bluuebunny/crossref_metadata_2025 huggingface dataset:
MMP-1, UCH-L1, and 20S Proteasome as Potential Biomarkers Supporting the Diagnosis of Brain Glioma
Authors: Oldak Lukasz , Chludzinska-Kasperuk Sylwia , Milewska Patrycja , Grubczak Kamil , Reszec Joanna , Gorodkiewicz Ewa
Published: October 2022

The diagnosis of brain gliomas is mainly based on imaging methods. The gold standard in this area is MRI. Recommendations for the prevention, diagnosis, and treatment of gliomas are periodically modified and updated. One of the diagnostic techniques used when a brain glioma is suspected is liquid biopsy. However, this technique requires further development to confirm its effectiveness. This paper presents a proposal of three potential biomarkers of brain gliomas—extracellular matrix metalloproteinase-1 (MMP-1), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and the 20S proteasome—which were quantified in blood plasma using SPRi biosensors. A statistical analysis of the results indicated no significant changes in the concentrations between the control group (K) and grades G1 and G2, and similarly between grades G3 and G4. However, the differences in the concentrations between the groups K/G1/G2 and G3/G4 were statistically significant. A positive average correlation was found between the concentrations of the proteins and the patient’s age. The individual tested proteins were also highly correlated with each other. Our work proposes a new diagnostic technique that may aid in the diagnosis of brain gliomas.
Ischemic Stroke, Lessons from the Past towards Effective Preclinical Models
Authors: Amado Beatriz , Melo Lúcia , Pinto Raquel , Lobo Andrea , Barros Pedro , Gomes João R.
Published: October 2022

Ischemic stroke is a leading cause of death worldwide, mainly in western countries. So far, approved therapies rely on reperfusion of the affected brain area, by intravenous thrombolysis or mechanical thrombectomy. The last approach constitutes a breakthrough in the field, by extending the therapeutic window to 16–24 h after stroke onset and reducing stroke mortality. The combination of pharmacological brain-protective strategies with reperfusion is the future of stroke therapy, aiming to reduce brain cell death and decrease patients’ disabilities. Recently, a brain-protective drug—nerinetide—reduced brain infarct and stroke mortality, and improved patients’ functional outcomes in clinical trials. The success of new therapies relies on bringing preclinical studies and clinical practice close together, by including a functional outcome assessment similar to clinical reality. In this review, we focused on recent upgrades of in vitro and in vivo stroke models for more accurate and effective evaluation of therapeutic strategies: from spheroids to organoids, in vitro models that include all brain cell types and allow high throughput drug screening, to advancements in in vivo preclinical mouse stroke models to mimic the clinical reality in surgical procedures, postsurgical care, and functional assessment.
Genetic Association Study and Machine Learning to Investigate Differences in Platelet Reactivity in Patients with Acute Ischemic Stroke Treated with Aspirin
Authors: Ikonnikova Anna , Anisimova Anastasia , Galkin Sergey , Gunchenko Anastasia , Abdukhalikova Zhabikai , Filippova Marina , Surzhikov Sergey , Selyaeva Lidia , Shershov Valery , Zasedatelev Alexander , Avdonina Maria , Nasedkina Tatiana
Published: October 2022

Aspirin resistance (AR) is a pressing problem in current ischemic stroke care. Although the role of genetic variations is widely considered, the data still remain controversial. Our aim was to investigate the contribution of genetic features to laboratory AR measured through platelet aggregation with arachidonic acid (AA) and adenosine diphosphate (ADP) in ischemic stroke patients. A total of 461 patients were enrolled. Platelet aggregation was measured via light transmission aggregometry. Eighteen single-nucleotide polymorphisms (SNPs) in ITGB3, GPIBA, TBXA2R, ITGA2, PLA2G7, HMOX1, PTGS1, PTGS2, ADRA2A, ABCB1 and PEAR1 genes and the intergenic 9p21.3 region were determined using low-density biochips. We found an association of rs1330344 in the PTGS1 gene with AR and AA-induced platelet aggregation. Rs4311994 in ADRA2A gene also affected AA-induced aggregation, and rs4523 in the TBXA2R gene and rs12041331 in the PEAR1 gene influenced ADP-induced aggregation. Furthermore, the effect of rs1062535 in the ITGA2 gene on NIHSS dynamics during 10 days of treatment was found. The best machine learning (ML) model for AR based on clinical and genetic factors was characterized by AUC = 0.665 and F1-score = 0.628. In conclusion, the association study showed that PTGS1, ADRA2A, TBXA2R and PEAR1 polymorphisms may affect laboratory AR. However, the ML model demonstrated the predominant influence of clinical features.
Epigenetic Features in Uterine Leiomyosarcoma and Endometrial Stromal Sarcomas: An Overview of the Literature
Authors: de Almeida Bruna Cristine , dos Anjos Laura Gonzalez , Dobroff Andrey Senos , Baracat Edmund Chada , Yang Qiwei , Al-Hendy Ayman , Carvalho Katia Candido
Published: October 2022

