bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Melatonin in the Inflammatory Process in Patients with Hyperglycemia and Leishmania Infection
Authors: Martins Thalissa Mariana de Moraes , Ferrari Felipe Rubin , de Queiroz Adriele Ataides , Dalcin Letícia Damas Leão , França Danielle Cristina Honorio , Honório-França Adenilda Cristina , França Eduardo Luzía , Fagundes-Triches Danny Laura Gomes
Published: August 2024

Type 2 diabetes mellitus is a metabolic disorder that causes chronic high blood sugar levels, and diabetic patients are more susceptible to infections. American cutaneous leishmaniasis is an infectious disease caused by a parasite that affects the skin and mucous membranes, leading to one or multiple ulcerative lesions. Chronic inflammation and functional changes in various organs and systems, including the immune system, are the primary causes of both diseases. Melatonin, an essential immunomodulatory, antioxidant, and neuroprotective agent, can benefit many immunological processes and infectious diseases, including leishmaniasis. Although, limited reports are available on diabetic patients with leishmaniasis. The literature suggests that melatonin may play a promising role in inflammatory disorders. This study was designed to assess melatonin levels and inflammatory mediators in diabetic patients affected by leishmaniasis. Blood samples from 25 individuals were analyzed and divided into four groups: a control group (without any diseases), a Leishmania-positive group, patients with type 2 diabetes mellitus, and patients with a combination of both diseases. This study measured the serum levels of melatonin through ELISA, while IL-4 and TNF-α were measured using flow cytometry, and C-reactive protein was measured through turbidimetry. This study found that patients with leishmaniasis significantly increased TNF-α and decreased melatonin levels. However, the group of diabetic patients with leishmaniasis showed higher melatonin levels than the control group. These observations suggest that TNF-α may influence melatonin production in patients with American cutaneous leishmaniasis, potentially contributing to the inflammatory characteristics of both diseases.
Metabolites from Marine Macroorganisms of the Red Sea Acting as Promoters or Inhibitors of Amylin Aggregation
Authors: Alghrably Mawadda , Tammam Mohamed A. , Koutsaviti Aikaterini , Roussis Vassilios , Lopez Xabier , Bennici Giulia , Sharfalddin Abeer , Almahasheer Hanan , Duarte Carlos M. , Emwas Abdul-Hamid , Ioannou Efstathia , Jaremko Mariusz
Published: August 2024

Amylin is part of the endocrine pancreatic system that contributes to glycemic control, regulating blood glucose levels. However, human amylin has a high tendency to aggregate, forming isolated amylin deposits that are observed in patients with type 2 diabetes mellitus. In search of new inhibitors of amylin aggregation, we undertook the chemical analyses of five marine macroorganisms encountered in high populations in the Red Sea and selected a panel of 10 metabolites belonging to different chemical classes to evaluate their ability to inhibit the formation of amyloid deposits in the human amylin peptide. The thioflavin T assay was used to examine the kinetics of amyloid aggregation, and atomic force microscopy was employed to conduct a thorough morphological examination of the formed fibrils. The potential ability of these compounds to interact with the backbone of peptides and compete with β-sheet formation was analyzed by quantum calculations, and the interactions with the amylin peptide were computationally examined using molecular docking. Despite their structural similarity, it could be observed that the hydrophobic and hydrogen bond interactions of pyrrolidinones 9 and 10 with the protein sheets result in one case in a stable aggregation, while in the other, they cause distortion from aggregation.
Burst-Suppression EEG Reactivity to Photic Stimulation—A Translational Biomarker in Hypoxic–Ischemic Brain Injury
Authors: Pâslaru Alexandru-Cătălin , Călin Alexandru , Morozan Vlad-Petru , Stancu Mihai , Tofan Laurențiu , Panaitescu Anca Maria , Zăgrean Ana-Maria , Zăgrean Leon , Moldovan Mihai
Published: August 2024

The reactivity of an electroencephalogram (EEG) to external stimuli is impaired in comatose patients showing burst-suppression (BS) patterns following hypoxic–ischemic brain injury (HIBI). We explored the reactivity of BS induced by isoflurane in rat models of HIBI and controls using intermittent photic stimulation (IPS) delivered to one eye. The relative time spent in suppression referred to as the suppression ratio (SR) was measured on the contralateral fronto-occipital cortical EEG channel. The BS reactivity (BSR) was defined as the decrease in the SR during IPS from the baseline before stimulation (SRPRE). We found that BSR increased with SRPRE. To standardize by anesthetic depth, we derived the BSR index (BSRi) as BSR divided by SRPRE. We found that the BSRi was decreased at 3 days after transient global cerebral ischemia in rats, which is a model of brain injury after cardiac arrest. The BSRi was also reduced 2 months after experimental perinatal asphyxia in rats, a model of birth asphyxia, which is a frequent neonatal complication in humans. Furthermore, Oxytocin attenuated BSRi impairment, consistent with a neuroprotective effect in this model. Our data suggest that the BSRi is a promising translational marker in HIBI which should be considered in future neuroprotection studies.
Waste Biomass Pretreatments for Biogas Yield Optimization and for the Extraction of Valuable High-Added-Value Products: Possible Combinations of the Two Processes toward a Biorefinery Purpose
Authors: Di Mario Jessica , Montegiove Nicolò , Gambelli Alberto Maria , Brienza Monica , Zadra Claudia , Gigliotti Giovanni
Published: August 2024

