bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the Risk Factors of Post Inflammatory Hyperpigmentation Complications with Nd-YAG Laser Toning Using LASSO-Based Algorithm
Authors: Liu Chao-Hong , Shieh Chin-Shiuh , Huang Tai-Lin , Lin Chih-Hsueh , Chao Pei-Ju , Huang Yu-Jie , Lee Hsiao-Fei , Yeh Shyh-An , Tseng Chin-Dar , Wu Jia-Ming , Leung Stephen Wan , Lee Tsair-Fwu
Published: March 2020

The neodymium-doped yttrium aluminum garnet (Nd-YAG) laser is used for removal of pigmented skin patches and rejuvenation of skin. However, complications such as hyperpigmentation, hypopigmentation, and petechiae can occur after frequent treatments. Therefore, identifying the risk factors for such complications is important. The development of a multivariable logistic regression model with least absolute shrinkage and selection operator (LASSO) is needed to provide valid predictions about the incidence of post inflammatory hyperpigmentation complication probability (PIHCP) among patients treated with Nd-YAG laser toning. A total of 125 female patients undergoing laser toning therapy between January 2014 and January 2016 were examined for post-inflammatory hyperpigmentation (PIH) complications. Factor analysis was performed using 15 potential predictive risk factors of PIH determined by a physician. The LASSO algorithm with cross-validation was used to select the optimal number of predictive risk factors from the potential factors for a multivariate logistic regression PIH complication model. The optimal number of predictive risk factors for the model was five: immediate endpoints of laser (IEL), α-hydroxy acid (AHA) peels, Fitzpatrick skin phototype (FSPT), acne, and melasma. The area under the receiver operating characteristic curve (AUC) was 0.79 (95% CI, 0.70–0.88) in the optimal model. The overall performance of the LASSO-based PIHCP model was satisfactory based on the AUC, Omnibus, Nagelkerke R2, and Hosmer–Lemeshow tests. This predictive risk factor model is useful to further optimize laser toning treatment related to PIH. The LASSO-based PIHCP model could be useful for decision-making.
Modelling, Simulation, and Management Strategy of an Electric Vehicle Charging Station Based on a DC Microgrid
Authors: Wang Dian , Locment Fabrice , Sechilariu Manuela
Published: March 2020

The rapid development of electric vehicles (EVs) increases the power demand, which causes an extra burden on the public grid, increasing the load fluctuations and, therefore, hindering the high penetration of EVs. In this paper, a real-time rule-based algorithm for electric vehicle (EV) charging stations empowered by a direct current (DC) microgrid is proposed. Such a DC microgrid model consists of EVs, an electrochemical storage system, a public grid connection, and photovoltaic sources. The EV charging station model is based on data-driven modelling while its management model takes into account discrete events. This paper focuses on power management strategy of an EV charging station under power limitation and considers most of the drivers’ choices. The EV charging system topology is presented and common problems during an EV charging process are discussed, e.g., disconnection operation, standby mode, shedding, and restoration operation. Furthermore, the proposed power management deals with the uncertainties of EV drivers’ behavior considering arbitrary and random choices through the human–computer interface. The simulation results obtained under MATLAB/Simulink verify the feasibility of the proposed management strategy that presents a good performance in terms of precise control.
Control Methods Comparison for the Real Quadrotor on an Innovative Test Stand
Authors: Chovancová Anežka , Fico Tomáš , Duchoň František , Dekan Martin , Chovanec Ľuboš , Dekanová Martina
Published: March 2020

This article is a continuation of our previously published work that presented a comparison of nine attitude quaternion-based controllers of the quadrotor in simulation environment. In this article, the best three controllers were implemented into the real quadrotor. Namely proportional derivative (PD), linear quadratic regulator (LQR) and backstepping quaternion-based control techniques were evaluated. As a suitable test stand was not available on the basis of literature analysis, the article also outlines the requirements and the development of a new innovative test stand. In order to provide a comprehensive overview, the hardware and software that was used is also presented in the article. The main contribution of this article is a performance comparison of the controllers, which was based on absolute quaternion (positioning) error and energy consumption.
Recovering Climate Data from Documentary Sources: A Study on the Climate in the South of Spain from 1792 to 1808
Authors: S. Rodrigo Fernando
Published: March 2020

This work analyses new climate data on Southern Spain during the period 1792–1808. The data source is the periodical Correo Mercantil de España y sus Indias (Mercantile Mail of Spain and the Spanish Indies), which published weekly summaries of the weather conditions in Spain over this period. The study focuses on the southern provinces, providing 2788 new records, some of them corresponding to areas with no previously recorded data (Córdoba, Jaén). The analysis indicates the predominance of cold and dry winters, cold and wet springs, warm and dry summers, and variable autumn conditions, cold and humid in the western provinces while warm and dry in the eastern provinces. Some examples of these situations are discussed.
Warm Rain in Southern West Africa: A Case Study at Savè
Authors: Reinares Martínez Irene , Chaboureau Jean-Pierre , Handwerker Jan
Published: March 2020

