bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetics of Familial Non-Medullary Thyroid Carcinoma (FNMTC)
Authors: Diquigiovanni Chiara , Bonora Elena
Published: May 2021

Non-medullary thyroid carcinoma (NMTC) is the most frequent endocrine tumor and originates from the follicular epithelial cells of the thyroid. Familial NMTC (FNMTC) has been defined in pedigrees where two or more first-degree relatives of the patient present the disease in absence of other predisposing environmental factors. Compared to sporadic cases, FNMTCs are often multifocal, recurring more frequently and showing an early age at onset with a worse outcome. FNMTC cases show a high degree of genetic heterogeneity, thus impairing the identification of the underlying molecular causes. Over the last two decades, many efforts in identifying the susceptibility genes in large pedigrees were carried out using linkage-based approaches and genome-wide association studies, leading to the identification of susceptibility loci and variants associated with NMTC risk. The introduction of next-generation sequencing technologies has greatly contributed to the elucidation of FNMTC predisposition, leading to the identification of novel candidate variants, shortening the time and cost of gene tests. In this review we report the most significant genes identified for the FNMTC predisposition. Integrating these new molecular findings in the clinical data of patients is fundamental for an early detection and the development of tailored therapies, in order to optimize patient management.
Research on Anal Squamous Cell Carcinoma: Systemic Therapy Strategies for Anal Cancer
Authors: Carr Ryan M. , Jin Zhaohui , Hubbard Joleen
Published: May 2021

Anal squamous cell carcinoma (ASCC) is a rare malignancy, with most cases associated with human papilloma virus and an increased incidence in immunocompromised patients. Progress in management of ASCC has been limited not only due to its rarity, but also the associated lack of research funding and social stigma. Historically, standard of care for invasive ASCC has been highly morbid surgical resection, requiring a permanent colostomy. Surgery was associated with disease recurrence in approximately half of the patients. However, the use of chemotherapy (5-fluorouracil and mitomycin C) concomitantly with radiation in the 1970s resulted in disease regression, curing a subset of patients and sparing them from morbid surgery. Validation of the use of systemic therapy in prospective trials was not achieved until approximately 20 years later. In this review, advancements and shortcomings in the use of systemic therapy in the management of ASCC will be discussed. Not only will standard-of-care systemic therapies for locoregional and metastatic disease be reviewed, but the evolving role of novel treatment strategies such as immune checkpoint inhibitors, HPV-based vaccines, and molecularly targeted therapies will also be covered. While advances in ASCC treatment have remained largely incremental, with increased biological insight, an increasing number of promising systemic treatment modalities are being explored.
Targeting CDK9 for Anti-Cancer Therapeutics
Authors: Mandal Ranadip , Becker Sven , Strebhardt Klaus
Published: May 2021

Cyclin Dependent Kinase 9 (CDK9) is one of the most important transcription regulatory members of the CDK family. In conjunction with its main cyclin partner—Cyclin T1, it forms the Positive Transcription Elongation Factor b (P-TEFb) whose primary function in eukaryotic cells is to mediate the positive transcription elongation of nascent mRNA strands, by phosphorylating the S2 residues of the YSPTSPS tandem repeats at the C-terminus domain (CTD) of RNA Polymerase II (RNAP II). To aid in this process, P-TEFb also simultaneously phosphorylates and inactivates a number of negative transcription regulators like 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) Sensitivity-Inducing Factor (DSIF) and Negative Elongation Factor (NELF). Significantly enhanced activity of CDK9 is observed in multiple cancer types, which is universally associated with significantly shortened Overall Survival (OS) of the patients. In these cancer types, CDK9 regulates a plethora of cellular functions including proliferation, survival, cell cycle regulation, DNA damage repair and metastasis. Due to the extremely critical role of CDK9 in cancer cells, inhibiting its functions has been the subject of intense research, resulting the development of multiple, increasingly specific small-molecule inhibitors, some of which are presently in clinical trials. The search for newer generation CDK9 inhibitors with higher specificity and lower potential toxicities and suitable combination therapies continues. In fact, the Phase I clinical trials of the latest, highly specific CDK9 inhibitor BAY1251152, against different solid tumors have shown good anti-tumor and on-target activities and pharmacokinetics, combined with manageable safety profile while the phase I and II clinical trials of another inhibitor AT-7519 have been undertaken or are undergoing. To enhance the effectiveness and target diversity and reduce potential drug-resistance, the future of CDK9 inhibition would likely involve combining CDK9 inhibitors with inhibitors like those against BRD4, SEC, MYC, MCL-1 and HSP90.
Phosphodiesterase 4D Depletion/Inhibition Exerts Anti-Oncogenic Properties in Hepatocellular Carcinoma
Authors: Ragusa Federica , Panera Nadia , Cardarelli Silvia , Scarsella Marco , Bianchi Marzia , Biagioni Stefano , Giorgi Mauro , Alisi Anna , Massimi Mara
Published: May 2021

