bluuebunny/crossref_metadata_2025 huggingface dataset:
Considering Urban Development Paths and Processes on Account of Adaptive Reuse Projects
Authors: Vardopoulos Ioannis , Stamopoulos Christos , Chatzithanasis Georgios , Michalakelis Christos , Giannouli Panagiota , Pastrapa Eleni
Published: April 2020

This article, as part of the ‘SUMcity’ research program, aims to give a comprehensive account of the regeneration that occurred in Athens by the adaptive reuse of the old FIX Brewery to house the new Hellenic National Museum of Contemporary Art (EMST). Adaptive reuse is an urban sustainability development evolving process, used to manage assets and resources efficiently, resulting in economic development, increased local attraction, and revitalized community engagement. Other than that, modern societies experience the dynamic stream of social media and smart city initiatives, amid a long-discussed and complex cultural heritage preservation backdrop. Notwithstanding the value added to the city, the interaction of sustainable development with adaptive reuse projects, culture, tourism, social media use, and smart city initiatives, along with the impact of this intangible relationship, has yet to be set in a more tangible form. Methodologically, a newly developed conceptual framework is used in order to re-define the (cor)relations among the existent concepts of sustainable development, smart city and cultural heritage. Subsequently, a primary questionnaire-based research is conducted on Instagram users’ geotagging the Hellenic National Museum of Contemporary Art (EMST), analyzing their views in an attempt to demonstrate the arising local potential and sustainability.
Magnetic-Based Enrichment of Rare Cells from High Concentrated Blood Samples
Authors: Wu Junhao , Raba Katharina , Guglielmi Rosa , Behrens Bianca , Van Dalum Guus , Flügen Georg , Koch Andreas , Patel Suraj , Knoefel Wolfram T. , Stoecklein Nikolas H. , Neves Rui P. L.
Published: April 2020

Here, we tested two magnetic-bead based systems for the enrichment and detection of rare tumor cells in concentrated blood products. For that, the defined numbers of cells from three pancreatic cancer cell lines were spiked in 108 peripheral blood mononuclear cells (PBMNCs) concentrated in 1 mL, mimicking diagnostic leukapheresis (DLA) samples, and samples were processed for circulating tumor cells (CTC) enrichment with the IsoFlux or the KingFisher systems, using different types of magnetic beads from the respective technology providers. Beads were conjugated with different anti-EpCAM and MUC-1 antibodies. Recovered cells were enumerated and documented by fluorescent microscopy. For the IsoFlux system, best performance was obtained with IsoFlux CTC enrichment kit, but these beads compromised the subsequent immunofluorescence staining. For the KingFisher system, best recoveries were obtained using Dynabeads Biotin Binder beads. These beads also allowed one to capture CTCs with different antibodies and the subsequent immunofluorescence staining. KingFisher instrument allowed a single and streamlined protocol for the enrichment and staining of CTCs that further prevented cell loss at the enrichment/staining interface. Both IsoFlux and KingFisher systems allowed the enrichment of cell line cells from the mimicked-DLA samples. However, in this particular experimental setting, the recovery rates obtained with the KingFisher system were globally higher, the system was more cost-effective, and it allowed higher throughput.
Circulating miR-21 as a Potential Biomarker for the Diagnosis of Oral Cancer: A Systematic Review with Meta-Analysis
Authors: Dioguardi Mario , Caloro Giorgia Apollonia , Laino Luigi , Alovisi Mario , Sovereto Diego , Crincoli Vito , Aiuto Riccardo , Coccia Erminia , Troiano Giuseppe , Lo Muzio Lorenzo
Published: April 2020

Head and neck squamous cell carcinoma (HNSCC) is one of the main neoformations of the head–neck region and is characterized by the presence of squamous carcinomatous cells of the multi-layered epithelium lining the oral cavity, larynx, and pharynx. The annual incidence of squamous cell carcinoma of the head and neck (HNSCC) comprises approximately 600,000 new cases globally. Currently, the 5-year survival from HNSCC is less than 50%. Surgical, radiotherapy, and chemotherapy treatments strongly compromise patient quality of life. MicroRNAs (miRNAs) are a family of small noncoding endogenous RNAs that function in regulating gene expression by regulating several biological processes, including carcinogenesis. The main upregulated microRNAs associated with oral carcinoma are miR-21, miR-455-5p, miR-155-5p, miR-372, miR-373, miR-29b, miR-1246, miR-196a, and miR-181, while the main downregulated miRNAs are miR-204, miR-101, miR-32, miR-20a, miR-16, miR-17, and miR-125b. miR-21 represents one of the first oncomirs studied. The present systematic review work was performed based on the preferred reporting items for systematic review and meta-analysis (PRISMA) protocol. A search was carried out in the PubMed and Scopus databases with the use of keywords. This search produced 628 records which, after the elimination of duplicates and the application of the inclusion and exclusion criteria, led to 7 included articles. The heterogeneity of the studies according to the odds ratio was high, with a Q value of 26.616 (p < 0.001), and the I2 was 77.457% for specificity. The heterogeneity was high, with a Q value of 25.243 (p < 0.001) and the I2 was 76.231% for sensitivity. The heterogeneity of data showed a Q value of 27.815 (p < 0.001) and the I2 was 78.429%. Therefore, the random-effects model was selected. The diagnostic odds ratio was 7.620 (95% CI 3.613–16.070). The results showed that the sensitivity was 0.771 (95% CI 0.680–0.842) (p < 0.001) while, for specificity, we found 0.663 (95% CI 0.538–0.770) (p < 0.001). The negative likelihood ratio (NLR) was 0.321 (95% CI 0.186–0.554), and the positive likelihood ratio (PLR) was 2.144 (95% CI 1.563–2.943). The summary ROC plot demonstrates that the diagnostic test presents good specificity and sensitivity, and the area under the curve (AUC), as calculated from the graph, was 0.79.
BCL-2 Proteins in Pathogenesis and Therapy of B-Cell Non-Hodgkin Lymphomas
Authors: Klanova Magdalena , Klener Pavel
Published: April 2020

