bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of Fuzzy-ISM-MICMAC in the Risk Analysis Affecting Swivel Bridge Construction Spanning Existing Railway Lines: A Case Study
Authors: Peng Chunyan , Wang Jiquan , Chen Huihua , Tang Runxi
Published: December 2023

Swivel bridge construction (SBC) technology has significant advantages in building bridges that span existing railway lines (ERLs), but it also entails complex risks from ‘skylight’ windows and railway boundaries. A notable challenge is the relationships and interdependencies among these risks, which collectively increase safety hazards through mutual influence. Prior research has typically focused on mitigating the risks inherent in particular tasks or operations, with less emphasis on the risks from interdependencies. A novel framework was developed to explore this research gap by integrating fuzzy logic, interpretive structural modeling (ISM) and the cross-impact matrix multiplication applied to classification (MICMAC) approach (Fuzzy-ISM-MICMAC) to investigate the relationships and interdependencies among the risks of SBC spanning ERLs and the critical points of risk control. Furthermore, the data collected from a literature review, a case analysis and expert interviews resulted in 28 risk factors. Then, the application of ISM distilled complex risk relationships into a clear, multilevel hierarchy, accurately illustrating the complex interrelationships among risk factors. Combined with MICMAC analysis, the research findings indicate that preliminary works such as the selection of construction technology, scheme design, construction rehearsal and the provision of safety facilities are essential for preventing risks in SBC spanning ERLs. We applied these findings to the double T-structure swivel construction of the Xiaojizhuang Bridge, where its practicality and efficiency were thoroughly tested and validated. This research’s critical contribution is identifying, clarifying and visualizing the interrelationships of the complex risk factors of SBC spanning ERLs and providing specific solutions for safety management in similar bridge construction projects. The research results and risk control recommendations offer valuable insights for managing other swivel bridge construction risks.
Compaction Characteristics of a Foam Asphalt Hot In-Place Recycling Asphalt Mixture
Authors: Sun Xupeng , Guo Dedong , Li Jin , Liu Zhen , Xu Meng , Hu Qinshuai , Xu Qi , Yang Shihua
Published: December 2023

This study investigates the application of foam asphalt (FA) to enhance the compaction effectiveness of a hot in-place recycling asphalt mixture (HIR-AM) during the HIR process of old road surfaces. Initially, the process parameters for FA preparation were determined through expansion-rate and half-life tests. Subsequently, the study focused on evaluating the impact of FA on the compaction quality of HIR-AM. Performance assessments were conducted through rutting tests, low-temperature bending tests, Hamburg wheel tracking tests, dynamic modulus analyses, and various other experiments to evaluate the road performance of HIR-FAM. Finally, the research findings were validated through practical engineering applications, and the construction process for HIR-FAM was summarized. The research results reveal that the optimal foaming temperature for SBS asphalt is 170 °C, with an ideal water content of 1.7%. Under the same compaction temperature, HIR-FAM demonstrated a significant reduction in void content, ranging from 3.8% to 21.2% compared to HIR-AM. Moreover, a higher proportion of FA usage resulted in a more substantial decrease in void content. Compared to HIR-AM, HIR-FAM exhibited notable improvements, including an 11.6% increase in dynamic stability, a 13.4% enhancement in bending strength, a 13.3% increase in maximum bending strain, an 8.1% improvement in residual stability, and an 8.5% boost in freeze–thaw splitting strength. Furthermore, HIR-FAM demonstrated superior water-thermal stability and resistance to low-frequency loads. Paving a test road verified that the adoption of foam asphalt in thermal recycling led to a compaction density increase of over 0.79% compared to traditional in situ thermal recycling sections, with improved compaction uniformity.
Low Post-Treatment Quality of Life and the High Incidence of Pain Are Common and Significantly Exacerbated in Depressed Head and Neck Patients Treated with Definitive Accelerated Radiotherapy
Authors: Heyda Alicja , Księżniak-Baran Dorota , Wygoda Andrzej , Składowski Krzysztof
Published: December 2023

(1) Background: The goal of this study is to evaluate psychological tolerance and health-related quality of life (QOL) in head and neck (HN) cancer patients treated with definitive accelerated radiotherapy (DART). (2) Methods: 76 recurrence-free patients eligible for the study, who were treated with DART in the CAIR-2 phase III clinical study (median of follow-up = 47 months), completed EORTC QLQ-C30 with the H&N35 module, Hospital Anxiety and Depression Scale (HADS) and Visual–Analog Scales (VAS) of pain in HN and the neck/arm areas. (3) Results: The most dominant symptoms measured with QLQ-C30 were as follows: fatigue (44/100), sleeplessness (39/100), financial problems (38/100) and pain (32/100). Within the H&N35, the highest scores were reported on the subscales of sticky saliva (60/100), mouth dryness (65/100) and increased intake of painkillers (50/100). Pain (VAS) was reported by 87% (HN area) and 78% (shoulder area) of the patients, with a mean score of 3/10. One-third of the patients reported depressive moods (HADS ≥ 15 points) with an average score of 12.5/42 p. The depressed group, who smoked more as compared to the non-depressed group before DART (96% vs. 78%) and required steroids treatment (85% vs. 58%) during DART, also scored significantly worse on 23 of the 35 subscales of QLQ-C30 and H&N35 and experienced more intense pain (VAS). Women and less-advanced patients scored better in several aspects of quality of life. (4) Conclusions: Patients treated with DART struggle with low quality of life and persistent treatment-related symptoms including constant pain. HNC survivors, especially those who are depressed, may require additional psychosocial, rehabilitation and medical intervention programmes.
A Novel Tissue-Free Method to Estimate Tumor-Derived Cell-Free DNA Quantity Using Tumor Methylation Patterns
Authors: Melton Collin , Freese Peter , Zhou Yifan , Shenoy Archana , Bagaria Siddhartha , Chang Christopher , Kuo Chih-Chung , Scott Eric , Srinivasan Subashini , Cann Gordon , Roychowdhury-Saha Manami , Chang Pei-Yun , Singh Amoolya
Published: December 2023

