bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Impact of Some Fixed Point Theorems on Dynamic Programming and RLC Circuit Models in R-Modular b-Metric-like Spaces
Authors: Girgin Ekber , Büyükkaya Abdurrahman , Kuru Neslihan Kaplan , Öztürk Mahpeyker
Published: July 2024

In this study, we significantly extend the concept of modular metric-like spaces to introduce the notion of b-metric-like spaces. Furthermore, by incorporating a binary relation R, we develop the framework of R-modular b-metric-like spaces. We establish a groundbreaking fixed point theorem for certain extensions of Geraghty-type contraction mappings, incorporating both 𝒵 simulation function and E-type contraction within this innovative structure. Moreover, we present several novel outcomes that stem from our newly defined notations. Afterwards, we introduce an unprecedented concept, the graphical modular b-metric-like space, which is derived from the binary relation R. Finally, we examine the existence of solutions for a class of functional equations that are pivotal in dynamic programming and in solving initial value problems related to the electric current in an RLC parallel circuit.
CD74-AKT Axis Is a Potential Therapeutic Target in Triple-Negative Breast Cancer
Authors: Wang Jingchao , Huang Daoyuan , Nguyen Thu Anh Thai , Phan Liem Minh , Wei Wenyi , Rezaeian Abdol-Hossein
Published: July 2024

Triple-negative breast cancer (TNBC) cells are often resistant to FAS (CD95)-mediated apoptosis, but the underlying molecular mechanism(s) is not fully understood yet. Notably, the expression of the type II transmembrane protein, CD74, is correlated with chemotherapy-resistant and more invasive forms of cancers via unknown mechanisms. Here, we analyzed gene expression pattern of cancer patients and/or patient-derived xenograft (PDX) models and found that mRNA and protein levels of CD74 are highly expressed in TNBC and correlated with cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT) properties. Mechanistically, we found that AKT activation is likely critical for maintaining CD74 expression and protein stability to favor its oncogenic functions. Physiologically, epidermal growth factor (EGF) along with CD74 could activate AKT signaling, likely through binding of phosphorylated AKT (S473) to CD74, whereas inhibition of AKT could impair stability of CD74. We also revealed that CD74 binds to FAS and interferes with the intrinsic signaling of FAS-mediated apoptosis. As such, selective targeting of the CD74/FAS complex using the AKT inhibitor along with the CD74-derived peptide could synergistically restore and activate FAS-mediated apoptosis. Therefore, our approach of mobilizing apoptosis pathways likely provides a rationale for TNBC treatment by targeting the CD74/FAS and CD74-AKT axes.
Physiological Adaptation of Fenneropenaeus chinensis in Response to Saline–Alkaline Stress Revealed by a Combined Proteomics and Metabolomics Method
Authors: Gao Tian , Wang Qiong , Sun Huarui , Liu Yang , Li Jitao , He Yuying
Published: July 2024

The rapid development of the mariculture industry has been hindered by limited coastal aquaculture space. To utilize the abundant inland saline–alkaline water, we studied the physiological effects of high carbonate alkalinity stress and high pH stress on Fenneropenaeus chinensis. The study employed quantitative proteomics by tandem mass tag (TMT) and non-targeted metabolomics analysis using a liquid chromatograph mass spectrometer (LC-MS) to understand the physiological and biochemical adaptive mechanisms of the hepatopancreas of F. chinensis in response to saline–alkaline stress at the molecular level. We designed two stress groups as follows: a high carbonate alkalinity (CA) group and a combined high carbonate alkalinity and high pH (CP) group. The study found that the protein and metabolic profiles of the two stress groups were changed, and the CP group, which was exposed to dual stresses, incurred more severe damage to the hepatopancreas compared to that of the CA group. After exposure to CA and CP, the hepatopancreas of F. chinensis showed significant alterations in 455 proteins and 50 metabolites, and 1988 proteins and 272 metabolites, respectively. In addition, F. chinensis upregulated the level of energy metabolism in the hepatopancreas to defend against osmotic imbalance caused by CA or CP stress, which was demonstrated by the significant upregulation of important proteins and metabolites in glycolysis, pyruvate metabolism, TCA cycle, and fatty acid oxidation. Additionally, pattern recognition receptors, the phenol oxidase system, and various immune-related metabolic enzymes and metabolites were also affected. The immune homeostasis of F. chinensis was affected by the alteration of the antioxidant system following exposure to CA or CP. These findings provide valuable information for F. chinensis saline–alkaline water cultivation practices.
Directed Evolution of Protein-Based Sensors for Anaerobic Biological Activation of Methane
Authors: Bahrami Moghadam Ehsan , Nguyen Nam , Wang Yixi , Cirino Patrick C.
Published: July 2024

Microbial alkane degradation pathways provide biological routes for converting these hydrocarbons into higher-value products. We recently reported the functional expression of a methyl-alkylsuccinate synthase (Mas) system in Escherichia coli, allowing for the heterologous anaerobic activation of short-chain alkanes. However, the enzymatic activation of methane via natural or engineered alkylsuccinate synthases has yet to be reported. To address this, we employed high-throughput screening to engineer the itaconate (IA)-responsive regulatory protein ItcR (WT-ItcR) from Yersinia pseudotuberculosis to instead respond to methylsuccinate (MS, the product of methane addition to fumarate), resulting in genetically encoded biosensors for MS. Here, we describe ItcR variants that, when regulating fluorescent protein expression in E. coli, show increased sensitivity, improved overall response, and enhanced specificity toward exogenously added MS relative to the wild-type repressor. Structural modeling and analysis of the ItcR ligand binding pocket provide insights into the altered molecular recognition. In addition to serving as biosensors for screening alkylsuccinate synthases capable of methane activation, MS-responsive ItcR variants also establish a framework for the directed evolution of other molecular reporters, targeting longer-chain alkylsuccinate products or other succinate derivatives.
The Influence of State Authenticity on the Sense of Meaning in Life of Middle School Students: Evidence from a Daily Diary Investigation and an Authenticity Enhancement Experiment
Authors: Yan Shan , Tang Weihai
Published: July 2024

