bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Deregulated Pathways, Key Regulators, and Novel miRNA-mRNA Interactions in HPV-Mediated Transformation
Authors: Babion Iris , Miok Viktorian , Jaspers Annelieke , Huseinovic Angelina , Steenbergen Renske D. M. , van Wieringen Wessel N. , Wilting Saskia M.
Published: March 2020

Next to a persistent infection with high-risk human papillomavirus (HPV), molecular changes are required for the development of cervical cancer. To identify which molecular alterations drive carcinogenesis, we performed a comprehensive and longitudinal molecular characterization of HPV-transformed keratinocyte cell lines. Comparative genomic hybridization, mRNA, and miRNA expression analysis of four HPV-containing keratinocyte cell lines at eight different time points was performed. Data was analyzed using unsupervised hierarchical clustering, integrated longitudinal expression analysis, and pathway enrichment analysis. Biological relevance of identified key regulatory genes was evaluated in vitro and dual-luciferase assays were used to confirm predicted miRNA-mRNA interactions. We show that the acquisition of anchorage independence of HPV-containing keratinocyte cell lines is particularly associated with copy number alterations. Approximately one third of differentially expressed mRNAs and miRNAs was directly attributable to copy number alterations. Focal adhesion, TGF-beta signaling, and mTOR signaling pathways were enriched among these genes. PITX2 was identified as key regulator of TGF-beta signaling and inhibited cell growth in vitro, most likely by inducing cell cycle arrest and apoptosis. Predicted miRNA-mRNA interactions miR-221-3p_BRWD3, miR-221-3p_FOS, and miR-138-5p_PLXNB2 were confirmed in vitro. Integrated longitudinal analysis of our HPV-induced carcinogenesis model pinpointed relevant interconnected molecular changes and crucial signaling pathways in HPV-mediated transformation.
A Comparative Analysis of Tumors and Plasma Circulating Tumor DNA in 145 Advanced Cancer Patients Annotated by 3 Core Cellular Processes
Authors: Larson Kristian , Kannaiyan Radhamani , Pandey Ritu , Chen Yuliang , Babiker Hani M. , Mahadevan Daruka
Published: March 2020

Matched-targeted and immune checkpoint therapies have improved survival in cancer patients, but tumor heterogeneity contributes to drug resistance. Our study categorized gene mutations from next generation sequencing (NGS) into three core processes. This annotation helps decipher complex biologic interactions to guide therapy. We collected NGS data on 145 patients who have failed standard therapy (2016 to 2018). One hundred and forty two patients had data for tissue (Caris MI/X) and plasma cell-free circulating tumor DNA (Guardant360) platforms. The mutated genes were categorized into cell fate (CF), cell survival (CS), and genome maintenance (GM). Comparative analysis was performed for concordance and discordance, unclassified mutations, trends in TP53 alterations, and PD-L1 expression. Two gene mutation maps were generated to compare each NGS platform. Mutated genes predominantly matched to CS with concordance between Guardant360 (64.4%) and Caris (51.5%). TP53 alterations comprised a significant proportion of the mutation pool in Caris and Guardant360, 14.7% and 13.1%, respectively. Twenty-six potentially actionable gene alterations were detected from matching ctDNA to Caris unclassified alterations. The CS core cellular process was the most prevalent in our study population. Clinical trials are warranted to investigate biomarkers for the three core cellular processes in advanced cancer patients to define the next best therapies.
STAT3 Mutation Is Associated with STAT3 Activation in CD30+ ALK− ALCL
Authors: Andersson Emma I. , Brück Oscar , Braun Till , Mannisto Susanna , Saikko Leena , Lagström Sonja , Ellonen Pekka , Leppä Sirpa , Herling Marco , Kovanen Panu E. , Mustjoki Satu
Published: March 2020

Peripheral T-cell lymphomas (PTCL) are a heterogeneous, and often aggressive group of non-Hodgkin lymphomas. Recent advances in the molecular and genetic characterization of PTCLs have helped to delineate differences and similarities between the various subtypes, and the JAK/STAT pathway has been found to play an important oncogenic role. Here, we aimed to characterize the JAK/STAT pathway in PTCL subtypes and investigate whether the activation of the pathway correlates with the frequency of STAT gene mutations. Patient samples from AITL (n = 30), ALCL (n = 21) and PTCL-NOS (n = 12) cases were sequenced for STAT3, STAT5B, JAK1, JAK3, and RHOA mutations using amplicon sequencing and stained immunohistochemically for pSTAT3, pMAPK, and pAKT. We discovered STAT3 mutations in 13% of AITL, 13% of ALK+ ALCL, 38% of ALK− ALCL and 17% of PTCL-NOS cases. However, no STAT5B mutations were found and JAK mutations were only present in ALK- ALCL (15%). Concurrent mutations were found in all subgroups except ALK+ ALCL where STAT3 mutations were always seen alone. High pY-STAT3 expression was observed especially in AITL and ALCL samples. When studying JAK-STAT pathway mutations, pY-STAT3 expression was highest in PTCLs harboring either JAK1 or STAT3 mutations and CD30+ phenotype representing primarily ALK− ALCLs. Further investigation is needed to elucidate the molecular mechanisms of JAK-STAT pathway activation in PTCL.
Current Understanding of RAD52 Functions: Fundamental and Therapeutic Insights
Authors: Gottifredi Vanesa , Wiesmüller Lisa
Published: March 2020