The ability to inhibit mitochondrial apoptosis is a hallmark of B-cell non-Hodgkin lymphomas (B-NHL). Activation of mitochondrial apoptosis is tightly controlled by members of B-cell leukemia/lymphoma-2 (BCL-2) family proteins via protein-protein interactions. Altering the balance between anti-apoptotic and pro-apoptotic BCL-2 proteins leads to apoptosis evasion and extended survival of malignant cells. The pro-survival BCL-2 proteins: B-cell leukemia/lymphoma-2 (BCL-2/BCL2), myeloid cell leukemia-1 (MCL-1/MCL1) and B-cell lymphoma-extra large (BCL-XL/BCL2L1) are frequently (over)expressed in B-NHL, which plays a crucial role in lymphoma pathogenesis, disease progression, and drug resistance. The efforts to develop inhibitors of anti-apoptotic BCL-2 proteins have been underway for several decades and molecules targeting anti-apoptotic BCL-2 proteins are in various stages of clinical testing. Venetoclax is a highly specific BCL-2 inhibitor, which has been approved by the US Food and Drug Agency (FDA) for the treatment of patients with chronic lymphocytic leukemia (CLL) and is in advanced clinical testing in other types of B-NHL. In this review, we summarize the biology of BCL-2 proteins and the mechanisms of how these proteins are deregulated in distinct B-NHL subtypes. We describe the mechanism of action of BH3-mimetics and the status of their clinical development in B-NHL. Finally, we summarize the mechanisms of sensitivity/resistance to venetoclax.
S100A4 Is a Biomarker of Tumorigenesis, EMT, Invasion, and Colonization of Host Organs in Experimental Malignant Mesothelioma
Authors: Nader Joëlle S. , Guillon Jordan , Petit Coralie , Boissard Alice , Franconi Florence , Blandin Stéphanie , Lambot Sylvia , Grégoire Marc , Verrièle Véronique , Nawrocki-Raby Béatrice , Birembaut Philippe , Coqueret Olivier , Guette Catherine , Pouliquen Daniel L.
Published: April 2020

Recent findings suggest that S100A4, a protein involved in communication between stromal cells and cancer cells, could be more involved than previously expected in cancer invasiveness. To investigate its cumulative value in the multistep process of the pathogenesis of malignant mesothelioma (MM), SWATH-MS (sequential window acquisition of all theoretical fragmentation spectra), an advanced and robust technique of quantitative proteomics, was used to analyze a collection of 26 preneoplastic and neoplastic rat mesothelial cell lines and models of MM with increasing invasiveness. Secondly, proteomic and histological analyses were conducted on formalin-fixed paraffin-embedded sections of liver metastases vs. primary tumor, and spleen from tumor-bearing rats vs. controls in the most invasive MM model. We found that S100A4, along with 12 other biomarkers, differentiated neoplastic from preneoplastic mesothelial cell lines, and invasive vs. non-invasive tumor cells in vitro, and MM tumors in vivo. Additionally, S100A4 was the only protein differentiating preneoplastic mesothelial cell lines with sarcomatoid vs. epithelioid morphology in relation to EMT (epithelial-to-mesenchymal transition). Finally, S100A4 was the most significantly increased biomarker in liver metastases vs. primary tumor, and in the spleen colonized by MM cells. Overall, we showed that S100A4 was the only protein that showed increased abundance in all situations, highlighting its crucial role in all stages of MM pathogenesis.
Hyaluronic Acid-Based Theranostic Nanomedicines for Targeted Cancer Therapy
Authors: Lee So Yun , Kang Moon Sung , Jeong Woo Yeup , Han Dong-Wook , Kim Ki Su
Published: April 2020

Hyaluronic acid (HA) is a natural mucopolysaccharide and has many useful advantages, including biocompatibility, non-immunogenicity, chemical versatility, non-toxicity, biodegradability, and high hydrophilicity. Numerous tumor cells overexpress several receptors that have a high binding affinity for HA, while these receptors are poorly expressed in normal body cells. HA-based drug delivery carriers can offer improved solubility and stability of anticancer drugs in biological environments and allow for the targeting of cancer treatments. Based on these benefits, HA has been widely investigated as a promising material for developing the advanced clinical cancer therapies in various formulations, including nanoparticles, micelles, liposomes, and hydrogels, combined with other materials. We describe various approaches and findings showing the feasibility of improvement in theragnosis probes through the application of HA.
Brigatinib and Alectinib for ALK Rearrangement-Positive Advanced Non-Small Cell Lung Cancer with or without Central Nervous System Metastasis: A Systematic Review and Network Meta-Analysis
Authors: Ando Koichi , Akimoto Kaho , Sato Hiroki , Manabe Ryo , Kishino Yasunari , Homma Tetsuya , Kusumoto Sojiro , Yamaoka Toshimitsu , Tanaka Akihiko , Ohmori Tohru , Sagara Hironori
Published: April 2020