Estimating the abundance of cell-free DNA (cfDNA) fragments shed from a tumor (i.e., circulating tumor DNA (ctDNA)) can approximate tumor burden, which has numerous clinical applications. We derived a novel, broadly applicable statistical method to quantify cancer-indicative methylation patterns within cfDNA to estimate ctDNA abundance, even at low levels. Our algorithm identified differentially methylated regions (DMRs) between a reference database of cancer tissue biopsy samples and cfDNA from individuals without cancer. Then, without utilizing matched tissue biopsy, counts of fragments matching the cancer-indicative hyper/hypo-methylated patterns within DMRs were used to determine a tumor methylated fraction (TMeF; a methylation-based quantification of the circulating tumor allele fraction and estimate of ctDNA abundance) for plasma samples. TMeF and small variant allele fraction (SVAF) estimates of the same cancer plasma samples were correlated (Spearman’s correlation coefficient: 0.73), and synthetic dilutions to expected TMeF of 10−3 and 10−4 had estimated TMeF within two-fold for 95% and 77% of samples, respectively. TMeF increased with cancer stage and tumor size and inversely correlated with survival probability. Therefore, tumor-derived fragments in the cfDNA of patients with cancer can be leveraged to estimate ctDNA abundance without the need for a tumor biopsy, which may provide non-invasive clinical approximations of tumor burden.
Exploiting the DNA Damage Response for Prostate Cancer Therapy
Authors: Stracker Travis H. , Osagie Oloruntoba I. , Escorcia Freddy E. , Citrin Deborah E.
Published: December 2023

Prostate cancers that progress despite androgen deprivation develop into castration-resistant prostate cancer, a fatal disease with few treatment options. In this review, we discuss the current understanding of prostate cancer subtypes and alterations in the DNA damage response (DDR) that can predispose to the development of prostate cancer and affect its progression. We identify barriers to conventional treatments, such as radiotherapy, and discuss the development of new therapies, many of which target the DDR or take advantage of recurring genetic alterations in the DDR. We place this in the context of advances in understanding the genetic variation and immune landscape of CRPC that could help guide their use in future treatment strategies. Finally, we discuss several new and emerging agents that may advance the treatment of lethal disease, highlighting selected clinical trials.
Epigenetic Alterations as Vital Aspects of Bortezomib Molecular Action
Authors: Kulig Piotr , Łuczkowska Karolina , Bakinowska Estera , Baumert Bartłomiej , Machaliński Bogusław
Published: December 2023

Bortezomib (BTZ) is widely implemented in the treatment of multiple myeloma (MM). Its main mechanism of action is very well established. BTZ selectively and reversibly inhibits the 26S proteasome. More precisely, it interacts with the chymotryptic site of the 20S proteasome and therefore inhibits the degradation of proteins. This results in the intracellular accumulation of misfolded or otherwise defective proteins leading to growth inhibition and apoptosis. As well as interfering with the ubiquitin–proteasome complex, BTZ elicits various epigenetic alterations which contribute to its cytotoxic effects as well as to the development of BTZ resistance. In this review, we summarized the epigenetic alterations elicited by BTZ. We focused on modifications contributing to the mechanism of action, those mediating drug-resistance development, and epigenetic changes promoting the occurrence of peripheral neuropathy. In addition, there are therapeutic strategies which are specifically designed to target epigenetic changes. Herein, we also reviewed epigenetic agents which might enhance BTZ-related cytotoxicity or restore the sensitivity to BTZ of resistant clones. Finally, we highlighted putative future perspectives regarding the role of targeting epigenetic changes in patients exposed to BTZ.
Novel Pathogenic Variants in Hereditary Cancer Syndromes in a Highly Heterogeneous Cohort of Patients: Insights from Multigene Analysis
Authors: Bilyalov Airat , Danishevich Anastasiia , Nikolaev Sergey , Vorobyov Nikita , Abramov Ivan , Pismennaya Ekaterina , Terehova Svetlana , Kosilova Yuliya , Primak Anastasiia , Stanoevich Uglesha , Lisica Tatyana , Shipulin German , Gamayunov Sergey , Kolesnikova Elena , Khatkov Igor , Gusev Oleg , Bodunova Natalia
Published: December 2023