In this Special Issue, we would like to focus on the various functions of the RAD52 helicase-like protein and the current implications of such findings for cancer treatment. Over the last few years, various laboratories have discovered particular activities of mammalian RAD52—both in S and M phase—that are distinct from the auxiliary role of yeast RAD52 in homologous recombination. At DNA double-strand breaks, RAD52 was demonstrated to spur alternative pathways to compensate for the loss of homologous recombination functions. At collapsed replication forks, RAD52 activates break-induced replication. In the M phase, RAD52 promotes the finalization of DNA replication. Its compensatory role in the resolution of DNA double-strand breaks has put RAD52 in the focus of synthetic lethal strategies, which is particularly relevant for cancer treatment.
You Have Got a Fast CAR: Chimeric Antigen Receptor NK Cells in Cancer Therapy
Authors: Pfefferle Aline , Huntington Nicholas D.
Published: March 2020

The clinical success stories of chimeric antigen receptor (CAR)-T cell therapy against B-cell malignancies have contributed to immunotherapy being at the forefront of cancer therapy today. Their success has fueled interest in improving CAR constructs, identifying additional antigens to target, and clinically evaluating them across a wide range of malignancies. However, along with the exciting potential of CAR-T therapy comes the real possibility of serious side effects. While the FDA has approved commercialized CAR-T cell therapy, challenges associated with manufacturing, costs, and related toxicities have resulted in increased attention being paid to implementing CAR technology in innate cytotoxic natural killer (NK) cells. Here, we review the current landscape of the CAR-NK field, from successful clinical implementation to outstanding challenges which remain to be addressed to deliver the full potential of this therapy to more patients.
Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian Cancer
Authors: Kubelac Paul , Genestie Catherine , Auguste Aurelie , Mesnage Soizick , Le Formal Audrey , Pautier Patricia , Gouy Sebastien , Morice Philippe , Bentivegna Enrica , Maulard Amandine , Adam Julien , Achimas-Cadariu Patriciu , Leary Alexandra
Published: March 2020

Ovarian cancer (OC) is sensitive to upfront chemotherapy, which is likely attributable to defects in DNA damage repair (DDR). Unfortunately, patients relapse and the evolution of DDR competency are poorly described. We examined the expression of proposed effectors in homologous recombination (HR: RAD51, ATM, FANCD2), error-prone non-homologous end-joining (NHEJ: 53BP1), and base excision repair pathways (BER: PAR and PARP1) in a cohort of sequential OC samples obtained at diagnosis, after neoadjuvant chemotherapy (NACT), and/or at relapse from a total of 147 patients. Immunohistochemical (IHC) expression was quantified using the H-score (0–300), where H ≤ 10 defined negativity. Before NACT, a significant number of cases lacked the expression of some effectors: 60%, 60%, and 24% were PAR-, FANCD2-, or RAD51-negative, with a reassuringly similar proportion of negative biomarkers after NACT. In multivariate analysis, there was a poorer progression-free survival (PFS) and overall survival (OS) for cases with competent HR at diagnosis (PRE-NACT 53BP1−/RAD51+, hazard ratio (HR) 3.13, p = 0.009 and HR 2.78, p = 0.024) and after NACT (POST-NACT FANCD2+/RAD51+ HR 1.89, p = 0.05 and HR 2.38, p = 0.02; POST-NACT PARP-1+/RAD51+ HR 1.79, p = 0.038 and HR 2.04, p = 0.034), reflecting proficient DNA repair. Overall, HR-competent tumors appeared to have a dismal prognosis in comparison with tumors utilizing NHEJ, as assessed either at baseline or post-NACT. Accurate knowledge of the HR status during treatment is clinically important for the efficient timing of platinum-based and targeted therapies with poly(ADP-ribose) polymerase inhibitors (PARPi).
The Microrna-143/145 Cluster in Tumors: A Matter of Where and When
Authors: Poli Valeria , Seclì Laura , Avalle Lidia
Published: March 2020

The establishment and spreading of cancer involve the acquirement of many biological functions including resistance to apoptosis, enhanced proliferation and the ability to invade the surrounding tissue, extravasate from the primary site, survive in circulating blood, and finally extravasate and colonize distant organs giving origin to metastatic lesions, the major cause of cancer deaths. Dramatic changes in the expression of protein coding genes due to altered transcription factors activity or to epigenetic modifications orchestrate these events, intertwining with a microRNA regulatory network that is often disrupted in cancer cells. microRNAs-143 and -145 represent puzzling players of this game, with apparently contradictory functions. They were at first classified as tumor suppressive due to their frequently reduced levels in tumors, correlating with cell survival, proliferation, and migration. More recently, pro-oncogenic roles of these microRNAs have been described, challenging their simplistic definition as merely tumor-suppressive. Here we review their known activities in tumors, whether oncogenic or onco-suppressive, and highlight how their expression and functions are strongly dependent on their complex regulation downstream and upstream of cytokines and growth factors, on the cell type of expression and on the specific tumor stage.
Proteome and Phosphoproteome Changes Associated with Prognosis in Acute Myeloid Leukemia
Authors: Aasebø Elise , Berven Frode S. , Bartaula-Brevik Sushma , Stokowy Tomasz , Hovland Randi , Vaudel Marc , Døskeland Stein Ove , McCormack Emmet , Batth Tanveer S. , Olsen Jesper V. , Bruserud Øystein , Selheim Frode , Hernandez-Valladares Maria
Published: March 2020

