bluuebunny/crossref_metadata_2025 huggingface dataset:
A Differential Measurement System for Surface Topography Based on a Modular Design
Authors: Cheng Fang , Zou Jingwu , Su Hang , Wang Yin , Yu Qing
Published: February 2020

In this paper, a novel design of a surface topography measurement system is proposed, to address the challenge of accurate measurement in a relatively large area. This system was able to achieve nanometer-scale accuracy in a measurement range of 100 mm × 100 mm. The high accuracy in a relatively large area was achieved by implementing two concepts: (1) A static coordinate system was configured to minimize the Abbe errors. (2) A differential measurement configuration was developed by setting up a confocal sensor and a film interferometry module to separate the motion error. In order to accommodate the differential measurement probes from both sides of the central stage and ensure the system rigidity with balanced supports, separate linear guides were introduced in this system. Therefore, the motion Degree of Freedom (DoF) was analyzed in order to address the challenge of an over-constrained mechanism due to multiple kinematic pairs. An optimal configuration and a quick assembly process were proposed accordingly. The experimental results presented in this paper showed that the proposed modular measurement system was able to achieve 10 nm accuracy in measuring the surface roughness and 100 nm accuracy in measuring the step height in the range of 100 mm × 100 mm. In summary, the novel concept of this study is the build of a high-accuracy system with conventional mechanical components.
Deep Learning Entrusted to Fog Nodes (DLEFN) Based Smart Agriculture
Authors: Lee Kyuchang , Silva Bhagya Nathali , Han Kijun
Published: February 2020

Colossal amounts of unstructured multimedia data are generated in the modern Internet of Things (IoT) environment. Nowadays, deep learning (DL) techniques are utilized to extract useful information from the data that are generated constantly. Nevertheless, integrating DL methods with IoT devices is a challenging issue due to their restricted computational capacity. Although cloud computing solves this issue, it has some problems such as service delay and network congestion. Hence, fog computing has emerged as a breakthrough way to solve the problems of using cloud computing. In this article, we propose a strategy that assigns a portion of the DL layers to fog nodes in a fog-computing-based smart agriculture environment. The proposed deep learning entrusted to fog nodes (DLEFN) algorithm decides the optimal layers of DL model to execute on each fog node, considering their available computing capacity and bandwidth. The DLEFN individually calculates the optimal layers for each fog node with dissimilar computational capacities and bandwidth. In a similar experimental environment, comparison results clearly showed that proposed method accommodated more DL application than other existing assignment methods and utilized resources efficiently while reducing network congestion and processing burden on the cloud.
A Robot Arm and Image-Guided Navigation Assisted Surgical System for Maxillary Repositioning in Orthognathic Surgery: A Phantom Skull-Based Trial
Authors: Han Jeong Joon , Woo Sang-Yoon , Yi Won-Jin , Hwang Soon Jung
Published: February 2020

This study aimed to present a simplified and safe method to reposition the bone segment with easy identification and removing bone interference using a robot arm and image-guided navigation and to assess the accuracy for maxillary orthognathic surgery on phantom skulls. A surgical system consists of a robot arm with specialized end-effector, and image-guided navigation including the optical tracking system. The end-effector was designed to reflect the surgical procedures including identification and removal of bone interference and repositioning of the bone segment. To evaluate the handling and accuracy of this system, 10 phantom-based experiments were conducted according to four surgical plans. Mean absolute deviations at the upper central incisor were 0.10 ± 0.15 mm medio-laterally, 0.05 ± 0.07 mm antero-posteriorly, and 0.12 ± 0.15 mm supero-inferiorly. There was no significant difference in deviations between anterior and posterior regions of the maxilla. The mean root mean square deviation was 0.18 ± 0.16 mm, and ranged from 0.05 mm to 0.54 mm. The robot arm and image-guided navigation assisted surgical system would be helpful to manage bone interferences and reposition bone segments with improved accuracy. Though further technological advances are necessary, this study may provide a basis for developing clinically applicable robot assisted system for orthognathic surgery.
Game-Based Resource Allocation Mechanism in B5G HetNets with Incomplete Information
Authors: Feng Weijia , Li Xiaohui
Published: February 2020

Ultra-dense and highly heterogeneous network (HetNet) deployments make the allocation of limited wireless resources among ubiquitous Internet of Things (IoT) devices an unprecedented challenge in 5G and beyond (B5G) networks. The interactions among mobile users and HetNets remain to be analyzed, where mobile users choose optimal networks to access and the HetNets adopt proper methods for allocating their own network resource. Existing works always need complete information among mobile users and HetNets. However, it is not practical in a realistic situation where important individual information is protected and will not be public to others. This paper proposes a distributed pricing and resource allocation scheme based on a Stackelberg game with incomplete information. The proposed model proves to be more practical by solving the problem that important information of either mobile users or HetNets is difficult to acquire during the resource allocation process. Considering the unknowability of channel gain information, the follower game among users is modeled as an incomplete information game, and channel gain is regarded as the type of each player. Given the pricing strategies of networks, users will adjust their bandwidth requesting strategies to maximize their expected utility. While based on the sub-equilibrium obtained in the follower game, networks will correspondingly update their pricing strategies to be optimal. The existence and uniqueness of Bayesian Nash equilibrium is proved. A probabilistic prediction method realizes the feasibility of the incomplete information game, and a reverse deduction method is utilized to obtain the game equilibrium. Simulation results show the superior performance of the proposed method.
Virtual View Synthesis Based on Asymmetric Bidirectional DIBR for 3D Video and Free Viewpoint Video
Authors: Chen Xiaodong , Liang Haitao , Xu Huaiyuan , Ren Siyu , Cai Huaiyu , Wang Yi
Published: February 2020

