bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Dicarboxymethyl Cellulose on the Prevention of Protein Haze Formation on White Wine
Authors: Gago Diana , Chagas Ricardo , Ferreira Luísa M.
Published: August 2021

Wine clarity is a critical aspect in the commercialization of white wines. The formation of wine haze can be attributed to the aggregation and precipitation of heat-unstable wine proteins. Bentonite fining is the commonly used method in winemaking for protein removal, but it is responsible for loss of wine volume and quality. Dicarboxymethyl cellulose (DCMC) was developed as a potential alternative to bentonite. Water-insoluble DCMC was prepared via catalyzed heterogeneous etherification using sodium chloromalonate and potassium iodide. White wine fining trials were benchmarked with different dosages of DCMC against a bentonite. A high-performance liquid chromatography method was optimized for protein quantification. The samples underwent heat stability tests to evaluate wine turbidity before and after fining. Results show that DCMC successfully reduced the wine protein content and turbidity. DCMC produced heat-stable wines with dosages higher than 0.25 g/L. The innovative application of DCMC in the wine sector shows potential due to its ability to stabilize white wines while overcoming problems associated with bentonite, such as lees production and loss of wine, contributing to a more sustainable process.
Evaluation of Genomic Prediction for Fusarium Head Blight Resistance with a Multi-Parental Population
Authors: Zhang Wentao , Boyle Kerry , Brule-Babel Anita , Fedak George , Gao Peng , Djama Zeinab Robleh , Polley Brittany , Cuthbert Richard , Randhawa Harpinder , Graf Robert , Jiang Fengying , Eudes Francois , Fobert Pierre R.
Published: August 2021

Fusarium head blight (FHB) resistance is quantitatively inherited, controlled by multiple minor effect genes, and highly affected by the interaction of genotype and environment. This makes genomic selection (GS) that uses genome-wide molecular marker data to predict the genetic breeding value as a promising approach to select superior lines with better resistance. However, various factors can affect accuracies of GS and better understanding how these factors affect GS accuracies could ensure the success of applying GS to improve FHB resistance in wheat. In this study, we performed a comprehensive evaluation of factors that affect GS accuracies with a multi-parental population designed for FHB resistance. We found larger sample sizes could get better accuracies. Training population designed by CDmean based optimization algorithms significantly increased accuracies than random sampling approach, while mean of predictor error variance (PEVmean) had the poorest performance. Different genomic selection models performed similarly for accuracies. Including prior known large effect quantitative trait loci (QTL) as fixed effect into the GS model considerably improved the predictability. Multi-traits models had almost no effects, while the multi-environment model outperformed the single environment model for prediction across different environments. By comparing within and across family prediction, better accuracies were obtained with the training population more closely related to the testing population. However, achieving good accuracies for GS prediction across populations is still a challenging issue for GS application.
Survival-Based Biomarker Module Identification Associated with Oral Squamous Cell Carcinoma (OSCC)
Authors: Singh Prithvi , Rai Arpita , Verma Amit Kumar , Alsahli Mohammed A. , Rahmani Arshad Husain , Almatroodi Saleh A. , Alrumaihi Faris , Dev Kapil , Sinha Anuradha , Sankhwar Shweta , Dohare Ravins
Published: August 2021

Head and neck squamous cell carcinoma (HNSC) is one of the most common malignant tumors worldwide with a high rate of morbidity and mortality, with 90% of predilections occurring for oral squamous cell carcinoma (OSCC). Cancers of the mouth account for 40% of head and neck cancers, including squamous cell carcinomas of the tongue, floor of the mouth, buccal mucosa, lips, hard and soft palate, and gingival. OSCC is the most devastating and commonly occurring oral malignancy, with a mortality rate of 500,000 deaths per year. This has imposed a strong necessity to discover driver genes responsible for its progression and malignancy. In the present study we filtered oral squamous cell carcinoma tissue samples from TCGA-HNSC cohort, which we followed by constructing a weighted PPI network based on the survival of patients and the expression profiles of samples collected from them. We found a total of 46 modules, with 18 modules having more than five edges. The KM and ME analyses revealed a single module (with 12 genes) as significant in the training and test datasets. The genes from this significant module were subjected to pathway enrichment analysis for identification of significant pathways and involved genes. Finally, the overlapping genes between gene sets ranked on the basis of weighted PPI module centralities (i.e., degree and eigenvector), significant pathway genes, and DEGs from a microarray OSCC dataset were considered as OSCC-specific hub genes. These hub genes were clinically validated using the IHC images available from the Human Protein Atlas (HPA) database.
The Role of Galectin-3 and ST2 in Cardiology: A Short Review
Authors: Merino-Merino Ana , Gonzalez-Bernal Jeronimo , Fernandez-Zoppino Dario , Saez-Maleta Ruth , Perez-Rivera Jose-Angel
Published: August 2021

Galectin-3 is a lectin that binds beta-galactosides. It is involved in cardiac remodeling and fibrosis through the activation of macrophages and fibroblasts. ST2 is secreted by myocardial cells due to cardiac overload. These two biomarkers have been traditionally studied in the field of heart failure to guide medical therapy and detect the progression of the disease. Nevertheless, there are novel evidences that connect galectin-3 and ST2 with coronary heart disease and, specifically, with atrial fibrillation. The aim of this article is to concisely review the diagnostic and prognostic role of galectin-3 and ST2 in different cardiac diseases.
Preparation of Affinity Purified Antibodies against ε-Glutaryl-Lysine Residues in Proteins for Investigation of Glutarylated Proteins in Animal Tissues
Authors: Artiukhov Artem V. , Kolesanova Ekaterina F. , Boyko Aleksandra I. , Chashnikova Anastasiya A. , Gnedoy Sergei N. , Kaehne Thilo , Ivanova Daria A. , Kolesnichenko Alyona V. , Aleshin Vasily A. , Bunik Victoria I.
Published: August 2021