Isoform D of type 4 phosphodiesterase (PDE4D) has recently been associated with several human cancer types with the exception of human hepatocellular carcinoma (HCC). Here we explored the role of PDE4D in HCC. We found that PDE4D gene/protein were over-expressed in different samples of human HCCs compared to normal livers. Accordingly, HCC cells showed higher PDE4D activity than non-tumorigenic cells, accompanied by over-expression of the PDE4D isoform. Silencing of PDE4D gene and pharmacological inhibition of protein activity by the specific inhibitor Gebr-7b reduced cell proliferation and increased apoptosis in HCC cells, with a decreased fraction of cells in S phase and a differential modulation of key regulators of cell cycle and apoptosis. PDE4D silencing/inhibition also affected the gene expression of several cancer-related genes, such as the pro-oncogenic insulin growth factor (IGF2), which is down-regulated. Finally, gene expression data, available in the CancerLivER data base, confirm that PDE4D over-expression in human HCCs correlated with an increased expression of IGF2, suggesting a new possible molecular network that requires further investigations. In conclusion, intracellular depletion/inhibition of PDE4D prevents the growth of HCC cells, displaying anti-oncogenic effects. PDE4D may thus represent a new biomarker for diagnosis and a potential adjuvant target for HCC therapy.
Prevention Strategies for Esophageal Cancer—An Expert Review
Authors: Marabotto Elisa , Pellegatta Gaia , Sheijani Afscin Djahandideh , Ziola Sebastiano , Zentilin Patrizia , De Marzo Maria Giulia , Giannini Edoardo Giovanni , Ghisa Matteo , Barberio Brigida , Scarpa Marco , Angriman Imerio , Fassan Matteo , Savarino Vincenzo , Savarino Edoardo
Published: May 2021

In the last 30 years, we have witnessed a rapid increase in the incidence and prevalence of esophageal cancer in many countries around the word. However, despite advancements in diagnostic technologies, the early detection of this cancer is rare, and its prognosis remains poor, with only about 20% of these patients surviving for 5 years. The two major forms are the esophageal squamous cell carcinoma (ESCC), which is particularly frequent in the so-called Asian belt, and the esophageal adenocarcinoma (EAC), which prevails in Western populations. This review provides a summary of the epidemiological features and risk factors associated with these tumors. Moreover, a major focus is posed on reporting and highlighting the various preventing strategies proposed by the most important international scientific societies, particularly in high-risk populations, with the final aim of detecting these lesions as early as possible and therefore favoring their definite cure. Indeed, we have conducted analysis with attention to the current primary, secondary and tertiary prevention guidelines in both ESCC and EAC, attempting to emphasize unresolved research and clinical problems related to these topics in order to improve our diagnostic strategies and management.
Natural Killer–Dendritic Cell Interactions in Liver Cancer: Implications for Immunotherapy
Authors: Cazzetta Valentina , Franzese Sara , Carenza Claudia , Della Bella Silvia , Mikulak Joanna , Mavilio Domenico
Published: May 2021

Natural killer (NK) and dendritic cells (DCs) are innate immune cells that play a crucial role in anti-tumor immunity. NK cells kill tumor cells through direct cytotoxicity and cytokine secretion. DCs are needed for the activation of adaptive immune responses against tumor cells. Both NK cells and DCs are subdivided in several subsets endowed with specialized effector functions. Crosstalk between NK cells and DCs leads to the reciprocal control of their activation and polarization of immune responses. In this review, we describe the role of NK cells and DCs in liver cancer, focusing on the mechanisms involved in their reciprocal control and activation. In this context, intrahepatic NK cells and DCs present unique immunological features, due to the constant exposure to non-self-circulating antigens. These interactions might play a fundamental role in the pathology of primary liver cancer, namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Additionally, the implications of these immune changes are relevant from the perspective of improving the cancer immunotherapy strategies in HCC and ICC patients.
Meta-Analysis of Survival and Development of a Prognostic Nomogram for Malignant Pleural Mesothelioma Treated with Systemic Chemotherapy
Authors: Kotecha Rupesh , Tonse Raees , Rubens Muni , Appel Haley , Albrecht Federico , Kaywin Paul , Alley Evan W. , Tom Martin C. , Mehta Minesh P.
Published: May 2021

(1) Purpose: Malignant pleural mesothelioma (MPM) is a rare cancer with an aggressive course. For patients who are medically inoperable or surgically unresectable, multi-agent systemic chemotherapy remains an accepted standard-of-care. The purpose of this meta-analysis is to provide baseline summative survival estimates as well as evaluate the influence of prognostic variables to provide comparative estimates for future trial designs. (2) Methods: Using PRISMA guidelines, a systematic review and meta-analysis was performed of MPM studies published from 2002–2019 obtained from the Medline database evaluating systemic therapy combinations for locally advanced or metastatic disease. Weighted random effects models were used to calculate survival estimates. The influence of proportions of known prognostic factors on overall survival (OS) were evaluated in the creation of a prognostic nomogram to estimate survival. The performance of this model was evaluated against data generated from one positive phase II study and two positive randomized trials. (3) Results: Twenty-four phase II studies and five phase III trials met the eligibility criteria; 2534 patients were treated on the included clinical studies. Ten trials included a platinum-pemetrexed-based treatment regimen, resulting in a pooled estimate of progression-free survival (PFS) of 6.7 months (95% CI: 6.2–7.2 months) and OS of 14.2 months (95% CI: 12.7–15.9 months). Fifteen experimental chemotherapy regimens have been tested in phase II or III studies, with a pooled median survival estimate of 13.5 months (95% CI: 12.6–14.6 months). Meta-regression analysis was used to estimate OS with platinum-pemetrexed using a variety of features, such as pathology (biphasic vs. epithelioid), disease extent (locally advanced vs. metastatic), ECOG performance status, age, and gender. The nomogram-predicted estimates and corresponding 95% CIs performed well when applied to recent randomized studies. (4) Conclusions: Given the rarity of MPM and the aggressive nature of the disease, innovative clinical trial designs with significantly greater randomization to experimental regimens can be performed using robust survival estimates from prior studies. This study provides baseline comparative values and also allows for accounting for differing proportions of known prognostic variables.
Immune Checkpoint Inhibitors in Prostate Cancer
Authors: Venkatachalam Shobi , McFarland Taylor R. , Agarwal Neeraj , Swami Umang
Published: May 2021

