bluuebunny/crossref_metadata_2025 huggingface dataset:
Income Disparities in Survival and Receipt of Neoadjuvant Chemotherapy and Pelvic Lymph Node Dissection for Muscle-Invasive Bladder Cancer
Authors: Antar Ryan M. , Xu Vincent E. , Adesanya Oluwafolajimi , Drouaud Arthur , Longton Noah , Gordon Olivia , Youssef Kirolos , Kfouri Jad , Azari Sarah , Tafuri Sean , Goddard Briana , Whalen Michael J.
Published: May 2024

Background: Muscle-invasive bladder cancer (MIBC) is a potentially fatal disease, especially in the setting of locally advanced or node-positive disease. Adverse outcomes have also primarily been associated with low-income status, as has been reported in other cancers. While the adoption of neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC) and pelvic lymph node dissection (PLND) has improved outcomes, these standard-of-care treatments may be underutilized in lower-income patients. We sought to investigate the economic disparities in NAC and PLND receipt and survival outcomes in MIBC. Methods: Utilizing the National Cancer Database, a retrospective cohort analysis of cT2-4N0-3M0 BCa patients with urothelial histology who underwent RC was conducted. The impact of income level on overall survival (OS) and the likelihood of receiving NAC and PLND was evaluated. Results: A total of 25,823 patients were included. This study found that lower-income patients were less likely to receive NAC and adequate PLND (≥15 LNs). Moreover, lower-income patients exhibited worse OS (Median OS 55.9 months vs. 68.2 months, p < 0.001). Our findings also demonstrated that higher income, treatment at academic facilities, and recent years of diagnosis were associated with an increased likelihood of receiving standard-of-care modalities and improved survival. Conclusions: Even after controlling for clinicodemographic variables, income independently influenced the receipt of standard MIBC treatments and survival. Our findings identify an opportunity to improve the quality of care for lower-income MIBC patients through concerted efforts to regionalize multi-modal urologic oncology care.
Impact of an Inter-Professional Clinic on Pancreatic Cancer Outcomes: A Retrospective Cohort Study
Authors: Moffat Gordon Taylor , Coyne Zachary , Albaba Hamzeh , Aung Kyaw Lwin , Dodd Anna , Espin-Garcia Osvaldo , Moura Shari , Gallinger Steven , Kim John , Fraser Adriana , Hutchinson Shawn , Moulton Carol-Anne , Wei Alice , McGilvray Ian , Dhani Neesha , Jang Raymond , Elimova Elena , Moore Malcolm , Prince Rebecca , Knox Jennifer
Published: May 2024

Background: Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges in diagnosis, staging, and appropriate treatment. Furthermore, patients with PDAC often experience complex symptomatology and psychosocial implications that require multi-disciplinary and inter-professional supportive care management from health professionals. Despite these hurdles, the implementation of inter-professional clinic approaches showed promise in enhancing clinical outcomes. To assess the effectiveness of such an approach, we examined the impact of the Wallace McCain Centre for Pancreatic Cancer (WMCPC), an inter-professional clinic for patients with PDAC at the Princess Margaret Cancer Centre (PM). Methods: This retrospective cohort study included all patients diagnosed with PDAC who were seen at the PM before (July 2012–June 2014) and after (July 2014–June 2016) the establishment of the WMCPC. Standard therapies such as surgery, chemotherapy, and radiation therapy remained consistent across both time periods. The cohorts were compared in terms of survival rates, disease stage, referral patterns, time to treatment, symptoms, and the proportion of patients assessed and supported by nursing and allied health professionals. Results: A total of 993 patients were included in the review, comprising 482 patients pre-WMCPC and 511 patients post-WMCPC. In the multivariate analysis, adjusting for ECOG (Eastern Cooperative Oncology Group) and stage, it was found that post-WMCPC patients experienced longer median overall survival (mOS, HR 0.84, 95% CI 0.72–0.98, p = 0.023). Furthermore, the time from referral to initial consultation date decreased significantly from 13.4 to 8.8 days in the post-WMCPC cohort (p < 0.001), along with a reduction in the time from the first clinic appointment to biopsy (14 vs. 8 days, p = 0.022). Additionally, patient-reported well-being scores showed improvement in the post-WMCPC cohort (p = 0.02), and these patients were more frequently attended to by nursing and allied health professionals (p < 0.001). Conclusions: The implementation of an inter-professional clinic for patients diagnosed with PDAC led to improvements in overall survival, patient-reported well-being, time to initial assessment visit and pathological diagnosis, and symptom management. These findings advocate for the adoption of an inter-professional clinic model in the treatment of patients with PDAC.
Thermodynamic Entropy-Based Fatigue Life Assessment Method for Nickel-Based Superalloy GH4169 at Elevated Temperature Considering Cyclic Viscoplasticity
Authors: Ding Shuiting , Xia Shuyang , Li Zhenlei , Zhou Huimin , Bao Shaochen , Li Bolin , Li Guo
Published: May 2024

