bluuebunny/crossref_metadata_2025 huggingface dataset:
LPS-Induced Garcia Effect and Its Pharmacological Regulation Mediated by Acetylsalicylic Acid: Behavioral and Transcriptional Evidence
Authors: Rivi Veronica , Batabyal Anuradha , Lukowiak Ken , Benatti Cristina , Rigillo Giovanna , Tascedda Fabio , Blom Joan M. C.
Published: August 2023

Lymnaea stagnalis learns and remembers to avoid certain foods when their ingestion is followed by sickness. This rapid, taste-specific, and long-lasting aversion—known as the Garcia effect—can be formed by exposing snails to a novel taste and 1 h later injecting them with lipopolysaccharide (LPS). However, the exposure of snails to acetylsalicylic acid (ASA) for 1 h before the LPS injection, prevents both the LPS-induced sickness state and the Garcia effect. Here, we investigated novel aspects of this unique form of conditioned taste aversion and its pharmacological regulation. We first explored the transcriptional effects in the snails’ central nervous system induced by the injection with LPS (25 mg), the exposure to ASA (900 nM), as well as their combined presentation in untrained snails. Then, we investigated the behavioral and molecular mechanisms underlying the LPS-induced Garcia effect and its pharmacological regulation by ASA. LPS injection, both alone and during the Garcia effect procedure, upregulated the expression levels of immune- and stress-related targets. This upregulation was prevented by pre-exposure to ASA. While LPS alone did not affect the expression levels of neuroplasticity genes, its combination with the conditioning procedure resulted in their significant upregulation and memory formation for the Garcia effect.
Synergy Assessment of Four Antimicrobial Bioactive Compounds for the Combinational Treatment of Bacterial Pathogens
Authors: Masterson Kevin , Major Ian , Lynch Mark , Rowan Neil
Published: August 2023

Antimicrobial resistance (AMR) has become a topic of great concern in recent years, with much effort being committed to developing alternative treatments for resistant bacterial pathogens. Drug combinational therapies have been a major area of research for several years, with modern iterations using combining well-established antibiotics and other antimicrobials with the aim of discovering complementary mechanisms. Previously, we characterised four GRAS antimicrobials that can withstand thermal polymer extrusion processes for novel medical device-based and therapeutic applications. In the present study, four antimicrobial bioactive—silver nitrate, nisin, chitosan and zinc oxide—were assessed for their potential combined use as an alternative synergistic treatment for AMR bacteria via a broth microdilution assay based on a checkerboard format. The bioactives were tested in arrangements of two-, three- and four-drug combinations, and their interactions were determined and expressed in terms of a synergy score. Results have revealed interesting interactions based on treatments against recognised test bacterial strains that cause human and animal infections, namely E. coli, S. aureus and S. epidermidis. Silver nitrate was seen to greatly enhance the efficacy of its paired treatment. Combinations with nisin, which is a lantibiotic, exhibited the most interesting results, as nisin has no effect against Gram-negative bacteria when used alone; however, it demonstrated antimicrobial effects when combined with silver nitrate or chitosan. This study constitutes the first study to both report on practical three- and four-drug combinational assays and utilise these methods for the assessment of established and emerging antimicrobials. The novel methods and results presented in this study show the potential to explore previously unknown drug combination compatibility measures in an ease-of-use- and high-throughput-based format, which can greatly help future research that aims to identify appropriate alternative treatments for AMR, including the screening of potential new bioactives biorefined from various sources.
Recent Advancements in AAV-Vectored Immunoprophylaxis in the Nonhuman Primate Model
Authors: Campbell Elena S. B. , Goens Melanie M. , Cao Wenguang , Thompson Brad , Susta Leonardo , Banadyga Logan , Wootton Sarah K.
Published: August 2023

Monoclonal antibodies (mAbs) are important treatment modalities for preventing and treating infectious diseases, especially for those lacking prophylactic vaccines or effective therapies. Recent advances in mAb gene cloning from naturally infected or immunized individuals has led to the development of highly potent human mAbs against a wide range of human and animal pathogens. While effective, the serum half-lives of mAbs are quite variable, with single administrations usually resulting in short-term protection, requiring repeated doses to maintain therapeutic concentrations for extended periods of time. Moreover, due to their limited time in circulation, mAb therapies are rarely given prophylactically; instead, they are generally administered therapeutically after the onset of symptoms, thus preventing mortality, but not morbidity. Adeno-associated virus (AAV) vectors have an established record of high-efficiency in vivo gene transfer in a variety of animal models and humans. When delivered to post-mitotic tissues such as skeletal muscle, brain, and heart, or to organs in which cells turn over slowly, such as the liver and lungs, AAV vector genomes assume the form of episomal concatemers that direct transgene expression, often for the lifetime of the cell. Based on these attributes, many research groups have explored AAV-vectored delivery of highly potent mAb genes as a strategy to enable long-term expression of therapeutic mAbs directly in vivo following intramuscular or intranasal administration. However, clinical trials in humans and studies in nonhuman primates (NHPs) indicate that while AAVs are a powerful and promising platform for vectored immunoprophylaxis (VIP), further optimization is needed to decrease anti-drug antibody (ADA) and anti-capsid antibody responses, ultimately leading to increased serum transgene expression levels and improved therapeutic efficacy. The following review will summarize the current landscape of AAV VIP in NHP models, with an emphasis on vector and transgene design as well as general delivery system optimization. In addition, major obstacles to AAV VIP, along with implications for clinical translation, will be discussed.
Glutathione: Lights and Shadows in Cancer Patients
Authors: Marini Herbert Ryan , Facchini Bianca Arianna , di Francia Raffaele , Freni José , Puzzolo Domenico , Montella Liliana , Facchini Gaetano , Ottaiano Alessandro , Berretta Massimiliano , Minutoli Letteria
Published: August 2023