Acute myeloid leukemia (AML) is a hematological cancer that mainly affects the elderly. Although complete remission (CR) is achieved for the majority of the patients after induction and consolidation therapies, nearly two-thirds relapse within a short interval. Understanding biological factors that determine relapse has become of major clinical interest in AML. We utilized liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify the protein changes and protein phosphorylation events associated with AML relapse in primary cells from 41 AML patients at time of diagnosis. Patients were defined as relapse-free if they had not relapsed within a five-year clinical follow-up after AML diagnosis. Relapse was associated with increased expression of RNA processing proteins and decreased expression of V-ATPase proteins. We also observed an increase in phosphorylation events catalyzed by cyclin-dependent kinases (CDKs) and casein kinase 2 (CSK2). The biological relevance of the proteome findings was supported by cell proliferation assays using inhibitors of V-ATPase (bafilomycin), CSK2 (CX-4945), CDK4/6 (abemaciclib) and CDK2/7/9 (SNS-032). While bafilomycin preferentially inhibited the cells from relapse patients, the kinase inhibitors were less efficient in these cells. This suggests that therapy against the upregulated kinases could also target the factors inducing their upregulation rather than their activity. This study, therefore, presents markers that could help predict AML relapse and direct therapeutic strategies.
Claudins: New Players in Human Fertility and Reproductive System Cancers
Authors: Kozieł Marta Justyna , Kowalska Karolina , Piastowska-Ciesielska Agnieszka Wanda
Published: March 2020

Claudins are major integral proteins of tight junctions (TJs), the apical cell–cell adhesions that enable maintaining polarity of epithelial cells, their differentiation, and cell signaling. A number of studies have indicated that claudins might play a crucial role in both physiology and pathogenesis. Their tissue-specific expression was originally linked to the development of different types of cancer and triggered a hope to use them as diagnostic or prognostic markers. However, it seems that their expression is more complex than that, and undoubtedly, claudins participate in one of the most important molecular events in cells. This review summarizes the recent research evaluating the role of claudins in fertility and the most common endocrine-dependent cancers in the reproductive system and highlights the crucial role of claudins both in human fertility and the most common cancers.
Cytoplasmic Cyclin E Is an Independent Marker of Aggressive Tumor Biology and Breast Cancer-Specific Mortality in Women over 70 Years of Age
Authors: Johnston Simon J. , Syed Binafsha M. , Parks Ruth M. , Monteiro Cíntia J. , Caruso Joseph A. , Green Andrew R. , Ellis Ian O. , Hunt Kelly K. , Karakas Cansu , Keyomarsi Khandan , Cheung Kwok-Leung
Published: March 2020

Multi-cohort analysis demonstrated that cytoplasmic cyclin E expression in primary breast tumors predicts aggressive disease. However, compared to their younger counterparts, older patients have favorable tumor biology and are less likely to die of breast cancer. Biomarkers therefore require interpretation in this specific context. Here, we assess data on cytoplasmic cyclin E from a UK cohort of older women alongside a panel of >20 biomarkers. Between 1973 and 2010, 813 women ≥70 years of age underwent initial surgery for early breast cancer, from which a tissue microarray was constructed (n = 517). Biomarker expression was assessed by immunohistochemistry. Multivariate analysis of breast cancer-specific survival was performed using Cox’s proportional hazards. We found that cytoplasmic cyclin E was the only biological factor independently predictive of breast cancer-specific survival in this cohort of older women (hazard ratio (HR) = 6.23, 95% confidence interval (CI) = 1.93–20.14; p = 0.002). At ten years, 42% of older patients with cytoplasmic cyclin E-positive tumors had died of breast cancer versus 8% of negative cases (p < 0.0005). We conclude that cytoplasmic cyclin E is an exquisite marker of aggressive tumor biology in older women. Patients with cytoplasmic cyclin E-negative tumors are unlikely to die of breast cancer. These data have the potential to influence treatment strategy in older patients.
Tumor Size Matters—Understanding Concomitant Tumor Immunity in the Context of Hypofractionated Radiotherapy with Immunotherapy
Authors: Nesseler Jean Philippe , Lee Mi-Heon , Nguyen Christine , Kalbasi Anusha , Sayre James W. , Romero Tahmineh , Nickers Philippe , McBride William H. , Schaue Dörthe
Published: March 2020

The purpose of this study was to determine the dynamic contributions of different immune cell subsets to primary and abscopal tumor regression after hypofractionated radiation therapy (hRT) and the impact of anti-PD-1 therapy. A bilateral syngeneic FSA1 fibrosarcoma model was used in immunocompetent C3H mice, with delayed inoculation to mimic primary and microscopic disease. The effect of tumor burden on intratumoral and splenic immune cell content was delineated as a prelude to hRT on macroscopic T1 tumors with 3 fractions of 8 Gy while microscopic T2 tumors were left untreated. This was performed with and without systemic anti-PD-1. Immune profiles within T1 and T2 tumors and in spleen changed drastically with tumor burden in untreated mice with infiltrating CD4+ content declining, while the proportion of CD4+ Tregs rose. Myeloid cell representation escalated in larger tumors, resulting in major decreases in the lymphoid:myeloid ratios. In general, activation of Tregs and myeloid-derived suppressor cells allow immunogenic tumors to grow, although their relative contributions change with time. The evidence suggests that primary T1 tumors self-regulate their immune content depending on their size and this can influence the lymphoid compartment of T2 tumors, especially with respect to Tregs. Tumor burden is a major confounding factor in immune analysis that has to be taken into consideration in experimental models and in the clinic. hRT caused complete local regression of primary tumors, which was accompanied by heavy infiltration of CD8+ T cells activated to express IFN-γ and PD-1; while certain myeloid populations diminished. In spite of this active infiltrate, primary hRT failed to generate the systemic conditions required to cause abscopal regression of unirradiated microscopic tumors unless PD-1 blockade, which on its own was ineffective, was added to the RT regimen. The combination further increased local and systemically activated CD8+ T cells, but few other changes. This study emphasizes the subtle interplay between the immune system and tumors as they grow and how difficult it is for local RT, which can generate a local immune response that may help with primary tumor regression, to overcome the systemic barriers that are generated so as to effect immune regression of even small abscopal lesions.
Clinical Relevance of Circulating Tumor Cells in Esophageal Cancer Detected by a Combined MACS Enrichment Method
Authors: Woestemeier Anna , Harms-Effenberger Katharina , Karstens Karl-F. , Konczalla Leonie , Ghadban Tarik , Uzunoglu Faik G. , Izbicki Jakob R. , Bockhorn Maximilian , Pantel Klaus , Reeh Matthias
Published: March 2020

