the development of a specific control on a real motor, followed by measurements of properties of a five-phase motor in normal and fault operation of one phase without and with control modification to enhance drive characteristics. The qualities and appropriateness of employing a five-phase motor as a drive in EV and HEV are then determined by comparing these results. Finally, a comparison of motor attributes is shown with and without control adjustment.
Chronic Effects of Fluoxetine on Danio rerio: A Biochemical and Behavioral Perspective
Authors: Correia Daniela , Domingues Inês , Faria Melissa , Oliveira Miguel
Published: February 2022

Fluoxetine is an antidepressant widely used to treat depressive and anxiety states. Due to its mode of action in the central nervous system (selective serotonin reuptake inhibitor (SSRI)), it becomes toxic to non-target organisms, leading to changes that are harmful to their survival. In this work, the effects of fluoxetine on juvenile zebrafish (Danio rerio) were evaluated, assessing biochemical (phase II biotransformation—glutathione S-transferase (GST), neurotransmission—acetylcholinesterase (ChE), energy metabolism—lactate dehydrogenase (LDH), and oxidative stress—glutathione peroxidase (GPx)) and behavior endpoints (swimming behavior, social behavior, and thigmotaxis) after 21 days exposure to 0 (control), 0.1, 1 and 10 µg/L. Biochemically, although chronic exposure did not induce significant effects on neurotransmission and energy metabolism, GPx activity was decreased after exposure to 10 µg/L of fluoxetine. At a behavioral level, exploratory and social behavior was not affected. However, changes in the swimming pattern of exposed fish were observed in light and dark periods (decreased locomotor activity). Overall, the data show that juvenile fish chronically exposed to fluoxetine may exhibit behavioral changes, affecting their ability to respond to environmental stressors and the interaction with other fish.
Mechanisms of Electron-Induced Chemistry in Molecular Ices
Authors: Schmidt Fabian , Borrmann Tobias , Mues Martin Philipp , Benter Sanna , Swiderek Petra , Bredehöft Jan Hendrik
Published: February 2022

Electron-induced chemistry is relevant to many processes that occur when ionizing radiation interacts with matter. This includes radiation damage, curing of polymers, and nanofabrication processes but also the formation of complex molecules in molecular ices grown on dust particles in space. High-energy radiation liberates from such materials an abundance of secondary electrons of which most have energies below 20 eV. These electrons efficiently trigger reactions when they attach to molecules or induce electronic excitation and further ionization. This review focuses on the present state of insight regarding the mechanisms of reactions induced by electrons with energies between 0 and 20 eV that lead to formation of larger products in binary ice layers consisting of small molecules (H2O, CO, CH3OH, NH3, CH4, C2H4, CH3CN, C2H6) or some derivatives thereof (C2H5NH2 and (C2H5)2NH, CH2=CHCH3). It summarizes our approach to identify products and quantify their amounts based on thermal desorption spectrometry (TDS) and electron-stimulated desorption (ESD) experiments performed in ultrahigh vacuum (UHV). The overview of the results demonstrates that, although the initial electron-molecule interaction is a non-thermal process, product formation from the resulting reactive species is often governed by subsequent reactions that follow well-known thermal and radical-driven mechanisms of organic chemistry.
LFA: A Lévy Walk and Firefly-Based Search Algorithm: Application to Multi-Target Search and Multi-Robot Foraging
Authors: Zedadra Ouarda , Guerrieri Antonio , Seridi Hamid
Published: February 2022

In the literature, several exploration algorithms have been proposed so far. Among these, Lévy walk is commonly used since it is proved to be more efficient than the simple random-walk exploration. It is beneficial when targets are sparsely distributed in the search space. However, due to its super-diffusive behavior, some tuning is needed to improve its performance, specifically when targets are clustered. Firefly algorithm is a swarm intelligence-based algorithm useful for intensive search, but its exploration rate is very limited. An efficient and reliable search could be attained by combining the two algorithms since the first one allows exploration space, and the second one encourages its exploitation. In this paper, we propose a swarm intelligence-based search algorithm called Lévy walk and Firefly-based Algorithm (LFA), which is a hybridization of the two aforementioned algorithms. The algorithm is applied to Multi-Target Search and Multi-Robot Foraging. Numerical experiments to test the performances are conducted on the robotic simulator ARGoS. A comparison with the original firefly algorithm proves the goodness of our contribution.
Systematic Investigation of the Effects of Multiple SV40 Nuclear Localization Signal Fusion on the Genome Editing Activity of Purified SpCas9
Authors: Shui Sailan , Wang Shaojie , Liu Jia
Published: February 2022