In cases of cellular injury, there is an observed increase in the production of reactive oxygen species (ROS). When this production becomes excessive, it can result in various conditions, including cancerogenesis. Glutathione (GSH), the most abundant thiol-containing antioxidant, is fundamental to re-establishing redox homeostasis. In order to evaluate the role of GSH and its antioxi-dant effects in patients affected by cancer, we performed a thorough search on Medline and EMBASE databases for relevant clinical and/or preclinical studies, with particular regard to diet, toxicities, and pharmacological processes. The conjugation of GSH with xenobiotics, including anti-cancer drugs, can result in either of two effects: xenobiotics may lose their harmful effects, or GSH conjugation may enhance their toxicity by inducing bioactivation. While being an interesting weapon against chemotherapy-induced toxicities, GSH may also have a potential protective role for cancer cells. New studies are necessary to better explain the relationship between GSH and cancer. Although self-prescribed glutathione (GSH) implementation is prevalent among cancer patients with the intention of reducing the toxic effects of anticancer treatments and potentially preventing damage to normal tissues, this belief lacks substantial scientific evidence for its efficacy in reducing toxicity, except in the case of cisplatin-related neurotoxicity. Therefore, the use of GSH should only be considered under medical supervision, taking into account the appropriate timing and setting.
Effect of Hydrogen Plasma Treatment on the Sensitivity of ZnO Based Electrochemical Non-Enzymatic Biosensor
Authors: Tolubayeva Diana B. , Gritsenko Lesya V. , Kedruk Yevgeniya Y. , Aitzhanov Madi B. , Nemkayeva Renata R. , Abdullin Khabibulla A.
Published: August 2023

Information on vitamin C—ascorbic acid (AA)—content is important as it facilitates the provision of dietary advice and strategies for the prevention and treatment of conditions associated with AA deficiency or excess. The methods of determining AA content include chromatographic techniques, spectrophotometry, and electrochemical methods of analysis. In the present work, an electrochemical enzyme-free ascorbic acid sensor for a neutral medium has been developed. The sensor is based on zinc oxide nanowire (ZnO NW) arrays synthesized via low-temperature chemical deposition (Chemical Bath Deposition) on the surface of an ITO substrate. The sensitivity of the electrochemical enzyme-free sensor was found to be dependent on the process treatments. The AA sensitivity values measured in a neutral PBS electrolyte were found to be 73, 44, and 92 µA mM−1 cm−2 for the ZnO NW-based sensors of the pristine, air-annealed (AT), and air-annealed followed by hydrogen plasma treatment (AT+PT), respectively. The simple H-plasma treatment of ZnO nanowire arrays synthesized via low-temperature chemical deposition has been shown to be an effective process step to produce an enzyme-free sensor for biological molecules in a neutral electrolyte for applications in health care and biomedical safety.
Label-Free DNA Biosensor Based on Reduced Graphene Oxide and Gold Nanoparticles
Authors: Chiticaru Elena Alina , Damian Celina Maria , Pilan Luisa , Ioniță Mariana
Published: August 2023

Currently available DNA detection techniques frequently require compromises between simplicity, speed, accuracy, and cost. Here, we propose a simple, label-free, and cost-effective DNA detection platform developed at screen-printed carbon electrodes (SPCEs) modified with reduced graphene oxide (RGO) and gold nanoparticles (AuNPs). The preparation of the detection platform involved a two-step electrochemical procedure based on GO reduction onto SPCEs followed by the electrochemical reduction of HAuCl4 to facilitate the post-grafting reaction with AuNPs. The final sensor was fabricated by the simple physical adsorption of a single-stranded DNA (ssDNA) probe onto a AuNPs–RGO/SPCE electrode. Each preparation step was confirmed by morphological and structural characterization using scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy, respectively. Furthermore, the electrochemical properties of the modified electrodes have been investigated by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The results demonstrated that the introduction of AuNPs onto RGO/SPCEs led to an enhancement in surface conductivity, a characteristic that favored an increased sensitivity in detection. The detection process relied on the change in the electrochemical signal induced by the binding of target DNA to the bioreceptor and was particularly monitored by the change in the charge transfer resistance of a [Fe(CN)6]4–/3– redox couple added in the test solution.
Visual Dysfunction in Parkinson’s Disease
Authors: Nieto-Escamez Francisco , Obrero-Gaitán Esteban , Cortés-Pérez Irene
Published: August 2023

