bluuebunny/crossref_metadata_2025 huggingface dataset:
Empowering Museum Experiences Applying Gamification Techniques Based on Linked Data and Smart Objects
Authors: López-Martínez Alejandro , Carrera Álvaro , Iglesias Carlos A.
Published: August 2020

Museums play a crucial role in preserving cultural heritage. However, the forms in which they display cultural heritage might not be the most effective at piquing visitors’ interest. Therefore, museums tend to integrate different technologies that aim to create engaging and memorable experiences. In this context, the emerging Internet of Things (IoT) technology results particularly promising due to the possibility of implementing smart objects in museums, granting exhibits advanced interaction capabilities. Gamification techniques are also a powerful technique to draw visitors’ attention. These often rely on interactive question-based games. A drawback of such games is that questions must be periodically regenerated, and this is a time-consuming task. To confront these challenges, this paper proposes a low-maintenance gamified smart object platform that automates the creation of questions by exploiting semantic web technologies. The platform has been implemented in a real-life scenario. The results obtained encourage the use of the platform in the museum considered. Therefore, it appears to be a promising work that could be extrapolated and adapted to other kinds of museums or cultural heritage institutions.
Performance Assessment of PPP Surveys with Open Source Software Using the GNSS GPS–GLONASS–Galileo Constellations
Authors: Angrisano Antonio , Dardanelli Gino , Innac Anna , Pisciotta Alessandro , Pipitone Claudia , Gaglione Salvatore
Published: August 2020

In this work, the performance of the multi-GNSS (Global Navigation Satellite System) Precise Point Positioning (PPP) technique, in static mode, is analyzed. Specifically, GPS (Global Positioning System), GLONASS, and Galileo systems are considered, and quantifying the Galileo contribution is one of the main objectives. The open source software RTKLib is adopted to process the data, with precise satellite orbits and clocks from CNES (Centre National d’Etudes Spatiales) and CLS (Collecte Localisation Satellites) analysis centers for International GNSS Service (IGS). The Iono-free model is used to correct ionospheric errors, the GOT-4.7 model is used to correct tidal effects, and Differential Code Biases (DCB) are taken from the Deutsche Forschungsanstalt für Luftund Raumfahrt (DLR) center. Two different tropospheric models are tested: Saastamoinen and Estimate ZTD (Zenith Troposhperic Delay). For the proposed study, a dataset of 31 days from a permanent GNSS station, placed in Palermo (Italy), and a dataset of 10 days from a static geodetic receiver, placed nearby the station, have been collected and processed by the most used open source software in the geomatic community. The considered GNSS configurations are seven: GPS only, GLONASS only, Galileo only, GPS+GLONASS, GPS+Galileo, GLONASS+Galileo, and GPS+GLONASS+Galileo. The results show significant performance improvement of the GNSS combinations with respect to single GNSS cases.
Assessment of Pohang Earthquake-Induced Liquefaction at Youngil-Man Port Using the UBCSAND2 Model
Authors: Doan Nhat-Phi , Park Sung-Sik , Lee Dong-Eun
Published: August 2020

The practical constitutive model UBCSAND2, which combines two-mobilized planes—a maximum shear stress plane and a horizontal plane within a framework of classical plasticity approach—is used to incorporate shear-induced effects in both loading and unloading as well as principal stress rotation effects. UBCSAND2 was calibrated by capturing cyclic direct simple shear (CDSS) test results of Pohang sand, which was collected from liquefied paddy fields due to the 2017 Pohang earthquake (Mw = 5.4) in South Korea. The model procedure focuses on simple shear condition because it best simulates field conditions under earthquake loading. The calibrated UBCSAND2 model is then used to assess the liquefaction-induced damages that occurred at the quay wall and backfill layer in Youngil-man port near the epicenter of the Pohang earthquake. The numerical results show that liquefaction mostly occurred in silty sand layers, in which the excess pore pressure ratio reached almost one. The estimated displacements of the quay wall and the predicted settlement of reclaimed area obtained from the analysis were in good agreement with those obtained from field measurements.
Farmers’ Perceptions of Climate Change and Agricultural Adaptation in Burkina Faso
Authors: Alvar-Beltrán Jorge , Dao Abdalla , Dalla Marta Anna , Heureux Ana , Sanou Jacob , Orlandini Simone
Published: August 2020

The Sahel region is considered a hotspot for climate change hazards and vulnerability of weather reliant sectors, including agriculture. Farmers in Burkina Faso have a long history of adapting their farming activities to frequent changes in climate. Using 150 in-person surveys, this study assesses farmers’ perceptions of climate change based on multiple climate variables, and reviews adaptation practices, including soil and water conservation strategies, in the Soudanian, Soudano-Sahelian, and Sahelian agroclimatic zones of Burkina Faso. In general, farmers are aware of changing climatic conditions, including increased temperatures, greater rainfall variability, heavier precipitation events, delayed onset, and premature offset of the rainy season. However, farmers perceive shifts in climate differently depending on their location and agroclimatic zone. As a result, different adaption strategies are implemented by farmers according to the climatic, societal, and economic context. Survey results show that in the Sahel, climate adaptation strategies rely on traditional knowledge and experimental approaches; whereas in the Soudanian zone, where weather conditions are more favorable for agriculture, adaptation practices are market oriented. These regional differences are important for targeting advisory services, planning processes, and decision-making to support the effective provision of weather and climate information services to the last mile.
Post-Translational Regulation of ARF: Perspective in Cancer
Authors: Seo Jinho , Seong Daehyeon , Lee Seung Ri , Oh Doo-Byoung , Song Jaewhan
Published: August 2020