The emergence of CRISPR-Cas9 technology has revolutionized both basic and translational biomedical research. For Cas9 nuclease to exert genome editing activity, nuclear localization signal (NLS) derived from simian virus 40 (SV40) T antigen is commonly installed as genetic fusion to direct the intracellular Cas9 proteins to the nucleus of cells. Notably, previous studies have shown that multiple SV40 NLS fusion can improve the targeting activity of Cas9-derived genome-editing and base-editing tools. In addition, the multi-NLS fusion can increase the intracellular activity of Cas9 in the forms of both constitutive expression and directly delivered Cas9-guide RNA ribonucleoprotein (RNP) complex. However, the relationship between NLS fusion and intracellular Cas9 activity has not been fully understood, including the dependency of activity on the number or organization of NLS fusion. In the present study, we constructed and purified a set of Streptococcus pyogenes Cas9 (SpCas9) variants containing one to four NLS repeats at the N- or C-terminus of the proteins and systematically analyzed the effects of multi-NLS fusion on the activity of SpCas9 RNPs. It was found that multi-NLS fusion could improve the intracellular activity as lipofected or nucleofected Cas9 RNPs. Importantly, multi-NLS fusion could enhance the genome-editing activity of SpCas9 RNPs in primary and stem/progenitor cells and mouse embryos.
Pond Assay for the Sensory Systems of Caenorhabditis elegans: A Novel Anesthesia-Free Method Enabling Detection of Responses to Extremely Low Chemical Concentrations
Authors: Suzuki Michiyo , Hattori Yuya , Saito Toshiyuki , Harada Yoshinobu
Published: February 2022

Chemotaxis in the nematode Caenorhabditis elegans has basically been examined using conventional assay methods. Although these can be problematic, for example, in their use of anesthesia, the method has never been improved. We propose a pond assay for the sensory systems (PASS) of C. elegans as a novel population-based method of behavioral analysis. The test solution is injected into a recess(es) formed on agar and the response of C. elegans to its odor and/or taste is examined. Once C. elegans individuals fall into recesses (ponds) filled with liquid, they cannot return to a solid medium. In this way, the animals are trapped with certainty without the use of anesthesia. The anesthesia used to keep animals in the attractant area in conventional chemotaxis assays is no longer required, allowing pure evaluation of the attractant or repellent response to specific substances. Furthermore, the assay itself can be greatly streamlined because the preparation can be completed simply by providing a recess(es) and filling the liquid. The present paper reports the detailed method and effectiveness of the novel PASS.
First Report of Epimeletic and Acoustic Behavior in Mediterranean Common Bottlenose Dolphins (Tursiops truncatus) Carrying Dead Calves
Authors: Pedrazzi Giulia , Giacomini Giancarlo , Pace Daniela Silvia
Published: February 2022

Epimeletic behavior toward dead calves has been frequently reported in cetaceans, mostly with females (presumed mothers) showing supportive behaviors such as carrying, lifting, or sinking, often assisted by “escort” individuals. However, information on acoustic production in such contexts is scarce. This report describes two observations of epimeletic behavior toward dead newborns in bottlenose dolphins and associated acoustic production. Data were collected at the Tiber River estuary (Rome, Mediterranean Sea, Italy) with one hydrophone for passive acoustic monitoring and two digital cameras. In both cases, an individual (presumed mother) acting as the main supporter and directly interacting with the carcass by lifting it (case 1) or sinking it (case 2) was observed. Another adult individual (escort) was present in both encounters showing standing-by and excitement behaviors (case 1) and supportive behavior (case 2). In both encounters, whistles, pulsed sounds, and bray-call elements were recorded. The consistent vocal activity observed likely conveyed context-specific information. A signature whistle in the first encounter was also recorded, likely emitted by the putative mother as a distress call. This report confirms the occurrence of epimeletic behavior in bottlenose dolphins and reports a preliminary description of the acoustic production when a dead calf is involved, providing additional information on this largely unknown topic.
Comparative Study of Adverse Drug Reactions Associated with Filgrastim and Pegfilgrastim Using the EudraVigilance Database
Authors: Rastogi Shruti , Kalaiselvan Vivekanandan , Bin Jardan Yousef A. , Zameer Saima , Sarwat Maryam
Published: February 2022