Metastatic prostate cancer is a lethal disease with limited treatment options. Immune checkpoint inhibitors have dramatically changed the treatment landscape of multiple cancer types but have met with limited success in prostate cancer. In this review, we discuss the preclinical studies providing the rationale for the use of immunotherapy in prostate cancer and underlying biological barriers inhibiting their activity. We discuss the predictors of response to immunotherapy in prostate cancer. We summarize studies evaluating immune checkpoint inhibitors either as a single agent or in combination with other checkpoint inhibitors or with other agents such as inhibitors of androgen axis, poly ADP-ribose polymerase (PARP), radium-223, radiotherapy, cryotherapy, tumor vaccines, chemotherapy, tyrosine kinase inhibitors, and granulocyte-macrophage colony-stimulating factor. We thereafter review future directions including the combination of immune checkpoint blockade with inhibitors of adenosine axis, bispecific T cell engagers, PSMA directed therapies, adoptive T-cell therapy, and multiple other miscellaneous agents.
Phenotypic Heterogeneity of Triple-Negative Breast Cancer Mediated by Epithelial–Mesenchymal Plasticity
Authors: Kvokačková Barbora , Remšík Ján , Jolly Mohit Kumar , Souček Karel
Published: May 2021

Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma known for its unusually aggressive behavior and poor clinical outcome. Besides the lack of molecular targets for therapy and profound intratumoral heterogeneity, the relatively quick overt metastatic spread remains a major obstacle in effective clinical management. The metastatic colonization of distant sites by primary tumor cells is affected by the microenvironment, epigenetic state of particular subclones, and numerous other factors. One of the most prominent processes contributing to the intratumoral heterogeneity is an epithelial–mesenchymal transition (EMT), an evolutionarily conserved developmental program frequently hijacked by tumor cells, strengthening their motile and invasive features. In response to various intrinsic and extrinsic stimuli, malignant cells can revert the EMT state through the mesenchymal–epithelial transition (MET), a process that is believed to be critical for the establishment of macrometastasis at secondary sites. Notably, cancer cells rarely undergo complete EMT and rather exist in a continuum of E/M intermediate states, preserving high levels of plasticity, as demonstrated in primary tumors and, ultimately, in circulating tumor cells, representing a simplified element of the metastatic cascade. In this review, we focus on cellular drivers underlying EMT/MET phenotypic plasticity and its detrimental consequences in the context of TNBC cancer.
Heterogeneous Circulating Tumor Cells in Sarcoma: Implication for Clinical Practice
Authors: Agnoletto Chiara , Caruso Chiara , Garofalo Cecilia
Published: May 2021

Bone and soft tissue sarcomas (STSs) represent a group of heterogeneous rare malignant tumors of mesenchymal origin, with a poor prognosis. Due to their low incidence, only a few studies have been reported addressing circulating tumor cells (CTCs) in sarcoma, despite the well-documented relevance for applications of liquid biopsy in precision medicine. In the present review, the most recent data relative to the detection and isolation of viable and intact CTCs in these tumors will be reviewed, and the heterogeneity in CTCs will be discussed. The relevance of epithelial–mesenchymal plasticity and stemness in defining the phenotypic and functional properties of these rare cells in sarcoma will be highlighted. Of note, the existence of dynamic epithelial–mesenchymal transition (EMT)-related processes in sarcoma tumors has only recently been related to their clinical aggressiveness. Also, the presence of epithelial cell adhesion molecule (EpCAM)-positive CTC in sarcoma has been weakly correlated with poor outcome and disease progression, thus proving the existence of both epithelial and mesenchymal CTC in sarcoma. The advancement in technologies for capturing and enumerating all diverse CTCs phenotype originating from these mesenchymal tumors are presented, and results provide a promising basis for clinical application of CTC detection in sarcoma.
Clinical Assay for the Early Detection of Colorectal Cancer Using Mass Spectrometric Wheat Germ Agglutinin Multiple Reaction Monitoring
Authors: Tsai I-Jung , Su Emily Chia-Yu , Tsai I-Lin , Lin Ching-Yu
Published: May 2021