Tumorigenesis can be induced by various stresses that cause aberrant DNA mutations and unhindered cell proliferation. Under such conditions, normal cells autonomously induce defense mechanisms, thereby stimulating tumor suppressor activation. ARF, encoded by the CDKN2a locus, is one of the most frequently mutated or deleted tumor suppressors in human cancer. The safeguard roles of ARF in tumorigenesis are mainly mediated via the MDM2-p53 axis, which plays a prominent role in tumor suppression. Under normal conditions, low p53 expression is stringently regulated by its target gene, MDM2 E3 ligase, which induces p53 degradation in a ubiquitin-proteasome-dependent manner. Oncogenic signals induced by MYC, RAS, and E2Fs trap MDM2 in the inhibited state by inducing ARF expression as a safeguard measure, thereby activating the tumor-suppressive function of p53. In addition to the MDM2-p53 axis, ARF can also interact with diverse proteins and regulate various cellular functions, such as cellular senescence, apoptosis, and anoikis, in a p53-independent manner. As the evidence indicating ARF as a key tumor suppressor has been accumulated, there is growing evidence that ARF is sophisticatedly fine-tuned by the diverse factors through transcriptional and post-translational regulatory mechanisms. In this review, we mainly focused on how cancer cells employ transcriptional and post-translational regulatory mechanisms to manipulate ARF activities to circumvent the tumor-suppressive function of ARF. We further discussed the clinical implications of ARF in human cancer.
Characterisation of the Expression of Neurotensin and Its Receptors in Human Colorectal Cancer and Its Clinical Implications
Authors: Qiu Shengyang , Nikolaou Stella , Zhu Jie , Jeffery Peter , Goldin Robert , Kinross James , Alexander James , Rasheed Shahnawaz , Tekkis Paris , Kontovounisios Christos
Published: August 2020

Introduction: Colorectal Cancer (CRC) accounts for 9% of cancer deaths globally. Hormonal pathways play important roles in some cancers. This study investigated the association of CRC expression of neurotensin (NTS), NTS receptors 1 and 3 (NTSR1 and NTSR3) and clinical outcomes. Methods: A prospective cohort study which quantifies the protein expression of NTS, NTSR1 and NTSR3 in human CRCs using immunohistochemistry. Expression levels were then compared with clinico-pathological outcome including histological grade, overall survival (OS) and disease-free survival (DFS). Results: Sixty-four patients were enrolled with median follow-up of 44.0 months. There was significantly higher expression of NTS in cancer tissue in CRC with higher T stages (p < 0.01), N stages (p = 0.03), and AJCC clinical stages (p = 0.04). There was significantly higher expression of NTS, NTSR1 and NTSR3 in cancer tissue compared to surrounding normal epithelium (median H-score 163.5 vs 97.3, p < 0.01). There was significantly shorter DFS in individuals with CRC with high levels of NTS compared to lower levels of NTS (35.8 months 95% CI 28.7–42.8 months vs 46.4 months 95% CI 42.2–50.5 months, respectively, p = 0.02). Above median NTS expression in cancer tissue was a significant risk factor for disease recurrence (HR 4.10, 95% CI 1.14–14.7, p = 0.03). Discussion: The expression of NTS and its receptors has the potential to be utilised as a predictive and prognostic marker in colorectal cancer for postoperative selection for adjuvant therapy and identify individuals for novel therapies targeting the neurotensinergic pathways. Conclusions: High NTS expression appears to be associated with more advanced CRC and worse DFS.
Doxazosin, a Classic Alpha 1-Adrenoceptor Antagonist, Overcomes Osimertinib Resistance in Cancer Cells via the Upregulation of Autophagy as Drug Repurposing
Authors: Suzuki Shuhei , Yamamoto Masahiro , Sanomachi Tomomi , Togashi Keita , Sugai Asuka , Seino Shizuka , Okada Masashi , Yoshioka Takashi , Kitanaka Chifumi
Published: August 2020

Osimertinib, which is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is an important anticancer drug because of its high efficacy and excellent safety profile. However, resistance against osimertinib is inevitable; therefore, therapeutic strategies to overcome the resistance are needed. Doxazosin, a classic quinazoline-based alpha 1-adrenoceptor antagonist is used to treat hypertension and benign prostatic hyperplasia with a known safety profile. The anticancer effects of doxazosin have been examined in various types of malignancies from the viewpoint of drug repositioning or repurposing. However, it currently remains unclear whether doxazosin sensitizes cancer cells to osimertinib. Herein, we demonstrated that doxazosin induced autophagy and enhanced the anticancer effects of osimertinib on the cancer cells and cancer stem cells of non-small cell lung cancer, pancreatic cancer, and glioblastoma at a concentration at which the growth of non-tumor cells was not affected. The osimertinib-sensitizing effects of doxazosin were suppressed by 3-methyladenine, an inhibitor of autophagy, which suggested that the effects of doxazosin were mediated by autophagy. The present study provides evidence for the efficacy of doxazosin as a combination therapy with osimertinib to overcome resistance against osimertinib.
Nanoelectrode Arrays Fabricated by Thermal Nanoimprint Lithography for Biosensing Application
Authors: Zanut Alessandra , Cian Alessandro , Cefarin Nicola , Pozzato Alessandro , Tormen Massimo
Published: August 2020

