bluuebunny/crossref_metadata_2025 huggingface dataset:
The Prognostic Value of Platelet–Lymphocyte Ratio, Neutrophil–Lymphocyte Ratio, and Monocyte–Lymphocyte Ratio in Head and Neck Squamous Cell Carcinoma (HNSCC)—A Retrospective Single Center Study and a Literature Review
Authors: Mireștean Camil Ciprian , Stan Mihai Cosmin , Iancu Roxana Irina , Iancu Dragoș Petru Teodor , Bădulescu Florinel
Published: November 2023

Introduction: Neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and pallets-to-lymphocyte ratio (PLR) are currently validated as cheap and accessible biomarkers in different types of solid tumors, including head and neck cancers (HNC). The purpose of the study: To evaluate the possible purposes and biomarker value of NLR, PLR, and MLR recorded pre-treatment (radiotherapy/chemotherapy) in HNC. Materials and methods: From 190 patients with HNC included in the oncology records in the oncology outpatient clinic of the Craiova County Emergency Hospital (from January 2002 to December 2022), 39 cases met the inclusion criteria (squamous cell carcinoma and the possibility to calculate the pre-treatment (chemotherapy/radiotherapy) value of NLR, PLR, and MLR. Overall survival (OS) values were correlated with NLR, PLR, and MLR. Results: The median values for NLR, PLR, and MLR were 6.15 (1.24–69), 200.79 (61.3–1775.0), and 0.53 (0.12–5.5), respectively. In the study, the mean values for NLR, PLR, and MLR of 2.88, 142.97, and 0.36, respectively, were obtained. The median OS in the study group was 11 months (1–120). Although a negative Pearson’s correlation was present, the relationship between the variables was only weak, with values of R = 0.07, p = 0.67, R = 0.02, p = 0.31, and R = 0.07, p = 0.62 being related to NLR, PLR, and MLR, respectively, in correlation with OS. The median values of NLR, PLR, and MLR were calculated (1.53, 90.32, and 0.18, respectively) for the HNC cases with pre-treatment values of NLR < 2 and for the HNC cases with NLR values ≥ 6 (23.5, 232.78, and 0.79, respectively). The median OS for cases with NLR < 2 and NLR ≥ 6 were 17.4 and 13 months, respectively. Conclusions: The comparative analysis of the data highlights a benefit to OS for cases low values of NLR. The role of not only borderline NLR values (between 2 and 6) as a prognostic marker in HNSCC but also the inclusion of PLR and MLR in a prognostic score must also be defined in the future. Prospective studies with more uniformly selected inclusion criteria could demonstrate the value of pre-treatment NLR, PLR, and MLR for treatment stratification through the intensification or de-escalation of non-surgical curative treatment in HNSCC.
Clustering-Based Multi-Region Coverage-Path Planning of Heterogeneous UAVs
Authors: Xiao Peng , Li Ni , Xie Feng , Ni Haihong , Zhang Min , Wang Ban
Published: November 2023

Unmanned aerial vehicles (UAVs) multi-area coverage-path planning has a broad range of applications in agricultural mapping and military reconnaissance. Compared to homogeneous UAVs, heterogeneous UAVs have higher application value due to their superior flexibility and efficiency. Nevertheless, variations in performance parameters among heterogeneous UAVs can significantly amplify computational complexity, posing challenges to solving the multi-region coverage path-planning problem. Consequently, this study studies a clustering-based method to tackle the multi-region coverage path-planning problem of heterogeneous UAVs. First, the constraints necessary during the planning process are analyzed, and a planning formula based on an integer linear programming model is established. Subsequently, this problem is decomposed into regional allocation and visiting order optimization subproblems. This study proposes a novel clustering algorithm that utilizes centroid iteration and spatiotemporal similarity to allocate regions and adopts the nearest-to-end policy to optimize the visiting order. Additionally, a distance-based bilateral shortest-selection strategy is proposed to generate region-scanning trajectories, which serve as trajectory references for real flight. Simulation results in this study prove the effective performance of the proposed clustering algorithm and region-scanning strategy.
Supported Open Learning and Decoloniality: Critical Reflections on Three Case Studies
Authors: Farrow Robert , Coughlan Tim , Goshtasbpour Fereshte , Pitt Beck
Published: November 2023

Open education has been highlighted as a route to social justice and decolonisation. This paper presents reflections on decolonisation processes pertaining to three educational technology projects conducted in Sub-Saharan Africa, Myanmar and Kenya, each of which featured contributions by The Open University (UK). Through recognising the importance of under-represented Global South perspectives, we consciously and critically reflect on our cases from a Global North framing to assess the extent to which the Supported Open Learning (SOL) model for engagement supports decolonisation and related processes. We use the categories of coloniality of being, coloniality of power, and coloniality of knowledge to structure our reflections. As open educational practice (OEP), the SOL model can offer a practical approach which emphasises equity and inclusion. SOL involves both an ethos and a set of pedagogical practices. This can support meaningful critical reflection and exchange while offering a pragmatic approach to the delivery of educational technology initiatives. In conclusion, a framework mapping features of SOL and their relation to decoloniality is offered.
The Cultural Impact of Video Games: A Systematic Review of the Literature
Authors: Cerezo-Pizarro Mario , Revuelta-Domínguez Francisco-Ignacio , Guerra-Antequera Jorge , Melo-Sánchez Jairo
Published: November 2023