Non-motor symptoms in Parkinson’s disease (PD) include ocular, visuoperceptive, and visuospatial impairments, which can occur as a result of the underlying neurodegenerative process. Ocular impairments can affect various aspects of vision and eye movement. Thus, patients can show dry eyes, blepharospasm, reduced blink rate, saccadic eye movement abnormalities, smooth pursuit deficits, and impaired voluntary and reflexive eye movements. Furthermore, visuoperceptive impairments affect the ability to perceive and recognize visual stimuli accurately, including impaired contrast sensitivity and reduced visual acuity, color discrimination, and object recognition. Visuospatial impairments are also remarkable, including difficulties perceiving and interpreting spatial relationships between objects and difficulties judging distances or navigating through the environment. Moreover, PD patients can present visuospatial attention problems, with difficulties attending to visual stimuli in a spatially organized manner. Moreover, PD patients also show perceptual disturbances affecting their ability to interpret and determine meaning from visual stimuli. And, for instance, visual hallucinations are common in PD patients. Nevertheless, the neurobiological bases of visual-related disorders in PD are complex and not fully understood. This review intends to provide a comprehensive description of visual disturbances in PD, from sensory to perceptual alterations, addressing their neuroanatomical, functional, and neurochemical correlates. Structural changes, particularly in posterior cortical regions, are described, as well as functional alterations, both in cortical and subcortical regions, which are shown in relation to specific neuropsychological results. Similarly, although the involvement of different neurotransmitter systems is controversial, data about neurochemical alterations related to visual impairments are presented, especially dopaminergic, cholinergic, and serotoninergic systems.
Autistic and Catatonic Spectrum Symptoms in Patients with Borderline Personality Disorder
Authors: Dell’Osso Liliana , Amatori Giulia , Cremone Ivan Mirko , Massimetti Enrico , Nardi Benedetta , Gravina Davide , Benedetti Francesca , Muscatello Maria Rosaria Anna , Pompili Maurizio , Politi Pierluigi , Vita Antonio , Maj Mario , Carpita Barbara
Published: August 2023

Background: Recent literature has shown that a considerable percentage of patients with severe mental disorders can develop, over time, full-blown or subthreshold catatonia. Some studies corroborate the model of an illness trajectory in which different mental disorders would be arranged along a continuum of severity until the development of catatonia. In such an illness pathway, autistic traits (AT) and borderline personality disorder (BPD) may represent important steps. In order to further explore the association between AT, BPD, and catatonia, the aim of this study was to compare catatonic spectrum symptoms and AT among patients with major depressive disorder (MDD), BPD, and healthy controls (CTL), also evaluating possible predictive dimensions of the different diagnoses. Methods: A total of 90 adults affected by BPD, 90 adults with a diagnosis of MDD, and 90 CTL, homogeneous in terms of gender and age, were recruited from six Italian university departments of psychiatry and assessed with the SCID-5-RV, the Catatonia Spectrum (CS), and the Adult Autism Subthreshold Autism Spectrum (AdAS Spectrum). Results: The total CS score was significantly higher in the BPD and MDD groups than in the CTL group, while the majority of CS domain scores were significantly higher in the BPD group than in the MDD group, which scored significantly higher than the CTL group. The total AdAS Spectrum score and the AdAS Spectrum domain scores were significantly higher in the BPD group than in the MDD group, which in turn scored significantly higher than the CTL group. The CS domains “psychomotor activity” and “impulsivity”, and AdAS Spectrum domains “verbal communication”, “empathy”, and “hyper-/hyporeactivity to sensory input” were associated with the risk of presenting a diagnosis of BPD.
Juvenile-Onset Recurrent Rhabdomyolysis Due to Compound Heterozygote Variants in the ACADVL Gene
Authors: Labella Beatrice , Lanzi Gaetana , Cotti Piccinelli Stefano , Caria Filomena , Damioli Simona , Risi Barbara , Bertella Enrica , Poli Loris , Padovani Alessandro , Filosto Massimiliano
Published: August 2023

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare autosomal recessive long-chain fatty acid oxidation disorder caused by mutations in the ACADVL gene. The myopathic form presents with exercise intolerance, exercise-related rhabdomyolysis, and muscle pain, usually starting during adolescence or adulthood. We report on a 17-year-old boy who has presented with exercise-induced muscle pain and fatigue since childhood. In recent clinical history, episodes of exercise-related severe hyperCKemia and myoglobinuria were reported. Electromyography was normal, and a muscle biopsy showed only “moth-eaten” fibers, and a mild increase in lipid storage in muscle fibers. NGS analysis displayed the already known heterozygote c.1769G>A variant and the unreported heterozygote c.523G>C change in ACADVL both having disease-causing predictions. Plasma acylcarnitine profiles revealed high long-chain acylcarnitine species levels, especially C14:1. Clinical, histopathological, biochemical, and genetic tests supported the diagnosis of VLCAD deficiency. Our report of a novel pathogenic missense variant in ACADVL expands the allelic heterogeneity of the disease. Since dietary treatment is the only therapy available for treating VLCAD deficiency and it is more useful the earlier it is started, prompt diagnosis is essential in order to minimize muscle damage and slow the disease progression.
Personalized Teaching Questioning Strategies Study Based on Learners’ Cognitive Structure Diagnosis
Authors: Zhao Yuan , Huang Tao , Wang Han , Geng Jing
Published: August 2023

