bluuebunny/crossref_metadata_2025 huggingface dataset:
Hidden Treasures: Macrophage Long Non-Coding RNAs in Lung Cancer Progression
Authors: Karger Annika , Nandigama Rajender , Stenzinger Albrecht , Grimminger Friedrich , Pullamsetti Soni Savai , Seeger Werner , Savai Rajkumar
Published: August 2021

Ever since RNA sequencing of whole genomes and transcriptomes became available, numerous RNA transcripts without having the classic function of encoding proteins have been discovered. Long non-coding RNAs (lncRNAs) with a length greater than 200 nucleotides were considered as “junk” in the beginning, but it has increasingly become clear that lncRNAs have crucial roles in regulating a variety of cellular mechanisms and are often deregulated in several diseases, such as cancer. Lung cancer is the leading cause of cancer-related deaths and has a survival rate of less than 10%. Immune cells infiltrating the tumor microenvironment (TME) have been shown to have a great effect on tumor development with macrophages being the major cell type within the TME. Macrophages can inherit an inflammatory M1 or an anti-inflammatory M2 phenotype. Tumor-associated macrophages, which are predominantly polarized to M2, favor tumor growth, angiogenesis, and metastasis. In this review, we aimed to describe the complex roles and functions of lncRNAs in macrophages and their influence on lung cancer development and progression through the TME.
NK Cell Therapy: A Rising Star in Cancer Treatment
Authors: Du Nawen , Guo Feifei , Wang Yufeng , Cui Jiuwei
Published: August 2021

Immunotherapy has become a robust and routine treatment strategy for patients with cancer; however, there are efficacy and safety issues that should be resolved. Natural killer (NK) cells are important innate immune cells that have attracted increasing attention owing to their major histocompatibility complex-independent immunosurveillance ability. These cells provide the first-line defense against carcinogenesis and are closely related to cancer development. However, NK cells are functionally suppressed owing to multiple immunosuppressive factors in the tumor microenvironment; thus, releasing the suppressed state of NK cells is an emergent project and a promising solution for immunotherapy. As a result, many clinical trials of NK cell therapy alone or in combination with other agents are currently underway. This review describes the current status of NK cell therapy for cancer treatment based on the effector function and releasing the inhibited state of NK cells in the cancer microenvironment.
Thermodynamic Genome-Scale Metabolic Modeling of Metallodrug Resistance in Colorectal Cancer
Authors: Herrmann Helena A. , Rusz Mate , Baier Dina , Jakupec Michael A. , Keppler Bernhard K. , Berger Walter , Koellensperger Gunda , Zanghellini Jürgen
Published: August 2021

Background: Mass spectrometry-based metabolomics approaches provide an immense opportunity to enhance our understanding of the mechanisms that underpin the cellular reprogramming of cancers. Accurate comparative metabolic profiling of heterogeneous conditions, however, is still a challenge. Methods: Measuring both intracellular and extracellular metabolite concentrations, we constrain four instances of a thermodynamic genome-scale metabolic model of the HCT116 colorectal carcinoma cell line to compare the metabolic flux profiles of cells that are either sensitive or resistant to ruthenium- or platinum-based treatments with BOLD-100/KP1339 and oxaliplatin, respectively. Results: Normalizing according to growth rate and normalizing resistant cells according to their respective sensitive controls, we are able to dissect metabolic responses specific to the drug and to the resistance states. We find the normalization steps to be crucial in the interpretation of the metabolomics data and show that the metabolic reprogramming in resistant cells is limited to a select number of pathways. Conclusions: Here, we elucidate the key importance of normalization steps in the interpretation of metabolomics data, allowing us to uncover drug-specific metabolic reprogramming during acquired metal-drug resistance.
Zebrafish Patient-Derived Xenografts Identify Chemo-Response in Pancreatic Ductal Adenocarcinoma Patients
Authors: Usai Alice , Di Franco Gregorio , Piccardi Margherita , Cateni Perla , Pollina Luca Emanuele , Vivaldi Caterina , Vasile Enrico , Funel Niccola , Palmeri Matteo , Dente Luciana , Falcone Alfredo , Giunchi Dimitri , Massolo Alessandro , Raffa Vittoria , Morelli Luca
Published: August 2021

It is increasingly evident the necessity of new predictive tools for the treatment of pancreatic ductal adenocarcinoma in a personalized manner. We present a co-clinical trial testing the predictiveness of zPDX (zebrafish patient-derived xenograft) for assessing if patients could benefit from a therapeutic strategy (ClinicalTrials.gov: XenoZ, NCT03668418). zPDX are generated xenografting tumor tissues in zebrafish embryos. zPDX were exposed to chemotherapy regimens commonly used. We considered a zPDX a responder (R) when a decrease ≥50% in the relative tumor area was reported; otherwise, we considered them a non-responder (NR). Patients were classified as Responder if their own zPDX was classified as an R for the chemotherapy scheme she/he received an adjuvant treatment; otherwise, we considered them a Non-Responder. We compared the cancer recurrence rate at 1 year after surgery and the disease-free survival (DFS) of patients of both groups. We reported a statistically significant higher recurrence rate in the Non-Responder group: 66.7% vs. 14.3% (p = 0.036), anticipating relapse/no relapse within 1 year after surgery in 12/16 patients. The mean DFS was longer in the R-group than the NR-group, even if not statistically significant: 19.2 months vs. 12.7 months, (p = 0.123). The proposed strategy could potentially improve preclinical evaluation of treatment modalities and may enable prospective therapeutic selection in everyday clinical practice.
Recent Advances in Enhancing the Therapeutic Index of PARP Inhibitors in Breast Cancer
Authors: Franchet Camille , Hoffmann Jean-Sébastien , Dalenc Florence
Published: August 2021

As poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with the deficiency of DNA double-strand (DSB) break repair by homologous recombination (HR), PARP inhibitors (PARPi) are currently used to treat breast cancers with mutated BRCA1/2 HR factors. Unfortunately, the increasingly high rate of PARPi resistance in clinical practice has dented initial hopes. Multiple resistance mechanisms and acquired vulnerabilities revealed in vitro might explain this setback. We describe the mechanisms and vulnerabilities involved, including newly identified modes of regulation of DSB repair that are now being tested in large cohorts of patients and discuss how they could lead to novel treatment strategies to improve the therapeutic index of PARPi.
Non-Canonical Role of PDK1 as a Negative Regulator of Apoptosis through Macromolecular Complexes Assembly at the ER–Mitochondria Interface in Oncogene-Driven NSCLC
Authors: De Rosa Viviana , Iommelli Francesca , Terlizzi Cristina , Leggiero Eleonora , Camerlingo Rosa , Altobelli Giovanna G. , Fonti Rosa , Pastore Lucio , Del Vecchio Silvana
Published: August 2021

Here, we tested whether co-targeting of glucose metabolism and oncogene drivers may enhance tumor response to tyrosine kinase inhibitors (TKIs) in NSCLC. To this end, pyruvate dehydrogenase kinase 1 (PDK1) was stably downregulated in oncogene-driven NSCLC cell lines exposed or not to TKIs. H1993 and H1975 cells were stably transfected with scrambled (shCTRL) or PDK1-targeted (shPDK1) shRNA and then treated with MET inhibitor crizotinib (1 µM), double mutant EGFRL858R/T790M inhibitor WZ4002 (1 µM) or vehicle for 48 h. The effects of PDK1 knockdown on glucose metabolism and apoptosis were evaluated in untreated and TKI-treated cells. PDK1 knockdown alone did not cause significant changes in glycolytic cascade, ATP production and glucose consumption, but it enhanced maximal respiration in shPDK1 cells when compared to controls. When combined with TKI treatment, PDK1 downregulation caused a strong enhancement of OXPHOS and a marked reduction in key glycolytic enzymes. Furthermore, increased levels of apoptotic markers were found in shPDK1 cells as compared to shCTRL cells after treatment with TKIs. Co-immunoprecipitation studies showed that PDK1 interacts with PKM2, Bcl-2 and Bcl-xL, forming macromolecular complexes at the ER–mitochondria interface. Our findings showed that downregulation of PDK1 is able to potentiate the effects of TKIs through the disruption of macromolecular complexes involving PKM2, Bcl-2 and Bcl-xL.
Pancreatic Cancer and Immunotherapy: A Clinical Overview
Authors: Timmer Florentine E. F. , Geboers Bart , Nieuwenhuizen Sanne , Dijkstra Madelon , Schouten Evelien A. C. , Puijk Robbert S. , de Vries Jan J. J. , van den Tol M. Petrousjka , Bruynzeel Anna M. E. , Streppel Mirte M. , Wilmink Johanna W. , van der Vliet Hans J. , Meijerink Martijn R. , Scheffer Hester J. , de Gruijl Tanja D.
Published: August 2021

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC’s immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms.
Citrate-Coated Superparamagnetic Iron Oxide Nanoparticles Enable a Stable Non-Spilling Loading of T Cells and Their Magnetic Accumulation
Authors: Boosz Philipp , Pfister Felix , Stein Rene , Friedrich Bernhard , Fester Lars , Band Julia , Mühlberger Marina , Schreiber Eveline , Lyer Stefan , Dudziak Diana , Alexiou Christoph , Janko Christina
Published: August 2021

T cell infiltration into a tumor is associated with a good clinical prognosis of the patient and adoptive T cell therapy can increase anti-tumor immune responses. However, immune cells are often excluded from tumor infiltration and can lack activation due to the immune-suppressive tumor microenvironment. To make T cells controllable by external forces, we loaded primary human CD3+ T cells with citrate-coated superparamagnetic iron oxide nanoparticles (SPIONs). Since the efficacy of magnetic targeting depends on the amount of SPION loading, we investigated how experimental conditions influence nanoparticle uptake and viability of cells. We found that loading in the presence of serum improved both the colloidal stability of SPIONs and viability of T cells, whereas stimulation with CD3/CD28/CD2 and IL-2 did not influence nanoparticle uptake. Furthermore, SPION loading did not impair cytokine secretion after polyclonal stimulation. We finally achieved 1.4 pg iron loading per cell, which was both located intracellularly in vesicles and bound to the plasma membrane. Importantly, nanoparticles did not spill over to non-loaded cells. Since SPION-loading enabled efficient magnetic accumulation of T cells in vitro under dynamic conditions, we conclude that this might be a good starting point for the investigation of in vivo delivery of immune cells.
Modulation of Cancer Cell Autophagic Responses by Graphene-Based Nanomaterials: Molecular Mechanisms and Therapeutic Implications
Authors: Ristic Biljana , Harhaji-Trajkovic Ljubica , Bosnjak Mihajlo , Dakic Ivana , Mijatovic Srdjan , Trajkovic Vladimir
Published: August 2021