Depth image-based rendering (DIBR) plays an important role in 3D video and free viewpoint video synthesis. However, artifacts might occur in the synthesized view due to viewpoint changes and stereo depth estimation errors. Holes are usually out-of-field regions and disocclusions, and filling them appropriately becomes a challenge. In this paper, a virtual view synthesis approach based on asymmetric bidirectional DIBR is proposed. A depth image preprocessing method is applied to detect and correct unreliable depth values around the foreground edges. For the primary view, all pixels are warped to the virtual view by the modified DIBR method. For the auxiliary view, only the selected regions are warped, which contain the contents that are not visible in the primary view. This approach reduces the computational cost and prevents irrelevant foreground pixels from being warped to the holes. During the merging process, a color correction approach is introduced to make the result appear more natural. In addition, a depth-guided inpainting method is proposed to handle the remaining holes in the merged image. Experimental results show that, compared with bidirectional DIBR, the proposed rendering method can reduce about 37% rendering time and achieve 97% hole reduction. In terms of visual quality and objective evaluation, our approach performs better than the previous methods.
Wire Arc Additive Manufacturing of Stainless Steels: A Review
Authors: Jin Wanwan , Zhang Chaoqun , Jin Shuoya , Tian Yingtao , Wellmann Daniel , Liu Wen
Published: February 2020

Wire arc additive manufacturing (WAAM) has been considered as a promising technology for the production of large metallic structures with high deposition rates and low cost. Stainless steels are widely applied due to good mechanical properties and excellent corrosion resistance. This paper reviews the current status of stainless steel WAAM, covering the microstructure, mechanical properties, and defects related to different stainless steels and process parameters. Residual stress and distortion of the WAAM manufactured components are discussed. Specific WAAM techniques, material compositions, process parameters, shielding gas composition, post heat treatments, microstructure, and defects can significantly influence the mechanical properties of WAAM stainless steels. To achieve high quality WAAM stainless steel parts, there is still a strong need to further study the underlying physical metallurgy mechanisms of the WAAM process and post heat treatments to optimize the WAAM and heat treatment parameters and thus control the microstructure. WAAM samples often show considerable anisotropy both in microstructure and mechanical properties. The new in-situ rolling + WAAM process is very effective in reducing the anisotropy, which also can reduce the residual stress and distortion. For future industrial applications, fatigue properties, and corrosion behaviors of WAAMed stainless steels need to be deeply studied in the future. Additionally, further efforts should be made to improve the WAAM process to achieve faster deposition rates and better-quality control.
Model Inter-Comparison for PM2.5 Components over urban Areas in Japan in the J-STREAM Framework
Authors: Yamaji Kazuyo , Chatani Satoru , Itahashi Syuichi , Saito Masahiko , Takigawa Masayuki , Morikawa Tazuko , Kanda Isao , Miya Yukako , Komatsu Hiroaki , Sakurai Tatsuya , Morino Yu , Kitayama Kyo , Nagashima Tatsuya , Shimadera Hikari , Uranishi Katsushige , Fujiwara Yuzuru , Hashimoto Tomoaki , Sudo Kengo , Misaki Takeshi , Hayami Hiroshi
Published: February 2020

A model inter-comparison of secondary pollutant simulations over urban areas in Japan, the first phase of Japan’s study for reference air quality modeling (J-STREAM Phase I), was conducted using 32 model settings. Simulated hourly concentrations of nitric oxide (NO) and nitrogen dioxide (NO2), which are primary pollutant precursors of particulate matter with a diameter of 2.5 µm or less (PM2.5), showed good agreement with the observed concentrations, but most of the simulated hourly sulfur oxide (SO2) concentrations were much higher than the observations. Simulated concentrations of PM2.5 and its components were compared to daily observed concentrations by using the filter pack method at selected ambient air pollution monitoring stations (AAPMSs) for each season. In general, most models showed good agreement with the observed total PM2.5 mass concentration levels in each season and provided goal or criteria levels of model ensemble statistics in warmer seasons. The good performances of these models were associated with the simulated reproducibility of some dominant components, sulfates (SO42−) and ammonium (NH4+). The other simulated PM2.5 components, i.e., nitrates (NO3−), elemental carbon (EC), and organic carbon (OC), often show clear deviations from the observations. The considerable underestimations (approximately 30 µg/m3 for total PM2.5) of all participant models found on heavily polluted days with approximately 40–50 µg/m3 for total PM2.5 indicated some problems in the simulated local meteorology such as the atmospheric stability. This model inter-comparison suggests that these deviations may be owing to a need for further improvements both in the emission inventories and additional formation pathways in chemical transport models, and meteorological conditions also require improvement to simulate elevated atmospheric pollutants. Additional accumulated observations are likely needed to further evaluate the simulated concentrations and improve the model performance.
Relationships between Exposure to Bioaerosols, Moldy Surface and Symptoms in French Mold-Damaged Homes
Authors: Delanoë Antoine , Heutte Natacha , Gente Stéphanie , Séguin Virginie , Garon David
Published: February 2020