There is a consensus that epigenetic alterations play a key role in cancer initiation and its biology. Studies evaluating the modification in the DNA methylation and chromatin remodeling patterns, as well as gene regulation profile by non-coding RNAs (ncRNAs) have led to the development of novel therapeutic approaches to treat several tumor types. Indeed, despite clinical and translational challenges, combinatorial therapies employing agents targeting epigenetic modifications with conventional approaches have shown encouraging results. However, for rare neoplasia such as uterine leiomyosarcomas (LMS) and endometrial stromal sarcomas (ESS), treatment options are still limited. LMS has high chromosomal instability and molecular derangements, while ESS can present a specific gene fusion signature. Although they are the most frequent types of “pure” uterine sarcomas, these tumors are difficult to diagnose, have high rates of recurrence, and frequently develop resistance to current treatment options. The challenges involving the management of these tumors arise from the fact that the molecular mechanisms governing their progression have not been entirely elucidated. Hence, to fill this gap and highlight the importance of ongoing and future studies, we have cross-referenced the literature on uterine LMS and ESS and compiled the most relevant epigenetic studies, published between 2009 and 2022.
Fast UV-Curable Zwitter-Wettable Coatings with Reliable Antifogging/Frost-Resisting Performances
Authors: Zhong Hao , Liu Xiaoxiao , Yu Boxin , Zhou Shengzhu
Published: October 2022

Antifogging surfaces with unique properties to migrate severe fog formation have gained extensive interest, which is of particular interest for transparent substrates to obtain high visibility and transparency. To date, a large number of strategies including superhydrophilic or superhydrophobic surfaces and titanium dioxide (TiO2)-based composite coatings have been developed based on different mechanisms. Although these surfaces exhibit effective antifogging properties, the rigid nanostructures, cumbersome preparation, and the need for UV light excitation largely limit their widespread applications. Herein, we report a zwitter-wettable antifogging and frost-resisting coating through a fast UV-curable cross-linking of copolymer with benzophenone groups. A series of random copolymers consisting of hydrophilic hydroxyethyl methacrylate (HEA), hydrophobic methyl methacrylate (MMA), and benzophenone-based acrylate units are developed by thermally triggered free-radical polymerization. Upon UV light irradiation, a highly efficient antifogging/frost-resisting coating is covalently bonded on a polycarbonate plate surface, maintaining a light transmission higher than 85%, which was confirmed in both high and low temperature anti-fog tests. Moreover, the wetting behaviors reveal that the antifogging performance exhibited by the zwitter-wettable surface mainly relies on its surface water-adsorbing capability to imbibe condensed water vapor on the surface outmost layer. Notably, the antifogging/frost-resisting behaviors can be well regulated by adjusting the hydrophilic/hydrophobic units, due to the proper balance between the water-adsorption and coating stability. Owing to its simplicity, low-cost preparation and high efficiency, this UV-curable acrylate antifogging coating may find a wide range of applications in various display devices in analytical and detection instruments.
DGFlow-SLAM: A Novel Dynamic Environment RGB-D SLAM without Prior Semantic Knowledge Based on Grid Segmentation of Scene Flow
Authors: Long Fei , Ding Lei , Li Jianfeng
Published: October 2022

Currently, using semantic segmentation networks to distinguish dynamic and static key points has become a mainstream designing method for semantic SLAM systems. However, the semantic SLAM systems must have prior semantic knowledge of relevant dynamic objects, and their processing speed is inversely proportional to the recognition accuracy. To simultaneously enhance the speed and accuracy for recognizing dynamic objects in different environments, a novel SLAM system without prior semantics called DGFlow-SLAM is proposed in this paper. A novel grid segmentation method is used in the system to segment the scene flow, and then an adaptive threshold method is used to roughly detect the dynamic objects. Based on this, a deep mean clustering segmentation method is applied to find potential dynamic targets. Finally, the results of grid segmentation and depth mean clustering segmentation are jointly used to find moving objects accurately, and all the feature points of the moving objects are removed on the premise of retaining the static part of the moving object. The experimental results show that on the dynamic sequence dataset of TUM RGB-D, compared with the DynaSLAM system with the highest accuracy for detecting moderate and violent motion and the DS-SLAM with the highest accuracy for detecting slight motion, DGflow-SLAM obtains similar accuracy results and improves the accuracy by 7.5%. In addition, DGflow-SLAM is 10 times and 1.27 times faster than DynaSLAM and DS-SLAM, respectively.
Data Structures and Algorithms for k-th Nearest Neighbours Conformational Entropy Estimation
Authors: Borelli Roberto , Dovier Agostino , Fogolari Federico
Published: October 2022

Entropy of multivariate distributions may be estimated based on the distances of nearest neighbours from each sample from a statistical ensemble. This technique has been applied on biomolecular systems for estimating both conformational and translational/rotational entropy. The degrees of freedom which mostly define conformational entropy are torsion angles with their periodicity. In this work, tree structures and algorithms to quickly generate lists of nearest neighbours for periodic and non-periodic data are reviewed and applied to biomolecular conformations as described by torsion angles. The effect of dimensionality, number of samples, and number of neighbours on the computational time is assessed. The main conclusion is that using proper data structures and algorithms can greatly reduce the complexity of nearest neighbours lists generation, which is the bottleneck step in nearest neighbours entropy estimation.
Generation of Dynamic Concentration Profile Using A Microfluidic Device Integrating Pneumatic Microvalves
Authors: Chen Chang , Li Panpan , Guo Tianruo , Chen Siyuan , Xu Dong , Chen Huaying
Published: October 2022