Electrochemical sensors are devices capable of detecting molecules and biomolecules in solutions and determining the concentration through direct electrical measurements. These systems can be miniaturized to a size less than 1 µm through the creation of small-size arrays of nanoelectrodes (NEA), offering advantages in terms of increased sensitivity and compactness. In this work, we present the fabrication of an electrochemical platform based on an array of nanoelectrodes (NEA) and its possible use for the detection of antigens of interest. NEAs were fabricated by forming arrays of nanoholes on a thin film of polycarbonate (PC) deposited on boron-doped diamond (BDD) macroelectrodes by thermal nanoimprint lithography (TNIL), which demonstrated to be a highly reliable and reproducible process. As proof of principle, gliadin protein fragments were physisorbed on the polycarbonate surface of NEAs and detected by immuno-indirect assay using a secondary antibody labelled with horseradish peroxidase (HRP). This method allows a successful detection of gliadin, in the range of concentration of 0.5–10 μg/mL, by cyclic voltammetry taking advantage from the properties of NEAs to strongly suppress the capacitive background signal. We demonstrate that the characteristics of the TNIL technology in the fabrication of high-resolution nanostructures together with their low-cost production, may allow to scale up the production of NEAs-based electrochemical sensing platform to monitor biochemical molecules for both food and biomedical applications.
Microfluidic-Based Electrochemical Immunosensing of Ferritin
Authors: Garg Mayank , Christensen Martin , Iles Alexander , Sharma Amit , Singh Suman , Pamme Nicole
Published: August 2020

Ferritin is a clinically important biomarker which reflects the state of iron in the body and is directly involved with anemia. Current methods available for ferritin estimation are generally not portable or they do not provide a fast response. To combat these issues, an attempt was made for lab-on-a-chip-based electrochemical detection of ferritin, developed with an integrated electrochemically active screen-printed electrode (SPE), combining nanotechnology, microfluidics, and electrochemistry. The SPE surface was modified with amine-functionalized graphene oxide to facilitate the binding of ferritin antibodies on the electrode surface. The functionalized SPE was embedded in the microfluidic flow cell with a simple magnetic clamping mechanism to allow continuous electrochemical detection of ferritin. Ferritin detection was accomplished via cyclic voltammetry with a dynamic linear range from 7.81 to 500 ng·mL−1 and an LOD of 0.413 ng·mL−1. The sensor performance was verified with spiked human serum samples. Furthermore, the sensor was validated by comparing its response with the response of the conventional ELISA method. The current method of microfluidic flow cell-based electrochemical ferritin detection demonstrated promising sensitivity and selectivity. This confirmed the plausibility of using the reported technique in point-of-care testing applications at a much faster rate than conventional techniques.
Frequency Shift of a SH-SAW Biosensor with Glutaraldehyde and 3-Aminopropyltriethoxysilane Functionalized Films for Detection of Epidermal Growth Factor
Authors: Lo Xue-Chang , Li Jen-Yu , Lee Ming-Tsang , Yao Da-Jeng
Published: August 2020

The frequency shift of a shear-horizontal surface-acoustic-wave (SH-SAW) biosensor in which the concentration of biomolecule is determined by the amount of its adsorption on the sensing film was studied. Simulation results were compared with experimental results to investigate its sensitivity and to develop a model to estimate the concentration of a cancer-related biomarker antigen epidermal growth factor (EGF) in the sample, with two types of sensing films, 3-aminopropyltriethoxysilane (APTES) and glutaraldehyde. With the concentration of the targeted biomarker varying from 0.2 to 5 ng/mL, a typical exponential relationship was found between the concentration and the frequency shift of the SH-SAW sensor. Measurement results showed a clear response of this immunosensor to the mass-loading effects of the antibody–antigen. The sensitivity of the glutaraldehyde film is greater than that of the APTES film owing to the chemisorption of the antibody. In the simulation, a shift of the SH-SAW resonant frequency due to added mass occurred on applying an incremental surface mass density on the sensing film, while in real applications, the concentration of the targeted biomarker to be absorbed in the sensing film is demanded. An empirical model was proposed to calculate the frequency shift in the simulation of the SH-SAW biosensor, corresponding to the concentration of specific biomolecules absorbed on a specific film. From the semi-empirical model, the sensitivity level is found to be 0.641 and 1.709 kHz/(ng/mL) for APTES and glutaraldehyde sensing films, respectively, at a biomarker concentration of less than 1 ng/mL. The developed method is useful for quickly estimating the frequency shift with respect to the concentration of the target molecules in the simulation for SH-SAW sensors.
Reply: Factors Influencing Central Nervous System Abnormalities in m.11778G>A Carriers
Authors: Grochowski Cezary , Jonak Kamil
Published: August 2020

First of all, I would like to thank the reader for their interest and taking the time to analyze our work [...]
Brain Metastases from Ovarian Cancer: Current Evidence in Diagnosis, Treatment, and Prognosis
Authors: Borella Fulvio , Bertero Luca , Morrone Antonio , Gambella Alessandro , Bovetti Marialuisa , Cosma Stefano , Carosso Andrea , Katsaros Dionyssios , Gemmiti Silvia , Preti Mario , Valabrega Giorgio , Scotto Giulia , Cassoni Paola , Benedetto Chiara
Published: August 2020

