bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Advances in Bioimage Analysis Methods for Detecting Skeletal Deformities in Biomedical and Aquaculture Fish Species
Authors: Kumar Navdeep , Marée Raphaël , Geurts Pierre , Muller Marc
Published: December 2023

Detecting skeletal or bone-related deformities in model and aquaculture fish is vital for numerous biomedical studies. In biomedical research, model fish with bone-related disorders are potential indicators of various chemically induced toxins in their environment or poor dietary conditions. In aquaculture, skeletal deformities are affecting fish health, and economic losses are incurred by fish farmers. This survey paper focuses on showcasing the cutting-edge image analysis tools and techniques based on artificial intelligence that are currently applied in the analysis of bone-related deformities in aquaculture and model fish. These methods and tools play a significant role in improving research by automating various aspects of the analysis. This paper also sheds light on some of the hurdles faced when dealing with high-content bioimages and explores potential solutions to overcome these challenges.
Thioacetamide-Induced Acute Liver Injury Increases Metformin Plasma Exposure by Downregulating Renal OCT2 and MATE1 Expression and Function
Authors: Zhi Hao , Dai Yidong , Su Lin , Yang Lu , Wu Wenhan , Wang Zehua , Zhu Xinyue , Liu Li , Aa Jiye , Yang Hanyu
Published: December 2023

Metformin plasma exposure is increased in rats with thioacetamide (TAA)-induced liver failure. The absorption, distribution, and excretion process of metformin is mainly mediated by organic cation transporters (OCTs) and multidrug and toxin extrusion transporters (MATEs). To investigate the mechanisms of the increase in TAA-induced metformin plasma exposure, we employed intestinal perfusion and urinary excretion assays to evaluate the changes in the absorption and excretion of metformin and used Western blotting to investigate the metformin-related transport proteins’ expression changes and mechanisms. The results showed that neither intestinal OCT2 expression nor metformin intestinal absorption were significantly altered by TAA-induced liver failure, while significantly decreased expression and function of renal OCT2 and MATE1 as well as impaired metformin excretion were observed in TAA rats. HK-2 cells were used as an in vitro model to explore the mechanism of liver-failure-mediated downregulation in renal OCT2 and MATE1. The results demonstrated that among numerous abnormal substances that changed in acute liver failure, elevated estrogen levels and tumor necrosis factor-α were the main factors mediating the downregulation of OCT2 and MATE1. In conclusion, this study highlights the downregulation of renal OCT2 and MATE1 in liver injury and its regulatory mechanism and reveals its roles in the increase in TAA-mediated metformin plasma exposure.
Antitumor Effect of Berberine Analogs in a Canine Mammary Tumor Cell Line and in Zebrafish Reporters via Wnt/β-Catenin and Hippo Pathways
Authors: Sammarco Alessandro , Beffagna Giorgia , Sacchetto Roberta , Vettori Andrea , Bonsembiante Federico , Scarin Giulia , Gelain Maria Elena , Cavicchioli Laura , Ferro Silvia , Geroni Cristina , Lombardi Paolo , Zappulli Valentina
Published: December 2023

The heterogeneous nature of human breast cancer (HBC) can still lead to therapy inefficacy and high lethality, and new therapeutics as well as new spontaneous animal models are needed to benefit translational HBC research. Dogs are primarily investigated since they spontaneously develop tumors that share many features with human cancers. In recent years, different natural phytochemicals including berberine, a plant alkaloid, have been reported to have antiproliferative activity in vitro in human cancers and rodent animal models. In this study, we report the antiproliferative activity and mechanism of action of berberine, its active metabolite berberrubine, and eight analogs, on a canine mammary carcinoma cell line and in transgenic zebrafish models. We demonstrate both in vitro and in vivo the significant effects of specific analogs on cell viability via the induction of apoptosis, also identifying their role in inhibiting the Wnt/β-catenin pathway and activating the Hippo signals with a downstream reduction in CTGF expression. In particular, the berberine analogs NAX035 and NAX057 show the highest therapeutic efficacy, deserving further analyses to elucidate their mechanism of action more in detail, and in vivo studies on spontaneous neoplastic diseases are needed, aiming at improving veterinary treatments of cancer as well as translational cancer research.
Plasma and Urinary Platelet Factor 4 as Biomarkers for Cardiovascular Risk in Children with Chronic Kidney Disease
Authors: Hsu Chien-Ning , Liao Wei-Ting , Chen Wei-Ling , Chang-Chien Guo-Ping , Lin Sufan , Tain You-Lin
Published: December 2023

Children suffering from chronic kidney disease (CKD) have a high risk of cardiovascular disease (CVD). The early detection and diagnosis of subclinical CVD in pediatric CKD can reduce mortality later in life. Plasma factor 4 (PF4) is a chemokine released by activated platelets. We examined whether or not PF4 in the plasma and urine, its kidney function normalized ratio, and fractional excretion have differential associations with CVD risk markers in 139 youths aged 3 to 18 years old with CKD stages G1–G4. Significant negative correlations were observed between plasma PF4 and cardiovascular surrogate markers, such as the left ventricular mass index (LVMI), carotid intima–media thickness (cIMT), and pulse wave velocity (PWV). The plasma PF4/creatinine (Cr) ratio was lower in CKD children with a high daytime BP and 24 h BP, high BP load, and nocturnal non-dipping status. After adjusting for confounders, the plasma PF4 and plasma PF4/Cr ratio still independently predicted an abnormal ABPM profile. In addition, both the plasma PF4 and plasma PF4/Cr ratio presented a negative correlation with the L-arginine and asymmetric dimethylarginine ratio. These findings provide convincing evidence supporting the link between PF4 and CVD markers in pediatric CKD. Our study highlights the importance of further research to assess the performance of PF4-related biomarkers in predicting CVD events and CKD progression in children with CKD.
Examining the Impact of Digital Human Gaze Expressions on Engagement Induction
Authors: Mok Subin , Park Sung , Whang Mincheol
Published: December 2023