This paper develops a thermodynamic entropy-based life prediction model to estimate the low-cycle fatigue (LCF) life of the nickel-based superalloy GH4169 at elevated temperature (650 °C). The gauge section of the specimen was chosen as the thermodynamic system for modeling entropy generation within the framework of the Chaboche viscoplasticity constitutive theory. Furthermore, an explicitly numerical integration algorithm was compiled to calculate the cyclic stress–strain responses and thermodynamic entropy generation for establishing the framework for fatigue life assessment. A thermodynamic entropy-based life prediction model is proposed with a damage parameter based on entropy generation considering the influence of loading ratio. Fatigue lives for GH4169 at 650 °C under various loading conditions were estimated utilizing the proposed model, and the results showed good consistency with the experimental results. Finally, compared to the existing classical models, such as Manson–Coffin, Ostergren, Walker strain, and SWT, the thermodynamic entropy-based life prediction model provided significantly better life prediction results.
Learning Traveling Solitary Waves Using Separable Gaussian Neural Networks
Authors: Xing Siyuan , Charalampidis Efstathios G.
Published: May 2024

In this paper, we apply a machine-learning approach to learn traveling solitary waves across various physical systems that are described by families of partial differential equations (PDEs). Our approach integrates a novel interpretable neural network (NN) architecture, called Separable Gaussian Neural Networks (SGNN) into the framework of Physics-Informed Neural Networks (PINNs). Unlike the traditional PINNs that treat spatial and temporal data as independent inputs, the present method leverages wave characteristics to transform data into the so-called co-traveling wave frame. This reformulation effectively addresses the issue of propagation failure in PINNs when applied to large computational domains. Here, the SGNN architecture demonstrates robust approximation capabilities for single-peakon, multi-peakon, and stationary solutions (known as “leftons”) within the (1+1)-dimensional, b-family of PDEs. In addition, we expand our investigations, and explore not only peakon solutions in the ab-family but also compacton solutions in (2+1)-dimensional, Rosenau-Hyman family of PDEs. A comparative analysis with multi-layer perceptron (MLP) reveals that SGNN achieves comparable accuracy with fewer than a tenth of the neurons, underscoring its efficiency and potential for broader application in solving complex nonlinear PDEs.
Results of a Competency-Based Approach to Prepare General Educators to Effectively Include Students with Disabilities
Authors: Harkins-Brown Andrea R. , Gillon Nicholas , Schanbacher Andrea
Published: May 2024

Research has shown that general educators may lack the competencies to effectively include students with disabilities, thus widening the gaps in outcomes between students with disabilities and their peers. In this study, we outline the development and implementation of a competency-based continuing education program, designed to equip general educators to effectively include students with disabilities (SWDs) and earn special education certification. This paper presents the results of a program evaluation conducted using both validated measures and author-developed instruments. Participants included general education teachers, instructional coaches, and those in similar roles. Results indicated that participants significantly increased their knowledge of professional standards, demonstrated knowledge in high-leverage practices, and showed high levels of self-efficacy to implement inclusive practices. We discuss these results, emphasizing the timeliness of this nontraditional approach and its implications for teacher preparation, research, and policy amid the troubling national special education teacher shortage. Namely, this approach epitomizes a model that allows leaders to strategically utilize their existing workforce to address vacancies in special education and emphasizes that the responsibility to support SWDs rests squarely upon all educators.
Cognitive Strategies of Second Language Vocabulary Inferencing: An Eye Tracking Study
Authors: Izmalkova Anna , Blinnikova Irina
Published: May 2024

In contextual vocabulary acquisition, second language learners address both morphological and contextual cues to infer the meanings of novel words. The study investigated cognitive strategies and their eye movement correlates in contextual vocabulary inferencing task. A sample of 30 healthy participants with normal or corrected to normal vision read an Intermediate-level text in English, aiming to define the meaning of 10 low-frequency words embedded in the text. Based on both unstructured and structured post-hoc reports, we attributed the inferencing process either to word-level processing, context-level processing, or discourse-level processing strategy. Eye movements were recorded on the target word and on the target word clause areas of interest. Inferencing success was associated with increased first fixation duration on the target word both for word- and context-level processing strategy, and increased dwell time on the target word clause for context-level processing strategy. Our findings emphasize the role of both morphological and contextual processing in vocabulary inferencing task.
TXAI-ADV: Trustworthy XAI for Defending AI Models against Adversarial Attacks in Realistic CIoT
Authors: Ojo Stephen , Krichen Moez , Alamro Meznah , Mihoub Alaeddine
Published: May 2024

Adversarial attacks are more prevalent in Consumer Internet of Things (CIoT) devices (i.e., smart home devices, cameras, actuators, sensors, and micro-controllers) because of their growing integration into daily activities, which brings attention to their possible shortcomings and usefulness. Keeping protection in the CIoT and countering emerging risks require constant updates and monitoring of these devices. Machine learning (ML), in combination with Explainable Artificial Intelligence (XAI), has become an essential component of the CIoT ecosystem due to its rapid advancement and impressive results across several application domains for attack detection, prevention, mitigation, and providing explanations of such decisions. These attacks exploit and steal sensitive data, disrupt the devices’ functionality, or gain unauthorized access to connected networks. This research generates a novel dataset by injecting adversarial attacks into the CICIoT2023 dataset. It presents an adversarial attack detection approach named TXAI-ADV that utilizes deep learning (Mutli-Layer Perceptron (MLP) and Deep Neural Network (DNN)) and machine learning classifiers (K-Nearest Neighbor (KNN), Support Vector Classifier (SVC), Gaussian Naive Bayes (GNB), ensemble voting, and Meta Classifier) to detect attacks and avert such situations rapidly in a CIoT. This study utilized Shapley Additive Explanations (SHAP) techniques, an XAI technique, to analyze the average impact of each class feature on the proposed models and select optimal features for the adversarial attacks dataset. The results revealed that, with a 96% accuracy rate, the proposed approach effectively detects adversarial attacks in a CIoT.
Optimised Congestion Management Using Curative Measures in Combined AC/DC Systems with Flexible AC Transmission Systems
Authors: Mende Denis , Hofmann Lutz
Published: May 2024