A warm-rain episode over southern West Africa is analyzed using unprecedented X-band radar observations from Savè, Benin and a Large-Eddy Simulation (LES) over a 240 × 240 km 2 domain. While warm rain contributes to 1% of the total rainfall in the LES, its spatial extent accounts for 24% of the area covered by rainfall. Almost all the warm-rain cells tracked in the observation and the LES have a size between 2 and 10 km and a lifetime varying from 5 to 60 min. During the nighttime, warm-rain cells are caused by the dissipation of large deep-convection systems while during the daytime they are formed by the boundary-layer thermals. The vertical extension of the warm-rain cells is limited by vertical wind shear at their top. In the simulation, their top is 1.6 km higher with respect to the radar observations due to the large-scale environment given by wrong initial conditions. This study shows the challenge of simulating warm rain in southern West Africa, a key phenomenon during the little dry season.
Methylation of the Suppressor Gene p16INK4a: Mechanism and Consequences
Authors: Tramontano Alfonso , Boffo Francesca Ludovica , Russo Giusi , De Rosa Mariarosaria , Iodice Ilaria , Pezone Antonio
Published: March 2020

Tumor suppressor genes in the CDKN2A/B locus (p15INK4b, p16INK4a, and p14ARF) function as biological barriers to transformation and are the most frequently silenced or deleted genes in human cancers. This gene silencing frequently occurs due to DNA methylation of the promoter regions, although the underlying mechanism is currently unknown. We present evidence that methylation of p16INK4a promoter is associated with DNA damage caused by interference between transcription and replication processes. Inhibition of replication or transcription significantly reduces the DNA damage and CpGs methylation of the p16INK4a promoter. We conclude that de novo methylation of the promoter regions is dependent on local DNA damage. DNA methylation reduces the expression of p16INK4a and ultimately removes this barrier to oncogene-induced senescence.
Does Cysteine Rule (CysR) Complete the CendR Principle? Increase in Affinity of Peptide Ligands for NRP-1 Through the Presence of N-Terminal Cysteine
Authors: Puszko Anna K. , Sosnowski Piotr , Raynaud Françoise , Hermine Olivier , Hopfgartner Gérard , Lepelletier Yves , Misicka Aleksandra
Published: March 2020

The structure-activity relationship of branched H-Lys(hArg)-Dab-Dhp-Arg-OH sequence analogues, modified with Cys-Asp or Cys at N-terminal amino acids (Lys, hArg), in VEGF-A165/Neuropilin-1 complex inhibition is presented. The addition of Cys residue led to a 100-fold decrease in the IC50 value, compared to the parent peptide. The change occurred regardless of coupling Cys to the free N-terminal amino group present in the main or the side chain. A few analogues extended by the attachment of Cys at the N-terminus of several potent NRP-1 peptide ligands documented in the literature are also presented. In all studied cases, the enhancement of inhibitory properties after the addition of Cys at the N-terminus is observed. It is particularly evident for the tetrapeptide derived from the C-terminus of VEGF-A165 (KPRR), suggesting that extending the K/RXXK/R motif (CendR) with the Cys moiety can significantly improve affinity to NRP-1 of CendR peptides.
Genomic Landscape and Mutational Spectrum of ADAMTS Family Genes in Mendelian Disorders Based on Gene Evidence Review for Variant Interpretation
Authors: Rim John Hoon , Choi Yo Jun , Gee Heon Yung
Published: March 2020

ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) are a family of multidomain extracellular protease enzymes with 19 members. A growing number of ADAMTS family gene variants have been identified in patients with various hereditary diseases. To understand the genomic landscape and mutational spectrum of ADAMTS family genes, we evaluated all reported variants in the ClinVar database and Human Gene Mutation Database (HGMD), as well as recent literature on Mendelian hereditary disorders associated with ADAMTS family genes. Among 1089 variants in 14 genes reported in public databases, 307 variants previously suggested for pathogenicity in Mendelian diseases were comprehensively re-evaluated using the American College of Medical Genetics and Genomics (ACMG) 2015 guideline. A total of eight autosomal recessive genes were annotated as being strongly associated with specific Mendelian diseases, including two recently discovered genes (ADAMTS9 and ADAMTS19) for their causality in congenital diseases (nephronophthisis-related ciliopathy and nonsyndromic heart valve disease, respectively). Clinical symptoms and affected organs were extremely heterogeneous among hereditary diseases caused by ADAMTS family genes, indicating phenotypic heterogeneity despite their structural and functional similarity. ADAMTS6 was suggested as presenting undiscovered pathogenic mutations responsible for novel Mendelian disorders. Our study is the first to highlight the genomic landscape of ADAMTS family genes, providing an appropriate genetic approach for clinical use.
Mesenchymal Cell Growth and Differentiation on a New Biocomposite Material: A Promising Model for Regeneration Therapy
Authors: Pomeraniec Leslie , Benayahu Dafna
Published: March 2020

Mesenchymal stem cells serve as the body’s reservoir for healing and tissue regeneration. In cases of severe tissue trauma where there is also a need for tissue organization, a scaffold may be of use to support the cells in the damaged tissue. Such a scaffold should be composed of a material that can biomimic the mechanical and biological properties of the target tissues in order to support autologous cell-adhesion, their proliferation, and differentiation. In this study, we developed and assayed a new biocomposite made of unique collagen fibers and alginate hydrogel that was assessed for the ability to support mesenchymal cell-proliferation and differentiation. Analysis over 11 weeks in vitro demonstrated that the scaffold was biocompatible and supports the cells viability and differentiation to produce tissue-like structures or become adipocyte under differentiation medium. When the biocomposite was enriched with nano particles (NPs), mesenchymal cells grew well after uptake of fluorescein isothiocyanate (FITC) labeled NPs, maintained their viability, migrated through the biocomposite, reached, and adhered to the tissue culture dish. These promising findings revealed that the scaffold supports the growth and differentiation of mesenchymal cells that demonstrate their full physiological function with no sign of material toxicity. The cells’ functionality performance indicates and suggests that the scaffold is suitable to be developed as a new medical device that has the potential to support regeneration and the production of functional tissue.
MBLinhibitors.com, a Website Resource Offering Information and Expertise for the Continued Development of Metallo-β-Lactamase Inhibitors
Authors: Cheng Zishuo , Thomas Caitlyn , Joyner Adam , Kimble Robert , Sturgill Aidan , Tran Nhu-Y , Vulcan Maya , Klinsky Spencer , Orea Diego , Platt Cody , Cao Fanpu , Li Bo , Yang Qilin , Yurkiewicz Cole , Fast Walter , Crowder Michael
Published: March 2020