With advancements in technology, digital humans are becoming increasingly sophisticated, with their application scope widening to include interactions with real people. However, research on expressions that facilitate natural engagement in interactions between real people and digital humans is scarce. With this study, we aimed to examine the differences in user engagement as measured by subjective evaluations, eye tracking, and electroencephalogram (EEG) responses relative to different gaze expressions in various conversational contexts. Conversational situations were categorized as face-to-face, face-to-video, and digital human interactions, with gaze expressions segmented into eye contact and gaze avoidance. Story stimuli incorporating twelve sentences verified to elicit positive and negative emotional responses were employed in the experiments after validation. A total of 45 participants (31 females and 14 males) underwent stimulation through positive and negative stories while exhibiting eye contact or gaze avoidance under each of the three conversational conditions. Engagement was assessed using subjective evaluation metrics in conjunction with measures of the subjects’ gaze and brainwave activity. The findings revealed engagement disparities between the face-to-face and digital-human conversation conditions. Notably, only positive stimuli elicited variations in engagement based on gaze expression across different conversation conditions. Gaze analysis corroborated the engagement differences, aligning with prior research on social sensitivity, but only in response to positive stimuli. This research departs from traditional studies of un-natural interactions with digital humans, focusing instead on interactions with digital humans designed to mimic the appearance of real humans. This study demonstrates the potential for gaze expression to induce engagement, regardless of the human or digital nature of the conversational dyads.
Low-Cost Plant-Based Metal and Metal Oxide Nanoparticle Synthesis and Their Use in Optical and Electrochemical (Bio)Sensors
Authors: Ciobotaru Iulia Corina , Oprea Daniela , Ciobotaru Constantin Claudiu , Enache Teodor Adrian
Published: December 2023

Technological progress has led to the development of analytical tools that promise a huge socio-economic impact on our daily lives and an improved quality of life for all. The use of plant extract synthesized nanoparticles in the development and fabrication of optical or electrochemical (bio)sensors presents major advantages. Besides their low-cost fabrication and scalability, these nanoparticles may have a dual role, serving as a transducer component and as a recognition element, the latter requiring their functionalization with specific components. Different approaches, such as surface modification techniques to facilitate precise biomolecule attachment, thereby augmenting recognition capabilities, or fine tuning functional groups on nanoparticle surfaces are preferred for ensuring stable biomolecule conjugation while preserving bioactivity. Size optimization, maximizing surface area, and tailored nanoparticle shapes increase the potential for robust interactions and enhance the transduction. This article specifically aims to illustrate the adaptability and effectiveness of these biosensing platforms in identifying precise biological targets along with their far-reaching implications across various domains, spanning healthcare diagnostics, environmental monitoring, and diverse bioanalytical fields. By exploring these applications, the article highlights the significance of prioritizing the use of natural resources for nanoparticle synthesis. This emphasis aligns with the worldwide goal of envisioning sustainable and customized biosensing solutions, emphasizing heightened sensitivity and selectivity.
Investigating Genetic and Environmental Substrates of the Relationship between Positive Mental Health and Biological Aging—A Study Protocol
Authors: Marcon Francesca , Salemi Miriam , D’Ippolito Cristina , Picardi Angelo , Toccaceli Virgilia , Nisticò Lorenza , Alviti Sabrina , Siniscalchi Ester , Salani Francesca , Varalda Giorgia Maria , Medda Emanuela , Fagnani Corrado
Published: December 2023

Background: The Italian National Institute of Health (Istituto Superiore di Sanità) funded a 30-month project (July 2021–January 2024) to conduct a twin study of the relationships between Positive Mental Health (PMH) and cellular longevity. Only a few previous studies have focused on the biomarkers of aging in relation to psychological well-being, and none of them exploited the potential of the twin design. Method: In this project, following the standard procedures of the Italian Twin Registry (ITR), we aim to recruit 200 adult twin pairs enrolled in the ITR. They are requested to complete a self-report questionnaire battery on PMH and to undergo a blood withdrawal for the assessment of aging biomarkers, i.e., telomere length and mitochondrial DNA functionality. The association between psychological and aging biomarker measures will be assessed, controlling for genetic and familial confounding effects using the twin study design. Results and conclusions: Biomarker assays are underway. Once data are available for the total study sample, statistical analyses will be performed. The project’s results may shed light on new mechanisms underlying the mind–body connection and may prove helpful to promote psychological well-being in conjunction with biological functioning.
Enhancing Indoor Environmental Quality and Sustainability in Post-Pandemic Office Settings: A Study on Displacement Ventilation Feasibility
Authors: Shen Jingchun , Chen Yang , Rajagopal Karthik Hejamadi
Published: December 2023

