bluuebunny/crossref_metadata_2025 huggingface dataset:
Are Cement Spacers and Beads Loaded with the Correct Antibiotic(s) at the Site of Periprosthetic Hip and Knee Joint Infections?
Authors: Anagnostakos Konstantinos , Sahan Ismail
Published: February 2021

The optimal impregnation of antibiotic-loaded bone cement in the treatment of periprosthetic hip and knee joint infection is unknown. It is also unclear, whether a suboptimal impregnation might be associated with a higher persistence of infection. A total of 93 patients (44 knee, 49 hip) were retrospectively evaluated, and the most common organism was a methicillin-resistant Staphylococcus epidermidis, followed by methicillin-susceptible Staphylococcus aureus. Of all the organisms, 37.1% were resistant against gentamicin and 54.2% against clindamycin. All organisms were susceptible against vancomycin. In 41 cases, gentamicin-loaded beads were inserted and in 52 cases, spacers: (2 loaded only with gentamicin, 18 with gentamicin + vancomycin, 19 with gentamicin + clindamycin, and 13 with gentamicin + vancomycin + clindamycin). The analysis of each antibiotic impregnation showed that complete susceptibility was present in 38.7% of the cases and partial susceptibility in 28%. In the remaining 33.3%, no precise statement can be made because either there was a culture-negative infection or the antibiotic(s) were not tested against the specific organism. At a mean follow-up of 27.9 months, treatment failure was observed in 6.7% of the cases. Independent of which antibiotic impregnation was used, when the organism was susceptible against the locally inserted antibiotics or not tested, reinfection or persistence of infection was observed in the great majority of cases. Future studies about the investigation of the optimal impregnation of antibiotic-loaded bone cement are welcome.
16S rRNA Sequencing Analysis of the Gut Microbiota in Broiler Chickens Prophylactically Administered with Antimicrobial Agents
Authors: Cuccato Matteo , Rubiola Selene , Giannuzzi Diana , Grego Elena , Pregel Paola , Divari Sara , Cannizzo Francesca Tiziana
Published: February 2021

In poultry production, gut microbiota (GM) plays a pivotal role and influences different host functions related to the efficiency of production performances. Antimicrobial (AM) use is one of the main factors affecting GM composition and functions. Although several studies have focused their attention on the role of AMs as growth promoters in the modulation of GM in broilers, the consequences of higher AM concentrations administered during prophylactic treatments need to be better elucidated. For this purpose, 16S rRNA gene sequencing was performed to evaluate the impact of different prophylactic AM protocols on the composition and diversity of the broiler GM. Diversity analysis has shown that AM treatment significantly affects alpha diversity in ileum and beta diversity in both ileum and caecum. In ileal samples, the Enterobacteriaceae family has been shown to be particularly affected by AM treatments. AMs have been demonstrated to affect GM composition in broiler. These findings indicate that withdrawal periods were not enough for the restoral of the original GM. Further studies are needed for a better elucidation of the negative effects caused by an altered GM in broilers.
Burkholderia Bacteria Produce Multiple Potentially Novel Molecules that Inhibit Carbapenem-Resistant Gram-Negative Bacterial Pathogens
Authors: Depoorter Eliza , De Canck Evelien , Coenye Tom , Vandamme Peter
Published: February 2021

Antimicrobial resistance in Gram-negative pathogens represents a global threat to human health. This study determines the antimicrobial potential of a taxonomically and geographically diverse collection of 263 Burkholderia (sensu lato) isolates and applies natural product dereplication strategies to identify potentially novel molecules. Antimicrobial activity is almost exclusively present in Burkholderia sensu stricto bacteria and rarely observed in the novel genera Paraburkholderia, Caballeronia, Robbsia, Trinickia, and Mycetohabitans. Fourteen isolates show a unique spectrum of antimicrobial activity and inhibited carbapenem-resistant Gram-negative bacterial pathogens. Dereplication of the molecules present in crude spent agar extracts identifies 42 specialized metabolites, 19 of which represented potentially novel molecules. The known identified Burkholderia metabolites include toxoflavin, reumycin, pyrrolnitrin, enacyloxin, bactobolin, cepacidin, ditropolonyl sulfide, and antibiotics BN-227-F and SF 2420B, as well as the siderophores ornibactin, pyochelin, and cepabactin. Following semipreparative fractionation and activity testing, a total of five potentially novel molecules are detected in active fractions. Given the molecular formula and UV spectrum, two of those putative novel molecules are likely related to bactobolins, and another is likely related to enacyloxins. The results from this study confirm and extend the observation that Burkholderia bacteria present exciting opportunities for the discovery of potentially novel bioactive molecules.
Implication of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Its Inhibitors in Alzheimer’s Disease Murine Models
Authors: Fragoso-Morales Leticia Guadalupe , Correa-Basurto José , Rosales-Hernández Martha Cecilia
Published: February 2021