Graphene-based nanomaterials (GNM) are plausible candidates for cancer therapeutics and drug delivery systems. Pure graphene and graphene oxide nanoparticles, as well as graphene quantum dots and graphene nanofibers, were all able to trigger autophagy in cancer cells through both transcriptional and post-transcriptional mechanisms involving oxidative/endoplasmic reticulum stress, AMP-activated protein kinase, mechanistic target of rapamycin, mitogen-activated protein kinase, and Toll-like receptor signaling. This was often coupled with lysosomal dysfunction and subsequent blockade of autophagic flux, which additionally increased the accumulation of autophagy mediators that participated in apoptotic, necrotic, or necroptotic death of cancer cells and influenced the immune response against the tumor. In this review, we analyze molecular mechanisms and structure–activity relationships of GNM-mediated autophagy modulation, its consequences for cancer cell survival/death and anti-tumor immune response, and the possible implications for the use of GNM in cancer therapy.
Expression of HDACs 1, 3 and 8 Is Upregulated in the Presence of Infiltrating Lymphocytes in Uveal Melanoma
Authors: Souri Zahra , Jochemsen Aart G. , Wierenga Annemijn P. A. , Kroes Wilma G. M. , Verdijk Rob M. , van der Velden Pieter A. , Luyten Gregorius P. M. , Jager Martine J.
Published: August 2021

In Uveal Melanoma (UM), an inflammatory phenotype is strongly associated with the development of metastases and with chromosome 3/BAP1 expression loss. As an increased expression of several Histone Deacetylases (HDACs) was associated with loss of chromosome 3, this suggested that HDAC expression might also be related to inflammation. We analyzed HDAC expression and the presence of leukocytes by mRNA expression in two sets of UM (Leiden and TCGA) and determined the T lymphocyte fraction through ddPCR. Four UM cell lines were treated with IFNγ (50IU, 200IU). Quantitative PCR (qPCR) was used for mRNA measurement of HDACs in cultured cells. In both cohorts (Leiden and TCGA), a positive correlation occurred between expression of HDACs 1, 3 and 8 and the presence of a T-cell infiltrate, while expression of HDACs 2 and 11 was negatively correlated with the presence of tumor-infiltrating macrophages. Stimulation of UM cell lines with IFNγ induced an increase in HDACs 1, 4, 5, 7 and 8 in two out of four UM cell lines. We conclude that the observed positive correlations between HDAC expression and chromosome 3/BAP1 loss may be related to the presence of infiltrating T cells.
HPV16 Load Is a Potential Biomarker to Predict Risk of High-Grade Cervical Lesions in High-Risk HPV-Infected Women: A Large Longitudinal French Hospital-Based Cohort Study
Authors: Baumann Antoine , Henriques Julie , Selmani Zohair , Meurisse Aurélia , Lepiller Quentin , Vernerey Dewi , Valmary-Degano Séverine , Paget-Bailly Sophie , Riethmuller Didier , Ramanah Rajeev , Mougin Christiane , Prétet Jean-Luc
Published: August 2021

High-risk HPV (hrHPV) testing has been implemented as a primary screening tool for cervical cancer in numerous countries. However, there is still a need for relevant triage strategies to manage hrHPV positive women to avoid excessive referral to colposcopy. The objective of this study was to assess, in women infected by hrHPV and presenting no or mild cytological abnormalities, HPV16 and HPV18 viral loads to predict the development of cervical high-grade lesion. Among 2102 women positive for hrHPV, 885 had no lesion or mild cytological abnormalities at baseline and had at least one follow-up (FU) visit. HPV16 and HPV18 prevalence was 25.9% and 8.4%, respectively. Of those women, 15% developed a high-grade lesion during the FU. An HPV16 viral load cut-off set at 3.2 log10GE/103 cells permitted to identify a subgroup of women at high risk of developing high-grade cervical lesion (HR = 2.67; 95% CI 1.80–3.97; p ≤ 0.0001). No specific HPV18 viral load threshold could have been defined in regard to the present study. In multivariate analysis, HPV16 load (absence/log10GE/103 cells < 3.2 vs. ≥3.2), RLU/PC 239 (1–100 pg/mL vs. >100 pg/mL) and cytology (normal vs abnormal) were independently associated with a significant increased risk of high-grade lesion development and were used to construct the prognostic score. In conclusion, HPV16 load is a relevant biomarker to identify women at high risk for developing cervical precancerous lesions.
Gene Panel Testing for Breast Cancer Reveals Differential Effect of Prior BRCA1/2 Probability
Authors: Evans D. Gareth , van Veen Elke M. , Woodward Emma R. , Harkness Elaine F. , Ellingford Jamie M. , Bowers Naomi L. , Wallace Andrew J. , Howell Sacha J. , Howell Anthony , Lalloo Fiona , Newman William G. , Smith Miriam J.
Published: August 2021