The COVID-19 pandemic has catalyzed global efforts toward transitioning to a sustainable society, driving rapid innovation in building technologies, working practices, building design, and whole life cycle environmental impact consideration. In this pursuit, this study explores the enduring impact of these on an alternative ventilation approach for both existing building renovations and new building implementations. Comparing displacement ventilation to mixed-mode ventilation in a Finnish office building with varying occupancy densities, this study examines indoor air quality (IAQ), thermal comfort, total building energy performance, and embodied carbon. The findings reveal that the basic case of mixed ventilation has a specified system primary energy value of 38.83 kWh/m2 (with 28 occupants) and 39.00 kWh/m2 (with 24 occupants), respectively. With the displacement ventilation alternative, it reduces this by 0.3% and 0.1%, enhancing thermal comfort and decreasing turbulence as well as having a marginal decrease in embodied carbon. In general, the study offers three-fold contributions: insights into post-pandemic office mechanical ventilation design with an emphasis on sustainability and ecological footprint considerations, a concrete case study addressing climate action and human-centric IAQ design, and a multifaceted analysis using the Environmental, Social, and Governance (ESG) paradigm, contributing to the groundwork for associated future research and policy progress.
Deep Learning-Based Automated Detection of Cracks in Historical Masonry Structures
Authors: Hacıefendioğlu Kemal , Altunışık Ahmet Can , Abdioğlu Tuğba
Published: December 2023

The efficient and precise identification of cracks in masonry stone structures caused by natural or human-induced factors within a specific region holds significant importance in detecting damage and subsequent secondary harm. In recent times, remote sensing technologies have been actively employed to promptly identify crack regions during repair and reinforcement activities. Enhanced image resolution has enabled more accurate and sensitive detection of these areas. This research presents a novel approach utilizing deep learning techniques for crack area detection in cellphone images, achieved through segmentation and object detection methods. The developed model, named the CAM-K-SEG segmentation model, combines Grad-CAM visualization and K-Mean clustering approaches with pre-trained convolutional neural network models. A comprehensive dataset comprising photographs of numerous historical buildings was utilized for training the model. To establish a comparative analysis, the widely used U-Net segmentation model was employed. The training and testing datasets for the developed technique were meticulously annotated and masked. The evaluation of the results was based on the Intersection-over-Union (IoU) metric values. Consequently, it was concluded that the CAM-K-SEG model exhibits suitability for object recognition and localization, whereas the U-Net model is well-suited for crack area segmentation.
Mechanical Performance of Concrete Segment Lining Structure of Shield Tunneling in Different Strata
Authors: Hu Hui , Xue Tao , Li Jianjun , Liu Peisi , Wang Bo , Liu Yun
Published: December 2023

There are many problems in the development of urban space in China. Among them, urban tunnels generally pass through many sections with very complicated geological conditions, and the construction will encounter great difficulties, so the mechanical behavior of shield segments in different complex strata is worth discussing. In this paper, the axial force, bending moment and pore water pressure of shield tunnel segments in the soft and hard uneven stratum, clay stratum and fully weathered granite stratum of overlying buildings are studied by establishing a rectangular element mechanical model based on the field test method. The analysis shows that the mechanical properties of shield tunnels in different strata are quite different, but their mechanical properties change stages are the same. The earth pressure on the left and right sides of the test ring is asymmetric in the soft and hard uneven stratum, and the vault pressure is much greater than the vault bottom pressure. The distribution of earth pressure in each position of the segment ring in clay stratum is relatively balanced, and the earth pressure on both sides is relatively small; in the fully weathered granite layer of the overlying building, the segment ring of the test ring is subjected to greater additional stress, and the internal force of the segment is much greater than that without the overlying building. Exploring the similarities and differences of segment stress in these three complex strata can provide an important basis for the design and construction of shield segments in complex strata.
Controlled Plasma Membrane Delivery of FGFR1 and Modulation of Signaling by a Novel Regulated Anterograde RTK Transport Pathway
Authors: Hinsch Claire Leist , Venkata Jagadish Kummetha , Hsu Tien , Dammai Vincent
Published: December 2023

How human FGFR1 localizes to the PM is unknown. Currently, it is assumed that newly synthesized FGFR1 is continuously delivered to the PM. However, evidence indicates that FGFR1 is mostly sequestered in intracellular post-Golgi vesicles (PGVs) under normal conditions. In this report, live-cell imaging and total internal reflection fluorescence microscopy (TIRFM) were employed to study the dynamics of these FGFR1-positive vesicles. We designed recombinant proteins to target different transport components to and from the FGFR1 vesicles. Mouse embryoid bodies (mEBs) were used as a 3D model system to confirm major findings. Briefly, we found that Rab2a, Rab6a, Rab8a, RalA and caveolins are integral components of FGFR1-positive vesicles, representing a novel compartment. While intracellular sequestration prevented FGFR1 activation, serum starvation and hypoxia stimulated PM localization of FGFR1. Under these conditions, FGFR1 C-terminus acts as a scaffold to assemble proteins to (i) inactivate Rab2a and release sequestration, and (ii) assemble Rab6a for localized activation of Rab8a and RalA-exocyst to deliver the receptor to the PM. This novel pathway is named Regulated Anterograde RTK Transport (RART). This is the first instance of RTK regulated through control of PM delivery.
Possibility of Using Conventional Computed Tomography Features and Histogram Texture Analysis Parameters as Imaging Biomarkers for Preoperative Prediction of High-Risk Gastrointestinal Stromal Tumors of the Stomach
Authors: Jovanovic Milica Mitrovic , Stefanovic Aleksandra Djuric , Sarac Dimitrije , Kovac Jelena , Jankovic Aleksandra , Saponjski Dusan J. , Tadic Boris , Kostadinovic Milena , Veselinovic Milan , Sljukic Vladimir , Skrobic Ognjan , Micev Marjan , Masulovic Dragan , Pesko Predrag , Ebrahimi Keramatollah
Published: December 2023