To date, no head-to-head trials have compared the efficacy of brigatinib and alectinib against anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p), ALK-inhibitor-naïve, advanced non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastasis. We conducted an indirect treatment comparison (ITC) between brigatinib and alectinib, with crizotinib as a common comparator, using a Bayesian model with non-informative prior distribution and assessed the between-study heterogeneity of the studies. The primary efficacy endpoint was progression-free survival (PFS), and efficacy was ranked using the surface under the cumulative ranking (SUCRA) curve values. ITC analysis showed that there were no significant differences in PFS between the brigatinib and alectinib arms. However, the SUCRA values revealed that alectinib ranked the highest by efficacy in the overall patient population, whereas brigatinib ranked the highest by efficacy in the CNS metastasis sub-group. Although there were no significant differences in the incidence of G3–5 adverse events between the brigatinib and alectinib arms in the overall patient population, the data were deemed insufficient for the CNS metastasis sub-group analysis. This study provides critical information to clinicians regarding the efficacy of brigatinib for ALK-p, ALK-inhibitor-naïve, advanced NSCLC patients, with and without CNS metastasis. Larger randomized, controlled trials are warranted to confirm our results.
Haute Couture or Ready-To-Wear? Tailored Pelvic Radiotherapy for Prostate Cancer Based on Individualized Sentinel Lymph Node Detection
Authors: Michaud Anne-Victoire , Samain Benoit , Ferrer Ludovic , Fleury Vincent , Dore Melanie , Colombie Mathilde , Dupuy Claire , Rio Emmanuel , Guimas Valentine , Rousseau Thierry , Le Thiec Maelle , Delpon Gregory , Rousseau Caroline , Supiot Stephane
Published: April 2020

Prostate cancer (PCa) pelvic radiotherapy fields are defined by guidelines that do not consider individual variations in lymphatic drainage. We examined the feasibility of personalized sentinel lymph node (SLN)-based pelvic irradiation in PCa. Among a SLN study of 202 patients, we retrospectively selected 57 patients with a high risk of lymph node involvement. Each single SLN clinical target volume (CTV) was individually segmented and pelvic CTVs were contoured according to Radiation Therapy Oncology Group (RTOG) guidelines. We simulated a radiotherapy plan delivering 46 Gy and calculated the dose received by each SLN. Among a total of 332 abdominal SLNs, 305 pelvic SLNs (beyond the aortic bifurcation) were contoured (mean 5.4/patient). Based on standard guidelines, CTV missed 67 SLNs (22%), mostly at the common iliac level (40 SLNs). The mean distance between iliac vessels and the SLN was 11mm, and despite a 15mm margin around the iliac vessels, 9% of SLNs were not encompassed by the CTV. Moreover, 42 SLNs (63%) did not receive 95% of the prescribed dose. Despite a consensus on contouring guidelines, a significant proportion of SLNs were not included in the pelvic CTV and did not receive the prescribed dose. A tailored approach based on individual SLN detection would avoid underdosing pelvic lymph nodes that potentially contain tumor cells.
Glucocorticoids Promote the Onset of Acute Experimental Colitis and Cancer by Upregulating mTOR Signaling in Intestinal Epithelial Cells
Authors: Zhang Zhengguo , Dong Lin , Jia Anna , Chen Xi , Yang Qiuli , Wang Yufei , Wang Yuexin , Liu Ruichen , Cao Yejin , He Ying , Bi Yujing , Liu Guangwei
Published: April 2020

The therapeutic effects of glucocorticoids on colitis and colitis-associated cancer are unclear. In this study, we investigated the therapeutic roles of glucocorticoids in acute experimental ulcerative colitis and colitis-associated cancer in mice and their immunoregulatory mechanisms. Murine acute ulcerative colitis was induced by dextran sulfate sodium (DSS) and treated with dexamethasone (Dex) at different doses. Dex significantly exacerbated the onset and severity of DSS-induced colitis and potentiated mucosal inflammatory macrophage and neutrophil infiltration, as well as cytokine production. Furthermore, under inflammatory conditions, the expression of the glucocorticoid receptor (GR) did not change significantly, while mammalian target of rapamycin (mTOR) signaling was higher in colonic epithelial cells than in colonic immune cells. The deletion of mTOR in intestinal epithelial cells, but not that in myeloid immune cells, in mice significantly ameliorated the severe course of colitis caused by Dex, including weight loss, clinical score, colon length, pathological damage, inflammatory cell infiltration and pro-inflammatory cytokine production. These data suggest that mTOR signaling in intestinal epithelial cells, mainly mTORC1, plays a critical role in the Dex-induced exacerbation of acute colitis and colitis-associated cancer. Thus, these pieces of evidence indicate that glucocorticoid-induced mTOR signaling in epithelial cells is required in the early stages of acute ulcerative colitis by modulating the dynamics of innate immune cell recruitment and activation.
TERT Promoter Mutations Differently Correlate with the Clinical Outcome of MAPK Inhibitor-Treated Melanoma Patients
Authors: Del Bianco Paola , Stagni Camilla , Giunco Silvia , Fabozzi Alessio , Elefanti Lisa , Pellegrini Stefania , Vecchiato Antonella , Pigozzo Jacopo , Zamuner Carolina , De Rossi Anita , De Nicolo Arcangela , Menin Chiara
Published: April 2020