The glutarylation of lysine residues in proteins attracts attention as a possible mechanism of metabolic regulation, perturbed in pathologies. The visualization of protein glutarylation by antibodies specific to ε-glutaryl-lysine residues may be particularly useful to reveal pathogenic mutations in the relevant enzymes. We purified such antibodies from the rabbit antiserum, obtained after sequential immunization with two artificially glutarylated proteins, using affinity chromatography on ε-glutaryl-lysine-containing sorbents. Employing these anti(ε-glutaryl-lysine)-antibodies for the immunoblotting analysis of rat tissues and mitochondria has demonstrated the sample-specific patterns of protein glutarylation. The study of the protein glutarylation in rat tissue homogenates revealed a time-dependent fragmentation of glutarylated proteins in these preparations. The process may complicate the investigation of potential changes in the acylation level of specific protein bands when studying time-dependent effects of the acylation regulators. In the rat brain, the protein glutarylation, succinylation and acetylation patterns obtained upon the immunoblotting of the same sample with the corresponding antibodies are shown to differ. Specific combinations of molecular masses of major protein bands in the different acylation patterns confirm the selectivity of the anti(ε-glutaryl-lysine)-antibodies obtained in this work. Hence, our affinity-purified anti(ε-glutaryllysine)-antibodies provide an effective tool to characterize protein glutarylation, revealing its specific pattern, compared to acetylation and succinylation, in complex protein mixtures.
Neutrophil in the Pancreatic Tumor Microenvironment
Authors: Jin Lin , Kim Hong Sun , Shi Jiaqi
Published: August 2021

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a poor prognosis and low survival rates. PDAC is characterized by a fibroinflammatory tumor microenvironment enriched by abundant fibroblasts and a variety of immune cells, contributing to its aggressiveness. Neutrophils are essential infiltrating immune cells in the PDAC microenvironment. Recent studies have identified several cellular mechanisms by which neutrophils are recruited to tumor lesion and promote tumorigenesis. This review summarizes the current understanding of the interplay between neutrophils, tumor cells, and other components in the PDAC tumor microenvironment. The prognosis and therapeutic implications of neutrophils in PDAC are also discussed.
Characterization of the Skeletal Muscle Secretome Reveals a Role for Extracellular Vesicles and IL1α/IL1β in Restricting Fibro/Adipogenic Progenitor Adipogenesis
Authors: Vumbaca Simone , Giuliani Giulio , Fiorentini Valeria , Tortolici Flavia , Cerquone Perpetuini Andrea , Riccio Federica , Sennato Simona , Gargioli Cesare , Fuoco Claudia , Castagnoli Luisa , Cesareni Gianni
Published: August 2021

Repeated mechanical stress causes injuries in the adult skeletal muscle that need to be repaired. Although muscle regeneration is a highly efficient process, it fails in some pathological conditions, compromising tissue functionality. This may be caused by aberrant cell–cell communication, resulting in the deposition of fibrotic and adipose infiltrates. Here, we investigate in vivo changes in the profile of skeletal muscle secretome during the regeneration process to suggest new targetable regulatory circuits whose failure may lead to tissue degeneration in pathological conditions. We describe the kinetic variation of expression levels of 76 secreted proteins during the regeneration process. In addition, we profile the gene expression of immune cells, endothelial cells, satellite cells, and fibro-adipogenic progenitors. This analysis allowed us to annotate each cell-type with the cytokines and receptors they have the potential to synthetize, thus making it possible to draw a cell–cell interaction map. We next selected 12 cytokines whose receptors are expressed in FAPs and tested their ability to modulate FAP adipogenesis and proliferation. We observed that IL1α and IL1β potently inhibit FAP adipogenesis, while EGF and BTC notably promote FAP proliferation. In addition, we characterized the cross-talk mediated by extracellular vesicles (EVs). We first monitored the modulation of muscle EV cargo during tissue regeneration. Using a single-vesicle flow cytometry approach, we observed that EVs differentially affect the uptake of RNA and proteins into their lumen. We also investigated the EV capability to interact with SCs and FAPs and to modulate their proliferation and differentiation. We conclude that both cytokines and EVs secreted during muscle regeneration have the potential to modulate adipogenic differentiation of FAPs. The results of our approach provide a system-wide picture of mechanisms that control cell fate during the regeneration process in the muscle niche.
Hypomethylating Agents (HMAs) as Salvage Therapy in Relapsed or Refractory AML: An Italian Multicentric Retrospective Study
Authors: Lessi Federica , Laurino Marica , Papayannidis Cristina , Vitagliano Orsola , Grimaldi Francesco , Lazzarotto Davide , Gottardi Michele , Crisà Elena , Riva Marta , Reda Gianluigi , Ermani Mario , Semenzato Gianpietro , Trentin Livio , Ferrara Felicetto
Published: August 2021