With this review, we provide the state of the art concerning brain metastases (BMs) from ovarian cancer (OC), a rare condition. Clinical, pathological, and molecular features, treatment options, and future perspectives are comprehensively discussed. Overall, a diagnosis of high-grade serous OC and an advanced disease stage are common features among patients who develop brain metastases. BRCA1 and BRCA2 gene mutations, as well as the expression of androgen receptors in the primary tumor, are emerging risk and prognostic factors which could allow one to identify categories of patients at greater risk of BMs, who could benefit from a tailored follow-up. Based on present data, a multidisciplinary approach combining surgery, radiotherapy, and chemotherapy seem to be the best approach for patients with good performance status, although the median overall survival (<1 year) remains largely disappointing. Hopefully, novel therapeutic avenues are being explored, like PARP inhibitors and immunotherapy, based on our improved knowledge regarding tumor biology, but further investigation is warranted.
Lymphotropic Viruses EBV, KSHV and HTLV in Latin America: Epidemiology and Associated Malignancies. A Literature-Based Study by the RIAL-CYTED
Authors: Chabay Paola , Lens Daniela , Hassan Rocio , Rodríguez Pinilla Socorro María , Valvert Gamboa Fabiola , Rivera Iris , Huamán Garaicoa Fuad , Ranuncolo Stella Maris , Barrionuevo Carlos , Morales Sánchez Abigail , Scholl Vanesa , De Matteo Elena , Preciado Ma. Victoria , Fuentes-Pananá Ezequiel M.
Published: August 2020

The Epstein–Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV) and human T-lymphotropic virus (HTLV-1) are lymphomagenic viruses with region-specific induced morbidity. The RIAL-CYTED aims to increase the knowledge of lymphoma in Latin America (LA), and, as such, we systematically analyzed the literature to better understand our risk for virus-induced lymphoma. We observed that high endemicity regions for certain lymphomas, e.g., Mexico and Peru, have a high incidence of EBV-positive lymphomas of T/NK cell origin. Peru also carries the highest frequency of EBV-positive classical Hodgkin lymphoma (HL) and EBV-positive diffuse large B cell lymphoma, not otherwise specified (NOS), than any other LA country. Adult T cell lymphoma is endemic to the North of Brazil and Chile. While only few cases of KSHV-positive lymphomas were found, in spite of the close correlation of Kaposi sarcoma and the prevalence of pathogenic types of KSHV. Both EBV-associated HL and Burkitt lymphoma mainly affect young children, unlike in developed countries, in which adolescents and young adults are the most affected, correlating with an early EBV seroconversion for LA population despite of lack of infectious mononucleosis symptoms. High endemicity of KSHV and HTLV infection was observed among Amerindian populations, with differences between Amazonian and Andean populations.
Characterization of the DNAM-1, TIGIT and TACTILE Axis on Circulating NK, NKT-Like and T Cell Subsets in Patients with Acute Myeloid Leukemia
Authors: Valhondo Isabel , Hassouneh Fakhri , Lopez-Sejas Nelson , Pera Alejandra , Sanchez-Correa Beatriz , Guerrero Beatriz , Bergua Juan M. , Arcos Maria Jose , Bañas Helena , Casas-Avilés Ignacio , Sanchez-Garcia Joaquin , Serrano Josefina , Martin Carmen , Duran Esther , Alonso Corona , Solana Rafael , Tarazona Raquel
Published: August 2020

Background: Acute myeloid leukemia (AML) remains a major clinical challenge due to poor overall survival, which is even more dramatic in elderly patients. TIGIT, an inhibitory receptor that interacts with CD155 and CD112 molecules, is considered as a checkpoint in T and NK cell activation. This receptor shares ligands with the co-stimulatory receptor DNAM-1 and with TACTILE. The aim of this work was to analyze the expression of DNAM-1, TIGIT and TACTILE in NK cells and T cell subsets in AML patients. Methods: We have studied 36 patients at the time of diagnosis of AML and 20 healthy volunteers. The expression of DNAM-1, TIGIT and TACTILE in NK cells and T cells, according to the expression of CD3 and CD56, was performed by flow cytometry. Results: NK cells, CD56− T cells and CD56+ T (NKT-like) cells from AML patients presented a reduced expression of DNAM-1 compared with healthy volunteers. An increased expression of TIGIT was observed in mainstream CD56− T cells. No differences were observed in the expression of TACTILE. Simplified presentation of incredibly complex evaluations (SPICE) analysis of the co-expression of DNAM-1, TIGIT and TACTILE showed an increase in NK and T cells lacking DNAM-1 and co-expressing TIGIT and TACTILE. Low percentages of DNAM-1−TIGIT+TACTILE+ NK cells and DNAM-1− TIGIT+TACTILE+ CD56− T cells were associated with a better survival of AML patients. Conclusions: The expression of DNAM-1 is reduced in NK cells and in CD4+ and CD8+ T cells from AML patients compared with those from healthy volunteers. An increased percentage of NK and T cells lacking DNAM-1 and co-expressing TIGIT and TACTILE is associated with patient survival, supporting the role of TIGIT as a novel candidate for checkpoint blockade.
Fecal microRNAs as Innovative Biomarkers of Intestinal Diseases and Effective Players in Host-Microbiome Interactions
Authors: Sarshar Meysam , Scribano Daniela , Ambrosi Cecilia , Palamara Anna Teresa , Masotti Andrea
Published: August 2020