Resistance is a major challenge in the management of mitogen-activated protein kinase inhibitor (MAPKi)-treated metastatic melanoma. Tumor genetic alterations can cause MAPK pathway reactivation, leading to lack of response and poor outcome. Characterization of the mutational profile in patients with melanoma might be crucial for patient-tailored treatment choices. Mutations in the promoter region of the telomerase reverse transcriptase gene (TERTprom) lead to increased TERT expression and telomerase activity and are frequent in BRAFV600 mutant melanoma. Reportedly, TERTprom, and BRAFV600 mutations cooperate in driving cancer progression and aggressiveness. We evaluated the effect of the TERTprom status on the clinical outcome in 97 MAPKi-treated melanoma patients. We observed that patients with the c.-146C > T mutation showed a significantly worse progression-free survival (PFS) compared to those carrying the c.-124C > T mutation and a two-fold increased risk of progression (median 5.4 vs. 9.5 months; hazard ratio (HR) 1.9; 95% confidence interval (CI) 1.2–3.2; p = 0.013). This trend was also observed for the overall survival (OS); melanoma patients with the c.-146C > T mutation showed a poorer prognosis compared to those with the c.-124C > T mutation (median 13.3 vs. 25.5 months; HR 1.9, 95% CI 1.1–3.3, p = 0.023). Our results disclose a different correlation of the two TERTprom mutations with MAPKi-treated melanoma patient outcome, highlighting a different impact of the pathway blockade.
Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility
Authors: Miller Henry E. , Gorthi Aparna , Bassani Nicklas , Lawrence Liesl A. , Iskra Brian S. , Bishop Alexander J. R.
Published: April 2020

Ewing sarcoma is an aggressive pediatric cancer of enigmatic cellular origins typically resulting from a single translocation event t (11; 22) (q24; q12). The resulting fusion gene, EWSR1-FLI1, is toxic or unstable in most primary tissues. Consequently, attempts to model Ewing sarcomagenesis have proven unsuccessful thus far, highlighting the need to identify the cellular features which permit stable EWSR1-FLI1 expression. By re-analyzing publicly available RNA-Sequencing data with manifold learning techniques, we uncovered a group of Ewing-like tissues belonging to a developmental trajectory between pluripotent, neuroectodermal, and mesodermal cell states. Furthermore, we demonstrated that EWSR1-FLI1 expression levels control the activation of these developmental trajectories within Ewing sarcoma cells. Subsequent analysis and experimental validation demonstrated that the capability to resolve R-loops and mitigate replication stress are probable prerequisites for stable EWSR1-FLI1 expression in primary tissues. Taken together, our results demonstrate how EWSR1-FLI1 hijacks developmental gene programs and advances our understanding of Ewing sarcomagenesis.
Natural Killer Cells: Tumor Surveillance and Signaling
Authors: Meza Guzman Lizeth G. , Keating Narelle , Nicholson Sandra E.
Published: April 2020

Natural killer (NK) cells play a pivotal role in cancer immunotherapy due to their innate ability to detect and kill tumorigenic cells. The decision to kill is determined by the expression of a myriad of activating and inhibitory receptors on the NK cell surface. Cell-to-cell engagement results in either self-tolerance or a cytotoxic response, governed by a fine balance between the signaling cascades downstream of the activating and inhibitory receptors. To evade a cytotoxic immune response, tumor cells can modulate the surface expression of receptor ligands and additionally, alter the conditions in the tumor microenvironment (TME), tilting the scales toward a suppressed cytotoxic NK response. To fully harness the killing power of NK cells for clinical benefit, we need to understand what defines the threshold for activation and what is required to break tolerance. This review will focus on the intracellular signaling pathways activated or suppressed in NK cells and the roles signaling intermediates play during an NK cytotoxic response.
Novel Liquid Biomarker Panels for A Very Early Response Capturing of NSCLC Therapies in Advanced Stages
Authors: Janke Florian , Bozorgmehr Farastuk , Wrenger Sabine , Dietz Steffen , Heussel Claus P. , Heussel Gudula , Silva Carlos F. , Rheinheimer Stephan , Feisst Manuel , Thomas Michael , Golpon Heiko , Günther Andreas , Sültmann Holger , Muley Thomas , Janciauskiene Sabina , Meister Michael , Schneider Marc A.
Published: April 2020

Computed tomography (CT) scans are the gold standard to measure treatment success of non-small cell lung cancer (NSCLC) therapies. Here, we investigated the very early tumor response of patients receiving chemotherapy or targeted therapies using a panel of already established and explorative liquid biomarkers. Blood samples from 50 patients were taken at baseline and at three early time points after therapy initiation. DNA mutations, a panel of 17 microRNAs, glycodelin, glutathione disulfide, glutathione, soluble caspase-cleaved cytokeratin 18 (M30 antigen), and soluble cytokeratin 18 (M65 antigen) were measured in serum and plasma samples. Baseline and first follow-up CT scans were evaluated and correlated with biomarker data. The detection rate of the individual biomarkers was between 56% and 100%. While only keratin 18 correlated with the tumor load at baseline, we found several individual markers correlating with the tumor response to treatment for each of the three time points of blood draws. A combination of the five best markers at each time point resulted in highly significant marker panels indicating therapeutic response (R2 = 0.78, R2 = 0.71, and R2 = 0.71). Our study demonstrates that an early measurement of biomarkers immediately after therapy start can assess tumor response to treatment and might support an adaptation of treatment to improve patients’ outcome.
Targeted Assessment of the EGFR Status as Reflex Testing in Treatment-Naive Non-Squamous Cell Lung Carcinoma Patients: A Single Laboratory Experience (LPCE, Nice, France)
Authors: Lassalle Sandra , Hofman Véronique , Heeke Simon , Benzaquen Jonathan , Long Elodie , Poudenx Michel , Lantéri Elisabeth , Boutros Jacques , Tanga Virginie , Zahaf Katia , Lalvée Salomé , Lespinet Virginie , Bordone Olivier , Félix Jean-Marc , Bonnetaud Christelle , Marquette Charles , Ilie Marius , Hofman Paul
Published: April 2020