Cancer is a major global public health challenge, affecting both quality of life and mortality. Recent advances in genetic research have uncovered hereditary cancer syndromes (HCS) that predispose individuals to malignant neoplasms. While traditional single-gene testing has focused on high-penetrance genes, the past decade has seen a shift toward multigene panels, which facilitate the analysis of multiple genes associated with specific HCS. This approach reveals variants in less-studied gene regions and improves our understanding of cancer predisposition. In a study composed of Russian patients with clinical signs of HCS, we used a multigene hereditary cancer panel and revealed 21.6% individuals with pathogenic or likely pathogenic genetic variants. BRCA1/BRCA2 mutations predominated, followed by the CHEK2 and ATM variants. Of note, 16 previously undescribed variants were identified in the MUTYH, GALNT12, MSH2, MLH1, MLH3, EPCAM, and POLE genes. The implications of the study extend to personalized cancer prevention and treatment strategies, especially in populations lacking extensive epidemiological data, such as Russia. Overall, our research provides valuable genetic insights that give the way for further investigation and advances in the understanding and management of hereditary cancer syndromes.
Assessment of the Psychosocial Impact of Pancreatic Cancer Surveillance in High-Risk Individuals
Authors: Anez-Bruzual Isabel , Coughlin Sarah , Clay Daniel , Heiman Jordan , Dungan Michaela , Weber Marina , Almario Christopher V. , Leung Galen , Ahmad Nuzhat A. , Ginsberg Gregory G. , Kochman Michael L. , Valverde Kathleen D. , Long Jessica M. , Katona Bryson W.
Published: December 2023

Objectives: Pancreatic cancer (PC) surveillance of high-risk individuals (HRIs) downstages PC and improves survival. However, it remains less clear whether PC surveillance has a positive psychosocial impact on HRIs. Herein, we aimed to define the attitudes and beliefs of HRIs undergoing PC surveillance, and the immediate and sustained psychosocial impact of PC surveillance in HRIs. Methods: 100 HRIs undergoing PC surveillance by endoscopic ultrasound (EUS) completed three surveys addressing different components of the psychosocial impact of PC surveillance. Logistic regression analyses were performed to identify predictive factors relating to these components. Results: Most HRIs reported increased perceived benefits of PC surveillance, self-efficacy, and perceived severity of PC. HRIs reported few negative emotions prior to surveillance and frequent positive emotions after surveillance. Compared to prior to surveillance, there was a 53.5% decrease in the level of distress reported by HRIs after surveillance, which was sustained for 4–6 weeks post-surveillance. Family history of PC and lower self-reported mental health were identified as predictors for increased perceived susceptibility to PC (p < 0.01) and greater change in distress pre- to post-surveillance (p < 0.01), respectively. Conclusions: Our findings suggest that PC surveillance can lead to sustained psychosocial benefits in HRIs.
Clinical Application of the Association between Genetic Alteration and Intraoperative Fluorescence Activity of 5-Aminolevulinic Acid during the Resection of Brain Metastasis of Lung Adenocarcinoma
Authors: Jeong Hyeon Yeong , Suh Won Jun , Kim Seung Hwan , Nam Taek Min , Jang Ji Hwan , Kim Kyu Hong , Kim Seok Hyun , Kim Young Zoon
Published: December 2023

The primary objective of this study was to investigate the association of certain genetic alterations and intraoperative fluorescent activity of 5-aminolevulinic acid (ALA) in brain metastasis (BM) of lung adenocarcinoma. A retrospective cohort study was conducted among 72 patients who underwent surgical resection of BM of lung adenocarcinoma at our institute for five years. Cancer cell infiltration was estimated by the intraoperative fluorescent activity of 5-ALA, and genetic alterations were analyzed by next-generation sequencing (NGS). The sensitivity and specificity for detecting cancer cell infiltration using 5-ALA were 87.5% and 96.4%, respectively. Genes associated with cell cycle regulation (p = 0.003) and cell proliferation (p = 0.044) were significantly associated with positive fluorescence activity of 5-ALA in the adjacent brain tissue. Genetic alterations in cell cycle regulation and cell proliferation were also associated with shorter recurrence-free survival (p = 0.013 and p = 0.042, respectively) and overall survival (p = 0.026 and p = 0.042, respectively) in the multivariate analysis. The results suggest that genetic alterations in cell cycle regulation and cell proliferation are associated with positive fluorescence activity of 5-ALA in the adjacent infiltrative brain tissue and influence the clinical outcome of BM of lung adenocarcinoma.
NK3.3-Derived Extracellular Vesicles Penetrate and Selectively Kill Treatment-Resistant Tumor Cells
Authors: McCune Allyson , Kornbluth Jacki
Published: December 2023

Cancer treatments often become ineffective due to the development of tumor resistance, leading to metastasis and relapse. Treatments may also fail because of their inability to access cells deep within the tumor tissue. When this occurs, new therapeutic agents are needed. We previously reported that NK3.3EVs, extracellular vesicles (EVs) derived from the normal human natural killer (NK) cell line, NK3.3, have strong cytotoxic activity against leukemia and breast cancer cell lines, without harming normal cells. Here, we used a three-dimensional (3D) MCF7 breast cancer mammosphere model to reproduce a more physiological environment that NK3.3EVs would encounter in vivo. NK3.3EVs penetrated MCF7 mammospheres, inducing death by apoptosis. We generated an imatinib-resistant K562 chronic myeloid leukemia (CML) cell line to investigate whether NK3.3EVs were able to kill tumor cells resistant to front-line chemotherapy. NK3.3EVs were even more cytotoxic to imatinib-resistant cells than parental cells, inducing apoptosis via caspase-3/-7 activation. The small population of cancer stem cells (CSCs) within tumors also contributes to therapeutic resistance. NK3.3EVs reduced the CSC-like CD34+/CD38− subpopulation in imatinib-resistant and parental K562 cultures and decreased CSC-associated expression of tumor-promoting genes. Our results provide strong evidence that NK3.3EVs may be a potential new immunotherapeutic agent for difficult-to-treat cancers.
Extracellular Signal-Regulated Kinases: One Pathway, Multiple Fates
Authors: Deschênes-Simard Xavier , Malleshaiah Mohan , Ferbeyre Gerardo
Published: December 2023