Second- and third-generation biorefineries enable the sustainable management of biomasses within the framework of circular economy principles. This approach aims to minimize waste biomass while generating high-value molecules and bio-energy, such as biogas. Biogas production is achieved via anaerobic digestion, a process where microorganisms metabolize organic compounds in the absence of oxygen to primarily produce CO2 and CH4. The efficiency of this process is closely linked to the composition of the biomass and, sometimes, characteristics of the initial matrix can impede the process. To address these challenges, various pretreatments are employed to enhance digestion efficiency and mitigate issues associated with biomass complexity. However, the implementation of pretreatments can be energy-intensive and costly. The extraction of valuable molecules from biomass for various applications can represent a form of pretreatment. This extraction process selectively removes recalcitrant molecules such as lignin and cellulose, which can hinder biodegradation, thereby adding new value to the biomass. These extracted molecules not only contribute to improved anaerobic digestion efficiency but also offer potential economic benefits by serving as valuable inputs across diverse industrial sectors. This article presents a detailed state of the art of the most widespread biomass pretreatments and specifies when biomass is pretreated to improve the biogas yield and, in contrast, when it is treated to extract high-added-value products. Finally, in order to define if the same treatment can be simultaneously applied for both goals, an experimental section was dedicated to the production of biogas from untreated olive mill wastewater and the same biomass after being freeze-dried and after the extraction of polyphenols and flavonoids. The use of pretreated biomass effectively improved the biogas production yield: the untreated olive mill wastewater led to the production of 147 mL of biogas, while after freeze-drying and after polyphenols/flavonoids extraction, the production was, respectively, equal to 169 mL and 268 mL of biogas.
Ceruloplasmin and Lipofuscin Serum Concentrations Are Associated with Presence of Hypertrophic Cardiomyopathy
Authors: Smyła-Gruca Wiktoria , Szczurek-Wasilewicz Wioletta , Skrzypek Michał , Romuk Ewa , Karmański Andrzej , Jurkiewicz Michał , Gąsior Mariusz , Osadnik Tadeusz , Banach Maciej , Jóźwiak Jacek J. , Szyguła-Jurkiewicz Bożena
Published: August 2024

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and cells’ ability to neutralize them by antioxidant systems. The role of oxidative stress in hypertrophic cardiomyopathy (HCM) is not fully understood. The aim of the study was to examine selected parameters of oxidative stress in patients with HCM compared to the control group. We enrolled 85 consecutive HCM patients and 97 controls without HCM. The groups were matched for sex, the body mass index, and age. Oxidative stress markers included superoxide dismutase (SOD), ceruloplasmin (CER), and lipofuscin (LPS). The median age of the HCM patients was 53 (40–63) years, and 41.2% of them were male. HCM patients, compared to the control ones, had significantly increased levels of CER and LPS. The areas under the receiver operating characteristics curves (AUC) indicated a good discriminatory power of CER (AUC 0.924, sensitivity 84%, and specificity 88%), an acceptable discriminatory power of LPS (AUC 0.740, sensitivity 66%, and specificity 72%), and poor discriminatory power of SOD (AUC 0.556, sensitivity 34%, and specificity 94%) for HCM detection. CER with good predictive strength, as well as LPS with acceptable predictive power, allows for HCM detection. The utility of SOD for HCM detection is limited.
MicroRNA Analysis of In Vitro Differentiation of Spermatogonial Stem Cells Using a 3D Human Testis Organoid System
Authors: Cohen Adam B. , Nikmehr Banafsheh , Abdelaal Omar A. , Escott Megan , Walker Stephen J. , Atala Anthony , Sadri-Ardekani Hooman
Published: August 2024

Spermatogenesis produces male gametes from spermatogonial stem cells (SSC), beginning at puberty. Modern-day laboratory techniques allow for the long-term culture of SSC and in vitro spermatogenesis. The specific biochemical processes that occur during spermatogenesis remain poorly understood. One particular element of spermatogenesis that has yet to be characterized is the role of microRNAs (miRNA), short, non-transcribed RNAs that act as post-translational regulators of gene activity. In this study, we seek to describe the presence of miRNA in a two-dimensional (2D) SSC culture and a 3D human testis organoid (HTO) system. Testicular cells were isolated from the frozen tissue of three brain-dead subjects, propagated in cultures for four to five weeks, and used to form 3D HTOs. Following organoid formation, differentiation of testicular cells was induced. RNA was isolated from the whole testis tissue (WT) showing in vivo conditions, HTO Day Zero (2D SSC culture), Day 2 HTOs, and Day 23 differentiated HTOs, then analyzed for changes in miRNA expression using the Nanostring nCounter miRNA panel. One hundred ninety-five miRNAs met the criteria for expression in WT, 186 in 2D culture, 190 in Day 2 HTOs, and 187 in differentiated HTOs. One hundred thirty-three miRNAs were common across all conditions, and 41, 17, 6, and 11 miRNAs were unique for WT, 2D culture, Day 2 HTOs, and differentiated HTOs, respectively. Twenty-two miRNAs were similar between WT and differentiated HTOS. We evaluated the miRNA expression profiles of progressively complex stages of testicular cell culture, culminating in a 3D organoid model capable of meiotic differentiation, and compared these to WT. We identified a great variance between the native tissue and the culture system; however, some miRNAs are preserved. These data may provide avenues for deeper understanding of spermatogenesis and the ability to improve this process in the laboratory. Research on miRNA continues to be an essential avenue for understanding human spermatogenesis.
Sustained Cognitive Improvement in Alzheimer’s Disease Patients Following a Precision Medicine Protocol: Case Series
Authors: Bredesen Dale E. , Ross Mary Kay , Ross Stephen
Published: August 2024