Colorectal cancer (CRC) is currently the third leading cause of cancer-related mortality in the world. U.S. Food and Drug Administration-approved circulating tumor markers, including carcinoembryonic antigen, carbohydrate antigen (CA) 19-9 and CA125 were used as prognostic biomarkers of CRC that attributed to low sensitivity in diagnosis of CRC. Therefore, our purpose is to develop a novel strategy for novel clinical biomarkers for early CRC diagnosis. We used mass spectrometry (MS) methods such as nanoLC-MS/MS, targeted LC-MS/MS, and stable isotope-labeled multiple reaction monitoring (MRM) MS coupled to test machine learning algorithms and logistic regression to analyze plasma samples from patients with early-stage CRC, late-stage CRC, and healthy controls (HCs). On the basis of our methods, 356 peptides were identified, 6 differential expressed peptides were verified, and finally three peptides corresponding wheat germ agglutinin (WGA)-captured proteins were semi-quantitated in 286 plasma samples (80 HCs and 206 CRCs). The novel peptide biomarkers combination of PF454–62, ITIH4429–438, and APOE198–207 achieved sensitivity 84.5%, specificity 97.5% and an AUC of 0.96 in CRC diagnosis. In conclusion, our study demonstrated that WGA-captured plasma PF454–62, ITIH4429–438, and APOE198–207 levels in combination may serve as highly effective early diagnostic biomarkers for patients with CRC.
CD26/DPP-4: Type 2 Diabetes Drug Target with Potential Influence on Cancer Biology
Authors: Kawakita Emi , Koya Daisuke , Kanasaki Keizo
Published: May 2021

DPP-4/CD26, a membrane-bound glycoprotein, is ubiquitously expressed and has diverse biological functions. Because of its enzymatic action, such as the degradation of incretin hormones, DPP-4/CD26 is recognized as the significant therapeutic target for type 2 diabetes (T2DM); DPP-4 inhibitors have been used as an anti-diabetic agent for a decade. The safety profile of DPP-4 inhibitors for a cardiovascular event in T2DM patients has been widely analyzed; however, a clear association between DPP-4 inhibitors and tumor biology is not yet established. Previous preclinical studies reported that DPP-4 suppression would impact tumor progression processes. With regard to this finding, we have shown that the DPP-4 inhibitor induces breast cancer metastasis and chemoresistance via an increase in its substrate C-X-C motif chemokine 12, and the consequent induction of epithelial-mesenchymal transition in the tumor. DPP-4/CD26 plays diverse pivotal roles beyond blood glucose control; thus, DPP-4 inhibitors can potentially impact cancer-bearing T2DM patients either favorably or unfavorably. In this review, we primarily focus on the possible undesirable effect of DPP-4 inhibition on tumor biology. Clinicians should note that the safety of DPP-4 inhibitors for diabetic patients with an existing cancer is an unresolved issue, and further mechanistic analysis is essential in this field.
Methane to Methanol through Heterogeneous Catalysis and Plasma Catalysis
Authors: Li Shangkun , Ahmed Rizwan , Yi Yanhui , Bogaerts Annemie
Published: May 2021

Direct oxidation of methane to methanol (DOMTM) is attractive for the increasing industrial demand of feedstock. In this review, the latest advances in heterogeneous catalysis and plasma catalysis for DOMTM are summarized, with the aim to pinpoint the differences between both, and to provide some insights into their reaction mechanisms, as well as the implications for future development of highly selective catalysts for DOMTM.
Recovery/Reuse of Heterogeneous Supported Spent Catalysts
Authors: Miceli Mariachiara , Frontera Patrizia , Macario Anastasia , Malara Angela
Published: May 2021

The rapid separation and efficient recycling of catalysts after a catalytic reaction are considered important requirements along with the high catalytic performances. In this view, although heterogeneous catalysis is generally less efficient if compared to the homogeneous type, it is generally preferred since it benefits from the easy recovery of the catalyst. Recycling of heterogeneous catalysts using traditional methods of separation such as extraction, filtration, vacuum distillation, or centrifugation is tedious and time-consuming. They are uneconomic processes and, hence, they cannot be carried out in the industrial scale. For these limitations, today, the research is devoted to the development of new methods that allow a good separation and recycling of catalysts. The separation process should follow a procedure economically and technically feasible with a minimal loss of the solid catalyst. The aim of this work is to provide an overview about the current trends in the methods of separation/recycling used in the heterogeneous catalysis.
The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after CNS Injury and Disease
Authors: Roy Debasish , Tedeschi Andrea
Published: May 2021

Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease.
The Role of Protein Arginine Methylation as Post-Translational Modification on Actin Cytoskeletal Components in Neuronal Structure and Function
Authors: Qualmann Britta , Kessels Michael M.
Published: May 2021