Due to the increasing demand for transport of electrical energy, measures for power flow control, congestion management, and higher utilisation of the existing grid play a decisive role in the transformation of the power system. Hence, enormous efforts must be undertaken using measures of congestion management. Modelling and integration of corresponding measures in optimisation tools to support grid and system operation and therewith reduce the resulting efforts become more important. This is especially true because of the high intermittency and decentralisation of renewable generation leading to increased complexity of the power system, higher loading of assets, and a growing need for control over flexible alternating current transmission systems (FACTS) and high-voltage direct current (HVDC) converters. This work therefore describes the implementation of optimised congestion management in an A Mathematical Programming Language (AMPL)-based nonlinear optimisation problem. AMPL is an effective tool to deal with highly complex problems of optimisation and scheduling. Therefore, the modelling of assets and flexibilities for power flow control in AC/DC systems in combination with an innovative grid operation strategy using predefined curative measures for the optimised use of the existing grid is introduced. The nonlinear mathematical optimisation aims at the optimal cost selection of flexibility measures. The application of the optimisation technique in a combined AC/DC system shows the optimal preventive and curative use of measures in operational congestion management. Simulation results prove that, by using predefined curative measures, the volume of cost-intensive preventive measures can significantly be reduced, especially in association with power flow control.
Recent Advances in Power Quality Analysis and Robust Control of Renewable Energy Sources in Power Grids
Authors: Vukadinović Dinko
Published: May 2024

In modern power grids with a large share of distributed power production, achieving high-power quality is a challenging task [...]
Prosumer Impact on Cellular Power Systems
Authors: Maiwald Jens , Schütte Tino
Published: May 2024

This paper explores the impact of an increasing number of prosumers in electricity supply systems and investigates how market mechanisms can mitigate the negative effects. The Regional Energy Market Model simulates a supply system based on cellular structures, employing agent-based modeling to capture individual behaviors and simulate real market dynamics. This study includes various supply scenarios, such as a solely photovoltaic scenario and a technically diversified scenario with biogas-fueled combined heat and power units. For each scenario, fixed and flexible pricing scenarios are simulated to analyze their effects. The findings reveal that systems heavily reliant on photovoltaics experience negative effects at certain points due to seasonal limitations, while technically diversified supply scenarios demonstrate fewer drawbacks. Flexible pricing systems stimulate demand in a manner beneficial to the system, creating regional added value, and contributing to the balance between generation and consumption, depending on the supply scenario. However, the study underscores that economic incentives alone are insufficient for balancing generation and consumption. The results highlight the importance of exploring opportunities through the interplay of economic incentive mechanisms and technical possibilities.
Empowering Students to Create Climate-Friendly Schools
Authors: Wagner Oliver , Tholen Lena , Albert-Seifried Sebastian , Swagemakers Julia
Published: May 2024

In Germany, there are over 32,000 schools, representing great potential for climate protection. On the one hand, this applies to educational work, as understanding the effects of climate change and measures to reduce GHG emissions is an important step to empower students with knowledge and skills. On the other hand, school buildings are often in bad condition, energy is wasted, and the possibilities for using renewable energies are hardly used. In our “Schools4Future” project, we enabled students and teachers to draw up their own CO2 balances, identify weaknesses in the building, detect wasted electricity, and determine the potential for using renewable energies. Emissions from the school cafeteria, school trips, and paper consumption could also be identified. The fact that the data can be collected by the students themselves provides increased awareness of the contribution made to the climate balance by the various school areas. The most climate-friendly school emits 297 kg whilst the school with the highest emissions emits over one ton CO2 per student and year. Our approach is suitable to qualify students in the sense of citizen science, carry out a scientific investigation, experience self-efficacy through one’s own actions, and engage politically regarding their concerns.
Convex Relaxations of Maximal Load Delivery for Multi-Contingency Analysis of Joint Electric Power and Natural Gas Transmission Networks
Authors: Tasseff Byron , Coffrin Carleton , Bent Russell
Published: May 2024