Data on the use of azacytidine and decitabine as salvage therapy for acute myeloid leukemia are limited. We retrospectively reviewed clinical records of 100 patients treated with hypomethylating agents (HMA) as salvage therapy in nine Italian institutions. A total of 24% of patients obtained a response to HMA (CR, PR, or CRi), while 26% showed a stable disease (SD); 50% of patients experienced progressive disease. Median OS was 6.5 months. OS in patients with de novo AML was 6.1 months, while OS in patients with secondary AML (sAML) was 12.3 months (p = 0.037). Median OS after HMA in patients with SD as best response to HMA was similar to median OS in patients with response to HMA (10.6 months vs. 13 months). On multivariate analysis, OS difference between patients who obtained a response versus patients who did not was significant (p = 0.0037). OS difference in sAML was significantly better than in de novo AML (p < 0.00001). HMA showed a remarkable efficacy in terms of response rate and OS in a subgroup of patients (sAMLs), historically characterized by a poor outcome. Therefore, 5Azacitidine and decitabine may represent a good clinical option in a selected patient population with relapsed or refractory AML, unsuitable for allo-HSCT.
Hepatic and Extrahepatic Insulin Clearance in Mice with Double Deletion of Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide Receptors
Authors: Morettini Micaela , Piersanti Agnese , Burattini Laura , Pacini Giovanni , Göbl Christian , Ahrén Bo , Tura Andrea
Published: August 2021

The aim of this study was to investigate whether incretins, at physiological levels, affect hepatic and/or extrahepatic insulin clearance. Hepatic and extrahepatic insulin clearance was studied in 31 double incretin receptor knockout (DIRKO) and 45 wild-type (WT) mice, which underwent an Intravenous Glucose Tolerance Test (IVGTT). A novel methodology based on mathematical modeling was designed to provide two sets of values (FEL-P1, CLP-P1; FEL-P2, CLP-P2) accounting for hepatic and extrahepatic clearance in the IVGTT first and second phases, respectively, plus the respective total clearances, CLT-P1 and CLT-P2. A statistically significant difference between DIRKO and WT was found in CLT-P1 (0.61 [0.48–0.82] vs. 0.51 [0.46–0.65] (median [interquartile range]); p = 0.02), which was reflected in the peripheral component, CLP-P1 (0.18 [0.13–0.27] vs. 0.15 [0.11–0.22]; p = 0.04), but not in the hepatic component, FEL-P1 (29.7 [26.7–34.9] vs. 28.9 [25.7–32.0]; p = 0.18). No difference was detected between DIRKO and WT in CLT-P2 (1.38 [1.13–1.75] vs. 1.69 [1.48–1.87]; p = 0.10), neither in CLP-P2 (0.72 [0.64–0.81] vs. 0.79 [0.69–0.87]; p = 0.27) nor in FEL-P2 (37.8 [35.1–43.1] vs. 39.8 [35.8–44.2]; p = 0.46). In conclusion, our findings suggest that the higher insulin clearance observed in DIRKO compared with WT during the IVGTT first phase may be due to its extrahepatic component.
Hydralazine and Enzalutamide: Synergistic Partners against Prostate Cancer
Authors: Lopes Nair , Pacheco Mariana Brütt , Soares-Fernandes Diana , Correia Margareta P. , Camilo Vânia , Henrique Rui , Jerónimo Carmen
Published: August 2021

Advanced prostate cancers frequently develop resistance to androgen-deprivation therapy with serious implications for patient survival. Considering their importance in this type of neoplasia, epigenetic modifications have drawn attention as alternative treatment strategies. The aim of this study was to assess the antitumoral effects of the combination of hydralazine, a DNA methylation inhibitor, with enzalutamide, an antagonist of the androgen receptor, in prostate cancer cell lines. Several biological parameters, such as cell viability, proliferation, DNA damage, and apoptosis, as well as clonogenic and invasive potential, were evaluated. The individual treatments with hydralazine and enzalutamide exerted growth-inhibitory effects in prostate cancer cells and their combined treatment displayed synergistic effects. The combination of these two drugs was very effective in decreasing malignant features of prostate cancer and may become an alternative therapeutic option for prostate cancer patient management.
Antibody Conjugates for Sarcoma Therapy: How Far along Are We?
Authors: Polito Letizia , Calafato Giulia , Bortolotti Massimo , Chiarelli Olivari Cecilia , Maiello Stefania , Bolognesi Andrea
Published: August 2021

Sarcomas are one of the most difficult type of cancer to manage and treat because of their extremely heterogeneous molecular and morphological features. Despite the progress made over the years in the establishment of standard protocols for high and low grading/staging sarcoma patients, mostly with chemotherapy and/or radiotherapy, 50% of treated patients experience relapse episodes. Because of this, in the last 20 years, new therapeutic approaches for sarcoma treatment have been evaluated in preclinical and clinical studies. Among them, antibody-based therapies have been the most studied. Immunoconjugates consist of a carrier portion, frequently represented by an antibody, linked to a toxic moiety, i.e., a drug, toxin, or radionuclide. While the efficacy of immunoconjugates is well demonstrated in the therapy of hematological tumors and more recently also of epithelial ones, their potential as therapeutic agents against sarcomas is still not completely explored. In this paper, we summarize the results obtained with immunoconjugates targeting sarcoma surface antigens, considering both preclinical and clinical studies. To date, the encouraging results obtained in preclinical studies allowed nine immunoconjugates to enter clinical trials, demonstrating the validity of immunotherapy as a promising pharmacological tool also for sarcoma therapy.
HMP-S7 Is a Novel Anti-Leukemic Peptide Discovered from Human Milk
Authors: Chiangjong Wararat , Panachan Jirawan , Vanichapol Thitinee , Pongsakul Nutkridta , Pongphitcha Pongpak , Siriboonpiputtana Teerapong , Lerksuthirat Tassanee , Nuntnarumit Pracha , Supapannachart Sarayut , Srisomsap Chantragan , Svasti Jisnuson , Hongeng Suradej , Chutipongtanate Somchai
Published: August 2021