Personalized education has been a widely shared goal pursued by Chinese and foreign educators. As the primary method of teacher–student interaction, the importance of personalized questioning is self-evident. Due to a lack of technical support, teachers rely on their teaching experience to ask questions without considering the learning situation of learners. This results in teaching questioning being unable to support learners’ learning. These questions are relatively shallow and cannot promote the construction and transfer of learners’ knowledge. Cognitive diagnostic technology could diagnose learners’ cognitive states and provide services for personalized teaching. Therefore, a personalized teaching questioning strategy based on learners’ cognitive structure diagnosis was proposed in this study. Firstly, we diagnosed learners’ cognitive structure through usability, distinguishability, and stability. Secondly, we discussed the types of questions that teachers should raise when facing learners in different situations. We also discussed the application of personalized teaching questioning strategies. The experiment took place at M Primary School in Ningxia, China, with the participation of one teacher and ninety-seven fourth-grade students. Seven lessons were observed and videotaped across a range of topics. The study revealed that personalized teaching questioning strategies could improve learners’ academic performance and subject literacy. They can also increase the number of teacher questioning, change the depth of teacher questioning content, and expand the scope of questioning subjects.
Examining the Relationship between Individualism and Pro-Environmental Behavior: The Moderating Role of Social Cohesion
Authors: Moon Kuk-Kyoung , Lee Seo-Hee , Jeong Seo-Yeon
Published: August 2023

Combining Hofstede’s cultural dimensions, value–belief–norm theory, and social exchange theory, this study explores the impact of individualism and social cohesion on pro-environmental behavior (PEB) as well as the moderating role of social cohesion in the individualism–PEB link in the context of Korean society. Using the 2021 Korean General Social Survey and multiple linear regression analyses, we found that individualism is negatively related to PEB, whereas social cohesion is positively related to PEB. Further analysis showed that social cohesion attenuates the negative relationship between individualism and PEB. Our findings suggest that although individuals with high levels of individualism are less likely to perform PEB than those with a high level of collectivism, social cohesion is a valuable community resource that encourages them to engage in eco-friendly activities even when they seek to achieve person-oriented goals and pursue their own interests. The implications and contributions of these findings regarding environmental psychology are discussed.
Natural and Architectural Convergence: A Model of Nature-Based Strategies in the Architectural Design Domain
Authors: Ahmed Chra Hunar , Rasul Hoshyar Qadir
Published: August 2023

Nature is the major source and basis for architectural design. It is beyond human ability to create the same unlimited changes and dimensions. One of the key actors in minimizing negative impacts on nature and the environment is the architect. Due to the different uses of nature in architectural design and the interdisciplinarity between the approaches and aspects of nature, this study aimed to explore the contributions of nature-based strategies to the architectural design domain and identify the comprehensive relationship between nature and architecture. Through using logical argument, the nature-based strategies of architectural design were classified according to four categories of architectural design principles in a predicted model. For testing and validating the model, one strategy, which included nine nature-based approaches of architectural design with 23 aspects, was evaluated, and the scopes of the approaches were identified. VOSviewer was used for data analysis, and the survey questionnaire method was used for the focus group of architects to evaluate Erbil City’s architectural design. In this survey, 328 responses were received, which were ranked using the four-point Likert scale (most of the time, some of the time, seldom, and never), and the t-test from SPSS software was used to compare the approaches of the selected nature-based strategy. The passive design was the only approach with a positive value from the t-test (3.805) with a p-value of 0.000. Among these 23 evaluated aspects, natural ventilation received the highest mean value (1.91).
Healthy Dwelling: The Perspective of Biophilic Design in the Design of the Living Space
Authors: Gong Yu , Zoltán Erzsébet Szeréna , János Gyergyák
Published: August 2023

As urbanization continues to advance rapidly, the emergence of biophilic design offers a positive perspective to address the alienation between humans and nature, becoming a hot research topic in areas related to human living environments. Biophilic design, as a design concept inspired by nature, has positive significance in promoting the development of ecological diversity and improving human physical and mental health. This paper makes a comparative analysis of two of China’s residential communities in the same high-density environment through the main influencing factors of plot ratio, greening rate, external facades environments, and internal living space. Starting from the five senses of the human body, namely, sight, hearing, touch, smell, and taste, this paper aims to investigate the design of living spaces through the lens of biophilic design, and proposes a biophilic design model, along with strategies and recommendations tailored to high-density urban environments, in the hope of serving as a valuable reference and source of inspiration for future healthy dwelling design.
Safety Assessment of the Main Beams of Historical Buildings Based on Multisource Data Fusion
Authors: Chen Ying , Zhang Ran , Li Yanfeng , Xie Jiyuan , Guo Dong , Song Laiqiang
Published: August 2023

Taking the main beams of historical buildings as the engineering background, existing theoretical research results related to influencing structural factors were used along with numerical simulation and data fusion methods to examine their integrity. Thus, the application of multifactor data fusion in the safety assessment of the main beams of historical buildings was performed. On the basis of existing structural safety assessment methods, neural networks and rough set theory were combined and applied to the safety assessment of the main beams of historical buildings. The bearing capacity of the main beams was divided into five levels according to the degree to which they met current requirements. The safety assessment database established by a Kohonen neural network was clustered. Thus, the specific evaluation indices corresponding to the five types of safety levels were presented. The rough neural network algorithm, integrating the rough set and neural network, was applied for data fusion with this database. The attribute reduction function of the rough set was used to reduce the input dimension of the neural network, which was trained, underwent a learning process, and then used for predictions. The trained neural network was applied for the safety assessment of the main beams of historical buildings, and six specific attribute index values corresponding to the main beams were directly input to obtain the current safety statuses of the buildings. Corresponding management suggestions were also provided.
An Integrated Model for Multi-Mode Resource-Constrained Multi-Project Scheduling Problems Considering Supply Management with Sustainable Approach in the Construction Industry under Uncertainty Using Evidence Theory and Optimization Algorithms
Authors: Ghoroqi Mahyar , Ghoddousi Parviz , Makui Ahmad , Shirzadi Javid Ali Akbar , Talebi Saeed
Published: August 2023