Arguably, the most important parameter in treating cognitive decline associated with Alzheimer’s disease is the length of time in which improvement, if achieved at all, is sustained. However, monotherapies such as donepezil and memantine are associated with a more rapid decline than no treatment in patients over multi-year follow-ups. Furthermore, anti-amyloid antibody treatment, which at best simply slows decline, is associated with accelerated cerebral atrophy, resulting in earlier dementia-associated brain volumes for those treated at the MCI stage than untreated patients. In contrast, a precision medicine approach, in which the multiple potential drivers of cognitive decline are identified for each patient and then targeted with a personalized protocol (such as ReCODE), has led to documented improvements in patients with cognitive decline, but long-term follow-up (>5 years) has not been reported previously. Therefore, here, we report sustained cognitive improvement, in some cases for over a decade, in patients treated with a precision medicine protocol—something that has not been reported in patients treated with anti-cholinesterase, glutamate receptor inhibitory, anti-amyloid, or other therapeutic methods. These case studies warrant long-term cohort studies to determine how frequently such sustained cognitive improvements occur in patients treated with precision medicine protocols.
Sodium Butyrate (NaB) and Sodium Propionate (NaP) Reduce Cyclin A2 Expression, Inducing Cell Cycle Arrest and Proliferation Inhibition of Different Breast Cancer Subtypes, Leading to Apoptosis
Authors: Ibrahim José-Noel , El-Hakim Sandy , Semaan Josiane , Ghosn Stéphanie , El Ayoubi Hiba , Elnar Arpiné Ardzivian , Tohme Najat , El Boustany Charbel
Published: August 2024

Sodium butyrate (NaB) and sodium propionate (NaP) have recently garnered attention for their role in regulating inflammation and controlling signaling pathways of cell growth and apoptosis, potentially preventing cancer development. However, their therapeutic effect and the underlying mechanisms involved remain elusive in breast cancer. This study aims at investigating the anticancer role of NaB and NaP in different types of breast cancer by assessing their antiproliferative effect on MCF-7 and MDA-MB-231 cells (through an MTT assay), as well as their ability to alter the cell cycle and cyclin expression (using flow cytometry and RT-qPCR, respectively), and to promote apoptosis (using Annexin V-FITC conjugated and sub-G1 phase techniques). MDA-MB-231 cell proliferation was inhibited by NaB and NaP in a dose- and time-dependent manner with respective IC50 values of 2.56 mM and 6.49 mM. Treatment induced cell arrest in the G1 phase which was further supported by the significant reduction in cyclin A2 and cyclin B1 expressions. Finally, NaB, and less significantly NaP, induced apoptosis in a dose-dependent manner with higher concentrations required for MDA-MB-231 than MCF-7. Our findings elucidate the cyclin-dependent inhibitory effect of NaB and NaP on the progression of different breast cancer subtypes, thus highlighting their therapeutic potential in breast cancer.
Cerebrospinal Fluid Total and Phosphorylated Tau Protein in Behavioral Variant Frontotemporal Dementia, Progressive Supranuclear Palsy, Corticobasal Syndrome and Non-Fluent Agrammatic Primary Progressive Aphasia: A Systematic Review and Meta-Analysis
Authors: Giagkou Nikolaos , Kapsali Ioanna , Brinia Maria-Evgenia , Constantinides Vasilios C.
Published: August 2024

(1) Background: Frontotemporal lobar degeneration (FTLD) is a generic term which refers to multiple pathologies, including FTLD-tau. The most common FTLD-tau diseases are Pick’s disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). These diseases share four major syndromes: behavioral variant frontotemporal dementia (bvFD), Richardson syndrome (RS), corticobasal syndrome (CBS) and non-fluent agrammatic primary progressive aphasia (nfa-PPA). The primary aim of this meta-analysis was to examine the diagnostic performance of CSF total (t-tau) and phosphorylated (p-tau) protein in bvFTD, RS, CBS, nfa-PPA and pathologically or genetically defined tauopathy. (2) Methods: A systematic review and meta-analysis was performed on all studies with >10 subjects in a bvFTD/RS/CBS/nfa-PPA group and control group and available data on CSF t-tau or p-tau (mean, SD). Cohen’s d was used to quantify the effect size of each study (3) Results: The PSP/tauopathy patients exhibited decreased levels of CSF p-tau compared to the control subjects. The CBS/bvFTD/nfa-PPA cohorts exhibited an increase in t-tau compared to the control groups. (4) Conclusions: Tauopathies may exhibit an inherent decrease in CSF p-tau. The admixture of AD patients in FTD cohorts and high heterogeneity among studies on rare diseases are significant confounding factors in FTLD studies.
Fourier Transform Ion Cyclotron Resonance Mass Spectrometry Applications for Metabolomics
Authors: Cochran Darcy , Powers Robert
Published: August 2024