The primary prophylaxis with filgrastim (FIL) and pegfilgrastim (PEG-F) is recommended to decrease the severity of chemotherapy-induced neutropenia (CIN). The commonly reported adverse drug reactions (ADRs) with FIL and PEG-F is bone pain. ADRs pertaining to FIL and PEG-F were extracted from the European EudraVigilance (EV) database. The Individual Case Safety Reports (ICSRs) obtained from EV database that reported FIL and PEG-F as the suspected drug were analyzed. Registered ADRs (from the groups “General disorders and administration site conditions”, “Blood and lymphatic system disorders”, “Musculoskeletal and connective tissue disorders” and “Investigations”) for FIL and PEG-F were collected from EV database from 2007 to 5 June 2021. The reporting odds ratio (ROR) was used to calculate ICSRs with most common ADRs related to FIL and PEG-F. A total of 17,403 ICSRs described the incidence of most common ADRs of FIL and PEG-F. The commonly reported ADRs for both drugs were pyrexia, bone pain, back pain, neutropenia and febrile neutropenia. The odds ratio of ICSRs belonging to the System Organ Class (SOC) “Investigations” (ROR 1.01 (CI 0.93–1.10)) revealed no significant difference in FIL and PEG-F. However, for the SOCs (General disorders and administration site conditions” and “Musculoskeletal and connective tissue disorders” ((ROR 1.14 (CI 1.06–1.21); ROR 1.21 (CI 1.18–1.32), respectively), an increased reporting probability with PEG-F was found. The authors reported a lower reporting probability for the SOC “Blood and lymphatic system disorders” for FIL versus PEG-F (ROR 0.75 (CI 0.70–0.80)). Our results have demonstrated that the occurrence of bone pain was similar with FIL and PEG-F. For the incidence of pyrexia and back pain, PEG-F was associated with a higher reporting probability as compared to FIL. However, the incidence of neutropenia and febrile neutropenia was higher in FIL compared to PEG-F. Further evaluation of data from real life is needed.
The Complement System in the Central Nervous System: From Neurodevelopment to Neurodegeneration
Authors: Chen Ying , Chu John Man Tak , Chang Raymond Chuen Chung , Wong Gordon Tin Chun
Published: February 2022

The functions of the complement system to both innate and adaptive immunity through opsonization, cell lysis, and inflammatory activities are well known. In contrast, the role of complement in the central nervous system (CNS) which extends beyond immunity, is only beginning to be recognized as important to neurodevelopment and neurodegeneration. In addition to protecting the brain against invasive pathogens, appropriate activation of the complement system is pivotal to the maintenance of normal brain function. Moreover, overactivation or dysregulation may cause synaptic dysfunction and promote excessive pro-inflammatory responses. Recent studies have provided insights into the various responses of complement components in different neurological diseases and the regulatory mechanisms involved in their pathophysiology, as well as a glimpse into targeting complement factors as a potential therapeutic modality. However, there remain significant knowledge gaps in the relationship between the complement system and different brain disorders. This review summarizes recent key findings regarding the role of different components of the complement system in health and pathology of the CNS and discusses the therapeutic potential of anti-complement strategies for the treatment of neurodegenerative conditions.
Hepatitis A Virus Cellular Receptor 1 (HAVcr-1) Initiates Prostate Cancer Progression in Human Cells via Hepatocyte Growth Factor (HGF)-Induced Changes in Junctional Integrity
Authors: Telford Emily A. , Sanders Andrew J. , Owen Sioned , Ruge Fiona , Harrison Gregory M. , Jiang Wen G. , Martin Tracey A.
Published: February 2022

Background: HAVcR-1 has been linked to cancer aetiology and may regulate junctional complexes, with its role in prostate cancer still unexplored. This study aims to investigate the expression of HAVcR-1 in prostate cancer samples and the exploration of the cellular/molecular impact of HAVcR-1. Methods: Levels of HAVcR-1 ectodomain in the serum of prostate cancer patients were compared to healthy controls, and assessed as the total protein and gene expression of HAVcR-1 and tissues sections. The manipulation of HAVcR-1 levels within prostate cancer cell lines determined changes in cell behaviour using in vitro cell models and barrier function assays. Protein/phosphoprotein levels were assessed using Western blotting. Results: Levels of HAVcR-1 ectodomain from serum were decreased in patients with prostate cancer. Ectodomain levels correlated with the Gleason score. Histologically, the total protein/gene expression of HAVcR-1 was overexpressed in prostate cancer. The overexpression of HAVcR-1 in prostate cancer cell lines resulted in key changes in cell behaviour and the phosphorylation of β-catenin with a concurrent decrease in membranous E-cadherin, increased nuclear β-catenin and increased cyclin D1 protein expression, which were associated with HGF-promoted changes in the barrier function. Conclusions: HAVcR-1 expression and ectodomain release coincides with the presence of prostate cancer; thus, indicating HAVcR-1 as a potential biomarker to aid in diagnostics, and implicating HAVcR-1 in the dysregulation of junctional complexes.
Identification of Altered Evoked and Non-Evoked Responses in a Heterologous Mouse Model of Endometriosis-Associated Pain
Authors: Tejada Miguel A. , Santos-Llamas Ana I. , Escriva Lesley , Tarin Juan J. , Cano Antonio , Fernández-Ramírez Maria J. , Nunez-Badinez Paulina , De Leo Bianca , Saunders Philippa T. K. , Vidal Victor , Barthas Florent , Vincent Katy , Sweeney Patrick J. , Sillito Rowland R. , Armstrong James Douglas , Nagel Jens , Gomez Raúl
Published: February 2022