Alzheimer’s disease (AD) is one of the main human dementias around the world which is constantly increasing every year due to several factors (age, genetics, environment, etc.) and there are no prevention or treatment options to cure it. AD is characterized by memory loss associated with oxidative stress (OS) in brain cells (neurons, astrocytes, microglia, etc.). OS can be produced by amyloid beta (Aβ) protein aggregation and its interaction with metals, mitochondrial damage and alterations between antioxidants and oxidant enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. NADPH oxidase produces reactive oxygen species (ROS) and it is overexpressed in AD, producing large amounts of superoxide anions and hydrogen peroxide which damage brain cells and the vasculature. In addition, it has been reported that NADPH oxidase causes an imbalance of pH which could also influence in the amyloid beta (Aβ) production. Therefore, NADPH oxidase had been proposed as a therapeutic target in AD. However, there are no drugs for AD treatment such as an NADPH oxidase inhibitor despite great efforts made to stabilize the ROS production using antioxidant molecules. So, in this work, we will focus our attention on NADPH oxidase (NOX2 and NOX4) in AD as well as in AD models and later discuss the use of NADPH oxidase inhibitor compounds in AD.
Waste-to-Energy Process to Recover Dangerous Pollutants in an Environmental Protected Area
Authors: Mora Pedro , Barettino Daniel , Ponce Antonio , Sánchez-Martín Laura , Llamas Bernardo
Published: February 2021

The present study aims to extract the polluting material from a lagoon and use it as an alternative fuel in cement industries. To this end, in the methodology will analyze two alternatives for the waste: fuel generation and incineration. The polluting material from the Arganda lagoon has highly calorific value to be used as fuel. Thus, not only are these wastes used, but also an area with potentially hazardous waste is decontaminated. After the extraction, which due to the characteristics of the material is chosen for the novel pumping extraction, and subsequent generation of fuel, the process for using this waste is through the distribution of the created fuel to nine cement plants in Spain, leading to significant environmental benefits. The results of the process shows an energy efficiency of 97% for using the waste as fuel, and a consumed energy of approximately 6000 kWh/t·waste to the process that leads to the desired environmental benefit. The use of waste contributes to the reduction of CO2 emissions and a decrease in the use of fossil fuels.
A Novel Automatic Modulation Classification Method Using Attention Mechanism and Hybrid Parallel Neural Network
Authors: Zhang Rui , Yin Zhendong , Wu Zhilu , Zhou Siyang
Published: February 2021

Automatic Modulation Classification (AMC) is of paramount importance in wireless communication systems. Existing methods usually adopt a single category of neural network or stack different categories of networks in series, and rarely extract different types of features simultaneously in a proper way. When it comes to the output layer, softmax function is applied for classification to expand the inter-class distance. In this paper, we propose a hybrid parallel network for the AMC problem. Our proposed method designs a hybrid parallel structure which utilizes Convolution Neural Network (CNN) and Gate Rate Unit (GRU) to extract spatial features and temporal features respectively. Instead of superposing these two categories of features directly, three different attention mechanisms are applied to assign weights for different types of features. Finally, a cosine similarity metric named Additive Margin softmax function, which can expand the inter-class distance and compress the intra-class distance simultaneously, is adopted for output. Simulation results demonstrate that the proposed method can achieve remarkable performance on an open access dataset.
A Bacterial Chemotaxis-Inspired Coordination Strategy for Coverage and Aggregation of Swarm Robots
Authors: Jiang Laihao , Mo Hongwei , Tian Peng
Published: February 2021

Many bio-inspired coordination strategies have been investigated for swarm robots. Bacterial chemotaxis exhibits a certain degree of intelligence, and has been developed some optimization algorithm for robot(s), e.g., bacterial foraging optimization algorithm (BFOA) and bacterial colony chemotaxis optimization algorithm (BCC). This paper proposes a bacterial chemotaxis-inspired coordination strategy (BCCS) of swarm robotic systems for coverage and aggregation. The coverage is the problem of finding a solution to uniformly deploy robots on a given bounded space. To solve this problem, this paper uses chaotic preprocessing to generate the initial positions of the robots. After the initialization, each robot calculates the area only covered by itself as the fitness function value. Then, each robot makes an action, running or rotating, depending on coordination strategy inspired bacterial chemotaxis. Moreover, we extend this solution and introduce a random factor to overcome aggregation, which is to guide robots to rendezvous at an unspecified point. The simulation results demonstrate the superior performance of the proposed coordination strategy in both success rate and an average number of iterations than other controllers.
Application of Inverse Neural Networks for Optimal Pretension of Absorbable Mini Plate and Screw System
Authors: Pimentel-Mendoza Alex Bernardo , Rico-Pérez Lázaro , Rosel-Solis Manuel Javier , Villarreal-Gómez Luis Jesús , Vega Yuridia , Dávalos-Ramírez José Omar
Published: February 2021

Mandibular fractures are common facial lesions typically treated with titanium plate and screw systems; nevertheless, this material is associated with secondary effects. Absorbable material for implants is an alternative to titanium, but there are also problems such as incomplete screw insertion and screw breakage due to high pretension in the screw caused by the insertion torque. The purpose of this paper is to find the optimal screw pretension (SP) in absorbable plate and screw systems by means of artificial neural network (ANN) and its inverse (ANNi). This optimal SP must satisfy a desired maximum von Mises strain (MVMS). For training the ANN, a database was generated by means of a design of experiments (DOE). Each DOE configuration was solved by means of finite element method (FEM) calculations. To obtain the optimal value for (SP) in the mini absorbable screw for fracture fixation, a strategy to invert the ANN is developed. Using the ANN coefficients, a sensitive study was performed to identify the influence of the design parameters in the MVMS. The optimal SP obtained was 14.9742 N. The MVMS condition was satisfied with an error less than 1.1% in comparison with FEM and ANN results. The screw shaft length is the most influencing MVMS parameter.
The Endophytic Microbiome as a Hotspot of Synergistic Interactions, with Prospects of Plant Growth Promotion
Authors: Vandana Udaya Kumar , Rajkumari Jina , Singha L. Paikhomba , Satish Lakkakula , Alavilli Hemasundar , Sudheer Pamidimarri D.V.N. , Chauhan Sushma , Ratnala Rambabu , Satturu Vanisri , Mazumder Pranab Behari , Pandey Piyush
Published: February 2021

