bluuebunny/crossref_metadata_2025 huggingface dataset:
Origanum majorana Essential Oil Triggers p38 MAPK-Mediated Protective Autophagy, Apoptosis, and Caspase-Dependent Cleavage of P70S6K in Colorectal Cancer Cells
Authors: Athamneh Khawlah , Alneyadi Aysha , Alsamri Halima , Alrashedi Asma , Palakott Abdulrasheed , El-Tarabily Khaled A. , Eid Ali H. , Al Dhaheri Yusra , Iratni Rabah
Published: March 2020

Colorectal cancer (CRC) is the third most common type of cancer in terms of incidence and mortality worldwide. Here we have investigated the anti-colon cancer potential of Origanum majorana essential oil (OMEO) and its underlying mechanisms of action. We showed that OMEO significantly inhibited the cellular viability and colony growth of human HT-29 colorectal cancer cells. OMEO induced protective autophagy, associated with downregulation of the mTOR/p70S6K pathway, and activated caspase-8 and caspase-9-dependent apoptosis. Blockade of autophagy with 3-methyladenine (3-MA) and chloroquine (CQ), two autophagy inhibitors, potentiated the OMEO-induced apoptotic cell death. Inversely, inhibition of apoptosis with the pan-caspase inhibitor, Z-VAD-FMK, significantly reduced cell death, suggesting that apoptosis represents the main mechanism of OMEO-induced cell death. Mechanistically, we found that OMEO induces protective autophagy and apoptotic cells death via the activation of the p38 MAPK signaling pathway. Pharmacological inhibition of p38 MAPK by the p38 inhibitors SB 202190 and SB 203580 not only significantly decreased apoptotic cell death, but also reduced the autophagy level in OMEO treated HT-29 cells. Strikingly, we found that OMEO also induces p38 MAPK-mediated caspase-dependent cleavage of p70S6K, a protein reported to be overexpressed in colon cancer and associated with drug resistance. Our findings suggest that OMEO inhibits colon cancer through p38 MAPK-mediated protective autophagy and apoptosis associated with caspase-dependent cleavage of p70S6K. To the best of our knowledge, this study is the first to report on the implications of the p38 MAPK signaling pathway in targeting p70S6K to caspase cleavage.
TP53 Mutations in Serum Circulating Cell-Free Tumor DNA As Longitudinal Biomarker for High-Grade Serous Ovarian Cancer
Authors: Vitale Silvia R. , Groenendijk Floris H. , van Marion Ronald , Beaufort Corine M. , Helmijr Jean C. , Jan Dubbink Hendrikus , N. M. Dinjens Winand , Ewing-Graham Patricia C. , Smolders Ramon , van Doorn Helena C. , Boere Ingrid A. , Berns Els M. J. J. , Helleman Jozien , Jansen Maurice P. H. M.
Published: March 2020

The aim of this study was to determine an optimal workflow to detect TP53 mutations in baseline and longitudinal serum cell free DNA (cfDNA) from high-grade serous ovarian carcinomas (HGSOC) patients and to define whether TP53 mutations are suitable as biomarker for disease. TP53 was investigated in tissue and archived serum from 20 HGSOC patients by a next-generation sequencing (NGS) workflow alone or combined with digital PCR (dPCR). AmpliSeq™-focused NGS panels and customized dPCR assays were used for tissue DNA and longitudinal cfDNAs, and Oncomine NGS panel with molecular barcoding was used for baseline cfDNAs. TP53 missense mutations were observed in 17 tissue specimens and in baseline cfDNA for 4/8 patients by AmpliSeq, 6/9 patients by Oncomine, and 4/6 patients by dPCR. Mutations in cfDNA were detected in 4/6 patients with residual disease and 3/4 patients with disease progression within six months, compared to 5/11 patients with no residual disease and 6/13 patients with progression after six months. Finally, mutations were detected at progression in 5/6 patients, but not during chemotherapy. NGS with molecular barcoding and dPCR were most optimal workflows to detect TP53 mutations in baseline and longitudinal serum cfDNA, respectively. TP53 mutations were undetectable in cfDNA during treatment but re-appeared at disease progression, illustrating its promise as a biomarker for disease monitoring.
Karyotypic Flexibility of the Complex Cancer Genome and the Role of Polyploidization in Maintenance of Structural Integrity of Cancer Chromosomes
Authors: Raftopoulou Christina , Roumelioti Fani-Marlen , Dragona Eleni , Gimelli Stefanie , Sloan-Béna Frédérique , Gorgoulis Vasilis , Antonarakis Stylianos E. , Gagos Sarantis
Published: March 2020