The growing relevance of video games in the social landscape requires an in-depth evaluation of the bidirectional influences of these adjacent contexts, among which the educational and cultural contexts stand out. This permeability allows the study of the cultural aspects surrounding the production and use of video games as tools for cultural dissemination. Our research enunciates, recognises, analyses and evaluates the impact of these tools with the aim of being taken into consideration by the scientific community and the general population, who most frequently consume, use and socialise through video games around the world. Based on this, a systematic literature review (SLR) was carried out using the Prisma 2020 Protocol, using the WOS and SCOPUS databases as documentary sources, and the selection of research articles that explore the cultural aspects of video games according to pre-established criteria. The final sample (N = 45) was subjected to a study that posed 12 research questions around which this work is structured. As a result, it is evident that video games have a direct impact on the transmission of culture. Patterns and agents of cultural representation, transmission and communication were identified, allowing researchers to evaluate the impact of video games on culture and to approach this object of study from an academic perspective, helping to open up other lines of research related to the influence of video games on the assimilation of culture, the learning of relevant issues related to it or the transmission of specific cultural elements.
An Evaluation of Directive-Based Parallelization on the GPU Using a Parboil Benchmark
Authors: Đukić Jovan , Mišić Marko
Published: November 2023

Heterogeneous architectures consisting of both central processing units and graphics processing units are common in contemporary computer systems. For that reason, several programming models have been developed to exploit available parallelism, such as low-level CUDA and OpenCL, and directive-based OpenMP and OpenACC. In this paper we explore and evaluate the applicability of OpenACC, which is a directive-based programming model for GPUs. We focus both on the performance and programming effort needed to parallelize the existing sequential algorithms for GPU execution. The evaluation is based on the benchmark suite Parboil, which consists of 11 different mini-applications from different scientific domains, both compute- and memory-bound. The results show that mini-apps parallelized with OpenACC can achieve significant speedups over sequential implementations and in some cases, even outperform CUDA implementations. Furthermore, there is less of a programming effort compared to low-level models, such as CUDA and OpenCL, because a majority of the work is left to the compiler and overall, the code needs less restructuring.
Alternatives for Transport, Storage in Port and Bunkering Systems for Offshore Energy to Green Hydrogen
Authors: Saborit Enrique , García-Rosales Vazquez Eduardo , Storch de Gracia Calvo M. Dolores , Rodado Nieto Gema María , Martínez Fondón Pablo , Abánades Alberto
Published: November 2023

Offshore electricity production, mainly by wind turbines, and, eventually, floating PV, is expected to increase renewable energy generation and their dispatchability. In this sense, a significant part of this offshore electricity would be directly used for hydrogen generation. The integration of offshore energy production into the hydrogen economy is of paramount importance for both the techno-economic viability of offshore energy generation and the hydrogen economy. An analysis of this integration is presented. The analysis includes a discussion about the current state of the art of hydrogen pipelines and subsea cables, as well as the storage and bunkering system that is needed on shore to deliver hydrogen and derivatives. This analysis extends the scope of most of the previous works that consider port-to-port transport, while we report offshore to port. Such storage and bunkering will allow access to local and continental energy networks, as well as to integrate offshore facilities for the delivery of decarbonized fuel for the maritime sector. The results of such state of the art suggest that the main options for the transport of offshore energy for the production of hydrogen and hydrogenated vectors are through direct electricity transport by subsea cables to produce hydrogen onshore, or hydrogen transport by subsea pipeline. A parametric analysis of both alternatives, focused on cost estimates of each infrastructure (cable/pipeline) and shipping has been carried out versus the total amount of energy to transport and distance to shore. For low capacity (100 GWh/y), an electric subsea cable is the best option. For high-capacity renewable offshore plants (TWh/y), pipelines start to be competitive for distances above approx. 750 km. Cost is highly dependent on the distance to land, ranging from 35 to 200 USD/MWh.
Assessment of Current Smart House Solutions: The Case of Portugal
Authors: Rego Nuno , Castro Rui , Silva Carlos Santos
Published: November 2023

The world is facing many challenges to keep up with growing energy demand and greenhouse gas and pollutant emissions. A possible solution is to integrate renewable energy sources (RESs) into residences and create energy management systems (EMSs) that reduce consumption and relieve the main grid in critical hours. This paper is focused on analyzing different EMSs using solar photovoltaic (PV) modules and three energy storage systems (ESSs) to increase savings without affecting the user’s needs, with thirty-three power consumption profiles and three energy tariffs over a 25-year investment to compare which solution presents the best economic result in each of the 297 analyzed scenarios. The results show that the higher the overall daily consumption values, the greater the profits for all EMSs. The lowest demand profiles lead to the best self-consumption and self-sufficiency results. PV-only systems with a tri-hourly tariff have the best overall results. In the case of battery operation, each case should be carefully analyzed in order to choose the correct technologies and tariff. The results also allowed us to verify that even though having more PV modules generates more energy, it can make a project less economically desirable.
AAEM Species Migration/Transformation during Co-Combustion of Carbonaceous Feedstocks and Synergy Behavior on Co-Combustion Reactivity: A Critical Review
Authors: Jiao Yue , Tian Lina , Yu Shu , Song Xudong , Wu Zhiliang , Wei Juntao , Xu Jie
Published: November 2023