Authenticity is a positive force for adolescent development. Taking middle school students as the main research objects, this paper examines the causal mechanism between state authenticity (SA) and sense of meaning in life through two studies: the diary method and authenticity level increase experiment. In study 1, through the daily diary data tracking investigation of 130 middle school students in daily life situations, the basic psychological needs (BPNs) and satisfaction with life (SWL) play a chain mediating role between state authenticity and sense of daily meaning in life. State authenticity has a one-way prediction effect on sense of meaning in life. In study 2, 140 participants were randomly divided into two groups (experimental group and control group). Middle school students in the experimental group were activated to recall the authenticity experience events to enhance the level of personal authenticity, and it was found that the subjects reported a higher sense of meaning in life. This study reveals the causal mechanism between authenticity and sense of meaning of life, which has positive practical significance for exploring ways to enhance the sense of meaning of life of middle school students.
Experimental Study on Key Techniques for the Construction of High Asphalt Concrete Core Rockfill Dam under Unfavorable Geological Conditions
Authors: Li Hao , He Jianxin , Zhong Shihua , Liu Liang , Yang Wu
Published: July 2024

Asphalt concrete core dams (ACCDs) have been widely constructed in Xinjiang, yet the design of materials and structures has mainly relied on empirical knowledge without substantial theoretical grounding. In this study, we carried out a large-scale relative density test of gravel material in Bamudun dam, studied the compaction characteristics of gravel material, and determined the relative density characteristic index, in order to provide a basis for the subsequent dam material rolling test and construction quality inspection. Furthermore, in order to improve the efficiency of dam construction in narrow valleys, we optimized the connection type between asphalt concrete core wall and bedrock, and proposed a rapid construction method of paving core wall after pouring mass concrete base on bedrock. Finally, we established a three-dimensional finite element model to systematically analyze the stress and deformation patterns of the dam body, core wall, and base of the ACCD at Bamudun. The results show that the maximum compressive stress suffered by the core wall during the full storage period is 1.62 MPa, there is no tensile stress, and the risk of hydraulic splitting is small. The stress and deformation levels of each part are within the safe range. This verifies the rationality of the rapid construction method. The research findings can provide a great theoretical significance and engineering value for the safe design and construction of ACCDs.
Applying Systems Thinking to Research into Risk Factors Influencing Earthmoving Equipment Operation Safety in Construction Sites
Authors: Soltanmohammadlou Nazi , Hon Carol K. H. , Drogemuller Robin
Published: July 2024

Earthmoving operations in the construction process are complex environments that involve interactions between equipment, the workforce, and materials within an overarching construction plan. Over the past two decades, researchers in construction have focused on improving the safety of construction earthmoving equipment due to their omnipresence in the construction environment. Although previous studies have explored safety risks and the causes of accidents involving construction earthmoving equipment, their approaches were common and lacked a comprehensive perspective. Hence, this systematic literature review applies Rasmussen’s (1997) risk management framework using a systems thinking approach to identify and classify the risk factors influencing earthmoving equipment operation safety in construction sites. Utilizing a multistep methodology, this research first identifies 38 risk factors pertinent to earthmoving equipment operations and then classifies them based on systems thinking. Social network analysis (SNA) is employed to analyze the data. The results show that most research on earthmoving equipment safety focuses on monitoring construction sites, but very little on government and regulatory roles. When considering the interdependencies of risk factors, safety training is the most important factor, followed by the largely overlooked earthmoving machinery characteristics and manufacturer’s performance. The results of this review inform both the research community and industry practitioners regarding the less-understood aspects of earthmoving equipment operation safety and future research directions.
Development of an AI Model Utilizing Buildings’ Thermal Mass to Optimize Heating Energy and Indoor Temperature in a Historical Building Located in a Cold Climate
Authors: Akander Jan , Bakhtiari Hossein , Ghadirzadeh Ali , Mattsson Magnus , Hayati Abolfazl
Published: July 2024

Historical buildings account for a significant portion of the energy use of today’s building stock, and there are usually limited energy saving measures that can be applied due to antiquarian and esthetic restrictions. The purpose of this case study is to evaluate the use of the building structure of a historical stone building as a heating battery, i.e., to periodically store thermal energy in the building’s structures without physically changing them. The stored heat is later utilized at times of, e.g., high heat demand, to reduce peaking as well as overall heat supply. With the help of Artificial Intelligence and Convolutional Neural Network Deep Learning Modelling, heat supply to the building is controlled by weather forecasting and a binary calendarization of occupancy for the optimization of energy use and power demand under sustained comfortable indoor temperatures. The study performed indicates substantial savings in total (by approximately 30%) and in peaking energy (by approximately 20% based on daily peak powers) in the studied building and suggests that the method can be applied to other, similar cases.
Evolution of Systemic Treatment for Hepatocellular Carcinoma: Changing Treatment Strategies and Concepts
Authors: Moriguchi Michihisa , Kataoka Seita , Itoh Yoshito
Published: July 2024