Background: The objective of this study is to determine the morphological computed tomography features of the tumor and texture analysis parameters, which may be a useful diagnostic tool for the preoperative prediction of high-risk gastrointestinal stromal tumors (HR GISTs). Methods: This is a prospective cohort study that was carried out in the period from 2019 to 2022. The study included 79 patients who underwent CT examination, texture analysis, surgical resection of a lesion that was suspicious for GIST as well as pathohistological and immunohistochemical analysis. Results: Textural analysis pointed out min norm (p = 0.032) as a histogram parameter that significantly differed between HR and LR GISTs, while min norm (p = 0.007), skewness (p = 0.035) and kurtosis (p = 0.003) showed significant differences between high-grade and low-grade tumors. Univariate regression analysis identified tumor diameter, margin appearance, growth pattern, lesion shape, structure, mucosal continuity, enlarged peri- and intra-tumoral feeding or draining vessel (EFDV) and max norm as significant predictive factors for HR GISTs. Interrupted mucosa (p < 0.001) and presence of EFDV (p < 0.001) were obtained by multivariate regression analysis as independent predictive factors of high-risk GISTs with an AUC of 0.878 (CI: 0.797–0.959), sensitivity of 94%, specificity of 77% and accuracy of 88%. Conclusion: This result shows that morphological CT features of GIST are of great importance in the prediction of non-invasive preoperative metastatic risk. The incorporation of texture analysis into basic imaging protocols may further improve the preoperative assessment of risk stratification.
Augmented Concentration of Isopentyl-Deoxynyboquinone in Tumors Selectively Kills NAD(P)H Quinone Oxidoreductase 1-Positive Cancer Cells through Programmed Necrotic and Apoptotic Mechanisms
Authors: Wang Jiangwei , Su Xiaolin , Jiang Lingxiang , Boudreau Matthew W. , Chatkewitz Lindsay E. , Kilgore Jessica A. , Zahid Kashif Rafiq , Williams Noelle S. , Chen Yaomin , Liu Shaohui , Hergenrother Paul J. , Huang Xiumei
Published: December 2023

Lung and breast cancers rank as two of the most common and lethal tumors, accounting for a substantial number of cancer-related deaths worldwide. While the past two decades have witnessed promising progress in tumor therapy, developing targeted tumor therapies continues to pose a significant challenge. NAD(P)H quinone oxidoreductase 1 (NQO1), a two-electron reductase, has been reported as a promising therapeutic target across various solid tumors. β-Lapachone (β-Lap) and deoxynyboquinone (DNQ) are two NQO1 bioactivatable drugs that have demonstrated potent antitumor effects. However, their curative efficacy has been constrained by adverse effects and moderate lethality. To enhance the curative potential of NQO1 bioactivatable drugs, we developed a novel DNQ derivative termed isopentyl-deoxynyboquinone (IP-DNQ). Our study revealed that IP-DNQ treatment significantly increased reactive oxygen species generation, leading to double-strand break (DSB) formation, PARP1 hyperactivation, and catastrophic energy loss. Notably, we discovered that this novel drug induced both apoptosis and programmed necrosis events, which makes it entirely distinct from other NQO1 bioactivatable drugs. Furthermore, IP-DNQ monotherapy demonstrated significant antitumor efficacy and extended mice survival in A549 orthotopic xenograft models. Lastly, we identified that in mice IP-DNQ levels were significantly elevated in the plasma and tumor compared with IB-DNQ levels. This study provides novel preclinical evidence supporting IP-DNQ efficacy in NQO1+ NSCLC and breast cancer cells.
Benchmarking Time-to-Treatment Initiation in Sarcoma Care Using Real-World-Time Data
Authors: Schärer Markus , Heesen Philip , Bode-Lesniewska Beata , Studer Gabriela , Fuchs Bruno
Published: December 2023

Benchmarking is a fundamental tool for enhancing quality within a patient-centered healthcare framework. This study presents an analysis of time-to-treatment initiation (TTI) for sarcoma patients, utilizing a database encompassing 266 cases from the Swiss Sarcoma Network. Our findings indicate a median TTI of 30 days across the cohort, with bone sarcomas and deep soft tissue sarcomas demonstrating a shorter median TTI of 28 days, followed by superficial soft tissue sarcomas at 42 days. The data reveal that the use of real-world-time data (RWTD) may account for a longer TTI observed, as it offers more comprehensive capture of patient journeys, unlike conventional datasets. Notably, variability in TTI was observed between different treatment institutions, which underscores the need for standardized processes across centers. We advocate for a selective referral system to specialized centers to prevent capacity overload and ensure timely treatment initiation. Our analysis also identified significant delays in TTI for unplanned ‘whoops’-resections, highlighting the importance of early specialist referral in optimizing treatment timelines. This study emphasizes the potential benefits of a streamlined, data-informed approach to sarcoma care. However, further research is required to establish the direct impact of integrated care models on TTI and patient outcomes in the context of sarcoma treatment.
A Rare Variant in MDH2 (rs111879470) Is Associated with Predisposition to Recurrent Breast Cancer in an Extended High-Risk Pedigree
Authors: Cannon-Albright Lisa A. , Stevens Jeff , Teerlink Craig C. , Facelli Julio C. , Allen-Brady Kristina , Welm Alana L.
Published: December 2023