Ongoing chromosomal instability in neoplasia (CIN) generates intratumor genomic heterogeneity and limits the efficiency of oncotherapeutics. Neoplastic human cells utilizing the alternative lengthening of telomeres (ALT)-pathway, display extensive structural and numerical CIN. To unravel patterns of genome evolution driven by oncogene-replication stress, telomere dysfunction, or genotoxic therapeutic interventions, we examined by comparative genomic hybridization five karyotypically-diverse outcomes of the ALT osteosarcoma cell line U2-OS. These results demonstrate a high tendency of the complex cancer genome to perpetuate specific genomic imbalances despite the karyotypic evolution, indicating an ongoing process of genome dosage maintenance. Molecular karyotyping in four ALT human cell lines showed that mitotic cells with low levels of random structural CIN display frequent evidence of whole genome doubling (WGD), suggesting that WGD may protect clonal chromosome aberrations from hypermutation. We tested this longstanding hypothesis in ALT cells exposed to gamma irradiation or to inducible DNA replication stress under overexpression of p21. Single-cell cytogenomic analyses revealed that although polyploidization promotes genomic heterogeneity, it also protects the complex cancer genome and hence confers genotoxic therapy resistance by generating identical extra copies of driver chromosomal aberrations, which can be spared in the process of tumor evolution if they undergo unstable or unfit rearrangements.
Muscle Loss after Chemoradiotherapy as a Biomarker of Distant Failures in Locally Advanced Cervical Cancer
Authors: Lee Jie , Lin Jhen-Bin , Wu Meng-Hao , Chang Chih-Long , Jan Ya-Ting , Chen Yu-Jen
Published: March 2020

This study aimed to evaluate whether computed tomography (CT)-based muscle measurement predicts distant failure in patients with locally advanced cervical cancer (LACC). Data from 278 patients with LACC who underwent chemoradiation therapy (CCRT) between 2004 and 2017 were analysed. Changes in the skeletal muscle index (SMI), skeletal muscle density, and total adipose tissue index during CCRT were calculated from CT images taken at the baseline and after CCRT. The predictive capability of CT-based muscle measurement for distant failure was evaluated using Cox proportional hazards regression, Harrell’s concordance index (C-index), and time-dependent receiver operating characteristic curves. SMI loss ≥ 5% was independently associated with worse distant recurrence-free survival (DRFS) (HR: 6.31, 95% CI: 3.18–12.53; p < 0.001). The addition of muscle change to clinical models, including International Federation of Gynaecology and Obstetrics (FIGO) stage, lymph nodes, pathology, and squamous cell carcinoma-antigen, achieved higher C-indices (0.824 vs. 0.756; p < 0.001). Models including muscle change had superior C-indices than those including weight change (0.824 vs. 0.758; p < 0.001). The area under the curve for predicting 3-year DRFS was the highest for the muscle-loss model (0.802, muscle-loss model; 0.635, clinical model; and 0.646, weight-loss model). Our study demonstrated that muscle loss after CCRT was independently associated with worse DRFS and that integrating muscle loss into models including classical prognostic factors improved the prediction of distant failure.
Thromboprophylaxis in the End-of-Life Cancer Care: The Update
Authors: Zabrocka Ewa , Sierko Ewa
Published: March 2020

Cancer patients are at increased risk for venous thromboembolism (VTE), which further increases with advanced stages of malignancy, prolonged immobilization, or prior history of thrombosis. To reduce VTE-related mortality, many official guidelines encourage the use of thromboprophylaxis (TPX) in cancer patients in certain situations, e.g., during chemotherapy or in the perioperative period. TPX in the end-of-life care, however, remains controversial. Most recommendations on VTE prophylaxis in cancer patients are based on the outcomes of clinical trials that excluded patients under palliative or hospice care. This translates to the paucity of official guidelines on TPX dedicated to this group of patients. The problem should not be underestimated as VTE is known to be associated with symptoms adversely impacting the quality of life (QoL), i.e., limb or chest pain, dyspnea, hemoptysis. In end-of-life care, where the assurance of the best possible QoL should be the highest priority, VTE prophylaxis may eliminate the symptom burden related to thrombosis. However, large randomized studies determining the benefits and risks profiles of TPX in patients nearing the end of life are lacking. This review summarized available data on TPX in this population, analyzed potential tools for VTE risk prediction in the view of this group of patients, and summarized the most current recommendations on TPX pertaining to terminal care.
The Controversial Roles of ADP-Ribosyl Hydrolases MACROD1, MACROD2 and TARG1 in Carcinogenesis
Authors: Feijs Karla , Cooper Christopher , Žaja Roko
Published: March 2020

Post-translational modifications (PTM) of proteins are crucial for fine-tuning a cell’s response to both intracellular and extracellular cues. ADP-ribosylation is a PTM, which occurs in two flavours: modification of a target with multiple ADP-ribose moieties (poly(ADP-ribosyl)ation or PARylation) or with only one unit (MARylation), which are added by the different enzymes of the PARP family (also known as the ARTD family). PARylation has been relatively well-studied, particularly in the DNA damage response. This has resulted in the development of PARP inhibitors such as olaparib, which are increasingly employed in cancer chemotherapeutic approaches. Despite the fact that the majority of PARP enzymes catalyse MARylation, MARylation is not as well understood as PARylation. MARylation is a dynamic process: the enzymes reversing intracellular MARylation of acidic amino acids (MACROD1, MACROD2, and TARG1) were discovered in 2013. Since then, however, little information has been published about their physiological function. MACROD1, MACROD2, and TARG1 have a ‘macrodomain’ harbouring the catalytic site, but no other domains have been identified. Despite the lack of information regarding their cellular roles, there are a number of studies linking them to cancer. However, some of these publications oppose each other, some rely on poorly-characterised antibodies, or on aberrant localisation of overexpressed rather than native protein. In this review, we critically assess the available literature on a role for the hydrolases in cancer and find that, currently, there is limited evidence for a role for MACROD1, MACROD2, or TARG1 in tumorigenesis.
Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin
Authors: Mariniello Marta , Petruzzelli Raffaella , Wanderlingh Luca G. , La Montagna Raffaele , Carissimo Annamaria , Pane Francesca , Amoresano Angela , Ilyechova Ekaterina Y. , Galagudza Michael M. , Catalano Federico , Crispino Roberta , Puchkova Ludmila V. , Medina Diego L. , Polishchuk Roman S.
Published: March 2020

Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy.
Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR Inhibition
Authors: Xing Jun , Bhuria Vikas , Bui Khac Cuong , Nguyen Mai Ly Thi , Hu Zexi , Hsieh Chih-Jen , Wittstein Kathrin , Stadler Marc , Wilkens Ludwig , Li Jun , Kalesse Markus , Bozko Przemyslaw , Plentz Ruben R.
Published: March 2020

Background: Hepatocellular carcinoma (HCC) represents a major health burden with limited curative treatment options. There is a substantial unmet need to develop innovative approaches to impact the progression of advanced HCC. Haprolid is a novel natural component isolated from myxobacteria. Haprolid has been reported as a potent selective cytotoxin against a panel of tumor cells in recent studies including HCC cells. The aims of this study are to evaluate the antitumor effect of haprolid in HCC and to understand its underlying molecular mechanisms. Methods: The efficacy of haprolid was evaluated in human HCC cell lines (Huh-7, Hep3B and HepG2) and xenograft tumors (NMRI-Foxn1nu mice with injection of Hep3B cells). Cytotoxic activity of haprolid was determined by the WST-1 and crystal violet assay. Wound healing, transwell and tumorsphere assays were performed to investigate migration and invasion of HCC cells. Apoptosis and cell-cycle distribution were measured by flow cytometry. The effects of haprolid on the Rb/E2F and Akt/mTOR pathway were examined by immunoblotting and immunohistochemistry. Results: haprolid treatment significantly inhibited cell proliferation, migration and invasion in vitro. The epithelial–mesenchymal transition (EMT) was impaired by haprolid treatment and the expression level of N-cadherin, vimentin and Snail was downregulated. Moreover, growth of HCC cells in vitro was suppressed by inhibition of G1/S transition, and partially by induction of apoptosis. The drug induced downregulation of cell cycle regulatory proteins cyclin A, cyclin B and CDK2 and induced upregulation of p21 and p27. Further evidence showed that these effects of haprolid were associated with Rb/E2F downregulation and Akt/mTOR inhibition. Finally, in vivo nude mice experiments demonstrated significant inhibition of tumor growth upon haprolid treatment. Conclusion: Our results show that haprolid inhibits the growth of HCC through dual inhibition of Rb/E2F and Akt/mTOR pathways. Therefore, haprolid might be considered as a new and promising candidate for the palliative therapy of HCC.
A High-Performing Plasma Metabolite Panel for Early-Stage Lung Cancer Detection
Authors: Zhang Lun , Zheng Jiamin , Ahmed Rashid , Huang Guoyu , Reid Jennifer , Mandal Rupasri , Maksymuik Andrew , Sitar Daniel S. , Tappia Paramjit S. , Ramjiawan Bram , Joubert Philippe , Russo Alessandro , Rolfo Christian D. , Wishart David S.
Published: March 2020

The objective of this research is to use metabolomic techniques to discover and validate plasma metabolite biomarkers for the diagnosis of early-stage non-small cell lung cancer (NSCLC). The study included plasma samples from 156 patients with biopsy-confirmed NSCLC along with age and gender-matched plasma samples from 60 healthy controls. A fully quantitative targeted mass spectrometry (MS) analysis (targeting 138 metabolites) was performed on all samples. The sample set was split into a discovery set and validation set. Metabolite concentration data, clinical data, and smoking history were used to determine optimal sets of biomarkers and optimal regression models for identifying different stages of NSCLC using the discovery sets. The same biomarkers and regression models were used and assessed on the validation models. Univariate and multivariate statistical analysis identified β-hydroxybutyric acid, LysoPC 20:3, PC ae C40:6, citric acid, and fumaric acid as being significantly different between healthy controls and stage I/II NSCLC. Robust predictive models with areas under the curve (AUC) > 0.9 were developed and validated using these metabolites and other, easily measured clinical data for detecting different stages of NSCLC. This study successfully identified and validated a simple, high-performing, metabolite-based test for detecting early stage (I/II) NSCLC patients in plasma. While promising, further validation on larger and more diverse cohorts is still required.
Retinol-Binding Protein 4 Accelerates Metastatic Spread and Increases Impairment of Blood Flow in Mouse Mammary Gland Tumors
Authors: Papiernik Diana , Urbaniak Anna , Kłopotowska Dagmara , Nasulewicz-Goldeman Anna , Ekiert Marcin , Nowak Marcin , Jarosz Joanna , Cuprych Monika , Strzykalska Aleksandra , Ugorski Maciej , Matkowski Rafał , Wietrzyk Joanna
Published: March 2020