Air quality in homes is a major concern in Europe, where people spend most of their time indoors. According to the World Health Organization, numerous houses are subject to dampness that can lead to mold growth, with associated health and economic consequences. Our goal was to characterize the human exposure to bioaerosols in French mold-damaged houses but also to study the effects of these bioaerosols as suffered by the inhabitants of these houses. A global approach including both field study and laboratory experimentation was used to investigate 48 mold-damaged homes. Among a wide fungal diversity, 101 viable species, Aspergillus versicolor, Penicillium chrysogenum and P. crustosum were observed as recurrent species and could be used as microbial indicators of indoor air quality. Statistical analyses highlighted a relationship between the concentrations of these recurrent molds and the levels of surface contamination by molds in homes. Fever, cough, dyspnea, flu-like symptoms were observed with several fungal strains (A. versicolor, P. chrysogenum and P. crustosum) or in relation to moldy odor. Relationships between particles of 2 to 15 µm diameter and headaches and dizziness were also observed. In our study, we identified a cutaneous effect (itching) in relationship to the airborne concentration of A. versicolor.
A Sequential Approach to Mild Distributions
Authors: Feichtinger Hans G.
Published: February 2020

The Banach Gelfand Triple ( S 0 , L 2 , S 0 ′ ) ( R d ) consists of S 0 ( R d ) , ∥ · ∥ S 0 , a very specific Segal algebra as algebra of test functions, the Hilbert space L 2 ( R d ) , ∥ · ∥ 2 and the dual space S 0 ′ ( R d ) , whose elements are also called “mild distributions”. Together they provide a universal tool for Fourier Analysis in its many manifestations. It is indispensable for a proper formulation of Gabor Analysis, but also useful for a distributional description of the classical (generalized) Fourier transform (with Plancherel’s Theorem and the Fourier Inversion Theorem as core statements) or the foundations of Abstract Harmonic Analysis, as it is not difficult to formulate this theory in the context of locally compact Abelian (LCA) groups. A new approach presented recently allows to introduce S 0 ( R d ) , ∥ · ∥ S 0 and hence ( S 0 ′ ( R d ) , ∥ · ∥ S 0 ′ ) , the space of “mild distributions”, without the use of the Lebesgue integral or the theory of tempered distributions. The present notes will describe an alternative, even more elementary approach to the same objects, based on the idea of completion (in an appropriate sense). By drawing the analogy to the real number system, viewed as infinite decimals, we hope that this approach is also more interesting for engineers. Of course it is very much inspired by the Lighthill approach to the theory of tempered distributions. The main topic of this article is thus an outline of the sequential approach in this concrete setting and the clarification of the fact that it is just another way of describing the Banach Gelfand Triple. The objects of the extended domain for the Short-Time Fourier Transform are (equivalence classes) of so-called mild Cauchy sequences (in short ECmiCS). Representatives are sequences of bounded, continuous functions, which correspond in a natural way to mild distributions as introduced in earlier papers via duality theory. Our key result shows how standard functional analytic arguments combined with concrete properties of the Segal algebra S 0 ( R d ) , ∥ · ∥ S 0 can be used to establish this natural identification.
Effects of Fish Predators on the Mass-Related Energetics of a Keystone Freshwater Crustacean
Authors: Glazier Douglas S. , Borrelli Jonathan J. , Hoffman Casandra L.
Published: February 2020

Little is known about how predators or their cues affect the acquisition and allocation of energy throughout the ontogeny of prey organisms. To address this question, we have been comparing the ontogenetic body-mass scaling of various traits related to energy intake and use between populations of a keystone amphipod crustacean inhabiting freshwater springs, with versus without fish predators. In this progress report, we analyze new and previously reported data to develop a synthetic picture of how the presence/absence of fish predators affects the scaling of food assimilation, fat content, metabolism, growth and reproduction in populations of Gammarus minus located in central Pennsylvania (USA). Our analysis reveals two major clusters of ‘symmorphic allometry’ (parallel scaling relationships) for traits related to somatic versus reproductive investment. In the presence of fish predators, the scaling exponents for somatic traits tend to decrease, whereas those for reproductive traits tend to increase. This divergence of scaling exponents reflects an intensified trade-off between somatic and reproductive investments resulting from low adult survival in the face of size-selective predation. Our results indicate the value of an integrated view of the ontogenetic size-specific energetics of organisms and its response to both top-down (predation) and bottom-up (resource supply) effects.
The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases
Authors: Fontecha-Barriuso Miguel , Martin-Sanchez Diego , Martinez-Moreno Julio , Monsalve Maria , Ramos Adrian , Sanchez-Niño Maria , Ruiz-Ortega Marta , Ortiz Alberto , Sanz Ana
Published: February 2020

Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD.
Knockdown of TFAM in Tumor Cells Retarded Autophagic Flux through Regulating p53 Acetylation and PISD Expression
Authors: Jiang Xu , Wang Jun
Published: February 2020