A significant fraction of breast cancer recurs, with lethal outcome, but specific genetic variants responsible have yet to be identified. Five cousin pairs with recurrent breast cancer from pedigrees with a statistical excess of recurrent breast cancer were sequenced to identify rare, shared candidate predisposition variants. The candidates were tested for association with breast cancer risk with UKBiobank data. Additional breast cancer cases were assayed for a subset of candidate variants to test for co-segregation. Three-dimensional protein structure prediction methods were used to investigate how the mutation under consideration is predicted to change structural and electrostatic properties in the mutated protein. One hundred and eighty-one rare candidate predisposition variants were shared in at least one cousin pair from a high-risk pedigree. A rare variant in MDH2 was found to segregate with breast-cancer-affected relatives in one extended pedigree. MDH2 is an estrogen-stimulated gene encoding the protein malate dehydrogenase, which catalyzes the reversible oxidation of malate to oxaloacetate. The molecular simulation results strongly suggest that the mutation changes the NAD+ binding pocket electrostatics of MDH2. This small sequencing study, using a powerful approach based on recurrent breast cancer cases from high-risk pedigrees, identified a set of strong candidate variants for inherited predisposition for breast cancer recurrence, including MDH2, which should be pursued in other resources.
Cytokine Modification of Adoptive Chimeric Antigen Receptor Immunotherapy for Glioblastoma
Authors: Pawlowski Kristen D. , Duffy Joseph T. , Gottschalk Stephen , Balyasnikova Irina V.
Published: December 2023

Chimeric antigen receptor (CAR) cell-based therapies have demonstrated limited success in solid tumors, including glioblastoma (GBM). GBMs exhibit high heterogeneity and create an immunosuppressive tumor microenvironment (TME). In addition, other challenges exist for CAR therapy, including trafficking and infiltration into the tumor site, proliferation, persistence of CARs once in the tumor, and reduced functionality, such as suboptimal cytokine production. Cytokine modification is of interest, as one can enhance therapy efficacy and minimize off-target toxicity by directly combining CAR therapy with cytokines, antibodies, or oncolytic viruses that alter cytokine response pathways. Alternatively, one can genetically modify CAR T-cells or CAR NK-cells to secrete cytokines or express cytokines or cytokine receptors. Finally, CARs can be genetically altered to augment or suppress intracellular cytokine signaling pathways for a more direct approach. Codelivery of cytokines with CARs is the most straightforward method, but it has associated toxicity. Alternatively, combining CAR therapy with antibodies (e.g., anti-IL-6, anti-PD1, and anti-VEGF) or oncolytic viruses has enhanced CAR cell infiltration into GBM tumors and provided proinflammatory signals to the TME. CAR T- or NK-cells secreting cytokines (e.g., IL-12, IL-15, and IL-18) have shown improved efficacy within multiple GBM subtypes. Likewise, expressing cytokine-modulating receptors in CAR cells that promote or inhibit cytokine signaling has enhanced their activity. Finally, gene editing approaches are actively being pursued to directly influence immune signaling pathways in CAR cells. In this review, we summarize these cytokine modification methods and highlight any existing gaps in the hope of catalyzing an improved generation of CAR-based therapies for glioblastoma.
Diagnostics and Treatment of Extrameningeal Solitary Fibrous Tumors
Authors: Janik Anna Maria , Terlecka Anna , Spałek Mateusz J. , Boye Kjetil , Szostakowski Bartłomiej , Chmiel Paulina , Szumera-Ciećkiewicz Anna , Bobak Klaudia , Świtaj Tomasz , Rutkowski Piotr , Czarnecka Anna M.
Published: December 2023

Solitary fibrous tumors (SFT) are rare mesenchymal neoplasms that account for less than 2% of all soft tissue masses. In the latest WHO 2020 Classification of Soft Tissue Tumors, extrameningeal SFT was listed as intermediate (rarely metastasizing) or malignant neoplasms. Due to the lack of characteristic clinical features, their diagnosis and treatment remain challenging. The pathogenesis of SFT is often associated with the presence of fusions of the NAB2-STAT6 gene on the 12q13 chromosome. Cytoplasmic CD34 positive staining is considerably characteristic for most SFTs; less frequently, factor XII, vimentin, bcl-2, and CD99 are present. A key factor in the diagnosis is the prevalent nuclear location of STAT6 expression. Radical resection is the mainstay of localized SFTs. In the case of unresectable disease, only radiotherapy or radio-chemotherapy may significantly ensure long-term local control of primary and metastatic lesions. To date, no practical guidelines have been published for the treatment of advanced or metastatic disease. Classical anthracycline-based chemotherapy is applicable. The latest studies suggest that antiangiogenic therapies should be considered after first-line treatment. Other drugs, such as imatinib, figitumumab, axitinib, and eribulin, are also being tested. Definitive radiotherapy appears to be a promising therapeutic modality. Since standards for the treatment of advanced and metastatic diseases are not available, further investigation of novel agents is necessary.
Navigating the Immune Maze: Pioneering Strategies for Unshackling Cancer Immunotherapy Resistance
Authors: Yao Liqin , Wang Qingqing , Ma Wenxue
Published: December 2023