Retinol-binding protein 4 (RBP4) is proposed as an adipokine that links obesity and cancer. We analyzed the role of RBP4 in metastasis of breast cancer in patients and in mice bearing metastatic 4T1 and nonmetastatic 67NR mammary gland cancer. We compared the metastatic and angiogenic potential of these cells transduced with Rbp4 (4T1/RBP4 and 67NR/RBP4 cell lines). Higher plasma levels of RBP4 were observed in breast cancer patients with metastatic tumors than in healthy donors and patients with nonmetastatic cancer. Increased levels of RBP4 were observed in plasma, tumor tissue, liver, and abdominal fat. Moreover, the blood vessel network was highly impaired in mice bearing 4T1 as compared to 67NR tumors. RBP4 transductants showed further impairment of blood flow and increased metastatic potential. Exogenous RBP4 increased lung settlement by 67NR and 4T1 cells. In vitro studies showed increased invasive and clonogenic potential of cancer cells treated with or overexpressing RBP4. This effect is not dependent on STAT3 phosphorylation. RBP4 enhances the metastatic potential of breast cancer tumors through a direct effect on cancer cells and through increased endothelial dysfunction and impairment of blood vessels within the tumor.
Preoperative Serum Thyroglobulin and Its Correlation with the Burden and Extent of Differentiated Thyroid Cancer
Authors: Kim Hosu , Park So Young , Choe Jun-Ho , Kim Jee Soo , Hahn Soo Yeon , Kim Sun Wook , Chung Jae Hoon , Jung Jaehoon , Kim Tae Hyuk
Published: March 2020

Lymph node metastasis (LNM) in differentiated thyroid cancer (DTC) is usually detected with preoperative ultrasonography; however, this has limited sensitivity for small metastases, and there is currently no predictive biomarker that can help to inform the extent of surgery required. We evaluated whether preoperative serum thyroglobulin levels can predict tumor burden and extent. We retrospectively reviewed the clinical records of 4029 DTC cases diagnosed and treated at a Samsung Medical Center between 1994 and 2016. We reviewed primary tumor size, number and location of LNM, and presence of distant metastases to reveal relationships between tumor burden and extent and preoperative serum thyroglobulin levels. We found a linear association between increasing preoperative thyroglobulin levels, the size of the primary tumor, and the number of LNM (r = 0.34, p < 0.001, r = 0.20, p < 0.001, respectively). Tumor extent also increased with each decile of increasing preoperative thyroglobulin level (r = 0.18, p < 0.001). Preoperative thyroglobulin levels of 13.15 ng/mL, 30.05 ng/mL, and 62.9 ng/mL were associated with the presence of ipsilateral lateral LNM, contralateral lateral LNM, and distant metastasis, respectively. Our results suggest that preoperative measurement of serum thyroglobulin may help to predict LNM and help to tailor surgery.
Preparation of Gd-Doped TiO2 Nanotube Arrays by Anodization Method and Its Photocatalytic Activity for Methyl Orange Degradation
Authors: Li Rui , Yang Jin , Xu Shiyin , Zhou Yushun , Wang Xuan , Peng Hailong , Du Jun
Published: March 2020

Gd-doped TiO2 nanotube arrays with 3D ordered and high specific surface (176 m2/g) area are successfully prepared on a Ti foil surface via an anodizing method. The characterizations of Gd-doped TiO2 nanotube arrays are carried out using X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscope (TEM), X-ray photoelectron spectroscopy (XPS), energy dispersive X-ray spectrometer (EDX), optical contact angle measurer, and ultraviolet (UV) fluorescence spectrophotometer, respectively. The results reveal that the Gd-doped TiO2 nanotube arrays form on the Ti foil surface with a length of about 50.5 μm and 100 nm in diameter, and the growth direction grown along the (101) direction of anatase crystal. Under the optimized reaction conditions (60 V, 10 h, 0.01mol/L Gd3+), the crystal phase of Gd-doped TiO2 show an excellent nanotube structure, possess a beneficial photocatalytic performance for methyl orange (MO) (Degradation rate was 95.8%) and an excellent hydrophilic property (The optical contact angle was 4.9°). After doping with Gd, the hydrophilic and photocatalytic properties of the TiO2 nanotubes are further improved.
Superior Adsorption and Photocatalytic Degradation Capability of Mesoporous LaFeO3/g-C3N4 for Removal of Oxytetracycline
Authors: Xu Ke , Yang Xiaosheng , Ruan Luda , Qi Shaolv , Liu Jianling , Liu Kaiyuan , Pan Shaoliang , Feng Guangwei , Dai Zeqin , Yang Xianjiong , Li Rong , Feng Jian
Published: March 2020

Mesoporous LaFeO3/g-C3N4 Z-scheme heterojunctions (LFC) were synthesized via the incorporation of LaFeO3 nanoparticles and porous g-C3N4 ultrathin nanosheets. The as prepared LFC were characterized by transmission electron microscopy, scanning electron microscopy, atomic force microscopy, X-ray photoelectron spectroscopy, powder X-ray diffraction, Raman spectra and N2 adsorption analysis. The structural analysis indicated that the reheating process and the addition of NH4Cl in the thermal polymerization were the key factors to get porous g-C3N4 ultrathin nanosheets and to obtain high specific surface areas of LFC. It remarkably enhanced the adsorption capacity and photocatalytic degradation of LFC for removal of oxytetracycline (OTC). The effect of the mass percentage of LaFeO3 in LFC, pH and temperature on the OTC adsorption was investigated. The LaFeO3/g-C3N4 heterojunction with 2 wt % LaFeO3 (2-LFC) exhibited highest saturated adsorption capacity (101.67 mg g−1) and largest photocatalytic degradation rate constant (1.35 L g−1 min−1), which was about 9 and 5 times higher than that of bulk g-C3N4 (CN), respectively. This work provided a facile method to prepare mesoporous LaFeO3/g-C3N4 heterojunctions with especially well adsorption and photocatalytic activities for OTC, which can facilitate its practical applications in pollution control.
Moderate Exercise Modulates Tumor Metabolism of Triple-Negative Breast Cancer
Authors: Vulczak Anderson , Souza Anderson de Oliveira , Ferrari Gustavo Duarte , Azzolini Ana Elisa Caleiro Seixas , Pereira-da-Silva Gabriela , Alberici Luciane Carla
Published: March 2020