Mitochondrial transcription factor A (TFAM) is required for mitochondrial DNA replication and transcription, which are essential for mitochondrial biogenesis. Previous studies reported that depleting mitochondrial functions by genetic deletion of TFAM impaired autophagic activities. However, the underlying mechanisms remain largely unknown. In the current study, we identified that knockdown of TFAM repressed the synthesis of autophagy bio-marker LC3-II in tumor cells and decreased the expression of phosphatidyl-serine decarboxylase (PISD). Besides, downregulation of PISD with siRNA reduced the level of LC3-II, indicating that depletion of TFAM retarded autophagy via inhibiting PISD expression. Furthermore, it was found that the tumor repressor p53 could stimulate the transcription and expression of PISD by binding the PISD enhancer. Additionally, the protein stability and transcriptional activity of p53 in TFAM knockdown tumor cells was attenuated, and this was associated with decreased acetylation, especially the acetylation of lysine 382 of p53. Finally, we identified that TFAM knockdown increased the NAD+/NADH ratio in tumor cells. This led to the upregulation of Sirtuin1 (SIRT1), a NAD-dependent protein deacetylase, to deacetylate p53 and attenuated its transcriptional activation on PISD. In summary, our study discovered a new mechanism regarding disturbed autophagy in tumor cells with mitochondrial dysfunction due to the depletion of TFAM.
Mesothelial-to-Mesenchymal Transition Contributes to the Generation of Carcinoma-Associated Fibroblasts in Locally Advanced Primary Colorectal Carcinomas
Authors: Gordillo Carlos H. , Sandoval Pilar , Muñoz-Hernández Patricia , Pascual-Antón Lucía , López-Cabrera Manuel , Jiménez-Heffernan José A.
Published: February 2020

During peritoneal metastasis, cancer cells spread from abdominal solid tumors, disseminate through the peritoneal fluid and attach to and invade through mesothelial cells (MCs) that line the peritoneum. Intestinal adenocarcinomas originating in the mucosa infiltrate the submucosa, muscle layer, and serosa in order to finally colonize the peritoneal cavity. However, the mechanism by which metastatic cells leave the primary tumor and reach the peritoneal cavity has not been previously described. Hence, we investigate whether MCs lining visceral peritoneum, through a mesothelial-to-mesenchymal transition (MMT), are a source of carcinoma-associated fibroblasts (CAFs), which could contribute to cancer progression toward the peritoneal cavity. CAFs detected in biopsies from patients with superficially invasive colorectal cancer differed from locally advanced tumors. An aberrant accumulation of myofibroblasts expressing mesothelial markers was found in the stroma of deeply infiltrative tumors located in the neighborhood of a frequently activated mesothelium. We suggest that MMT is a key event in the early stages of peritoneal dissemination.
Neutrophil Extracellular Trap Formation Correlates with Favorable Overall Survival in High Grade Ovarian Cancer
Authors: Muqaku Besnik , Pils Dietmar , Mader Johanna C. , Aust Stefanie , Mangold Andreas , Muqaku Liridon , Slany Astrid , Del Favero Giorgia , Gerner Christopher
Published: February 2020

It is still a question of debate whether neutrophils, often found in the tumor microenvironment, mediate tumor-promoting or rather tumor-inhibiting activities. The present study focuses on the involvement of neutrophils in high grade serous ovarian cancer (HGSOC). Macroscopic features classify two types of peritoneal tumor spread in HGSOC. Widespread and millet sized lesions characterize the miliary type, while non-miliary metastases are larger and associated with better prognosis. Multi-omics and FACS data were generated from ascites samples. Integrated data analysis demonstrates a significant increase of neutrophil extracellular trap (NET)-associated molecules in non-miliary ascites samples. A co-association network analysis performed with the ascites data further revealed a striking correlation between NETosis-associated metabolites and several eicosanoids. The congruence of data generated from primary neutrophils with ascites analyses indicates the predominance of NADPH oxidase 2 (NOX)-independent NETosis. NETosis is associated with protein S100A8/A9 release. An increase of the S100A8/CRP abundance ratio was found to correlate with favorable survival of HGSOC patients. The analysis of additional five independent proteome studies with regard to S100A8/CRP ratios confirmed this observation. In conclusion, NET formation seems to relate with better cancer patient outcome.
Germline Variants in Phosphodiesterase Genes and Genetic Predisposition to Pediatric Adrenocortical Tumors
Authors: Pinto Emilia Modolo , Faucz Fabio R. , Paza Luana Z. , Wu Gang , Fernandes Elizabeth S. , Bertherat Jerome , Stratakis Constantine A. , Lalli Enzo , Ribeiro Raul C. , Rodriguez-Galindo Carlos , Figueiredo Bonald C. , Zambetti Gerard P.
Published: February 2020