The plant root is the primary site of interaction between plants and associated microorganisms and constitutes the main components of plant microbiomes that impact crop production. The endophytic bacteria in the root zone have an important role in plant growth promotion. Diverse microbial communities inhabit plant root tissues, and they directly or indirectly promote plant growth by inhibiting the growth of plant pathogens, producing various secondary metabolites. Mechanisms of plant growth promotion and response of root endophytic microorganisms for their survival and colonization in the host plants are the result of complex plant-microbe interactions. Endophytic microorganisms also assist the host to sustain different biotic and abiotic stresses. Better insights are emerging for the endophyte, such as host plant interactions due to advancements in ‘omic’ technologies, which facilitate the exploration of genes that are responsible for plant tissue colonization. Consequently, this is informative to envisage putative functions and metabolic processes crucial for endophytic adaptations. Detection of cell signaling molecules between host plants and identification of compounds synthesized by root endophytes are effective means for their utilization in the agriculture sector as biofertilizers. In addition, it is interesting that the endophytic microorganism colonization impacts the relative abundance of indigenous microbial communities and suppresses the deleterious microorganisms in plant tissues. Natural products released by endophytes act as biocontrol agents and inhibit pathogen growth. The symbiosis of endophytic bacteria and arbuscular mycorrhizal fungi (AMF) affects plant symbiotic signaling pathways and root colonization patterns and phytohormone synthesis. In this review, the potential of the root endophytic community, colonization, and role in the improvement of plant growth has been explained in the light of intricate plant-microbe interactions.
Systematic Review of Effectiveness of Chitosan as a Biofunctionalizer of Titanium Implants
Authors: López-Valverde Nansi , López-Valverde Antonio , Ramírez Juan Manuel
Published: February 2021

Chitosan is a natural polysaccharide extracted from the shells of crustaceans that has been proposed as a scaffold in tissue engineering. Certain studies have proven a greater osseointegration of titanium surfaces that are functionalized with chitosan. The MEDLINE, CENTRAL, PubMed, and Web of Science databases were electronically searched for in vivo studies. Seven studies met the inclusion criteria. Animal models, implant site, chitosan incorporation methods, and methods of analysis were emphasized. The selected studies were individually discussed regarding the coatings, osseointegration potential, and suitability of the experimental models used, analyzing their limitations. We concluded that chitosan-biofunctionalized titanium surfaces have greater osseointegration capacity that uncoated control titanium alloys.
Gene Expression Changes after Parental Exposure to Metals in the Sea Urchin Affect Timing of Genetic Programme of Embryo Development
Authors: Masullo Tiziana , Biondo Girolama , Natale Marilena Di , Tagliavia Marcello , Bennici Carmelo Daniele , Musco Marianna , Ragusa Maria Antonietta , Costa Salvatore , Cuttitta Angela , Nicosia Aldo
Published: February 2021

It is widely accepted that phenotypic traits can be modulated at the epigenetic level so that some conditions can affect the progeny of exposed individuals. To assess if the exposure of adult animals could result in effects on the offspring, the Mediterranean sea urchin and its well-characterized gene regulatory networks (GRNs) was chosen as a model. Adult animals were exposed to known concentrations of zinc and cadmium (both individually and in combination) for 10 days, and the resulting embryos were followed during the development. The oxidative stress occurring in parental gonads, embryo phenotypes and mortality, and the expression level of a set of selected genes, including members of the skeletogenic and endodermal GRNs, were evaluated. Increased oxidative stress at F0, high rates of developmental aberration with impaired gastrulation, in association to deregulation of genes involved in skeletogenesis (dri, hex, sm50, p16, p19, msp130), endodermal specification (foxa, hox11/13b, wnt8) and epigenetic regulation (kat2A, hdac1, ehmt2, phf8 and UBE2a) occurred either at 24 or 48 hpf. Results strongly indicate that exposure to environmental pollutants can affect not only directly challenged animals but also their progeny (at least F1), influencing optimal timing of genetic programme of embryo development, resulting in an overall impairment of developmental success.
Deoxycholic Acid Upregulates Serum Golgi Protein 73 through Activating NF-κB Pathway and Destroying Golgi Structure in Liver Disease
Authors: Yang Danli , Yao Mingjie , Yan Ying , Liu Yanna , Wen Xiajie , Chen Xiangmei , Lu Fengmin
Published: February 2021