Triple-negative breast cancer (TNBC) stands out for its aggressiveness and accelerated rate of proliferation. Evidence shows that exercise may exert antitumorigenic effects, but the biochemical mechanisms underlying them remain unclear. Our objective was to evaluate the ability of exercise to modulate tumor growth and energy metabolism in an experimental TNBC model. Female BALB/c mice were sedentary or trained for 12 weeks and inoculated with 1 × 104 4T1 cells in the eighth week. Analyzes of macronutrient oxidation, mitochondrial respiration, and expression of genes related to cell metabolism were performed. The results showed that the trained group had a smaller tumor mass and the mitochondria in the tumors presented lower respiratory rates in the state of maximum electron transport capacity. Additionally, the tumors of the exercised group showed a higher expression of genes related to tumor suppressors, while the genes linked with cellular growth were similar between groups. Furthermore, the training modulated the corporal macronutrient oxidation to almost exclusive carbohydrate oxidation, while the sedentary condition metabolized both carbohydrate and lipids. Therefore, the exercise reduced tumor growth, with an impact on mitochondrial and macronutrient metabolism. Our results shed light on the understanding of the antitumorigenic effects of physical exercise, particularly regarding the metabolic transformations in TNBC.
Innate and Autoimmunity in the Pathogenesis of Inherited Retinal Dystrophy
Authors: Hollingsworth T. J. , Gross Alecia K.
Published: March 2020

Inherited retinal dystrophies (RDs) are heterogenous in many aspects including genes involved, age of onset, rate of progression, and treatments. While RDs are caused by a plethora of different mutations, all result in the same outcome of blindness. While treatments, both gene therapy-based and drug-based, have been developed to slow or halt disease progression and prevent further blindness, only a small handful of the forms of RDs have treatments available, which are primarily for recessively inherited forms. Using immunohistochemical methods coupled with electroretinography, optical coherence tomography, and fluorescein angiography, we show that in rhodopsin mutant mice, the involvement of both the innate and the autoimmune systems could be a strong contributing factor in disease progression and pathogenesis. Herein, we show that monocytic phagocytosis and inflammatory cytokine release along with protein citrullination, a major player in forms of autoimmunity, work to enhance the progression of RD associated with a rhodopsin mutation.
Perspectives for Glyco-Engineering of Recombinant Biopharmaceuticals from Microalgae
Authors: Barolo Lorenzo , Abbriano Raffaela M. , Commault Audrey S. , George Jestin , Kahlke Tim , Fabris Michele , Padula Matthew P. , Lopez Angelo , Ralph Peter J. , Pernice Mathieu
Published: March 2020

Microalgae exhibit great potential for recombinant therapeutic protein production, due to lower production costs, immunity to human pathogens, and advanced genetic toolkits. However, a fundamental aspect to consider for recombinant biopharmaceutical production is the presence of correct post-translational modifications. Multiple recent studies focusing on glycosylation in microalgae have revealed unique species-specific patterns absent in humans. Glycosylation is particularly important for protein function and is directly responsible for recombinant biopharmaceutical immunogenicity. Therefore, it is necessary to fully characterise this key feature in microalgae before these organisms can be established as industrially relevant microbial biofactories. Here, we review the work done to date on production of recombinant biopharmaceuticals in microalgae, experimental and computational evidence for N- and O-glycosylation in diverse microalgal groups, established approaches for glyco-engineering, and perspectives for their application in microalgal systems. The insights from this review may be applied to future glyco-engineering attempts to humanize recombinant therapeutic proteins and to potentially obtain cheaper, fully functional biopharmaceuticals from microalgae.
Vascular Smooth Muscle Cell-Derived Exosomal MicroRNAs Regulate Endothelial Cell Migration Under PDGF Stimulation
Authors: Heo Jeongyeon , Yang Hee Cheol , Rhee Won Jong , Kang Hara
Published: March 2020