Introduction. Current modalities to predict tumor recurrence and survival in esophageal cancer are insufficient. Even in lymph node-negative patients, a locoregional and distant relapse is common. Hence, more precise staging methods are needed. So far, only the CellSearch system was used to detect circulating tumor cells (CTC) with clinical relevance in esophageal cancer patients. Studies analyzing different CTC detection assays using advanced enrichment techniques to potentially increase the sensitivity are missing. Methods. In this single-center, prospective study, peripheral blood samples from 90 esophageal cancer patients were obtained preoperatively and analyzed for the presence of CTCs by Magnetic Cell Separation (MACS) enrichment (combined anti-cytokeratin and anti-epithelial cell adhesion molecules (EpCAM)), with subsequent immunocytochemical staining. Data were correlated with clinicopathological parameters and patient outcomes. Results. CTCs were detected in 25.6% (23/90) of the patients by combined cytokeratin/EpCAM enrichment (0–150 CTCs/7.5 mL). No significant correlation between histopathological parameters and CTC detection was found. Survival analysis revealed that the presence of more than two CTCs correlated with significantly shorter overall survival (OS) and progression-free survival (PFS). Conclusion. With the use of cytokeratin as an additional enrichment target, the CTC detection rate in esophageal cancer patients can be elevated and displays the heterogeneity of cytokeratin (CK) and EpCAM expression. The presence of >2CTCs correlated with a shorter relapse-free and overall survival in a univariate analysis, but not in a multivariate setting. Moreover, our results suggest that the CK7/8+/EpCAM+ or CK7/8+/EpCAM− CTC subtype does not lead to an advanced tumor staging tool in non-metastatic esophageal cancer (EC) patients.
Anti-Cancer Potential of Two Plasma-Activated Liquids: Implication of Long-Lived Reactive Oxygen and Nitrogen Species
Authors: Griseti Elena , Merbahi Nofel , Golzio Muriel
Published: March 2020

Cold atmospheric plasma-exposed culture medium may efficiently kill cancer cells in vitro. Due to the complexity of the medium obtained after plasma exposure, less complex physiological liquids, such as saline solutions and saline buffers, are gathering momentum. Among the plethora of reactive oxygen and nitrogen species (RONS) that are produced in these plasma-activated liquids, hydrogen peroxide, nitrite and nitrate appear to be mainly responsible for cytotoxic and genotoxic effects. Here, we evaluated the anti-cancer potential of plasma-activated phosphate-buffered saline (P-A PBS) and sodium chloride 0.9% (P-A NaCl), using a three-dimensional tumor model. Two epithelial cancer cell lines were used to evaluate cellular effects of either P-A PBS or P-A NaCl. Human colorectal cancer cells HCT 116 and human ovarian carcinoma, SKOV-3 were used to investigate the manner by which different cell types respond to different plasma-activated liquids treatments. Our investigations indicate that P-A PBS is more efficient than P-A NaCl mainly because RONS are produced in larger quantities. Indeed, we show that the cytotoxicity of these liquids directly correlates with the concentration of hydrogen peroxide and nitrite. Moreover, P-A PBS induced a faster-occurring and more pronounced cell death, which arose within deeper layers of the 3D multicellular spheroid models.
Integrative Analyses of Multilevel Omics Reveal Preneoplastic Breast to Possess a Molecular Landscape That is Globally Shared with Invasive Basal-Like Breast Cancer
Authors: Ju Zhenlin , Bhardwaj Anjana , Embury Matthew , Singh Harpreet , Gunaratne Preethi , Bedrosian Isabelle , Wang Jing
Published: March 2020

To characterize molecular changes accompanying the stepwise progression to breast cancer and to identify functional target pathways, we performed miRNA and RNA sequencing using MCF10A cell lines based model system that replicates the multi-step progression involving normal, preneoplastic, ductal carcinoma in situ, and invasive carcinoma cells, where the carcinoma most resemble the basal-like subgroup of human breast cancers. These analyses suggest that 70% of miRNA alterations occurred during the initial progression from normal to a preneoplastic stage. Most of these early changes reflected a global upregulation of miRNAs. This was consistent with a global increase in the miRNA-processing enzyme DICER, which was upregulated as a direct result of loss of miRNA let-7b-5p. Several oncogenic and tumor suppressor pathways were also found to change early, prior to histologic stigmata of cancer. Our finding that most genomic changes in the progression to basal-like breast cancer occurred in the earliest stages of histologic progression has implications for breast cancer prevention and selection of appropriate control tissues in molecular studies. Furthermore, in support of a functional significance of let-7b-5p loss, we found its low levels to predict poor disease-free survival and overall survival in breast cancer patients.
Recent Advances in Enzyme-Nanostructure Biocatalysts with Enhanced Activity
Authors: An Jing , Li Galong , Zhang Yifan , Zhang Tingbin , Liu Xiaoli , Gao Fei , Peng Mingli , He Yuan , Fan Haiming
Published: March 2020