Recent increases in gas-fired power generation have engendered increased interdependencies between natural gas and power transmission systems. These interdependencies have amplified existing vulnerabilities in gas and power grids, where disruptions can require the curtailment of load in one or both systems. Although typically operated independently, coordination of these systems during severe disruptions can allow for targeted delivery to lifeline services, including gas delivery for residential heating and power delivery for critical facilities. To address the challenge of estimating maximum joint network capacities under such disruptions, we consider the task of determining feasible steady-state operating points for severely damaged systems while ensuring the maximal delivery of gas and power loads simultaneously, represented mathematically as the nonconvex joint Maximal Load Delivery (MLD) problem. To increase its tractability, we present a mixed-integer convex relaxation of the MLD problem. Then, to demonstrate the relaxation’s effectiveness in determining bounds on network capacities, exact and relaxed MLD formulations are compared across various multi-contingency scenarios on nine joint networks ranging in size from 25 to 1191 nodes. The relaxation-based methodology is observed to accurately and efficiently estimate the impacts of severe joint network disruptions, often converging to the relaxed MLD problem’s globally optimal solution within ten seconds.
Empowering Sustainability: Understanding Determinants of Consumer Investment in Microgrid Technology in the UAE
Authors: Sajwani Hussain Abdalla , Soudan Bassel , Olabi Abdul Ghani
Published: May 2024

This study aims to analyze the determinants that influence the consumers’ disposition to invest in microgrid technology in the United Arab Emirates (UAE). This research offers valuable insights for policymakers on investors’ motivations to develop strategies to foster microgrid technology adoption through end-user investments leading to a reduction in microgrid high capital cost. The study employed descriptive statistics, correlation, and regression analyses to analyze the responses of a sample of property owners to a quantitative survey. The study examines such variables as strategic alignment, profitability, digitization, renewable energy utilization, CO2 emission reduction, and disaster recovery readiness. The data collected reveal a moderate level of understanding and cost-awareness of microgrid technology among the respondents, with a mean of 2.46 out of 5. Notably, the data highlight the significant influence of strategic alignment with the UAE’s national energy goals on the respondents’ inclination to invest in microgrids, with a strong positive correlation of 0.942 at the 0.01 level (two-tailed). By comparison, profitability and disaster recovery have a comparatively weaker correlation. Furthermore, based on the data collected during this study, it has been determined that there is a strong value added by the microgrid initiatives considering the UAE’s strategic direction and the positive influence of reduced CO2. The regression models used were highly significant at F = 85.690. There is an acceptable level of multicollinearity with VIF values ranging from 1.087 to 2.155. UAE Strategy has low collinearity. UAE Strategy emerges as the only significant predictor of willingness to invest (p < 0.001) in the stepwise regression analysis. The analysis shows that villa and townhouse owners are willing to invest in community microgrid given that it is aligned with UAE strategy and leads to CO2 emissions reduction.
MD3F: Multivariate Distance Drift Diffusion Framework for High-Dimensional Datasets
Authors: Zielinski Jessica , Corby Patricia , Alekseyenko Alexander V.
Published: May 2024

High-dimensional biomedical datasets have become easier to collect in the last two decades with the advent of multi-omic and single-cell experiments. These can generate over 1000 measurements per sample or per cell. More recently, focus has been drawn toward the need for longitudinal datasets, with the appreciation that important dynamic changes occur along transitions between health and disease. Analysis of longitudinal omics data comes with many challenges, including type I error inflation and corresponding loss in power when thousands of hypothesis tests are needed. Multivariate analysis can yield approaches with higher statistical power; however, multivariate methods for longitudinal data are currently limited. We propose a multivariate distance-based drift-diffusion framework (MD3F) to tackle the need for a multivariate approach to longitudinal, high-throughput datasets. We show that MD3F can result in surprisingly simple yet valid and powerful hypothesis testing and estimation approaches using generalized linear models. Through simulation and application studies, we show that MD3F is robust and can offer a broadly applicable method for assessing multivariate dynamics in omics data.
Investigation into the Anti-Acne Effects of Castanea sativa Mill Leaf and Its Pure Ellagitannin Castalagin in HaCaT Cells Infected with Cutibacterium acnes
Authors: Piazza Stefano , Martinelli Giulia , Maranta Nicole , Pozzoli Carola , Fumagalli Marco , Nicolaci Vincenzo , Sonzogni Elisa , Colombo Luca , Sangiovanni Enrico , Dell’Agli Mario
Published: May 2024

Acne vulgaris is a prevalent skin disorder affecting many young individuals, marked by keratinization, inflammation, seborrhea, and colonization by Cutibacterium acnes (C. acnes). Ellagitannins, known for their antibacterial and anti-inflammatory properties, have not been widely studied for their anti-acne effects. Chestnut (Castanea sativa Mill., C. sativa), a rich ellagitannin source, including castalagin whose acne-related bioactivity was previously unexplored, was investigated in this study. The research assessed the effect of C. sativa leaf extract and castalagin on human keratinocytes (HaCaT) infected with C. acnes, finding that both inhibited IL-8 and IL-6 release at concentrations below 25 μg/mL. The action mechanism was linked to NF-κB inhibition, without AP-1 involvement. Furthermore, the extract displayed anti-biofilm properties and reduced CK-10 expression, indicating a potential role in mitigating inflammation, bacterial colonization, and keratosis. Castalagin’s bioactivity mirrored the extract’s effects, notably in IL-8 inhibition, NF-κB inhibition, and biofilm formation at low μM levels. Other polyphenols, such as flavonol glycosides identified via LC-MS, might also contribute to the extract’s biological activities. This study is the first to explore ellagitannins’ potential in treating acne, offering insights for developing chestnut-based anti-acne treatments pending future in vivo studies.
Vitamin Nutritional Status in Patients with Pancreatic Cancer: A Narrative Review
Authors: Azzini Elena , Furini Tiziano , Polito Angela , Scalfi Luca , Pinto Alessandro , Gasperi Valeria , Savini Isabella ,   on behalf of the SINU “Nutrition in Oncology” Working Group
Published: May 2024