Intercellular communication between vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) is essential for the maintenance of vascular homeostasis. The presence of exosomes, a recently discovered player in vascular cell communication, has been associated with vascular disease progression. However, the detailed mechanism of how the signal mediated by exosomes affects the function of vascular cells during vascular pathogenesis is yet to be further understood. In this study, we investigated the expression of exosomal microRNAs (miRNAs) secreted by VSMCs and their functional relevance to ECs in pathogenesis, including their role in processes such as platelet-derived growth factor (PDGF) stimulation. We observed that PDGF stimulation contributes to a change in exosomal miRNA release from VSMCs; specifically, miR-1246, miR-182, and miR-486 were deficient in exosomes derived from PDGF-stimulated VSMCs. The reduced miRNA expression in these exosomes is associated with an increase in EC migration. These findings increase our understanding of exosome-mediated crosstalk between vascular cells under a pathological condition.
Effective Synergy of Sorafenib and Nutrient Shortage in Inducing Melanoma Cell Death through Energy Stress
Authors: Antunes Fernanda , Pereira Gustavo J. S. , Saito Renata F. , Buri Marcus V. , Gagliardi Mara , Bincoletto Claudia , Chammas Roger , Fimia Gian Maria , Piacentini Mauro , Corazzari Marco , Smaili Soraya Soubhi
Published: March 2020

Skin melanoma is one of the most aggressive and difficult-to-treat human malignancies, characterized by poor survival rates, thus requiring urgent novel therapeutic approaches. Although metabolic reprogramming has represented so far, a cancer hallmark, accumulating data indicate a high plasticity of cancer cells in modulating cellular metabolism to adapt to a heterogeneous and continuously changing microenvironment, suggesting a novel therapeutic approach for dietary manipulation in cancer therapy. To this aim, we exposed melanoma cells to combined nutrient-restriction/sorafenib. Results indicate that cell death was efficiently induced, with apoptosis representing the prominent feature. In contrast, autophagy was blocked in the final stage by this treatment, similarly to chloroquine, which also enhanced melanoma cell sensitization to combined treatment. Energy stress was evidenced by associated treatment with mitochondrial dysfunction and glycolysis impairment, suggesting metabolic stress determining melanoma cell death. A reduction of tumor growth after cycles of intermittent fasting together with sorafenib treatment was also observed in vivo, reinforcing that the nutrient shortage can potentiate anti-melanoma therapy. Our findings showed that the restriction of nutrients by intermittent fasting potentiates the effects of sorafenib due to the modulation of cellular metabolism, suggesting that it is possible to harness the energy of cancer cells for the treatment of melanoma.
Fabrication of Dentin-Pulp-Like Organoids Using Dental-Pulp Stem Cells
Authors: Jeong Sang Yun , Lee Soonchul , Choi Woo Hee , Jee Joo Hyun , Kim Hyung-Ryong , Yoo Jongman
Published: March 2020

We developed a novel dentin-pulp-like organoid. It has both stem-cell and odontoblast characteristics using a mesenchymal cell lineage of human dental-pulp stem cells (hDPSCs). The mixture of hDPSCs and Matrigel was transferred into the maintenance medium (MM) and divided into four different groups according to how long they were maintained in the odontogenic differentiation medium (ODM). All organoids were harvested at 21 days and analyzed to find the optimal differentiation condition. To assess the re-fabrication of dentin-pulp-like organoid, after dissociation of the organoids, it was successfully regenerated. Additionally, its biological activity was confirmed by analyzing changes of relevant gene expression and performing a histology analysis after adding Biodentine® into the ODM. The organoid was cultured for 11 days in the ODM (ODM 11) had the most features of both stem cells and differentiated cells (odontoblasts) as confirmed by relevant gene expression and histology analyses. Micro-computed tomography and an electron microscope also showed mineralization and odontoblastic differentiation. Finally, ODM 11 demonstrated a biologically active response to Biodentine® treatment. In conclusion, for the first time, we report the fabrication of a dentin-pulp-like organoid using mesenchymal stem cells. This organoid has potential as a future therapeutic strategy for tooth regeneration.
Flexure Strength and Fracture Propagation in Zirconia Ceramic Composites with Exfoliated Graphene Nanoplatelets
Authors: Gallardo-López Ángela , Castillo-Seoane Javier , Muñoz-Ferreiro Carmen , López-Pernía Cristina , Morales-Rodríguez Ana , Poyato Rosalía
Published: March 2020

In this work, the flexure strength and fracture propagation mechanisms in yttria tetragonal zirconia (3YTZP) dense composites with 1 and 5 vol.% exfoliated graphene nanoplatelets (e-GNP) were assessed. The composite powders were processed by dry planetary ball milling to exfoliate the as-received GNP, and then densified by spark plasma sintering (SPS). The hardness and Young’s modulus were measured by Vickers indentation and the impulse-echo technique, respectively. Flexural strength and modulus were estimated by four-point bending tests. Finally, cracks originated by Vickers indentations were analyzed by scanning electron microscopy (SEM). The Raman spectra and SEM observations showed a reduction in the number of graphene layers and most remarkably in the lateral size of the e-GNP, achieving a very homogeneous distribution in the ceramic matrix. The hardness, elastic modulus, and flexural strength of the 3YTZP matrix did not vary significantly with the addition of 1 vol.% e-GNP, but they decreased when the content increased to 5 vol.%. The addition of e-GNP to 3YTZP increased its reliability under bending, and the small lateral size of the e-GNP produced isotropic fracture propagation. However, the energy dissipation mechanisms conventionally attributed to the larger GNP such as fracture deflection or blocking were limited.
Effect of Thickness on Tribological Behavior of Hydrogen Free Diamond-like Carbon Coating
Authors: Huang Biao , Zhou Qiong , Zhang Er-geng
Published: March 2020