Over the past decade, short non-coding microRNAs (miRNAs), including circulating and fecal miRNAs have emerged as important modulators of various cellular processes by regulating the expression of target genes. Recent studies revealed the role of miRNAs as powerful biomarkers in disease diagnosis and for the development of innovative therapeutic applications in several human conditions, including intestinal diseases. In this review, we explored the literature and summarized the role of identified dysregulated fecal miRNAs in intestinal diseases, with particular focus on colorectal cancer (CRC) and celiac disease (CD). The aim of this review is to highlight one fascinating aspect of fecal miRNA function related to gut microbiota shaping and bacterial metabolism influencing. The role of miRNAs as “messenger” molecules for inter kingdom communications will be analyzed to highlight their role in the complex host-bacteria interactions. Moreover, whether fecal miRNAs could open up new perspectives to develop novel suitable biomarkers for disease detection and innovative therapeutic approaches to restore microbiota balance will be discussed.
Targeted Cellular Micropharmacies: Cells Engineered for Localized Drug Delivery
Authors: Gardner Thomas J. , Bourne Christopher M. , Dacek Megan M. , Kurtz Keifer , Malviya Manish , Peraro Leila , Silberman Pedro C. , Vogt Kristen C. , Unti Mildred J. , Brentjens Renier , Scheinberg David
Published: August 2020

The recent emergence of engineered cellular therapies, such as Chimeric antigen receptor (CAR) CAR T and T cell receptor (TCR) engineered T cells, has shown great promise in the treatment of various cancers. These agents aggregate and expand exponentially at the tumor site, resulting in potent immune activation and tumor clearance. Moreover, the ability to elaborate these cells with therapeutic agents, such as antibodies, enzymes, and immunostimulatory molecules, presents an unprecedented opportunity to specifically modulate the tumor microenvironment through cell-mediated drug delivery. This unique pharmacology, combined with significant advances in synthetic biology and cell engineering, has established a new paradigm for cells as vectors for drug delivery. Targeted cellular micropharmacies (TCMs) are a revolutionary new class of living drugs, which we envision will play an important role in cancer medicine and beyond. Here, we review important advances and considerations underway in developing this promising advancement in biological therapeutics.
Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma
Authors: Mukherjee Nabanita , Amato Carol M. , Skees Jenette , Todd Kaleb J. , Lambert Karoline A. , Robinson William A. , Van Gulick Robert , Weight Ryan M. , Dart Chiara R. , Tobin Richard P. , McCarter Martin D. , Fujita Mayumi , Norris David A. , Shellman Yiqun G.
Published: August 2020

There is an urgent need to develop treatments for patients with melanoma who are refractory to or ineligible for immune checkpoint blockade, including patients who lack BRAF-V600E/K mutations. This is often the case in patients diagnosed with rare melanoma subtypes such as mucosal and acral melanoma. Here, we analyzed data from the cutaneous melanoma The Cancer Genome Atlas Network (TCGA) transcriptomic and proteomic databases for differential expression of apoptosis molecules between melanomas with or without BRAF hotspot mutations. Our data indicated higher B-cell CLL/lymphoma 2 (BCL2) expression in melanoma without BRAF hotspot mutations, suggesting that BH3 mimetics, such as ABT-199 (venetoclax, a small molecule against BCL2), may be a potential therapeutic option for these patients. We explored the efficacy of combining two BH3 mimetics, ABT-199 and a myeloid cell leukemia sequence 1 (MCL1) inhibitor (S63845 or S64315/MIK665) in cutaneous, mucosal and acral melanomas, in vitro and in vivo. Our data indicate this combination induced cell death in a broad range of melanoma cell lines, including melanoma initiating cell populations, and was more potent in melanoma cells without BRAF-V600E/K mutations. Our knockdown/knockout experiments suggest that several pro-apoptotic BCL2 family members, BCL2-like 11 (apoptosis facilitator) (BIM), phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) or BID, play a role in the combination-induced effects. Overall, our study supports the rationale for combining an MCL1 inhibitor with a BCL2 inhibitor as a therapeutic option in patients with advanced melanoma.
Cancer Cell Acid Adaptation Gene Expression Response Is Correlated to Tumor-Specific Tissue Expression Profiles and Patient Survival
Authors: Yao Jiayi , Czaplinska Dominika , Ialchina Renata , Schnipper Julie , Liu Bin , Sandelin Albin , Pedersen Stine Falsig
Published: August 2020

The acidic pH of the tumor microenvironment plays a critical role in driving cancer development toward a more aggressive phenotype, but the underlying mechanisms are unclear. To this end, phenotypic and genotypic changes induced by adaptation of cancer cells to chronic acidosis have been studied. However, the generality of acid adaptation patterns across cell models and their correlation to the molecular phenotypes and aggressiveness of human cancers are essentially unknown. Here, we define an acid adaptation expression response shared across three cancer cell models, dominated by metabolic rewiring, extracellular matrix remodeling, and altered cell cycle regulation and DNA damage response. We find that many genes which are upregulated by acid adaptation are significantly correlated to patient survival, and more generally, that there are clear correlations between acid adaptation expression response and gene expression change between normal and tumor tissues, for a large subset of cancer patients. Our data support the notion that tumor microenvironment acidity is one of the key factors driving the selection of aggressive cancer cells in human patient tumors, yet it also induces a growth-limiting genotype that likely limits cancer cell growth until the cells are released from acidosis, for instance during invasion.
The Role of Necroptosis in ROS-Mediated Cancer Therapies and Its Promising Applications
Authors: Hsu Sheng-Kai , Chang Wen-Tsan , Lin I-Ling , Chen Yih-Fung , Padalwar Nitin Balkrushna , Cheng Kai-Chun , Teng Yen-Ni , Wang Chi-Huei , Chiu Chien-Chih
Published: August 2020