The aim of this study was to develop and refine a heterologous mouse model of endometriosis-associated pain in which non-evoked responses, more relevant to the patient experience, were evaluated. Immunodeficient female mice (N = 24) were each implanted with four endometriotic human lesions (N = 12) or control tissue fat (N = 12) on the abdominal wall using tissue glue. Evoked pain responses were measured biweekly using von Frey filaments. Non-evoked responses were recorded weekly for 8 weeks using a home cage analysis (HCA). Endpoints were distance traveled, social proximity, time spent in the center vs. outer areas of the cage, drinking, and climbing. Significant differences between groups for von Frey response, climbing, and drinking were detected on days 14, 21, and 35 post implanting surgery, respectively, and sustained for the duration of the experiment. In conclusion, a heterologous mouse model of endometriosis-associated evoked a non-evoked pain was developed to improve the relevance of preclinical models to patient experience as a platform for drug testing.
Emerging Evidence and Treatment Perspectives from Randomized Clinical Trials in Systemic Sclerosis: Focus on Interstitial Lung Disease
Authors: Aragona Caterina Oriana , Versace Antonio Giovanni , Ioppolo Carmelo , La Rosa Daniela , Lauro Rita , Tringali Maria Concetta , Tomeo Simona , Ferlazzo Guido , Roberts William Neal , Bitto Alessandra , Irrera Natasha , Bagnato Gianluca
Published: February 2022

Systemic sclerosis (SSc) is a complex rare autoimmune disease with heterogeneous clinical manifestations. Currently, interstitial lung disease (ILD) and cardiac involvement (including pulmonary arterial hypertension) are recognized as the leading causes of SSc-associated mortality. New molecular targets have been discovered and phase II and phase III clinical trials published in the last 5 years on SSc-ILD will be discussed in this review. Details on the study design; the drug tested and its dose; the inclusion and exclusion criteria of the study; the concomitant immunosuppression; the outcomes and the duration of the study were reviewed. The two most common drugs used for the treatment of SSc-ILD are cyclophosphamide and mycophenolate mofetil, both supported by randomized controlled trials. Additional drugs, such as nintedanib and tocilizumab, have been approved to slow pulmonary function decline in SSc-ILD. In this review, we discuss the therapeutic alternatives for SSc management, offering the option to customize the design of future studies to stratify SSc patients and provide a patient-specific treatment according to the new emerging pathogenic features of SSc-ILD.
Oxidative Stress, Inflammation and Connexin Hemichannels in Muscular Dystrophies
Authors: González-Jamett Arlek , Vásquez Walter , Cifuentes-Riveros Gabriela , Martínez-Pando Rafaela , Sáez Juan C. , Cárdenas Ana M.
Published: February 2022

Muscular dystrophies (MDs) are a heterogeneous group of congenital neuromuscular disorders whose clinical signs include myalgia, skeletal muscle weakness, hypotonia, and atrophy that leads to progressive muscle disability and loss of ambulation. MDs can also affect cardiac and respiratory muscles, impairing life-expectancy. MDs in clude Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy and limb-girdle muscular dystrophy. These and other MDs are caused by mutations in genes that encode proteins responsible for the structure and function of skeletal muscles, such as components of the dystrophin-glycoprotein-complex that connect the sarcomeric-actin with the extracellular matrix, allowing contractile force transmission and providing stability during muscle contraction. Consequently, in dystrophic conditions in which such proteins are affected, muscle integrity is disrupted, leading to local inflammatory responses, oxidative stress, Ca2+-dyshomeostasis and muscle degeneration. In this scenario, dysregulation of connexin hemichannels seem to be an early disruptor of the homeostasis that further plays a relevant role in these processes. The interaction between all these elements constitutes a positive feedback loop that contributes to the worsening of the diseases. Thus, we discuss here the interplay between inflammation, oxidative stress and connexin hemichannels in the progression of MDs and their potential as therapeutic targets.
Familial Predisposition to Leiomyomata: Searching for Protective Genetic Factors
Authors: Kuznetsova Maria V. , Sogoyan Nelly S. , Donnikov Andrew J. , Trofimov Dmitry Y. , Adamyan Leila V. , Mishina Natalia D. , Shubina Jekaterina , Zelensky Dmitry V. , Sukhikh Gennady T.
Published: February 2022