Cancer immunotherapy has ushered in a transformative era in oncology, offering unprecedented promise and opportunities. Despite its remarkable breakthroughs, the field continues to grapple with the persistent challenge of treatment resistance. This resistance not only undermines the widespread efficacy of these pioneering treatments, but also underscores the pressing need for further research. Our exploration into the intricate realm of cancer immunotherapy resistance reveals various mechanisms at play, from primary and secondary resistance to the significant impact of genetic and epigenetic factors, as well as the crucial role of the tumor microenvironment (TME). Furthermore, we stress the importance of devising innovative strategies to counteract this resistance, such as employing combination therapies, tailoring immune checkpoints, and implementing real-time monitoring. By championing these state-of-the-art methods, we anticipate a paradigm that blends personalized healthcare with improved treatment options and is firmly committed to patient welfare. Through a comprehensive and multifaceted approach, we strive to tackle the challenges of resistance, aspiring to elevate cancer immunotherapy as a beacon of hope for patients around the world.
Human Intestinal Organoids and Microphysiological Systems for Modeling Radiotoxicity and Assessing Radioprotective Agents
Authors: Bouges Eloïse , Segers Charlotte , Leys Natalie , Lebeer Sarah , Zhang Jianbo , Mastroleo Felice
Published: December 2023

Radiotherapy is a commonly employed treatment for colorectal cancer, yet its radiotoxicity-related impact on healthy tissues raises significant health concerns. This highlights the need to use radioprotective agents to mitigate these side effects. This review presents the current landscape of human translational radiobiology, outlining the limitations of existing models and proposing engineering solutions. We delve into radiotherapy principles, encompassing mechanisms of radiation-induced cell death and its influence on normal and cancerous colorectal cells. Furthermore, we explore the engineering aspects of microphysiological systems to represent radiotherapy-induced gastrointestinal toxicity and how to include the gut microbiota to study its role in treatment failure and success. This review ultimately highlights the main challenges and future pathways in translational research for pelvic radiotherapy-induced toxicity. This is achieved by developing a humanized in vitro model that mimics radiotherapy treatment conditions. An in vitro model should provide in-depth analyses of host-gut microbiota interactions and a deeper understanding of the underlying biological mechanisms of radioprotective food supplements. Additionally, it would be of great value if these models could produce high-throughput data using patient-derived samples to address the lack of human representability to complete clinical trials and improve patients’ quality of life.
A Novel Approach: Investigating the Intracellular Clearance Mechanism of Glyceraldehyde-Derived Advanced Glycation End-Products Using the Artificial Checkpoint Kinase 1 d270KD Mutant as a Substrate Model
Authors: Takeda Kenji , Sakai-Sakasai Akiko , Kajinami Kouji , Takeuchi Masayoshi
Published: December 2023

Advanced glycation end-products (AGEs), formed through glyceraldehyde (GA) as an intermediate in non-enzymatic reactions with intracellular proteins, are cytotoxic and have been implicated in the pathogenesis of various diseases. Despite their significance, the mechanisms underlying the degradation of GA-derived AGEs (GA-AGEs) remain unclear. In the present study, we found that N-terminal checkpoint kinase 1 cleavage products (CHK1-CPs) and their mimic protein, d270WT, were degraded intracellularly post-GA exposure. Notably, a kinase-dead d270WT variant (d270KD) underwent rapid GA-induced degradation, primarily via the ubiquitin–proteasome pathway. The high-molecular-weight complexes formed by the GA stimulation of d270KD were abundant in the RIPA-insoluble fraction, which also contained high levels of GA-AGEs. Immunoprecipitation experiments indicated that the high-molecular-weight complexes of d270KD were modified by GA-AGEs and that p62/SQSTM1 was one of its components. The knockdown of p62 or treatment with chloroquine reduced the amount of high-molecular-weight complexes in the RIPA-insoluble fraction, indicating its involvement in the formation of GA-AGE aggregates. The present results suggest that the ubiquitin–proteasome pathway and p62 play a role in the degradation and aggregation of intracellular GA-AGEs. This study provides novel insights into the mechanisms underlying GA-AGE metabolism and may lead to the development of novel therapeutic strategies for diseases associated with the accumulation of GA-AGEs.
Evaluation of Mono- and Bi-Functional GLOBE-Based Vectors for Therapy of β-Thalassemia by HBBAS3 Gene Addition and Mutation-Specific RNA Interference
Authors: Koniali Lola , Flouri Christina , Kostopoulou Markela I. , Papaioannou Nikoletta Y. , Papasavva Panayiota L. , Naiisseh Basma , Stephanou Coralea , Demetriadou Anthi , Sitarou Maria , Christou Soteroula , Antoniou Michael N. , Kleanthous Marina , Patsali Petros , Lederer Carsten W.
Published: December 2023