Phosphodiesterases (PDEs) form a superfamily of enzymes that catalyze the hydrolysis of cyclic nucleotides adenosine 3′5′-cyclic monophosphate (cAMP) and guanosine 3′5′-cyclic monophosphate (cGMP) to their inactive 5′ monophosphates. cAMP plays a critical role as a second messenger in endocrine tissues, and activation of cAMP signaling has been reported in endocrine tumors. Germline variants in PDEs have been associated with benign cortisol-secreting adrenocortical adenomas and testicular germ cell cancer but not adrenocortical carcinoma. We performed whole genome sequencing (WGS) and whole exome sequencing (WES) of paired blood and tumor samples from 37 pediatric adrenocortical tumors (ACTs). Germline inactivating variants in PDEs were observed in 9 of 37 (24%) patients. Tumor DNA analysis revealed loss of heterozygosity, with maintenance of the mutated allele in all cases. Our results suggest that germline variants in PDEs and other regulators of the cAMP-signaling pathway may contribute to pediatric adrenocortical tumorigenesis, perhaps by cooperating with germline hypomorphic mutant TP53 alleles and uniparental disomy of chromosome 11p15 (Beckwith–Wiedemann syndrome).
The Impact of Normalization Approaches to Automatically Detect Radiogenomic Phenotypes Characterizing Breast Cancer Receptors Status
Authors: Castaldo Rossana , Pane Katia , Nicolai Emanuele , Salvatore Marco , Franzese Monica
Published: February 2020

In breast cancer studies, combining quantitative radiomic with genomic signatures can help identifying and characterizing radiogenomic phenotypes, in function of molecular receptor status. Biomedical imaging processing lacks standards in radiomic feature normalization methods and neglecting feature normalization can highly bias the overall analysis. This study evaluates the effect of several normalization techniques to predict four clinical phenotypes such as estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and triple negative (TN) status, by quantitative features. The Cancer Imaging Archive (TCIA) radiomic features from 91 T1-weighted Dynamic Contrast Enhancement MRI of invasive breast cancers were investigated in association with breast invasive carcinoma miRNA expression profiling from the Cancer Genome Atlas (TCGA). Three advanced machine learning techniques (Support Vector Machine, Random Forest, and Naïve Bayesian) were investigated to distinguish between molecular prognostic indicators and achieved an area under the ROC curve (AUC) values of 86%, 93%, 91%, and 91% for the prediction of ER+ versus ER−, PR+ versus PR−, HER2+ versus HER2−, and triple-negative, respectively. In conclusion, radiomic features enable to discriminate major breast cancer molecular subtypes and may yield a potential imaging biomarker for advancing precision medicine.
Monitoring Immune Responses in Neuroblastoma Patients during Therapy
Authors: Szanto Celina L. , Cornel Annelisa M. , Vijver Saskia V. , Nierkens Stefan
Published: February 2020

Neuroblastoma (NBL) is the most common extracranial solid tumor in childhood. Despite intense treatment, children with this high-risk disease have a poor prognosis. Immunotherapy showed a significant improvement in event-free survival in high-risk NBL patients receiving chimeric anti-GD2 in combination with cytokines and isotretinoin after myeloablative consolidation therapy. However, response to immunotherapy varies widely, and often therapy is stopped due to severe toxicities. Objective markers that help to predict which patients will respond or develop toxicity to a certain treatment are lacking. Immunotherapy guided via immune monitoring protocols will help to identify responders as early as possible, to decipher the immune response at play, and to adjust or develop new treatment strategies. In this review, we summarize recent studies investigating frequency and phenotype of immune cells in NBL patients prior and during current treatment protocols and highlight how these findings are related to clinical outcome. In addition, we discuss potential targets to improve immunogenicity and strategies that may help to improve therapy efficacy. We conclude that immune monitoring during therapy of NBL patients is essential to identify predictive biomarkers to guide patients towards effective treatment, with limited toxicities and optimal quality of life.
The Labyrinth of Renal Cell Carcinoma
Authors: Manini Claudia , López José I.
Published: February 2020

Renal cell carcinoma (RCC) ranks in the top-ten list of malignancies both in males and females [...]
Nanotechnology-Based Biopolymeric Oral Delivery Platforms for Advanced Cancer Treatment
Authors: Chivere Vanessa T. , Kondiah Pierre P. D. , Choonara Yahya E. , Pillay Viness
Published: February 2020

Routes of drug administration and their corresponding physiochemical characteristics play major roles in drug therapeutic efficiency and biological effects. Each route of delivery has favourable aspects and limitations. The oral route of delivery is the most convenient, widely accepted and safe route. However, the oral route of chemotherapeutics to date have displayed high gastric degradation, low aqueous solubility, poor formulation stability and minimum intestinal absorption. Thus, mainstream anti-cancer drugs in current formulations are not suitable as oral chemotherapeutic formulations. The use of biopolymers such as chitosan, gelatin, hyaluronic acid and polyglutamic acid, for the synthesis of oral delivery platforms, have potential to help overcome problems associated with oral delivery of chemotherapeutics. Biopolymers have favourable stimuli-responsive properties, and thus can be used to improve oral bioavailability of anti-cancer drugs. These biopolymeric formulations can protect gastric-sensitive drugs from pH degradation, target specific binding sites for targeted absorption and consequently control drug release. In this review, the use of various biopolymers as oral drug delivery systems for chemotherapeutics will be discussed.
Clinico-Biological Implications of Modified Levels of Cytokines in Chronic Lymphocytic Leukemia: A Possible Therapeutic Role
Authors: Allegra Alessandro , Musolino Caterina , Tonacci Alessandro , Pioggia Giovanni , Casciaro Marco , Gangemi Sebastiano
Published: February 2020