Systemic therapy for hepatocellular carcinoma (HCC) has undergone substantial advancements. With the advent of atezolizumab plus bevacizumab (ATZ/BEV) combination therapy, followed by durvalumab plus tremelimumab, the era of immunotherapy for HCC has commenced. The emergence of systemic treatment with high response rates has led to improvements in overall survival while enabling conversion to radical surgical resection in some patients with HCC. In patients with intermediate-stage HCC, new treatment strategies combining systemic treatment and transcatheter arterial chemoembolization (TACE) are under development in clinical trials. Moreover, the addition of local therapies, such as TACE, to systemic treatment according to the treatment effect could achieve a certain percentage of complete response. In the IMbrave050 trial, the efficacy of ATZ/BEV combination therapy was validated in patients predicted to have a high risk of recurrence, especially in those who had undergone radical surgery or radiofrequency ablation for HCC. Therefore, systemic treatment for HCC is entering a new phase for all disease stages. The objective of this review is to organize the current position of systemic therapy for each HCC stage and discuss the development of new treatment methods and strategies, with a focus on regimens incorporating immune checkpoint inhibitors, along with future prospects.
Enhancing Medical Imaging Segmentation with GB-SAM: A Novel Approach to Tissue Segmentation Using Granular Box Prompts
Authors: Villanueva-Miranda Ismael , Rong Ruichen , Quan Peiran , Wen Zhuoyu , Zhan Xiaowei , Yang Donghan M. , Chi Zhikai , Xie Yang , Xiao Guanghua
Published: July 2024

Recent advances in foundation models have revolutionized model development in digital pathology, reducing dependence on extensive manual annotations required by traditional methods. The ability of foundation models to generalize well with few-shot learning addresses critical barriers in adapting models to diverse medical imaging tasks. This work presents the Granular Box Prompt Segment Anything Model (GB-SAM), an improved version of the Segment Anything Model (SAM) fine-tuned using granular box prompts with limited training data. The GB-SAM aims to reduce the dependency on expert pathologist annotators by enhancing the efficiency of the automated annotation process. Granular box prompts are small box regions derived from ground truth masks, conceived to replace the conventional approach of using a single large box covering the entire H&E-stained image patch. This method allows a localized and detailed analysis of gland morphology, enhancing the segmentation accuracy of individual glands and reducing the ambiguity that larger boxes might introduce in morphologically complex regions. We compared the performance of our GB-SAM model against U-Net trained on different sizes of the CRAG dataset. We evaluated the models across histopathological datasets, including CRAG, GlaS, and Camelyon16. GB-SAM consistently outperformed U-Net, with reduced training data, showing less segmentation performance degradation. Specifically, on the CRAG dataset, GB-SAM achieved a Dice coefficient of 0.885 compared to U-Net’s 0.857 when trained on 25% of the data. Additionally, GB-SAM demonstrated segmentation stability on the CRAG testing dataset and superior generalization across unseen datasets, including challenging lymph node segmentation in Camelyon16, which achieved a Dice coefficient of 0.740 versus U-Net’s 0.491. Furthermore, compared to SAM-Path and Med-SAM, GB-SAM showed competitive performance. GB-SAM achieved a Dice score of 0.900 on the CRAG dataset, while SAM-Path achieved 0.884. On the GlaS dataset, Med-SAM reported a Dice score of 0.956, whereas GB-SAM achieved 0.885 with significantly less training data. These results highlight GB-SAM’s advanced segmentation capabilities and reduced dependency on large datasets, indicating its potential for practical deployment in digital pathology, particularly in settings with limited annotated datasets.
Mohs Micrographic Surgery for Cutaneous Squamous Cell Carcinoma
Authors: Zürcher Sven , Martignoni Zora , Hunger Robert E. , Benzaquen Michael , Seyed Jafari S. Morteza
Published: July 2024

Background: The first-line treatment of the localized form of cutaneous squamous cell carcinoma (cSCC) remains surgical excision. Either conventional excision (CE) with margins or Mohs micrographic surgery (MMS) may be preferred, depending on the risk factors of cSCC, the characteristics of the tumor, and the available technical facilities. Methods: This article presents a systematic review of the current literature spanning from 1974 to 2023, comparing outcomes of cSCC treated with MMS versus cSCC treated with conventional excision. Results: Out of the 6821 records identified through the database search, a total of 156 studies were screened, of which 10 were included in the review. The majority of the included studies showed that treatment of cSCC with MMS consistently exhibits a significantly lower risk of recurrence compared to treatment with CE. In addition, MMS is emerging as the preferred technique for the resection of cSCC located in aesthetically or functionally challenging anatomical areas. Conclusion: The studies generally demonstrate that MMS is a safer and more effective treatment of cSCC than CE. Nevertheless, outcomes such as recurrence rates and cost-effectiveness should be assessed more precisely, in order to allow for a more tailored approach in determining the appropriate indication for the use of MMS.
Clinical Characteristics and Special Considerations in the Management of Rare Melanoma Subtypes
Authors: Shannon Adrienne B. , Zager Jonathan S. , Perez Matthew C.
Published: July 2024