Co-combustion is a crucial route for the high-efficiency utilization and clean conversion of different carbonaceous feedstocks (biomass, coal, petroleum coke, etc.). The migration and transformation of alkali and alkaline earth metals (AAEMs) are not only related to ash-related issues in actual application, but also directly affect the reaction behavior of binary particles during co-conversion. This review paper summarizes research progress in the detection methods (online and offline) and influencing factors (feedstock type, feedstock blending ratio, reaction temperature, reaction time) of AAEMs migration and transformation during the co-combustion of carbonaceous feedstocks. Furthermore, it provides a detailed summary of research progress on factors (feedstock blending ratio, heating rate, etc.) influencing the co-combustion reactivity of carbonaceous feedstocks, synergy behavior, and its mechanisms. The influence of feedstock type on AAEMs migration and transformation during co-combustion is mainly related to the composition categories, chemical forms and contents of intrinsic mineral in binary feedstocks. The increase in the combustion temperature will intensify the release of inherent AAEMs in carbonaceous feedstocks, and promote AAEM deactivation. For high K and Cl-containing biomass, a higher biomass proportion in blends would result in more AAEMs release during the co-combustion process. Conversely, an increase in coal proportion in blends will directly favor the reduction or inhibition of AAEMs release. Synergy behavior during co-pyrolysis and subsequent char co-combustion is usually presented as an inhibition effect and an synergistic effect, respectively. The synergistic mechanisms of carbonaceous feedstock co-combustion reactions can be divided into two categories: non-catalytic synergistic mechanisms related to the excitation and migration of biomass-based free radicals and catalytic synergistic mechanisms related to biomass-based AAEMs catalysis. Additionally, future research prospects are also proposed based on the systematic review.
The Use of Coherence Functions of Acoustic Emission Signals as a Method for Diagnosing Wind Turbine Blades
Authors: Bejger Artur , Drzewieniecki Jan Bohdan , Bartoszko Przemysław , Frank Ewelina
Published: November 2023

Acoustic emission (AE) is one of the methods of non-destructive evaluation (NDE), and functions by means of detecting elastic waves caused by dynamic movements in AE sources, such as cracking in various material structures. In the case of offshore wind turbines, the most vulnerable components are their blades. Therefore, the authors proposed a method using AE to diagnose wind turbine blades. In the identification of their condition during monitoring, it was noted that the changes characterising blade damage involve non-linear phenomena; hence, wave phenomena do not occur in the principal components of the amplitudes or their harmonics. When the authors used the inverse transformation in the signal analysis process, which essentially leads to finding a signal measure, it allowed them to distinguish the wave spectrum of an undamaged system from one in which the material structure of the blade was damaged. The characteristic frequencies of individual phenomena interacting with the blade of a working turbine provide the basis for the introduction of filters (or narrowband sensors) that will increase the quality of the diagnosis itself. Considering the above, the use of the coherence function was proposed as an important measure of a diagnostic signal, reflecting a given condition of the blade.
Enhanced Performance in PMSG-Based Wind Turbine Systems: Experimental Validation of Adaptive Backstepping Control Design
Authors: Mourabit Youness El , Salime Hassna , Bossoufi Badre , Motahhir Saad , Derouich Aziz , Mobayen Saleh , Zhilenkov Anton
Published: November 2023

Ensuring the quality and stability of the electrical grid is of utmost importance during the phase of electrical energy production. As wind energy plays an increasingly significant role in a country’s energy composition, maintaining stability and optimal quality has emerged as a prerequisite for the generated electricity. This article aims to devise a dynamic nonlinear algorithm that can be implemented in the wind energy conversion system (WECS) featuring a direct-drive permanent magnet synchronous generator (PMSG). Notably, the adaptive backstepping control relies on the nonlinear model of the controlled system. It harnesses the principles of the Lyapunov stability theory to regulate various parameters and uphold the overall system’s stability. Employing simulation analysis through the Matlab–Simulink environment, the proposed control strategy is evaluated using a 1.5 MW wind turbine. The results showcase the robust capability of the suggested control algorithm: it effectively maintains the DC bus voltage and produces high-quality electrical energy with a total harmonic distortion (THD) below 0.38%. Moreover, the algorithm demonstrates added resilience. The practical viability of the adaptive control algorithm is validated through an experimental study on the dSPACE DS1104 prototyping platform. This study underscores the algorithm’s proficiency in achieving all control objectives under diverse wind scenarios.
Cell-Free Supernatant of Lactiplantibacillus plantarum 90: A Clean Label Strategy to Improve the Shelf Life of Ground Beef Gel and Its Bacteriostatic Mechanism
Authors: Wang Jing , Xu Lilan , Gu Luping , Lv Yuanqi , Li Junhua , Yang Yanjun , Meng Xiangren
Published: November 2023