Background: Assessment of actionable EGFR mutations is mandatory for treatment-naïve advanced or metastatic non-squamous lung carcinoma (NSLC), but the results need to be obtained in less than 10 working days. For rapid EGFR testing, an EGFR-specific polymerase chain reaction (PCR) assay is an alternative and simple approach compared to next generation sequencing (NGS). Here, we describe how a rapid EGFR-specific PCR assay can be implemented in a single laboratory center (LPCE, Nice, France) as reflex testing in treatment-naïve NSLC. Methods: A total of 901 biopsies from NSLC with more than 10% of tumor cells were prospectively and consecutively evaluated for EGFR mutation status between November 2017 and December 2019 using the Idylla system (Biocartis NV, Mechelen, Belgium). NGS was performed for nonsmokers with NSLC wild type for EGFR, ALK, ROS1, and BRAF and with less than 50% PD-L1 positive cells using the Hotspot panel (Thermo Fisher Scientific, Waltham, MA, USA). Results: Results were obtained from 889/901 (97%) biopsies with detection of EGFR mutations in 114/889 (13%) cases using the Idylla system. Among the 562 EGFR wild type tumors identified with Idylla, NGS detected one actionable and one nonactionable EGFR mutation. Conclusions: Rapid and targeted assessment of EGFR mutations in treatment-naïve NSLC can be implemented in routine clinical practice. However, it is mandatory to integrate this approach into a molecular algorithm that allows evaluation of potentially actionable genomic alterations other than EGFR mutations.
Special Issue: Coordination Chemistry and Catalysis
Authors: Martins Luísa M. D. R. S.
Published: April 2020

Coordination chemistry plays a key role in the design of functionalized materials, organic and template synthesis, biological systems and catalytic processes [...]
Efficient Waste to Energy Conversion Based on Co-CeO2 Catalyzed Water-Gas Shift Reaction
Authors: Kim Kyoung-Jin , Lee Yeol-Lim , Na Hyun-Suk , Ahn Seon-Yong , Shim Jae-Oh , Jeon Byong-Hun , Roh Hyun-Seog
Published: April 2020

Waste to energy technology is attracting attention to overcome the upcoming environmental and energy issues. One of the key-steps is the water-gas shift (WGS) reaction, which can convert the waste-derived synthesis gas (H2 and CO) to pure hydrogen. Co–CeO2 catalysts were synthesized by the different methods to derive the optimal synthetic method and to investigate the effect of the preparation method on the physicochemical characteristics of Co–CeO2 catalysts in the high-temperature water-gas shift (HTS) reaction. The Co–CeO2 catalyst synthesized by the sol-gel method featured a strong metal to support interaction and the largest number of oxygen vacancies compared to other catalysts, which affects the catalytic activity. As a result, the Co–CeO2 catalyst synthesized by the sol-gel method exhibited the highest WGS activity among the prepared catalysts, even in severe conditions (high CO concentration: ~38% in dry basis and high gas hourly space velocity: 143,000 h−1).
Noggin Inhibits IL-1β and BMP-2 Expression, and Attenuates Cartilage Degeneration and Subchondral Bone Destruction in Experimental Osteoarthritis
Authors: Chien Szu-Yu , Tsai Chun-Hao , Liu Shan-Chi , Huang Chien-Chung , Lin Tzu-Hung , Yang Yu-Zhen , Tang Chih-Hsin
Published: April 2020

Osteoarthritis (OA) is a chronic inflammatory and progressive joint disease that results in cartilage degradation and subchondral bone remodeling. The proinflammatory cytokine interleukin 1 beta (IL-1β) is abundantly expressed in OA and plays a crucial role in cartilage remodeling, although its role in the activity of chondrocytes in cartilage and subchondral remodeling remains unclear. In this study, stimulating chondrogenic ATDC5 cells with IL-1β increased the levels of bone morphogenetic protein 2 (BMP-2), promoted articular cartilage degradation, and enhanced structural remodeling. Immunohistochemistry staining and microcomputed tomography imaging of the subchondral trabecular bone region in the experimental OA rat model revealed that the OA disease promotes levels of IL-1β, BMP-2, and matrix metalloproteinase 13 (MMP-13) expression in the articular cartilage and enhances subchondral bone remodeling. The intra-articular injection of Noggin protein (a BMP-2 inhibitor) attenuated subchondral bone remodeling and disease progression in OA rats. We also found that IL-1β increased BMP-2 expression by activating the mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and specificity protein 1 (Sp1) signaling pathways. We conclude that IL-1β promotes BMP-2 expression in chondrocytes via the MEK/ERK/Sp1 signaling pathways. The administration of Noggin protein reduces the expression of IL-1β and BMP-2, which prevents cartilage degeneration and OA development.
Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss
Authors: Collin Gayle B. , Gogna Navdeep , Chang Bo , Damkham Nattaya , Pinkney Jai , Hyde Lillian F. , Stone Lisa , Naggert Jürgen K. , Nishina Patsy M. , Krebs Mark P.
Published: April 2020

Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. The progression of PR cell loss with postnatal age was documented in mutant alleles of genes grouped by biological function. As anticipated, a wide range in the onset and rate of cell loss was observed among the reported models. The analysis underscored relationships between RD genes and ciliary function, transcription-coupled DNA damage repair, and cellular chloride homeostasis. Comparing the mouse gene list to human RD genes identified in the RetNet database revealed that mouse models are available for 40% of the known human diseases, suggesting opportunities for future research. This work may provide insight into the molecular players and pathways through which PR degenerative disease occurs and may be useful for planning translational studies.
Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging
Authors: Ghosh Rajeshwary , Vinod Vishaka , Symons J. David , Boudina Sihem
Published: April 2020

Cardiovascular disease (CVD) is the number one cause of death in the United States. Advancing age is a primary risk factor for developing CVD. Estimates indicate that 20% of the US population will be ≥65 years old by 2030. Direct expenditures for treating CVD in the older population combined with indirect costs, secondary to lost wages, are predicted to reach $1.1 trillion by 2035. Therefore, there is an eminent need to discover novel therapeutic targets and identify new interventions to delay, lessen the severity, or prevent cardiovascular complications associated with advanced age. Protein and organelle quality control pathways including autophagy/lysosomal and the ubiquitin-proteasome systems, are emerging contributors of age-associated myocardial dysfunction. In general, two findings have sparked this interest. First, strong evidence indicates that cardiac protein degradation pathways are altered in the heart with aging. Second, it is well accepted that damaged and misfolded protein aggregates and dysfunctional mitochondria accumulate in the heart with age. In this review, we will: (i) define the different protein and mitochondria quality control mechanisms in the heart; (ii) provide evidence that each quality control pathway becomes dysfunctional during cardiac aging; and (iii) discuss current advances in targeting these pathways to maintain cardiac function with age.
The Molecular Mechanisms Underlying Prostaglandin D2-Induced Neuritogenesis in Motor Neuron-Like NSC-34 Cells
Authors: Nango Hiroshi , Kosuge Yasuhiro , Yoshimura Nana , Miyagishi Hiroko , Kanazawa Takanori , Hashizaki Kaname , Suzuki Toyofumi , Ishige Kumiko
Published: April 2020

Prostaglandins are a group of physiologically active lipid compounds derived from arachidonic acid. Our previous study has found that prostaglandin E2 promotes neurite outgrowth in NSC-34 cells, which are a model for motor neuron development. However, the effects of other prostaglandins on neuronal differentiation are poorly understood. The present study investigated the effect of prostaglandin D2 (PGD2) on neuritogenesis in NSC-34 cells. Exposure to PGD2 resulted in increased percentages of neurite-bearing cells and neurite length. Although D-prostanoid receptor (DP) 1 and DP2 were dominantly expressed in the cells, BW245C (a DP1 agonist) and 15(R)-15-methyl PGD2 (a DP2 agonist) had no effect on neurite outgrowth. Enzyme-linked immunosorbent assay demonstrated that PGD2 was converted to 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) under cell-free conditions. Exogenously applied 15d-PGJ2 mimicked the effect of PGD2 on neurite outgrowth. GW9662, a peroxisome proliferator-activated receptor–gamma (PPARγ) antagonist, suppressed PGD2-induced neurite outgrowth. Moreover, PGD2 and 15d-PGJ2 increased the protein expression of Islet-1 (the earliest marker of developing motor neurons), and these increases were suppressed by co-treatment with GW9662. These results suggest that PGD2 induces neuritogenesis in NSC-34 cells and that PGD2-induced neurite outgrowth was mediated by the activation of PPARγ through the metabolite 15d-PGJ2.
A Novel Approach to Deliver Therapeutic Extracellular Vesicles Directly into the Mouse Kidney via Its Arterial Blood Supply
Authors: Ullah Mujib , Liu Daniel D. , Rai Sravanthi , Razavi Mehdi , Choi Jeff , Wang Jing , Concepcion Waldo , Thakor Avnesh S.
Published: April 2020

Diseases of the kidney contribute a significant morbidity and mortality burden on society. Localized delivery of therapeutics directly into the kidney, via its arterial blood supply, has the potential to enhance their therapeutic efficacy while limiting side effects associated with conventional systemic delivery. Targeted delivery in humans is feasible given that we can access the renal arterial blood supply using minimally invasive endovascular techniques and imaging guidance. However, there is currently no described way to reproduce or mimic this approach in a small animal model. Here, we develop in mice a reproducible microsurgical technique for the delivery of therapeutics directly into each kidney, via its arterial blood supply. Using our technique, intra-arterially (IA) injected tattoo dye homogenously stained both kidneys, without staining any other organ. Survival studies showed no resulting mortality or iatrogenic kidney injury. We demonstrate the therapeutic potential of our technique in a mouse model of cisplatin-induced acute kidney injury (AKI). IA injection of mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) successfully reversed AKI, with reduced physiological and molecular markers of kidney injury, attenuated inflammation, and restoration of proliferation and regeneration markers. This reproducible delivery technique will allow for further pre-clinical translational studies investigating other therapies for the treatment of renal pathologies.
Uncovering the Translational Regulatory Activity of the Tumor Suppressor BRCA1
Authors: Berthel Elise , Vincent Anne , Eberst Lauriane , Torres Adrian Gabriel , Dacheux Estelle , Rey Catherine , Marcel Virginie , Paraqindes Hermes , Lachuer Joël , Catez Frédéric , de Pouplana Lluis Ribas , Treilleux Isabelle , Diaz Jean-Jacques , Dalla Venezia Nicole
Published: April 2020