In this study, the multi-mode resource-constrained multi-project scheduling problems (MMRCMPSPs) considering supply management and sustainable approach in the construction industry under uncertain conditions have been investigated using evidence theory to mathematical modeling and solving by multi-objective optimization algorithms. In this regard, a multi-objective mathematical model has been proposed, in which the first objective function aims to maximize a weighted selection of projects based on economic, environmental, technical, social, organizational, and competitive factors; the second objective function is focused on maximizing profit, and the third objective function is aimed at minimizing the risk of supply management. Moreover, various components, such as interest rates, carbon penalties, and other implementation limitations and additional constraints, have also been considered in the modeling and mathematical relationships to improve the model’s performance and make it more relevant to real-world conditions and related issues, leading to better practical applications. In the mathematical modeling adopted, the processing time of project activities has been considered uncertain, and the evidence theory has been utilized. This method can provide a flexible and rational approach based on evidence and knowledge in the face of uncertainty. In addition, to solve the proposed multi-objective mathematical model, metaheuristic optimization algorithms, such as the differential evolution (DE) algorithm based on the Pareto archive, have been used, and for evaluating the results, the non-dominated sorting genetic algorithm II (NSGA-II) has also been employed. Furthermore, the results have been compared based on multi-objective evaluation criteria, such as quality metric (QM), spacing metric (SM), and diversity metric (DM). It is worth noting that to investigate the performance and application of the proposed model, multiple evaluations have been conducted on sample problems with different dimensions, as well as a case study on residential apartment construction projects by a contracting company. In this respect, the answers obtained from solving the model using the multi-objective DE algorithm were better and superior to the NSGA-II algorithm and had a more favorable performance. Generally, the results indicate that using the integrated multi-objective mathematical model in the present research for managing and scheduling multi-mode resource-constrained multi-project problems, especially in the construction industry, can lead to an optimal state consistent with the desired objectives and can significantly improve the progress and completion of projects.
Maintenance Chemotherapy for Patients with Rhabdomyosarcoma
Authors: Bisogno Gianni , Minard-Colin Veronique , Jenney Meriel. , Ferrari Andrea , Chisholm Julia , Di Carlo Daniela , Hjalgrim Lisa Lyngsie , Orbach Daniel , Merks Johannes Hendrikus Maria , Casanova Michela
Published: August 2023

Maintenance chemotherapy (MC) defines the administration of prolonged relatively low-intensity chemotherapy with the aim of “maintaining” tumor complete remission. This paper aims to report an update of the RMS2005 trial, which demonstrated better survival for patients with high-risk localized rhabdomyosarcoma (RMS) when MC with vinorelbine and low-dose cyclophosphamide was added to standard chemotherapy, and to discuss the published experience on MC in RMS. In the RMS2005 study, the outcome for patients receiving MC vs. those who stopped the treatment remains superior, with a 5-year disease-free survival of 78.1% vs. 70.1% (p = 0.056) and overall survival of 85.0% vs. 72.4% (p = 0.008), respectively. We found seven papers describing MC in RMS, but only one randomized trial that did not demonstrate any advantage when MC with eight courses of trofosfamide/idarubicine alternating with trofosfamide/etoposide has been employed in high-risk RMS. The use of MC showed better results in comparison to high-dose chemotherapy in non-randomized studies, including metastatic patients, and demonstrated feasibility and tolerability in relapsed RMS. Many aspects of MC in RMS need to be investigated, including the best drug combination and the optimal duration. The ongoing EpSSG trial will try to answer some of these questions.
Challenges in Pharmacological Intervention in Perilipins (PLINs) to Modulate Lipid Droplet Dynamics in Obesity and Cancer
Authors: Bombarda-Rocha Victória , Silva Dany , Badr-Eddine Allal , Nogueira Patrícia , Gonçalves Jorge , Fresco Paula
Published: August 2023

Perilipins (PLINs) are the most abundant proteins in lipid droplets (LD). These LD-associated proteins are responsible for upgrading LD from inert lipid storage structures to fully functional organelles, fundamentally integrated in the lipid metabolism. There are five distinct perilipins (PLIN1–5), each with specific expression patterns and metabolic activation, but all capable of regulating the activity of lipases on LD. This plurality creates a complex orchestrated mechanism that is directly related to the healthy balance between lipogenesis and lipolysis. Given the essential role of PLINs in the modulation of the lipid metabolism, these proteins can become interesting targets for the treatment of lipid-associated diseases. Since reprogrammed lipid metabolism is a recognized cancer hallmark, and obesity is a known risk factor for cancer and other comorbidities, the modulation of PLINs could either improve existing treatments or create new opportunities for the treatment of these diseases. Even though PLINs have not been, so far, directly considered for pharmacological interventions, there are many established drugs that can modulate PLINs activity. Therefore, the aim of this study is to assess the involvement of PLINs in diseases related to lipid metabolism dysregulation and whether PLINs can be viewed as potential therapeutic targets for cancer and obesity.
Deciphering Machine Learning Decisions to Distinguish between Posterior Fossa Tumor Types Using MRI Features: What Do the Data Tell Us?
Authors: Tanyel Toygar , Nadarajan Chandran , Duc Nguyen Minh , Keserci Bilgin
Published: August 2023