Generating and maintaining the concentration dilutions of diffusible molecules in microchannels is critical for high-throughput chemical and biological analysis. Conventional serial network microfluidic technologies can generate high orders of arbitrary concentrations by a predefined microchannel network. However, a previous design requires a large occupancy area and is unable to dynamically generate different profiles in the same chip, limiting its applications. This study developed a microfluidic device enabling dynamic variations of both the concentration in the same channel and the concentration distribution in multiple channels by adjusting the flow resistance using programmable pneumatic microvalves. The key component (the pneumatic microvalve) allowed dynamic adjustment of the concentration profile but occupied a tiny space. Additionally, a Matlab program was developed to calculate the flow rates and flow resistance of various sections of the device, which provided theoretical guidance for dimension design. In silico investigations were conducted to evaluate the microvalve deformation with widths from 100 to 300 µm and membrane thicknesses of 20 and 30 µm under the activation pressures between 0 and 2000 mbar. The flow resistance of the deformed valve was studied both numerically and experimentally and an empirical model for valve flow resistance with the form of Rh=aebP was proposed. Afterward, the fluid flow in the valve region was characterized using Micro PIV to further demonstrate the adjustment mechanism of the flow resistance. Then, the herringbone structures were employed for fast mixing to allow both quick variation of concentration and minor space usage of the channel network. Finally, an empirical formula-supported computational program was developed to provide the activation pressures required for the specific concentration profile. Both linear (Ck = −0.2k + 1) and nonlinear (Ck = (110)k) concentration distribution in four channels were varied using the same device by adjusting microvalves. The device demonstrated the capability to control the concentration profile dynamically in a small space, offering superior application potentials in analytical chemistry, drug screening, and cell biology research.
Application of Microfluidics in Drug Development from Traditional Medicine
Authors: Li Xue , Fan Xiaoming , Li Zhu , Shi Lina , Liu Jinkuan , Luo Hongzhi , Wang Lijun , Du Xiaoxin , Chen Wenzhu , Guo Jiuchuan , Li Chenzhong , Liu Shan
Published: October 2022

While there are many clinical drugs for prophylaxis and treatment, the search for those with low or no risk of side effects for the control of infectious and non-infectious diseases is a dilemma that cannot be solved by today’s traditional drug development strategies. The need for new drug development strategies is becoming increasingly important, and the development of new drugs from traditional medicines is the most promising strategy. Many valuable clinical drugs have been developed based on traditional medicine, including drugs with single active ingredients similar to modern drugs and those developed from improved formulations of traditional drugs. However, the problems of traditional isolation and purification and drug screening methods should be addressed for successful drug development from traditional medicine. Advances in microfluidics have not only contributed significantly to classical drug development but have also solved many of the thorny problems of new strategies for developing new drugs from traditional drugs. In this review, we provide an overview of advanced microfluidics and its applications in drug development (drug compound synthesis, drug screening, drug delivery, and drug carrier fabrication) with a focus on its applications in conventional medicine, including the separation and purification of target components in complex samples and screening of active ingredients of conventional drugs. We hope that our review gives better insight into the potential of traditional medicine and the critical role of microfluidics in the drug development process. In addition, the emergence of new ideas and applications will bring about further advances in the field of drug development.
Real-Time Monitoring of Breath Biomarkers with A Magnetoelastic Contactless Gas Sensor: A Proof of Concept
Authors: Peña Alvaro , Aguilera Juan Diego , Matatagui Daniel , de la Presa Patricia , Horrillo Carmen , Hernando Antonio , Marín Pilar
Published: October 2022

In the quest for effective gas sensors for breath analysis, magnetoelastic resonance-based gas sensors (MEGSs) are remarkable candidates. Thanks to their intrinsic contactless operation, they can be used as non-invasive and portable devices. However, traditional monitoring techniques are bound to slow detection, which hinders their application to fast bio-related reactions. Here we present a method for real-time monitoring of the resonance frequency, with a proof of concept for real-time monitoring of gaseous biomarkers based on resonance frequency. This method was validated with a MEGS based on a Metglass 2826 MB microribbon with a polyvinylpyrrolidone (PVP) nanofiber electrospun functionalization. The device provided a low-noise (RMS = 1.7 Hz), fast (<2 min), and highly reproducible response to humidity (Δf = 46–182 Hz for 17–95% RH), ammonia (Δf = 112 Hz for 40 ppm), and acetone (Δf = 44 Hz for 40 ppm). These analytes are highly important in biomedical applications, particularly ammonia and acetone, which are biomarkers related to diseases such as diabetes. Furthermore, the capability of distinguishing between breath and regular air was demonstrated with real breath measurements. The sensor also exhibited strong resistance to benzene, a common gaseous interferent in breath analysis.
Electrochemical Sensor Based on Ni-Co Layered Double Hydroxide Hollow Nanostructures for Ultrasensitive Detection of Sumatriptan and Naproxen
Authors: Beitollahi Hadi , Dourandish Zahra , Tajik Somayeh , Sharifi Fatemeh , Jahani Peyman Mohammadzadeh
Published: October 2022