Lactic acid bacteria metabolites can be used as a clean-label strategy for meat products due to their “natural” and antibacterial properties. In this study, the feasibility of using cell-free supernatant of Lactiplantibacillus plantarum 90 (LCFS) as a natural antibacterial agent in ground beef was investigated. The sensitivity of LCFS to pH, heat and protease, as well as the changes of enzyme activities of alkaline phosphatase (AKP) and Na+/K+-ATP together with the morphology of indicator bacteria after LCFS treatment, were analyzed to further explore the antibacterial mechanism of LCFS. The results showed that the addition of 0.5% LCFS inhibited the growth of microorganisms in the ground beef gel and extended its shelf-life without affecting the pH, cooking loss, color and texture characteristics of the product. In addition, the antibacterial effect of LCFS was the result of the interaction of organic acids and protein antibacterial substances in destroying cell structures (cell membrane, etc.) to achieve the purpose of bacteriostasis. This study provides a theoretical basis for the application of LCFS in meat products and a new clean-label strategy for the food industry.
Additive-Free Method for Enhancing the Volume Phase Transition Rate in Light-Responsive Hydrogels: A Study of Micro-Nano Bubble Water on PNIPAM-co-AAc Hydrogels
Authors: Kuroki Saho , Kubota Masaya , Haraguchi Ryota , Oishi Yushi , Narita Takayuki
Published: November 2023

Light-responsive hydrogels containing light-thermal convertible pigments have received interest for their possible applications in light-responsive shutters, valves, drug delivery systems, etc. However, their utility is limited by the slow response time. In this study, we investigated the use of micro-nano bubble water as a preparation solvent to accelerate the volume phase transition kinetics of poly(N-isopropylacrylamide-co-acrylic acid) (PNIPAM-co-AAc) hydrogels. The hydrogels were characterized by dynamic light scattering (DLS) and dissolved oxygen (DO) measurements. The mechanical properties, surface morphology, and chemical composition of the hydrogels were analyzed by Young’s modulus measurements, scanning electron microscopy (SEM), and Fourier transform infrared (FT-IR) spectroscopy, respectively. The results showed that hydrogels prepared with bubble water changed the volume transition rate by more than two orders of magnitude by simply changing the standing time of the bubble water for only a few hours. The cooperative diffusion coefficients obtained from the light-induced volume transition kinetics correlated linearly with Young’s modulus and metastable state swelling ratio. Our results suggest that bubbles act as efficient water channels, thereby modulating the response rate and providing a simple, additive-free method for preparing hydrogels with a wide range of response rates.
Ion Partition in Polyelectrolyte Gels and Nanogels
Authors: Chremos Alexandros , Mussel Matan , Douglas Jack F. , Horkay Ferenc
Published: November 2023

Polyelectrolyte gels provide a load-bearing structural framework for many macroscopic biological tissues, along with the organelles within the cells composing tissues and the extracellular matrices linking the cells at a larger length scale than the cells. In addition, they also provide a medium for the selective transportation and sequestration of ions and molecules necessary for life. Motivated by these diverse problems, we focus on modeling ion partitioning in polyelectrolyte gels immersed in a solution with a single type of ionic valence, i.e., monovalent or divalent salts. Specifically, we investigate the distribution of ions inside the gel structure and compare it with the bulk, i.e., away from the gel structure. In this first exploratory study, we neglect solvation effects in our gel by modeling the gels without an explicit solvent description, with the understanding that such an approach may be inadequate for describing ion partitioning in real polyelectrolyte gels. We see that this type of model is nonetheless a natural reference point for considering gels with solvation. Based on our idealized polymer network model without explicit solvent, we find that the ion partition coefficients scale with the salt concentration, and the ion partition coefficient for divalent ions is higher than for monovalent ions over a wide range of Bjerrum length (lB) values. For gels having both monovalent and divalent salts, we find that divalent ions exhibit higher ion partition coefficients than monovalent salt for low divalent salt concentrations and low lB. However, we also find evidence that the neglect of an explicit solvent, and thus solvation, provides an inadequate description when compared to experimental observations. Thus, in future work, we must consider both ion and polymer solvation to obtain a more realistic description of ion partitioning in polyelectrolyte gels.
Endodontic Dentistry: Analysis of Dentinal Stress and Strain Development during Shaping of Curved Root Canals
Authors: Iosif Laura , Dimitriu Bogdan , Niţoi Dan Florin , Amza Oana
Published: November 2023

Background: Endodontic shaping causes stress and strain in the root canal dentin. Dentin microcracks have the potential to be later followed by root fractures occurring under the occlusal load. The aim of our research was to theoretically determine the values of such dentinal states of stress and strain during the endodontic shaping of curved root canals using finite element analysis (FEA). Methods: To highlight the stress concentrations in dentin, two geometric models were created considering the volume of the curved dental root and the contact between the endodontic file and the root canal walls. The application of forces with different values was simulated both on a uniform curved root canal and on a root canal with an apical third curvature of 25° as they would be applied during the preparation of a root canal. Results: In the case of the first model, which was acted upon with a force of 5 N, the deformations of the root canal appeared along the entire working length, reaching the highest values in the apical third of the root, although there were no geometric changes in the shape of the root canal. Regarding the second root model, with an apical third curvature of 25°, although the applied force was 2 N, the deformations were accompanied by geometric changes in the shape of the root, especially in the upper part of the apical third. At a higher force of 7 N exerted on the endodontic file, the geometric shape changed, and the deformation reached extreme critical values. The resulting tensile stresses appearing in the experimental structure varied similarly to the deformations. Conclusions: Significant stress and strain can develop, especially in the apical third of curved root canals during their shaping, and the risk of cracks is higher for endodontically treated teeth presenting severe curvatures in the apical third of the root.
Genes, Genetics and Breeding of Tomato
Authors: Ge Pingfei , Zhang Yuyang
Published: November 2023