This comprehensive review delves into the multifaceted aspects of ERK signaling and the intricate mechanisms underlying distinct cellular fates. ERK1 and ERK2 (ERK) govern proliferation, transformation, epithelial–mesenchymal transition, differentiation, senescence, or cell death, contingent upon activation strength, duration, and context. The biochemical mechanisms underlying these outcomes are inadequately understood, shaped by signaling feedback and the spatial localization of ERK activation. Generally, ERK activation aligns with the Goldilocks principle in cell fate determination. Inadequate or excessive ERK activity hinders cell proliferation, while balanced activation promotes both cell proliferation and survival. Unraveling the intricacies of how the degree of ERK activation dictates cell fate requires deciphering mechanisms encompassing protein stability, transcription factors downstream of ERK, and the chromatin landscape.
Surgical Trends and Complications in Partial and Radical Nephrectomy: Results from the GRAND Study
Authors: Pyrgidis Nikolaos , Schulz Gerald Bastian , Stief Christian , Blajan Iulia , Ivanova Troya , Graser Annabel , Staehler Michael
Published: December 2023

Background: We aimed to evaluate the current trends in renal cancer surgery, as well as to compare the perioperative outcomes of partial versus radical nephrectomy. Methods: We used the GeRmAn Nationwide inpatient Data (GRAND), provided by the Research Data Center of the Federal Bureau of Statistics (2005–2021). We report the largest study in the field, with 317,843 patients and multiple patient-level analyses. Results: Overall, 123,924 (39%) patients underwent partial and 193,919 (61%) underwent radical nephrectomy in Germany from 2005 to 2021. Of them, 57,308 (18%) were operated on in low-, 142,702 (45%) in intermediate-, and 117,833 (37%) in high-volume centers. A total of 249,333 (78%) patients underwent open, 44,994 (14%) laparoscopic, and 23,516 (8%) robotic nephrectomy. The number of patients undergoing renal surgery remained relatively stable from 2005 to 2021. Over the study period, the utilization of partial nephrectomy increased threefold, while radical nephrectomy decreased by about 40%. After adjusting for major risk factors in the multivariate regression analysis, radical nephrectomy was associated with 3.2-fold higher odds (95% CI: 3.2 to 3.9, p < 0.001) of 30-day mortality, longer hospitalization by 1.9 days (95% CI: 1.9 to 2, p < 0.001), and higher inpatient costs by EUR 1778 (95% CI: 1694 to 1862, p < 0.001) compared to partial nephrectomy. Furthermore, radical nephrectomy had a higher risk of in-hospital transfusion (p < 0.001), sepsis (p < 0.001), acute respiratory failure (p < 0.001), acute kidney disease (p < 0.001), acute thromboembolism (p < 0.001), surgical wound infection (p < 0.001), ileus (p < 0.001), intensive care unit admission (p < 0.001), and pancreatitis (p < 0.001). Conclusions: More patients are offered partial nephrectomy in Germany. Patients undergoing radical nephrectomy present with a higher rate of concomitant risk factors and have increased perioperative morbidity and mortality, prolonged hospitalization, and increased in-hospital costs.
Recurrence-Free Survival and Disease-Specific Survival in Patients with Pancreatic Neuroendocrine Neoplasms: A Single-Center Retrospective Study of 413 Patients
Authors: Møller Stine , Langer Seppo W. , Slott Cecilie , Krogh Jesper , Hansen Carsten Palnæs , Kjaer Andreas , Holmager Pernille , Klose Marianne , Garbyal Rajendra Singh , Knigge Ulrich , Andreassen Mikkel
Published: December 2023

Introduction: The prognosis and impact of different prognostic factors in pancreatic neuroendocrine neoplasms (pNEN) remain controversial. Aim: To investigate prognostic factors for recurrence-free survival and disease-specific survival in patients with pNEN, divided into three groups: patients undergoing surveillance (tumor size < 2 cm, group 1), patients followed after curative-intended surgery (group 2), and patients with unresectable disease or residual tumors after resection (group 3). Method: A single-center retrospective study including consecutive patients over a 20-year period. Multivariate Cox regression analyses were performed to identify risk factors. Results: 413 patients were included, with a mean (SD) age of 62 ± 14 years. In group 1 (n = 51), median (IQR) follow-up was 29 (21–34) months, and tumor size was 1.0 (0.8–1.4) cm. One progressed and had a tumor resection. In group 2 (n = 165), follow-up 59 (31–102) months, median tumor size 2 (1.2–3.4) cm, median Ki-67 index 5 (3–10)%, the 5-year recurrence rate was 21%. Tumor size (p < 0.001), Ki-67 index (p = 0.02), and location in the pancreatic head (p < 0.001) were independent risk factors. In group 3 (n = 197), follow-up 19 (6–46) months, median tumor size 4.2 (2.6–7.0) cm, Ki-67 index 17 (9–64)%, the median disease-specific survival was 22 (6–75) months—99 in NET G1; 54 in NET G2; 14 in NET G3; and 6 months in neuroendocrine carcinomas (NEC). Age (p = 0.029), plasma chromogranin A (p = 0.014), and proliferation, expressed by grade (p = 0.001) and Ki-67 index (p < 0.001), were risk factors. Conclusion: Growth in pNET < 2 cm requiring surgery was observed in 1/51. Tumor size, Ki-67 index, and location in the head were prognostic factors for disease recurrence, while age, plasma chromogranin A, and proliferation predicted mortality in patients with unresectable disease or residual tumors after resection.
Predictive Factors in Metastatic Melanoma Treated with Immune Checkpoint Inhibitors: From Clinical Practice to Future Perspective
Authors: Poletto Stefano , Paruzzo Luca , Nepote Alessandro , Caravelli Daniela , Sangiolo Dario , Carnevale-Schianca Fabrizio
Published: December 2023