Golgi protein 73 (GP73) is upregulated in a variety of liver diseases, yet the detailed mechanism is poorly characterized. We analyzed GP73 in a retrospective cohort including 4211 patients with chronic liver disease (CLD) or hepatocellular carcinoma (HCC). The effect of deoxycholic acid (DCA) and nuclear factor-kappa B (NF-κB) on expression and release of GP73 in Huh-7 and SMMC7721 cells were studied. A mouse study was used to confirm our findings in vivo. A positive correlation was found between serum GP73 and total bile acid (TBA) in cirrhotic patients (r = 0.540, p < 0.001), higher than that in non-cirrhotic CLD (r = 0.318, p < 0.001) and HCC (r = 0.353, p < 0.001) patients. In Huh-7 and SMMC7721 cells, DCA upregulated the expression and release of GP73 in a dose- and time-dependent manner. After overexpressing NF-κB p65, the promoter activity, GP73 messenger RNA (mRNA) level, and supernatant GP73 level were increased. The promotion effect of DCA on GP73 release was attenuated after inhibiting the NF-κB pathway. Mutating the binding sites of NF-κB in the sequence of the GP73 promoter led to a declined promoting effect of DCA on GP73. The upregulation role of DCA in GP73 expression through the NF-κB pathway was confirmed in vivo. In addition, exposure to DCA caused disassembly of Golgi apparatus. In summary, DCA upregulates the expression and release of GP73 via activating the NF-κB pathway and destroying the Golgi structure.
Prion Diseases: A Unique Transmissible Agent or a Model for Neurodegenerative Diseases?
Authors: Ritchie Diane L. , Barria Marcelo A.
Published: February 2021

The accumulation and propagation in the brain of misfolded proteins is a pathological hallmark shared by many neurodegenerative diseases such as Alzheimer’s disease (Aβ and tau), Parkinson’s disease (α-synuclein), and prion disease (prion protein). Currently, there is no epidemiological evidence to suggest that neurodegenerative disorders are infectious, apart from prion diseases. However, there is an increasing body of evidence from experimental models to suggest that other pathogenic proteins such as Aβ and tau can propagate in vivo and in vitro in a prion-like mechanism, inducing the formation of misfolded protein aggregates such as amyloid plaques and neurofibrillary tangles. Such similarities have raised concerns that misfolded proteins, other than the prion protein, could potentially transmit from person-to-person as rare events after lengthy incubation periods. Such concerns have been heightened following a number of recent reports of the possible inadvertent transmission of Aβ pathology via medical and surgical procedures. This review will provide a historical perspective on the unique transmissible nature of prion diseases, examining their impact on public health and the ongoing concerns raised by this rare group of disorders. Additionally, this review will provide an insight into current evidence supporting the potential transmissibility of other pathogenic proteins associated with more common neurodegenerative disorders and the potential implications for public health.
Novel Ex Vivo Model to Examine the Mechanism and Relationship of Esophageal Microbiota and Disease
Authors: Cass Samuel , Hamilton Catherine , Miller Aaron , Jupiter Daniel , Khanipov Kamil , Booth Adam , Pyles Richard , Krill Timothy , Reep Gabriel , Okereke Ikenna
Published: February 2021

Rates of esophageal cancer have increased over the last 40 years. Recent clinical research has identified correlations between the esophageal microbiome and disease. However, mechanisms of action have been difficult to elucidate performing human experimentation. We propose an ex vivo model, which mimics the esophagus and is ideal for mechanistic studies on the esophageal microbiome and resultant transcriptome. To determine the microbiome and transcriptome profile of the human distal esophagus, the microbiome was assessed in 74 patients and the transcriptome profile was assessed in 37 patients with and without Barrett’s esophagus. Thereafter, an ex vivo model of the esophagus was created using an air–liquid interfaced (ALI) design. This design created a sterile apical surface and a nutrient-rich basal surface. An epithelial layer was grown on the apical surface. A normal microbiome and Barrett’s microbiome was harvested and created from patients during endoscopic examination of the esophagus. There was a distinct microbiome in patients with Barrett’s esophagus. The ex vivo model was successfully created with a squamous epithelial layer on the apical surface of the ex vivo system. Using this ex vivo model, multiple normal esophageal and Barrett’s esophageal cell lines will be created and used for experimentation. Each microbiome will be inoculated onto the sterile apical surface of each cell line. The resultant microbiome and transcriptome profile on each surface will be measured and compared to results in the human esophagus to determine the mechanism of the microbiome interaction.
Value and Unmet Needs in Non-Invasive Human Papillomavirus (HPV) Testing for Oropharyngeal Cancer
Authors: Kacew Alec J. , Hanna Glenn J.
Published: February 2021

The burden of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) has risen, now representing the most common HPV-related malignancy. For years, researchers have explored the utility of measuring HPV-related markers from mouth, throat, and blood samples, often with the aim of gathering more information about an existing HPV-related tumor in a given patient. We review the widely varying methods for collecting and testing saliva and blood samples and offer guidance for standardizing these practices. We then review an array of clinical contexts in which non-invasive testing holds the most promise for potentially addressing unmet needs. In particular, such testing could help clinicians and researchers monitor the effects of vaccination and treatment. Meanwhile, due to the currently incomplete understanding of how carrying HPV relates to infection and subsequent oncogenesis, non-invasive testing methods may not be suitable for the screening setting at this time.
Functional Interaction among lncRNA HOTAIR and MicroRNAs in Cancer and Other Human Diseases
Authors: Cantile Monica , Di Bonito Maurizio , Tracey De Bellis Maura , Botti Gerardo
Published: February 2021