In this work, Ni-Co layered double hydroxide (Ni–Co LDH) hollow nanostructures were synthesized and characterized by X-ray diffraction (XRD), field emission-scanning electron microscopy (FE-SEM), and Fourier-transform infrared spectroscopy (FT-IR) techniques. A screen-printed electrode (SPE) surface was modified with as-fabricated Ni–Co LDHs to achieve a new sensing platform for determination of sumatriptan. The electrochemical behavior of the Ni–Co LDH-modified SPE (Ni-CO LDH/SPE) for sumatriptan determination was investigated using voltammetric methods. Compared with bare SPE, the presence of Ni-Co LDH was effective in the enhancement of electron transport rate between the electrode and analyte, as well as in the significant reduction of the overpotential of sumatriptan oxidation. Differential pulse voltammetry (DPV) was applied to perform a quantitative analysis of sumatriptan. The linearity range was found to be between 0.01 and 435.0 μM. The limits of detection (LOD) and sensitivity were 0.002 ± 0.0001 μM and 0.1017 ± 0.0001 μA/μM, respectively. In addition, the performance of the Ni-CO LDH/SPE for the determination of sumatriptan in the presence of naproxen was studied. Simultaneous analysis of sumatriptan with naproxen showed well-separated peaks leading to a quick and selective analysis of sumatriptan. Furthermore, the practical applicability of the prepared Ni-CO LDH/SPE sensor was examined in pharmaceutical and biological samples with satisfactory recovery results.
In-Plane Lateral Performance of AAC Block Walls Reinforced with CFPR Sheets
Authors: Saad Ahmad S. , Ahmed Taha A. , Radwan Ali I.
Published: October 2022

This study evaluates the structural behavior of aerated autoclave concrete (AAC) blocks laterally loaded in the in-plane direction under quasi-static loading. The study started with the evaluation of the basic physical properties of the AAC blocks, including its structural properties (individually and as part of an assembly), followed by large-scale testing of two (half-scaled) walls constructed with commercially available AAC blocks. The first wall was unreinforced, similar to the commonly used construction technique for low-rise houses where AAC blocks are utilized. The second one was internally reinforced with short dowels connecting the foundation to the walls through their lower block rows and externally reinforced with carbon-fiber-reinforced polymer (CFRP) sheets through the entire wall height. The reinforcement scheme was conducted in such a way that does not delay construction time. Reinforcing the wall significantly increased the strength of the wall in the in-plane direction. The reinforced wall exhibited increased initial stiffness, higher ductility, and larger energy dissipation, in addition to a change in the failure mode. The unreinforced wall failure mode was dominated by blocks sliding, while the reinforced wall failure was dominated by compressive shear failure with wall uplifting. The findings of this study can be implemented to increase the lateral strength of unreinforced new houses and can also be extended to strengthen existing houses built with unreinforced AAC blocks.
Prediction of Unstable Hydrodynamic Forces on Submerged Structures under the Water Surface Using a Data-Driven Modeling Approach
Authors: Nguyen Van My , Phan Hoang Nam , Phan Thanh Hoang
Published: October 2022

Catastrophic failures of partially or fully submerged structures, e.g., offshore platforms, hydrokinetic turbine blades, bridge decks, etc., due to the dynamic impact of free surface flows such as waves or floods have revealed the need to evaluate their reliability. In this respect, an accurate estimation of hydrodynamic forces and their relationship to instability in structures is required. The computational fluid dynamics (CFD) solver is known as a powerful tool to identify dynamic characteristics of flow; however, it commonly consumes a huge computational cost, especially in cases of re-simulations needed. In this paper, an efficient surrogate model based on the Gaussian process is developed to rapidly predict the nonlinear hydrodynamic pressure coefficients on submerged bodies near the water surface. For this purpose, a CFD model is first developed, which is based on a two-dimensional incompressible Navier–Stokes solver incorporating free surface treatment and turbulent flow models. Then, an experimental design is adopted to generate initial training samples considering the effect of the submerged body shape ratio and flow Re number. Surrogate models of hydrodynamic pressure coefficients and their instability based on Gaussian process modeling are established using the outcome from the CFD simulations, where optimal trend and correlation functions are also investigated. Once surrogate models are obtained, the mean and oscillation amplitudes of hydrodynamic pressure coefficients on a submerged rectangular body, which represents the shape of most civil structures, can be rapidly predicted without the attempt at re-simulation. The findings can be practically applied in rapidly assessing hydrodynamic forces and their instability of existing submerged civil structures or in designing new structures, where a suitable shape ratio should be adopted to avoid flow-induced instability of hydrodynamic forces.
The Impacts of Urban Configurations on Outdoor Thermal Perceptions: Case Studies of Flat Bandar Tasik Selatan and Surya Magna in Kuala Lumpur
Authors: Yola Lin , Adekunle Timothy O. , Ayegbusi Olutobi G.
Published: October 2022

This study assesses the impacts of urban configurations on thermal perceptions in Flat Bandar Tasik Selatan (FBTS) and Surya Magna (SM) in Kuala Lumpur, Malaysia. It aims to understand the impacts of urban configurations on thermal perceptions in outdoor spaces. The study addresses the following research questions: (1) Do urban configurations influence outdoor comfort? (2) Do urban configurations also have significant impacts on thermal perceptions? We mapped out the sites to understand their configurations. The research considered on-site measurements of the environmental conditions and carried out modelling and simulations (ENVI-met V3.1) of the sites. Mathematical models (Wet-Bulb Globe Temperature (WBGT), Universal Thermal Climate Index (UTCI), and Standard Effective Temperature (SET)) were used to determine the thermal indices and the impact of the urban configurations on outdoor comfort. The thermal indices varied from 25.44 to 34.75 °C. In terms of the main contribution of this work, the results show that in hot and humid climate regions, urban configurations plus other design variables (e.g., orientation towards the Sun’s path) and environmental parameters influence occupants’ comfort and perceptions. Our findings show that high solar radiation and the need for a better thermal environment in hot and humid climates are the contributing factors for developing alternative urban configurations.
Experimental Procedures of Accelerated Aging and Evaluation of Effectiveness of Nanostructured Products for the Protection of Volterra (Italy) Panchina Stone
Authors: Fernandez Federica , Germinario Silvia , Montagno Roberta , Basile Roberta , Borgioli Leonardo , Laviano Rocco
Published: October 2022