The introduction of immunotherapy revolutionized the treatment landscape in metastatic melanoma. Despite the impressive results associated with immune checkpoint inhibitors (ICIs), only a portion of patients obtain a response to this treatment. In this scenario, the research of predictive factors is fundamental to identify patients who may have a response and to exclude patients with a low possibility to respond. These factors can be host-associated, immune system activation-related, and tumor-related. Patient-related factors can vary from data obtained by medical history (performance status, age, sex, body mass index, concomitant medications, and comorbidities) to analysis of the gut microbiome from fecal samples. Tumor-related factors can reflect tumor burden (metastatic sites, lactate dehydrogenase, C-reactive protein, and circulating tumor DNA) or can derive from the analysis of tumor samples (driver mutations, tumor-infiltrating lymphocytes, and myeloid cells). Biomarkers evaluating the immune system activation, such as IFN-gamma gene expression profile and analysis of circulating immune cell subsets, have emerged in recent years as significantly correlated with response to ICIs. In this manuscript, we critically reviewed the most updated literature data on the landscape of predictive factors in metastatic melanoma treated with ICIs. We focus on the principal limits and potentiality of different methods, shedding light on the more promising biomarkers.
SkinLesNet: Classification of Skin Lesions and Detection of Melanoma Cancer Using a Novel Multi-Layer Deep Convolutional Neural Network
Authors: Azeem Muhammad , Kiani Kaveh , Mansouri Taha , Topping Nathan
Published: December 2023

Skin cancer is a widespread disease that typically develops on the skin due to frequent exposure to sunlight. Although cancer can appear on any part of the human body, skin cancer accounts for a significant proportion of all new cancer diagnoses worldwide. There are substantial obstacles to the precise diagnosis and classification of skin lesions because of morphological variety and indistinguishable characteristics across skin malignancies. Recently, deep learning models have been used in the field of image-based skin-lesion diagnosis and have demonstrated diagnostic efficiency on par with that of dermatologists. To increase classification efficiency and accuracy for skin lesions, a cutting-edge multi-layer deep convolutional neural network termed SkinLesNet was built in this study. The dataset used in this study was extracted from the PAD-UFES-20 dataset and was augmented. The PAD-UFES-20-Modified dataset includes three common forms of skin lesions: seborrheic keratosis, nevus, and melanoma. To comprehensively assess SkinLesNet’s performance, its evaluation was expanded beyond the PAD-UFES-20-Modified dataset. Two additional datasets, HAM10000 and ISIC2017, were included, and SkinLesNet was compared to the widely used ResNet50 and VGG16 models. This broader evaluation confirmed SkinLesNet’s effectiveness, as it consistently outperformed both benchmarks across all datasets.
Cardiomyocyte-Specific Loss of Glutamyl-prolyl-tRNA Synthetase Leads to Disturbed Protein Homeostasis and Dilated Cardiomyopathy
Authors: Wu Jiangbin , Hollinger Jared , Bonanno Emily , Jiang Feng , Yao Peng
Published: December 2023

Glutamyl-prolyl-tRNA synthetase (EPRS1), an aminoacyl-tRNA synthetase (ARS) ligating glutamic acid and proline to their corresponding tRNAs, plays an essential role in decoding proline codons during translation elongation. The physiological function of EPRS1 in cardiomyocytes (CMs) and the potential effects of the CM-specific loss of Eprs1 remain unknown. Here, we found that heterozygous Eprs1 knockout in CMs does not cause any significant changes in CM hypertrophy induced by pressure overload, while homozygous knockout leads to dilated cardiomyopathy, heart failure, and lethality at around 1 month after Eprs1 deletion. The transcriptomic profiling of early-stage Eprs1 knockout hearts suggests a significantly decreased expression of multiple ion channel genes and an increased gene expression in proapoptotic pathways and integrated stress response. Proteomic analysis shows decreased protein expression in multi-aminoacyl-tRNA synthetase complex components, fatty acids, and branched-chain amino acid metabolic enzymes, as well as a compensatory increase in cytosolic translation machine-related proteins. Immunoblot analysis indicates that multiple proline-rich proteins were reduced at the early stage, which might contribute to the cardiac dysfunction of Eprs1 knockout mice. Taken together, this study demonstrates the physiological and molecular outcomes of loss-of-function of Eprs1 in vivo and provides valuable insights into the potential side effects on CMs, resulting from the EPRS1-targeting therapeutic approach.
CREB Is Indispensable to KIT Function in Human Skin Mast Cells—A Positive Feedback Loop between CREB and KIT Orchestrates Skin Mast Cell Fate
Authors: Bal Gürkan , Schneikert Jean , Li Zhuoran , Franke Kristin , Tripathi Shiva Raj , Zuberbier Torsten , Babina Magda
Published: December 2023