Over the past decades, promising therapies targeting different signaling pathways have emerged. Among these pathways, apoptosis has been well investigated and targeted to design diverse chemotherapies. However, some patients are chemoresistant to these therapies due to compromised apoptotic cell death. Hence, exploring alternative treatments aimed at different mechanisms of cell death seems to be a potential strategy for bypassing impaired apoptotic cell death. Emerging evidence has shown that necroptosis, a caspase-independent form of cell death with features between apoptosis and necrosis, can overcome the predicament of drug resistance. Furthermore, previous studies have also indicated that there is a close correlation between necroptosis and reactive oxygen species (ROS); both necroptosis and ROS play significant roles both under human physiological conditions such as the regulation of inflammation and in cancer biology. Several small molecules used in experiments and clinical practice eliminate cancer cells via the modulation of ROS and necroptosis. The molecular mechanisms of these promising therapies are discussed in detail in this review.
Decomposition of Ruthenium Olefin Metathesis Catalyst
Authors: Jawiczuk Magdalena , Marczyk Anna , Trzaskowski Bartosz
Published: August 2020

Ruthenium olefin metathesis catalysts are one of the most commonly used class of catalysts. There are multiple reviews on their uses in various branches of chemistry and other sciences but a detailed review of their decomposition is missing, despite a large number of recent and important advances in this field. In particular, in the last five years several new mechanism of decomposition, both olefin-driven as well as induced by external agents, have been suggested and used to explain differences in the decomposition rates and the metathesis activities of both standard, N-heterocyclic carbene-based systems and the recently developed cyclic alkyl amino carbene-containing complexes. Here we present a review which explores the last 30 years of the decomposition studied on ruthenium olefin metathesis catalyst driven by both intrinsic features of such catalysts as well as external chemicals.
Epithelial Cell Adhesion Molecule: An Anchor to Isolate Clinically Relevant Circulating Tumor Cells
Authors: Eslami-S Zahra , Cortés-Hernández Luis Enrique , Alix-Panabières Catherine
Published: August 2020

In the last few decades, the epithelial cell adhesion molecule (EpCAM) has received increased attention as the main membrane marker used in many enrichment technologies to isolate circulating tumor cells (CTCs). Although there has been a great deal of progress in the implementation of EpCAM-based CTC detection technologies in medical settings, several issues continue to limit their clinical utility. The biology of EpCAM and its role are not completely understood but evidence suggests that the expression of this epithelial cell-surface protein is crucial for metastasis-competent CTCs and may not be lost completely during the epithelial-to-mesenchymal transition. In this review, we summarize the most significant advantages and disadvantages of using EpCAM as a marker for CTC enrichment and its potential biological role in the metastatic cascade.
Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology
Authors: Hampe Christiane S. , Eisengart Julie B. , Lund Troy C. , Orchard Paul J. , Swietlicka Monika , Wesley Jacob , McIvor R. Scott
Published: August 2020

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in organs and tissues. If untreated, patients with the severe phenotype die within the first decade of life. Early diagnosis is crucial to prevent the development of fatal disease manifestations, prominently cardiac and respiratory disease, as well as cognitive impairment. However, the initial symptoms are nonspecific and impede early diagnosis. This review discusses common phenotypic manifestations in the order in which they develop. Similarities and differences in the three animal models for MPS I are highlighted. Earliest symptoms, which present during the first 6 months of life, include hernias, coarse facial features, recurrent rhinitis and/or upper airway obstructions in the absence of infection, and thoracolumbar kyphosis. During the next 6 months, loss of hearing, corneal clouding, and further musculoskeletal dysplasias develop. Finally, late manifestations including lower airway obstructions and cognitive decline emerge. Cardiac symptoms are common in MPS I and can develop in infancy. The underlying pathogenesis is in the intra- and extracellular accumulation of partially degraded GAGs and infiltration of cells with enlarged lysosomes causing tissue expansion and bone deformities. These interfere with the proper arrangement of collagen fibrils, disrupt nerve fibers, and cause devastating secondary pathophysiological cascades including inflammation, oxidative stress, and other disruptions to intracellular and extracellular homeostasis. A greater understanding of the natural history of MPS I will allow early diagnosis and timely management of the disease facilitating better treatment outcomes.
Discovery of Molecular DNA Methylation-Based Biomarkers through Genome-Wide Analysis of Response Patterns to BCG for Bladder Cancer
Authors: Ilijazi Dafina , Pulverer Walter , Ertl Iris E. , Lemberger Ursula , Kimura Shoji , Abufaraj Mohammad , D’Andrea David , Pradere Benjamin , Bruchbacher Andreas , Graf Anna , Soria Francesco , Susani Martin , Haitel Andrea , Molinaro Luca , Pycha Armin , Comploj Evi , Pabinger Stephan , Weinhäusel Andreas , Egger Gerda , Shariat Shahrokh F. , Hassler Melanie R.
Published: August 2020