Machine learning (ML) models have become capable of making critical decisions on our behalf. Nevertheless, due to complexity of these models, interpreting their decisions can be challenging, and humans cannot always control them. This paper provides explanations of decisions made by ML models in diagnosing four types of posterior fossa tumors: medulloblastoma, ependymoma, pilocytic astrocytoma, and brainstem glioma. The proposed methodology involves data analysis using kernel density estimations with Gaussian distributions to examine individual MRI features, conducting an analysis on the relationships between these features, and performing a comprehensive analysis of ML model behavior. This approach offers a simple yet informative and reliable means of identifying and validating distinguishable MRI features for the diagnosis of pediatric brain tumors. By presenting a comprehensive analysis of the responses of the four pediatric tumor types to each other and to ML models in a single source, this study aims to bridge the knowledge gap in the existing literature concerning the relationship between ML and medical outcomes. The results highlight that employing a simplistic approach in the absence of very large datasets leads to significantly more pronounced and explainable outcomes, as expected. Additionally, the study also demonstrates that the pre-analysis results consistently align with the outputs of the ML models and the clinical findings reported in the existing literature.
Small Cell Lung Cancer: Emerging Targets and Strategies for Precision Therapy
Authors: Patel Shruti R. , Das Millie
Published: August 2023

Small cell lung cancer is an aggressive subtype of lung cancer with limited treatment options. Precision medicine has revolutionized cancer treatment for many tumor types but progress in SCLC has been slower due to the lack of targetable biomarkers. This review article provides an overview of emerging strategies for precision therapy in SCLC. Targeted therapies include targeted kinase inhibitors, monoclonal antibodies, angiogenesis inhibitors, antibody–drug conjugates, PARP inhibitors, and epigenetic modulators. Angiogenesis inhibitors and DNA-damaging agents, such as PARP and ATR inhibitors, have been explored in SCLC with limited success to date although trials are ongoing. The potential of targeting DLL3, a NOTCH ligand, through antibody–drug conjugates, bispecific T-cell engagers, and CAR T-cell therapy, has opened up new therapeutic options moving forward. Additionally, new research in epigenetic therapeutics in reversing transcriptional repression, modulating anti-tumor immunity, and utilizing antibody–drug conjugates to target cell surface-specific targets in SCLC are also being investigated. While progress in precision therapy for SCLC has been challenging, recent advancements provide optimism for improved treatment outcomes. However, several challenges remain and will need to be addressed, including drug resistance and tumor heterogeneity. Further research and biomarker-selected clinical trials are necessary to develop effective precision therapies for SCLC patients.
MicroRNAs Derived from Extracellular Vesicles: Keys to Understanding SARS-CoV-2 Vaccination Response in Cancer Patients?
Authors: Almeida Beatriz , Dias Tânia , Teixeira Ana , Dias Francisca , Medeiros Rui
Published: August 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provoked a global pandemic identified as coronavirus disease (COVID-19), with millions of deaths worldwide. However, several important questions regarding its impact on public health remain unanswered, such as the impact of vaccination on vulnerable subpopulations such as cancer patients. Cytokine storm and a sustained inflammatory state are commonly associated with immune cell depletion, being manifested in most immunocompromised individuals. This strong immunosuppression can lead to a dysfunctional antiviral response to natural viral infection and compromised vaccination response. Extracellular vesicles (EVs) are membrane-bound vesicles released from cells that are involved in intercellular communication. EVs carry various molecules including microRNAs that play a crucial role in COVID-19 pathophysiology, influencing cellular responses. This review summarizes the state of the art concerning the role of EV-derived miRNAs in COVID-19 infection and their potential use as prognosis biomarkers for vaccination response in cancer patients.
Whole Exome Sequencing of Thymoma Patients Exhibiting Exceptional Responses to Pemetrexed Monotherapy
Authors: Tanaka Tomohiro , Goto Yasushi , Horie Masafumi , Masuda Ken , Shinno Yuki , Matsumoto Yuji , Okuma Yusuke , Yoshida Tatsuya , Horinouchi Hidehito , Motoi Noriko , Yatabe Yasushi , Watanabe Shunichi , Yamamoto Noboru , Ohe Yuichiro
Published: August 2023