LncRNAs are a class of non-coding RNAs mostly involved in regulation of cancer initiation, metastatic progression, and drug resistance, through participation in post-transcription regulatory processes by interacting with different miRNAs. LncRNAs are able to compete with endogenous RNAs by binding and sequestering miRNAs and thereby regulating the expression of their target genes, often represented by oncogenes. The lncRNA HOX transcript antisense RNA (HOTAIR) represents a diagnostic, prognostic, and predictive biomarker in many human cancers, and its functional interaction with miRNAs has been described as crucial in the modulation of different cellular processes during cancer development. The aim of this review is to highlight the relation between lncRNA HOTAIR and different microRNAs in human diseases, discussing the contribution of these functional interactions, especially in cancer development and progression.
Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction
Authors: Giacosa Sofia , Pillet Catherine , Séraudie Irinka , Guyon Laurent , Wallez Yann , Roelants Caroline , Battail Christophe , Evrard Bertrand , Chalmel Frédéric , Barette Caroline , Soleilhac Emmanuelle , Fauvarque Marie-Odile , Franquet Quentin , Sarrazin Clément , Peilleron Nicolas , Fiard Gaëlle , Long Jean-Alexandre , Descotes Jean-Luc , Cochet Claude , Filhol Odile
Published: February 2021

Kinase-targeted agents demonstrate antitumor activity in advanced metastatic clear cell renal cell carcinoma (ccRCC), which remains largely incurable. Integration of genomic approaches through small-molecules and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. The 786-O cell line represents a model for most ccRCC that have a loss of functional pVHL (von Hippel-Lindau). A multiplexed assay was used to study the cellular fitness of a panel of engineered ccRCC isogenic 786-O VHL− cell lines in response to a collection of targeted cancer therapeutics including kinase inhibitors, allowing the interrogation of over 2880 drug–gene pairs. Among diverse patterns of drug sensitivities, investigation of the mechanistic effect of one selected drug combination on tumor spheroids and ex vivo renal tumor slice cultures showed that VHL-defective ccRCC cells were more vulnerable to the combined inhibition of the CK2 and ATM kinases than wild-type VHL cells. Importantly, we found that HIF-2α acts as a key mediator that potentiates the response to combined CK2/ATM inhibition by triggering ROS-dependent apoptosis. Importantly, our findings reveal a selective killing of VHL-deficient renal carcinoma cells and provide a rationale for a mechanism-based use of combined CK2/ATM inhibitors for improved patient care in metastatic VHL-ccRCC.
Oxidation of Innate Immune Checkpoint CD47 on Cancer Cells with Non-Thermal Plasma
Authors: Lin Abraham , Razzokov Jamoliddin , Verswyvel Hanne , Privat-Maldonado Angela , De Backer Joey , Yusupov Maksudbek , Cardenas De La Hoz Edgar , Ponsaerts Peter , Smits Evelien , Bogaerts Annemie
Published: February 2021

Non-thermal plasma (NTP) therapy has been emerging as a promising cancer treatment strategy, and recently, its ability to locally induce immunogenic cancer cell death is being unraveled. We hypothesized that the chemical species produced by NTP reduce immunosuppressive surface proteins and checkpoints that are overexpressed on cancerous cells. Here, 3D in vitro tumor models, an in vivo mouse model, and molecular dynamics simulations are used to investigate the effect of NTP on CD47, a key innate immune checkpoint. CD47 is immediately modulated after NTP treatment and simulations reveal the potential oxidized salt-bridges responsible for conformational changes. Umbrella sampling simulations of CD47 with its receptor, signal-regulatory protein alpha (SIRPα), demonstrate that the induced-conformational changes reduce its binding affinity. Taken together, this work provides new insight into fundamental, chemical NTP-cancer cell interaction mechanisms and a previously overlooked advantage of present NTP cancer therapy: reducing immunosuppressive signals on the surface of cancer cells.
BMI1-Inhibitor PTC596 in Combination with MCL1 Inhibitor S63845 or MEK Inhibitor Trametinib in the Treatment of Acute Leukemia
Authors: Seipel Katja , Kopp Basil , Bacher Ulrike , Pabst Thomas
Published: February 2021

Purpose: Prognosis for acute myeloid leukemia (AML) patients is poor, particularly in TP53 mutated AML, secondary, relapsed, and refractory AML, and in patients unfit for intensive treatment, thus highlighting an unmet need for novel therapeutic approaches. The combined use of compounds targeting the stem cell oncoprotein BMI1 and activating the tumor suppressor protein p53 may represent a promising novel treatment option for poor risk AML patients. Experimental Design: The BMI1 inhibitor PTC596, MCL1 inhibitor S63845, and MEK inhibitor trametinib, as well as the p53 activator APR-246 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells. AML cells represented all major morphologic and molecular subtypes including FLT3-ITD and FLT3 wild type, NPM1 mutant and wild type, as well as TP53 mutant and wild type AML cell lines and a variety of patient derived AML cells. Results: AML cell lines were variably susceptible to PTC596 and to combination treatments with PTC596 and MCL1 inhibitor S63845, MEK inhibitor trametinib, or TP53 activator APR-246, independent of TP53 mutational status. Susceptibility of patient samples for PTC596 in combination with S63845 or trametinib was significant for the majority of adverse risk primary and secondary AML with minimal efficacy in favorable risk AML, and correlated significantly with CD34 positivity of the samples. BMI1 and MN1 gene expression, and MCL1 and MEK1 protein levels were identified as biomarkers for response to PTC596 combination treatments. Conclusions: The combination of PTC596 and S63845 may be an effective treatment in CD34+ adverse risk AML with elevated MN1 gene expression and MCL1 protein levels, while PTC596 and trametinib may be more effective in CD34+ adverse risk AML with elevated BMI1 gene expression and MEK protein levels.
Bringing Onco-Innovation to Europe’s Healthcare Systems: The Potential of Biomarker Testing, Real World Evidence, Tumour Agnostic Therapies to Empower Personalised Medicine
Authors: Horgan Denis , Ciliberto Gennaro , Conte Pierfranco , Curigliano Giuseppe , Seijo Luis , Montuenga Luis M. , Garassino Marina , Penault-Llorca Frederique , Galli Fabrizia , Ray-Coquard Isabelle , Querleu Denis , Riegman Peter , Kerr Keith , Van Poppel Hein , Bjartell Anders , Codacci-Pisanelli Giovanni , Koeva-Balabanova Jasmina , Paradiso Angelo , Maravic Zorana , Fotaki Vassiliki , Malats Nuria , Bernini Chiara , Buglioni Simonetta , Kent Alastair , Munzone Elisabetta , Belina Ivica , Van Meerbeeck Jan , Duffy Michael , Jagielska Beata , Capoluongo Ettore
Published: February 2021