Due to the high mortality rate in Western countries, pancreatic cancer is considered one of the big killers, leaving patients and their families with little hope upon diagnosis. Although surgical and drug therapies are critical for cancer patients to improve life expectancy and alleviation of suffering, nutrition plays a key role in improving cancer treatment outcomes. This narrative review, conducted as part of the activities of the Italian Society of Human Nutrition (SINU) working group in oncology, focuses on the prevalence of vitamin malnutrition among pancreatic cancer patients. The results of the literature search show that pancreatic cancer patients are at a heightened risk of water-soluble vitamin deficiencies, particularly of vitamins B1, B3, and B6. Additionally, they also face an increased risk of deficiency of fat-soluble vitamins. Among these vitamins, the potential role of vitamin D in pancreatic cancer has garnered the most attention, with its plasma levels being identified as a significant factor in patient survival. Investigating vitamin nutritional status could provide valuable insights for incorporating nutritional approaches into the prevention and treatment of pancreatic cancer, thereby reducing the exacerbation of symptoms associated with the diagnosis.
Secreted Aspartic Proteinases: Key Factors in Candida Infections and Host-Pathogen Interactions
Authors: Bras Grazyna , Satala Dorota , Juszczak Magdalena , Kulig Kamila , Wronowska Ewelina , Bednarek Aneta , Zawrotniak Marcin , Rapala-Kozik Maria , Karkowska-Kuleta Justyna
Published: May 2024

Extracellular proteases are key factors contributing to the virulence of pathogenic fungi from the genus Candida. Their proteolytic activities are crucial for extracting nutrients from the external environment, degrading host defenses, and destabilizing the internal balance of the human organism. Currently, the enzymes most frequently described in this context are secreted aspartic proteases (Saps). This review comprehensively explores the multifaceted roles of Saps, highlighting their importance in biofilm formation, tissue invasion through the degradation of extracellular matrix proteins and components of the coagulation cascade, modulation of host immune responses via impairment of neutrophil and monocyte/macrophage functions, and their contribution to antifungal resistance. Additionally, the diagnostic challenges associated with Candida infections and the potential of Saps as biomarkers were discussed. Furthermore, we examined the prospects of developing vaccines based on Saps and the use of protease inhibitors as adjunctive therapies for candidiasis. Given the complex biology of Saps and their central role in Candida pathogenicity, a multidisciplinary approach may pave the way for innovative diagnostic strategies and open new opportunities for innovative clinical interventions against candidiasis.
Fetal Hypoglycemia Induced by Placental SLC2A3-RNA Interference Alters Fetal Pancreas Development and Transcriptome at Mid-Gestation
Authors: Kennedy Victoria C. , Lynch Cameron S. , Tanner Amelia R. , Winger Quinton A. , Gad Ahmed , Rozance Paul J. , Anthony Russell V.
Published: May 2024

Glucose, the primary energy substrate for fetal oxidative processes and growth, is transferred from maternal to fetal circulation down a concentration gradient by placental facilitative glucose transporters. In sheep, SLC2A1 and SLC2A3 are the primary transporters available in the placental epithelium, with SLC2A3 located on the maternal-facing apical trophoblast membrane and SLC2A1 located on the fetal-facing basolateral trophoblast membrane. We have previously reported that impaired placental SLC2A3 glucose transport resulted in smaller, hypoglycemic fetuses with reduced umbilical artery insulin and glucagon concentrations, in addition to diminished pancreas weights. These findings led us to subject RNA derived from SLC2A3-RNAi (RNA interference) and NTS-RNAi (non-targeting sequence) fetal pancreases to qPCR followed by transcriptomic analysis. We identified a total of 771 differentially expressed genes (DEGs). Upregulated pathways were associated with fat digestion and absorption, particularly fatty acid transport, lipid metabolism, and cholesterol biosynthesis, suggesting a potential switch in energetic substrates due to hypoglycemia. Pathways related to molecular transport and cell signaling in addition to pathways influencing growth and metabolism of the developing pancreas were also impacted. A few genes directly related to gluconeogenesis were also differentially expressed. Our results suggest that fetal hypoglycemia during the first half of gestation impacts fetal pancreas development and function that is not limited to β cell activity.
Berberis vulgaris L. Root Extract as a Multi-Target Chemopreventive Agent against Colon Cancer Causing Apoptosis in Human Colon Adenocarcinoma Cell Lines
Authors: Och Anna , Lemieszek Marta Kinga , Cieśla Marek , Jedrejek Dariusz , Kozłowska Aleksandra , Pawelec Sylwia , Nowak Renata
Published: May 2024