Background: Bacillus Calmette-Guérin (BCG) immunotherapy, the standard adjuvant intravesical therapy for some intermediate and most high-risk non-muscle invasive bladder cancers (NMIBCs), suffers from a heterogenous response rate. Molecular markers to help guide responses are scarce and currently not used in the clinical setting. Methods: To identify novel biomarkers and pathways involved in response to BCG immunotherapy, we performed a genome-wide DNA methylation analysis of NMIBCs before BCG therapy. Genome-wide DNA methylation profiles of DNA isolated from tumors of 26 BCG responders and 27 failures were obtained using the Infinium MethylationEPIC BeadChip. Results: Distinct DNA methylation patterns were found by genome-wide analysis in the two groups. Differentially methylated CpG sites were predominantly located in gene promoters and gene bodies associated with bacterial invasion of epithelial cells, chemokine signaling, endocytosis, and focal adhesion. In total, 40 genomic regions with a significant difference in methylation between responders and failures were detected. The differential methylation state of six of these regions, localized in the promoters of the genes GPR158, KLF8, C12orf42, WDR44, FLT1, and CHST11, were internally validated by bisulfite-sequencing. GPR158 promoter hypermethylation was the best predictor of BCG failure with an AUC of 0.809 (p-value < 0.001). Conclusions: Tumors from BCG responders and BCG failures harbor distinct DNA methylation profiles. Differentially methylated DNA regions were detected in genes related to pathways involved in bacterial invasion of cells or focal adhesion. We identified candidate DNA methylation biomarkers that may help to predict patient prognosis after external validation in larger, well-designed cohorts.
Electrochemical Behavior of Al–Al9Co2 Alloys in Sulfuric Acid
Authors: Sfikas Athanasios K. , Lekatou Angeliki G.
Published: August 2020

Al–Co alloys of various Co contents (2–20 wt.% Co) were fabricated by vacuum arc melting (VAM) with the scope to investigate the influence of cobalt on the microstructure and corrosion resistance of Al in 1 M H2SO4. The obtained microstructures were directional, consisting of Al9Co2 platelets (grown to coarse acicular plates as the Co content increased) uniformly dispersed in an Al-matrix. Alloying Al with Co did not decrease the rate of uniform corrosion of Al but it considerably increased its passivation ability. Moreover, all Al–Co alloys displayed lower uniform corrosion rate and notably higher passivation ability than market leading Al-alloys. The underlying mechanisms during anodic polarization in 1 M H2SO4 were identified and correlated with the microstructure. High Co content alloys (7–20 wt.% Co) presented superior passivation ability in 1 M H2SO4 as compared to the low Co content alloys.
A Personal History of Using Crystals and Crystallography to Understand Biology and Advanced Drug Discovery
Authors: Blundell Tom
Published: August 2020

Over the past 60 years, the use of crystals to define structures of complexes using X-ray analysis has contributed to the discovery of new medicines in a very significant way. This has been in understanding not only small-molecule inhibitors of proteins, such as enzymes, but also protein or peptide hormones or growth factors that bind to cell surface receptors. Experimental structures from crystallography have also been exploited in software to allow prediction of structures of important targets based on knowledge of homologues. Crystals and crystallography continue to contribute to drug design and provide a successful example of academia–industry collaboration.
AFLP-Based Analysis of Variation and Population Structure in Mutagenesis Induced Faba Bean
Authors: Nurmansyah  , Alghamdi Salem S. , Migdadi Hussein M. , Khan Muhammad A. , Afzal Muhammad
Published: August 2020

Genetic diversity enrichment is urgently necessary to develop climate-resilient faba bean cultivars. The present study aimed to measure the enrichment of genetic diversity and changes in the population structure of faba bean, following induced mutagenesis. 120 samples, including 116 M2 mutant plants, generated by exposing the ILB4347 accession to four mutagen treatments (25 and 50 Gray gamma radiation and 0.01%, and 0.05% diethyl sulfate) and four reference genotypes were characterized using 11 amplified fragment length polymorphism (AFLP) primer combinations. The AFLP markers generated 1687 polymorphic alleles, including 756 alleles (45%) that were detected infrequently (f ≤ 0.1). The total allele count of the mutant plants ranged from 117 to 545. We observed a wide range of banding patterns and counts among the mutant plants, showing the high genetic diversity induced by mutation. Mutations also changed the population structure, by altering 31.78% of the total membership coefficient (Q). Although mutations changed the population structure, Nei’s genetic distance showed that the mutant population remained closely related to its control parent. This is the first report examining genetic diversity and population changes in faba bean mutant populations and, thus, could facilitate the application of induced mutagenesis during faba bean breeding.
A Review of Dry Eye Questionnaires: Measuring Patient-Reported Outcomes and Health-Related Quality of Life
Authors: Okumura Yuichi , Inomata Takenori , Iwata Nanami , Sung Jaemyoung , Fujimoto Keiichi , Fujio Kenta , Midorikawa-Inomata Akie , Miura Maria , Akasaki Yasutsugu , Murakami Akira
Published: August 2020