Therapy via the gene addition of the anti-sickling βAS3-globin transgene is potentially curative for all β-hemoglobinopathies and therefore of particular clinical and commercial interest. This study investigates GLOBE-based lentiviral vectors (LVs) for βAS3-globin addition and evaluates strategies for an increased β-like globin expression without vector dose escalation. First, we report the development of a GLOBE-derived LV, GLV2-βAS3, which, compared to its parental vector, adds anti-sickling action and a transcription-enhancing 848-bp transcription terminator element, retains high vector titers and allows for superior β-like globin expression in primary patient-derived hematopoietic stem and progenitor cells (HSPCs). Second, prompted by our previous correction of HBBIVSI−110(G>A) thalassemia based on RNApol(III)-driven shRNAs in mono- and combination therapy, we analyzed a series of novel LVs for the RNApol(II)-driven constitutive or late-erythroid expression of HBBIVSI−110(G>A)-specific miRNA30-embedded shRNAs (shRNAmiR). This included bifunctional LVs, allowing for concurrent βAS3-globin expression. LVs were initially compared for their ability to achieve high β-like globin expression in HBBIVSI−110(G>A)-transgenic cells, before the evaluation of shortlisted candidate LVs in HBBIVSI−110(G>A)-homozygous HSPCs. The latter revealed that β-globin promoter-driven designs for monotherapy with HBBIVSI−110(G>A)-specific shRNAmiRs only marginally increased β-globin levels compared to untransduced cells, whereas bifunctional LVs combining miR30-shRNA with βAS3-globin expression showed disease correction similar to that achieved by the parental GLV2-βAS3 vector. Our results establish the feasibility of high titers for LVs containing the full HBB transcription terminator, emphasize the importance of the HBB terminator for the high-level expression of HBB-like transgenes, qualify the therapeutic utility of late-erythroid HBBIVSI−110(G>A)-specific miR30-shRNA expression and highlight the exceptional potential of GLV2-βAS3 for the treatment of severe β-hemoglobinopathies.
Infrapatellar Fat Pad Modulates Osteoarthritis-Associated Cytokine and MMP Expression in Human Articular Chondrocytes
Authors: Wisniewska Ewa , Laue Dominik , Spinnen Jacob , Kuhrt Leonard , Kohl Benjamin , Bußmann Patricia , Meier Carola , Schulze-Tanzil Gundula , Ertel Wolfgang , Jagielski Michal
Published: December 2023

Osteoarthritis (OA) most frequently affects the knee joint and is associated with an elevated expression of cytokines and extracellular cartilage matrix (ECM), degrading enzymes such as matrix metalloproteinases (MMPs). Differences in gene expression of the intra-articularly located infrapatellar fat pad (IPFP) and other fatty tissue suggest its autonomous function, yet its role in OA pathogenesis remains unknown. Human IPFPs and articular cartilage were collected from OA patients undergoing total knee arthroplasty, and biopsies from the IPFP of healthy patients harvested during knee arthroscopy served as controls (CO). Isolated chondrocytes were co-cultured with either osteoarthritic (OA) or CO-IPFPs in a transwell system. Chondrocyte expression of MMP1, -3, -13, type 1 and 2 collagens, interleukin IL1β, IL6, IL10, and tumor necrosis factor TNFα was analyzed by RTD-PCR at day 0 and day 2, and TNFα secretion was analyzed by ELISA. The cytokine release in IPFPs was assessed by an array. Results: Both IPFPs (CO, OA) significantly reduced the expression of type 2 collagen and TNFα in chondrocytes. On the other hand, only CO-IPFP suppressed the expression of type 1 collagen and significantly induced the MMP13 expression. On the contrary, IL1β and IL6 were significantly induced when exposed to OA-IPFP. Conclusions: The partial loss of the suppressive effect on type 1 collagen gene expression found for OA-IPFP shows the pathological remodeling and dedifferentiation potential of the OA-IPFP on the chondrocytes. However, the significant suppression of TNFα implies that the OA- and CO-IPFP could also exhibit a protective role in the knee joint, preventing the progress of inflammation.
Tailoring Mechanical Properties of a-C:H:Cr Coatings
Authors: Bagherpour Alireza , Baral Paul , Colla Marie-Stéphane , Orekhov Andrey , Idrissi Hosni , Haye Emile , Pardoen Thomas , Lucas Stéphane
Published: December 2023

The development of coatings with tunable performances is critical to meet a wide range of technological applications each one with different requirements. Using the plasma-enhanced chemical vapor deposition (PECVD) process, scientists can create hydrogenated amorphous carbon coatings doped with metal (a-C:H:Me) with a broad range of mechanical properties, varying from those resembling polymers to ones resembling diamond. These diverse properties, without clear relations between the different families, make the material selection and optimization difficult but also very rich. An innovative approach is proposed here based on projected performance indices related to fracture energy, strength, and stiffness in order to classify and optimize a-C:H:Me coatings. Four different a-C:H:Cr coatings deposited by PECVD with Ar/C2H2 discharge under different bias voltage and pressures are investigated. A path is found to produce coatings with a selective critical energy release rate between 5–125 J/m2 without compromising yield strength (1.6–2.7 GPa) and elastic limit (≈0.05). Finally, fine-tuned coatings are categorized to meet desired applications under different testing conditions.
Tribological and Corrosion Performance of CrAlN/CrN Coatings in Artificial Seawater under Varied Nitrogen Pressures
Authors: Li Man , Yu Yunjiang , Zou Changwei , Tian Canxin , Xiang Yanxiong
Published: December 2023

This study employed arc ion plating technology to deposit CrAlN/CrN coatings on stainless steel substrates, adjusting deposition pressures ranging from 1.0 Pa to 4.0 Pa. A detailed analysis of the coatings’ microstructure, wear, and corrosion features was performed using X-ray diffraction, scanning electron microscopy, nanoindentation, tribometers, profilometers, and electrochemical workstations. The study revealed that the crystalline structure of the CrAlN/CrN coatings primarily consists of cubic crystals of AlN, (Cr, Al)N, and CrN. Diffraction peak intensity analysis revealed preferential orientation in the CrAlN coatings along the (111) and (200) crystal planes. As the pressure increased to 3.0 Pa, the content of Al elements peaked, and the columnar structure became denser; at this point, the H/E* ratio reached a maximum of 0.079, indicating excellent delamination and fracture resistance of the CrAlN/CrN coating at this pressure. Tests in artificial seawater environments showed that with the increase in nitrogen pressure, the friction coefficient gradually decreased, reaching its lowest at 3 Pa, approximately 0.19. The wear rate trend aligned with the friction coefficient, recorded at a mere 2.20 × 10−7 mm3/Nm. Electrochemical polarization curve tests revealed that at 3 Pa pressure, the CrAlN/CrN coating had a corrosion potential of −0.04 V, a polarization resistance of 9.28 × 105 Ω·cm2, and a very low corrosion current of 4.81 × 10−8 A/cm2, demonstrating excellent corrosion resistance.
Physicomechanical Properties of Gypsum with Mineral Additions at Elevated Temperatures
Authors: Wang Junjie , Liu Engui
Published: December 2023