Rapid and continuing advances in biomarker testing are not being matched by uptake in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. The potential that genomics has brought to biomarker testing in diagnosis, prediction and research is being realised, pre-eminently in many cancers, but also in an ever-wider range of conditions—notably BRCA1/2 testing in ovarian, breast, pancreatic and prostate cancers. Nevertheless, the implementation of genetic testing in clinical routine setting is still challenging. Development is impeded by country-related heterogeneity, data deficiencies, and lack of policy alignment on standards, approval—and the role of real-world evidence in the process—and reimbursement. The acute nature of the problem is compellingly illustrated by the particular challenges facing the development and use of tumour agnostic therapies, where the gaps in preparedness for taking advantage of this innovative approach to cancer therapy are sharply exposed. Europe should already have in place a guarantee of universal access to a minimum suite of biomarker tests and should be planning for an optimum testing scenario with a wider range of biomarker tests integrated into a more sophisticated health system articulated around personalised medicine. Improving healthcare and winning advantages for Europe’s industrial competitiveness and innovation require an appropriate policy framework—starting with an update to outdated recommendations. We show herein the main issues and proposals that emerged during the previous advisory boards organised by the European Alliance for Personalized Medicine which mainly focus on possible scenarios of harmonisation of both oncogenetic testing and management of cancer patients.
Effects of Supports BET Surface Areas on Membrane Electrode Assembly Performance at High Current Loads
Authors: Kumar Mohanta Paritosh , Ripa Masuma Sultana , Regnet Fabian , Jörissen Ludwig
Published: February 2021

In this work, we investigated the influence of catalyst supports, particularly Brunauer, Emmett, and Teller (BET) surface area of the catalyst support materials, on membrane electrode assembly (MEA) performance. Keeping the anode catalyst layer (CL), membrane, Pt loading, and operating condition unchanged, we prepared cathode CLs using catalysts of identical Pt content (30 wt% Pt) which were supported on carbon black materials having different BET surface areas. We observed optimum cell voltage at high current load when using cathode catalyst layers prepared from catalysts supported on carbons having medium-BET surface area. High-BET surface area supports, although beneficial at low current density as well as low-BET surface area supports, led to increased voltage losses at high current load due to mass transport limitations which can be explained by the electrochemically active surface area available and water management in the catalyst layer.
Influence of Substrate Materials on Nucleation and Properties of Iridium Thin Films Grown by ALD
Authors: Schmitt Paul , Beladiya Vivek , Felde Nadja , Paul Pallabi , Otto Felix , Fritz Torsten , Tünnermann Andreas , Szeghalmi Adriana V.
Published: February 2021

Ultra-thin metallic films are widely applied in optics and microelectronics. However, their properties differ significantly from the bulk material and depend on the substrate material. The nucleation, film growth, and layer properties of atomic layer deposited (ALD) iridium thin films are evaluated on silicon wafers, BK7, fused silica, SiO2, TiO2, Ta2O5, Al2O3, HfO2, Ru, Cr, Mo, and graphite to understand the influence of various substrate materials. This comprehensive study was carried out using scanning electron and atomic force microscopy, X-ray reflectivity and diffraction, four-point probe resistivity and contact angle measurements, tape tests, and Auger electron spectroscopy. Within few ALD cycles, iridium islands occur on all substrates. Nevertheless, their size, shape, and distribution depend on the substrate. Ultra-thin (almost) closed Ir layers grow on a Ta2O5 seed layer after 100 cycles corresponding to about 5 nm film thickness. In contrast, the growth on Al2O3 and HfO2 is strongly inhibited. The iridium growth on silicon wafers is overall linear. On BK7, fused silica, SiO2, TiO2, Ta2O5, Ru, Cr, and graphite, three different growth regimes are distinguishable. The surface free energy of the substrates correlates with their iridium nucleation delay. Our work, therefore, demonstrates that substrates can significantly tailor the properties of ultra-thin films.
Influence of Artificially Macroscopical Drilling on the Crystal Growth Orientation of Single Domain SmBCO Bulk Superconductor
Authors: Wang Miao , Liu Yuguang , Wang Xiaomei , Xian Hang , Yang Wan-min
Published: February 2021