Whilst panel testing of an extended group of genes including BRCA1/2 is commonplace, these studies have not been subdivided by histiotype or by a priori BRCA1/2 probability. Patients with a breast cancer diagnosis undergoing extended panel testing were assessed for frequency of actionable variants in breast cancer genes other than BRCA1/2 by histiotype and Manchester score (MS) to reflect a priori BRCA1/2 likelihood. Rates were adjusted by prior testing for BRCA1/2 in an extended series. 95/1398 (6.3%) who underwent panel testing were found to be positive for actionable non-BRCA1/2 breast/ovarian cancer genes (ATM, BARD1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, TP53). As expected, PALB2, CHEK2 and ATM were predominant with 80-(5.3%). The highest rate occurred in Grade-3 ER+/HER2− breast cancers-(9.6%). Rates of non-BRCA actionable genes was fairly constant over all likelihoods of BRCA1/2 but adjusted rates were three times higher with MS < 9 (BRCA1/2 = 1.5%, other = 4.7%), but was only 1.6% compared to 79.3% with MS ≥ 40. Although rates of detection of non-BRCA actionable genes are relatively constant across BRCA1/2 likelihoods this disguises an overall adjusted low frequency in high-likelihood families which have been heavily pre-tested for BRCA1/2. Any loss of detection sensitivity for BRCA1/2 actionable variants in breast cancer panels should lead to bespoke BRCA1/2 testing being conducted first.
The Role of Positron Emission Tomography/Computed Tomography (PET/CT) for Staging and Disease Response Assessment in Localized and Locally Advanced Pancreatic Cancer
Authors: Ghidini Michele , Vuozzo Marta , Galassi Barbara , Mapelli Paola , Ceccarossi Virginia , Caccamo Lucio , Picchio Maria , Dondossola Daniele
Published: August 2021

Pancreatic Cancer (PC) has a poor prognosis, with a 5-year survival rate of only 9%. Even after radical surgical procedures, PC patients have poor survival rates, with a high chance of relapse (70–80%). Imaging is involved in all aspects of the clinical management of PC, including detection and characterization of primary tumors and their resectability, assessment of vascular, perineural and lymphatic invasion and detection of distant metastases. The role of Positron Emission Tomography/Computed Tomography (PET/CT) in detecting PC is still controversial, with the international guidelines not recommending its routine use. However, in resectable PC, PET/CT may play a role in assessing PC stage and grade and potential resectability after neoadjuvant treatment. Quantitative image analysis (radiomics) and new PET/CT radiotracers account for future developments in metabolic imaging and may further improve the relevance of this technique in several aspects of PC. In the present review, the current state of the art and future directions of PET/CT in resectable PC are presented.
The Role of Total Parenteral Nutrition in Patients with Peritoneal Carcinomatosis: A Systematic Review and Meta-Analysis
Authors: Ong Xing-Yi Sarah , Sultana Rehena , Tan Joey Wee-Shan , Tan Qiu Xuan , Wong Jolene Si Min , Chia Claramae Shulyn , Ong Chin-Ann Johnny
Published: August 2021

Peritoneal carcinomatosis (PC) is often associated with malnutrition and an inability to tolerate enteral feeding. Although total parenteral nutrition (TPN) can be lifesaving for patients with no other means of nutritional support, its use in the management of PC patients remains controversial. Therefore, a systematic review and meta-analysis was performed to evaluate the benefit of TPN on the overall survival of PC patients, in accordance with PRISMA guidelines. A total of 187 articles were screened; 10 were included in this review and eight were included in the meta-analysis. The pooled median overall survival of patients who received TPN was significantly higher than patients who did not receive TPN (p = 0.040). When only high-quality studies were included, a significant survival advantage was observed in PC patients receiving TPN (p < 0.001). Subgroup analysis of patients receiving chemotherapy demonstrated a significant survival benefit (p = 0.008) associated with the use of TPN. In conclusion, TPN may improve survival outcomes in PC patients. However, further studies are needed to conclude more definitively on the effect of TPN.
The Effects of Multidisciplinary Team Meetings on Clinical Practice for Colorectal, Lung, Prostate and Breast Cancer: A Systematic Review
Authors: Kočo Lejla , Weekenstroo Harm H. A. , Lambregts Doenja M. J. , Sedelaar J. P. Michiel , Prokop Mathias , Fütterer Jurgen J. , Mann Ritse M.
Published: August 2021

Objective: The aim of our systematic review is to identify the effects of multidisciplinary team meetings (MDTM) for lung, breast, colorectal and prostate cancer. Methods: Our systematic review, performed following PRISMA guidelines, included studies examining the impact of MDTMs on treatment decisions, patient and process outcomes. Electronic databases PUBMED, EMBASE, Cochrane Library and Web of Science were searched for articles published between 2000 and 2020. Risk of bias and level of evidence were assessed using the ROBINS-I tool and GRADE scale. Results: 41 of 13,246 articles were selected, evaluating colorectal (21), lung (10), prostate (6) and breast (4) cancer. Results showed that management plans were changed in 1.6–58% of cases after MDTMs. Studies reported a significant impact of MDTMs on surgery type, and a reduction of overall performed surgery after MDTM. Results also suggest that CT and MRI imaging significantly increased after MDTM implementation. Survival rate increased significantly with MDTM discussions according to twelve studies, yet three studies did not show significant differences. Conclusions: Despite heterogeneous data, MDTMs showed a significant impact on management plans, process outcomes and patient outcomes. To further explore the impact of MDTMs on the quality of healthcare, high-quality research is needed.
Refractory Metal Oxide–Doped Titanate Nanotubes: Synthesis and Photocatalytic Activity under UV/Visible Light Range
Authors: Kim Min-Sang , Choi Hyun-Joo , Sekino Tohru , Kim Young-Do , Kim Se-Hoon
Published: August 2021