The brain encompasses a complex network of neurons with exceptionally elaborated morphologies of their axonal (signal-sending) and dendritic (signal-receiving) parts. De novo actin filament formation is one of the major driving and steering forces for the development and plasticity of the neuronal arbor. Actin filament assembly and dynamics thus require tight temporal and spatial control. Such control is particularly effective at the level of regulating actin nucleation-promoting factors, as these are key components for filament formation. Arginine methylation represents an important post-translational regulatory mechanism that had previously been mainly associated with controlling nuclear processes. We will review and discuss emerging evidence from inhibitor studies and loss-of-function models for protein arginine methyltransferases (PRMTs), both in cells and whole organisms, that unveil that protein arginine methylation mediated by PRMTs represents an important regulatory mechanism in neuritic arbor formation, as well as in dendritic spine induction, maturation and plasticity. Recent results furthermore demonstrated that arginine methylation regulates actin cytosolic cytoskeletal components not only as indirect targets through additional signaling cascades, but can also directly control an actin nucleation-promoting factor shaping neuronal cells—a key process for the formation of neuronal networks in vertebrate brains.
AGMO Inhibitor Reduces 3T3-L1 Adipogenesis
Authors: Fischer Caroline , Wilken-Schmitz Annett , Hernandez-Olmos Victor , Proschak Ewgenij , Stark Holger , Fleming Ingrid , Weigert Andreas , Thurn Manuela , Hofmann Martine , Werner Ernst R. , Geisslinger Gerd , Niederberger Ellen , Watschinger Katrin , Tegeder Irmgard
Published: May 2021

Alkylglycerol monooxygenase (AGMO) is a tetrahydrobiopterin (BH4)-dependent enzyme with major expression in the liver and white adipose tissue that cleaves alkyl ether glycerolipids. The present study describes the disclosure and biological characterization of a candidate compound (Cp6), which inhibits AGMO with an IC50 of 30–100 µM and 5–20-fold preference of AGMO relative to other BH4-dependent enzymes, i.e., phenylalanine-hydroxylase and nitric oxide synthase. The viability and metabolic activity of mouse 3T3-L1 fibroblasts, HepG2 human hepatocytes and mouse RAW264.7 macrophages were not affected up to 10-fold of the IC50. However, Cp6 reversibly inhibited the differentiation of 3T3-L1 cells towards adipocytes, in which AGMO expression was upregulated upon differentiation. Cp6 reduced the accumulation of lipid droplets in adipocytes upon differentiation and in HepG2 cells exposed to free fatty acids. Cp6 also inhibited IL-4-driven differentiation of RAW264.7 macrophages towards M2-like macrophages, which serve as adipocyte progenitors in adipose tissue. Collectively, the data suggest that pharmacologic AGMO inhibition may affect lipid storage.
Profiling Non-Coding RNA Changes Associated with 16 Different Engineered Nanomaterials in a Mouse Airway Exposure Model
Authors: Ndika Joseph , Karisola Piia , Kinaret Pia , Ilves Marit , Alenius Harri
Published: May 2021

Perturbations in cellular molecular events and their associated biological processes provide opportunities for hazard assessment based on toxicogenomic profiling. Long non-coding RNAs (lncRNAs) are transcribed from DNA but are typically not translated into full-length proteins. Via epigenetic regulation, they play important roles in organismal response to environmental stress. The effects of nanoparticles on this important part of the epigenome are understudied. In this study, we investigated changes in lncRNA associated with hazardous inhalatory exposure of mice to 16 engineered nanomaterials (ENM)–4 ENM (copper oxide, multi-walled carbon nanotubes, spherical titanium dioxide, and rod-like titanium dioxide particles) with 4 different surface chemistries (pristine, COOH, NH2, and PEG). Mice were exposed to 10 µg of ENM by oropharyngeal aspiration for 4 consecutive days, followed by cytological analyses and transcriptomic characterization of whole lung tissues. The number of significantly altered non-coding RNA transcripts, suggestive of their degrees of toxicity, was different for each ENM type. Particle surface chemistry and shape also had varying effects on lncRNA expression. NH2 and PEG caused the strongest and weakest responses, respectively. Via correlational analyses to mRNA expression from the same samples, we could deduce that significantly altered lncRNAs are potential regulators of genes involved in mitotic cell division and DNA damage response. This study sheds more light on epigenetic mechanisms of ENM toxicity and also emphasizes the importance of the lncRNA superfamily as toxicogenomic markers of adverse ENM exposure.
The Impact of Chlorambucil and Valproic Acid on Cell Viability, Apoptosis and Expression of p21, HDM2, BCL2 and MCL1 Genes in Chronic Lymphocytic Leukemia
Authors: Lipska Katarzyna , Filip Agata , Gumieniczek Anna
Published: May 2021

Malignant cells in chronic lymphocytic leukemia (CLL) show resistance to apoptosis, as well as to chemotherapy, which are related to deletions or mutations of TP53, high expression of MCL1 and BCL2 genes and other abnormalities. Thus, the main goal of the present study was to assess the impact of chlorambucil (CLB) combined with valproic acid (VPA), a known antiepileptic drug and histone deacetylation inhibitor, on apoptosis of the cells isolated from 17 patients with CLL. After incubation with CLB (17.5 µM) and VPA (0.5 mM), percentage of apoptosis, as well as expression of two TP53 target genes (p21 and HDM2) and two genes from Bcl-2 family (BCL2 and MCL1), were tested. As a result, an increased percentage of apoptosis was observed for CLL cells treated with CLB and VPA, and with CLB alone. Under the treatment with the drug combination, the expression of p21 gene was visibly higher than under the treatment with CLB alone. At the same time, the cultures under CLB treatment showed visibly higher expression of BCL2 than the cultures with VPA alone. Thus, the present study strongly suggests further investigations on the CLB and VPA combination in CLL treatment.
Electronic Surveillance and Security Applications of Magnetic Microwires
Authors: Zhukova Valentina , Corte-Leon Paula , Blanco Juan Maria , Ipatov Mihail , Gonzalez Julian , Zhukov Arcady
Published: May 2021