A large drilled single domain SmBa2Cu3O7−δ (SmBCO) bulk superconductor with a diameter of 32 mm and different hole sizes was successfully fabricated using the modified top-seeded infiltration and growth (TSIG) process. The morphology, superconducting properties, and grain boundary orientation growth of the drilled SmBCO samples were investigated. It was found that not only are the properties of the drilled sample equivalent to those of normal SmBCO bulk superconductors, but also the NdBCO seed crystal can be well controlled because of the increase in the specific surface area in the solid phase pellet. In addition, the growth orientation along the tangent direction of the holes was first noticed in the drilled single domain SmBCO bulk superconductor. This conclusion is highly important for the accurate control of the growth temperature of high temperature bulk superconductors.
Investigation of Elastic Properties of the Single-Crystal Nickel-Base Superalloy CMSX-4 in the Temperature Interval between Room Temperature and 1300 °C
Authors: Epishin Alexander , Fedelich Bernard , Finn Monika , Künecke Georgia , Rehmer Birgit , Nolze Gert , Leistner Claudia , Petrushin Nikolay , Svetlov Igor
Published: February 2021

The elastic properties of the single-crystal nickel-base superalloy CMSX-4 used as a blade material in gas turbines were investigated by the sonic resonance method in the temperature interval between room temperature and 1300 °C. Elastic constants at such high temperatures are needed to model the mechanical behavior of blade material during manufacturing (hot isostatic pressing) as well as during technical accidents which may happen in service (overheating). High reliability of the results was achieved using specimens of different crystallographic orientations, exciting various vibration modes as well as precise measurement of the material density and thermal expansion required for modeling the resonance frequencies by finite element method. Combining the results measured in this work and literature data the elastic constants of the γ- and γ′-phases were predicted. This prediction was supported by measurement of the temperature dependence of the γ′-fraction. All data obtained in this work are given in numerical or analytical forms and can be easily used for different scientific and engineering calculations.
Proton Pump Inhibitors and Oncologic Treatment Efficacy: A Practical Review of the Literature for Oncologists
Authors: Uchiyama Angel A. T. , Silva Pedro A. I. A. , Lopes Moisés S. M. , Yen Cheng T. , Ricardo Eliza D. , Mutão Taciana , Pimenta Jefferson R. , Machado Larissa M. , Shimba Denis S. , Peixoto Renata D.
Published: February 2021

Proton pump inhibitors (PPIs) are the most commonly used anti-acid drugs worldwide, including among cancer patients. However, drug-drug interactions between PPIs and other agents may lead to decreased drug absorption with possible reduced therapeutic benefit, or even increased toxicity. Unfortunately, only scarce data exist regarding the safety of concomitant PPI use with anti-cancer agents. We aim at reviewing current evidence on this possible interaction by dividing anti-cancer agents by class. Until further data is available, we encourage healthcare providers to limit unnecessary PPI overuse.
Two-Dimensional Aortic Size Normalcy: A Novelty Detection Approach
Authors: Frasconi Paolo , Baracchi Daniele , Giusti Betti , Kura Ada , Spaziani Gaia , Cherubini Antonella , Favilli Silvia , Di Lenarda Andrea , Pepe Guglielmina , Nistri Stefano
Published: February 2021

Background: To develop a tool for assessing normalcy of the thoracic aorta (TA) by echocardiography, based on either a linear regression model (Z-score), or a machine learning technique, namely one-class support vector machine (OC-SVM) (Q-score). Methods: TA diameters were measured in 1112 prospectively enrolled healthy subjects, aging 5 to 89 years. Considering sex, age and body surface area we developed two calculators based on the traditional Z-score and the novel Q-score. The calculators were compared in 198 adults with TA > 40 mm, and in 466 patients affected by either Marfan syndrome or bicuspid aortic valve (BAV). Results: Q-score attained a better Area Under the Curve (0.989; 95% CI 0.984–0.993, sensitivity = 97.5%, specificity = 95.4%) than Z-score (0.955; 95% CI 0.942–0.967, sensitivity = 81.3%, specificity = 93.3%; p < 0.0001) in patients with TA > 40 mm. The prevalence of TA dilatation in Marfan and BAV patients was higher as Z-score > 2 than as Q-score < 4% (73.4% vs. 50.09%, p < 0.00001). Conclusions: Q-score is a novel tool for assessing TA normalcy based on a model requiring less assumptions about the distribution of the relevant variables. Notably, diameters do not need to depend linearly on anthropometric measurements. Additionally, Q-score can capture the joint distribution of these variables with all four diameters simultaneously, thus accounting for the overall aortic shape. This approach results in a lower rate of predicted TA abnormalcy in patients at risk of TA aneurysm. Further prognostic studies will be necessary for assessing the relative effectiveness of Q-score versus Z-score.
Corneal Analysis with Swept Source Optical Coherence Tomography in Patients with Coexisting Cataract and Fuchs Endothelial Corneal Dystrophy
Authors: Nowińska Anna , Chlasta-Twardzik Edyta , Dembski Michał , Ulfik-Dembska Klaudia , Wylęgała Edward
Published: February 2021