In order to determine genetic loci associated with decreasing risk of uterine leiomyomata (UL), a genome-wide association study (GWAS) was performed. We analyzed a group of patients with a family history of UL and a control group consisting of patients without uterine fibroids and a family predisposition to this pathology. Six significant single nucleotide polymorphisms were selected for PCR-genotyping of a large data set of patients with UL. All investigated loci (rs3020434, rs11742635, rs124577644, rs12637801, rs2861221, and rs17677069) demonstrated the lower frequency of minor alleles within a group of women with UL, especially in a subgroup consisting of patients with UL and a familial history of leiomyomata. We also found that the minor allele frequencies of these SNPs in our control group were higher than those across the Caucasian population in all. Based on the obtained data, an evaluation of the common risk of UL was performed. Further work will pave the way to create a specific SNP-panel and allow us to estimate a genotype-based leiomyoma incidence risk. Subsequent studies of genetic variability in a group of patients with a familial predisposition to UL will allow us to make the prediction of the development and course of the disease more individualized, as well as to give our patients personalized recommendations about individual reproductive strategies.
Cigarette Smoking and Human Gut Microbiota in Healthy Adults: A Systematic Review
Authors: Antinozzi Martina , Giffi Monica , Sini Nicolò , Gallè Francesca , Valeriani Federica , De Vito Corrado , Liguori Giorgio , Romano Spica Vincenzo , Cattaruzza Maria Sofia
Published: February 2022

The intestinal microbiota is a crucial regulator of human health and disease because of its interactions with the immune system. Tobacco smoke also influences the human ecosystem with implications for disease development. This systematic review aims to analyze the available evidence, until June 2021, on the relationship between traditional and/or electronic cigarette smoking and intestinal microbiota in healthy human adults. Of the 2645 articles published in PubMed, Scopus, and Web of Science, 13 were included in the review. Despite differences in design, quality, and participants’ characteristics, most of the studies reported a reduction in bacterial species diversity, and decreased variability indices in smokers’ fecal samples. At the phylum or genus level, the results are very mixed on bacterial abundance both in smokers and non-smokers with two exceptions. Prevotella spp. appears significantly increased in smokers and former smokers but not in electronic cigarette users, while Proteobacteria showed a progressive increase in Desulfovibrio with the number of pack-years of cigarette (p = 0.001) and an increase in Alphaproteobacteria (p = 0.04) in current versus never smokers. This attempt to systematically characterize the effects of tobacco smoking on the composition of gut microbiota gives new perspectives on future research in smoking cessation and on a new possible use of probiotics to contrast smoke-related dysbiosis.
Preventive Effects of a Human Hematopoietic Mesenchymal Stem Cell (hHMSC) Therapy in Ovalbumin-Induced Food Allergy
Authors: Lee Dong-Geon , Lee Yu-Jin , Park Song-Hee , Park Hye-Ree , Kang Hoon , Kim Jung-Eun
Published: February 2022

No effective therapeutic strategies have been developed against food allergies. Immunomodulation during early infant period could prevent the development of food allergies. We investigated the preventive effects of human hematopoietic mesenchymal stem cells (hHMSCs) in mice with ovalbumin (OVA)-induced food allergy. BALB/c mice with OVA-induced food allergy were divided into 3 groups, and each group was treated with hHMSCs or hHMSC culture medium (hHMSC-CM) or saline. Ear thickness, allergy score, rectal temperature, and diarrhea occurrence were checked. Total IgE, OVA-specific IgE, and mucosal mast cell protease-1 (mMCP-1) were measured by ELISA. Other allergic parameters were analyzed using histology specimens, RT-PCR, and flow cytometry. Treatment with hHMSCs or hHMSC-CM significantly suppressed the frequency of anaphylactic response and rectal temperature decline, reduced diarrhea, total IgE, OVA-specific IgE, and mMCP-1. While the treatment decreased the level of Th2 cytokines, it enhanced IL-10 and TGF-β1 mRNA. Exposure to hHMSC or hHMSC-CM did not generate regulatory T cells, but reduced mast cells. The immunomodulatory effect on the Th2 cytokines was greater in hHMSC-CM than in hHMSCs. hHMSC treatment may be a promising preventive intervention against food allergy. Further studies are needed to elucidate the key substances released from hHMSC to induce immune tolerance.
Prognostic Significance of Admission Glucose Combined with Hemoglobin A1c in Acute Ischemic Stroke Patients with Reperfusion Therapy
Authors: Wang Anmo , Cui Ting , Wang Changyi , Zhu Qiange , Zhang Xuening , Li Shucheng , Yang Yuan , Shang Wenzuo , Wu Bo
Published: February 2022