Tomato (Solanum lycopersicum) is widely cultivated and is one of the most important vegetable crops in the world, with great economic significance [...]
Alcohol Prevention in Urgent and Emergency Care (APUEC): Development and Evaluation of Workforce Digital Training on Screening, Brief Intervention, and Referral for Treatment
Authors: Blake Holly , Adams Emma J. , Chaplin Wendy J. , Morris Lucy , Mahmood Ikra , Taylor Michael G. , Langmack Gillian , Jones Lydia , Miller Philip , Coffey Frank
Published: November 2023

Excessive alcohol consumption carries a significant health, social and economic burden. Screening, brief intervention and referral to treatment (SBIRT) is one approach to identifying patients with excessive alcohol consumption and providing interventions to help them reduce their drinking. However, healthcare workers in urgent and emergency care settings do not routinely integrate SBIRT into clinical practice and raise a lack of training as a barrier to SBIRT delivery. Therefore, “Alcohol Prevention in Urgent and Emergency Care” (APUEC) training was developed, delivered, and evaluated. APUEC is a brief, stand-alone, multimedia, interactive digital training package for healthcare workers. The aim of APUEC is to increase positive attitudes, knowledge, confidence and skills related to SBIRT through the provision of (a) education on the impact of alcohol and the role of urgent and emergency care in alcohol prevention, and (b) practical guidance on patient assessment, delivery of brief advice and making referral decisions. Development involved collaborative–participatory design approaches and a rigorous six-step ASPIRE methodology (involving n = 28 contributors). APUEC was delivered to healthcare workers who completed an online survey (n = 18) and then participated in individual qualitative interviews (n = 15). Analysis of data was aligned with Levels 1–3 of the Kirkpatrick Model of Training Evaluation. Survey data showed that all participants (100%) found the training useful and would recommend it to others. Insights from the qualitative data showed that APUEC digital training increases healthcare workers’ perceived knowledge, confidence and skills related to alcohol prevention in urgent and emergency care settings. Participants viewed APUEC to be engaging and relevant to urgent and emergency care workers. This digital training was perceived to be useful for workforce skills development and supporting the implementation of SBIRT in clinical practice. While the impact of APUEC on clinician behaviour and patient outcomes is yet to be tested, APUEC digital training could easily be embedded within education and continuing professional development programmes for healthcare workers and healthcare trainees of any discipline. Ultimately, this may facilitate the integration of SBIRT into routine care and contribute to population health improvement.
Prostate-Specific Membrane Antigen (PSMA) Expression Predicts Need for Early Treatment in Prostate Cancer Patients Managed with Active Surveillance
Authors: Ahmadi Elham , Wang Simon , Gouran-Savadkoohi Mohammad , Douvi Georgia , Isfahanian Naghmeh , Tsakiridis Nicole , Faught Brent E. , Cutz Jean-Claude , Sur Monalisa , Chawla Satish , Pond Gregory R. , Steinberg Gregory R. , Brown Ian , Tsakiridis Theodoros
Published: November 2023

Metabolic dysregulation is an early event in carcinogenesis. Here, we examined the expression of enzymes involved in de novo lipogenesis (ATP-citrate lyase: ACLY), glucose uptake (Glucose Transporter 1: GLUT1), and folate–glutamate metabolism (Prostate-Specific Membrane Antigen: PSMA) as potential biomarkers of risk for early prostate cancer progression. Patients who were managed initially on active surveillance with a Gleason score of 6 or a low-volume Gleason score of 7 (3 + 4) were accrued from a prostate cancer diagnostic assessment program. Patients were asked to donate their baseline diagnostic biopsy tissues and permit access to their clinical data. PSMA, GLUT1, and ACLY expression were examined with immunohistochemistry (IHC) in baseline biopsies, quantitated by Histologic Score for expression in benign and malignant glands, and compared with patient time remaining on active surveillance (time-on-AS). All three markers showed trends for elevated expression in malignant compared to benign glands, which was statistically significant for ACLY. On univariate analysis, increased PSMA and GLUT1 expression in malignant glands was associated with shorter time-on-AS (HR: 5.06, [CI 95%: 1.83–13.94] and HR: 2.44, [CI 95%: 1.10–5.44], respectively). Malignant ACLY and benign gland PSMA and GLUT1 expression showed non-significant trends for such association. On multivariate analysis, overexpression of PSMA in malignant glands was an independent predictor of early PC progression (p = 0.006). This work suggests that the expression of metabolic enzymes determined by IHC on baseline diagnostic prostate biopsies may have value as biomarkers of risk for rapid PC progression. PSMA may be an independent predictor of risk for progression and should be investigated further in systematic studies.
Data Mining Suggests That CXCL14 Gene Silencing in Colon Cancer Is Due to Promoter Methylation
Authors: Wang Yanjing , Wang Siyi , Niu Yuchen , Ma Buyong , Li Jingjing
Published: November 2023