In an effort to facilitate the discovery of new, improved inhibitors of the metallo-β-lactamases (MBLs), a new, interactive website called MBLinhibitors.com was developed. Despite considerable efforts from the science community, there are no clinical inhibitors of the MBLs, which are now produced by human pathogens. The website, MBLinhibitors.com, contains a searchable database of known MBL inhibitors, and inhibitors can be searched by chemical name, chemical formula, chemical structure, Simplified Molecular-Input Line-Entry System (SMILES) format, and by the MBL on which studies were conducted. The site will also highlight a “MBL Inhibitor of the Month”, and researchers are invited to submit compounds for this feature. Importantly, MBLinhibitors.com was designed to encourage collaboration, and researchers are invited to submit their new compounds, using the “Submit” function on the site, as well as their expertise using the “Collaboration” function. The intention is for this site to be interactive, and the site will be improved in the future as researchers use the site and suggest improvements. It is hoped that MBLinhibitors.com will serve as the one-stop site for any important information on MBL inhibitors and will aid in the discovery of a clinically useful MBL inhibitor.
BioShell 3.0: Library for Processing Structural Biology Data
Authors: Macnar Joanna M. , Szulc Natalia A. , Kryś Justyna D. , Badaczewska-Dawid Aleksandra E. , Gront Dominik
Published: March 2020

BioShell is an open-source package for processing biological data, particularly focused on structural applications. The package provides parsers, data structures and algorithms for handling and analyzing macromolecular sequences, structures and sequence profiles. The most frequently used routines are accessible by a set of easy-to-use command line utilities for a Linux environment. The full functionality of the package assumes knowledge of C++ or Python to assemble an application using this software library. Since the last publication that announced the version 2.0, the package has been greatly expanded and rewritten in C++ standard 11 (C++11) to improve its modularity and efficiency. A new testing platform has been implemented to continuously test the correctness and integrity of the package. More than two hundred test programs have been published to provide simple examples that can be used as templates. This makes BioShell an easy to use library that greatly speeds up development of bioinformatics applications and web services without compromising computational efficiency.
Why Does Knocking Out NACHO, But Not RIC3, Completely Block Expression of α7 Nicotinic Receptors in Mouse Brain?
Authors: Deshpande Anish , Vinayakamoorthy Remitha M. , Garg Brijesh K. , Thummapudi Jaya Prakash , Oza Gauri , Adhikari Ketaki , Agarwal Aayush , Dalvi Parnika , Iyer Swetha , Thulasi Raman Sarulatha , Ramesh Vijay , Rameshbabu Akshitha , Rezvaya Alexandra , Sukumaran Sneha , Swaminathan Sweta , Tilak Bhargav , Wang Zhiyuan , Tran Phu V. , Loring Ralph H.
Published: March 2020

Alpha7 nicotinic acetylcholine receptors (α7nAChRs) are interesting not only because of their physiological effects, but because this receptor requires chaperones to traffic to cell surfaces (measured by alpha-bungarotoxin [αBGT] binding). While knockout (KO) animals and antibodies that react across species exist for tmem35a encoding the protein chaperone NACHO, commercially available antibodies against the chaperone RIC3 that allow Western blots across species have not been generally available. Further, no effects of deleting RIC3 function (ric3 KO) on α7nAChR expression are reported. Finally, antibodies against α7nAChRs have shown various deficiencies. We find mouse macrophages bind αBGT but lack NACHO. We also report on a new α7nAChR antibody and testing commercially available anti-RIC3 antibodies that react across species allowing Western blot analysis of in vitro cultures. These antibodies also react to specific RIC3 splice variants and single-nucleotide polymorphisms. Preliminary autoradiographic analysis reveals that ric3 KOs show subtle αBGT binding changes across different mouse brain regions, while tmem35a KOs show a complete loss of αBGT binding. These findings are inconsistent with effects observed in vitro, as RIC3 promotes αBGT binding to α7nAChRs expressed in HEK cells, even in the absence of NACHO. Collectively, additional regulatory factors are likely involved in the in vivo expression of α7nAChRs.
A Spanish Consensus on the Use of Safinamide for Parkinson’s Disease in Clinical Practice
Authors: Pagonabarraga Javier , Arbelo José Matías , Grandas Francisco , Luquin Maria-Rosario , Martínez Martín Pablo , Rodríguez-Oroz Mari Cruz , Valldeoriola Francesc , Kulisevsky Jaime
Published: March 2020