Owing to their unique physicochemical properties and comparable size to biomacromolecules, functional nanostructures have served as powerful supports to construct enzyme-nanostructure biocatalysts (nanobiocatalysts). Of particular importance, recent years have witnessed the development of novel nanobiocatalysts with remarkably increased enzyme activities. This review provides a comprehensive description of recent advances in the field of nanobiocatalysts, with systematic elaboration of the underlying mechanisms of activity enhancement, including metal ion activation, electron transfer, morphology effects, mass transfer limitations, and conformation changes. The nanobiocatalysts highlighted here are expected to provide an insight into enzyme–nanostructure interaction, and provide a guideline for future design of high-efficiency nanobiocatalysts in both fundamental research and practical applications.
The Influence of the Gold Particle Size on the Catalytic Oxidation of 5-(Hydroxymethyl)furfural
Authors: Schade Oliver , Dolcet Paolo , Nefedov Alexei , Huang Xiaohui , Saraçi Erisa , Wöll Christof , Grunwaldt Jan-Dierk
Published: March 2020

For the production of chemicals from biomass, new selective processes are required. The selective oxidation of 5-(Hydroxymethyl)furfural (HMF), a promising platform molecule in fine chemistry, to 2,5-furandicarboxylic acid (FDCA) is considered a promising approach and requires the oxidation of two functional groups. In this study, Au/ZrO2 catalysts with different mean particle sizes were prepared by a chemical reduction method using tetrakis(hydroxymethyl)phosphonium chloride (THPC) and tested in HMF oxidation. The catalyst with the smallest mean particle size (2.1 nm) and the narrowest particle size distribution was highly active in the oxidation of the aldehyde moiety of HMF, but less active in alcohol oxidation. On the other hand, increased activity in FDCA synthesis up to 92% yield was observed over catalysts with a larger mean particle size (2.7 nm), which had a large fraction of small and some larger particles. A decreasing FDCA yield over the catalyst with the largest mean particle size (2.9 nm) indicates that the oxidation of both functional groups require different particle sizes and hint at the presence of an optimal particle size for both oxidation steps. The activity of Au particles seems to be influenced by surface steps and H bonding strength, the latter particularly in aldehyde oxidation. Therefore, the presence of both small and some larger Au particles seem to give catalysts with the highest catalytic activity.
Therapeutic Advances of Stem Cell-Derived Extracellular Vesicles in Regenerative Medicine
Authors: Yin Lei , Liu Xiaotian , Shi Yinghong , Ocansey Dickson Kofi Wiredu , Hu Yuyan , Li Xiaoxi , Zhang Chenxiao , Xu Wenrong , Qian Hui
Published: March 2020

Extracellular vesicles (EVs), which are the main paracrine components of stem cells, mimic the regenerative capacity of these cells. Stem cell-derived EVs (SC-EVs) have been used for the treatment of various forms of tissue injury in preclinical trials through maintenance of their stemness, induction of regenerative phenotypes, apoptosis inhibition, and immune regulation. The efficiency of SC-EVs may be enhanced by selecting the appropriate EV-producing cells and cell phenotypes, optimizing cell culture conditions for the production of optimal EVs, and further engineering the EVs produced to transport therapeutic and targeting molecules.
Pro-Inflammatory Priming of Umbilical Cord Mesenchymal Stromal Cells Alters the Protein Cargo of Their Extracellular Vesicles
Authors: Hyland Mairead , Mennan Claire , Wilson Emma , Clayton Aled , Kehoe Oksana
Published: March 2020

Umbilical cord mesenchymal stromal cells (UCMSCs) have shown an ability to modulate the immune system through the secretion of paracrine mediators, such as extracellular vesicles (EVs). However, the culture conditions that UCMSCs are grown in can alter their secretome and thereby affect their immunomodulatory potential. UCMSCs are commonly cultured at 21% O2 in vitro, but recent research is exploring their growth at lower oxygen conditions to emulate circulating oxygen levels in vivo. Additionally, a pro-inflammatory culture environment is known to enhance UCMSC anti-inflammatory potential. Therefore, this paper examined EVs from UCMSCs grown in normal oxygen (21% O2), low oxygen (5% O2) and pro-inflammatory conditions to see the impact of culture conditions on the EV profile. EVs were isolated from UCMSC conditioned media and characterised based on size, morphology and surface marker expression. EV protein cargo was analysed using a proximity-based extension assay. Results showed that EVs had a similar size and morphology. Differences were found in EV protein cargo, with pro-inflammatory primed EVs showing an increase in proteins associated with chemotaxis and angiogenesis. This showed that the UCMSC culture environment could alter the EV protein profile and might have downstream implications for their functions in immunomodulation.
Indirect Role of AQP4b and AQP4d Isoforms in Dynamics of Astrocyte Volume and Orthogonal Arrays of Particles
Authors: Lisjak Marjeta , Potokar Maja , Zorec Robert , Jorgačevski Jernej
Published: March 2020