Rare histologic subtypes of melanoma, including acral, mucosal, uveal, and desmoplastic melanomas, only make up 5% of all diagnosed melanomas and are often underrepresented in large, randomized trials. Recent advancements in systemic therapy have shown marked improvement in pathologic response rates, improving progression-free and overall survival among cutaneous melanoma patients, but there are limited data to demonstrate improved survival among rarer subtypes of melanoma. Acral melanoma has a poor response to immunotherapy and is associated with worse survival. Mucosal melanoma has a large variability in its presentation, a poor prognosis, and a low mutational burden. Uveal melanoma is associated with a high rate of liver metastasis; recent adoption of infusion and perfusion therapies has demonstrated improved survival among these patients. Desmoplastic melanoma, a high-risk cutaneous melanoma, is associated with high locoregional recurrence rates and mutational burden, suggesting this melanoma may have enhanced response to immunotherapy. While these variants of melanoma represent distinct disease entities, this review highlights the clinicopathologic characteristics and treatment recommendations for each of these rare melanomas and highlights the utility of modern therapies for each of them.
A New Vista of Aldehyde Dehydrogenase 1A3 (ALDH1A3): New Specific Inhibitors and Activity-Based Probes Targeting ALDH1A3 Dependent Pathways in Glioblastoma, Mesothelioma and Other Cancers
Authors: Magrassi Lorenzo , Pinton Giulia , Luzzi Sabino , Comincini Sergio , Scravaglieri Andrea , Gigliotti Valentina , Bernardoni Bianca Laura , D’Agostino Ilaria , Juretich Francesca , La Motta Concettina , Garavaglia Silvia
Published: July 2024

Aldehyde dehydrogenases of the subfamily 1A (ALDH1A) are enzymes necessary for the oxidation of all-trans or 9-cis retinal to retinoic acid (RA). Retinoic acid and its derivatives are important for normal development and maintenance of epithelia, reproduction, memory, and immune function in adults. Moreover, in recent years, it has been demonstrated that ALDH1A members are also expressed and functional in several human cancers where their role is not limited to the synthesis of RA. Here, we review the current knowledge about ALDH1A3, one of the 1A isoforms, in cancers with an emphasis on two of the deadliest tumors that affect humans: glioblastoma multiforme and mesothelioma. In both tumors, ALDH1A3 is considered a negative prognostic factor, and its level correlates with excessive proliferation, chemoresistance, and invasiveness. We also review the recent attempts to develop both ALDH1A3-selective inhibitors for cancer therapy and ALDH1A3-specific fluorescent substrates for fluorescence-guided tumor resection.
Incidence, Characteristics and Survival Rates of Bladder Cancer after Rectosigmoid Cancer Radiation
Authors: Angelis Mario de , Siech Carolin , Di Bello Francesco , Peñaranda Natali Rodriguez , Goyal Jordan A. , Tian Zhe , Longo Nicola , Chun Felix K. H. , Puliatti Stefano , Saad Fred , Shariat Shahrokh F. , Longoni Mattia , Gandaglia Giorgio , Moschini Marco , Montorsi Francesco , Briganti Alberto , Karakiewicz Pierre I.
Published: July 2024

Background: Historical external beam radiation therapy (EBRT) for rectosigmoid cancer (RCa) predisposed patients to an increased risk of secondary bladder cancer (BCa). However, no contemporary radiotherapy studies are available. We addressed this knowledge gap. Materials and methods: Within the Surveillance, Epidemiology, and End Results database (2000–2020), we identified non-metastatic RCa patients who either underwent radiotherapy (EBRT+) or did not (EBRT-). Cumulative incidence plots and multivariable competing risk regression models (CRR) were fitted to address rates of BCa after RCa. In the subgroup of BCa patients, the same methodology addressed BCa-specific mortality (BCSM) according to EBRT exposure status. Results: Of the 188,658 non-metastatic RCa patients, 54,562 (29%) were EBRT+ vs. 134,096 (73%) who were EBRT-. In the cumulative incidence plots, the ten-year BCa rates were 0.7% in EBRT+ vs. 0.7% in EBRT- patients (p = 0.8). In the CRR, EBRT+ status was unrelated to BCa rates (multivariable HR: 1.1, p = 0.8). In the subgroup of 1416 patients with BCa after RCa, 443 (31%) were EBRT+ vs. 973 (69%) who were EBRT-. In the cumulative incidence plots, the ten-year BCSM rates were 10.6% in EBRT+ vs. 12.1% in EBRT- patients (p = 0.7). In the CRR, EBRT+ status was unrelated to subsequent BCSM rates (multivariable HR: 0.9, p = 0.9). Conclusion: Although historical EBRT for RCa predisposed patients to higher BCa rates, contemporary EBRT for RCa is not associated with increased subsequent BCa risk. Moreover, in patients with BCa after RCa, exposure to EBRT does not affect BCSM.
Genotype–Phenotype Correlation in Neurofibromatosis Type 1: Evidence for a Mild Phenotype Associated with Splicing Variants Leading to In-Frame Skipping of NF1 Exon 24 [19a]
Authors: Chen Yunjia , Fu Yulong , Koczkowska Magdalena , Callens Tom , Gomes Alicia , Liu Jian , Bradley William , Brown Bryce , Shaw Brandon , D’Agostino Daniela , Fu Chuanhua , Wallis Deeann
Published: July 2024

Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder caused by loss-of-function variants in the NF1 gene. As of 20 November 2023, over 5000 distinct pathogenic or likely pathogenic variants have been reported in public databases. However, only a few NF1 genotype–phenotype correlations have been established so far. In this study, we present findings on 40 individuals with NF1, comprising 26 unrelated probands and 14 affected relatives, who carry one of nine NF1 heterozygous pathogenic splicing variants, all of which result in the in-frame skipping of exon 24 [19a] (NM_000267.3:r.3114_3197del, p.Asn1039_Arg1066del). These variants include c.3114-2A>G, c.3114-1G>A, c.3196A>G, c.3197G>A, c.3197G>T, c.3197+1G>A, c.3197+1G>T, c.3197+2T>C, and c.3197+3A>T. Among individuals with these variants, none exhibit externally visible plexiform neurofibromas, histopathologically confirmed cutaneous or subcutaneous neurofibromas, symptomatic spinal neurofibromas, or symptomatic optic pathway gliomas. The most prevalent, and sometimes sole, clinical feature observed in this cohort is multiple café-au-lait macules, with or without skinfold freckles: 85% and 60.5% of the individuals display six or more café-au-lait macules and freckles, respectively. In comparison to established NF1 genotype–phenotype correlations, these patients demonstrate highly similar clinical presentations to those associated with the NF1 pathogenic variant c.2970_2972del (p.Met992del), known for resulting in the mildest clinical features. Despite the generally mild phenotype, cognitive impairment, developmental delay, and/or learning difficulties are still observed in 33.3% of these patients, suggesting that learning challenges remain a prominent aspect of the phenotypic presentation in these individuals and necessitate specialized care. This newly established genotype–phenotype correlation will assist clinicians in improving the management of patients harboring NF1 exon 24 [19a] skipping variants and provide a new therapeutic target for NF1 treatment.
Prognostic Evaluation of Piezo2 Channels in Mammary Gland Carcinoma
Authors: Martín-Sanz Raquel , Rodrigues-Françoso Aline , García-Mesa Yolanda , García-Alonso Francisco Javier , Gómez-Muñoz María Asunción , Malmierca-González Sandra , Salazar-Blázquez Rocío , García-Suárez Olivia , Feito Jorge
Published: July 2024

In the last decade, a group of Ca2+ channels called Piezo were discovered, demonstrating a decisive role in the cellular response to mechanical stimuli and being essential in the biological behavior of cells regarding the extracellular compartment. Several investigations have suggested a potential role in carcinogenesis, with a tumor suppressor role in some cases but increased expression in several high-grade neoplasms. Regarding Piezo2 expression in mammary gland neoplasms, a protective role for Piezo2 was initially suggested, but a subsequent study demonstrated a relationship between Piezo2 expression and the highly aggressive triple-negative phenotype of breast carcinoma. A cohort of 125 patients with clinical follow-up was chosen to study Piezo2 expression and clarify its clinical implications using the same immunohistochemical evaluation performed for other breast carcinoma parameters. Fisher’s exact test was chosen to identify potential relationships between the different variables. A significant association was found with the Ki67 proliferation index, but not with mitoses. The tendency of most proliferative tumors was to have an increased score for Piezo2. A similar association was found between Piezo2 expression and perineural invasion.
Purinergic Ca2+ Signaling as a Novel Mechanism of Drug Tolerance in BRAF-Mutant Melanoma
Authors: Stauffer Philip E. , Brinkley Jordon , Jacobson David A. , Quaranta Vito , Tyson Darren R.
Published: July 2024

Drug tolerance is a major cause of relapse after cancer treatment. Despite intensive efforts, its molecular basis remains poorly understood, hampering actionable intervention. We report a previously unrecognized signaling mechanism supporting drug tolerance in BRAF-mutant melanoma treated with BRAF inhibitors that could be of general relevance to other cancers. Its key features are cell-intrinsic intracellular Ca2+ signaling initiated by P2X7 receptors (purinergic ligand-gated cation channels) and an enhanced ability for these Ca2+ signals to reactivate ERK1/2 in the drug-tolerant state. Extracellular ATP, virtually ubiquitous in living systems, is the ligand that can initiate Ca2+ spikes via P2X7 channels. ATP is abundant in the tumor microenvironment and is released by dying cells, ironically implicating treatment-initiated cancer cell death as a source of trophic stimuli that leads to ERK reactivation and drug tolerance. Such a mechanism immediately offers an explanation of the inevitable relapse after BRAFi treatment in BRAF-mutant melanoma and points to actionable strategies to overcome it.
Is There an Added Value of Quantitative DCE-MRI by Magnetic Resonance Dispersion Imaging for Prostate Cancer Diagnosis?
Authors: Jager Auke , Oddens Jorg R. , Postema Arnoud W. , Miclea Razvan L. , Schoots Ivo G. , Nooijen Peet G. T. A. , van der Linden Hans , Barentsz Jelle O. , Heijmink Stijn W. T. P. J. , Wijkstra Hessel , Mischi Massimo , Turco Simona
Published: July 2024