The effects of film thickness on the tribological behavior have been investigated for hydrogen-free diamond-like carbon coating in this paper. The film was deposited on cemented carbide substrate (YG10C) by applying a high power impulse magnetron sputtering (HiPIMS) technique. The reciprocating ball on the disc test was conducted on the film with different thicknesses from 0.66~1.26 μm against the ZrO2 ball. The friction coefficient and wear resistance of the coating with different thickness showed a unimodal change. Numerous defects were observed on the surface of the film with a thickness of 0.66 μm and the wear mechanism was mainly plow-grinding. Therefore, the steady-state friction coefficient reached the maximum value of 0.22. The coating with a thickness of 1.01 μm had a higher sp3 content and a smoother, dense surface. A graphite transfer layer with low shear strength was detected on the ZrO2 ball against the film with a thickness of 1.01 μm, which led to the reduction in friction, thus the steady-state friction coefficient reached the minimum value of 0.10. However, the internal stress of the film increased with increasing thickness due to the distortion of the bond angle of internal structure when the film was bombarded by high-energy particles. The peeling coating was observed under reciprocating sliding, which both played the role of plowing and boundary lubrication film. The steady-state friction coefficient was 0.14 with a coating thickness of 1.26 μm. As a result, the hydrogen-free diamond-like carbon coating with optimized thickness shows a smooth and compact surface, low internal stress, high sp3 content, and better tribological properties.
High-Pressure Synthesis and Superconducting Properties of NaCl-Type In1−xPbxTe (x = 0–0.8)
Authors: Katsuno Masayoshi , Jha Rajveer , Hoshi Kazuhisa , Sogabe Ryota , Goto Yosuke , Mizuguchi Yoshikazu
Published: March 2020

We have investigated the Pb-substitution effect upon the superconductivity of NaCl-type In1−xPbxTe. Polycrystalline samples with x = 0–0.8 were synthesized using high-pressure synthesis. The lattice parameter was systematically increased by Pb substitution. For x ≤ 0.6, bulk superconductivity was observed, and the superconducting transition temperature increased from 3 K (for InTe) to 5 K by Pb substitutions. From analyses of specific heat jumps at the superconducting transition, conventional (phonon-mediated) weak-coupling pairing mechanisms were suggested for In1−xPbxTe.
Growth and Characterization of (Tb,Yb) Co-Doping Sprayed ZnO Thin Films
Authors: El hat A. , Chaki I. , Essajai R. , Mzerd A. , Schmerber G. , Regragui M. , Belayachi A. , Sekkat Z. , Dinia A. , Slaoui A. , Abd-Lefdil M.
Published: March 2020

Structural, optical and electrical properties of (ytterbium/terbium) co-doped ZnO thin films deposited on glass substrates using the spray pyrolysis method were investigated. The films exhibited the hexagonal wurtzite structure with a preferential orientation along (002) direction. No secondary phase was observed in the X-ray diffraction detection limit. Atomic force microscopy (AFM) was performed and root means square roughness (RMS) of our samples decreased with terbium content. Photoluminescence measurements showed a luminescence band at 980 nm which is characteristic of Yb3+ transition between the electronic levels 2F5/2 to 2F7/2. This is experimental evidence for an efficient energy transfer from the ZnO matrix to Yb. Hall Effect measurements gave a low electrical resistivity value around 6.0 × 10−3 Ω.cm. Such characteristics make these films of interest to photovoltaic devices.
Guided Optical Modes in Metal-Cladded Tunable Hyperbolic Metamaterial Slab Waveguides
Authors: Kieliszczyk Marcin , Janaszek Bartosz , Tyszka-Zawadzka Anna , Szczepański Paweł
Published: March 2020

We have theoretically investigated metal-cladded waveguides of tunable hyperbolic metamaterial (THMM) cores, employing graphene sheets as a tunable layer, in terms of guided waves propagation over near- to mid-infrared range, following the effective medium approximation. We have proven that these subwavelength guiding structures offer a number of effects usually not found in other types of waveguides, including controllable propagation gap and number of modes, inversion of power flow direction with respect to phase velocity, TM mode propagation, and absence of the fundamental mode, which occur as a result of controlled change of the guiding layer dispersion regime. This is the first time that the above-mentioned effects are obtained with a single, voltage-controlled waveguiding structure comprising graphene sheets and a dielectric, although the presented methodology allows us to incorporate other tunable materials beyond graphene equally well. We believe that such or similar structures, feasible by means of current planar deposition techniques, will ultimately find their practical applications in optical signal processing, controlled phase matching, controlled coupling, signal modulation, or the enhancement of nonlinear effects.
Spatial Pattern of Species Richness among Terrestrial Mammals in China
Authors: Chi Yao , Wang Jiechen , Xi Changbai , Qian Tianlu , Sheng Caiying
Published: March 2020

We describe large-scale patterns of terrestrial mammal distribution in China by using geographical information system (GIS) spatial analysis. Mammal taxa, examined by species, family, and order, were binned into 10 km × 10 km grids to explore the relationship between their spatial distribution and geographical factors potentially affecting the same. The spatial pattern of species richness revealed four agglomerations: high richness in the south, low in north, and two low richness areas in eastern and western China. Species richness patterns in Carnivora was the most similar to overall terrestrial mammals’ richness; however, species richness in different orders exhibited distributions distinct from the overall pattern. We found a negative relationship between richness and latitude gradient. Species richness was most strongly correlated with forested ecosystems, and was found to be higher at an elevation of 2000~2200 m, with greater altitudinal variation indicative of higher species richness.
In Praise of Quantum Uncertainty
Authors: Cohen Eliahu , Carmi Avishy
Published: March 2020