Metabolomics is an interdisciplinary field that aims to study all metabolites < 1500 Da that are ubiquitously found within all organisms. Metabolomics is experiencing exponential growth and commonly relies on high-resolution mass spectrometry (HRMS). Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) is a form of HRMS that is particularly well suited for metabolomics research due to its exceptionally high resolution (105–106) and sensitivity with a mass accuracy in parts per billion (ppb). In this regard, FT-ICR-MS can provide valuable insights into the metabolomics analysis of complex biological systems due to unique capabilities such as the easy separation of isobaric and isomeric species, isotopic fine structure analysis, spatial resolution of metabolites in cells and tissues, and a high confidence (<1 ppm mass error) in metabolite identification. Alternatively, the large and complex data sets, long acquisition times, high cost, and limited access mainly through national mass spectrometry facilities may impede the routine adoption of FT-ICR-MS by metabolomics researchers. This review examines recent applications of FT-ICR-MS metabolomics in the search for clinical and non-human biomarkers; for the analysis of food, beverage, and environmental samples; and for the high-resolution imaging of tissues and other biological samples. We provide recent examples of metabolomics studies that highlight the advantages of FT-ICR-MS for the detailed and reliable characterization of the metabolome. Additionally, we offer some practical considerations for implementing FT-ICR-MS into a research program by providing a list of FT-ICR-MS facilities and by identifying different high-throughput interfaces, varieties of sample types, analysis methods (e.g., van Krevelen diagrams, Kendrick mass defect plot, etc.), and sample preparation and handling protocols used in FT-ICR-MS experiments. Overall, FT-ICR-MS holds great promise as a vital research tool for advancing metabolomics investigations.
Implementation of Rapid Nucleic Acid Amplification Based on the Super Large Thermoelectric Cooler Rapid Temperature Rise and Fall Heating Module
Authors: Cheng Jianxin , Zhang Enjia , Sun Rui , Zhang Kaihuan , Zhang Fangzhou , Zhao Jianlong , Feng Shilun , Liu Bo
Published: August 2024

In the rapid development of molecular biology, nucleic acid amplification detection technology has received more and more attention. The traditional polymerase chain reaction (PCR) instrument has poor refrigeration performance during its transition from a high temperature to a low temperature in the temperature cycle, resulting in a longer PCR amplification cycle. Peltier element equipped with both heating and cooling functions was used, while the robust adaptive fuzzy proportional integral derivative (PID) algorithm was also utilized as the fundamental temperature control mechanism. The heating and cooling functions were switched through the state machine mode, and the PCR temperature control module was designed to achieve rapid temperature change. Cycle temperature test results showed that the fuzzy PID control algorithm was used to accurately control the temperature and achieve rapid temperature rise and fall (average rising speed = 11 °C/s, average falling speed = 8 °C/s) while preventing temperature overcharging, maintaining temperature stability, and achieving ultra-fast PCR amplification processes (45 temperature cycle time < 19 min). The quantitative results show that different amounts of fluorescence signals can be observed according to the different concentrations of added viral particles, and an analytical detection limit (LoD) as low as 10 copies per μL can be achieved with no false positive in the negative control. The results show that the TEC amplification of nucleic acid has a high detection rate, sensitivity, and stability. This study intended to solve the problem where the existing thermal cycle temperature control technology finds it difficult to meet various new development requirements, such as the rapid, efficient, and miniaturization of PCR.
Investigating the Impact of the AI-Supported 5E (AI-s5E) Instructional Model on Spatial Ability
Authors: Gürefe Nejla , Sarpkaya Aktaş Gülfem , Öksüz Hava
Published: August 2024

Improving students’ spatial abilities is an important goal in education. Spatial ability is a skill needed in many fields, such as science, mathematics, engineering, and architecture. Since this ability can be improved through training, this study adopted a quasi-experimental design to investigate the effects of an artificial intelligence-supported 5E (AI-s5E) instructional model on students’ spatial visualization, spatial relationships, and spatial orientation performances that explain their spatial abilities. A total of 43 students from two classes at a secondary school in western Turkey were recruited to participate in this study. One of the classes was the experimental group (f = 23), which adopted the AI-s5E approach, and the other class was the control group (f = 20), which adopted the traditional teaching model. The results showed that the integration of the AI-s5E instructional approach into education improved students’ spatial abilities and sub-dimensions. In light of the findings, it can be recommended that AI applications, which have a positive and significant impact on spatial skills, can be integrated into teachers’ lessons and even included in curriculum programs.
Linking Self-Esteem to Problematic Mobile Phone Use: A Moderated Mediation Model of Fear of Missing Out and Ruminative Subtypes
Authors: Yang Xiujuan , Liu Qingqi , Gao Lingfeng , Wang Guojun , Liu Tiebang
Published: August 2024

Low self-esteem has been identified as a risk factor for problematic mobile phone use (PMPU). However, the magnitude of self-esteem’s effect on PMPU varied across different studies. Drawing on the Interaction of Person-Affect-Cognition-Execution model and the response styles theory, this study developed a moderated mediation model to investigate the mediating role of fear of missing out (FoMO) and the moderating roles of ruminative subtypes (i.e., brooding and reflection) in the relationship between self-esteem and PMPU. We conducted a cross-sectional survey among 806 undergraduate students (Mage = 19.35 years, SD = 1.18) using the convenience sampling method. Results showed that self-esteem was negatively associated with PMPU. Mediation analysis revealed that the association between self-esteem and PMPU was mediated by FoMO. Furthermore, moderated mediation analyses revealed that the mediating effect of FoMO was moderated by both brooding and reflection, such that the indirect effect became stronger for individuals with higher levels of brooding/reflection. These findings add to previous research by shedding light on how (i.e., mediation) and under what conditions (i.e., moderation) self-esteem is associated with PMPU and have implications for early prevention and intervention of individual PMPU.
Studyholism as a New Potential OCD-Related Disorder: What Evidence Have We Gathered until Now? A Narrative Review
Authors: Loscalzo Yura
Published: August 2024