B-cell chronic lymphocytic leukemia (B-CLL) is the main cause of mortality among hematologic diseases in Western nations. B-CLL is correlated with an intense alteration of the immune system. The altered functions of innate immune elements and adaptive immune factors are interconnected in B-CLL and are decisive for its onset, evolution, and therapeutic response. Modifications in the cytokine balance could support the growth of the leukemic clone via a modulation of cellular proliferation and apoptosis, as some cytokines have been reported to be able to affect the life of B-CLL cells in vivo. In this review, we will examine the role played by cytokines in the cellular dynamics of B-CLL patients, interpret the contradictions sometimes present in the literature regarding their action, and evaluate the possibility of manipulating their production in order to intervene in the natural history of the disease.
Cannabinoids and Hormone Receptor-Positive Breast Cancer Treatment
Authors: Dobovišek Luka , Krstanović Fran , Borštnar Simona , Debeljak Nataša
Published: February 2020

Breast cancer (BC) is the most common cancer in women worldwide. Approximately 70–80% of BCs express estrogen receptors (ER), which predict the response to endocrine therapy (ET), and are therefore hormone receptor-positive (HR+). Endogenous cannabinoids together with cannabinoid receptor 1 and 2 (CB1, CB2) constitute the basis of the endocannabinoid system. Interactions of cannabinoids with hypothalamic–pituitary–gonadal axis hormones are well documented, and two studies found a positive correlation between peak plasma endogenous cannabinoid anandamide with peak plasma 17β-estradiol, luteinizing hormone and follicle-stimulating hormone levels at ovulation in healthy premenopausal women. Do cannabinoids have an effect on HR+ BC? In this paper we review known and possible interactions between cannabinoids and specific HR+ BC treatments. In preclinical studies, CB1 and CB2 agonists (i.e., anandamide, THC) have been shown to inhibit the proliferation of ER positive BC cell lines. There is less evidence for antitumor cannabinoid action in HR+ BC in animal models and there are no clinical trials exploring the effects of cannabinoids on HR+ BC treatment outcomes. Two studies have shown that tamoxifen and several other selective estrogen receptor modulators (SERM) can act as inverse agonists on CB1 and CB2, an interaction with possible clinical consequences. In addition, cannabinoid action could interact with other commonly used endocrine and targeted therapies used in the treatment of HR+ BC.
Highly Expressed miR-375 is not an Intracellular Oncogene in Merkel Cell Polyomavirus-Associated Merkel Cell Carcinoma
Authors: Fan Kaiji , Zebisch Armin , Horny Kai , Schrama David , Becker Jürgen C.
Published: February 2020

miR-375 is a highly abundant miRNA in Merkel cell carcinoma (MCC). In other cancers, it acts as either a tumor suppressor or oncogene. While free-circulating miR-375 serves as a surrogate marker for tumor burden in patients with advanced MCC, its function within MCC cells has not been established. Nearly complete miR-375 knockdown in MCC cell lines was achieved using antagomiRs via nucleofection. The cell viability, growth characteristics, and morphology were not altered by this knockdown. miR-375 target genes and related signaling pathways were determined using Encyclopedia of RNA Interactomes (ENCORI) revealing Hippo signaling and epithelial to mesenchymal transition (EMT)-related genes likely to be regulated. Therefore, their expression was analyzed by multiplexed qRT-PCR after miR-375 knockdown, demonstrating only a limited change in expression. In summary, highly effective miR-375 knockdown in classical MCC cell lines did not significantly change the cell viability, morphology, or oncogenic signaling pathways. These observations render miR-375 an unlikely intracellular oncogene in MCC cells, thus suggesting that likely functions of miR-375 for the intercellular communication of MCC should be addressed.
Mitochondrial Calcium Regulation of Redox Signaling in Cancer
Authors: Delierneux Céline , Kouba Sana , Shanmughapriya Santhanam , Potier-Cartereau Marie , Trebak Mohamed , Hempel Nadine
Published: February 2020

Calcium (Ca2+) uptake into the mitochondria shapes cellular Ca2+ signals and acts as a key effector for ATP generation. In addition, mitochondria-derived reactive oxygen species (mROS), produced as a consequence of ATP synthesis at the electron transport chain (ETC), modulate cellular signaling pathways that contribute to many cellular processes. Cancer cells modulate mitochondrial Ca2+ ([Ca2+]m) homeostasis by altering the expression and function of mitochondrial Ca2+ channels and transporters required for the uptake and extrusion of mitochondrial Ca2+. Regulated elevations in [Ca2+]m are required for the activity of several mitochondrial enzymes, and this in turn regulates metabolic flux, mitochondrial ETC function and mROS generation. Alterations in both [Ca2+]m and mROS are hallmarks of many tumors, and elevated mROS is a known driver of pro-tumorigenic redox signaling, resulting in the activation of pathways implicated in cellular proliferation, metabolic alterations and stress-adaptations. In this review, we highlight recent studies that demonstrate the interplay between [Ca2+]m and mROS signaling in cancer.
Extracellular Matrix Features Discriminate Aggressive HER2-Positive Breast Cancer Patients Who Benefit from Trastuzumab Treatment
Authors: Rybinska Ilona , Sandri Marco , Bianchi Francesca , Orlandi Rosaria , De Cecco Loris , Gasparini Patrizia , Campiglio Manuela , Paolini Biagio , Sfondrini Lucia , Tagliabue Elda , Triulzi Tiziana
Published: February 2020