Water channel aquaporin 4 (AQP4) plays a key role in the regulation of water homeostasis in the central nervous system (CNS). It is predominantly expressed in astrocytes lining blood–brain and blood–liquor boundaries. AQP4a (M1), AQP4c (M23), and AQP4e, present in the plasma membrane, participate in the cell volume regulation of astrocytes. The function of their splicing variants, AQP4b and AQP4d, predicted to be present in the cytoplasm, is unknown. We examined the cellular distribution of AQP4b and AQP4d in primary rat astrocytes and their role in cell volume regulation. The AQP4b and AQP4d isoforms exhibited extensive cytoplasmic localization in early and late endosomes/lysosomes and in the Golgi apparatus. Neither isoform localized to orthogonal arrays of particles (OAPs) in the plasma membrane. The overexpression of AQP4b and AQP4d isoforms in isoosmotic conditions reduced the density of OAPs; in hypoosmotic conditions, they remained absent from OAPs. In hypoosmotic conditions, the AQP4d isoform was significantly redistributed to early endosomes, which correlated with the increased trafficking of AQP4-laden vesicles. The overexpression of AQP4d facilitated the kinetics of cell swelling, without affecting the regulatory volume decrease. Therefore, although they reside in the cytoplasm, AQP4b and AQP4d isoforms may play an indirect role in astrocyte volume changes.
Inhibition of Gastrin-Releasing Peptide Attenuates Phosphate-Induced Vascular Calcification
Authors: Park Hyun-Joo , Kim Yeon , Kim Mi-Kyoung , Hwang Jae Joon , Kim Hyung Joon , Bae Soo-Kyung , Bae Moon-Kyoung
Published: March 2020

Vascular calcification is the pathological deposition of calcium/phosphate in the vascular system and is closely associated with cardiovascular morbidity and mortality. Here, we investigated the role of gastrin-releasing peptide (GRP) in phosphate-induced vascular calcification and its potential regulatory mechanism. We found that the silencing of GRP gene and treatment with the GRP receptor antagonist, RC-3095, attenuated the inorganic phosphate-induced calcification of vascular smooth muscle cells (VSMCs). This attenuation was caused by inhibiting phenotype change, apoptosis and matrix vesicle release in VSMCs. Moreover, the treatment with RC-3095 effectively ameliorated phosphate-induced calcium deposition in rat aortas ex vivo and aortas of chronic kidney disease in mice in vivo. Therefore, the regulation of the GRP-GRP receptor axis may be a potential strategy for treatment of diseases associated with excessive vascular calcification.
Muscle Progenitors Derived from Extraocular Muscles Express Higher Levels of Neurotrophins and their Receptors than other Cranial and Limb Muscles
Authors: Carrero-Rojas Génova , Benítez-Temiño Beatriz , Pastor Angel M. , Davis López de Carrizosa Mª América
Published: March 2020

Extraocular muscles (EOMs) show resistance to muscle dystrophies and sarcopenia. It has been recently demonstrated that they are endowed with different types of myogenic cells, all of which present an outstanding regenerative potential. Neurotrophins are important modulators of myogenic regeneration and act promoting myoblast proliferation, enhancing myogenic fusion rates and protecting myotubes from inflammatory stimuli. Here, we adapted the pre-plate cell isolation technique to obtain myogenic progenitors from the rat EOMs, and quantified their in vitro expression of neurotrophins and their receptors by RT–qPCR and immunohistochemistry, respectively. The results were compared with the expression on progenitors isolated from buccinator, tongue and limb muscles. Our quantitative analysis of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT-3) transcripts showed, for the first time, that EOMs-derived cells express more of these factors and that they expressed TrkA, but not TrkB and TrkC receptors. On the contrary, the immunofluorescence analysis demonstrated high expression of p75NTR on all myogenic progenitors, with the EOMs-derived cells showing higher expression. Taken together, these results suggest that the intrinsic trophic differences between EOMs-derived myogenic progenitors and their counterparts from other muscles could explain why those cells show higher proliferative and fusion rates, as well as better regenerative properties.
A Role for Endoplasmic Reticulum Stress in Intracerebral Hemorrhage
Authors: Mohammed Thangameeran Shaik Ismail , Tsai Sheng-Tzung , Hung Hsiang-Yi , Hu Wei-Fen , Pang Cheng-Yoong , Chen Shin-Yuan , Liew Hock-Kean
Published: March 2020

The endoplasmic reticulum (ER) is an intracellular organelle that performs multiple functions, such as lipid biosynthesis, protein folding, and maintaining intracellular calcium homeostasis. Thus, conditions wherein the ER is unable to fold proteins is defined as ER stress, and an inbuilt quality control mechanism, called the unfolded protein response (UPR), is activated during ER stress, which serves as a recovery system that inhibits protein synthesis. Further, based on the severity of ER stress, the response could involve both proapoptotic and antiapoptotic phases. Intracerebral hemorrhage (ICH) is the second most common subtype of cerebral stroke and many lines of evidence have suggested a role for the ER in major neurological disorders. The injury mechanism during ICH includes hematoma formation, which in turn leads to inflammation, elevated intracranial pressure, and edema. A proper understanding of the injury mechanism(s) is required to effectively treat ICH and closing the gap between our current understanding of ER stress mechanisms and ICH injury can lead to valuable advances in the clinical management of ICH.
Do Geese Facilitate or Compete with Wintering Hooded Cranes (Grus monacha) for Forage Resources?
Authors: Zhu Zhengrong , Zhou Lizhi , Yu Chao , Cheng Lei , Xu Wenbin , Song Yunwei
Published: March 2020