Chemotherapy in childhood leukemia is associated with late morbidity in leukemic survivors, while certain patient subsets are relatively resistant to standard chemotherapy. It is therefore important to identify new agents with sensitivity and selectivity towards leukemic cells, while having less systemic toxicity. Peptide-based therapeutics has gained a great deal of attention during the last few years. Here, we used an integrative workflow combining mass spectrometric peptide library construction, in silico anticancer peptide screening, and in vitro leukemic cell studies to discover a novel anti-leukemic peptide having 3+ charges and an alpha helical structure, namely HMP-S7, from human breast milk. HMP-S7 showed cytotoxic activity against four distinct leukemic cell lines in a dose-dependent manner but had no effect on solid malignancies or representative normal cells. HMP-S7 induced leukemic cell death by penetrating the plasma membrane to enter the cytoplasm and cause the leakage of lactate dehydrogenase, thus acting in a membranolytic manner. Importantly, HMP-S7 exhibited anti-leukemic effects against patient-derived leukemic cells ex vivo. In conclusion, HMP-S7 is a selective anti-leukemic peptide with promise, which requires further validation in preclinical and clinical studies.
Differentiation Behaviour of Adipose-Derived Stromal Cells (ASCs) Seeded on Polyurethane-Fibrin Scaffolds In Vitro and In Vivo
Authors: Radeloff Katrin , Weiss Dorothee , Hagen Rudolf , Kleinsasser Norbert , Radeloff Andreas
Published: August 2021

Adipose-derived stromal cells (ASCs) are a promising cell source for tissue engineering and regenerative medicine approaches for cartilage replacement. For chondrogenic differentiation, human (h)ASCs were seeded on three-dimensional polyurethane (PU) fibrin composites and induced with a chondrogenic differentiation medium containing TGF-ß3, BMP-6, and IGF-1 in various combinations. In addition, in vitro predifferentiated cell-seeded constructs were implanted into auricular cartilage defects of New Zealand White Rabbits for 4 and 12 weeks. Histological, immunohistochemical, and RT-PCR analyses were performed on the constructs maintained in vitro to determine extracellular matrix (ECM) deposition and expression of specific cartilage markers. Chondrogenic differentiated constructs showed a uniform distribution of cells and ECM proteins. RT-PCR showed increased gene expression of collagen II, collagen X, and aggrecan and nearly stable expression of SOX-9 and collagen I. Rabbit (r)ASC-seeded PU-fibrin composites implanted in ear cartilage defects of New Zealand White Rabbits showed deposition of ECM with structures resembling cartilage lacunae by Alcian blue staining. However, extracellular calcium deposition became detectable over the course of 12 weeks. RT-PCR showed evidence of endochondral ossification during the time course with the expression of specific marker genes (collagen X and RUNX-2). In conclusion, hASCs show chondrogenic differentiation capacity in vitro with the expression of specific marker genes and deposition of cartilage-specific ECM proteins. After implantation of predifferentiated rASC-seeded PU-fibrin scaffolds into a cartilage defect, the constructs undergo the route of endochondral ossification.
Targeted Toxins for the Treatment of Prostate Cancer
Authors: Wolf Philipp
Published: August 2021

Prostate cancer is the second most common cancer and the fifth leading cause of cancer deaths worldwide. Despite improvements in diagnosis and treatment, new treatment options are urgently needed for advanced stages of the disease. Targeted toxins are chemical conjugates or fully recombinant proteins consisting of a binding domain directed against a target antigen on the surface of cancer cells and a toxin domain, which is transported into the cell for the induction of apoptosis. In the last decades, targeted toxins against prostate cancer have been developed. Several challenges, however, became apparent that prevented their direct clinical use. They comprise immunogenicity, low target antigen binding, endosomal entrapment, and lysosomal/proteasomal degradation of the targeted toxins. Moreover, their efficacy is impaired by prostate tumors, which are marked by a dense microenvironment, low target antigen expression, and apoptosis resistance. In this review, current findings in the development of targeted toxins against prostate cancer in view of effective targeting, reduction of immunogenicity, improvement of intracellular trafficking, and overcoming apoptosis resistance are discussed. There are promising approaches that should lead to the clinical use of targeted toxins as therapeutic alternatives for advanced prostate cancer in the future.
Development of a Point-of-Care System Based on White Light Reflectance Spectroscopy: Application in CRP Determination
Authors: Tsounidi Dimitra , Koukouvinos Georgios , Christianidis Vasilios , Legaki Evangelia , Giogli Vasiliki , Panagiotopoulou Konstantina , Taka Styliani , Ekaterinidi Zoi , Kakabakos Sotirios , Raptis Ioannis , Petrou Panagiota
Published: August 2021