In this multicenter, retrospective study, we evaluated the added value of magnetic resonance dispersion imaging (MRDI) to standard multiparametric MRI (mpMRI) for PCa detection. The study included 76 patients, including 51 with clinically significant prostate cancer (csPCa), who underwent radical prostatectomy and had an mpMRI including dynamic contrast-enhanced MRI. Two radiologists performed three separate randomized scorings based on mpMRI, MRDI and mpMRI+MRDI. Radical prostatectomy histopathology was used as the reference standard. Imaging and histopathology were both scored according to the Prostate Imaging-Reporting and Data System V2.0 sector map. Sensitivity and specificity for PCa detection were evaluated for mpMRI, MRDI and mpMRI+MRDI. Inter- and intra-observer variability for both radiologists was evaluated using Cohen’s Kappa. On a per-patient level, sensitivity for csPCa for radiologist 1 (R1) for mpMRI, MRDI and mpMRI+MRDI was 0.94, 0.82 and 0.94, respectively. For the second radiologist (R2), these were 0.78, 0.94 and 0.96. R1 detected 4% additional csPCa cases using MRDI compared to mpMRI, and R2 detected 20% extra csPCa cases using MRDI. Inter-observer agreement was significant only for MRDI (Cohen’s Kappa = 0.4250, p = 0.004). The results of this study show the potential of MRDI to improve inter-observer variability and the detection of csPCa.
Decoding the Dynamics of Circulating Tumor DNA in Liquid Biopsies
Authors: Turabi Khadija , Klute Kelsey , Radhakrishnan Prakash
Published: July 2024

Circulating tumor DNA (ctDNA), a fragment of tumor DNA found in the bloodstream, has emerged as a revolutionary tool in cancer management. This review delves into the biology of ctDNA, examining release mechanisms, including necrosis, apoptosis, and active secretion, all of which offer information about the state and nature of the tumor. Comprehensive DNA profiling has been enabled by methods such as whole genome sequencing and methylation analysis. The low abundance of the ctDNA fraction makes alternative techniques, such as digital PCR and targeted next-generation exome sequencing, more valuable and accurate for mutation profiling and detection. There are numerous clinical applications for ctDNA analysis, including non-invasive liquid biopsies for minimal residual disease monitoring to detect cancer recurrence, personalized medicine by mutation profiling for targeted therapy identification, early cancer detection, and real-time evaluation of therapeutic response. Integrating ctDNA analysis into routine clinical practice creates promising avenues for successful and personalized cancer care, from diagnosis to treatment and follow-up.
Metal-Catalyzed Thermo-Catalytic Decomposition and Continuous Catalyst Generation
Authors: Nkiawete Mpila Makiesse , Vander Wal Randy Lee
Published: July 2024

In this study, metal dusting is utilized to initiate a two-stage thermo-catalytic decomposition (TCD) process. Stage 1 starts with metal-catalyzed TCD, and in stage 2 the metal-catalyzed carbon catalyzes additional TCD. TEM is presented of the early- versus late-stage TCD to qualitatively illustrate the second-stage TCD by the metal-catalyzed carbons. Corresponding SEM illustrates differences in growth type and surface density between early versus late reaction times, with backscattered imaging differentiating the first- versus second-stage TCD. TGA supports the microscopic inference of a second carbon phase by the presence of an early (low-temperature) reaction peak, characteristic of low-structure or disordered carbon as the second-stage TCD carbon. Raman analysis confirms that the second-stage carbon deposit is more disordered and unstructured, especially at 1000 °C, supported by the ID/IG and La value changes from 0.068 to 0.936 and 65 nm to 4.7 nm, respectively. To further confirm second-stage TCD occurrence upon pre-catalyzed carbons, two carbon blacks are tested. Exposing a combination of edge and basal or exclusively basal sites for the graphitized form, they afford a direct comparison of TCD carbon nanostructure dependence upon the initial carbon catalyst nanostructure. Pre-oxidation of the stainless-steel wool (SSW) prior to TCD is advantageous, accelerating TCD rates and increasing carbon yield relative to the nascent SSW for an equivalent reaction duration.
New and Facile Preparation Method for Highly Active Iron Oxide Catalysts for CO Oxidation
Authors: Schlicher Steffen , Schoch Roland , Prinz Nils , Zobel Mirijam , Bauer Matthias
Published: July 2024

This work presents a new and facile route for the preparation of iron oxide-based catalysts supported on alumina, which enables the targeted synthesis of catalysts with an increased amount of isolated tetrahedrally coordinated iron centers compared to a conventional impregnation procedure, and therefore leads to an increase in activity for CO oxidation reaction. By a multi-step impregnation–calcination protocol, the catalysts were synthesized with iron loadings of between 1 and 10 wt%, and their catalytic activity was then compared with a 10 wt% loaded catalyst prepared by conventional single impregnation. With a loading of 8 wt%, the presented catalysts showed an improved catalytic activity regarding light-off and full conversion temperatures compared to this reference. Through the application of several analytical methods (PXRD, PDF, DRUVS, SEM, XAFS), the improved catalytic activity can be correlated with an increased amount of isolated iron centers and a significantly reduced fraction of agglomerates or particles.
Effect of the Second-Shell Coordination Environment on the Performance of P-Block Metal Single-Atom Catalysts for the Electrosynthesis of Hydrogen Peroxide
Authors: Wu Yidi , Zhang Yuxiang , Lin Sen
Published: July 2024