Berberis vulgaris L. (Berberidaceae) is a shrub that has been widely used in European folk medicine as an anti-inflammatory and antimicrobial agent. The purpose of our study was to elucidate the mechanisms of the chemopreventive action of the plant’s methanolic root extract (BVR) against colon cancer cells. Studies were conducted in human colon adenocarcinoma cell lines (LS180 and HT-29) and control colon epithelial CCD841 CoN cells. According to the MTT assay, after 48 h of cell exposure, the IC50 values were as follows: 4.3, 46.1, and 50.2 µg/mL for the LS180, HT-29, and CCD841 CoN cells, respectively, showing the greater sensitivity of the cancer cells to BVR. The Cell Death Detection ELISAPLUS kit demonstrated that BVR induced programmed cell death only against HT-29 cells. Nuclear double staining revealed the great proapoptotic BVR properties in HT-29 cells and subtle effect in LS180 cells. RT-qPCR with the relative quantification method showed significant changes in the expression of genes related to apoptosis in both the LS180 and HT-29 cells. The genes BCL2L1 (126.86–421.43%), BCL2L2 (240–286.02%), CASP3 (177.19–247.83%), and CASP9 (157.99–243.75%) had a significantly elevated expression, while BCL2 (25–52.03%) had a reduced expression compared to the untreated control. Furthermore, in a panel of antioxidant tests, BVR showed positive effects (63.93 ± 0.01, 122.92 ± 0.01, and 220.29 ± 0.02 mg Trolox equivalents (TE)/g in the DPPH•, ABTS•+, and ORAC assays, respectively). In the lipoxygenase (LOX) inhibition test, BVR revealed 62.60 ± 0.87% of enzyme inhibition. The chemical composition of BVR was determined using a UHPLC-UV-CAD-MS/MS analysis and confirmed the presence of several known alkaloids, including berberine, as well as other alkaloids and two derivatives of hydroxycinnamic acid (ferulic and sinapic acid hexosides). The results are very promising and encourage the use of BVR as a comprehensive chemopreventive agent (anti-inflammatory, antioxidant, and pro-apoptotic) in colorectal cancer, and were widely discussed alongside data from the literature.
EGCG Disrupts the LIN28B/Let-7 Interaction and Reduces Neuroblastoma Aggressiveness
Authors: Cocchi Simona , Greco Valentina , Sidarovich Viktoryia , Vigna Jacopo , Broso Francesca , Corallo Diana , Zasso Jacopo , Re Angela , Rosatti Emanuele Filiberto , Longhi Sara , Defant Andrea , Ladu Federico , Sanna Vanna , Adami Valentina , D’Agostino Vito G. , Sturlese Mattia , Sechi Mario , Aveic Sanja , Mancini Ines , Sighel Denise , Quattrone Alessandro
Published: May 2024

Neuroblastoma (NB) is the most commonly diagnosed extracranial solid tumor in children, accounting for 15% of all childhood cancer deaths. Although the 5-year survival rate of patients with a high-risk disease has increased in recent decades, NB remains a challenge in pediatric oncology, and the identification of novel potential therapeutic targets and agents is an urgent clinical need. The RNA-binding protein LIN28B has been identified as an oncogene in NB and is associated with a poor prognosis. Given that LIN28B acts by negatively regulating the biogenesis of the tumor suppressor let-7 miRNAs, we reasoned that selective interference with the LIN28B/let-7 miRNA interaction would increase let-7 miRNA levels, ultimately leading to reduced NB aggressiveness. Here, we selected (−)-epigallocatechin 3-gallate (EGCG) out of 4959 molecules screened as the molecule with the best inhibitory activity on LIN28B/let-7 miRNA interaction and showed that treatment with PLC/PLGA-PEG nanoparticles containing EGCG (EGCG-NPs) led to an increase in mature let-7 miRNAs and a consequent inhibition of NB cell growth. In addition, EGCG-NP pretreatment reduced the tumorigenic potential of NB cells in vivo. These experiments suggest that the LIN28B/let-7 miRNA axis is a good therapeutic target in NB and that EGCG, which can interfere with this interaction, deserves further preclinical evaluation.
Hydroxytyrosol, a Promising Supplement in the Management of Human Stroke: An Exploratory Study
Authors: Naranjo Ángela , Álvarez-Soria M. Josefa , Aranda-Villalobos Pilar , Martínez-Rodríguez Ana M. , Martínez-Lara Esther , Siles Eva
Published: May 2024

Hydroxytyrosol (HT) is a bioactive olive oil phenol with beneficial effects in a number of pathological situations. We have previously demonstrated that an HT-enriched diet could serve as a beneficial therapeutic approach to attenuate ischemic-stroke-associated damage in mice. Our exploratory pilot study examined this effect in humans. Particularly, a nutritional supplement containing 15 mg of HT/day was administered to patients 24 h after the onset of stroke, for 45 days. Biochemical and oxidative-stress-related parameters, blood pressure levels, serum proteome, and neurological and functional outcomes were evaluated at 45 and 90 days and compared to a control group. The main findings were that the daily administration of HT after stroke could: (i) favor the decrease in the percentage of glycated hemoglobin and diastolic blood pressure, (ii) control the increase in nitric oxide and exert a plausible protective effect in oxidative stress, (iii) modulate the evolution of the serum proteome and, particularly, the expression of apolipoproteins, and (iv) be beneficial for certain neurological and functional outcomes. Although a larger trial is necessary, this study suggests that HT could be a beneficial nutritional complement in the management of human stroke.
Molecular Design Using Selected Concentration Effects in Optically Activated Fluorescent Matrices
Authors: Lewkowicz Aneta , Walczewska-Szewc Katarzyna , Czarnomska Martyna , Gruszczyńska Emilia , Pierpaoli Mattia , Bogdanowicz Robert , Gryczyński Zygmunt
Published: May 2024