Background: Elevated admission glucose and hemoglobin A1c (HbA1c) levels have been suggested to be associated with 90-day functional outcomes in acute ischemic stroke (AIS) patients with endovascular thrombectomy (EVT). However, whether the prognostic significance of admission glucose and that of HbA1c have a joint effect on patients with intravascular thrombolysis (IVT) and/or EVT remains unclear. This study aimed to explore the association between admission glucose combined with HbA1c and outcomes in patients with reperfusion therapy. Methods: Consecutive AIS patients treated with IVT and/or EVT between 2 January 2018 and 27 February 2021 in West China hospital were enrolled. Admission glucose and HbA1c levels were measured at admission. Participants were divided into four groups according to admission glucose level (categorical variable: <7.8 and ≥7.8 mmol/L) and HbA1c level (categorical variable: <6.5% and ≥6.5%): normal glucose and normal HbA1c (NGNA), normal glucose and high HbA1c (NGHA), high glucose and normal HbA1c (HGNA), and high glucose and high HbA1c (HGHA). The primary outcome was an unfavorable functional outcome defined as a modified Rankin Scale (mRS) ≥ 3. The secondary outcome was all-cause mortality at 90 days. Results: A total of 519 patients (mean age, 69.0 ± 13.4 years; 53.8% males) were included. Patients in the HGHA group had a significantly increased risk of unfavorable functional outcome (OR, 1.81; 95%CI, 1.01–3.23) and mortality (OR, 1.75; 95%CI, 1.01–3.06) at 90 days compared with those in the NGNA group after adjustment for confounders. There was no significant association between NGHA (OR, 0.43; 95%CI, 0.12–1.53) or HGNA (OR, 1.46; 95%CI, 0.84–2.56) and outcomes compared to the NGNA group. Conclusion: The combination of high admission glucose and high HbA1c level was significantly associated with unfavorable functional outcome and mortality at 90 days in AIS patients with reperfusion therapy.
An Experimental Investigation on the Effects of Limestone Fines in Manufactured Sands on the Performance of Magnesia Ammonium Phosphate Mortar
Authors: Mao Wenting , Cao Chunpeng , Li Xincheng , Qian Jueshi , Dang Yudong
Published: February 2022

Magnesium ammonium phosphate cement (MAPC) prepared with ammonium dihydrogen phosphate (NH4H2PO4, ADP) and dead-burned Magnesium oxide (MgO) is a new type of rapid patch repair material for concrete structures. In order to reduce the material costs of MAPC mortar, manufactured limestone sands, being a more widely-available resource with lower cost, was investigated in this study as an alternative to quartz sands for the preparation of MAPC mortar. The limestone fines in manufactured sands were found to be the key factor that influences properties of MAPC mortar by causing bubbling and volume expansion before hardening. As a result, the mechanical strength of MAPC mortar decreased with the increasing content of limestone fines due to increased porosity. According to microstructure analysis, the mechanism of these negative effects can be inferred as the reaction between limestone fines and ADP with the gas generation of CO2 and NH3. This reaction mainly occurred during a short period before setting while most limestone fines remained unreactive in the hardened MAPC mortar. Based on the above detailed experimental findings on the effects of limestone fines in manufactured sand on the properties of MAPC mortar, this paper pointed out that effective defoaming methods for inhibiting bubbling was the key to the utilization of manufactured sands in preparation of high performance MAPC mortar.
The Impact of Frailty Screening on Radiation Treatment Modification
Authors: Fernández-Camacho Encarnación , Ferrer-Ramos Carlos , Morilllo-Macías Virginia , Rodríguez-Cordón Marta , Sánchez-Iglesias Ángel , Beato-Tortajada Inmaculada , Francés-Muñoz Alicia , Muelas-Soria Rodrigo , Piquer-Camañes Teresa , Santafé-Jiménez Ana Isabel , Aznar-Tortonda Vanessa , Ferrer-Albiach Carlos
Published: February 2022

Background: Care overburden makes it difficult to perform comprehensive geriatric assessments (CGAs) in oncology settings. We analyzed if screening tools modified radiotherapy in oncogeriatric patients. Methods: Patients ≥ 65 years, irradiated between December 2020 and March 2021 at the Hospital Provincial de Castellón, completed the frailty G8 and estimated survival Charlson questionnaires. The cohort was stratified between G8 score ≤ 14 (fragile) or >14 (robust); the cutoff point for the Charlson index was established at five. Results: Of 161 patients; 69.4% were male, the median age was 75 years (range 65–91), and the prevailing performance status (PS) was 0–1 (83.1%). Overall, 28.7% of the cohort were frail based on G8 scores, while the estimated survival at 10 years was 2.25% based on the Charlson test. The treatment administered changed up to 21% after frailty analysis. The therapies prescribed were 5.8 times more likely to be modified in frail patients based on the G8 test. In addition, patients ≥ 85 years (p = 0.01), a PS ≥ 2 (p = 0.008), and limited mobility (p = 0.024) were also associated with a potential change. Conclusions: CGAs remain the optimal assessment tool in oncogeriatry. However, we found that the G8 fragility screening test, which is easier to integrate into patient consultations, is a reliable and efficient aid to rapid decision making.
Comparative Panel Sequencing of DNA Variants in cf-, ev- and tumorDNA for Pancreatic Ductal Adenocarcinoma Patients
Authors: Waldenmaier Mareike , Schulte Lucas , Schönfelder Jonathan , Fürstberger Axel , Kraus Johann M. , Daiss Nora , Seibold Tanja , Morawe Mareen , Ettrich Thomas J. , Kestler Hans A. , Kahlert Christoph , Seufferlein Thomas , Eiseler Tim
Published: February 2022