Hydrogen peroxide (H2O2) is an important chemical with a diverse range of industrial applications in chemical synthesis and medical disinfection. The traditional anthraquinone oxidation process, with high energy consumption and complexity, is being replaced by cost-effective and environmentally friendly alternatives. In order to explore suitable catalysts for the electrocatalytic synthesis of H2O2, the stability of B,N-doped graphene loaded with various p-block metal (PM) single atoms (i.e., PM-NxBy: x and y represent the number of atoms of N and B, respectively) and the effects of different numbers and positions of B dopants in the second coordination shell on the catalytic performance were studied by density functional theory (DFT) calculations. The results show that Ga-N4B6 and Sb-N4B6 exhibit enhanced stability and 2e− oxygen reduction reaction (ORR) activity and selectivity. Their thermodynamic overpotential η values are 0.01 V, 0.03 V for Ga-N4B6’s two configurations and 0.02 V, 0 V for Sb-N4B6’s two configurations. Electronic structure calculations indicate that the PM single atom adsorbs OOH* intermediates and transfers electrons into them, resulting in the activation of the O-O bond, which facilitates the subsequent hydrogenation reaction. In summary, Sb-N4B6 and Ga-N4B6 exhibit extraordinary 2e− ORR performance, and their predicted activities are comparable to those of known outstanding catalysts (such as PtHg4 alloy). We propose effective strategies on how to enhance the 2e− ORR activities of carbon materials, elucidate the origin of the activity of potential catalysts, and provide insights for the design and development of electrocatalysts that can be used for H2O2 production.
HPV Detection in Breast Tumors and Associated Risk Factors in Northeastern Brazil
Authors: Nascimento Kamylla Conceição Gomes , São Marcos Bianca de França , Fontes Pedro Henrique Bezerra , Isídio Beatriz Eda de Oliveira , Leão Stephanie Loureiro , da Silva Gabriel Romulo Parente , Lussón David Beltrán , dos Santos Daffany Luana , Leal Lígia Rosa Sales , Espinoza Benigno Cristofer Flores , de Macêdo Larissa Silva , de França Neto Pedro Luiz , Silva Anna Jéssica Duarte , Silva Neto Jacinto Costa , Santos Vanessa Emanuelle Pereira , de Freitas Antonio Carlos
Published: July 2024

Breast cancer risk factors include lifestyle, genetic–hormonal influences, and viral infections. Human papillomavirus (HPV), known primarily as the etiological agent of cervical cancer, also appears active in breast carcinogenesis, as evidenced in our study of 56 patients from northeastern Brazil. We assessed the clinical and sociodemographic characteristics, correlating them with various breast cancer tumor types. HPV detection involved amplifying the L1 region, with viral load measured using the E2/E6 ratio and viral activity indicated by E5 oncogene expression. Predominantly, patients over 56 years of age with healthy lifestyles showed a high incidence of invasive ductal carcinoma and triple-negative breast cancer. HPV was detected in 35.7% of cases, mostly HPV16, which is associated with high viral loads (80 copies per cell) and significant E5 expression. These results hint at a possible link between HPV and breast carcinogenesis, necessitating further studies to explore this association and the underlying viral mechanisms.
Modeling Autonomous Vehicle Responses to Novel Observations Using Hierarchical Cognitive Representations Inspired Active Inference
Authors: Nozari Sheida , Krayani Ali , Marin Pablo , Marcenaro Lucio , Gomez David Martin , Regazzoni Carlo
Published: July 2024

Equipping autonomous agents for dynamic interaction and navigation is a significant challenge in intelligent transportation systems. This study aims to address this by implementing a brain-inspired model for decision making in autonomous vehicles. We employ active inference, a Bayesian approach that models decision-making processes similar to the human brain, focusing on the agent’s preferences and the principle of free energy. This approach is combined with imitation learning to enhance the vehicle’s ability to adapt to new observations and make human-like decisions. The research involved developing a multi-modal self-awareness architecture for autonomous driving systems and testing this model in driving scenarios, including abnormal observations. The results demonstrated the model’s effectiveness in enabling the vehicle to make safe decisions, particularly in unobserved or dynamic environments. The study concludes that the integration of active inference with imitation learning significantly improves the performance of autonomous vehicles, offering a promising direction for future developments in intelligent transportation systems.
Population Structure of Aetobatus narinari (Myliobatiformes) Caught by the Artisanal Fishery in Northeast Brazil
Authors: Araújo Priscila R. V. , Postaire Bautisse D. , Feldheim Kevin A. , Bassos-Hull Kim , Lessa Rosangela , Ajemian Matthew J.
Published: July 2024

In Brazil, the Whitespotted Eagle Ray Aetobatus narinari is considered data-deficient due to the scarcity of basic information on its biology, ecology, and vulnerability to capture. Despite this, the species is caught by artisanal fishing along most of the coast, especially in the northeast of Brazil. This study analyzed mitochondrial DNA data in specimens of A. narinari caught by artisanal fishing in the northeast coast of Brazil to understand their population structure. For this, 42 individuals were sequenced at three mitochondrial genes: cytochrome oxidase 1 (COI), cytochrome b (Cytb), and NADH dehydrogenase subunit 4 (ND4). Concatenated COI-Cytb-ND4 sequences yielded 14 haplotypes, with moderate haplotype diversity (h = 0.646), low nucleotide diversity (π = 0.00087), and low fixation index ΦST values, indicating no population structure. Our results suggest that there is only one population of A. narinari in the study area. Genetic studies can contribute to improving management plans in these areas, avoiding the overexploitation of this and other species.
The Diagnostic Accuracy of Electrical Impedance Spectroscopy-Assisted Colposcopy, HPV mRNA Test, and P16/Ki67 Immunostaining as CIN2+ Predictors in Greek Population
Authors: Tsampazis Nikolaos , Vavoulidis Eleftherios , Margioula-Siarkou Chrysoula , Symeonidou Marianthi , Intzes Stergios , Papanikolaou Alexios , Dinas Konstantinos , Daniilidis Angelos
Published: July 2024