CXCL14 is one of the most evolutionarily conserved members of the chemokine family and is constitutionally expressed in multiple organs, suggesting that it is involved in the homeostasis maintenance of the system. CXCL14 is highly expressed in colon epithelial cells and shows obvious gene silencing in clinical colon cancer samples, suggesting that its silencing is related to the immune escape of cancer cells. In this paper, we analyzed the expression profiles of multiple human clinical colon cancer datasets and mouse colon cancer models to reveal the variation trend of CXCL14 expression during colitis, colon polyps, primary colon cancer, and liver metastases. The relationship between CXCL14 gene silencing and promoter hypermethylation was revealed through the colorectal carcinoma methylation database. The results suggest that CXCL14 is a tumor suppressor gene in colorectal carcinoma which is activated first and then silenced during the process of tumor occurrence and deterioration. Promoter hypermethylation is the main cause of CXCL14 silencing. The methylation level of CXCL14 is correlated with the anatomic site of tumor occurrence, positively correlated with patient age, and associated with prognosis. Reversing the hypermethylation of CXCL14 may be an epigenetic therapy for colon cancer.
Estrobolome and Hepatocellular Adenomas—Connecting the Dots of the Gut Microbial β-Glucuronidase Pathway as a Metabolic Link
Authors: Bucurica Sandica , Lupanciuc Mihaela , Ionita-Radu Florentina , Stefan Ion , Munteanu Alice Elena , Anghel Daniela , Jinga Mariana , Gaman Elena Laura
Published: November 2023

Hepatocellular adenomas are benign endothelial tumors of the liver, mostly associated with female individual users of estrogen-containing medications. However, the precise factors underlying the selective development of hepatic adenomas in certain females remain elusive. Additionally, the conventional profile of individuals prone to hepatic adenoma is changing. Notably, male patients exhibit a higher risk of malignant progression of hepatocellular adenomas, and there are instances where hepatic adenomas have no identifiable cause. In this paper, we theorize the role of the human gastrointestinal microbiota, specifically, of bacterial species producing β-glucuronidase enzymes, in the development of hepatic adenomas through the estrogen recycling pathway. Furthermore, we aim to address some of the existing gaps in our knowledge of pathophysiological pathways which are not yet subject to research or need to be studied further. As microbial β-glucuronidases proteins recycle estrogen and facilitate the conversion of inactive estrogen into its active form, this process results in elevated levels of unbound plasmatic estrogen, leading to extended exposure to estrogen. We suggest that an imbalance in the estrobolome could contribute to sex hormone disease evolution and, consequently, to the advancement of hepatocellular adenomas, which are estrogen related.
Development of Apoptotic-Cell-Inspired Antibody–Drug Conjugate for Effective Immune Modulation
Authors: Lee Gyeongwoo , Iwase Taishu , Matsumoto Shunsuke , Nabil Ahmed , Ebara Mitsuhiro
Published: November 2023

Background: Apoptotic cells’ phosphoserine (PS) groups have a significant immunosuppressive effect. They inhibit proinflammatory signals by interacting with various immune cells, including macrophages, dendritic cells, and CD4+ cells. Previously, we synthesized PS-group-immobilized polymers and verified their immunomodulatory effects. Despite its confirmed immunomodulatory potential, the PS group has not been considered as a payload for antibody–drug conjugates (ADCs) in a targeted anti-inflammatory approach. Aim: We conducted this research to introduce an apoptotic-cell-inspired antibody–drug conjugate for effective immunomodulation. Method: Poly(2-hydroxyethyl methacrylate-co-2-methacryloyloxyethyl phosphorylserine) (p(HEMA-co-MPS)) was synthesized as a payload using RAFT polymerization, and goat anti-mouse IgG was selected as a model antibody, which was conjugated with the synthesized p(HEMA-co-MPS) via 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-Hydroxysuccinimide (EDC/NHS) reaction. The antibody-binding affinity, anti-inflammatory potential, and cytotoxicity measurements were evaluated. Results: We successfully synthesized ADCs with a significant anti-inflammatory effect and optimized the antibody–polymer ratio to achieve the highest antibody-binding affinity. Conclusion: We successfully introduced p(HEMA-co-MPS) to IgG without decreasing the anti-inflammatory potential of the polymer while maintaining its targeting ability. We suggest that the antibody–polymer ratio be appropriately adjusted for effective therapy. In the future, this technology can be applied to therapeutic antibodies, such as Tocilizumab or Abatacept.
Mesenchymal Stem Cells in the Pathogenesis and Therapy of Autoimmune and Autoinflammatory Diseases
Authors: Zaripova Lina N. , Midgley Angela , Christmas Stephen E. , Beresford Michael W. , Pain Clare , Baildam Eileen M. , Oldershaw Rachel A.
Published: November 2023

Mesenchymal stem cells (MSCs) modulate immune responses and maintain self-tolerance. Their trophic activities and regenerative properties make them potential immunosuppressants for treating autoimmune and autoinflammatory diseases. MSCs are drawn to sites of injury and inflammation where they can both reduce inflammation and contribute to tissue regeneration. An increased understanding of the role of MSCs in the development and progression of autoimmune disorders has revealed that MSCs are passive targets in the inflammatory process, becoming impaired by it and exhibiting loss of immunomodulatory activity. MSCs have been considered as potential novel cell therapies for severe autoimmune and autoinflammatory diseases, which at present have only disease modifying rather than curative treatment options. MSCs are emerging as potential therapies for severe autoimmune and autoinflammatory diseases. Clinical application of MSCs in rare cases of severe disease in which other existing treatment modalities have failed, have demonstrated potential use in treating multiple diseases, including rheumatoid arthritis, systemic lupus erythematosus, myocardial infarction, liver cirrhosis, spinal cord injury, multiple sclerosis, and COVID-19 pneumonia. This review explores the biological mechanisms behind the role of MSCs in autoimmune and autoinflammatory diseases. It also covers their immunomodulatory capabilities, potential therapeutic applications, and the challenges and risks associated with MSC therapy.
Evaluation of the Allelic Variations in Vernalisation (VRN1) and Photoperiod (PPD1) Genes and Genetic Diversity in a Spanish Spelt Wheat Collection
Authors: Palomino Carmen , Cabrera Adoración
Published: November 2023