This study synthesized refractory metal-oxide-doped titanate nanotubes (TNTs) using a hydrothermal process and investigated their photocatalytic activity under ultraviolet and visible light irradiation. Refractory metal doping ions such as Mo6+ and W6+ can be supplied from molybdenum oxide and tungsten oxide sources. The refractory metal-doped TNT may act as an electron trap or enhance the adsorption capacity, which increases the number of active sites and promotes separation efficiency.
Spectroscopic Analyses of Changes in Photocatalytic and Catalytic Activities of Mn- and Ni-Ion Doped and Base-Treated Reduced Graphene Oxide
Authors: Lee Hangil , Kim Hyun Sung
Published: August 2021

While reduced graphene oxide (rGO) is used widely as a catalyst, its catalytic activity can be improved significantly by modifying it with a metal. In this study, we compared the photocatalytic and catalytic properties of base-treated rGO particles and transition-metal-ion-doped rGO based on the oxidation reaction of thiophenol and the photocatalytic degradation of 4-chlorophenol. Since the two catalytic activities are related to the changes in the electronic structure of rGO, X-ray photoemission spectroscopy, X-ray absorption spectroscopy, and Raman spectroscopy were performed. When rGO was doped with Mn2+ ions, its catalytic properties improved with respect to both reactions. The changes in the electronic structure of rGO are attributed to the formation of defect structures on the rGO surface via a reaction between the doped Mn2+ ions and oxygen of the rGO surface. Thus, the results show that the doping of rGO with Mn ions in the +2-charge state (stable oxide form: MnO) enhances its catalytic and photocatalytic activities. Hence, this study provides new insights into the use of defect-controlled rGO as a novel catalyst.
Pathophysiological Roles of Abnormal Axon Initial Segments in Neurodevelopmental Disorders
Authors: Fujitani Masashi , Otani Yoshinori , Miyajima Hisao
Published: August 2021

The 20–60 μm axon initial segment (AIS) is proximally located at the interface between the axon and cell body. AIS has characteristic molecular and structural properties regulated by the crucial protein, ankyrin-G. The AIS contains a high density of Na+ channels relative to the cell body, which allows low thresholds for the initiation of action potential (AP). Molecular and physiological studies have shown that the AIS is also a key domain for the control of neuronal excitability by homeostatic mechanisms. The AIS has high plasticity in normal developmental processes and pathological activities, such as injury, neurodegeneration, and neurodevelopmental disorders (NDDs). In the first half of this review, we provide an overview of the molecular, structural, and ion-channel characteristics of AIS, AIS regulation through axo-axonic synapses, and axo−glial interactions. In the second half, to understand the relationship between NDDs and AIS, we discuss the activity-dependent plasticity of AIS, the human mutation of AIS regulatory genes, and the pathophysiological role of an abnormal AIS in NDD model animals and patients. We propose that the AIS may provide a potentially valuable structural biomarker in response to abnormal network activity in vivo as well as a new treatment concept at the neural circuit level.
Expansion of Myeloid Derived Suppressor Cells Contributes to Platelet Activation by L-Arginine Deprivation during SARS-CoV-2 Infection
Authors: Sacchi Alessandra , Grassi Germana , Notari Stefania , Gili Simona , Bordoni Veronica , Tartaglia Eleonora , Casetti Rita , Cimini Eleonora , Mariotti Davide , Garotto Gabriele , Beccacece Alessia , Marchioni Luisa , Bibas Michele , Nicastri Emanuele , Ippolito Giuseppe , Agrati Chiara
Published: August 2021

Massive platelet activation and thrombotic events characterize severe COVID-19, highlighting their critical role in SARS-CoV-2-induced immunopathology. Since there is a well-described expansion of myeloid-derived suppressor cells (MDSC) in severe COVID-19, we evaluated their possible role in platelet activation during SARS-CoV-2 infection. During COVID-19, a lower plasmatic L-arginine level was observed compared to healthy donors, which correlated with MDSC frequency. Additionally, activated GPIIb/IIIa complex (PAC-1) expression was higher on platelets from severe COVID-19 patients compared to healthy controls and inversely correlated with L-arginine plasmatic concentration. Notably, MDSC were able to induce PAC-1 expression in vitro by reducing L-arginine concentration, indicating a direct role of PMN-MDSC in platelet activation. Accordingly, we found a positive correlation between ex vivo platelet PAC-1 expression and PMN-MDSC frequency. Overall, our data demonstrate the involvement of PMN-MDSC in triggering platelet activation during COVID-19, highlighting a novel role of MDSC in driving COVID-19 pathogenesis.
Mesenchymal Stem Cells in Adipose Tissue and Extracellular Vesicles in Ovarian Cancer Patients: A Bridge toward Metastatic Diffusion or a New Therapeutic Opportunity?
Authors: Storti Gabriele , Scioli Maria Giovanna , Kim Bong-Sung , Terriaca Sonia , Fiorelli Elena , Orlandi Augusto , Cervelli Valerio
Published: August 2021