Safinamide is an approved drug for the treatment of motor fluctuations in Parkinson’s disease (PD). Scarce data are available on its use in clinical practice. A group of Spanish movement disorders specialists was convened to review the use of safinamide across different clinical scenarios that may guide neurologists in clinical practice. Eight specialists with recognized expertise in PD management elaborated the statements based on available evidence in the literature and on their clinical experience. The RAND/UCLA method was carried, with final conclusions accepted after a 2-round modified Delphi process. Higher level of agreement between panellists was reached for the following statements. Safinamide significantly improves mean daily OFF time without troublesome dyskinesias. Adjunctive treatment with safinamide is associated with motor improvements in patients with mid-to-late PD. The efficacy of safinamide on motor fluctuations is maintained at long-term, with no increase over time in dyskinesias severity. The clinical benefits of safinamide on pain and depression remain unclear. Safinamide presents a similar incidence of adverse events compared with placebo. The efficacy and safety of safinamide shown in the pivotal clinical trials are reproduced in clinical practice, with improvement of parkinsonian symptoms, decrease of daily OFF time, control of dyskinesias at the long term, and good tolerability and safety.
Injury of Corticospinal Tract in a Patient with Subarachnoid Hemorrhage as Determined by Diffusion Tensor Tractography: A Case Report
Authors: Park Chan-Hyuk , Ryu Hyeong , Kim Chang-Hwan , Joa Kyung-Lim , Kim Myeong-Ok , Jung Han-Young
Published: March 2020

We report diffusion tensor tractography (DTT) of the corticospinal tract (CST) in a patient with paresis of all four limbs following subarachnoid hemorrhage (SAH) with intraventricular hemorrhage (IVH) after the rupture of an anterior communicating artery (ACoA) aneurysm rupture. The 73-year-old female was admitted to our emergency room in a semi-comatose mental state. After coil embolization—an acute SAH treatment—she was transferred to our rehabilitation department with motor weakness development, two weeks after SAH. Upon admission, she was alert but she complained of motor weakness (upper limbs: MRC 3/5, and lower limbs: MRC 1/5). Four weeks after onset, DTT showed that the bilateral CSTs failed to reach the cerebral cortex. The left CST demonstrated a wide spread of fibers within the corona radiata as well as significantly lower tract volume (TV) and higher fractional anisotropy (FA) as well as mean diffusivity (MD) compared to the controls. On the other hand, the right CST shifted to the posterior region at the corona radiata, and MD values of the right CST were significantly higher when compared to the controls. Changes in both CSTs were attributed to vasogenic edema and compression caused by untreated hydrocephalus. We demonstrate in this case, two different pathophysiological entitles, contributing to this patient’s motor weakness after SAH.
Insomnia Might Influence the Thickness of Choroid, Retinal Nerve Fiber and Inner Plexiform Layer
Authors: Sahbaz Cigdem , Elbay Ahmet , Ozcelik Mine , Ozdemir Hakan
Published: March 2020

Sleep may play a fundamental role in retinal regulation and the degree of retinal variables. However, no clinical study has investigated optical coherence tomography (OCT) parameters in patients with primary insomnia. All participants were evaluated with the insomnia severity index (ISI) and the Pittsburgh sleep quality index (PSQI). The retinal nerve fiber layer (RNFL), ganglion cell layer (GC), inner plexiform layer (IPL), macula and choroidal (CH) thickness were compared between 52 drug-naïve patients with primary insomnia and 45 age-gender-BMI-smoke status matched healthy controls (HC). The patients with primary insomnia differed from the HC regarding RNFL-Global (p = 0.024) and RNFL-Nasal inferior (p = 0.010); IPL-Temporal (p < 0.001), IPL-Nasal (p < 0.001); CH-Global (p < 0.001), CH-Temporal (p = 0.004), CH-Nasal (p < 0.001), and CH-Fovea (p = 0.019). ISI correlated with RNFL-Global and RNFL-Nasal inferior. The regression analysis revealed that ISI was the significant predictor for the thickness of RNFL- Nasal inferior (p = 0.020), RNFL-Global (p = 0.031), and CH-Nasal (p = 0.035) in patients with primary insomnia. Sleep disorders are seen commonly in patients with psychiatric, including ocular diseases. Adjusting the effect of insomnia can help to clarify the consistency in findings of OCT.
Modeling of an Aerogel-Based “Thermal Break” for Super-Insulated Window Frames
Authors: Cannavale Alessandro , Martellotta Francesco , Berardi Umberto , Rubino Chiara , Liuzzi Stefania , De Carlo Vincenzo , Ayr Ubaldo
Published: March 2020

Research activities in the field of innovative fixtures are continuously aiming at increasing their thermal and optical performances to offer optimal exploitation of daylight and solar gains, providing effective climate screen, according to increasing standards for indoor comfort and energy saving. Within this work, we designed an innovative aerogel-based “thermal break” for window frames, so as to consistently reduce the frame conductance. Then, we compared the performance of this new frame both with currently used and obsolete frames, present in most of the existing building stock. Energy savings for heating and cooling were assessed for different locations and confirmed the potential role played by super-insulating materials in fixtures for extremely rigid climates.
Global RNA Expression and DNA Methylation Patterns in Primary Anaplastic Thyroid Cancer
Authors: Ravi Naveen , Yang Minjun , Mylona Nektaria , Wennerberg Johan , Paulsson Kajsa
Published: March 2020