Allelic variation within genes controlling the vernalisation requirement (VRN1) and photoperiod response (PPD1) determines the adaptation of wheat to different environmental growing conditions as well as influences other traits related to grain yield. This study aimed to screen a Spanish spelt wheat collection using gene-specific molecular markers for VRN-A1, VRN-B1, VRN-D1, and PPD-D1 loci and to phenotype for heading date (HD) in both field and greenhouse experiments under a long photoperiod and without vernalisation. Fifty-five spelt genotypes (91.7%) exhibited a spring growth habit, and all of them carried at least one dominant VRN1 allele, whereas five (8.3%) genotypes had a winter growth habit, and they carried the triple recessive allele combination. The Vrn-D1s was the most frequent allele in the studied set of spelt accessions, and it was found in combination with both the dominant Vrn-A1b and/or Vrn-B1a alleles in 88.3% of the spelt accessions tested. All spelt accessions carried the photoperiod-sensitive Ppd-D1b allele, which may explain the late heading of spelt germplasm compared to the commercial spring bread wheat Setenil used as a control. The least significant difference test showed significant differences between allelic combinations, the earliest accessions being those carrying two or three dominant alleles, followed by the one-gene combinations. In addition, the genetic diversity was evaluated through capillary electrophoresis using 15 wheat simple sequence repeat (SSR) markers. Most markers had high levels of polymorphism, producing 95 different alleles which ranged between 53 and 279 bp in size. Based on the polymorphic information content values obtained (from 0.51 to 0.97), 12 out of the 15 SSRs were catalogued as informative markers (values > 0.5). According to the dendrogram generated, the spelt accessions clustered as a separate group from the commercial bread wheat Setenil. Knowledge of VRN1 and PPD1 alleles, heading time, and genetic variability using SSR markers is valuable for spelt wheat breeding programs.
In Silico Exploration of the Trypanothione Reductase (TryR) of L. mexicana
Authors: Barrera-Téllez Francisco J. , Prieto-Martínez Fernando D. , Hernández-Campos Alicia , Martínez-Mayorga Karina , Castillo-Bocanegra Rafael
Published: November 2023

Human leishmaniasis is a neglected tropical disease which affects nearly 1.5 million people every year, with Mexico being an important endemic region. One of the major defense mechanisms of these parasites is based in the polyamine metabolic pathway, as it provides the necessary compounds for its survival. Among the enzymes in this route, trypanothione reductase (TryR), an oxidoreductase enzyme, is crucial for the Leishmania genus’ survival against oxidative stress. Thus, it poses as an attractive drug target, yet due to the size and features of its catalytic pocket, modeling techniques such as molecular docking focusing on that region is not convenient. Herein, we present a computational study using several structure-based approaches to assess the druggability of TryR from L. mexicana, the predominant Leishmania species in Mexico, beyond its catalytic site. Using this consensus methodology, three relevant pockets were found, of which the one we call σ-site promises to be the most favorable one. These findings may help the design of new drugs of trypanothione-related diseases.
A Multi-Omics Approach Revealed Common Dysregulated Pathways in Type One and Type Two Endometrial Cancers
Authors: Capaci Valeria , Monasta Lorenzo , Aloisio Michelangelo , Sommella Eduardo , Salviati Emanuela , Campiglia Pietro , Basilicata Manuela Giovanna , Kharrat Feras , Licastro Danilo , Di Lorenzo Giovanni , Romano Federico , Ricci Giuseppe , Ura Blendi
Published: November 2023

Endometrial cancer (EC) is the most frequent gynecologic cancer in postmenopausal women. Pathogenetic mechanisms that are related to the onset and progression of the disease are largely still unknown. A multi-omics strategy can help identify altered pathways that could be targeted for improving therapeutical approaches. In this study we used a multi-omics approach on four EC cell lines for the identification of common dysregulated pathways in type 1 and 2 ECs. We analyzed proteomics and metabolomics of AN3CA, HEC1A, KLE and ISHIKAWA cell lines by mass spectrometry. The bioinformatic analysis identified 22 common pathways that are in common with both types of EC. In addition, we identified five proteins and 13 metabolites common to both types of EC. Western blotting analysis on 10 patients with type 1 and type 2 EC and 10 endometria samples confirmed the altered abundance of NPEPPS. Our multi-omics analysis identified dysregulated proteins and metabolites involved in EC tumor growth. Further studies are needed to understand the role of these molecules in EC. Our data can shed light on common pathways to better understand the mechanisms involved in the development and growth of EC, especially for the development of new therapies.
Drug-Induced Conformational Dynamics of P-Glycoprotein Underlies the Transport of Camptothecin Analogs
Authors: Mensah Gershon A. K. , Schaefer Katherine G. , Bartlett Michael G. , Roberts Arthur G. , King Gavin M.
Published: November 2023