The aims of the research were to evaluate the effectiveness of the application of nanostructured products on Volterra calcarenite stone and to define the experimental conditions and procedures of accelerated aging tests, able to simulate different degradation on the studied lithotype. The work focused on methods of performing accelerated aging tests in order to simulate different effects of environmental decay involving stone used on a historical site. The rock samples were examined before and after three treatment types: cyclic salt spray chamber, cycles of freezing–thawing and cycles of thermal shock. After each artificial aging cycle, changes in appearance were noted and chemical and physical properties were measured so that the differences between untreated and treated samples could be compared. After applying nanostructured products on the sample surfaces, and assessing the effects of the accelerated aging, the protective performance of the coatings was evaluated using the contact angle test to evaluate the surface hygroscopicity. Moreover, scanning electron microscope (SEM-EDS) analysis was performed before and after each application of nanostructured coating to evaluate changes in the surface morphology. Results demonstrated that Panchina stone showed a high durability to the aging tests, and artificial degradation effects were not largely visible. The nanostructured products seem to be suitable for stone protection by virtue of their good compatibility and effectiveness.
Measuring Street Network Efficiency and Block Sizes in Superblocks—Addressing the Gap between Policy and Practice
Authors: Anabtawi Rim , Scoppa Martin
Published: October 2022

This paper uses quantitative methods to evaluate the application of street connectivity policies stated by Abu Dhabi’s Urban Planning Council (UPC) on newly developed projects. The evaluation of the study was performed by measuring efficiency, i.e., how short and direct are paths between residential and nonresidential destinations to understand the ability of street networks to support sustainable transportation modes in the Capital District project. Efficiency is measured in twelve neighborhoods of the Capital District using Pedestrian Route Directness (PRD), a metric that meets Estidama—Abu Dhabi Green Rating System—walkability standards. Observation and analysis of the current stage of development show that more than 58% of the neighborhoods failed the route efficiency test to connect residential plots to one another. In addition, more than 40% of the neighborhood’s residential plots could not efficiently connect to nonresidential plots. The study includes recommendations for policymakers and project developers to enhance the street infrastructure to correlate with Estidama ratings by taking advantage of sikkak, the alleyways system that is found in other neighborhoods in the city. Significantly, recommendations are based on rigorous quantitative analyses that can be used for implementation in real-world projects, thus strengthening the connection between policy and practice.
Deep Learning Models for Automated Assessment of Breast Density Using Multiple Mammographic Image Types
Authors: Rigaud Bastien , Weaver Olena O. , Dennison Jennifer B. , Awais Muhammad , Anderson Brian M. , Chiang Ting-Yu D. , Yang Wei T. , Leung Jessica W. T. , Hanash Samir M. , Brock Kristy K.
Published: October 2022

Recently, convolutional neural network (CNN) models have been proposed to automate the assessment of breast density, breast cancer detection or risk stratification using single image modality. However, analysis of breast density using multiple mammographic types using clinical data has not been reported in the literature. In this study, we investigate pre-trained EfficientNetB0 deep learning (DL) models for automated assessment of breast density using multiple mammographic types with and without clinical information to improve reliability and versatility of reporting. 120,000 for-processing and for-presentation full-field digital mammograms (FFDM), digital breast tomosynthesis (DBT), and synthesized 2D images from 5032 women were retrospectively analyzed. Each participant underwent up to 3 screening examinations and completed a questionnaire at each screening encounter. Pre-trained EfficientNetB0 DL models with or without clinical history were optimized. The DL models were evaluated using BI-RADS (fatty, scattered fibroglandular densities, heterogeneously dense, or extremely dense) versus binary (non-dense or dense) density classification. Pre-trained EfficientNetB0 model performances were compared using inter-observer and commercial software (Volpara) variabilities. Results show that the average Fleiss’ Kappa score between-observers ranged from 0.31–0.50 and 0.55–0.69 for the BI-RADS and binary classifications, respectively, showing higher uncertainty among experts. Volpara-observer agreement was 0.33 and 0.54 for BI-RADS and binary classifications, respectively, showing fair to moderate agreement. However, our proposed pre-trained EfficientNetB0 DL models-observer agreement was 0.61–0.66 and 0.70–0.75 for BI-RADS and binary classifications, respectively, showing moderate to substantial agreement. Overall results show that the best breast density estimation was achieved using for-presentation FFDM and DBT images without added clinical information. Pre-trained EfficientNetB0 model can automatically assess breast density from any images modality type, with the best results obtained from for-presentation FFDM and DBT, which are the most common image archived in clinical practice.
Intraoperative Extra Corporeal Membrane Oxygenator for Lung Cancer Resections Does Not Impact Circulating Tumor Cells
Authors: Petrella Francesco , Zorzino Laura , Frassoni Samuele , Bagnardi Vincenzo , Casiraghi Monica , Bardoni Claudia , Mohamed Shehab , Musso Valeria , Simonini Emanuele , Rossi Fabiana , Alamanni Francesco , Venturino Marco , Spaggiari Lorenzo
Published: October 2022