Anaplastic thyroid cancer (ATC) is one of the most malignant tumors, with a median survival of only a few months. The tumorigenic processes of this disease have not yet been completely unraveled. Here, we report an mRNA expression and DNA methylation analysis of fourteen primary ATCs. ATCs clustered separately from normal thyroid tissue in unsupervised analyses, both by RNA expression and by DNA methylation. In expression analysis, enrichment of cell-cycle-related genes as well as downregulation of genes related to thyroid function were seen. Furthermore, ATC displayed a global hypomethylation of the genome but with hypermethylation of CpG islands. Notably, several cancer-related genes displayed a correlation between RNA expression and DNA methylation status, including MTOR, NOTCH1, and MAGI1. Furthermore, TSHR and SLC26A7, encoding the thyroid-stimulating hormone receptor and an iodine receptor highly expressed in normal thyroid, respectively, displayed low expression as well as aberrant gene body DNA methylation. This study is the largest investigation of global DNA methylation in ATC to date. It shows that aberrant DNA methylation is common in ATC and likely contributes to tumorigenesis in this disease. Future explorations of novel treatments should take this into consideration.
Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours
Authors: Chruściel Elżbieta , Urban-Wójciuk Zuzanna , Arcimowicz Łukasz , Kurkowiak Małgorzata , Kowalski Jacek , Gliwiński Mateusz , Marjański Tomasz , Rzyman Witold , Biernat Wojciech , Dziadziuszko Rafał , Montesano Carla , Bernardini Roberta , Marek-Trzonkowska Natalia
Published: March 2020

In recent years, much research has been focused on the field of adoptive cell therapies (ACT) that use native or genetically modified T cells as therapeutic tools. Immunotherapy with T cells expressing chimeric antigen receptors (CARs) demonstrated great success in the treatment of haematologic malignancies, whereas adoptive transfer of autologous tumour infiltrating lymphocytes (TILs) proved to be highly effective in metastatic melanoma. These encouraging results initiated many studies where ACT was tested as a treatment for various solid tumours. In this review, we provide an overview of the challenges of T cell-based immunotherapies of solid tumours. We describe alternative approaches for choosing the most efficient T cells for cancer treatment in terms of their tumour-specificity and phenotype. Finally, we present strategies for improvement of anti-tumour potential of T cells, including combination therapies.
Vitamin C Restricts the Emergence of Acquired Resistance to EGFR-Targeted Therapies in Colorectal Cancer
Authors: Lorenzato Annalisa , Magrì Alessandro , Matafora Vittoria , Audrito Valentina , Arcella Pamela , Lazzari Luca , Montone Monica , Lamba Simona , Deaglio Silvia , Siena Salvatore , Bertotti Andrea , Trusolino Livio , Bachi Angela , Di Nicolantonio Federica , Bardelli Alberto , Arena Sabrina
Published: March 2020

The long-term efficacy of the Epidermal Growth Factor Receptor (EGFR)-targeted antibody cetuximab in advanced colorectal cancer (CRC) patients is limited by the emergence of drug-resistant (persister) cells. Recent studies in other cancer types have shown that cells surviving initial treatment with targeted agents are often vulnerable to alterations in cell metabolism including oxidative stress. Vitamin C (VitC) is an antioxidant agent which can paradoxically trigger oxidative stress at pharmacological dose. Here we tested the hypothesis that VitC in combination with cetuximab could restrain the emergence of secondary resistance to EGFR blockade in CRC RAS/BRAF wild-type models. We found that addition of VitC to cetuximab impairs the emergence of drug persisters, limits the growth of CRC organoids, and significantly delays acquired resistance in CRC patient-derived xenografts. Mechanistically, proteomic and metabolic flux analysis shows that cetuximab blunts carbohydrate metabolism by blocking glucose uptake and glycolysis, beyond promoting slow but progressive ROS production. In parallel, VitC disrupts iron homeostasis and further increases ROS levels ultimately leading to ferroptosis. Combination of VitC and cetuximab orchestrates a synthetic lethal metabolic cell death program triggered by ATP depletion and oxidative stress, which effectively limits the emergence of acquired resistance to anti-EGFR antibodies. Considering that high-dose VitC is known to be safe in cancer patients, our findings might have clinical impact on CRC patients treated with anti-EGFR therapies.
Pathogenesis and Clinical Management of Uterine Serous Carcinoma
Authors: Zhang Li , Kwan Suet Ying , Wong Kwong Kwok , Soliman Pamela T. , Lu Karen H. , Mok Samuel C.
Published: March 2020

Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer that has not been well characterized. It accounts for less than 10% of all endometrial cancers and 80% of endometrial cancer–related deaths. Currently, staging surgery together with chemotherapy or radiotherapy, especially vaginal cuff brachytherapy, is the main treatment strategy for USC. Whole-exome sequencing combined with preclinical and clinical studies are verifying a series of effective and clinically accessible inhibitors targeting frequently altered genes, such as HER2 and PI3K3CA, in varying USC patient populations. Some progress has also been made in the immunotherapy field. The PD-1/PD-L1 pathway has been found to be activated in many USC patients, and clinical trials of PD-1 inhibitors in USC are underway. This review updates the progress of research regarding the molecular pathogenesis and putative clinical management of USC.
Long-Term Deleterious Effects of Short-term Hyperoxia on Cancer Progression—Is Brain-Derived Neurotrophic Factor an Important Mediator? An Experimental Study
Authors: Tiron Adrian , Ristescu Irina , Postu Paula A. , Tiron Crina E. , Zugun-Eloae Florin , Grigoras Ioana
Published: March 2020