Ovarian cancer is one of the deadliest malignancies among women. Approximately 75% of the patients with ovarian cancer are diagnosed with advanced disease that already has metastasis, particularly to the omentum. The omentum constitutes the ideal soil for ovarian cancer metastasis due to a complex intraperitoneal milieu that favors and supports the whole metastatic process. Adipose-derived stem/stromal cells (ADSCs) are part of this microenvironment and foster tumor progression via sustained paracrine secretion, including extracellular vesicles (EVs). Nonetheless, the preferential relationship between ADSCs, ADSC-derived EVs, and ovarian cancer cells could be exploited to use ADSCs and EVs as a vehicle for anti-cancer therapies. This review will analyze the strict relations between tumor progression, metastatic disease, and adipose tissue with its staminal components. In addition, we will describe the crosstalk and biologic relationship between ADSCs and tumor cells, the role of EVs in intercellular communication, the establishment of drug resistance, metastatic capacity, and ovarian cancer progression. We will analyze the new therapeutic opportunities in treating ovarian cancer offered by ADSCs and EVs as a vehicle for therapeutic molecules to target precisely tumor cells and limit the systemic adverse effects. Finally, we will discuss the limitations of these therapeutic approaches.
Intersection of Redox Chemistry and Ubiquitylation: Post-Translational Modifications Required for Maintaining Cellular Homeostasis and Neuroprotection
Authors: Kane Emma I. , Waters Kelly L. , Spratt Donald E.
Published: August 2021

Neurodegeneration has been predominantly recognized as neuronal breakdown induced by the accumulation of aggregated and/or misfolded proteins and remains a preliminary factor in age-dependent disease. Recently, critical regulating molecular mechanisms and cellular pathways have been shown to induce neurodegeneration long before aggregate accumulation could occur. Although this opens the possibility of identifying biomarkers for early onset diagnosis, many of these pathways vary in their modes of dysfunction while presenting similar clinical phenotypes. With selectivity remaining difficult, it is promising that these neuroprotective pathways are regulated through the ubiquitin-proteasome system (UPS). This essential post-translational modification (PTM) involves the specific attachment of ubiquitin onto a substrate, specifically marking the ubiquitin-tagged protein for its intracellular fate based upon the site of attachment, the ubiquitin chain type built, and isopeptide linkages between different ubiquitin moieties. This review highlights both the direct and indirect impact ubiquitylation has in oxidative stress response and neuroprotection, and how irregularities in these intricate processes lead towards the onset of neurodegenerative disease (NDD).
Play Behaviors in Children during the COVID-19 Pandemic: A Review of the Literature
Authors: Kourti Anastasia , Stavridou Androniki , Panagouli Eleni , Psaltopoulou Theodora , Tsolia Maria , Sergentanis Theodoros N. , Tsitsika Artemis
Published: August 2021

Play is a key factor for children’s healthy psychological, emotional, social, and cognitive development. During the COVID-19 pandemic, it has been postulated that children’s play was affected, not only regarding the time children spent playing but also in terms of the qualitative characteristics of play. The aim of this review was to investigate how children’s play has changed during the COVID-19 pandemic. A review was conducted in the PubMed, Google Scholar, EMBASE, SCOPUS, ERIC, PsycInfo, and JSTOR databases up to 6 December 2020. Furthermore, references of eligible studies as well as of relevant articles were searched using a snowballing technique. The search retrieved 17 eligible studies, conducted in Europe and North America. In general, outdoor play was reduced during the pandemic; on the other hand, there was an increase in indoor play and in videogames-screen time. COVID-19 was present in children’s pretend play. Children’s play was a key contributor to children’s mood and wellbeing. Furthermore, teachers were especially concerned about how children’s play was affected during the lockdown measures. There is evidence that children’s play habits were affected during the COVID-19 pandemic; further research is required, especially cross-culturally oriented.
A Novel Comparative Study Based on the Economic Feasibility of the Ceramic Nanoparticles Role’s in Improving the Properties of the AA5250 Nanocomposites
Authors: Abushanab Waheed Sami , Moustafa Essam B. , Melaibari Ammar A. , Kotov Anton D. , Mosleh Ahmed O.
Published: August 2021

In this paper, AA5250 aluminum sheets are reinforced with boron nitride (BN), silicon carbide (SiC), aluminum oxide (Al2O3), and vanadium carbide (VC). The nanocomposites metal matrix are manufactured using friction stir processing (FSP). A novel analytical comparison based on an assessment of mechanical, physical properties and the cost of manufactured materials was conducted to help the engineers and designers choose the most economically feasible nanocomposite. The results revealed extra grain refining for all composites in the stirred zone (SZ) due to the Zener-pinning mechanism. The smallest grain size was obtained in AA5250/BN, and it decreased 20 times that of the base metal (BM). The highest wear resistance was achieved in AA5250/SiC, followed by AA5250/VC and AA5250/BN. The lowest coefficient of friction was obtained for AA5250/BN due to the self-lubrication property of BN; which was μ = 0.28. SiC AA5250 had the highest hardness, increasing three times more than the base metal in terms of its hardness. There was a detailed discussion of the probable explanations for the improvements. However, the outstanding characteristics of the BN nanoparticles, the AA5250/BN was reported to be lower than the AA5250/SiC. In comparison, the AA5250/SiC nanocomposite exhibits the optimum value due to its fitting for different properties relative to the cost.
Preparation and Characterization of PU/PET Matrix Gradient Composites with Microwave-Absorbing Function
Authors: Gu Wenyan , Zhan Rong , Li Rui , Liu Jiaxin , Zhang Jiaqiao
Published: August 2021