This study focused on defining the characteristic features of keratometry and pachymetry elevation maps based on swept source optical coherence tomography (SS OCT) in Fuchs endothelial corneal dystrophy (FECD) eyes with a coexisting cataract. 70 eyes of 35 patients diagnosed with FECD and a coexisting cataract and 70 control eyes were included in this prospective, controlled, observational, cross-sectional study. Features characteristic of intermediately affected eyes included an increased corneal thinnest thickness (CTT) (p = 0.01), 3 and 6 mm asymmetry (p < 0.0001), higher order Fourier indices (p < 0.05 and p ≤ 0.0001, respectively), chord µ, and a posterior Ectasia Screening Index (pESI) (p < 0.01). The lack of agreement between the anterior and posterior elevation map and a significant area of negative values in the posterior map were detected. In advanced FECD eyes, our study additionally revealed decreased posterior keratometry steep (Ks), keratometry flat (Kf), keratometry average (AvgK), eccentricity (Ecc), an increased corneal apex thickness (CAT), and decreased 3 and 6 mm posterior spherical indices (p < 0.0001 for all of the above). Characteristic features of subclinical FECD, independent of the corneal thickness, can be detected by SS OCT and should be considered during the preoperative assessment of patients with a coexisting cataract.
A Self-Spatial Adaptive Weighting Based U-Net for Image Segmentation
Authors: Cho Choongsang , Lee Young Han , Park Jongyoul , Lee Sangkeun
Published: February 2021

Semantic image segmentation has a wide range of applications. When it comes to medical image segmentation, its accuracy is even more important than those of other areas because the performance gives useful information directly applicable to disease diagnosis, surgical planning, and history monitoring. The state-of-the-art models in medical image segmentation are variants of encoder-decoder architecture, which is called U-Net. To effectively reflect the spatial features in feature maps in encoder-decoder architecture, we propose a spatially adaptive weighting scheme for medical image segmentation. Specifically, the spatial feature is estimated from the feature maps, and the learned weighting parameters are obtained from the computed map, since segmentation results are predicted from the feature map through a convolutional layer. Especially in the proposed networks, the convolutional block for extracting the feature map is replaced with the widely used convolutional frameworks: VGG, ResNet, and Bottleneck Resent structures. In addition, a bilinear up-sampling method replaces the up-convolutional layer to increase the resolution of the feature map. For the performance evaluation of the proposed architecture, we used three data sets covering different medical imaging modalities. Experimental results show that the network with the proposed self-spatial adaptive weighting block based on the ResNet framework gave the highest IoU and DICE scores in the three tasks compared to other methods. In particular, the segmentation network combining the proposed self-spatially adaptive block and ResNet framework recorded the highest 3.01% and 2.89% improvements in IoU and DICE scores, respectively, in the Nerve data set. Therefore, we believe that the proposed scheme can be a useful tool for image segmentation tasks based on the encoder-decoder architecture.
A Neural Network Classifier with Multi-Valued Neurons for Analog Circuit Fault Diagnosis
Authors: Aizenberg Igor , Belardi Riccardo , Bindi Marco , Grasso Francesco , Manetti Stefano , Luchetta Antonio , Piccirilli Maria Cristina
Published: February 2021

In this paper, we present a new method designed to recognize single parametric faults in analog circuits. The technique follows a rigorous approach constituted by three sequential steps: calculating the testability and extracting the ambiguity groups of the circuit under test (CUT); localizing the failure and putting it in the correct fault class (FC) via multi-frequency measurements or simulations; and (optional) estimating the value of the faulty component. The fabrication tolerances of the healthy components are taken into account in every step of the procedure. The work combines machine learning techniques, used for classification and approximation, with testability analysis procedures for analog circuits.
A Feasibility Study of 2-D Microwave Thorax Imaging Based on the Supervised Descent Method
Authors: Zhang Haolin , Li Maokun , Yang Fan , Xu Shenheng , Yin Yan , Zhou Hongyu , Yang Yubo , Zeng Sihang , Shao Jianchong
Published: February 2021

In this paper, the application of the supervised descent method (SDM) for 2-D microwave thorax imaging is studied. The forward modeling problem is solved by the finite element-boundary integral (FE-BI) method. According to the prior information of human thorax, a 3-ellipse training set is generated offline. Then, the average descent direction between an initial background model and the training models is calculated. Finally, the reconstruction of the testing thorax model is achieved based on the average descent directions online. The feasibility using One-Step SDM for thorax imaging is studied. Numerical results indicate that the structural information of thorax can be reconstructed. It has potential for real-time imaging in future clinical diagnosis.
Planning and Research of Distribution Feeder Automation with Decentralized Power Supply
Authors: Huang Yen-Chih , Chang Wen-Ching , Hsu Hsuan , Kuo Cheng-Chien
Published: February 2021

The high penetration of distributed generation in distributed energy systems causes the variation of power loss and makes the power grid become more complicated, so this paper takes various types of optimal algorithms into account and simulates the feeder reconfiguration on the IEEE-33 system as well as the Taiwan power system. The simulation verifies linear population size reduction of successful history-based adaptive differential evolution (L-SHADE) and particle swarm optimization (PSO) fitness in different systems and provides the recommended location of distributed energy. The proposed method keeps the voltage bound of 0.95 to 1.03 p.u. of Taiwan regulation. In the IEEE-33 system, we achieved a 52.57% power loss reduction after feeder reconfiguration, and a 70.55% power loss reduction after the distributed generator was implemented and feeder reconfiguration. Under the variation of load demand and power generation of the Taiwan power system, we establish the system models by forecasting one-day load demand. Then, we propose a one-day feeder switch operation strategy by considering the switches’ operation frequency with the reduction of 83.3% manual operation and recommend feeder automation to achieve feeder power loss reduction, voltage profile improvement and get regional power grid resilient configuration.