Perioperative factors promoting cancer recurrence and metastasis are under scrutiny. While oxygen toxicity is documented in several acute circumstances, its implication in tumor evolution is poorly understood. We investigated hyperoxia long-term effects on cancer progression and some underlying mechanisms using both in vitro and in vivo models of triple negative breast cancer (TNBC). We hypothesized that high oxygen exposure, even of short duration, may have long-term effects on cancer growth. Considering that hyperoxic exposure results in reactive oxygen species (ROS) formation, increased oxidative stress and increased Brain-Derived Neurotrophic Factor (BDNF) expression, BDNF may mediate hyperoxia effects offering cancer cells a survival advantage by increased angiogenesis and epithelial mesenchymal transition (EMT). Human breast epithelial MCF10A, human MDA-MB-231 and murine 4T1 TNBC were investigated in 2D in vitro system. Cells were exposed to normoxia or hyperoxia (40%, 60%, 80% O2) for 6 h. We evaluated ROS levels, cell viability and the expression of BDNF, HIF-1α, VEGF-R2, Vimentin and E-Cadherin by immunofluorescence. The in vivo model consisted of 4T1 inoculation in Balb/c mice and tumor resection 2 weeks after and 6 h exposure to normoxia or hyperoxia (40%, 80% O2). We measured lung metastases and the same molecular markers, immediately and 4 weeks after surgery. The in vitro study showed that short-term hyperoxia exposure (80% O2) of TNBC cells increases ROS, increases BDNF expression and that promotes EMT and angiogenesis. The in vivo data indicates that perioperative hyperoxia enhances metastatic disease and this effect could be BDNF mediated.
Cancer-testis Antigen FATE1 Expression in Adrenocortical Tumors Is Associated with A Pervasive Autoimmune Response and Is A Marker of Malignancy in Adult, but Not Children, ACC
Authors: Doghman-Bouguerra Mabrouka , Finetti Pascal , Durand Nelly , Parise Ivy Zortéa S. , Sbiera Silviu , Cantini Giulia , Canu Letizia , Hescot Ségolène , Figueiredo Mirna M. O. , Komechen Heloisa , Sbiera Iuliu , Nesi Gabriella , Paci Angelo , Al Ghuzlan Abir , Birnbaum Daniel , Baudin Eric , Luconi Michaela , Fassnacht Martin , Figueiredo Bonald C. , Bertucci François , Lalli Enzo
Published: March 2020

The SF-1 transcription factor target gene FATE1 encodes a cancer-testis antigen that has an important role in regulating apoptosis and response to chemotherapy in adrenocortical carcinoma (ACC) cells. Autoantibodies directed against FATE1 were previously detected in patients with hepatocellular carcinoma. In this study, we investigated the prevalence of circulating anti-FATE1 antibodies in pediatric and adult patients with adrenocortical tumors using three different methods (immunofluorescence, ELISA and Western blot). Our results show that a pervasive anti-FATE1 immune response is present in those patients. Furthermore, FATE1 expression is a robust prognostic indicator in adult patients with ACC and is associated with increased steroidogenic and decreased immune response gene expression. These data can open perspectives for novel strategies in ACC immunotherapy.
Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo
Authors: Hum Nicholas R. , Sebastian Aimy , Gilmore Sean F. , He Wei , Martin Kelly A. , Hinckley Aubree , Dubbin Karen R. , Moya Monica L. , Wheeler Elizabeth K. , Coleman Matthew A. , Loots Gabriela G.
Published: March 2020

Current pre-clinical models of cancer fail to recapitulate the cancer cell behavior in primary tumors primarily because of the lack of a deeper understanding of the effects that the microenvironment has on cancer cell phenotype. Transcriptomic profiling of 4T1 murine mammary carcinoma cells from 2D and 3D cultures, subcutaneous or orthotopic allografts (from immunocompetent or immunodeficient mice), as well as ex vivo tumoroids, revealed differences in molecular signatures including altered expression of genes involved in cell cycle progression, cell signaling and extracellular matrix remodeling. The 3D culture platforms had more in vivo-like transcriptional profiles than 2D cultures. In vivo tumors had more cells undergoing epithelial-to-mesenchymal transition (EMT) while in vitro cultures had cells residing primarily in an epithelial or mesenchymal state. Ex vivo tumoroids incorporated aspects of in vivo and in vitro culturing, retaining higher abundance of cells undergoing EMT while shifting cancer cell fate towards a more mesenchymal state. Cellular heterogeneity surveyed by scRNA-seq revealed that ex vivo tumoroids, while rapidly expanding cancer and fibroblast populations, lose a significant proportion of immune components. This study emphasizes the need to improve in vitro culture systems and preserve syngeneic-like tumor composition by maintaining similar EMT heterogeneity as well as inclusion of stromal subpopulations.
Hypoxia-Induced Adaptations of miRNomes and Proteomes in Melanoma Cells and Their Secreted Extracellular Vesicles
Authors: Walbrecq Geoffroy , Lecha Odile , Gaigneaux Anthoula , Fougeras Miriam R. , Philippidou Demetra , Margue Christiane , Tetsi Nomigni Milène , Bernardin François , Dittmar Gunnar , Behrmann Iris , Kreis Stephanie
Published: March 2020

Reduced levels of intratumoural oxygen are associated with hypoxia-induced pro-oncogenic events such as invasion, metabolic reprogramming, epithelial–mesenchymal transition, metastasis and resistance to therapy, all favouring cancer progression. Small extracellular vesicles (EV) shuttle various cargos (proteins, miRNAs, DNA and others). Tumour-derived EVs can be taken up by neighbouring or distant cells in the tumour microenvironment, thus facilitating intercellular communication. The quantity of extracellular vesicle secretion and their composition can vary with changing microenvironmental conditions and disease states. Here, we investigated in melanoma cells the influence of hypoxia on the content and number of secreted EVs. Whole miRNome and proteome profiling revealed distinct expression patterns in normoxic or hypoxic growth conditions. Apart from the well-known miR-210, we identified miR-1290 as a novel hypoxia-associated microRNA, which was highly abundant in hypoxic EVs. On the other hand, miR-23a-5p and -23b-5p were consistently downregulated in hypoxic conditions, while the protein levels of the miR-23a/b-5p-predicted target IPO11 were concomitantly upregulated. Furthermore, hypoxic melanoma EVs exhibit a signature consisting of six proteins (AKR7A2, DDX39B, EIF3C, FARSA, PRMT5, VARS), which were significantly associated with a poor prognosis for melanoma patients, indicating that proteins and/or miRNAs secreted by cancer cells may be exploited as biomarkers.
Imaging Features and Patterns of Metastasis in Non-Small Cell Lung Cancer with RET Rearrangements
Authors: Digumarthy Subba R. , Mendoza Dexter P. , Lin Jessica J. , Rooney Marguerite , Do Andrew , Chin Emily , Yeap Beow Y. , Shaw Alice T. , Gainor Justin F.
Published: March 2020