The development of methods and miniaturized systems for fast and reliable quantitative determinations at the Point-of-Care is a top challenge and priority in diagnostics. In this work, a compact bench-top system, based on White Light Reflectance Spectroscopy, is introduced and evaluated in an application with high clinical interest, namely the determination of C-Reactive protein (CRP) in human blood samples. The system encompassed all the necessary electronic and optical components for the performance of the assay, while the dedicated software provided the sequence and duration of assay steps, the reagents flow rate, the real-time monitoring of sensor response, and data processing to deliver in short time and accurately the CPR concentration in the sample. The CRP assay included two steps, the first comprising the binding of sample CRP onto the chip immobilized capture antibody and the second the reaction of the surface immunosorbed CRP molecules with the detection antibody. The assay duration was 12 min and the dynamic range was from 0.05 to 200 μg/mL, covering both normal values and acute inflammation incidents. There was an excellent agreement between CRP values determined in human plasma samples using the developed device with those received for the same samples by a standard diagnostic laboratory method.
Serum and Tissue Level of TLR9 in EBV-Associated Oropharyngeal Cancer
Authors: Stępień Ewa , Strycharz-Dudziak Małgorzata , Malm Maria , Drop Bartłomiej , Polz-Dacewicz Małgorzata
Published: August 2021

The Epstein–Barr virus (EBV) is associated with the development of various epithelial malignancies including cancer in the head and neck region. Several studies have shown that Toll-like receptors (TLRs) are required for an innate immune response to infection with human DNA viruses, e.g., EBV. During viral infections, TLR response may influence the transformation to malignancy. The aim of the study was to assess TLR9 serum and tissue level in EBV(+) and EBV(−) oropharyngeal cancer patients. The study involved 78 patients: 42 EBV(+) and 36 EBV(−). EBV DNA was detected in fresh frozen tumor tissue. TLR9 level was measured in homogenate of tumor tissue and in serum. Moreover, in serum samples IL-10, VEGF, TGFβ, TNFα and antibodies against EBV were detected using ELISA test. TLR9 level was significantly lower in EBV(+) patients, both in tissue and serum, while EBVCA, EBNA and VEGF level was statistically higher in EBV(+) patients. An increase in EBVCA and EBNA antibodies titer was correlated with a TLR9 level decrease. TLR9 level was higher in poorly-differentiated tumors (G3), in tumor of larger dimensions (T3-T4) and with lymph nodes involvement (N3-N4) but without statistical significance. High levels of anti-EA antibodies in the majority of EBV(+) patients may point to the reactivation of EBV infection.
Breast Cancer Aptamers: Current Sensing Targets, Available Aptamers, and Their Evaluation for Clinical Use in Diagnostics
Authors: Varty Kathleen , O’Brien Connor , Ignaszak Anna
Published: August 2021

Breast cancer is the most commonly occurring cancer in women worldwide, and the rate of diagnosis continues to increase. Early detection and targeted treatment towards histological type is crucial to improving outcomes, but current screening methods leave some patients at risk of late diagnosis. The risk of late diagnosis and progressed disease is of particular concern for young women as current screening methods are not recommended early in life. Aptamers are oligonucleotides that can bind with high specificity to target molecules such as proteins, peptides, and other small molecules. They are relatively cheap to produce and are invariable from batch to batch, making them ideal for use in large-scale clinical or screening programs. The use of aptamers for breast cancer screening, diagnosis, and therapeutics is promising, but comparison of these aptamers and their corresponding biomarkers for use in breast cancer is significantly lacking. Here, we compare the currently available aptamers for breast cancer biomarkers and their respective biomarkers, as well as highlight the electrochemical sensors that are in development.
In Uveal Melanoma, Angiopoietin-2 but Not Angiopoietin-1 Is Increased in High-Risk Tumors, Providing a Potential Druggable Target
Authors: ten Voorde Anna M.W. , Wierenga Annemijn P.A. , Nell Rogier J. , van der Velden Pieter A. , Luyten Gregorius P.M. , Verdijk Robert M. , Jager Martine J.
Published: August 2021

Uveal melanoma (UM) metastasize haematogeneously, and tumor blood vessel density is an important prognostic factor. We hypothesized that proangiogenic factors such as angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), two targetable cytokines, might play a role in tumor development and metastatic behavior. mRNA levels of ANG-1 and ANG-2 were determined in 64 tumors using an Illumina HT-12 v4 mRNA chip and compared to clinical, pathologic, and genetic tumor parameters. Tissue expression was also determined by immunohistochemistry (IHC). Samples of aqueous humor were collected from 83 UM-containing enucleated eyes and protein levels that were determined in a multiplex proximity extension assay. High tissue gene expression of ANG-2, but not of ANG-1, was associated with high tumor thickness, high largest basal diameter, involvement of the ciliary body, and with UM-related death (ANG-2 mRNA p < 0.001; ANG-2 aqueous protein p < 0.001). The presence of the ANG-2 protein in aqueous humor correlated with its mRNA expression in the tumor (r = 0.309, p = 0.03). IHC showed that ANG-2 was expressed in macrophages as well as tumor cells. The presence of ANG-2 in the tumor and in aqueous humor, especially in high-risk tumors, make ANG-2 a potential targetable cytokine in uveal melanoma.
A Novel Orthotopic Liver Cancer Model for Creating a Human-like Tumor Microenvironment
Authors: Qiu Rong , Murata Soichiro , Cheng Chao , Mori Akihiro , Nie Yunzhong , Mikami Satoshi , Hasegawa Shunsuke , Tadokoro Tomomi , Okamoto Satoshi , Taniguchi Hideki
Published: August 2021