Foraging is the key behavior of waterbirds, which profoundly affects the survival of their population, and it is affected by interspecific interaction. At Shengjin Lake in China, owing to the reduced availability of suitable habitats for a large population of migratory waterbirds (especially wild geese) over winter, mixed species foraging inevitably occurs. This study aimed to investigate whether mixed-species foraging affects the foraging of hooded cranes (Grus monacha). Fields surveys were carried out at Shengjin Lake from November 2018 to March 2019. Mixed-species foraging was surveyed between the flocks of hooded cranes and three species of geese, greater white-fronted geese (Anser albifrons), lesser white-fronted geese (Anser erythropus) and bean geese (Anser fabalis). Instantaneous scanning and focal animal methods were used to collect behavioral samples of hooded cranes. The quadrat method was used to survey the food density in three habitats: meadows, mudflats, and paddy fields. The results showed that the foraging success rate of hooded cranes was not significantly correlated with food density and the relative flock size in the mixed-species foraging flock in meadows, but a significant negative correlation with the relative flock size in mudflats. However in paddy fields it was a significant positive correlation with the relative flock size. Foraging efforts of hooded cranes were negatively correlated with food density and positively correlated with the relative flock size in meadows. In mudflats, foraging efforts of hooded cranes had a significant positively correlation with the relative flock size, however, there was a significant negative correlation with the relative flock size in paddy fields. To sum up, larger numbers of geese mixed with hooded cranes has a favorable effect on the foraging of hooded cranes in meadows and mudflats, however, the reverse was observed in the paddy fields.
A Data Secured Communication System Design Procedure with a Chaotic Carrier and Synergetic Observer
Authors: Mushenko Alexey , Dzuba Julia , Nekrasov Alexey , Fidge Colin
Published: March 2020

We have considered the problem of secure communication by means of chaotic carrier communication channels. Data protection is provided if the signal in the communication channel looks like a stochastic or noisy one, i.e., by the steganography property, and also by using advanced and secured approaches of mixing a useful signal into a chaotic carrier. The problem is to find effective and efficient techniques for useful signal reconstruction at the receiver side. We firstly use a synergetic nonlinear mathematical observer to recover the two useful signals transmitted simultaneously over a single communication channel. Compared to a known observer, the synergetic one operates with initial nonlinear models, i.e., it may be applied directly to chaotic systems. In that system structure, we consider the useful signals as unobservable variables and estimate them by the given model of a chaotic generator. A chaotic data transmission system with two channels is demonstrated; the presented mathematical procedure explains the steps of synergetic two-channel observer design. Computer simulation results prove the viability of our approach. The proposed data transmission scheme and the observer design procedure provide effective transmission and reconstruction of informational signals. Reconstruction error is up to approximately 25% but has a very short pulses shape and could be eliminated with further analog or digital filtering algorithms. As an example application, simulation of image transmission and recovery is demonstrated. The study’s results may be used as a basis for further research into secure data transmission system design.
Researching Why-Not Questions in Skyline Query Based on Orthogonal Range
Authors: Sun Ping , Liang Caimei , Li Guohui , Yuan Ling
Published: March 2020

This paper aims to answer “why-not” questions in skyline queries based on the orthogonal query range (i.e., ORSQ). These queries retrieve skyline points within a rectangular query range, which improves query efficiency. Answering why-not questions in ORSQ can help users analyze query results and make decisions. We discuss the causes of why-not questions in ORSQ. Then, we outline how to modify the why-not point and the orthogonal query range so that the why-not point is included in the result of the skyline query based on the orthogonal range. When the why-not point is in the orthogonal range, we show how to modify the why-not point and narrow the orthogonal range. We also present how to expand the orthogonal range when the why-not point is not in the orthogonal range. We effectively combine query refinement and data modification techniques to produce meaningful answers. The experimental results demonstrate that the proposed algorithms have high-quality explanations for why-not questions in ORSQ in the real and synthetic datasets.
An Efficient and Credible Multi-Source Trust Fusion Mechanism Based on Time Decay for Edge Computing
Authors: Kong Wenping , Li Xiaoyong , Hou Liyang , Li Yanrong
Published: March 2020

With the development of 5G, user terminal computing moves up and cloud computing sinks, thus forming a computing fusion at the edge. Edge computing with high-efficiency, real-time, and fast features will become part of 5G construction. Utilizing distributed computing and storage resources at the edge of the network to perform distributed data processing tasks can alleviate the load on the cloud computing center, which is also the development trend of edge computing. When a malicious node exists, the error information feedback by the node will affect the result of local perception decision. To solve the problem of malicious behavior of the node, a node trust evaluation mechanism of interactive behavior is introduced. The trust mechanism for edge computing network environments is introduced as a novel security solution. First, the key thought of the trust mechanism proposed in this paper is to establish a trust relationship between edge nodes in open edge computing environment. Then, a multi-source trust fusion algorithm based on time decay aggregates direct interaction trust and different third-party recommendation trust to calculate the global trust of the evaluated nodes. Finally, simulation experiments show that the algorithm has a certain degree of improvement in computational efficiency and interaction success rate over other existing models, which reduces the situation of malicious node deception.
Experimental Study of Fracture Propagation: The Application in Energy Mining
Authors: Cheng Yuxiang , Zhang Yanjun
Published: March 2020