In 2017, Loscalzo and Giannini introduced the new potential clinical condition of studyholism (or obsession toward study) and a comprehensive model including its possible antecedents and outcomes. Then, emphasizing the value of avoiding an aprioristic (addiction) framework in analyzing problematic overstudying, they suggested conducting research on this new construct to unveil its internalizing and/or externalizing nature while also avoiding the over-pathologizing of a common behavior such as studying. Seven years after the first publication about studyholism, growing evidence concerning its antecedents suggested that studyholism might be defined as an OCD-related disorder (or, more generally, as an internalizing disorder). Moreover, the research about its outcomes highlighted that it is a problem behavior deserving attention as it is associated with academic, psychological, physical, and social downsides. Therefore, this paper aims to review the scientific literature published concerning studyholism to illuminate if it might be conceptualized as an OCD-related disorder based on its symptomatology, antecedents, and impact on individuals’ academic, physical, and psychological functioning. Given that it is a new construct, it is of critical value to systematize the findings gathered until now as it can help scholars interested in students’ well-being to have a clear understanding concerning the importance of screening studyholism since childhood, as this will help favor academic success and well-being and reduce the risk for school dropout. Finally, this paper presents an agenda for future research on studyholism, and it highlights the importance of further analyzing problematic overstudying using different theoretical perspectives (such as the behavioral addiction conceptualization) to unveil its real nature.
Assessment of the Compound Damping of a System with Parallelly Coupled Anti-Seismic Devices
Authors: Bratu Polidor , Dragomir Claudiu-Sorin , Dobre Daniela
Published: August 2024

(1) Background: Romanian earthquakes caused severe damage over time to a significant number of constructions, and that is why efforts are being made to make structural systems safer. (2) Methods: For structural systems with protection against seismic actions or vibrational actions that have linear viscous dissipation devices, the requirement to assess the equivalent modal damping rate for the entire functional assembly related to the other dynamic parameters arises. (3) Results: This article presents the analytical development of formulas for the compound damping and circular frequency when anti-seismic devices have different dynamic characteristics and their application in order to solve some real engineering cases of bridges and viaducts in Romania with distinct viscoelastic supports. In support of this idea, some experimental tests on a beam system resting on two different anti-seismic elastic supports highlighted the fact that the compound damping of the system can be calculated with the relations established in this paper, provided that the displacements in the horizontal direction of excitation are in the linear domain. Also, we determined the seismic response considering the Vrancea 1977 accelerogram for critical damping ratios of 5% and 18.5%, and then we obtained the variation in the factor of transmissibility depending on the frequency, in order to highlight the optimized value of the equivalent amortization/damping. (4) Conclusions: In the specific context of Romanian seismicity, seismic isolation through the use of isolators with different characteristics represents an optimal technical solution, and it is also optimal from an economic point of view, with an appropriate level of dynamic isolation obtained.
Stress Analysis of a Concrete Pipeline in a Semi-Infinite Seabed under the Action of Elliptical Cosine Waves Based on the Seepage Equation
Authors: Ju Haiyan , Xu Manqing , Xu Bin , Fu Mingfu , Zeng Kaihua , Jiang Haibo
Published: August 2024

This study aims to investigate the mechanical response of a submarine concrete pipeline under wave action in shallow waters, taking into account factors such as the compressibility of pores and the permeability of the seabed. The control equation of the elliptical cosine wave theory is adopted to simulate the action of waves. In order to simulate the interaction between the solid skeleton and pore fluid, the concept of a “porous medium” is used to establish the transient seepage control equation. Utilizing the stress and displacement conditions at the interface of the ideal fluid media, porous media, and concrete pipeline, the numerical solutions for the internal force and pore pressure of the concrete pipeline buried in a semi-infinite thickness seabed were obtained; meanwhile, the effects of changes in the gas content in pore water and changes in the seabed permeability coefficient on a concrete pipeline were analyzed. The numerical calculation results show that, with the increase in the gas content in the pore water, the amplitude of the pore pressure on the pipeline surface decreases, and both the horizontal and vertical forces acting on the pipeline decrease; the amplitude of the pore pressure on the pipeline surface increases with the increase in seabed permeability and decreases with the enhancement of seabed permeability anisotropy; the improvement of the seabed permeability or enhancement of the permeability anisotropy can increase the horizontal force acting on the pipeline. This study provides a reference for the stability evaluation of submarine concrete pipelines under wave action in shallow water areas.
An Experimental Study on the Performance of Materials for Repairing Cracks in Tunnel Linings under Erosive Environments
Authors: Zhang Wenliang , Wang Yufeng , Nan Xiaocong , Sun Shangqu , Ma Yanhui , Wu Yankai
Published: August 2024