Applications in security and electronic surveillance require a combination of excellent magnetic softness with good mechanical and anticorrosive properties and low dimensionality. We overviewed the feasibility of using glass-coated microwires for electronic article surveillance and security applications, as well as different routes of tuning the magnetic properties of individual microwires or microwire arrays, making them quite attractive for electronic article surveillance and security applications. We provide the routes for tuning the hysteresis loops’ nonlinearity by the magnetostatic interaction between the microwires in the arrays of different types of amorphous microwires. The presence of neighboring microwire (either Fe- or Co-based) significantly affects the hysteresis loop of the whole microwires array. In a microwires array containing magnetically bistable microwires, we observed splitting of the initially rectangular hysteresis loop with a number of Barkhausen jumps correlated with the number of magnetically bistable microwires. Essentially, nonlinear and irregular hysteresis loops have been observed in mixed arrays containing Fe- and Co-rich microwires. The obtained nonlinearity in hysteresis loops allowed to increase the harmonics and tune their magnetic field dependencies. On the other hand, several routes allowing to tune the switching field by either postprocessing or modifying the magnetoelastic anisotropy have been reviewed. Nonlinear hysteresis loops have been also observed upon devitrification of amorphous microwires. Semihard magnetic microwires have been obtained by annealing of Fe–Pt–Si microwires. The observed unique combination of magnetic properties together with thin dimensions and excellent mechanical and anticorrosive properties provide excellent perspectives for the use of glass-coated microwires for security and electronic surveillance applications.
The Appropriateness of Glycerin Enema in Pediatric Patients Visiting the Emergency Department
Authors: Kim Min-Jung , Choi Yoo-Jin , Lee Jin-Hee , Kwon Hyuksool , Suh Dongbum
Published: May 2021

Objectives: We determined whether glycerin enemas were appropriately prescribed in pediatric fecal impaction patients using the Leech score and identified factors that influenced the prescription of glycerin enemas in the pediatric emergency department (PED). Methods: We included patients who received a glycerin enema at the PED of a tertiary teaching hospital. We divided the study subjects into two groups on the basis of their Leech scores: an appropriate enema group (Leech score ≥ 8), and an inappropriate enema group (Leech score < 8). Logistic regression was performed to determine the factors associated with glycerin enema administration. Results: The data of 998 patients, including 446 patients in the inappropriate enema group (Leech score 5.2 ± 1.7) and 552 patients in the appropriate enema group (Leech score 10.1 ± 1.7), were analyzed. A discharge diagnosis of fecal impaction was observed significantly more frequently (57.1%) in the appropriate enema group, and nonspecific abdominal pain (8.3%) and acute gastroenteritis (40.8%) were diagnosed significantly more frequently in the inappropriate enema group (p < 0.05). Constipation (2.8%) and irritability (3.0%) were slightly more common in the appropriate enema group than in the inappropriate enema group (p < 0.05). According to multiple logistic regression, subjects aged 2–8 years (2–4 years, OR 4.24; 4–8 years, OR 2.83), with vomiting (OR 1.72), with irritability (OR 4.52), and with a prolonged last defecation day (OR 1.2) were most likely to receive appropriate enema administration (p < 0.05). Conclusion: The results showed that in those aged 2–8 years, with vomiting and irritability, and with a prolonged last defecation day, an enema was generally administered appropriately.
Network Pharmacology and Molecular Docking Combined to Analyze the Molecular and Pharmacological Mechanism of Pinellia ternata in the Treatment of Hypertension
Authors: Zhai Zhaowei , Tao Xinru , Alami Mohammad Murtaza , Shu Shaohua , Wang Xuekui
Published: May 2021

Hypertension is a cardiovascular disease that causes great harm to health and life, affecting the function of important organs and accompanied by a variety of secondary diseases, which need to be treated with drugs for a long time. P. ternata alone or combination with western medicine has played an important role in traditional Chinese medicine. Although P. ternata is used clinically to treat hypertension, its functional molecular mechanism and pharmacological mechanism have not been elucidated. Therefore, in this study, the potentially effective components, and targets of P. ternata in the treatment of hypertension were screened by the method of network pharmacology, and the mechanism of P. ternata in the treatment of hypertension was analyzed by constructing a component-target relationship network, PPI interaction network, targets’ function analysis, and molecular docking. In the study, 12 potentially effective components and 88 targets were screened, and 3 potential protein modules were found and analyzed after constructing a PPI network using targets. In addition, 10 targets were selected as core targets of the PPI network. After that, the targets were analyzed by Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, the molecular docking method is used to study the interaction between the targets and the active components. The above evidence shows that the mechanism of P. ternata in the treatment of hypertension is complicated, as it acts in many ways, mainly by affecting nerve signal transmission, cell proliferation, and apoptosis, calcium channels, and so on. The binding between targets and active components mainly depends on Pi bonds and hydrogen bonds. Using the method of network pharmacology and molecular docking to analyze the mechanism of P. ternata in the treatment of hypertension will help to provide a better scientific basis for the combined use of traditional Chinese medicine and western medicine, and will better help to improve the quality of P. ternata and point out its direction.
Three-Phase State Estimation for Distribution-Grid Analytics
Authors: Nainar Karthikeyan , Iov Florin
Published: May 2021