Gypsum, from either nature or industrial by-products, can be a lower-cost and cleaner alternative binder to Portland cement used in construction projects, such as affordable housing in developing countries. Although various building products have successfully used gypsum as the binder, some drawbacks of this material have still been claimed, for example, in the aspects of mechanical strength and some other physical properties. Using mineral additions to gypsum seems to be a possible solution to create composite gypsum with improved properties. This work has investigated the possibility of two common minerals (silica flour and talc powder) in modifying composite gypsum’s physical and mechanical performance at elevated temperatures (100–1100 °C), including hydration, strength, thermal conduction and stability, and microstructure. The results suggest that 10% gypsum replacement by silica flour or talc powder modifies gypsum’s physical and mechanical properties, with silica flour performing better than talc powder. The performance of composite gypsum at elevated temperatures depends on the treatment temperature and reflects the combined effects of gypsum phase change and the filler effects of silica flour or talc powder. Thermal treatment at ≤200 °C increased the thermal resistance of all gypsum boards but decreased their compressive strength. Thermal treatment at ≥300 °C significantly increased the compressive strength of gypsum with silica flour and talc powder but induced intensive microcracks and thus failed the thermal insulation. This investigation indicates that silica flour can potentially raise the mechanical performance of gypsum. At the same time, talc powder can hold water and lubricate, which may help with the continuous hydration of gypsum phases and the rheology of its mixtures.
Physicochemical Characteristics, Fatty Acid Profile, and In Vitro Antioxidant Activity Evaluation of Sacha Inchi Seed Oil from Indonesia
Authors: Maya Ira , Winardi Devani Olivia , Amalia Eri , Mita Soraya Ratnawulan , Kusumawulan Cahya Khairani , Putriana Norisca Aliza , Sriwidodo Sriwidodo
Published: December 2023

Free radicals can cause damage to the structure of the dermis layer, which makes skin lose its elasticity and leads to the formation of wrinkles. A strategy to prevent this problem is by using antioxidants. A plant that has been reported to contain good antioxidant activity is sacha inchi seed (Plukenetia volubilis L.); apart from that, its oil has quite a high omega-3 content and potentially can act as an anti-aging agent stimulating the skin-cell-regeneration process, maintaining skin moisture and elasticity and stimulating collagen production. This research aims to analyze the physicochemical characteristics and determine the fatty acid profile, the levels of vitamins A, D, and E, and the antioxidant activity of sacha inchi seed oil. This research was conducted through eight main stages: sacha inchi seed extraction, quality parameters checking, phytochemical screening, determining fatty acid profiles, vitamin analysis, antioxidant activity tests, microbiological contamination tests, and heavy-metal contamination tests. In this study, quality inspection results were obtained: organoleptic form (liquid), color (yellow), odor (typical), relative density value (0.91 g/cm3), acid number (0.38 ± 0.02 mg/g), peroxide value (11.01 mEq/Kg), iodine value (179.32 g/100 g), and refractive index (1.479). The phytochemical screening results of sacha inchi seed oil were positive for containing flavonoids, triterpenoids, and steroids. The results of the fatty acid profile were omega-3 (48.5%), omega-6 (34.8%), and omega-9 (7.7%). The results of the vitamin contents analysis were vitamin A (123.42 mg/100 g), vitamin D (899.46 mg/100 g), and vitamin E (145.06 mg/100 g). The antioxidant activity test showed an IC50 value of 8.859 ppm (very strong), and the microbial and heavy-metal contamination tests were negative.
Impact of Structural Strain in Perovskite Epitaxial Thin Films on Their Functional Properties
Authors: Andrei Florin , Dinescu Maria , Ion Valentin , Craciun Floriana , Birjega Ruxandra , Scarisoreanu Nicu Doinel
Published: December 2023

The strain engineering effects induced by different means, e.g., the substrate lattice mismatch and/or chemical doping, on the functional properties of perovskite thin films have triggered interest in the use of these materials in different applications such as energy storage/generation or photonics. The effects of the film’s thickness and strain state of the structure for the lead-free perovskite ferrite-based materials (BiFeO3-BFO; Y-doped BiFeO3-BYFO; LaFeO3-LFO) on their functional properties are highlighted here. As was previously demonstrated, the dielectric properties of BFO epitaxial thin films are strongly affected by the film thickness and by the epitaxial strain induced by the lattice mismatch between substrate and film. Doping the BiFeO3 ferroelectric perovskite with rare-earth elements or inducing a high level of structural deformation into the crystalline structure of LaFeO3 thin films have allowed the tuning of functional properties of these materials, such as dielectric, optical or photocatalytic ones. These changes are presented in relation to the appearance of complex ensembles of nanoscale phase/nanodomains within the epitaxial films due to strain engineering. However, it is a challenge to maintain the same level of epitaxial strain present in ultrathin films (<10 nm) and to preserve or tune the positive effects in films of thicknesses usually higher than 30 nm.