In the field of microwave-absorbing materials, functional powder has always been the focus of research. In order to fabricate lightweight and flexible garment materials with microwave-absorbing function, the current work was carried out. Firstly, the general properties of polyurethane (PU) matrix composites reinforced with various microwave-absorbing powders were studied, and the carbon nanotubes (CNTs)/Fe3O4/PU film was proven to have the best general properties. Secondly, the needle-punched polyester (PET) nonwoven fabrics in 1 mm-thickness were impregnated into PU resin with the same composition of raw material as Fe3O4/CNTs/PU film, thereby the microwave-absorbing nonwovens with gradient structure were prepared. Moreover, the absorbing properties of the CNTs/Fe3O4/PU/PET gradient composites were tested and analyzed. Finally, the relationship between the mass ratio of CNTs and Fe3O4, and the microwave-absorbing properties was studied. The results show that the mass ratio of CNTs/Fe3O4 has a significant effect on the microwave-absorbing property of CNTs/Fe3O4/PU/PET. When the mass ratio of CNTs/Fe3O4 is 1:1, the prepared CNTs/Fe3O4/PU/PET gradient composite can achieve effective reflection loss in the range of more than 2 GHz in Ku-band (12–18 GHz), and the minimum reflection loss reaches −17.19 dB.
Viral Infection, COVID-19 in Pregnancy and Lactating Women: What Is Known?
Authors: Ciarambino Tiziana , Crispino Pietro , Giordano Mauro
Published: August 2021

Introduction. Viral infections during pregnancy have always been considered to cause complications and adverse events and birth defects during pregnancy. In particular, we do not have any therapeutic or preventive tools aimed at protecting the mother and fetus during the gestational period during pandemics. Methods. The studies were identified by using the PubMed database published until 30 April 2021. The search was performed by using the following keywords: viral infection, SARS-CoV-2, COVID-19, vaccine, pregnancy, gestational period, pandemics, vaccination, complication, adverse events, drugs. Results. It has been reported that viral infections are considered to cause complications and adverse events during pregnancy. In this regard, pregnancy is associated with higher mortality rates and complications during viral infections. In fact, maternal immunization represents a unique approach to protect newborns from several infectious diseases. Conclusion. European Board and College of Obstetrics and Gynecology (EBCOG) and International public health institutions (WHO, CDC) report the recommendations about the use of vaccines during pregnancy.
Use of Propensity Score Matching to Compare Short Outcomes from Transoral and External Surgical Approaches in Patients with Deep-Lobe Parotid Pleomorphic Adenomas
Authors: Fan Yue , Li Shuguang , Yu Shuting , Zhu Xiaoli , Shi Xiaohua , Li Wuyi , Gao Zhiqiang , Chen Xingming
Published: August 2021

To compare the outcomes of patients who had deep-lobe parotid gland pleomorphic adenomas (PAs) that extended into the parapharyngeal space after surgical treatment, using a transoral approach or an external approach. One hundred and twelve eligible patients, with deep-lobe parotid gland PAs, were enrolled in this retrospective study. The surgical outcomes were compared for patients who received a transoral approach and an external approach, using 1:1 propensity score matching (PSM). The outcome measures were recurrence rate, facial nerve deficit, Frey’s syndrome, and hospitalization time. The median follow-up time was 4.8 years. After PSM, the transoral approach and external approach groups had no statistically significant difference in recurrence (10.3% vs. 3.4%; p = 0.201). The transoral approach group had no facial nerve deficit, but 5 of 29 patients (17.2%) in the external approach group had transient facial nerve paralysis (p = 0.052). The external approach group had a longer hospitalization time than the transoral approach group (5 vs. 4 days, p = 0.0017). The use of a transoral surgical approach to treat patients with deep-lobe parotid gland PAs led to low recurrence, shorter hospitalization times, and good functional and cosmetic outcomes.
A GIS Modeling Study of the Distribution of Viviparous Invasive Alien Fish Species in Eastern Europe in Terms of Global Climate Change, as Exemplified by Poecilia reticulata Peters, 1859 and Gambusia holbrooki Girarg, 1859
Authors: Nekrasova Oksana , Tytar Volodymyr , Pupins Mihails , Čeirāns Andris , Marushchak Oleksii , Skute Arturs
Published: August 2021

The potential distribution of tropical fish species in Eastern Europe—Gambusia holbrooki (introduced for biological control) and Poecilia reticulata (aquarium species, found in waste waters of big cities)—tend to be of particular interest in terms of global climate change. After GIS modeling of our own data and findings listed in the GBIF databases (2278 points for G. holbrooki and 1410 points for P. reticulata) using the Maxent package and ‘ntbox’ package in R, 18 uncorrelated variables of 35 Bioclim climatic parameters from CliMond dataset, it was found out that by 2090 guppies will appear in the south of Ukraine (Danube river’s estuary, as well as in several places in the Caucasus and Turkey with habitat suitability > 0.3–0.5). G. holbrooki will also slightly expand its range in Europe. Limiting factors for G. holbrooki distribution are: bio1 (Annual mean temperature, optimum +12–+24 °C) and bio19 (Precipitation of coldest quarter (mm). Limiting factors for P. reticulata are: bio1 (optimum +14–+28 °C), bio4 (Temperature seasonality), bio3 (Isothermality). Unlike G. holbrooki, guppies prefer warmer waters. Such thermophilic fish species do not compete with the native ichthyofauna, but they can occupy niches in anthropogenically transformed habitats, playing an important role as agents of biological control.
Genetic Diversity and Population Structure of Two Endangered Neotropical Parrots Inform In Situ and Ex Situ Conservation Strategies
Authors: Campos Carlos I. , Martinez Melinda A. , Acosta Daniel , Diaz-Luque Jose A. , Berkunsky Igor , Lamberski Nadine L. , Cruz-Nieto Javier , Russello Michael A. , Wright Timothy F.
Published: August 2021