Background: Pemetrexed is used for the chemotherapy of advanced thymoma. Exceptional responses of thymoma to pemetrexed treatment are not frequently observed. The underlying genetic mechanism of the exceptional responses remains unclear. We used whole-exome sequencing to explore the specific genomic aberrations that lead to an extreme and durable response. Methods: Whole-exome sequencing using NovaSeq6000 (150 bp paired-end sequencing) was performed on nine formalin-fixed paraffin-embedded tissues from patients with advanced thymomas treated with pemetrexed (two exceptional responders and seven typical responders). Results: We identified 284 somatic single-nucleotide variants (SNVs; 272 missense, 8 missense/splice-site, 3 stop-gain, and 1 stop-gain/splice-site), 34 insertions and deletions (Indels; 33 frameshift and one splice region), and 21 copy number variations (CNVs; 15 gains and six losses). No difference in the number of SNVs variants and distribution of deleterious Indels was observed between the exceptional and typical responders. Interestingly, arm-level chromosomal CNVs (15 gains and six losses) were detected in four patients, including an exceptional responder. The highest number of arm-level CNVs was observed in an exceptional responder. Conclusion: Exceptional responders to pemetrexed for metastatic thymomas may be characterized by arm-level CNVs. Further, whole-genome and RNA sequencing studies should be performed.
A Personalized Risk Model for Azacitidine Outcome in Myelodysplastic Syndrome and Other Myeloid Neoplasms Identified by Machine Learning Model Utilizing Real-World Data
Authors: Sharplin Kirsty , Proudman William , Chhetri Rakchha , Tran Elizabeth Ngoc Hoa , Choong Jamie , Kutyna Monika , Selby Philip , Sapio Aidan , Friel Oisin , Khanna Shreyas , Singhal Deepak , Damin Michelle , Ross David , Yeung David , Thomas Daniel , Kok Chung H. , Hiwase Devendra
Published: August 2023

Azacitidine is an approved therapy for higher-risk myelodysplastic syndrome (MDS). However, only 30–40% patients respond to azacitidine, and the responses may take up to six cycles to become evident. Delayed responses and the myelosuppressive effects of azacitidine make it challenging to predict which patients will benefit. This is further compounded by a lack of uniform prognostic tools to identify patients at risk of early treatment failure. Hence, we performed a retrospective analysis of 273 consecutive azacytidine-treated patients. The median overall survival was 16.25 months with only 9% alive at 5 years. By using pre-treatment variables incorporated into a random forest machine learning model, we successfully identified those patients unlikely to benefit from azacytidine upfront (7.99 vs. 22.8 months, p < 0.0001). This model also identified those who required significantly more hospitalizations and transfusion support. Notably, it accurately predicted survival outcomes, outperforming the existing prognostic scoring system. By integrating somatic mutations, we further refined the model and identified three distinct risk groups with significant differences in survival (5.6 vs. 10.5 vs. 43.5 months, p < 0.0001). These real-world findings emphasize the urgent need for personalized prediction tools tailored to hypomethylating agents, reducing unnecessary complications and resource utilization in MDS treatment.
Genetic Profiling of Cell-Free DNA in Liquid Biopsies: A Complementary Tool for the Diagnosis of B-Cell Lymphomas and the Surveillance of Measurable Residual Disease
Authors: Figaredo Gloria , Martín-Muñoz Alejandro , Barrio Santiago , Parrilla Laura , Campos-Martín Yolanda , Poza María , Rufián Laura , Algara Patrocinio , De La Torre Marina , Jiménez Ubieto Ana , Martínez-López Joaquín , Casado Luis-Felipe , Mollejo Manuela
Published: August 2023

Purpose: To assess the potential value of LiqBio as a complementary tool for diagnosis and surveillance of BCL. Methods: This prospective multi-center study included 78 patients (25 follicular lymphomas (FL) and 53 large B-cell lymphomas (LBCL)). We performed next-generation sequencing (NGS) of cfDNA LiqBio and paired gDNA tissue biopsies at diagnosis and compared the mutational statuses. Also, through NGS of LiqBio, we identified MRD biomarkers and compared this novel LiqBio–MRD method with PET/CT in detecting MRD at follow-up. Results: We identified mutations in 71% of LiqBio and 95% of tissue biopsies, and found a correlation between variant allele frequency of somatic mutations. Additionally, we identified mutations in 73% of LiqBio from patients with no available tissue samples or no mutations in them. Regarding the utility of LiqBio–MRD as a dynamic monitoring tool, when compared with the PET/CT method, a lower sensitivity was observed for LiqBio–MRD at 92.3% (vs. 100% for PET/CT), but a higher specificity of 91.3% (vs. 86.9% for PET/CT). Conclusion: Genetic profiling of tumor cfDNA in plasma LiqBio is a complementary tool for BCL diagnosis and MRD surveillance.
Synthesis and Biological Evaluation of Cyclobutane-Based β3 Integrin Antagonists: A Novel Approach to Targeting Integrins for Cancer Therapy
Authors: Sutherland Mark , Gordon Andrew , Al-Shammari Fatemah O. F. O. , Throup Adam , Cilia La Corte Amy , Philippou Helen , Shnyder Steven D. , Patterson Laurence H. , Sheldrake Helen M.
Published: August 2023