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. This study aims to develop a new method to generate an HCC mouse model with a human tumor, and imitates the tumor microenvironment (TME) of clinical patients. Here, we have generated functional, three-dimensional sheet-like human HCC organoids in vitro, using luciferase-expressing Huh7 cells, human iPSC-derived endothelial cells (iPSC-EC), and human iPSC-derived mesenchymal cells (iPSC-MC). The HCC organoid, capped by ultra-purified alginate gel, was implanted into the disrupted liver using an ultrasonic homogenizer in the immune-deficient mouse, which improved the survival and engraftment rate. We successfully introduced different types of controllable TME into the model and studied the roles of TME in HCC tumor growth. The results showed the role of the iPSC-EC and iPSC-MC combination, especially the iPSC-MC, in promoting HCC growth. We also demonstrated that liver fibrosis could promote HCC tumor growth. However, it is not affected by non-alcoholic fatty liver disease. Furthermore, the implantation of HCC organoids to humanized mice demonstrated that the immune response is important in slowing down tumor growth at an early stage. In conclusion, we have created an HCC model that is useful for studying HCC development and developing new treatment options in the future.
The Renin–Angiotensin System in the Tumor Microenvironment of Glioblastoma
Authors: O’Rawe Michael , Kilmister Ethan J. , Mantamadiotis Theo , Kaye Andrew H. , Tan Swee T. , Wickremesekera Agadha C.
Published: August 2021

Glioblastoma (GB) is an aggressive primary brain tumor. Despite intensive research over the past 50 years, little advance has been made to improve the poor outcome, with an overall median survival of 14.6 months following standard treatment. Local recurrence is inevitable due to the quiescent cancer stem cells (CSCs) in GB that co-express stemness-associated markers and components of the renin–angiotensin system (RAS). The dynamic and heterogeneous tumor microenvironment (TME) plays a fundamental role in tumor development, progression, invasiveness, and therapy resistance. There is increasing evidence showing the critical role of the RAS in the TME influencing CSCs via its upstream and downstream pathways. Drugs that alter the hallmarks of cancer by modulating the RAS present a potential new therapeutic alternative or adjunct to conventional treatment of GB. Cerebral and GB organoids may offer a cost-effective method for evaluating the efficacy of RAS-modulating drugs on GB. We review the nexus between the GB TME, CSC niche, and the RAS, and propose re-purposed RAS-modulating drugs as a potential therapeutic alternative or adjunct to current standard therapy for GB.
Stem Cell Theory of Cancer: Origin of Tumor Heterogeneity and Plasticity
Authors: Tu Shi-Ming , Zhang Miao , Wood Christopher G. , Pisters Louis L.
Published: August 2021

In many respects, heterogeneity is one of the most striking revelations and common manifestations of a stem cell origin of cancer. We observe heterogeneity in myriad mixed tumors including testicular, lung, and breast cancers. We recognize heterogeneity in diverse tumor subtypes in prostate and kidney cancers. From this perspective, we illustrate that one of the main stem-ness characteristics, i.e., the ability to differentiate into diverse and multiple lineages, is central to tumor heterogeneity. We postulate that cancer subtypes can be meaningless and useless without a proper theory about cancer’s stem cell versus genetic origin and nature. We propose a unified theory of cancer in which the same genetic abnormalities, epigenetic defects, and microenvironmental aberrations cause different effects and lead to different outcomes in a progenitor stem cell versus a mature progeny cell. We need to recognize that an all-encompassing genetic theory of cancer may be incomplete and obsolete. A stem cell theory of cancer provides greater universality, interconnectivity, and utility. Although genetic defects are pivotal, cellular context is paramount. When it concerns tumor heterogeneity, perhaps we need to revisit the conventional wisdom of precision medicine and revise our current practice of targeted therapy in cancer care.
Comparison of Quantification of Target-Specific Accumulation of [18F]F-siPSMA-14 in the HET-CAM Model and in Mice Using PET/MRI
Authors: Löffler Jessica , Hamp Carmen , Scheidhauer Ellen , Di Carlo Daniel , Solbach Christoph , Abaei Alireza , Hao Li , Glatting Gerhard , Beer Ambros J. , Rasche Volker , Winter Gordon
Published: August 2021

Assessment of biodistribution and specific tumor accumulation is essential for the development of new radiopharmaceuticals and requires animal experiments. The HET-CAM (hens-egg test—chorioallantoic membrane) model can be used in combination with the non-invasive imaging modalities PET and MRI for pre-selection during radiopharmaceutical development to reduce the number of animal experiments required. Critical to the acceptance of this model is the demonstration of the quantifiability and reproducibility of these data compared to the standard animal model. Tumor accumulation and biodistribution of the PSMA-specific radiotracer [18F]F-siPSMA-14 was analyzed in the chick embryo and in an immunodeficient mouse model. Evaluation was based on MRI and PET data in both models. γ-counter measurements and histopathological analyses complemented these data. PSMA-specific accumulation of [18F]F-siPSMA-14 was successfully demonstrated in the HET-CAM model, similar to the results obtained by mouse model studies. The combination of MR and PET imaging allowed precise quantification of peptide accumulation, initial assessment of biodistribution, and accurate determination of tumor volume. Thus, the use of the HET-CAM model is suitable for the pre-selection of new radiopharmaceuticals and potentially reduces animal testing in line with the 3Rs principles of animal welfare.
NH3-Selective Catalytic Reduction of NOx to N2 over Ceria Supported WOx Based Catalysts: Influence of Tungsten Content
Authors: El Arrouji Imane , Chen Cuirong , Toyir Jamil , Larabi Cherif , Szeto Kai C. , de Mallmann Aimery , Taoufik Mostafa , Oulmekki Abdallah
Published: August 2021