Addressing the current lining cracking problem in coastal tunnels, this paper independently introduces a novel type of repair material for tunnel lining cracks—the composite repair material consisting of waterborne epoxy resin and ultrafine cement (referred to as EC composite repair material). Through indoor testing, we have analyzed the change rule of the mass change rate, compressive strength, flexural strength, and chloride ion concentration of the repair material samples in erosive environments, with the dosage of each component in the EC composite repair material being varied. We have also investigated the working performance, mechanical properties, and microstructure of the repair material. The results of this study show that when the proportion of each component of ultrafine cement, waterborne epoxy resin, waterborne epoxy curing agent, waterborne polyurethane, defoamer, and water is 100:50:50:2.5:0.5:30, the performance of the EC composite repair material in a chloride ion-rich environment is optimal in all aspects. When the mixing ratio of each component of the EC composite repair material is as stated above, the repair material exhibits the best performance in a chloride ion erosion environment. With this ratio of components in the EC composite repair material, the fluidity, setting time, compressive strength, flexural strength, and bond strength of the repair material in a chloride ion erosion environment can meet the requirements of relevant specifications, and it is highly effective in repairing tunnel lining cracks. The polymeric film formed by the reaction between the waterborne epoxy resin emulsion and the curing agent fills the pores between the hydration products, resulting in a densely packed internal structure of EC composite repair material with enhanced erosion resistance, making it very suitable for repairing cracks in tunnel linings in erosive environments.
Combined Fluorescence-Guided Surgery with 5-Aminolevulinic Acid and Fluorescein in Glioblastoma: Technical Description and Report of 100 Cases
Authors: Pesaresi Alessandro , La Cava Pietro , Bonada Marta , Zeppa Pietro , Melcarne Antonio , Cofano Fabio , Fiaschi Pietro , Garbossa Diego , Bianconi Andrea
Published: August 2024

Background: Fluorescence-guided resection (FGR) of glioblastomas has been previously explored with the use of 5-amivelulinic acid (5-ALA) and sodium fluoresceine (SF), allowing us to maximize the extent of resection (EoR). In this study, we highlight the most relevant concerns regarding this technique and present the methods and results from the experience of our center. Methods: A case series of 100 patients operated on in AOU Città della Salute e della Scienza in Turin with a histological diagnosis of glioblastoma (grade IV, according to WHO 2021) was retrospectively analyzed. Both 5-ALA and SF were administered and intraoperatively assessed with an optical microscope. Results: 5-ALA is the only approved drug for FGR in glioblastoma, reporting an increased EoR. Nevertheless, SF can be positively used in addition to 5-ALA to reduce the risk of false positives without increasing the rate of adverse effects. In our experience, SF was used to guide the initial phase of resection while 5-ALA was used to visualize tumor spots within the surgical cavity. In 96% of cases, gross total resection was achieved, with supra-maximal resection in 11% of cases. Conclusions: Combined FGR using 5-ALA and SF seems to be a promising method of increasing the extent of resection and to improving the prognosis in glioblastoma patients.
Liver X Receptors Enhance Epithelial to Mesenchymal Transition in Metastatic Prostate Cancer Cells
Authors: Bouchareb Erwan , Dallel Sarah , De Haze Angélique , Damon-Soubeyrand Christelle , Renaud Yoan , Baabdaty Elissa , Vialat Marine , Fabre Julien , Pouchin Pierre , De Joussineau Cyrille , Degoul Françoise , Sanmukh Swapnil , Gendronneau Juliette , Sanchez Phelipe , Gonthier-Gueret Céline , Trousson Amalia , Morel Laurent , Lobaccaro Jean Marc , Kocer Ayhan , Baron Silvère
Published: August 2024

Prostate cancer (PCa) is one of the most common cancers in men. Metastasis is the leading cause of death in prostate cancer patients. One of the crucial processes involved in metastatic spread is the “epithelial–mesenchymal transition” (EMT), which allows cells to acquire the ability to invade distant organs. Liver X Receptors (LXRs) are nuclear receptors that have been demonstrated to regulate EMT in various cancers, including hepatic cancer. Our study reveals that the LXR pathway can control pro-invasive cell capacities through EMT in prostate cancer, employing ex vivo and in vivo approaches. We characterized the EMT status of the commonly used LNCaP, DU145, and PC3 prostate cancer cell lines through molecular and immunohistochemistry experiments. The impact of LXR activation on EMT function was also assessed by analyzing the migration and invasion of these cell lines in the absence or presence of an LXR agonist. Using in vivo experiments involving NSG-immunodeficient mice xenografted with PC3-GFP cells, we were able to study metastatic spread and the effect of LXRs on this process. LXR activation led to an increase in the accumulation of Vimentin and Amphiregulin in PC3. Furthermore, the migration of PC3 cells significantly increased in the presence of the LXR agonist, correlating with an upregulation of EMT. Interestingly, LXR activation significantly increased metastatic spread in an NSG mouse model. Overall, this work identifies a promoting effect of LXRs on EMT in the PC3 model of advanced prostate cancer.
Synergistic Strategies for Castration-Resistant Prostate Cancer: Targeting AR-V7, Exploring Natural Compounds, and Optimizing FDA-Approved Therapies
Authors: Rahman Muntajin , Akter Khadija , Ahmed Kazi Rejvee , Fahim Md. Maharub Hossain , Aktary Nahida , Park Moon Nyeo , Shin Sang-Won , Kim Bonglee
Published: August 2024