Power-distribution grids consist of assets such as transformers, cables, and switches, of which the proper utilization is essential for the provision of a secure and reliable power supply to end customers. Distribution-system operators (DSOs) are responsible for the operation and maintenance of these assets. Due to the increased use of renewable sources such as wind and solar, grid assets are prone to operation conditions outside safe boundaries, such as overloading, large voltage unbalance, and a rise in voltage. At present, distribution grids are poorly monitored by DSOs, and the above-mentioned problems may thereby go unnoticed until the failure of a critical asset occurs. The deployment of smart meters in distribution grids has enabled measurements of grid variables such as power, current, and voltage. However, their measurements are used only for billing purposes, and not for monitoring and improving the operating condition of distribution grids. In this paper, a state-estimation algorithm is proposed that utilizes smart-meter data for offline analysis, and estimates the loading of grid assets and power losses. Single- and three-phase state-estimation algorithms are compared through simulation studies on a real-life low-voltage distribution grid using measured smart-meter data. The three-phase state-estimation algorithm based on the nonlinear weighted least-squares method was found to be more accurate in estimating cable loading and line power losses. The proposed method is useful for DSOs to analyze power flows in their distribution grids and take necessary actions such as grid upgrades or the rerouting of power flows.
Developing a Hybrid Optimization Algorithm for Optimal Allocation of Renewable DGs in Distribution Network
Authors: Awad Ayman , Abdel-Mawgoud Hussein , Kamel Salah , Ibrahim Abdalla A. , Jurado Francisco
Published: May 2021

Distributed generation (DG) is becoming a prominent key spot for research in recent years because it can be utilized in emergency/reserve plans for power systems and power quality improvement issues, besides its drastic impact on the environment as a greenhouse gas (GHG) reducer. For maximizing the benefits from such technology, it is crucial to identify the best size and location for DG that achieves the required goal of installing it. This paper presents an investigation of the optimized allocation of DG in different modes using a proposed hybrid technique, the tunicate swarm algorithm/sine-cosine algorithm (TSA/SCA). This investigation is performed on an IEEE-69 Radial Distribution System (RDS), where the impact of such allocation on the system is evaluated by NEPLAN software.
Tire/Road Rolling Resistance Modeling: Discussing the Surface Macrotexture Effect
Authors: Kane Malal , Riahi Ebrahim , Do Minh-Tan
Published: May 2021

This paper deals with the modeling of rolling resistance and the analysis of the effect of pavement texture. The Rolling Resistance Model (RRM) is a simplification of the no-slip rate of the Dynamic Friction Model (DFM) based on modeling tire/road contact and is intended to predict the tire/pavement friction at all slip rates. The experimental validation of this approach was performed using a machine simulating tires rolling on road surfaces. The tested pavement surfaces have a wide range of textures from smooth to macro-micro-rough, thus covering all the surfaces likely to be encountered on the roads. A comparison between the experimental rolling resistances and those predicted by the model shows a good correlation, with an R2 exceeding 0.8. A good correlation between the MPD (mean profile depth) of the surfaces and the rolling resistance is also shown. It is also noticed that a random distribution and pointed shape of the summits may also be an inconvenience concerning rolling resistance, thus leading to the conclusion that beyond the macrotexture, the positivity of the texture should also be taken into account. A possible simplification of the model by neglecting the damping part in the constitutive model of the rubber is also noted.
Improving the Quality of Friction Stir Welds in Aluminium Alloys
Authors: Ehiasarian Arutiun , Purandare Yashodhan , Sugumaran Arunprabhu , Hovsepian Papken , Hatto Peter , De Backer Jeroen
Published: May 2021

The Stationary Shoulder Friction Stir Welding (SS-FSW) technique benefits from reduced heat input, improved mechanical properties and surface finish of the weld, avoiding the need for post weld processing. Coatings on the tool probe and the shoulder for welding of aggressive Aluminium alloys have rarely been successful. Such coatings must be well adherent and inert. In this study, coated tools were used for SS-FSW of AA6082-T6 alloy. Performance of a nanoscale multilayer TiAlN/VN coating deposited by High Power Impulse Magnetron Sputtering (HIPIMS) technology was compared with amorphous Diamond Like Carbon (a-C:H) by Plasma Assisted Chemical Vapour Deposition (PACVD), AlTiN deposited by arc evaporation and TiBCN along with TiB2 produced by Chemical Vapour Deposition (CVD) methods. The TiAlN/VN coating was found to have low affinity to aluminium, acceptable coefficient of friction and provided excellent weld quality by inhibiting intermixing between the tool and workpiece materials resulting in a significant reduction in tool wear.
Simulation to Microtopography Formation of CBN Active Abrasives on a Honing Wheel Surface
Authors: Gao Yang , Ren Xiaoqiang , Han Jiang , Wang Fuwei , Liang Yuan , Liu Lin
Published: May 2021