Quantum uncertainty has a tremendous explanatory power. Coherent superposition, quantum equations of motion, entanglement, nonlocal correlations, dynamical nonlocality, contextuality, discord, counterfactual protocols, weak measurements, quantization itself, and even preservation of causality can be traced back to quantum uncertainty. We revisit and extend our previous works, as well as some other works of the community, in order to account for the above claims. Special emphasis is given to the connection between uncertainty and nonlocality, two notions which evolved quite independently and may seem distinct but, in fact, are tightly related. Indeterminism, or more precisely, locally consistent indeterminism, should be understood as the enabler of most quantum phenomena (and possibly all of them).
Robust Model Selection Criteria Based on Pseudodistances
Authors: Toma Aida , Karagrigoriou Alex , Trentou Paschalini
Published: March 2020

In this paper, we introduce a new class of robust model selection criteria. These criteria are defined by estimators of the expected overall discrepancy using pseudodistances and the minimum pseudodistance principle. Theoretical properties of these criteria are proved, namely asymptotic unbiasedness, robustness, consistency, as well as the limit laws. The case of the linear regression models is studied and a specific pseudodistance based criterion is proposed. Monte Carlo simulations and applications for real data are presented in order to exemplify the performance of the new methodology. These examples show that the new selection criterion for regression models is a good competitor of some well known criteria and may have superior performance, especially in the case of small and contaminated samples.
Quality of Feedback in Higher Education: A Review of Literature
Authors: Haughney Kathryn , Wakeman Shawnee , Hart Laura
Published: March 2020

In raising the standards for professional educators, higher educators must be prepared to provide the highest quality feedback on student performance and work products toward improved outcomes. This review of the literature examined the major findings of 70 quantitative, mixed methods, or qualitative studies found in higher education journals across a range of disciplines. Multiple recommendations and results for feedback emerged which fall into the categories described by Susan Brookhart. This review found research for each of Brookhart’s categories, with results indicating differences between the perceptions of adherence to sound feedback practices versus the reality of implementation, the potential for innovative tool use, and a disagreement about the effectiveness of peers for providing effective feedback. Indicators for quality within the research confirmed the importance of commonly accepted standards such as positivity, specificity, timeliness, and encouraging active student participation. Additionally, trends and themes indicated a need for the consistent implementation of the feedback exchange process and flexibility to account for student input/preferences. Greater consistency toward the application of these quality indicators should be undertaken when determining the quality of higher education feedback for preservice teachers prior to undertaking summative licensure assessments.
An Autonomous Path Controller in a System on Chip for Shrimp Robot
Authors: Barrios-dV Sergio , Lopez-Franco Michel , Rios Jorge D. , Arana-Daniel Nancy , Lopez-Franco Carlos , Alanis Alma Y.
Published: March 2020

This paper presents a path planning and trajectory tracking system for a BlueBotics Shrimp III®, which is an articulate mobile robot for rough terrain navigation. The system includes a decentralized neural inverse optimal controller, an inverse kinematic model, and a path-planning algorithm. The motor control is obtained based on a discrete-time recurrent high order neural network trained with an extended Kalman filter, and an inverse optimal controller designed without solving the Hamilton Jacobi Bellman equation. To operate the whole system in a real-time application, a Xilinx Zynq® System on Chip (SoC) is used. This implementation allows for a good performance and fast calculations in real-time, in a way that the robot can explore and navigate autonomously in unstructured environments. Therefore, this paper presents the design and implementation of a real-time system for robot navigation that integrates, in a Xilinx Zynq® System on Chip, algorithms of neural control, image processing, path planning, and inverse kinematics and trajectory tracking.
On the Kelvin Transformation in Finite Difference Implementations
Authors: Gold Gerald
Published: March 2020

Finite difference operators were applied on a Delaunay mesh. This way it is possible to discretize a radial boundary that is used to perform a Kelvin mapping of an additional outer domain to virtually extend the computation domain to infinity. With an example two-wire problem, the performance of this approach is shown in comparison with a conventional calculation domain and with the analytical solution, respectively. The presented implementation delivers a more precise approximation to the real values and at the same time requires a smaller system of equations—i.e., allows for faster computations.
A Benders’ Decomposition Approach for Renewable Generation Investment in Distribution Systems
Authors: Montoya-Bueno Sergio , Muñoz-Hernandez Jose , Contreras Javier , Baringo Luis
Published: March 2020

A model suitable to obtain where and when renewable energy sources (RES) should be allocated as part of generation planning in distribution systems is formulated. The proposed model starts from an existing two-stage stochastic mixed-integer linear programming (MILP) problem including investment and scenario-dependent operation decisions. The aim is to minimize photovoltaic and wind investment costs, operation costs, as well as total substation costs including the cost of the energy bought from substations and energy losses. A new Benders’ decomposition framework is used to decouple the problem between investment and operation decisions, where the latter can be further decomposed into a set of smaller problems per scenario and planning period. The model is applied to a 34-bus system and a comparison with a MILP model is presented to show the advantages of the model proposed.