Skin mast cells (MCs) are critical effector cells in acute allergic reactions, and they contribute to chronic dermatoses like urticaria and atopic and contact dermatitis. KIT represents the cells‘ crucial receptor tyrosine kinase, which orchestrates proliferation, survival, and functional programs throughout the lifespan. cAMP response element binding protein (CREB), an evolutionarily well-conserved transcription factor (TF), regulates multiple cellular programs, but its function in MCs is poorly understood. We recently reported that CREB is an effector of the SCF (Stem Cell Factor)/KIT axis. Here, we ask whether CREB may also act upstream of KIT to orchestrate its functioning. Primary human MCs were isolated from skin and cultured in SCF+IL-4 (Interleukin-4). Pharmacological inhibition (666-15) and RNA interference served to manipulate CREB function. We studied KIT expression using flow cytometry and RT-qPCR, KIT-mediated signaling using immunoblotting, and cell survival using scatterplot and caspase-3 activity. The proliferation and cycle phases were quantified following BrdU incorporation. Transient CREB perturbation resulted in reduced KIT expression. Conversely, microphthalmia transcription factor (MITF) was unnecessary for KIT maintenance. KIT attenuation secondary to CREB was associated with heavily impaired KIT functional outputs, like anti-apoptosis and cell cycle progression. Likewise, KIT-elicited phosphorylation of ERK1/2 (Extracellular Signal-Regulated Kinase 1/2), AKT, and STAT5 (Signal Transducer and Activator of Transcription) was substantially diminished upon CREB inhibition. Surprisingly, the longer-term interference of CREB led to complete cell elimination, in a way surpassing KIT inhibition. Collectively, we reveal CREB as non-redundant in MCs, with its absence being incompatible with skin MCs’ existence. Since SCF/KIT regulates CREB activity and, vice versa, CREB is required for KIT function, a positive feedforward loop between these elements dictates skin MCs’ fate.
The Biological and Clinical Role of the Telomerase Reverse Transcriptase Gene in Glioblastoma: A Potential Therapeutic Target?
Authors: Di Nunno Vincenzo , Aprile Marta , Bartolini Stefania , Gatto Lidia , Tosoni Alicia , Ranieri Lucia , De Biase Dario , Asioli Sofia , Franceschi Enrico
Published: December 2023

Glioblastoma IDH-wildtype represents the most lethal and frequent primary tumor of the central nervous system. Thanks to important scientific efforts, we can now investigate its deep genomic assessment, elucidating mutated genes and altered biological mechanisms in addition to its clinical aggressiveness. The telomerase reverse transcriptase gene (TERT) is the most frequently altered gene in solid tumors, including brain tumors and GBM IDH-wildtype. In particular, it can be observed in approximately 80–90% of GBM IDH-wildtype cases. Its clonal distribution on almost all cancer cells makes this gene an optimal target. However, the research of effective TERT inhibitors is complicated by several biological and clinical obstacles which can be only partially surmounted. Very recently, novel immunological approaches leading to TERT inhibition have been investigated, offering the potential to develop an effective target for this altered protein. Here, we perform a narrative review investigating the biological role of TERT alterations on glioblastoma and the principal obstacles associated with TERT inhibitions in this population. Moreover, we discuss possible combination treatment strategies to overcome these limitations.
Impact of Europium and Niobium Doping on Hafnium Oxide (HfO2): Comparative Analysis of Sol–Gel and Combustion Synthesis Methods
Authors: Laganovska Katrina , Vitola Virginija , Einbergs Ernests , Bite Ivita , Zolotarjovs Aleksejs , Leimane Madara , Tunens Gatis , Smits Krisjanis
Published: December 2023

This study compares HfO2 ceramics synthesized using sol–gel and combustion methods, emphasizing the impact of the method of synthesis on the resulting properties of the material. The research findings illustrate morphological differences between sol–gel and combustion-derived HfO2. While sol–gel samples displayed irregular nanoparticles with pronounced boundaries, combustion samples revealed more homogeneous structures with particles tending towards coalescence. It was discerned that Eu3+ doping induced oxygen vacancies, stabilizing the tetragonal phase, while subsequent doping with Nb5+ significantly reduced these vacancies, which was also observed in photoluminescence analysis. Furthermore, combustion synthesis left fewer organic residues, with urea presence during synthesis contributing to residual organic components in the material. XPS analysis was used to evaluate the presence of oxygen-deficient hafnia sub-oxide in the samples. The study underscores the important role of tailored synthesis methods in optimizing the properties and applications of HfO2.
New Polymorph of β-Cyclodextrin with a Higher Bioavailability
Authors: Gatiatulin Askar K. , Balakhontsev Ilya S. , Talashmanova Sofia M. , Ziganshin Marat A. , Gorbatchuk Valery V.
Published: December 2023

A new polymorph of anhydrous β-cyclodextrin (polymorph III) was obtained and characterized for the first time using powder X-ray diffraction, infrared spectroscopy, and thermal analysis. The solution enthalpy and time of dissolution in water were determined using solution calorimetry for this polymorph and compared with those of the dried commercial form of β-cyclodextrin (polymorph I), its amorphous form, and 2-hydroxypropyl-β-cyclodextrin. The specific heat capacities of polymorphs I and III were determined using differential scanning calorimetry across a wide range of temperatures, providing enthalpy and Gibbs energy values for the polymorphic transition at 298 K. The affinities of polymorph III and 2-hydroxypropyl-β-cyclodextrin for water were characterized by determining their hydration isotherms, which provided values of hydration Gibbs energy. Being energy-rich, the new-found polymorph of β-cyclodextrin has a significantly higher dissolution rate and an increased affinity for water compared with the dried commercial form of β-cyclodextrin. These properties render the new polymorph promising in industrial applications for guest inclusion in aqueous solutions and pastes, and may be a desirable alternative for water-soluble β-cyclodextrin derivatives.
Video-Recorded Airway Suctioning of Clear and Meconium-Stained Amniotic Fluid and Associated Short-Term Outcomes in Moderately and Severely Depressed Preterm and Term Infants
Authors: Berisha Gazmend , Kvenshagen Line Norman , Boldingh Anne Marthe , Nakstad Britt , Blakstad Elin , Rønnestad Arild Erland , Solevåg Anne Lee
Published: December 2023