Pancreatic ductal adenocarcinomas (PDACs) are tumors with poor prognosis and limited treatment options. Personalized medicine aims at characterizing actionable DNA variants by next-generation sequencing, thereby improving treatment strategies and outcomes. Fine-needle tumor biopsies are currently the gold standard to acquire samples for DNA profiling. However, liquid biopsies have considerable advantages as they are minimally invasive and frequently obtainable and thus may help to monitor tumor evolution over time. However, which liquid analyte works best for this purpose is currently unclear. Our study aims to directly compare tumor-, circulating free (cf-) and extracellular vesicle-derived (ev)DNA by panel sequencing of matching patient material. We evaluated copy number variations (CNVs), single nucleotide variants (SNVs) and insertions and deletions (indels). Our data show that evDNA contains significantly larger DNA fragments up to 5.5 kb, in line with previous observations. Stringent bioinformatic processing revealed a significant advantage of evDNA with respect to cfDNA concerning detection performance for SNVs and a numerical increase for indels. A combination of ev- and cfDNA was clearly superior for SNV detection, as compared to either single analyte, thus potentially improving actionable variant prediction upon further optimization. Finally, calling of CNVs from liquid biopsies still remained challenging and uninformative.
Effective Penetration of a Liposomal Formulation of Bleomycin through Ex-Vivo Skin Explants from Two Different Species
Authors: Ferrari Giulia , Pang Lisa Y. , De Moliner Fabio , Vendrell Marc , Reardon Richard J. M. , Higgins Andrew J. , Chopra Sunil , Argyle David J.
Published: February 2022

Bleomycin is a chemotherapy agent that, when administered systemically, can cause severe pulmonary toxicity. Bleosome is a novel formulation of bleomycin encapsulated in ultra-deformable (UD) liposomes that may be applicable as a topical chemotherapy for diseases such as non-melanoma skin cancer. To date, the ability of Bleosome to effectively penetrate through the skin has not been evaluated. In this study, we investigated the ability of Bleosome to penetrate through ex vivo skin explants from dogs and horses. We visualized the penetration of UD liposomes through the skin by transmission electron microscopy. However, to effectively image the drug itself we fluorescently labeled bleomycin prior to encapsulation within liposomes and utilized multiphoton microscopy. We showed that UD liposomes do not penetrate beyond the stratum corneum, whereas bleomycin is released from UD liposomes and can penetrate to the deeper layers of the epidermis. This is the first study to show that Bleosome can effectively penetrate through the skin. We speculate that UD liposomes are penetration enhancers in that UD liposomes carry bleomycin through the outer skin to the stratum corneum and then release the drug, allowing diffusion into the deeper layers. Our results are comparative in dogs and horses and warrant further studies on the efficacy of Bleosome as topical treatment.
Completion of FLOT Therapy, Regardless of Tumor Regression, Significantly Improves Overall Survival in Patients with Esophageal Adenocarcinoma
Authors: Stüben Björn-Ole , Stuhlfelder Jakob , Kemper Marius , Tachezy Michael , Ghadban Tarik , Izbicki Jakob Robert , Bokemeyer Carsten , Sinn Marianne , Karstens Karl-Frederick , Reeh Matthias
Published: February 2022

Esophageal cancer is the eighth most common cancer worldwide, with poor prognosis and high mortality. The combination of surgery and systemic therapy provide the best chances for long-term survival. The purpose of this study was to analyze the impact of the FLOT protocol on the overall survival of patients following surgery for esophageal adenocarcinoma, with a focus on the patients who did not benefit in terms of pathological remission from the neoadjuvant therapy. A retrospective analysis of all the patients who underwent esophagectomies from 2012 to 2017 for locally advanced adenocarcinomas of the esophagus at a tertiary medical center was performed. The results show that the completion of systemic therapy, regardless of the tumor regression grading, had a significant positive impact on the overall survival. The patients with complete regression and complete systemic therapy showed the best outcomes. Anastomotic insufficiency did not negatively impact the long-term survival, while complications of the systemic therapy led to significantly reduced overall survival. We conclude that adjuvant systemic therapy should, when possible, always be completed, regardless of the tumor regression, following an esophagectomy.
Preoperative Magnetic Resonance Image and Computerized Tomography Findings Predictive of Facial Nerve Invasion in Patients with Parotid Cancer without Preoperative Facial Weakness—A Retrospective Observational Study
Authors: Cho Won Ki , Lee Min Kyoung , Choi Young Jun , Lee Yoon Se , Choi Seung-Ho , Nam Soon Yuhl , Kim Sang Yoon
Published: February 2022