Rearranged during transfection proto-oncogene (RET) fusions represent a potentially targetable oncogenic driver in non-small cell lung cancer (NSCLC). Imaging features and metastatic patterns of advanced RET fusion-positive (RET+) NSCLC are not well established. Our goal was to compare the imaging features and patterns of metastases in RET+, ALK+ and ROS1+ NSCLC. Patients with RET+, ALK+, or ROS1+ NSCLC seen at our institution between January 2014 and December 2018 with available pre-treatment imaging were identified. The clinicopathologic features, imaging characteristics, and the distribution of metastases were reviewed and compared. We identified 215 patients with NSCLC harboring RET, ALK, or ROS1 gene fusion (RET = 32; ALK = 116; ROS1 = 67). Patients with RET+ NSCLC were older at presentation compared to ALK+ and ROS1+ patients (median age: RET = 64 years; ALK = 51 years, p < 0.001; ROS = 54 years, p = 0.042) and had a higher frequency of neuroendocrine histology (RET = 12%; ALK = 2%, p = 0.025; ROS1 = 0%, p = 0.010). Primary tumors in RET+ patients were more likely to be peripheral (RET = 69%; ALK = 47%, p = 0.029; ROS1 = 36%, p = 0.003), whereas lobar location, size, and density were comparable across the three groups. RET+ NSCLC was associated with a higher frequency of brain metastases at diagnosis compared to ROS1+ NSCLC (RET = 32%, ROS1 = 10%; p = 0.039. Metastatic patterns were otherwise similar across the three molecular subgroups, with high incidences of lymphangitic carcinomatosis, pleural metastases, and sclerotic bone metastases. RET+ NSCLC shares several distinct radiologic features and metastatic spread with ALK+ and ROS1+ NSCLC. These features may suggest the presence of RET fusions and help identify patients who may benefit from further molecular genotyping.
Establishment and Molecular Phenotyping of Organoids from the Squamocolumnar Junction Region of the Uterine Cervix
Authors: Maru Yoshiaki , Kawata Akira , Taguchi Ayumi , Ishii Yoshiyuki , Baba Satoshi , Mori Mayuyo , Nagamatsu Takeshi , Oda Katsutoshi , Kukimoto Iwao , Osuga Yutaka , Fujii Tomoyuki , Hippo Yoshitaka
Published: March 2020

The metaplastic epithelium of the transformation zone (TZ) including the squamocolumnar junction (SCJ) of the uterine cervix is a prime target of human papilloma virus (HPV) infection and subsequent cancer development. Due to the lack of adequate in vitro models for SCJ, however, investigations into its physiological roles and vulnerability to carcinogenesis have been limited. By using Matrigel-based three-dimensional culture techniques, we propagated organoids derived from the normal SCJ region, along with metaplastic squamous cells in the TZ. Consisting predominantly of squamous cells, organoids basically exhibited a dense structure. However, at least in some organoids, a small but discrete population of mucin-producing endocervix cells co-existed adjacent to the squamous cell population, virtually recapitulating the configuration of SCJ in a TZ background. In addition, transcriptome analysis confirmed a higher expression level of many SCJ marker genes in organoids, compared to that in the immortalized cervical cell lines of non-SCJ origin. Thus, the obtained organoids appear to mimic cervical SCJ cells and, in particular, metaplastic squamous cells from the TZ, likely providing a novel platform in which HPV-driven cervical cancer development could be investigated.
Emerging Role of Circulating Tumor Cells in Gastric Cancer
Authors: Thanh Huong Phung , Gurshaney Sanjeev , Thanh Binh Nguyen , Gia Pham Anh , Hoang Nguyen Huy , Thanh Nguyen Xuan , Pham-The Hai , Tran Phuong-Thao , Truong Vu Khanh , Xuan Duong Nhuong , Pelucchi Claudio , La Vecchia Carlo , Boffetta Paolo , Nguyen Hung D. , Luu Hung N.
Published: March 2020

With over 1 million incidence cases and more than 780,000 deaths in 2018, gastric cancer (GC) was ranked as the 5th most common cancer and the 3rd leading cause of cancer deaths worldwide. Though several biomarkers, including carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4), have been identified, their diagnostic accuracies were modest. Circulating tumor cells (CTCs), cells derived from tumors and present in body fluids, have recently emerged as promising biomarkers, diagnostically and prognostically, of cancers, including GC. In this review, we present the landscape of CTCs from migration, to the presence in circulation, biologic properties, and morphologic heterogeneities. We evaluated clinical implications of CTCs in GC patients, including diagnosis, prognosis, and therapeutic management, as well as their application in immunotherapy. On the one hand, major challenges in using CTCs in GC were analyzed, from the differences of cut-off values of CTC positivity, to techniques used for sampling, storage conditions, and CTC molecular markers, as well as the unavailability of relevant enrichment and detection techniques. On the other hand, we discussed future perspectives of using CTCs in GC management and research, including the use of circulating tumor microembolies; of CTC checkpoint blockade in immunotherapy; and of organoid models. Despite the fact that there are remaining challenges in techniques, CTCs have potential as novel biomarkers and/or a non-invasive method for diagnostics, prognostics, and treatment monitoring of GC, particularly in the era of precision medicine.
Factors Associated with Health-Related Quality of Life in Women with Breast Cancer in the Middle East: A Systematic Review
Authors: El Haidari Rana , Abbas Linda Abou , Nerich Virginie , Anota Amélie
Published: March 2020