A series of HPW/CeO2 catalysts generated from 12-tungstophosphoric acid, H3PW12O40 (HPW), supported on ceria and presenting different tungsten loadings (2, 4.5, 9, 16, and 40 wt% W) were prepared and characterized by N2 physisorption, XRD, IR, Raman, and UV-Vis. The different characterization techniques suggested that low loading of tungsten resulted in mainly isolated sites, while high tungsten loading produced polymeric or tungsten clusters. Those materials exhibited high activity in NH3-SCR of NOx into N2. Moreover, the series of experiments indicated that low loading in tungsten (2% HPW/CeO2) displayed the highest activity with a remarkable N2 selectivity (99%) at medium-high temperature (300–515 °C), owing to the high amount of monomeric tungstate coverage on the catalyst surface.
IL7-Fc Enhances the Efficacy of Adoptive T Cell Therapy under Lymphopenic Conditions in a Murine Melanoma Model
Authors: Yu Eun M. , Cho Eunjung , Singh Rohit , Kim Seon-Hee , Han Chungyong , Han Seongeun , Lee Don G. , Kim Young H. , Kwon Byoung S. , Choi Beom K.
Published: August 2021

Adoptive cell therapy (ACT) using tumor-reactive T cells is a promising form of immunotherapy to specifically target cancer. However, the survival and functional maintenance of adoptively transferred T cells remains a challenge, ultimately limiting their efficacy. Here, we evaluated the use of recombinant IL7-Fc in ACT. In a lymphopenic murine melanoma model, IL7-Fc treatment led to the enhanced inhibition of tumor growth with an increased number of adoptively transferred CD8+ T cells in tumor tissue and tumor-draining lymph nodes. Additionally, IL7-Fc further enhanced anti-tumor responses that were induced by recombinant human IL2 in the same mouse model. In contrast, in an immunocompetent murine melanoma model, IL7-Fc dampened the anti-tumor immunity. Further, IL7-Fc decreased the proliferation of adoptively transferred and immune-activated tumor-reactive CD8+ T cells in immunocompetent mice by inducing the massive expansion of endogenous T cells, thereby limiting the space for adoptively transferred T cells. Our data suggest that IL7-Fc is principally beneficial for enhancing the efficacy of tumor-reactive T-cells in lymphopenic conditions for the ACT.
Inborn Errors in the LRR Domain of Nod2 and Their Potential Consequences on the Function of the Receptor
Authors: Alipoor Shamila D. , Mirsaeidi Mehdi
Published: August 2021

The innate immune system plays a critical role in the early detection of pathogens, primarily by relying on pattern-recognition receptor (PRR) signaling molecules. Nucleotide-binding oligomerization domain 2 (NOD2) is a cytoplasmic receptor that recognizes invading molecules and danger signals inside the cells. Recent studies highlight the importance of NOD2′s function in maintaining the homeostasis of human body microbiota and innate immune responses, including induction of proinflammatory cytokines, regulation of autophagy, modulation of endoplasmic reticulum (ER) stress, etc. In addition, there is extensive cross-talk between NOD2 and the Toll-like receptors that are so important in the induction and tuning of adaptive immunity. Polymorphisms of NOD2′s encoding gene are associated with several pathological conditions, highlighting NOD2′s functional importance. In this study, we summarize NOD2′s role in cellular signaling pathways and take a look at the possible consequences of common NOD2 polymorphisms on the structure and function of this receptor.
Synthesis and Pressure-Assisted Sintering of CaCu3Ti4O12 Dielectrics
Authors: Petrášek Jan , Ctibor Pavel , Sedláček Josef , Lukáč Frantisek
Published: August 2021

In this paper, we examined the dielectric properties of CaCu3Ti4O12 (CCTO) ceramics fabricated by various routes and discussed the most important conditions affecting their dielectric behavior. We prepared feedstock powder using a molten salt route and compared it with a commercial powder. Both powders were sintered using SPS. For some samples, annealing was applied after sintering. Other samples were obtained by high-pressure forming and conventional sintering, using both powders. Phase composition, porosity and microhardness were evaluated in comparison with the literature. The results showed that a sintering temperature just below or equal to 1000 °C should be set for the SPS process. However, the best dielectric characteristics were obtained in samples prepared by high-pressure forming and conventional sintering, which showed a relative permittivity of 22,000 and a loss tangent of 0.13 at 1 MHz.
Identification of Weather Influences on Flight Punctuality Using Machine Learning Approach
Authors: Kaewunruen Sakdirat , Sresakoolchai Jessada , Xiang Yue
Published: August 2021

One of the top long-term threats to airport resilience is extreme climate-induced conditions, which negatively affect the airport and flight operations. Recent examples, including hurricanes, storms, extreme temperatures (cold/hot), and heavy rains, have damaged airport facilities, interrupted air traffic, and caused higher operational costs. With the development of civil aviation and the pre-COVID-19 surging demand for flights, the passengers’ complaints of flight delay increased, according to FoxBusiness. This study aims to discover the weather factors affecting flight punctuality and determine a high-dimensional scale of consequences stemming from weather conditions and flight operational aspects. Machine learning has been developed in correlation with the weather and statistical data for operations at Birmingham Airport as a case study. The cross-correlated datasets have been kindly provided by Birmingham Airport and the Meteorological Office. The scope and emphasis of this study is placed on the machine learning application to practical flight punctuality prediction in relation to climate conditions. Random forest, artificial neural network, support vector machine, and linear regression are used to develop predictive models. Grid-search and cross-validation are used to select the best parameters. The model can grasp the trend of flight punctuality rates well where R2 is 0.80 and the root mean square error (RMSE) is less than 15% using the model developed by random forest technique. The insights derived from this study will help Airport Authorities and the Insurance industry in predicting the scale of consequences in order to promptly enact and enable adaptative airport climate resilience plans, including air traffic rescheduling, financial resilience to climate variances and extreme weather conditions.
Effect of Vacuum Annealing on Microstructure and Hot-Salt Corrosion Behavior of CoNiCrAlY/YSZ/LaMgAl11O19 Double-Ceramic Coating
Authors: Xue Guanming , Sun Yingchao , Xiang Ling , Wang Zhiguo , Hu Suying , Xie Zhiwen
Published: August 2021