Hydraulic fracturing has been widely used in recent years as a key technology to improve energy mining efficiency in petroleum and geothermal industries. Laboratory hydraulic fracturing experiments recently were completed in six large-scale 300 × 300 × 300 mm rock specimens to better understand this complex process of hydraulic fracturing. When injection flow rate increases from 5 to 30 mL/min. The fracture initiation pressures and breakdown pressures increase, the propagation times and post-fracturing pressures decrease. The fracture geometries are observed and analyzed, mean injection power is proposed and results show that it could be used to roughly estimate the fracture total lengths. Moreover, the fracture permeabilities based on the pressure data are calculated and linearly ascend with the increase of injection flow rates. These results can provide some reasonable advice for implementing hydraulic fracturing reservoir simulations and improving energy production efficiency on application to field-scale operation.
Series DC Arc Simulation of Photovoltaic System Based on Habedank Model
Authors: Li Xinran , Pan Chenyun , Luo Dongmei , Sun Yaojie
Published: March 2020

Despite the rapid development of photovoltaic (PV) industry, direct current (DC) fault arc remains a major threat to the safety of PV system and personnel. While extensive research on DC fault arc has been conducted, little attention has been paid to the long-time interactions between the PV system and DC arc. In this paper, a simulation system with an arc model and PV system model is built to overcome the inconvenience of the fault-arc experiments and understand the mechanism of these interactions. For this purpose, the characteristics of the series DC arc in a small grid-connected PV system are first investigated under uniform irradiance. Then, by comparing with different arc models, the Habedank model is selected to simulate the fault arc and a method to determine its parameters under DC arc condition is proposed. The trends of simulated arc waveforms are consistent with the measured data, whose fitting degree in adjusted R-squared is between 0.946 and 0.956. Finally, a phenomenon observed during the experiment, that the negative perturbation of the maximum power point tracking (MPPT) algorithm can reduce the arc current, is explained by the proposed model.
Development of Algorithms for Effective Resource Allocation among Highway–Rail Grade Crossings: A Case Study for the State of Florida
Authors: Kavoosi Masoud , Dulebenets Maxim A. , Pasha Junayed , Abioye Olumide F. , Moses Ren , Sobanjo John , Ozguven Eren E.
Published: March 2020

Smart cities directly rely on a variety of elements, including water, gas, electricity, buildings, services, transportation networks, and others. Lack of properly designed transportation networks may cause different economic and safety concerns. Highway–rail grade crossings are known to be a hazardous point in the transportation network, considering a remarkable number of accidents recorded annually between highway users and trains, and even solely between highway users at highway–rail grade crossings. Hence, safety improvement at highway–rail grade crossings is a challenging issue for smart city authorities, given limitations in monetary resources. In this study, two optimization models are developed for resource allocation among highway–rail grade crossings to minimize the overall hazard and the overall hazard severity, taking into account the available budget limitations. The optimization models are solved by CPLEX to the global optimality. Moreover, some heuristic algorithms are proposed as well. A case study focusing on the public highway–rail grade crossings in the State of Florida is performed to evaluate the effectiveness of the developed optimization models and the solution methodologies. In terms of the computational time, all the solution approaches are found to be effective decision support tools from the practical standpoint. Moreover, the results demonstrate that some of the developed heuristic algorithms can provide near-optimal solutions. Therefore, the smart city authorities can utilize the proposed heuristics as decision support tools for effective resource allocation among highway–rail grade crossings.
Multi-Faceted Analysis of Systematic Risk-Based Wind Energy Investment Decisions in E7 Economies Using Modified Hybrid Modeling with IT2 Fuzzy Sets
Authors: Qiu Dejun , Dinçer Hasan , Yüksel Serhat , Ubay Gözde Gülseven
Published: March 2020

This study aimed to analyze the systematic risks of wind energy investments. Within this framework, E7 countries are included in the scope of the examination. A large literature review was carried out and 12 different systematic risk factors that could exist in wind energy investments were identified. The analysis process of the study consisted of two different stages. First, the specified risk criteria were weighted with the help of the interval type 2 (IT2) fuzzy decision-making trial and evaluation laboratory (DEMATEL) method. Second, E7 countries were ranked according to the risk management effectiveness in wind energy investments. In this process, the IT2 fuzzy Vlsekriterijumska Optimizacija I Kompromisno Resenje (VIKOR) approach was taken into consideration. The findings show that volatility in exchange rates and interest rates were the most important risks in wind energy investments. In addition, it was determined that China and Indonesia were the most successful countries in managing risks in wind energy investments. In contrast, India, Russia, and Turkey were determined to be the least successful. Additionally, the IT2 fuzzy technique for order preference by similarity to ideal solution (TOPSIS) method was applied as a robustness check of the extended VIKOR method. It was concluded that the ranking results of the IT2 fuzzy TOPSIS method were similar to the results of the IT2 fuzzy VIKOR. It can be understood that the proposed ranking method was consistent with the comparative analysis results. From this point of view, it was observed that countries should take measures regarding their exchange rate and interest rate risks in order to increase the efficiency in wind energy investments. In this context, companies should first ensure that they do not have a foreign exchange short position in their balance sheets by conducting an effective financial analysis. In addition, it is important to use financial derivatives to minimize the exchange rate and interest rate risks. Using these results, it will be possible to manage this risk by taking the reverse position for the existing foreign currency and interest risk. In this way, it will be possible to increase the efficiency of wind energy investments, which will contribute to the social and economic development of each respective country.