Objective: To evaluate the diagnostic accuracy of Electrical Impedance Spectroscopy (EIS)-assisted colposcopy in detecting CIN2+ Greek women towards standalone colposcopy, HPV mRNA testing, and p16/Ki67 immunostaining. Methods: We conducted a cross-sectional observational study at the Cervical Pathology Clinic of the 2nd Obstetrics-Gynecology University Department of Hippokration Hospital Thessaloniki involving 316 patients from January 2022 to August 2023. All participants provided liquid-based cervical samples for cytology, HPV mRNA testing, and p16/Ki67 immunostaining. Main Outcome Measures: Subsequently, participants underwent both standalone colposcopy and EIS/ZedScan-assisted colposcopy, followed by cervical punch biopsies. Results: The incorporation of EIS significantly enhanced the sensitivity of colposcopy, increasing it from 54.17% to 100%, equivalent to that of HPV mRNA testing and p16/Ki67 immunostaining, while achieving a high specificity (95.45%). The specificities observed with EIS/ZedScan-assisted and standalone colposcopy were notably superior to those of HPV-related biomarkers (HPV mRNA test and p16/Ki67 immunostaining). When compared to standalone colposcopy, HPV mRNA testing, and p16/Ki67 immunostaining, EIS/ZedScan-assisted colposcopy demonstrated the most favorable combination of Positive and Negative Predictive Values, at 90.57% and 100%, respectively. The inclusion of EIS/ZedScan in colposcopy led to the detection of 44 additional cases of true CIN2+ (100% of the total CIN2+ confirmed histologically) that were missed by standalone colposcopy. This discovery suggests a 45.83% increase in the detection of CIN2+ cases. Conclusions: The integration of EIS with colposcopy has demonstrated effectiveness in detecting cervical lesions, resulting in a significant detection increase of CIN2+ cases while offering optimal levels of sensitivity, specificity, and predictive values for CIN2+ detection.
Pre- and Post-Operative Cone Beam Computed Tomography Assessment of the Temporomandibular Joint in Patients with Orthognathic Surgery
Authors: Vogl Thomas J. , Zyada Wael , Helal Rania , Naguib Nagy N. , Lingwal Neelam , Nour-Eldin Nour-Eldin A.
Published: July 2024

This study aimed to compare the pre- and post-operative temporomandibular joint (TMJ) condylar position in dentofacial deformity (DFD) patients who had orthognathic surgeries using cone beam computed tomography (CBCT). A retrospective study evaluating the pre- and post-operative CBCT for 79 DFD patients (equivalent to 158 TMJs) (mean age = 26.62 ± 9.5 years) with a bilateral sagittal split osteotomy with or without Le Fort I surgeries (n = 29 Class II DFD, n = 50 Class III DFD) was performed. This included the compartmental measurement of TMJ spaces, in addition to the measurement of intercondylar distances and angles. Condylar position centricity was assessed using the Pullinger and Hollender formula. Clinical data were analysed for DFD class, the type of surgery and post-operative CBCT timing. Pre- and post-operative measurements were compared statistically using a paired t-test, Wilcoxon signed-rank test, and Stuart–Maxwell test. TMJ condyles tended to relocate post-operatively in a posterosuperior position with internal rotation in Class II DFD and a superior position with internal rotation in Class III DFD. However, the overall changes were within <0.5 mm translation and <4° rotation and the number of concentrically positioned condyles (according to the Pullinger and Hollender formula) did not change significantly. Orthognathic surgery is associated with minor post-operative translational and rotational condylar positional changes in Class II and III DFDs.
Accuracy and Consistency of Confidence Limits for Monosyllable Identification Scores Derived Using Simulation, the Harrell–Davis Estimator, and Nonlinear Quantile Regression
Authors: Narne Vijaya Kumar , Mohan Dhanya , Avileri Sruthi Das , Jain Saransh , Ravi Sunil Kumar , Yerraguntla Krishna , Almudhi Abdulaziz , Moore Brian C. J.
Published: July 2024

Background: Audiological diagnosis and rehabilitation often involve the assessment of whether the maximum speech identification score (PBmax) is poorer than expected from the pure-tone average (PTA) threshold. This requires the estimation of the lower boundary of the PBmax values expected for a given PTA (one-tailed 95% confidence limit, CL). This study compares the accuracy and consistency of three methods for estimating the 95% CL. Method: The 95% CL values were estimated using a simulation method, the Harrell–Davis (HD) estimator, and non-linear quantile regression (nQR); the latter two are both distribution-free methods. The first two methods require the formation of sub-groups with different PTAs. Accuracy and consistency in the estimation of the 95% CL were assessed by applying each method to many random samples of 50% of the available data and using the fitted parameters to predict the data for the remaining 50%. Study sample: A total of 642 participants aged 17 to 84 years with sensorineural hearing loss were recruited from audiology clinics. Pure-tone audiograms were obtained and PBmax scores were measured using monosyllables at 40 dB above the speech recognition threshold or at the most comfortable level. Results: For the simulation method, 6.7 to 8.2% of the PBmax values fell below the 95% CL for both ears, exceeding the target value of 5%. For the HD and nQR methods, the PBmax values fell below the estimated 95% CL for approximately 5% of the ears, indicating good accuracy. Consistency, estimated from the standard deviation of the deviations from the target value of 5%, was similar for all the methods. Conclusions: The nQR method is recommended because it has good accuracy and consistency, and it does not require the formation of arbitrary PTA sub-groups.