Background: The aim of this study was to investigate delivery room airway suctioning and associated short-term outcomes in depressed infants. Methods: This is a single-centre prospective observational study of transcribed video recordings of preterm (gestational age, GA < 37 weeks) and term (GA ≥ 37 weeks) infants with a 5 min Apgar score ≤ 7. We analysed the association between airway suctioning, breathing, bradycardia and prolonged resuscitation (≥10 min). For comparison, non-suctioned infants with a 5 min Apgar score ≤ 7 were included. Results: Two hundred suction episodes were performed in 19 premature and 56 term infants. Breathing improved in 1.9% of premature and 72.1% of term infants, and remained unchanged in 84.9% of premature and 27.9% of term infants after suctioning. In our study, 61 (81.3%) preterm and term infants who were admitted to the neonatal intensive care unit experienced bradycardia after airway suctioning. However, the majority of the preterm and more than half of the term infants were bradycardic before the suction procedure was attempted. Among the non-airway suctioned infants (n = 26), 73.1% experienced bradycardia, with 17 non-airway suctioned infants being admitted to the neonatal intensive care unit. There was a need for resuscitation ≥ 10 min in 8 (42.1%) preterm and 32 (57.1%) term infants who underwent airway suctioning, compared to 2 (33.3%) preterm and 19 (95.0%) term infants who did not receive airway suctioning. Conclusions: In the infants that underwent suctioning, breathing improved in most term, but not preterm infants. More non-suctioned term infants needed prolonged resuscitation. Airway suctioning was not directly associated with worsening of breathing, bradycardia, or extended resuscitation needs.
Update on Fever of Unknown Origin in Children: Focus on Etiologies and Clinical Approach
Authors: Trapani Sandra , Fiordelisi Adele , Stinco Mariangela , Resti Massimo
Published: December 2023

Fever of unknown origin (FUO) can be caused by four etiological categories of diseases. The most common cause of FUO in children is represented by infections, followed by inflammatory conditions and neoplastic causes; a decreasing quote remains still without diagnosis. Despite the fact that several diagnostic and therapeutic approaches have been proposed since the first definition of FUO, none of them has been fully validated in pediatric populations. A focused review of the patient’s history and a thorough physical examination may offer helpful hints in suggesting a likely diagnosis. The diagnostic algorithm should proceed sequentially, and invasive testing should be performed only in select cases, possibly targeted by a diagnostic suspect. Pioneering serum biomarkers have been developed and validated; however, they are still far from becoming part of routine clinical practice. Novel noninvasive imaging techniques have shown promising diagnostic accuracy; however, their positioning in the diagnostic algorithm of pediatric FUO is still not clear. This narrative review aims to provide a synopsis of the existent literature on FUO in children, with its major causes and possible diagnostic workup, to help the clinician tackle the complex spectrum of pediatric FUO in everyday clinical practice.
Effect of Sintering Temperature on High-Entropy Alloy Particle Reinforced Aluminum Matrix Composites via Vacuum Hot-Pressing Sintering
Authors: Zhang Liang , Fang Weilin , Tian Wenbin , Yuan Zhanwei
Published: December 2023

In this paper, Al0.6CoCrFeNi/5052 aluminum matrix composites were prepared at different sintering temperatures (550–700 °C) by vacuum hot-pressing sintering. The effects of sintering temperature on composites were studied by testing the morphology, phase composition and mechanical properties of the composites, which were characterized by uniaxial compression experiments, X-ray diffraction, scanning electron microscope, electron probe and nanoindentation. The results show that the prepared composites have high strength and very good ductility with sintering temperature lower than 700 °C. When the sintering temperature is above 550 °C, the interface layer is formed in the composite material. As the sintering temperature increases, the formation method of the interface layer changes. The generation of the interface layer has a significant effect on the mechanical properties of the composites.
Improvement of the Electrocatalytic Properties for the Methanol Oxidation Reaction (MOR) of the CoPt Alloy
Authors: Dragos-Pinzaru Oana-Georgiana , Racila Luiza , Buema Gabriela , Tabakovic Ibro , Lupu Nicoleta
Published: December 2023

The commercialization of the Direct Methanol Fuel Cell (DMFC) is limited due to the high cost and low efficiency of the electrocatalysts. In this context, the development of new electrocatalysts able to efficiently oxidize the methanol and to have at the same time low price and high stability is one of the researcher’s milestones. In this work, CoPt alloys with different Pt content were prepared, and the efficiency of the alloys to be used as electrocatalysts for the methanol oxidation reaction (MOR) was investigated. Our data show that the electrocatalytic performance of the CoPt electrodeposited alloys is strongly influenced by the synthesis conditions, mainly by the potential applied during the synthesis. The best electrocatalytic activity was obtained for the samples prepared at −0.8 V/SCE.
Numerical Simulation of the Residual Stress at the Interface between Thermal Barrier Coating and Nickel-Based Single-Crystal Superalloy Based on Crystal Plasticity Theory
Authors: Liu Shuainan , Wang Weize , Yang Ting , Liu Yangguang , Liu Chen , Yang Xixi , Zhang Xiaoqin
Published: December 2023