BRCA1 inactivation is a hallmark of familial breast cancer, often associated with aggressive triple negative breast cancers. BRCA1 is a tumor suppressor with known functions in DNA repair, transcription regulation, cell cycle control, and apoptosis. In the present study, we demonstrate that BRCA1 is also a translational regulator. We previously showed that BRCA1 was implicated in translation regulation. Here, we asked whether translational control could be a novel function of BRCA1 that contributes to its tumor suppressive activity. A combination of RNA-binding protein immunoprecipitation, microarray analysis, and polysome profiling, was used to identify the mRNAs that were specifically deregulated under BRCA1 deficiency. Western blot analysis allowed us to confirm at the protein level the deregulated translation of a subset of mRNAs. A unique and dedicated cohort of patients with documented germ-line BRCA1 pathogenic variant statues was set up, and tissue microarrays with the biopsies of these patients were constructed and analyzed by immunohistochemistry for their content in each candidate protein. Here, we show that BRCA1 translationally regulates a subset of mRNAs with which it associates. These mRNAs code for proteins involved in major programs in cancer. Accordingly, the level of these key proteins is correlated with BRCA1 status in breast cancer cell lines and in patient breast tumors. ADAT2, one of these key proteins, is proposed as a predictive biomarker of efficacy of treatments recently recommended to patients with BRCA1 deficiency. This study proposes that translational control may represent a novel molecular mechanism with potential clinical impact through which BRCA1 is a tumor suppressor.
Dynamically Operated Fischer–Tropsch Synthesis in PtL—Part 2: Coping with Real PV Profiles
Authors: Loewert Marcel , Riedinger Michael , Pfeifer Peter
Published: April 2020

Climate change calls for a paradigm shift in the primary energy generation that comes with new challenges to store and transport energy. A decentralization of energy conversion can only be implemented with novel methods in process engineering. In the second part of our work, we took a deeper look into the load flexibility of microstructured Fischer–Tropsch synthesis reactors to elucidate possible limits of dynamic operation. Real data from a 10 kW photovoltaic system is used to calculate a dynamic H2 feed flow, assuming that electrolysis is capable to react on power changes accordingly. The required CO flow for synthesis could either originate from a constantly operated biomass gasification or from a direct air capture that produces CO2; the latter is assumed to be dynamically converted into synthesis gas with additional hydrogen. Thus two cases exist, the input is constantly changing in syngas ratio or flow rate. These input data were used to perform challenging experiments with the pilot scale setup. Both cases were compared. While it appeared that a fluctuating flow rate is tolerable for constant product composition, a coupled temperature-conversion relationship model was developed. It allows keeping the conversion and product distribution constant despite highly dynamic feed flow conditions.
The Child Life Challenges Scale (CLCS): Associations of a Single-Item Rating of Global Child Adversity with Children’s Total Life Stressors and Parents’ Childhood Adversity
Authors: Merrick Jillian S. , Labella Madelyn H. , Narayan Angela J. , Desjardins Christopher D. , Barnes Andrew J. , Masten Ann S.
Published: April 2020

Background: Although many existing measures tabulate specific risk factors to yield cumulative risk indices, there is a need for low-burden strategies to estimate general adversity exposure. Aims and Methods: This study introduces a brief, new measure of lifetime adversity, the Child Life Challenges Scale (CLCS), and examines its validity in a sample of parents and children residing in emergency housing. The CLCS comprises a single global item for rating cumulative life challenges utilizing either a paper-pencil scale or a sliding scale on a tablet. Parents are provided with anchor examples of mild and extreme challenges and asked to mark a location along the scale reflecting number and severity of challenges in their children’s lives to date. Study participants included 99 parents and their 3- to 6-year-old children. Results: CLCS scores were moderately associated with children’s parent-reported total life stressors, and these associations were robust to controls for parental history of adversity, parental distress, and family demographics. Control variables also did not moderate associations between CLCS scores and total life stressors, suggesting that the CLCS functions similarly across a range of sociodemographic risk. Paper-pencil and tablet versions showed similar convergent validity. Conclusion: The CLCS shows promise as an efficient measure for estimating children’s lifetime adversity with minimal parent or administrator burden.
Nanoscale Correlations of Ice Adhesion Strength and Water Contact Angle
Authors: Rønneberg Sigrid , Xiao Senbo , He Jianying , Zhang Zhiliang
Published: April 2020

Surfaces with low ice adhesion represent a promising strategy to achieve passive anti-icing performance. However, as a successful and robust low ice adhesion surface must be tested under realistic conditions at low temperatures and for several types of ice, the initial screening of potential low ice adhesion surfaces requires large resources. A theoretical relation between ice adhesion and water wettability in the form of water contact angle exists, but there is disagreement on whether this relation holds for experiments. In this study, we utilised molecular dynamics simulations to examine the fundamental relations between ice adhesion and water contact angle on an ideal graphene surface. The results show a significant correlation according to the theoretic predictions, indicating that the theoretical relation holds for the ice and water when discarding surface material deformations and other experimental factors. The reproduction of the thermodynamic theory at the nanoscale is important due to the gap between experimental observations and theoretical models. The results in this study represent a step forward towards understanding the fundamental mechanisms of water–solid and ice–solid interactions, and the relationship between them.
Numerical Studies on the Thermal Performances of Electroosmotic Flow in Y-Shaped Microchannel Heat Sink
Authors: Jing Dalei , Song Jian
Published: April 2020