P-glycoprotein (Pgp) plays a pivotal role in drug bioavailability and multi-drug resistance development. Understanding the protein’s activity and designing effective drugs require insight into the mechanisms underlying Pgp-mediated transport of xenobiotics. In this study, we investigated the drug-induced conformational changes in Pgp and adopted a conformationally-gated model to elucidate the Pgp-mediated transport of camptothecin analogs (CPTs). While Pgp displays a wide range of conformations, we simplified it into three model states: ‘open-inward’, ‘open-outward’, and ‘intermediate’. Utilizing acrylamide quenching of Pgp fluorescence as a tool to examine the protein’s tertiary structure, we observed that topotecan (TPT), SN-38, and irinotecan (IRT) induced distinct conformational shifts in the protein. TPT caused a substantial shift akin to AMPPNP, suggesting ATP-independent ‘open-outward’ conformation. IRT and SN-38 had relatively moderate effects on the conformation of Pgp. Experimental atomic force microscopy (AFM) imaging supports these findings. Further, the rate of ATPase hydrolysis was correlated with ligand-induced Pgp conformational changes. We hypothesize that the separation between the nucleotide-binding domains (NBDs) creates a conformational barrier for substrate transport. Substrates that reduce the conformational barrier, like TPT, are better transported. The affinity for ATP extracted from Pgp-mediated ATP hydrolysis kinetics curves for TPT was about 2-fold and 3-fold higher than SN-38 and IRT, respectively. On the contrary, the dissociation constants (KD) determined by fluorescence quenching for these drugs were not significantly different. Saturation transfer double difference (STDD) NMR of TPT and IRT with Pgp revealed that similar functional groups of the CPTs are accountable for Pgp-CPTs interactions. Efforts aimed at modifying these functional groups, guided by available structure-activity relationship data for CPTs and DNA-Topoisomerase-I complexes, could pave the way for the development of more potent next-generation CPTs.
Machine Learning Quantification of Intraepithelial Tumor-Infiltrating Lymphocytes as a Significant Prognostic Factor in High-Grade Serous Ovarian Carcinomas
Authors: Machuca-Aguado Jesús , Conde-Martín Antonio Félix , Alvarez-Muñoz Alejandro , Rodríguez-Zarco Enrique , Polo-Velasco Alfredo , Rueda-Ramos Antonio , Rendón-García Rosa , Ríos-Martin Juan José , Idoate Miguel A.
Published: November 2023

The prognostic and predictive role of tumor-infiltrating lymphocytes (TILs) has been demonstrated in various neoplasms. The few publications that have addressed this topic in high-grade serous ovarian carcinoma (HGSOC) have approached TIL quantification from a semiquantitative standpoint. Clinical correlation studies, therefore, need to be conducted based on more accurate TIL quantification. We created a machine learning system based on H&E-stained sections using 76 molecularly and clinically well-characterized advanced HGSOC. This system enabled immune cell classification. These immune parameters were subsequently correlated with overall survival (OS) and progression-free survival (PFI). An intense colonization of the tumor cords by TILs was associated with a better prognosis. Moreover, the multivariate analysis showed that the intraephitelial (ie) TILs concentration was an independent and favorable prognostic factor both for OS (p = 0.02) and PFI (p = 0.001). A synergistic effect between complete surgical cytoreduction and high levels of ieTILs was evidenced, both in terms of OS (p = 0.0005) and PFI (p = 0.0008). We consider that digital analysis with machine learning provided a more accurate TIL quantification in HGSOC. It has been demonstrated that ieTILs quantification in H&E-stained slides is an independent prognostic parameter. It is possible that intraepithelial TIL quantification could help identify candidate patients for immunotherapy.
A New MPPT-Based Extended Grey Wolf Optimizer for Stand-Alone PV System: A Performance Evaluation versus Four Smart MPPT Techniques in Diverse Scenarios
Authors: Silaa Mohammed Yousri , Barambones Oscar , Bencherif Aissa , Rahmani Abdellah
Published: November 2023

Photovoltaic (PV) systems play a crucial role in clean energy systems. Effective maximum power point tracking (MPPT) techniques are essential to optimize their performance. However, conventional MPPT methods exhibit limitations and challenges in real-world scenarios characterized by rapidly changing environmental factors and various operating conditions. To address these challenges, this paper presents a performance evaluation of a novel extended grey wolf optimizer (EGWO). The EGWO has been meticulously designed in order to improve the efficiency of PV systems by rapidly tracking and maintaining the maximum power point (MPP). In this study, a comparison is made between the EGWO and other prominent MPPT techniques, including the grey wolf optimizer (GWO), equilibrium optimization algorithm (EOA), particle swarm optimization (PSO) and sin cos algorithm (SCA) techniques. To evaluate these MPPT methods, a model of a PV module integrated with a DC/DC boost converter is employed, and simulations are conducted using Simulink-MATLAB software under standard test conditions (STC) and various environmental conditions. In particular, the results demonstrate that the novel EGWO outperforms the GWO, EOA, PSO and SCA techniques and shows fast tracking speed, superior dynamic response, high robustness and minimal power fluctuations across both STC and variable conditions. Thus, a power fluctuation of 0.09 W could be achieved by using the proposed EGWO technique. Finally, according to these results, the proposed approach can offer an improvement in energy consumption. These findings underscore the potential benefits of employing the novel MPPT EGWO to enhance the efficiency and performance of MPPT in PV systems. Further exploration of this intelligent technique could lead to significant advancements in optimizing PV system performance, making it a promising option for real-world applications.