This study investigated the potential effect of vacuum annealing on the microstructure and hot salt corrosion behavior of CoNiCrAlY/YSZ/LaMgAl11O19 (LMA) double-ceramic coatings. A hot-salt corrosion test revealed that sprayed coatings exhibited an unsatisfactory anti-corrosion performance, and the LMA layer underwent severe fracture and corrosion degradation. Vacuum annealing induced a prominent recrystallization of the amorphous phase in LMA layer, triggering severe volume shrinkage and microcrack initiation. The recrystallization and volume shrinkage of the LMA layer were aggravated by an increase in the annealing temperature. The annealed coating with a higher fraction of the LaMA phase showed superior resistance to hot-salt corrosion. However, the salt mixture diffused simultaneously along the microcracks and eventually eroded into the YSZ layer. These results confirmed that vacuum annealing significantly enhanced the hot-salt corrosion resistance of the LMA layer. However, it deteriorated the barrier effect of the salt mixture through microcrack formation.
High-Speed Laser Cladding on Thin-Sheet-Substrates—Influence of Process Parameters on Clad Geometry and Dilution
Authors: Sommer Niklas , Stredak Florian , Böhm Stefan
Published: August 2021

Laser-based Directed Energy Deposition (DED-LB) represents a production method of growing importance for cladding and additive manufacturing through the use of metal powders. Yet, most studies utilize substrate materials with thicknesses of multiple millimeters, for which laser cladding of thin-sheet substrates with thicknesses less than 1 mm have only been scarcely studied in the literature. Most studies cover the use of pulsed laser sources, since sheet distortion due to excess energy input is a key problem in laser cladding of thin-sheet substrates. Hence, the authors of the present investigation seek to expand the boundaries of cladding thin-sheet substrates through the use of a high-speed laser cladding approach which utilizes a continuous-wave, ytterbium fiber laser and traverse speeds of 90 mms−1 to clad stainless steel sheets with a thickness of 0.8mm. Furthermore, fundamental process–property relationships for the target values of clad width, clad height, and dilution depth are studied and thoroughly discussed. Additionally, process maps for the target values are established based on manifold experiments, and the significance of process parameters on target values is studied using analysis of variance. The results demonstrate that clad widths as high as 1413 μm and dilution depths as low as 144 μm can be obtained by high-speed laser cladding of thin-sheet substrates. Thus, pathways toward thin-sheet substrates with enhanced performance are opened.
Effects of Fractional Derivatives with Different Orders in SIS Epidemic Models
Authors: Balzotti Caterina , D’Ovidio Mirko , Lai Anna Chiara , Loreti Paola
Published: August 2021

We study epidemic Susceptible–Infected–Susceptible (SIS) models in the fractional setting. The novelty is to consider models in which the susceptible and infected populations evolve according to different fractional orders. We study a model based on the Caputo derivative, for which we establish existence results of the solutions. Furthermore, we investigate a model based on the Caputo–Fabrizio operator, for which we provide existence of solutions and a study of the equilibria. Both models can be framed in the context of SIS models with time-varying total population, in which the competition between birth and death rates is macroscopically described by the fractional orders of the derivatives. Numerical simulations for both models and a direct numerical comparison are also provided.
Are Papers Asking Questions Cited More Frequently in Computer Science?
Authors: Fiala Dalibor , Král Pavel , Dostal Martin
Published: August 2021

In this article, we test the hypothesis that computer science papers asking questions (i.e., those with a question mark at the end of their title) are cited more frequently than those that do not have this property. To this end, we analyze a data set of almost two million records on computer science papers indexed in the Web of Science database and focus our investigation on the mean number of citations per paper of its specific subsets. The main finding is that the average number of citations per paper of the so-called “asking papers” is greater by almost 20% than that of other papers, and that this difference is statistically significant.
Bee Guilds’ Responses to Urbanization in Neotropics: A Case Study
Authors: Guimarães Alves Sônia , Gaglianone Maria Cristina
Published: August 2021

The consequent deforestation of urban sprawl is one of the causes of the decline of wild bee communities. In this context, urban green areas (UGA) may play an important role and constitute refuge areas for bees. This study analyzed the influence of UGA conditions and their surroundings in bee guilds’ responses in a medium-sized Brazilian city (Campos dos Goytacazes, RJ). The bees were sampled for 12 months (2017–2018) in 12 UGAs, and bee abundance and species richness were evaluated in guilds considering: nesting behavior, nesting site, and trophic specialization. We used as explanatory variables conditions of UGAs—the number of trees (NT), diameter at breast height (DBH), flower cover (FC), plant richness (PR), percentage of paving (PV)—and of their surroundings—paving (SPV) and the number of buildings (NB). Results showed 80% of eusocial bees, 82% nest in cavities, and 99% were generalists. FC, DBH, and NB mainly explained the responses of different guilds in study areas from all explanatory variables. Thus, this study confirms different responses associated with bee guilds’ attributes. In order to conserve bee diversity, city planning must include more green areas with large flower covers and avoid long corridors of high buildings that can impact bee dispersion.