Residual stress plays an important role in the formation and growth of cracks in thermal barrier coatings and single-crystal superalloy substrates. In this study, a finite element model for a planar double-layer thermal barrier coating and a crystal plasticity finite element model based on dislocation slip-induced plastic deformation of single-crystal materials were established to analyze the residual stress in the coatings and the substrate, considering the creep and crystal plasticity of the substrate materials. The simulation results show that the thermal barrier coatings bear most of the stress generated by high temperatures, and the residual stress of the substrate is small. By comparing the two material properties to calculate the interface stress when the amplitude of the interface between the substrate and the coating is 30 μm and the thickness of the thermal grown oxide layer is 5 µm, the interfacial stress of the substrate at the macro scale was found to be similar to the interfacial stress at the micro slip system scale. Based on the cumulative shear strain, it was determined that the [001]-, [011]-, and [111]-oriented alloys activated the 12, 8, and 4 groups, respectively, under the combined action of thermal stress and centrifugal force of the coating. Comparing the activation of different initial orientation slip systems and the magnitude of the yield stress provides a theoretical foundation to study the structural integrity of single-crystal alloys.
Ionospheric Error Models for Satellite-Based Navigation—Paving the Road towards LEO-PNT Solutions
Authors: Imad Majed , Grenier Antoine , Zhang Xiaolong , Nurmi Jari , Lohan Elena
Published: December 2023

Low Earth Orbit (LEO) constellations have recently gained tremendous attention in the navigational field due to their larger constellation size, faster geometry variations, and higher signal power levels than Global Navigation Satellite Systems (GNSS), making them favourable for Position, Navigation, and Timing (PNT) purposes. Satellite signals are heavily attenuated from the atmospheric layers, especially from the ionosphere. Ionospheric delays are, however, expected to be smaller in signals from LEO satellites than GNSS due to their lower orbital altitudes and higher carrier frequency. Nevertheless, unlike for GNSS, there are currently no standardized models for correcting the ionospheric errors in LEO signals. In this paper, we derive a new model called Interpolated and Averaged Memory Model (IAMM) starting from existing International GNSS Service (IGS) data and based on the observation that ionospheric effects repeat every 11 years. Our IAMM model can be used for ionospheric corrections for signals from any satellite constellation, including LEO. This model is constructed based on averaging multiple ionospheric data and reflecting the electron content inside the ionosphere. The IAMM model’s primary advantage is its ability to be used both online and offline without needing real-time input parameters, thus making it easy to store in a device’s memory. We compare this model with two benchmark models, the Klobuchar and International Reference Ionosphere (IRI) models, by utilizing GNSS measurement data from 24 scenarios acquired in several European countries using both professional GNSS receivers and Android smartphones. The model’s behaviour is also evaluated on LEO signals using simulated data (as measurement data based on LEO signals are still not available in the open-access community; we show a significant reduction in ionospheric delays in LEO signals compared to GNSS. Finally, we highlight the remaining open challenges toward viable ionospheric-delay models in an LEO-PNT context.
NLP Sentiment Analysis and Accounting Transparency: A New Era of Financial Record Keeping
Authors: Faccia Alessio , McDonald Julie , George Babu
Published: December 2023

Transparency in financial reporting is crucial for maintaining trust in financial markets, yet fraudulent financial statements remain challenging to detect and prevent. This study introduces a novel approach to detecting financial statement fraud by applying sentiment analysis to analyse the textual data within financial reports. This research aims to identify patterns and anomalies that might indicate fraudulent activities by examining the language and sentiment expressed across multiple fiscal years. The study focuses on three companies known for financial statement fraud: Wirecard, Tesco, and Under Armour. Utilising Natural Language Processing (NLP) techniques, the research analyses polarity (positive or negative sentiment) and subjectivity (degree of personal opinion) within the financial statements, revealing intriguing patterns. Wirecard showed a consistent tone with a slight decrease in 2018, Tesco exhibited marked changes in the fraud year, and Under Armour presented subtler shifts during the fraud years. While the findings present promising trends, the study emphasises that sentiment analysis alone cannot definitively detect financial statement fraud. It provides insights into the tone and mood of the text but cannot reveal intentional deception or financial discrepancies. The results serve as supplementary information, enriching traditional financial analysis methods. This research contributes to the field by exploring the potential of sentiment analysis in financial fraud detection, offering a unique perspective that complements quantitative methods. It opens new avenues for investigation and underscores the need for an integrated, multidimensional approach to fraud detection.
The Doubly Linked Tree of Singly Linked Rings: Providing Hard Real-Time Database Operations on an FPGA
Authors: Lohmann Simon , Tutsch Dietmar
Published: December 2023

We present a hardware data structure specifically designed for FPGAs that enables the execution of the hard real-time database CRUD operations using a hybrid data structure that combines trees and rings. While the number of rows and columns has to be limited for hard real-time execution, the actual content can be of any size. Our structure restricts full navigational freedom to every but the leaf layer, thus keeping the memory overhead for the data stored in the leaves low. Although its nodes differ in function, all have exactly the same size and structure, reducing the number of cascaded decisions required in the database operations. This enables fast and efficient hardware implementation on FPGAs. In addition to the usual comparison with known data structures, we also analyze the tradeoff between the memory consumption of our approach and a simplified version that is doubly linked in all layers.