This paper numerically studies the thermal performances of electroosmotic flow (EOF) in a symmetric Y-shaped microchannel heat sink (MCHS) having a constant total channel surface area, that is, constant convective heat transfer area. It is found that the average convective heat transfer coefficient of EOF increases with the increasing driven voltage, which is attributed to the increase of EOF flowrate with the increasing driven voltage. However, the maximum MCHS temperature shows an increasing after decreasing trend with the driven voltage owing to the dramatically increasing Joule heating when the voltage is large enough. Further, both the maximum MCHS temperature and average convective heat transfer coefficient are sensitive to the cross-sectional dimensions of the Y-shaped microchannels. The thermal performances of EOF in the Y-shaped MCHS show a strengthening to weakening trend with the increasing daughter-to-parent channel diameter ratio of the Y-shaped microchannel with circular cross-sectional shape, and show a similar strengthening to weakening trend with the increasing daughter-to-parent channel width ratio and the increasing microchannel height of the Y-shaped microchannel with rectangular cross-sectional shape. These cross-sectional dimension dependences of thermal performances are related to the increasing to decreasing trend of EOF flowrate changing with the microchannel cross-sectional dimensions.
Effects of Tool Coatings on Energy Consumption in Micro-Extrusion of Aluminum Alloy 6063
Authors: Sucharitpwatskul Sedthawatt , Mahayotsanun Numpon , Bureerat Sujin , Dohda Kuniaki
Published: April 2020

The tool wear rate and energy consumption were typically unknown in micro-extrusion, which made it difficult to optimize the tool design for both the final part quality and production cost. This study investigated the effects of tool coatings on energy consumption in the micro-extrusion of aluminum alloy 6063. Three main factors were considered in this study: (1) tool coating types, (2) bearing length, and (3) extrusion ratio. The micro-extrusion finite element simulation model was developed and validated with the micro-extrusion experiment. The results showed that increasing bearing lengths led to the increase in tool wear rate and energy consumption for all the coating types. The decreasing coefficient of friction values of the tool-billet interface led to a decrease in energy consumption. High hardness values of the tool surface and low bearing lengths helped increase tool life. Low values of coefficient of friction and bearing lengths helped decrease energy consumption.
Mechanical Response of Carbon Nanotube Bundle to Lateral Compression
Authors: Abdullina Dina U. , Korznikova Elena A. , Dubinko Volodymyr I. , Laptev Denis V. , Kudreyko Alexey A. , Soboleva Elvira G. , Dmitriev Sergey V. , Zhou Kun
Published: April 2020

Structure evolution and mechanical response of the carbon nanotube (CNT) bundle under lateral biaxial compression is investigated in plane strain conditions using the chain model. In this model, tensile and bending rigidity of CTN walls, and the van der Waals interactions between them are taken into account. Initially the bundle in cross section is a triangular lattice of circular zigzag CNTs. Under increasing strain control compression, several structure transformations are observed. Firstly, the second-order phase transition leads to the crystalline structure with doubled translational cell. Then the first-order phase transition takes place with the appearance of collapsed CNTs. Further compression results in increase of the fraction of collapsed CNTs at nearly constant compressive stress and eventually all CNTs collapse. It is found that the potential energy of the CNT bundle during deformation changes mainly due to bending of CNT walls, while the contribution from the walls tension-compression and from the van der Waals energies is considerably smaller.
Capacitance Characteristics and Breakdown Mechanism of AlGaN/GaN Metal–Semiconductor–Metal Varactors and their Anti-Surge Application
Authors: Shih Chien-Fu , Hsieh Yu-Li , Chang Liann-Be , Jeng Ming-Jer , Ding Zi-Xin , Huang Shao-An
Published: April 2020

The AlGaN/GaN materials with a wide band gap, high electron mobility, and high breakdown voltage are suitable for manufacturing high-power and high-frequency electronic devices. In this study, metal Schottky contact electrodes of different dimensions are prepared on AlGaN/GaN wafers to fabricate metal–semiconductor–metal (MSM) varactors. Voltage-dependent capacitance and breakdown voltages of the varactors are measured and studied. The corresponding breakdown mechanisms of varactors with different electrode gaps are proposed. Furthermore, an anti-surge application using GaN-based MSM varactors in a signal transmission module is demonstrated, and its surge suppression capability is shown. We believe that our study will be beneficial in developing surge protection circuits for RF applications.
Pitting Corrosion Resistance on Annealing Treated Super Duplex Stainless Steel S32750
Authors: Liu Shuang , Yue Chaohua , Chen Xi , Zhu Qiuhua , Tu Yiyou
Published: April 2020

The pitting corrosion resistance of S32750 super duplex stainless steel, annealing treated at temperatures of 950–1200 °C for 20–60 min, was investigated using potentiodynamic polarization tests. The results show that the volume fractions of ferrite in the S32750 duplex stainless steel increased from 48.9% to 68.4% as annealing temperatures increased from 950 to 1200 °C. The pitting potential of the sample increased first and then decreased from an annealing temperature of 950 to 1050 °C, and the highest pitting potential was observed after annealing at 1050 °C for 35 min. The pitting corrosion resistance of S32750 stainless steel is due to the combination of pitting resistance equivalent number (PREN) value, phase fraction and grain boundary area fraction, and the imbalance of corrosion potential.