Castration-resistant prostate cancer (CRPC) remains a significant therapeutic challenge due to its resistance to standard androgen deprivation therapy (ADT). The emergence of androgen receptor splice variant 7 (AR-V7) has been implicated in CRPC progression, contributing to treatment resistance. Current treatments, including first-generation chemotherapy, androgen receptor blockers, radiation therapy, immune therapy, and PARP inhibitors, often come with substantial side effects and limited efficacy. Natural compounds, particularly those derived from herbal medicine, have garnered increasing interest as adjunctive therapeutic agents against CRPC. This review explores the role of AR-V7 in CRPC and highlights the promising benefits of natural compounds as complementary treatments to conventional drugs in reducing CRPC and overcoming therapeutic resistance. We delve into the mechanisms of action underlying the anti-CRPC effects of natural compounds, showcasing their potential to enhance therapeutic outcomes while mitigating the side effects associated with conventional therapies. The exploration of natural compounds offers promising avenues for developing novel treatment strategies that enhance therapeutic outcomes and reduce the adverse effects of conventional CRPC therapies. These compounds provide a safer, more effective approach to managing CRPC, representing a significant advancement in improving patient care.
Preclinical Efficacy of VTX-0811: A Humanized First-in-Class PSGL-1 mAb Targeting TAMs to Suppress Tumor Growth
Authors: Novobrantseva Tatiana , Manfra Denise , Ritter Jessica , Razlog Maja , O’Nuallain Brian , Zafari Mohammad , Nowakowska Dominika , Basinski Sara , Phennicie Ryan T. , Nguyen Phuong A. , Brehm Michael A. , Sazinsky Stephen , Feldman Igor
Published: August 2024

Omnipresent suppressive myeloid populations in the tumor microenvironment limit the efficacy of T-cell-directed immunotherapies, become more inhibitory after administration of T-cell checkpoint inhibitors, and are overall associated with worse survival of cancer patients. In early clinical trials, positive outcomes have been demonstrated for therapies aimed at repolarizing suppressive myeloid populations in the tumor microenvironment. We have previously described the key role of P-selectin glycoprotein ligand-1 (PSGL-1) in maintaining an inhibitory state of tumor-associated macrophages (TAMs), most of which express high levels of PSGL-1. Here we describe a novel, first-in-class humanized high-affinity monoclonal antibody VTX-0811 that repolarizes human macrophages from an M2-suppressive phenotype towards an M1 inflammatory phenotype, similar to siRNA-mediated knockdown of PSGL-1. VTX-0811 binds to PSGL-1 of human and cynomolgus macaque origins without inhibiting PSGL-1 interaction with P- and L-Selectins or VISTA. In multi-cellular assays and in patient-derived human tumor cultures, VTX-0811 leads to the induction of pro-inflammatory mediators. RNAseq data from VTX-0811 treated ex vivo tumor cultures and M2c macrophages show similar pathways being modulated, indicating that the mechanism of action translates from isolated macrophages to tumors. A chimeric version of VTX-0811, consisting of the parental murine antibody in a human IgG4 backbone, inhibits tumor growth in a humanized mouse model of cancer. VTX-0811 is exceptionally well tolerated in NHP toxicology assessment and is heading into clinical evaluation after successful IND clearance.
Assessment of Photoactivated Chlorophyllin Production of Singlet Oxygen and Inactivation of Foodborne Pathogens
Authors: Pablos Cristina , Marugán Javier , van Grieken Rafael , Hamilton Jeremy W. J. , Ternan Nigel G. , Dunlop Patrick S. M.
Published: August 2024

Singlet oxygen (1O2) is known to have antibacterial activity; however, production can involve complex processes with expensive chemical precursors and/or significant energy input. Recent studies have confirmed the generation of 1O2 through the activation of photosensitizer molecules (PSs) with visible light in the presence of oxygen. Given the increase in the incidence of foodborne diseases associated with cross-contamination in food-processing industries, which is becoming a major concern, food-safe additives, such as chlorophyllins, have been studied for their ability to act as PSs. The fluorescent probe Singlet Oxygen Sensor Green (SOSG®) was used to estimate 1O2 formation upon the irradiation of traditional PSs (rose bengal (RB), chlorin 6 (ce6)) and novel chlorophyllins, sodium magnesium (NaChl) and sodium copper (NaCuChl), with both simulated-solar and visible light. NaChl gave rise to a similar 1O2 production rate when compared to RB and ce6. Basic mixing was shown to introduce sufficient oxygen to the PS solutions, preventing the limitation of the 1O2 production rate. The NaChl-based inactivation of Gram-positive S. aureus and Gram-negative E. coli was demonstrated with a 5-log reduction with UV–Vis light. The NaChl-based inactivation of Gram-positive S. aureus was accomplished with a 2-log reduction after 105 min of visible-light irradiation and a 3-log reduction following 150 min of exposure from an initial viable bacterial concentration of 106 CFU mL−1. CHS-NaChl-based photosensitization under visible light enhanced Gram-negative E. coli inactivation and provided a strong bacteriostatic effect preventing E. coli proliferation. The difference in the ability of NaChl and CHS-NaChl complexes to inactivate Gram-positive and Gram-negative bacteria was confirmed to result from the cell wall structure, which impacted PS–bacteria attachment and therefore the production of localized singlet oxygen.
Perivascular Adipose Tissue and Perivascular Adipose Tissue-Derived Extracellular Vesicles: New Insights in Vascular Disease
Authors: Sigdel Smara , Udoh Gideon , Albalawy Rakan , Wang Jinju
Published: August 2024