Background: The diagnosis of active neoplastic disease was traditionally judged an absolute contraindication for extracorporeal membrane oxygenator (ECMO) because of the fear of tumor cells being scattered or seeded. The aim of this study is to compare the number of circulating tumor cells (CTCs) before and after surgery in patients receiving lung cancer resection with and without intraoperative ECMO support. Methods: This is a prospective, non-randomized, two-arms observational study comparing the number of CTCs before and after surgery in patients receiving lung cancer resection with and without intraoperative ECMO support. The ECMO arm includes patients suffering from lung cancer undergoing pulmonary resection with planned intraoperative ECMO support. The non-ECMO arm includes patients suffering from non-early-stage lung cancer undergoing pulmonary resection without planned intraoperative ECMO support. Results: Twenty patients entered the study, eight in the ECMO arm and twelve in the non-ECMO arm. We did not observe any significant difference between the ECMO and non-ECMO groups in terms of postoperative complications (p = 1.00), ICU stay (p = 0.30), hospital stay (p = 0.23), circulating tumor cells’ increase or decrease after surgery (p = 0.24), and postoperative C-reactive protein and C-reactive protein increase (p = 0.80). The procedures in the non-ECMO arm were significantly longer than those in the ECMO arm (p = 0.043). Conclusions: Intraoperative ECMO for lung cancer resections did not impact CTC increase or decrease after the procedure.
Upregulation of Receptor Tyrosine Kinase Activity and Stemness as Resistance Mechanisms to Akt Inhibitors in Breast Cancer
Authors: Tsang Tiffany , He Qingling , Cohen Emily B. , Stottrup Casey , Lien Evan C. , Zhang Huiqi , Lau C. Geoffrey , Chin Y. Rebecca
Published: October 2022

The PI3K/Akt pathway is frequently deregulated in human cancers, and multiple Akt inhibitors are currently under clinical evaluation. Based on the experience from other molecular targeted therapies, however, it is likely that acquired resistance will be developed in patients treated with Akt inhibitors. We established breast cancer models of acquired resistance by prolonged treatment of cells with allosteric or ATP-competitive Akt inhibitors. Phospho-Receptor tyrosine kinase (Phospho-RTK) arrays revealed hyper-phosphorylation of multiple RTKS, including EGFR, Her2, HFGR, EhpB3 and ROR1, in Akt-inhibitor-resistant cells. Importantly, resistance can be overcome by treatment with an EGFR inhibitor. We further showed that cancer stem cells (CSCs) are enriched in breast tumor cells that have developed resistance to Akt inhibitors. Several candidates of CSC regulators, such as ID4, are identified by RNA sequencing. Cosmic analysis indicated that sensitivity of tumor cells to Akt inhibitors can be predicted by ID4 and stem cell/epithelial–mesenchymal transition pathway targets. These findings indicate the potential of targeting the EGFR pathway and CSC program to circumvent Akt inhibitor resistance in breast cancer.
The Expression of the Immunoproteasome Subunit PSMB9 Is Related to Distinct Molecular Subtypes of Uterine Leiomyosarcoma
Authors: Maia Falcão Raul , Kokaraki Georgia , De Wispelaere Wout , Amant Frédéric , De Souza Gustavo Antônio , de Souza Jorge Estefano Santana , Carlson Joseph Woodward , Petta Tirzah Braz
Published: October 2022

Background: Uterine leiomyosarcoma (uLMS) are rare and malignant tumors that arise in the myometrium cells and whose diagnosis is based on histopathological features. Identifying diagnostic biomarkers for uLMS is a challenge due to molecular heterogeneity and the scarcity of samples. In vivo and in vitro models for uLMS are urgently needed. Knockout female mice for the catalytic subunit of the immunoproteasome PSMB9 (MIM:177045) develop spontaneous uLMS. This study aimed to analyze the role of PSMB9 in uLMS tumorigenesis and patient outcome. Methods: Molecular data from 3 non-related uLMS cohorts were integrated and analyzed by proteotranscriptomic using gene expression and protein abundance levels in 68 normal adjacent myometrium (MM), 66 uterine leiomyoma (LM), and 67 uLMS. Results: the immunoproteasome pathway is upregulated and the gene PMSB9 shows heterogeneous expression values in uLMS. Quartile group analysis showed no significant difference between groups high and low PSMB9 expression groups at 3-years overall survival (OS). Using CYBERSORTx analysis we observed 9 out of 17 samples in the high group clustering together due to high M2 macrophages and CD4 memory resting, and high CD8+/PSMB9 ratio was associated with better OS. The main pathway regulated in the high group is IFNγ and in the low is the ECM pathway dependent on the proto-oncogene SRC. Conclusion: these findings suggest 2 subtypes of uLMS (immune-related and ECM-related) with different candidate mechanisms of malignancy.
Comparative Evaluation of Tumor-Infiltrating Lymphocytes in Companion Animals: Immuno-Oncology as a Relevant Translational Model for Cancer Therapy
Authors: Pinard Christopher J. , Lagree Andrew , Lu Fang-I , Klein Jonathan , Oblak Michelle L. , Salgado Roberto , Cardenas Juan Carlos Pinto , Brunetti Barbara , Muscatello Luisa Vera , Sarli Giuseppe , Foschini Maria Pia , Hardas Alexandros , Castillo Simon P. , AbdulJabbar Khalid , Yuan Yinyin , Moore David A. , Tran William T.
Published: October 2022