Molecular physics plays a pivotal role in various fields, including medicine, pharmaceuticals, and broader industrial applications. This study aims to enhance the methods for producing specific optically active materials with distinct spectroscopic properties at the molecular level, which are crucial for these sectors, while prioritizing human safety in both production and application. Forensic science, a significant socio-economic field, often employs hazardous substances in analyzing friction ridges on porous surfaces, posing safety concerns. In response, we formulated novel, non-toxic procedures for examining paper evidence, particularly thermal papers. Our laboratory model utilizes a polyvinyl alcohol polymer as a rigid matrix to emulate the thermal paper’s environment, enabling precise control over the spectroscopic characteristics of 1,8-diazafluoro-9-one (DFO). We identified and analyzed the cyclodimer 1,8-diazafluoren-9-one (DAK DFO), which is a non-toxic and biocompatible alternative for revealing forensic marks. The reagents used to preserve fingerprints were optimized for their effectiveness and stability. Using stationary absorption and emission spectroscopy, along with time-resolved emission studies, we verified the spectroscopic attributes of the new structures under deliberate aggregation conditions. Raman spectroscopy and quantum mechanical computations substantiated the cyclodimer’s configuration. The investigation provides robust scientific endorsement for the novel compound and its structural diversity, influenced by the solvatochromic sensitivity of the DFO precursor. Our approach to monitoring aggregation processes signifies a substantial shift in synthetic research paradigms, leveraging simple chemistry to yield an innovative contribution to forensic science methodologies.
Paricalcitol Has a Potent Anti-Inflammatory Effect in Rat Endothelial Denudation-Induced Intimal Hyperplasia
Authors: Baeza Ciro , Pintor-Chocano Arancha , Carrasco Susana , Sanz Ana , Ortiz Alberto , Sanchez-Niño Maria Dolores
Published: May 2024

Neointimal hyperplasia is the main cause of vascular graft failure in the medium term. Vitamin D receptor activation modulates the biology of vascular smooth muscle cells and has been reported to protect from neointimal hyperplasia following endothelial injury. However, the molecular mechanisms are poorly understood. We have now explored the impact of the selective vitamin D receptor activator, paricalcitol, on neointimal hyperplasia, following guidewire-induced endothelial cell injury in rats, and we have assessed the impact of paricalcitol or vehicle on the expression of key cell stress factors. Guidewire-induced endothelial cell injury caused neointimal hyperplasia and luminal stenosis and upregulated the expression of the growth factor growth/differentiation factor-15 (GDF-15), the cytokine receptor CD74, NFκB-inducing kinase (NIK, an upstream regulator of the proinflammatory transcription factor NFκB) and the chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2). Immunohistochemistry confirmed the increased expression of the cellular proteins CD74 and NIK. Paricalcitol (administered in doses of 750 ng/kg of body weight, every other day) had a non-significant impact on neointimal hyperplasia and luminal stenosis. However, it significantly decreased GDF-15, CD74, NIK and MCP-1/CCL2 mRNA expression, which in paricalcitol-injured arteries remained within the levels found in control vehicle sham arteries. In conclusion, paricalcitol had a dramatic effect, suppressing the stress response to guidewire-induced endothelial cell injury, despite a limited impact on neointimal hyperplasia and luminal stenosis. This observation identifies novel molecular targets of paricalcitol in the vascular system, whose differential expression cannot be justified as a consequence of improved tissue injury.
Emerging Topics in Metal Complexes: Pharmacological Activity
Authors: Ścibior Agnieszka , Aureliano Manuel , Llopis Juan
Published: May 2024

This Special Issue (SI), ”Emerging Topics in Metal Complexes: Pharmacological Activity”, includes reports updating our knowledge on metals with multidirectional biological properties and metal-containing compounds/complexes for their potential therapeutic applications, with a focus on strategies improving their pharmacological features [...]
Extreme Tolerance of Extraocular Muscles to Diseases and Aging: Why and How?
Authors: Titova Angelina , Nikolaev Sergey , Bilyalov Airat , Filatov Nikita , Brovkin Sergei , Shestakov Dmitrii , Khatkov Igor , Pismennaya Ekaterina , Bondarev Vyacheslav , Antyuxina Margarita , Shagimardanova Elena , Bodunova Natalia , Gusev Oleg
Published: May 2024