(1) Background: Facial nerve resection with reconstruction helps achieve optimal outcomes in the treatment of facial nerve invasion (FNI) of parotid cancer. Preoperative imaging is crucial to predict facial nerve reconstruction. The radiological findings of CT or MRI may predict FNI in the parotid cancer even without facial paralysis. Methods: We retrospectively reviewed the records of 151 patients without facial nerve paralysis before surgery who had undergone tumor resection. Previously untreated parotid cancers were included. (2) Results: The median follow-up duration was 62 months (range: 24–120 months). The FNI (+) group (n = 30) showed a significantly worse 5-year overall survival compared with the FNI (−) group (75.5 vs. 93.9%; hazard ratio = 4.19; 95% confidence interval: 1.74–10.08; p = 0.001). The tumor margin, tumor size, presence in the anterolateral parotid region (area 3), retromandibular vein involvement, distance from the stylomastoid foramen to the upper tumor margin, and a high tumor grade were significant factors related to FNI in the univariate analysis. A spiculated tumor margin, the tumor size (2.2 cm), and presence in area 3 were factors predicting FNI in the logistic regression model (p = 0.020, 0.005, and 0.050, respectively; odds ratio: 4.02, 6.40, and 8.16, respectively). (3) Conclusions: The tumor size (≥2.2 cm), spiculated margin, and presence in area 3 as presented in CT and MRI may help clinicians preoperatively predict FNI in patients with parotid cancer and establish an appropriate surgical plan.
Organotypic Epithelial Raft Cultures as a Three-Dimensional In Vitro Model of Merkel Cell Carcinoma
Authors: Temblador Arturo , Topalis Dimitrios , van den Oord Joost , Andrei Graciela , Snoeck Robert
Published: February 2022

Merkel cell carcinoma (MCC) is a rare type of skin cancer for which an in vitro model is still lacking. MCC tumorigenesis is associated either with the integration of Merkel cell polyomavirus into the host genome, or with the accumulation of somatic mutations upon chronic exposure to UV light. Transgenic animals expressing the viral oncoproteins, which are constitutively expressed in virus-related MCC, do not fully recapitulate MCC. Although cell-line-derived xenografts have been established for the two subtypes of MCC, they still present certain limitations. Here, we generated organotypic epithelial raft cultures (OERCs) of MCC by using primary human keratinocytes and both virus-positive and virus-negative MCC cell lines. The primary human keratinocytes and the tumor cells were grown on top of a dermal equivalent. Histological and immunohistochemical examination of the rafts confirmed the growth of MCC cells. Furthermore, gene expression analysis revealed differences in the expression profiles of the distinct tumor cells and the keratinocytes at the transcriptional level. In summary, considering the limited availability of patient samples, OERCs of MCC may constitute a suitable model for evaluating the efficacy and selectivity of new drug candidates against MCC; moreover, they are a potential tool to study the oncogenic mechanisms of this malignancy.
New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas
Authors: Igaz Peter
Published: February 2022

This article collection includes 16 scientific papers that present the current state of the art of genetics and genomics research in the fascinating field of adrenal tumors [...]
Salvage Treatment for Progressive Brain Metastases in Breast Cancer
Authors: Spałek Mateusz Jacek , Mandat Tomasz
Published: February 2022

Survival of patients with breast cancer has increased in recent years due to the improvement of systemic treatment options. Nevertheless, the occurrence of brain metastases is associated with a poor prognosis. Moreover, most drugs do not penetrate the central nervous system because of the blood–brain barrier. Thus, confirmed intracranial progression after local therapy is especially challenging. The available methods of salvage treatment include surgery, stereotactic radiosurgery (SRS), fractionated stereotactic radiotherapy (FSRT), whole-brain radiotherapy, and systemic therapies. This narrative review discusses possible strategies of salvage treatment for progressive brain metastases in breast cancer. It covers possibilities of repeated local treatment using the same method as applied previously, other methods of local therapy, and options of salvage systemic treatment. Repeated local therapy may provide a significant benefit in intracranial progression-free survival and overall survival. However, it could lead to significant toxicity. Thus, the choice of optimal methods should be carefully discussed within the multidisciplinary tumor board.