We previously identified an extracellular matrix (ECM) gene expression pattern in breast cancer (BC), called ECM3, characterized by a high expression of genes encoding structural ECM proteins. Since ECM is reportedly implicated in response to therapy of BCs, the aim of this work is to investigate the prognostic and predictive value of ECM3 molecular classification in HER2-positive BCs. ECM3 resulted in a robust cluster that identified a subset of 25–37% of HER2-positive tumors with molecular aggressive features. ECM3 was significantly associated with worse prognosis in two datasets of HER2-positive BCs untreated with adjuvant therapy. Analyses carried out on two of our cohorts of patients treated or not with adjuvant trastuzumab showed association of ECM3 with worse prognosis only in patients not treated with trastuzumab. Moreover, investigating a dataset that includes gene profile data of tumors treated with neoadjuvant trastuzumab plus chemotherapy or chemotherapy alone, ECM3 was associated with increased pathological complete response if treated with trastuzumab. In the in vivo experiments, increased diffusion and trastuzumab activity were found in tumors derived from injection of HER2-positive cells with Matrigel that creates an ECM-rich tumor environment. Taken together, these results indicate that HER2-positive BCs classified as ECM3 have an aggressive phenotype but they are sensitive to trastuzumab treatment.
Animal, Fungi, and Plant Genome Sequences Harbor Different Non-Canonical Splice Sites
Authors: Frey Katharina , Pucker Boas
Published: February 2020

Most protein-encoding genes in eukaryotes contain introns, which are interwoven with exons. Introns need to be removed from initial transcripts in order to generate the final messenger RNA (mRNA), which can be translated into an amino acid sequence. Precise excision of introns by the spliceosome requires conserved dinucleotides, which mark the splice sites. However, there are variations of the highly conserved combination of GT at the 5′ end and AG at the 3′ end of an intron in the genome. GC-AG and AT-AC are two major non-canonical splice site combinations, which have been known for years. Recently, various minor non-canonical splice site combinations were detected with numerous dinucleotide permutations. Here, we expand systematic investigations of non-canonical splice site combinations in plants across eukaryotes by analyzing fungal and animal genome sequences. Comparisons of splice site combinations between these three kingdoms revealed several differences, such as an apparently increased CT-AC frequency in fungal genome sequences. Canonical GT-AG splice site combinations in antisense transcripts are a likely explanation for this observation, thus indicating annotation errors. In addition, high numbers of GA-AG splice site combinations were observed in Eurytemora affinis and Oikopleura dioica. A variant in one U1 small nuclear RNA (snRNA) isoform might allow the recognition of GA as a 5′ splice site. In depth investigation of splice site usage based on RNA-Seq read mappings indicates a generally higher flexibility of the 3′ splice site compared to the 5′ splice site across animals, fungi, and plants.
TRPC1 Regulates the Activity of a Voltage-Dependent Nonselective Cation Current in Hippocampal CA1 Neurons
Authors: Kepura Frauke , Braun Eva , Dietrich Alexander , Plant Tim D.
Published: February 2020

The cation channel subunit TRPC1 is strongly expressed in central neurons including neurons in the CA1 region of the hippocampus where it forms complexes with TRPC4 and TRPC5. To investigate the functional role of TRPC1 in these neurons and in channel function, we compared current responses to group I metabotropic glutamate receptor (mGluR I) activation and looked for major differences in dendritic morphology in neurons from TRPC1+/+ and TRPC1−/− mice. mGluR I stimulation resulted in the activation of a voltage-dependent nonselective cation current in both genotypes. Deletion of TRPC1 resulted in a modification of the shape of the current-voltage relationship, leading to an inward current increase. In current clamp recordings, the percentage of neurons that responded to depolarization in the presence of an mGluR I agonist with a plateau potential was increased in TRPC1−/− mice. There was also a small increase in the minor population of CA1 neurons that have more than one apical dendrite in TRPC1−/− mice. We conclude that TRPC1 has an inhibitory effect on receptor-operated nonselective cation channels in hippocampal CA1 neurons probably as a result of heterotetramer formation with other TRPC isoforms, and that TRPC1 deletion has only minor effects on dendritic morphology.
Flexible Players within the Sheaths: The Intrinsically Disordered Proteins of Myelin in Health and Disease
Authors: Raasakka Arne , Kursula Petri
Published: February 2020