A key aspect in the conservation of endangered populations is understanding patterns of genetic variation and structure, which can provide managers with critical information to support evidence-based status assessments and management strategies. This is especially important for species with small wild and larger captive populations, as found in many endangered parrots. We used genotypic data to assess genetic variation and structure in wild and captive populations of two endangered parrots, the blue-throated macaw, Ara glaucogularis, of Bolivia, and the thick-billed parrot, Rhynchopsitta pachyrhyncha, of Mexico. In the blue-throated macaw, we found evidence of weak genetic differentiation between wild northern and southern subpopulations, and between wild and captive populations. In the thick-billed parrot we found no signal of differentiation between the Madera and Tutuaca breeding colonies or between wild and captive populations. Similar levels of genetic diversity were detected in the wild and captive populations of both species, with private alleles detected in captivity in both, and in the wild in the thick-billed parrot. We found genetic signatures of a bottleneck in the northern blue-throated macaw subpopulation, but no such signal was identified in any other subpopulation of either species. Our results suggest both species could potentially benefit from reintroduction of genetic variation found in captivity, and emphasize the need for genetic management of captive populations.
What to Look Out for in a Newborn with Multiple Papulonodular Skin Lesions at Birth
Authors: Fraitag Sylvie , Boccara Olivia
Published: August 2021

Multiple papulonodular skin lesions at birth can indicate the presence of various benign and malignant disorders. Although the lesions’ clinical aspect (color and consistency, in particular) may steer the clinician towards one disorder or another (infantile myofibromatosis, xanthogranuloma, or metastatic neuroblastoma), the diagnosis can only be confirmed by the histopathologic assessment of a biopsy. In neonates, a rapid but accurate diagnosis is critical because skin lesions may be the first manifestation of a malignant disorder like leukemia cutis or metastatic neuroblastoma. Here, we review the various disorders that may manifest themselves as multiple skin lesions at birth.
A New Total Uncertainty Measure from A Perspective of Maximum Entropy Requirement
Authors: Zhang Yu , Huang Fanghui , Deng Xinyang , Jiang Wen
Published: August 2021

The Dempster-Shafer theory (DST) is an information fusion framework and widely used in many fields. However, the uncertainty measure of a basic probability assignment (BPA) is still an open issue in DST. There are many methods to quantify the uncertainty of BPAs. However, the existing methods have some limitations. In this paper, a new total uncertainty measure from a perspective of maximum entropy requirement is proposed. The proposed method can measure both dissonance and non-specificity in BPA, which includes two components. The first component is consistent with Yager’s dissonance measure. The second component is the non-specificity measurement with different functions. We also prove the desirable properties of the proposed method. Besides, numerical examples and applications are provided to illustrate the effectiveness of the proposed total uncertainty measure.
Distributional Replication
Authors: Beare Brendan K.
Published: August 2021

A function which transforms a continuous random variable such that it has a specified distribution is called a replicating function. We suppose that functions may be assigned a price, and study an optimization problem in which the cheapest approximation to a replicating function is sought. Under suitable regularity conditions, including a bound on the entropy of the set of candidate approximations, we show that the optimal approximation comes close to achieving distributional replication, and close to achieving the minimum cost among replicating functions. We discuss the relevance of our results to the financial literature on hedge fund replication; in this case, the optimal approximation corresponds to the cheapest portfolio of market index options which delivers the hedge fund return distribution.
Thermal Robustness of Entanglement in a Dissipative Two-Dimensional Spin System in an Inhomogeneous Magnetic Field
Authors: Sadiek Gehad , Almalki Samaher
Published: August 2021

Recently new novel magnetic phases were shown to exist in the asymptotic steady states of spin systems coupled to dissipative environments at zero temperature. Tuning the different system parameters led to quantum phase transitions among those states. We study, here, a finite two-dimensional Heisenberg triangular spin lattice coupled to a dissipative Markovian Lindblad environment at finite temperature. We show how applying an inhomogeneous magnetic field to the system at different degrees of anisotropy may significantly affect the spin states, and the entanglement properties and distribution among the spins in the asymptotic steady state of the system. In particular, applying an inhomogeneous field with an inward (growing) gradient toward the central spin is found to considerably enhance the nearest neighbor entanglement and its robustness against the thermal dissipative decay effect in the completely anisotropic (Ising) system, whereas the beyond nearest neighbor ones vanish entirely. The spins of the system in this case reach different steady states depending on their positions in the lattice. However, the inhomogeneity of the field shows no effect on the entanglement in the completely isotropic (XXX) system, which vanishes asymptotically under any system configuration and the spins relax to a separable (disentangled) steady state with all the spins reaching a common spin state. Interestingly, applying the same field to a partially anisotropic (XYZ) system does not just enhance the nearest neighbor entanglements and their thermal robustness but all the long-range ones as well, while the spins relax asymptotically to very distinguished spin states, which is a sign of a critical behavior taking place at this combination of system anisotropy and field inhomogeneity.