Objectives: The aim of the present systematic review was to identify the factors that potentially influence health-related quality of life (HRQoL) in women with breast cancer (BC) in the Middle East. Methods: A systematic search of the PubMed, Ovid Medline, Cochrane, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and Ebscohost databases was conducted to identify all relevant articles published in peer-reviewed journals up to April 2018. The keywords were “Health related quality of life”, “Breast Cancer”, and “Middle East countries”. The Newcastle–Ottawa (NOS) scale was used to evaluate the methodological quality of the included studies. Due to the methodological heterogeneity of the identified studies, no statistical pooling of the individual effect estimates was carried out; instead, the results were summarized descriptively. Results: A total of 5668 articles were screened and 33 studies were retained. The vast majority of these studies were cross-sectional and only two were longitudinal prospective studies. Concerning the methodological quality, only 39% were of high quality. Our comprehensive literature review identified several modifiable and non-modifiable risk factors associated with HRQoL, including sociodemographic, clinical, and treatment-related factors as well as behavioral and psychosocial factors. Conclusion: This study has many implications for clinical practice and may provide a framework for establishing policy interventions to improve HRQoL among women with BC. Healthcare systems in the Middle East are encouraged to develop interventional programs targeting modifiable factors, particularly socio-demographic, behavioral, and psychosocial factors.
Oxaliplatin-Induced DHX9 Phosphorylation Promotes Oncogenic Circular RNA CCDC66 Expression and Development of Chemoresistance
Authors: Lin Ya-Chi , Yu Ya-Shan , Lin Hui-Hsuan , Hsiao Kuei-Yang
Published: March 2020

Circular RNA (circRNA), generated through backsplicing in which the downstream splice donor joins the upstream splice acceptor, is a novel class of RNA molecules. Our previous study found that a novel oncogenic circRNA—consisting exon 8–10 of CCDC66—is aberrantly expressed in colorectal cancer (CRC) tissues and cells. The failure of treatment for colorectal cancer is typically associated with recurrent and chemoresistant cancerous tissues. In this study, we aimed to investigate the role(s) of circCCDC66 during the development of chemoresistance. We discovered that the expression level of circCCDC66 is elevated in colorectal cancer cells with resistance to oxaliplatin. Knockdown of circCCDC66 caused the downregulation of a subset of genes which are regulated by circCCDC66-associated miRNAs and related to the modulation of apoptosis and the cell cycle, suppressing cell survival, promoting oxaliplatin-induced apoptosis and, thus, hindering the development of oxaliplatin-resistance (OxR). The induction of circCCDC66 was dependent on the time-course and dose of oxaliplatin treatment. Our analyses revealed that DHX9 harbors two phosphorylation sites of phosphatidylinositol 3-kinase-related kinases (PI3KKs) close to substrate-binding domains. Blockage of phosphorylation by either PI3KK inhibitors or nonphosphorable mutants of DHX9 decreased the oxaliplatin-induced circCCDC66 expression and the ability to develop chemoresistant cells. Taken together, we demonstrated and linked the functional role of DHX9 phosphorylation to oncogenic circCCDC66 expression during the development of resistance to oxaliplatin, providing a mechanistic insight for the development of therapeutic strategies to recurring/chemoresistant colorectal cancer.
Carbon-Ion Beam Irradiation Alone or in Combination with Zoledronic acid Effectively Kills Osteosarcoma Cells
Authors: Kim Eun Ho , Kim Mi-Sook , Takahashi Akihisa , Suzuki Masao , Vares Guillaume , Uzawa Akiko , Fujimori Akira , Ohno Tatsuya , Sai Sei
Published: March 2020

Osteosarcoma (OSA) is the most common malignant bone tumor in children and adolescents. The overall five-year survival rate for all bone cancers is below 70%; however, when the cancer has spread beyond the bone, it is about 15–30%. Herein, we evaluated the effects of carbon-ion beam irradiation alone or in combination with zoledronic acid (ZOL) on OSA cells. Carbon-ion beam irradiation in combination with ZOL significantly inhibited OSA cell proliferation by arresting cell cycle progression and initiating KHOS and U2OS cell apoptosis, compared to treatments with carbon-ion beam irradiation, X-ray irradiation, and ZOL alone. Moreover, we observed that this combination greatly inhibited OSA cell motility and invasion, accompanied by the suppression of the Pi3K/Akt and MAPK signaling pathways, which are related to cell proliferation and survival, compared to individual treatments with carbon-ion beam or X-ray irradiation, or ZOL. Furthermore, ZOL treatment upregulated microRNA (miR)-29b expression; the combination with a miR-29b mimic further decreased OSA cell viability via activation of the caspase 3 pathway. Thus, ZOL-mediated enhancement of carbon-ion beam radiosensitivity may occur via miR-29b upregulation; co-treatment with the miR-29b mimic further decreased OSA cell survival. These findings suggest that the carbon-ion beam irradiation in combination with ZOL has high potential to increase OSA cell death.