Myelin ensheathes selected axonal segments within the nervous system, resulting primarily in nerve impulse acceleration, as well as mechanical and trophic support for neurons. In the central and peripheral nervous systems, various proteins that contribute to the formation and stability of myelin are present, which also harbor pathophysiological roles in myelin disease. Many myelin proteins have common attributes, including small size, hydrophobic segments, multifunctionality, longevity, and regions of intrinsic disorder. With recent advances in protein biophysical characterization and bioinformatics, it has become evident that intrinsically disordered proteins (IDPs) are abundant in myelin, and their flexible nature enables multifunctionality. Here, we review known myelin IDPs, their conservation, molecular characteristics and functions, and their disease relevance, along with open questions and speculations. We place emphasis on classifying the molecular details of IDPs in myelin, and we correlate these with their various functions, including susceptibility to post-translational modifications, function in protein–protein and protein–membrane interactions, as well as their role as extended entropic chains. We discuss how myelin pathology can relate to IDPs and which molecular factors are potentially involved.
T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis
Authors: Kunkl Martina , Frascolla Simone , Amormino Carola , Volpe Elisabetta , Tuosto Loretta
Published: February 2020

Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the progressive loss of axonal myelin in several areas of the central nervous system (CNS) that is responsible for clinical symptoms such as muscle spasms, optic neuritis, and paralysis. The progress made in more than one decade of research in animal models of MS for clarifying the pathophysiology of MS disease validated the concept that MS is an autoimmune inflammatory disorder caused by the recruitment in the CNS of self-reactive lymphocytes, mainly CD4+ T cells. Indeed, high levels of T helper (Th) cells and related cytokines and chemokines have been found in CNS lesions and in cerebrospinal fluid (CSF) of MS patients, thus contributing to the breakdown of the blood–brain barrier (BBB), the activation of resident astrocytes and microglia, and finally the outcome of neuroinflammation. To date, several types of Th cells have been discovered and designated according to the secreted lineage-defining cytokines. Interestingly, Th1, Th17, Th1-like Th17, Th9, and Th22 have been associated with MS. In this review, we discuss the role and interplay of different Th cell subpopulations and their lineage-defining cytokines in modulating the inflammatory responses in MS and the approved as well as the novel therapeutic approaches targeting T lymphocytes in the treatment of the disease.
Melatonin Orchestrates Lipid Homeostasis through the Hepatointestinal Circadian Clock and Microbiota during Constant Light Exposure
Authors: Hong Fan , Pan Shijia , Xu Pengfei , Xue Tingting , Wang Jialin , Guo Yuan , Jia Li , Qiao Xiaoxiao , Li Letong , Zhai Yonggong
Published: February 2020

Misalignment between natural light rhythm and modern life activities induces disruption of the circadian rhythm. It is mainly evident that light at night (LAN) interferes with the human endocrine system and contributes to the increasing rates of obesity and lipid metabolic disease. Maintaining hepatointestinal circadian homeostasis is vital for improving lipid homeostasis. Melatonin is a chronobiotic substance that plays a main role in stabilizing bodily rhythm and has shown beneficial effects in protecting against obesity. Based on the dual effect of circadian rhythm regulation and antiobesity, we tested the effect of melatonin in mice under constant light exposure. Exposure to 24-h constant light (LL) increased weight and insulin resistance compared with those of the control group (12-h light–12-h dark cycle, LD), and simultaneous supplementation in the melatonin group (LLM) ameliorated this phenotype. Constant light exposure disturbed the expression pattern of a series of transcripts, including lipid metabolism, circadian regulation and nuclear receptors in the liver. Melatonin also showed beneficial effects in improving lipid metabolism and circadian rhythm homeostasis. Furthermore, the LL group had increased absorption and digestion of lipids in the intestine as evidenced by the elevated influx of lipids in the duodenum and decrease in the efflux of lipids in the jejunum. More interestingly, melatonin ameliorated the gut microbiota dysbiosis and improved lipid efflux from the intestine. Thus, these findings offer a novel clue regarding the obesity-promoting effect attributed to LAN and suggest a possibility for obesity therapy by melatonin in which melatonin could ameliorate rhythm disorder and intestinal dysbiosis.
Plasma Membrane Transporters as Biomarkers and Molecular Targets in Cholangiocarcinoma
Authors: Marin Jose J.G. , Macias Rocio I.R. , Cives-Losada Candela , Peleteiro-Vigil Ana , Herraez Elisa , Lozano Elisa
Published: February 2020

The dismal prognosis of patients with advanced cholangiocarcinoma (CCA) is due, in part, to the extreme resistance of this type of liver cancer to available chemotherapeutic agents. Among the complex mechanisms accounting for CCA chemoresistance are those involving the impairment of drug uptake, which mainly occurs through transporters of the superfamily of solute carrier (SLC) proteins, and the active export of drugs from cancer cells, mainly through members of families B, C and G of ATP-binding cassette (ABC) proteins. Both mechanisms result in decreased amounts of active drugs able to reach their intracellular targets. Therefore, the “cancer transportome”, defined as the set of transporters expressed at a given moment in the tumor, is an essential element for defining the multidrug resistance (MDR) phenotype of cancer cells. For this reason, during the last two decades, plasma membrane transporters have been envisaged as targets for the development of strategies aimed at sensitizing cancer cells to chemotherapy, either by increasing the uptake or reducing the export of antitumor agents by modulating the expression/function of SLC and ABC proteins, respectively. Moreover, since some elements of the transportome are differentially expressed in CCA, their usefulness as biomarkers with diagnostic and prognostic purposes in CCA patients has been evaluated.