The Arg-Gly-Asp (RGD)-binding family of integrin receptors, and notably the β3 subfamily, are key to multiple physiological processes involved in tissue development, cancer proliferation, and metastatic dissemination. While there is compelling preclinical evidence that both αvβ3 and αIIbβ3 are important anticancer targets, most integrin antagonists developed to target the β3 integrins are highly selective for αvβ3 or αIIbβ3. We report the design, synthesis, and biological evaluation of a new structural class of ligand-mimetic β3 integrin antagonist. These new antagonists combine a high activity against αvβ3 with a moderate affinity for αIIbβ3, providing the first evidence for a new approach to integrin targeting in cancer.
Pseudogenes in Cancer: State of the Art
Authors: Nakamura-García Arturo Kenzuke , Espinal-Enríquez Jesús
Published: August 2023

Pseudogenes are duplicates of protein-coding genes that have accumulated multiple detrimental alterations, rendering them unable to produce the protein they encode. Initially disregarded as “junk DNA” due to their perceived lack of functionality, research on their biological roles has been hindered by this assumption. Nevertheless, recent focus has shifted towards these molecules due to their abnormal expression in cancer phenotypes. In this review, our objective is to provide a thorough overview of the current understanding of pseudogene formation, the mechanisms governing their expression, and the roles they may play in promoting tumorigenesis.
Tumor Bed Boost Radiotherapy in the Conservative Treatment of Breast Cancer: A Review of Intra-Operative Techniques and Outcomes
Authors: Sanz Javier , Eraso Arantxa , Ibáñez Reyes , Williams Rachel , Algara Manuel
Published: August 2023

Conservative surgery is the preferred treatment in the management of breast cancer followed by adjuvant whole-breast irradiation. Since the tumor bed is the main site of relapse, boost doses are conveniently administered according to risk factors for local relapse to increase the efficacy of the treatment. The benefit of a radiation boost is well established and it can be performed by several techniques like brachytherapy, external radiation or intraoperative radiotherapy. Greater precision in localizing the tumor cavity, immediacy and increased biological response are the main advantages of intraoperative boost irradiation. This modality of treatment can be performed by means of mobile electron accelerators or low-photon X-ray devices. There is a lot of research and some published series analyzing the results of the use of an intraoperative boost as an adjuvant treatment, after neoadjuvant systemic therapy and in combination with some reconstructive surgeries. This review discusses advantages of intraoperative radiotherapy and presents the main results of a boost in terms of local control, survival, tolerance and cosmesis.
BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers
Authors: Castellani Giorgia , Buccarelli Mariachiara , Arasi Maria Beatrice , Rossi Stefania , Pisanu Maria Elena , Bellenghi Maria , Lintas Carla , Tabolacci Claudio
Published: August 2023

Melanoma is an aggressive form of skin cancer resulting from the malignant transformation of melanocytes. Recent therapeutic approaches, including targeted therapy and immunotherapy, have improved the prognosis and outcome of melanoma patients. BRAF is one of the most frequently mutated oncogenes recognised in melanoma. The most frequent oncogenic BRAF mutations consist of a single point mutation at codon 600 (mostly V600E) that leads to constitutive activation of the BRAF/MEK/ERK (MAPK) signalling pathway. Therefore, mutated BRAF has become a useful target for molecular therapy and the use of BRAF kinase inhibitors has shown promising results. However, several resistance mechanisms invariably develop leading to therapeutic failure. The aim of this manuscript is to review the role of BRAF mutational status in the pathogenesis of melanoma and its impact on differentiation and inflammation. Moreover, this review focuses on the mechanisms responsible for resistance to targeted therapies in BRAF-mutated melanoma and provides an overview of circulating biomarkers including circulating tumour cells, circulating tumour DNA, and non-coding RNAs.
Photoelectrocatalytic Oxidation of Sulfamethazine on TiO2 Electrodes
Authors: Philippidis Nikolaos , Pavlidou Eleni , Sotiropoulos Sotiris , Kokkinos Petros , Mantzavinos Dionissios , Poulios Ioannis
Published: August 2023

The photoelectrocatalytic degradation and mineralization of sulfamethazine (SMT), a sulfonamide drug, were explored in aqueous solution. Working electrodes with TiO2 coatings on Ti substrates (TiO2/Ti) were used, which were produced by the dip coating method. TiO2 film electrodes were analyzed by scanning electron microscopy (SEM) and X-ray diffraction (XRD) following annealing at 500 °C for 1.5 h. To photoelectrochemically characterize them, photocurrents vs. applied potential curves were used. The photoelectrocatalytic efficiency (PEC) of the TiO2/Ti electrodes regarding the oxidation of SMT has been assessed with reference to degradation and mineralization under different experimental conditions. The selected drug molecule was effectively degraded following the Langmuir–Hinshelwood (L-H) kinetic model. The degradation efficiency was shown to increase with increasing applied potential bias up to +1.5 V vs. Ag/AgCl. It was found to be more favorable in acidic environments compared to alkaline ones. A decrease in the destruction rate constant was recorded when the pH was increased from 3 to 5.6 (natural pH) and 9. The decomposition rate was shown to first increase and subsequently reach a saturation value at high concentrations of SMT, indicating that the degradation also depends on other parameters (e.g., the rate of the charge or the mass transfer on the electrode double layer). The results of the photoelectrocatalytic experiments were compared to those of electrochemical (EC) and photocatalytic (PC) degradation of SMT. A significant enhancement was recorded in the case of the PEC degradation, leading at +1.5 V to an increase of the apparent rate constants of degradation, k, and mineralization, kTOC, of 153 and 298%, respectively, compared to the simple photocatalytic process.