The microtopography of a honing wheel surface composed of active abrasive grains is the key factor affecting the honing characteristics, and control of it is a sufficient condition to realize high-efficiency precision honing. Based on the magnetron sputtering method and phase field method, a theoretical model of cubic boron nitride (CBN) coating formation on a honing wheel surface is established. The physical vapor deposition (PVD) discrete phase field equation is solved by the finite difference method. A MATLAB program is compiled to simulate the formation process and micromorphology of the CBN coating on the honing wheel surface. A Taguchi method is designed to study the relationships of the sputtering time, substrate temperature, gas flow rate, and reaction space with the number of active abrasives and the length, width, height, and size of the abrasives. The simulation results are highly similar to the scanning electron microscopy (SEM) examinations, which shows that the model can accurately and effectively simulate the abrasive morphology of the wheel surface under different process conditions and provide a theoretical basis for the prediction and control of the CBN wear morphology on a honing wheel surface.
Particle Deposition to Silica Surfaces Functionalized with Cationic Polyelectrolytes
Authors: Kosior Dominik , Maroni Plinio , Borkovec Michal
Published: May 2021

Positively charged water-solid interfaces are prepared by adsorption of a cationic polyelectrolyte poly(diallyldimethylammonium chloride) (PDADMAC) from aqueous solutions to planar silica substrates. These substrates are characterized by atomic force microscopy (AFM), optical reflectivity, and streaming current measurements. By tuning the amount of adsorbed polyelectrolyte, the surface charge of the substrate can be systematically varied. These substrates are further used to study deposition of sulfate latex nanoparticles, which is also accomplished by optical reflectivity. This deposition process is found to be consistent with an extension of the random sequential adsorption (RSA) model in a semi-quantitative fashion. Such deposition studies were further used to ascertain that the substrates obtained by in situ and ex situ functionalization behave in an identical fashion.
The Design of WASPEC: A Fully Personalised Moodle System Using Semantic Web Technologies
Authors: Apoki Ufuoma Chima
Published: May 2021

Personalisation in e-learning systems has become a major research area in recent times, as online learning is gradually evolving to become a major part of formal education. While there exist several learning management systems with a wide range of capabilities, one thing that remains inefficient is a standard framework for sharing knowledge across different platforms and, also, the inability of such systems to provide personalisation to the learning process by default. A large number of systems that have been implemented to provide personalisation apply few parameters and are course-specific; thus, flexibility, reusability, and scalability are greatly reduced. In this paper, we propose a framework for personalised learning, Weighted Agent System for Personalised E-learning Curriculum (WASPEC) implemented with Moodle, which is independent of the learning management system and provides the possibility of incorporating multiple personalisation parameters. This is accomplished with the combined use of web services, semantic web ontologies, and pedagogical agents, providing dynamic personalisation in the background of the e-learning system. This also provides added advantages of the possibility of sharing knowledge with other systems and reusability.
All-Fiber Frequency Shifter Based on an Acousto-Optic Tunable Filter Cascaded with a Tapered Fiber-Coupled Microcavity
Authors: Han Xiaofang , Hu Yue , Li Jiwei , Chang Pengfa , Gao Feng , Dong Xiao , Bo Fang , Zhang Wending , Zhang Guoquan , Xu Jingjun
Published: May 2021

An all-fiber acousto-optic frequency shifter (AOFS) based on an acousto-optic tunable filter (AOTF) cascaded with a packaged tapered fiber (TF)-coupled microsphere was proposed and demonstrated in both theory and experiment. The configuration has the advantages of easy alignment, robustness, compact size, and low cost, which will improve its further application, such as in the optical heterodyne detection technique (OHDT).
On Novel Copper Based Alloys Development via Friction Stir Alloying
Authors: Moiduddin Khaja , Siddiquee Arshad Noor , Abidi Mustufa Haider , Mian Syed Hammad , Mohammed Muneer Khan
Published: May 2021

Friction stir alloying (FSA) of commercially pure Cu with Ni, Zn, and Mg is implemented in the current study. Mechanical and microstructural aspects of the successfully fabricated alloy structure have been examined. Energy dispersive X-ray spectroscopy revealed a uniform distribution of alloying elements and coalescence at the atomic level. The compositional and grain size heterogeneity is managed in the stir zone, allowing for microstructural control with FSA. Thus, the present study is essential for the development of novel materials whose fabrication requires temperature well below the melting point of base metals. The alloying process is found to be accompanied by ultra-refined grains, with the smallest grain size being ~0.44 μm. The fabricated alloy managed to retain the FCC phase, and no brittle intermetallic compounds formed, according to X-ray diffraction. The fabricated alloy exhibits maximum and average microhardness enhancements of 18.4% and 6%, respectively. Tensile properties have also been investigated and correlated with microstructural morphology. A shift toward grain bimodality has also been documented, which is a highly sought-after property nowadays, especially to overcome the strength-ductility trade-off.