Despite the important role of preclinical experiments to characterize tumor biology and molecular pathways, there are ongoing challenges to model the tumor microenvironment, specifically the dynamic interactions between tumor cells and immune infiltrates. Comprehensive models of host-tumor immune interactions will enhance the development of emerging treatment strategies, such as immunotherapies. Although in vitro and murine models are important for the early modelling of cancer and treatment-response mechanisms, comparative research studies involving veterinary oncology may bridge the translational pathway to human studies. The natural progression of several malignancies in animals exhibits similar pathogenesis to human cancers, and previous studies have shown a relevant and evaluable immune system. Veterinary oncologists working alongside oncologists and cancer researchers have the potential to advance discovery. Understanding the host-tumor-immune interactions can accelerate drug and biomarker discovery in a clinically relevant setting. This review presents discoveries in comparative immuno-oncology and implications to cancer therapy.
MITF Is Regulated by Redox Signals Controlled by the Selenoprotein Thioredoxin Reductase 1
Authors: Kline Chelsey D. , Anderson Madeleine , Bassett John W. , Kent Gail , Berryman Rachel , Honeggar Matthew , Ito Shosuke , Wakamatsu Kazumasa , Indra Arup K. , Moos Philip J. , Leachman Sancy A. , Cassidy Pamela B.
Published: October 2022

TR1 and other selenoproteins have paradoxical effects in melanocytes and melanomas. Increasing selenoprotein activity with supplemental selenium in a mouse model of UV-induced melanoma prevents oxidative damage to melanocytes and delays melanoma tumor formation. However, TR1 itself is positively associated with progression in human melanomas and facilitates metastasis in melanoma xenografts. Here, we report that melanocytes expressing a microRNA directed against TR1 (TR1low) grow more slowly than control cell lines and contain significantly less melanin. This phenotype is associated with lower tyrosinase (TYR) activity and reduced transcription of tyrosinase-like protein-1 (TYRP1). Melanoma cells in which the TR1 gene (TXNRD1) was disrupted using Crispr/Cas9 showed more dramatic effects including the complete loss of the melanocyte-specific isoform of MITF; other MITF isoforms were unaffected. We provide evidence that TR1 depletion results in oxidation of MITF itself. This newly discovered mechanism for redox modification of MITF has profound implications for controlling both pigmentation and tumorigenesis in cells of the melanocyte lineage.
Prehabilitation in Modern Colorectal Cancer Surgery: A Comprehensive Review
Authors: Bausys Augustinas , Kryzauskas Marius , Abeciunas Vilius , Degutyte Austeja Elzbieta , Bausys Rimantas , Strupas Kestutis , Poskus Tomas
Published: October 2022

Colorectal cancer remains the third most prevalent cancer worldwide, exceeding 1.9 million new cases annually. Surgery continues to be the gold standard treatment option. Unfortunately, colorectal cancer surgery carries significant postoperative morbidity and mortality. Moreover, most rectal cancer patients and some patients with locally advanced colon cancer require preoperative neoadjuvant therapy. It improves long-term outcomes but impairs patients’ physical fitness and thus further increases surgical risk. Recently, prehabilitation has gained interest as a novel strategy to reduce treatment-related morbidity for patients undergoing colorectal cancer surgery. However, the concept is still in its infancy, and the role of prehabilitation remains controversial. In this comprehensive review, we sum up present evidence on prehabilitation before colorectal cancer surgery. Available studies are very heterogenous in interventions and investigated outcomes. Nonetheless, all trials show at least some positive effects of prehabilitation on patients’ physical, nutritional, or psychological status or even reduced postoperative morbidity. Unfortunately, the optimal prehabilitation program remains undetermined; therefore, this concept cannot be widely implemented. Future studies investigating optimal prehabilitation regimens for patients undergoing surgery for colorectal cancer are necessary.
Untargeted Metabolomics Exploration of the Growth Stage-Dependent Chemical Space of the Sclareol-Converting Biocatalyst Hyphozyma roseonigra
Authors: Ncube Efficient N. , Sitole Lungile , Steenkamp Paul A. , Steenkamp Lucia H. , Dubery Ian A.
Published: October 2022

Hyphozyma roseonigra is a dimorphic yeast used as a biocatalyst to convert sclareol, a plant diterpenoid to ambradiol. The latter is an intermediate in the synthesis of ambrafuran, a high-value chemical in the fragrance industry. Unfortunately, little is known about the underlying biochemistry of this microorganism. In this study, the integration of multi-platform-based metabolomics was used to better comprehend H. roseonigra from a biochemical perspective. The focus on metabolomic changes during growth and development was accomplished using untargeted LC–MS and NMR analyses. Cell suspensions were grown in batch culture over a 14-day period, and cells from the early-, log-, and stationary phases were harvested every second day using platform-compatible extraction procedures. Following chemometric analysis of LC–MS and NMR data acquired from both intra- and extracellular extracts, the identified discriminatory ions annotated from the endo- and exometabolomes (metabo-fingerprinting and metabo-footprinting) were found to fall predominantly in the primary metabolism class. Pathway mapping and feature-based network correlation analysis assisted in gaining insights into the active metabolic pathways during growth and development and did not flag terpene synthesis. This study provides novel insights into the basic metabolic capabilities of H. roseonigra and suggests that sclareol is metabolized as the detoxification of a hydrophobic xenobiotic compound.
The Effect of a Pex3 Mutation on Hearing and Lipid Content of the Inner Ear
Authors: Kochaj Rafael M. , Martelletti Elisa , Ingham Neil J. , Buniello Annalisa , Sousa Bebiana C. , Wakelam Michael J. O. , Lopez-Clavijo Andrea F. , Steel Karen P.
Published: October 2022