Perivascular adipose tissue (PVAT) is a special deposit of fat tissue surrounding the vasculature. Previous studies suggest that PVAT modulates the vasculature function in physiological conditions and is implicated in the pathogenesis of vascular diseases. Understanding how PVAT influences vasculature function and vascular disease progression is important. Extracellular vesicles (EVs) are novel mediators of intercellular communication. EVs encapsulate molecular cargo such as proteins, lipids, and nucleic acids. EVs can influence cellular functions by transferring the carried bioactive molecules. Emerging evidence indicates that PVAT-derived EVs play an important role in vascular functions under health and disease conditions. This review will focus on the roles of PVAT and PVAT-EVs in obesity, diabetic, and metabolic syndrome-related vascular diseases, offering novel insights into therapeutic targets for vascular diseases.
Analysis of Cytotoxic Granules and Constitutively Produced Extracellular Vesicles from Large Granular Lymphocytic Leukemia Cell Lines
Authors: Ploeger Lara , Kaleja Patrick , Tholey Andreas , Lettau Marcus , Janssen Ottmar
Published: August 2024

Background: Large granular lymphocyte leukemias (LGLLs) are rare lymphoproliferative malignancies caused by clonal expansion of granular lymphocytes. T-cell LGLL and natural killer (NK) cell LGLL are defined based on their cellular origin. Their clinical manifestation and pathophysiology vary depending on the subtype and include, e.g., neutropenia, anemia, recurrent infections, and autoimmunity. A limited number of available patient-derived cell lines are considered valuable tools to study the biology of these malignancies. They differ in the expression of lineage-specific surface markers, but generally contain cytotoxic effector molecules in characteristic granules. Methods: We investigated the presence and release of lysosome-associated effector proteins in patient-derived LGLL cell lines by flow and imaging cytometry, by Western blotting and by bottom–up proteomics profiling. Results: The tested cell lines did not express FasL (CD178), but did express CD26/DPP4+. Intracellularly, we detected major differences in the abundance and subcellular distribution of granzymes, perforin, and granulysin. Similar differences were seen in enriched lysosome-related effector vesicles (LREVs). The proteomics profiling of enriched EVs from an NK-LGLL line (NKL) and a T-LGLL line (MOTN-1), confirmed individual profiles of effector molecules. Conclusion: Our analyses underscore the individual distribution of effector proteins but also open new routes to define the role of intra- and extracellular granules in the disease manifestation or pathology of LGLLs.
Combined High—Throughput Proteomics and Random Forest Machine-Learning Approach Differentiates and Classifies Metabolic, Immune, Signaling and ECM Intra-Tumor Heterogeneity of Colorectal Cancer
Authors: Contini Cristina , Manconi Barbara , Olianas Alessandra , Guadalupi Giulia , Schirru Alessandra , Zorcolo Luigi , Castagnola Massimo , Messana Irene , Faa Gavino , Diaz Giacomo , Cabras Tiziana
Published: August 2024

Colorectal cancer (CRC) is a frequent, worldwide tumor described for its huge complexity, including inter-/intra-heterogeneity and tumor microenvironment (TME) variability. Intra-tumor heterogeneity and its connections with metabolic reprogramming and epithelial–mesenchymal transition (EMT) were investigated with explorative shotgun proteomics complemented by a Random Forest (RF) machine-learning approach. Deep and superficial tumor regions and distant-site non-tumor samples from the same patients (n = 16) were analyzed. Among the 2009 proteins analyzed, 91 proteins, including 23 novel potential CRC hallmarks, showed significant quantitative changes. In addition, a 98.4% accurate classification of the three analyzed tissues was obtained by RF using a set of 21 proteins. Subunit E1 of 2-oxoglutarate dehydrogenase (OGDH-E1) was the best classifying factor for the superficial tumor region, while sorting nexin-18 and coatomer-beta protein (beta-COP), implicated in protein trafficking, classified the deep region. Down- and up-regulations of metabolic checkpoints involved different proteins in superficial and deep tumors. Analogously to immune checkpoints affecting the TME, cytoskeleton and extracellular matrix (ECM) dynamics were crucial for EMT. Galectin-3, basigin, S100A9, and fibronectin involved in TME–CRC–ECM crosstalk were found to be differently variated in both tumor regions. Different metabolic strategies appeared to be adopted by the two CRC regions to uncouple the Krebs cycle and cytosolic glucose metabolism, promote lipogenesis, promote amino acid synthesis, down-regulate bioenergetics in mitochondria, and up-regulate oxidative stress. Finally, correlations with the Dukes stage and budding supported the finding of novel potential CRC hallmarks and therapeutic targets.
Gastrointestinal Cancer Patient Derived Organoids at the Frontier of Personalized Medicine and Drug Screening
Authors: Yang Zhenjie , Yu Jun , Wong Chi Chun
Published: August 2024

Cancer is a leading cause of death worldwide. Around one-third of the total global cancer incidence and mortality are related to gastrointestinal (GI) cancers. Over the past few years, rapid developments have been made in patient-derived organoid (PDO) models for gastrointestinal cancers. By closely mimicking the molecular properties of their parent tumors in vitro, PDOs have emerged as powerful tools in personalized medicine and drug discovery. Here, we review the current literature on the application of PDOs of common gastrointestinal cancers in the optimization of drug treatment strategies in the clinic and their rising importance in pre-clinical drug development. We discuss the advantages and limitations of gastrointestinal cancer PDOs and outline the microfluidics-based strategies that improve the throughput of PDO models in order to extract the maximal benefits in the personalized medicine and drug discovery process.