The extraocular muscles (EOMs) possess unique characteristics that set them apart from other skeletal muscles. These muscles, responsible for eye movements, exhibit remarkable resistance to various muscular dystrophies and aging, presenting a significant contrast to the vulnerability of skeletal muscles to these conditions. In this review, we delve into the cellular and molecular underpinnings of the distinct properties of EOMs. We explore their structural complexity, highlighting differences in fiber types, innervation patterns, and developmental origins. Notably, EOM fibers express a diverse array of myosin heavy-chain isoforms, retaining embryonic forms into adulthood. Moreover, their motor innervation is characterized by a high ratio of nerve fibers to muscle fibers and the presence of unique neuromuscular junctions. These features contribute to the specialized functions of EOMs, including rapid and precise eye movements. Understanding the mechanisms behind the resilience of EOMs to disease and aging may offer insights into potential therapeutic strategies for treating muscular dystrophies and myopathies affecting other skeletal muscles.
Podocyte-Specific Deletion of MCP-1 Fails to Protect against Angiotensin II- or Adriamycin-Induced Glomerular Disease
Authors: Bondi Corry D. , Hartman Hannah L. , Rush Brittney M. , Tan Roderick J.
Published: May 2024

Investigating the role of podocytes in proteinuric disease is imperative to address the increasing global burden of chronic kidney disease (CKD). Studies strongly implicate increased levels of monocyte chemoattractant protein-1 (MCP-1/CCL2) in proteinuric CKD. Since podocytes express the receptor for MCP-1 (i.e., CCR2), we hypothesized that podocyte-specific MCP-1 production in response to stimuli could activate its receptor in an autocrine manner, leading to further podocyte injury. To test this hypothesis, we generated podocyte-specific MCP-1 knockout mice (Podo-Mcp-1fl/fl) and exposed them to proteinuric injury induced by either angiotensin II (Ang II; 1.5 mg/kg/d, osmotic minipump) or Adriamycin (Adr; 18 mg/kg, intravenous bolus). At baseline, there were no between-group differences in body weight, histology, albuminuria, and podocyte markers. After 28 days, there were no between-group differences in survival, change in body weight, albuminuria, kidney function, glomerular injury, and tubulointerstitial fibrosis. The lack of protection in the knockout mice suggests that podocyte-specific MCP-1 production is not a major contributor to either Ang II- or Adr-induced glomerular disease, implicating that another cell type is the source of pathogenic MCP-1 production in CKD.
Development of a Static Avascular and Dynamic Vascular Human Skin Equivalent Employing Collagen/Keratin Hydrogels
Authors: Zuniga Kameel , Ghousifam Neda , Shaffer Lucy , Brocklehurst Sean , Van Dyke Mark , Christy Robert , Natesan Shanmugasundaram , Rylander Marissa Nichole
Published: May 2024

One of the primary complications in generating physiologically representative skin tissue is the inability to integrate vasculature into the system, which has been shown to promote the proliferation of basal keratinocytes and consequent keratinocyte differentiation, and is necessary for mimicking representative barrier function in the skin and physiological transport properties. We created a 3D vascularized human skin equivalent (VHSE) with a dermal and epidermal layer, and compared keratinocyte differentiation (immunomarker staining), epidermal thickness (H&E staining), and barrier function (transepithelial electrical resistance (TEER) and dextran permeability) to a static, organotypic avascular HSE (AHSE). The VHSE had a significantly thicker epidermal layer and increased resistance, both an indication of increased barrier function, compared to the AHSE. The inclusion of keratin in our collagen hydrogel extracellular matrix (ECM) increased keratinocyte differentiation and barrier function, indicated by greater resistance and decreased permeability. Surprisingly, however, endothelial cells grown in a collagen/keratin extracellular environment showed increased cell growth and decreased vascular permeability, indicating a more confluent and tighter vessel compared to those grown in a pure collagen environment. The development of a novel VHSE, which incorporated physiological vasculature and a unique collagen/keratin ECM, improved barrier function, vessel development, and skin structure compared to a static AHSE model.
An Assessment of the Effectiveness and Safety of Chimeric Antigen Receptor T-Cell Therapy in Multiple Myeloma Patients with Relapsed or Refractory Disease: A Systematic Review and Meta-Analysis
Authors: Pereira Rita , Bergantim Rui
Published: May 2024

Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, and its incidence is rising. Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a novel treatment, with the potential to improve the survival and quality of life of patients with relapsed/refractory multiple myeloma (rrMM). In this systematic review and meta-analysis, conducted in accordance with PRISMA guidelines, we aim to provide a concise overview of the latest developments in CAR-T therapy, assess their potential implications for clinical practice, and evaluate their efficacy and safety outcomes based on the most up-to-date evidence. A literature search conducted from 1 January 2019 to 12 July 2023 on Medline/PubMed, Scopus, and Web of Science identified 2273 articles, of which 29 fulfilled the specified criteria for inclusion. Our results offer robust evidence supporting CAR-T cell therapy’s efficacy in rrMM patients, with an encouraging 83.21% overall response rate (ORR). A generally safe profile was observed, with grade ≥ 3 cytokine release syndrome (CRS) at 7.12% and grade ≥ 3 neurotoxicity at 1.37%. A subgroup analysis revealed a significantly increased ORR in patients with fewer antimyeloma regimens, while grade ≥ 3 CRS was more common in those with a higher proportion of high-risk cytogenetics and prior exposure to BCMA therapy.