Peroxisome biogenesis disorders (due to PEX gene mutations) are associated with symptoms that range in severity and can lead to early childhood death, but a common feature is hearing impairment. In this study, mice carrying Pex3 mutations were found to show normal auditory development followed by an early-onset progressive increase in auditory response thresholds. The only structural defect detected in the cochlea at four weeks old was the disruption of synapses below inner hair cells. A conditional approach was used to establish that Pex3 expression is required locally within the cochlea for normal hearing, rather than hearing loss being due to systemic effects. A lipidomics analysis of the inner ear revealed a local reduction in plasmalogens in the Pex3 mouse mutants, comparable to the systemic plasmalogen reduction reported in human peroxisome biogenesis disorders. Thus, mice with Pex3 mutations may be a useful tool to understand the physiological basis of peroxisome biogenesis disorders.
Hematopoietic Cells Influence Vascular Development in the Retina
Authors: Asare-Bediako Bright , Adu-Agyeiwaah Yvonne , Abad Antonio , Li Calzi Sergio , Floyd Jason L. , Prasad Ram , DuPont Mariana , Asare-Bediako Richmond , Bustelo Xose R. , Grant Maria B.
Published: October 2022

Hematopoietic cells play a crucial role in the adult retina in health and disease. Monocytes, macrophages, microglia and myeloid angiogenic cells (MACs) have all been implicated in retinal pathology. However, the role that hematopoietic cells play in retinal development is understudied. The temporal changes in recruitment of hematopoietic cells into the developing retina and the phenotype of the recruited cells are not well understood. In this study, we used the hematopoietic cell-specific protein Vav1 to track and investigate hematopoietic cells in the developing retina. By flow cytometry and immunohistochemistry, we show that hematopoietic cells are present in the retina as early as P0, and include microglia, monocytes and MACs. Even before the formation of retinal blood vessels, hematopoietic cells localize to the inner retina where they eventually form networks that intimately associate with the developing vasculature. Loss of Vav1 lead to a reduction in the density of medium-sized vessels and an increased inflammatory response in retinal astrocytes. When pups were subjected to oxygen-induced retinopathy, hematopoietic cells maintained a close association with the vasculature and occasionally formed ‘frameworks’ for the generation of new vessels. Our study provides further evidence for the underappreciated role of hematopoietic cells in retinal vasculogenesis and the formation of a healthy retina.
Molecular Defense Response of Pine Trees (Pinus spp.) to the Parasitic Nematode Bursaphelenchus xylophilus
Authors: Modesto Inês , Mendes André , Carrasquinho Isabel , Miguel Célia M.
Published: October 2022

Pine wilt disease (PWD) is a severe environmental problem in Eastern Asia and Western Europe, devastating large forest areas and causing significant economic losses. This disease is caused by the pine wood nematode (PWN), Bursaphelenchus xylophilus, a parasitic migratory nematode that infects the stem of conifer trees. Here we review what is currently known about the molecular defense response in pine trees after infection with PWN, focusing on common responses in different species. By giving particular emphasis to resistance mechanisms reported for selected varieties and families, we identified shared genes and pathways associated with resistance, including the activation of oxidative stress response, cell wall lignification, and biosynthesis of terpenoids and phenylpropanoids. The role of post-transcriptional regulation by small RNAs in pine response to PWN infection is also discussed, as well as the possible implementation of innovative RNA-interference technologies, with a focus on trans-kingdom small RNAs. Finally, the defense response induced by elicitors applied to pine plants before PWN infection to prompt resistance is reviewed. Perspectives about the impact of these findings and future research approaches are discussed.
The Effect of Heat Shock on Myogenic Differentiation of Human Skeletal-Muscle-Derived Mesenchymal Stem/Stromal Cells
Authors: Mikšiūnas Rokas , Labeit Siegfried , Bironaitė Daiva
Published: October 2022

Muscle injuries, degenerative diseases and other lesions negatively affect functioning of human skeletomuscular system and thus quality of life. Therefore, the investigation of molecular mechanisms, stimulating myogenic differentiation of primary skeletal-muscle-derived mesenchymal stem/stromal cells (SM-MSCs), is actual and needed. The aim of the present study was to investigate the myogenic differentiation of CD56 (neural cell adhesion molecule, NCAM)-positive and -negative SM-MSCs and their response to the non-cytotoxic heat stimulus. The SM-MSCs were isolated from the post operation muscle tissue, sorted by flow cytometer according to the CD56 biomarker and morphology, surface profile, proliferation and myogenic differentiation has been investigated. Data show that CD56(+) cells were smaller in size, better proliferated and had significantly higher levels of CD146 (MCAM) and CD318 (CDCP1) compared with the CD56(−) cells. At control level, CD56(+) cells significantly more expressed myogenic differentiation markers MYOD1 and myogenin (MYOG) and better differentiated to the myogenic direction. The non-cytotoxic heat stimulus significantly stronger stimulated expression of myogenic markers in CD56(+) than in CD56(−) cells that correlated with the multinucleated cell formation. Data show that regenerative properties of CD56(+) SM-MSCs can be stimulated by an extracellular stimulus and be used as a promising skeletal muscle regenerating tool in vivo.