Dry eye disease (DED) is among the most common eye diseases and is becoming increasingly prevalent. Its symptoms cause a long-term decline in patients’ health-related quality of life (HRQL). Inconsistencies often occur between the clinical findings and the subjective symptoms of DED. Therefore, a holistic, balanced, and quantitative evaluation of the subjective symptoms and HRQL using patient-reported outcome questionnaires, in addition to clinical findings, is crucial for accurate DED assessment in patients. This paper reviewed the characteristics of current dry eye questionnaires, including their objectives, number of questions, inclusion of HRQL-related items, and whether they were properly evaluated for psychometric properties. Twenty-four questionnaires were identified; among them, the following six questionnaires that included items assessing HRQL and were properly evaluated for psychometric properties are recommended: the Ocular Surface Disease Index, Impact of Dry Eye in Everyday Life, Dry Eye-Related Quality-of-life Score, University of North Carolina Dry Eye Management Scale, Chinese version of Dry Eye-Related Quality of Life, and 25-Item National Eye Institute Visual Function Questionnaire. Dry eye questionnaires have different objectives and are available in different languages. Therefore, medical practitioners should confirm the characteristics of applicable questionnaires before selecting the most appropriate ones.
Immunological and Microbiological Profiling of Cumulative Risk Score for Periodontitis
Authors: Liukkonen Joonas , Gürsoy Ulvi K. , Könönen Eija , Akhi Ramin , Salminen Aino , Liljestrand John M. , Pradhan-Palikhe Pratikshya , Pietiäinen Milla , Sorsa Timo , Persson G. Rutger , Mäntylä Päivi , Buhlin Kåre , Paju Susanna , Sinisalo Juha , Hörkkö Sohvi , Pussinen Pirkko J.
Published: August 2020

The cumulative risk score (CRS) is a mathematical salivary diagnostic model to define an individual’s risk of having periodontitis. In order to further validate this salivary biomarker, we investigated how periodontal bacteria, lipopolysaccharide (LPS), and systemic and local host immune responses relate to CRS. Subgingival plaque, saliva, and serum samples collected from 445 individuals were used in the analyses. Plaque levels of 28 microbial species, especially those of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Porphyromonas endodontalis, Prevotella intermedia, and Tannerella forsythia, and serum and salivary levels of IgA and IgG against these five species were determined. Additionally, LPS activity was measured. High CRS associated strongly with all IgA/IgG antibody and LPS levels in saliva, whereas in serum the associations were not that obvious. In the final logistic regression model, the best predictors of high CRS were saliva IgA burden against the five species (OR 7.04, 95% CI 2.25–22.0), IgG burden (3.79, 1.78–8.08), LPS (2.19, 1.38–3.47), and the sum of 17 subgingival Gram-negative species (6.19, 2.10–18.3). CRS is strongly associated with microbial biomarker species of periodontitis and salivary humoral immune responses against them.
aMMP-8 Point-of-Care/Chairside Oral Fluid Technology as a Rapid, Non-Invasive Tool for Periodontitis and Peri-Implantitis Screening in a Medical Care Setting
Authors: Lähteenmäki Hanna , Umeizudike Kehinde A. , Heikkinen Anna Maria , Räisänen Ismo T. , Rathnayake Nilminie , Johannsen Gunnar , Tervahartiala Taina , Nwhator Solomon O. , Sorsa Timo
Published: August 2020

This communication article addresses currently available rapid non-invasive methods to screen and detect periodontitis and dental peri-implantitis. In this regard, oral fluid biomarkers have been researched extensively but self-reported oral health (SROH)-questionnaires have also been developed. Both alternatives may offer a quick and easy way to screen and detect diseased patients. Active matrix metalloproteinase (aMMP-8) is one of the most validated biomarkers for screening and detecting periodontal breakdown related to periodontitis and peri-implantitis and monitoring their treatment effects revealing successful, less- and non-successful treatment results. Currently available aMMP-8 lateral-flow technologies allow this kind of analysis, as demonstrated here, to be conducted quantitatively online and real-time as point-of-care/chairside testing in dental and even medical care settings. In this study, an aMMP-8 peri-implant sulcular fluid point-of-care-test diagnosed peri-implantitis and healthy implants far more accurately than bleeding-on-probing or the other biomarkers, such as polymorphonuclear (PMN)/neutrophil elastase, myeloperoxidase and MMP-9. Although, SROH-questionnaires allow screening in similar settings but they lack the information about the current disease activity of periodontitis and peri-implantitis, which is of essential value in periodontal diagnostics and treatment monitoring. Thus, both methods can be considered as adjunct methods for periodontitis and peri-implant diagnostics, but the value of oral fluid biomarkers analysis does not seem to be substitutable.
Photobiomodulation and Oral Mucositis: A Systematic Review
Authors: Cronshaw Mark , Parker Steven , Anagnostaki Eugenia , Mylona Valina , Lynch Edward , Grootveld Martin
Published: August 2020

Oral mucositis (OM) is a debilitating complication of chemotherapy, and head and neck radiotherapy. In an effort to offer the best possible advice within the limitations of published research, a systematic review with an extended discussion and commentary on dosimetry and dose delivery is presented. Using keywords as listed, Pubmed, Google Scholar and Cochrane databases were searched during a period extending from 1995 to 2019. A total of 782 abstracts were identified. A total of 50 papers were analysed, and of these, 29 satisfied criteria required for systematic review in accordance with an optimized PRISMA statement. Clinical outcome as reported was subject to analysis with respect to time of intervention, incidence and severity of oral mucositis, and pain amelioration, and a comprehensive combined univariate and multivariate statistical analysis of the methods employed was performed. Recommendations are made with respect to the timing of the intervention. Moreover, there is an extended discussion available on the treatment care rationale of photobiomodulation (PBM), and its adjunctive association with OM. In conclusion, early prophylactic application offers clear advantages in clinical management. The many studies and associated variables and covariables assessed here revealed a choice of delivery techniques, associated wavelengths and many further indices to consider with regard to the accomplishment of optical parameters. It is therefore our recommendation that clinicians use PBM as a therapy with a full and proper understanding and training in order to optimise the clinical effects achievable.