bluuebunny/crossref_metadata_2025 huggingface dataset:
Codes between Poles: Linking Transcriptomic Insights into the Neurobiology of Bipolar Disorder
Authors: Garcia Jon Patrick T. , Tayo Lemmuel L.
Published: September 2024

Bipolar disorder (BPD) is a serious psychiatric condition that is characterized by the frequent shifting of mood patterns, ranging from manic to depressive episodes. Although there are already treatment strategies that aim at regulating the manifestations of this disorder, its etiology remains unclear and continues to be a question of interest within the scientific community. The development of RNA sequencing techniques has provided newer and better approaches to studying disorders at the transcriptomic level. Hence, using RNA-seq data, we employed intramodular connectivity analysis and network pharmacology assessment of disease-associated variants to elucidate the biological pathways underlying the complex nature of BPD. This study was intended to characterize the expression profiles obtained from three regions in the brain, which are the nucleus accumbens (nAcc), the anterior cingulate cortex (AnCg), and the dorsolateral prefrontal cortex (DLPFC), provide insights into the specific roles of these regions in the onset of the disorder, and present potential targets for drug design and development. The nAcc was found to be highly associated with genes responsible for the deregulated transcription of neurotransmitters, while the DLPFC was greatly correlated with genes involved in the impairment of components crucial in neurotransmission. The AnCg did show association with some of the expressions, but the relationship was not as strong as the other two regions. Furthermore, disease-associated variants or single nucleotide polymorphisms (SNPs) were identified among the significant genes in BPD, which suggests the genetic interrelatedness of such a disorder and other mental illnesses. DRD2, GFRA2, and DCBLD1 were the genes with disease-associated variants expressed in the nAcc; ST8SIA2 and ADAMTS16 were the genes with disease-associated variants expressed in the AnCg; and FOXO3, ITGA9, CUBN, PLCB4, and RORB were the genes with disease-associated variants expressed in the DLPFC. Aside from unraveling the molecular and cellular mechanisms behind the expression of BPD, this investigation was envisioned to propose a new research pipeline in studying the transcriptome of psychiatric disorders to support and improve existing studies.
An 11-mer Synthetic Peptide Suppressing Aggregation of Aβ25-35 and Resolving Its Aggregated Form Improves Test Performance in an Aβ25-35-Induced Alzheimer’s Mouse Model
Authors: Nakamura Rina , Matsuda Akira , Higashi Youichirou , Hayashi Yoshihiro , Konishi Motomi , Saito Motoaki , Akizawa Toshifumi
Published: September 2024

There is a high demand for the development of drugs against Alzheimer’s disease (AD), which is related to the misfolding and aggregation of Amyloid-β (Aβ), due to the increasing number of patients with AD. In our present study, we aimed to assess the aggregation inhibitory effect of various synthetic YS-peptides on Aβ25-35 to identify an applicable peptide for clinical use for AD treatment and prevention. Suppression and aggregate resolution activities of YS-peptides against Aβ25-35 were evaluated using a Thioflavin T assay and scanning electron microscopy (SEM). Structure–activity relationship studies revealed that YS-RD11 (RETLVYLTHLD) and YS-RE16 (RETLVYLTHLDYDDTE) showed suppression and aggregate-resolution activities. The effect of YS-peptides on phagocytosis in microglial cells (BV-2 cells) demonstrated that YS-RD11 and YS-RE16 activated the phagocytic ability of microglia. In the Aβ25-35-induced AD mouse model, YS-RD11 prevented and improved the deficits in short-term memory. In conclusion, YS-RD11 is a suitable candidate therapeutic drug against AD and uses a strategy similar to that used for antibodies.
Pro-Resolving Inflammatory Effects of a Marine Oil Enriched in Specialized Pro-Resolving Mediators (SPMs) Supplement and Its Implication in Patients with Post-COVID Syndrome (PCS)
Authors: Gracia Aznar Asun , Moreno Egea Fernando , Gracia Banzo Rafael , Gutierrez Rocio , Rizo Jose Miguel , Rodriguez-Ledo Pilar , Nerin Isabel , Regidor Pedro-Antonio
Published: September 2024

Objectives: This study aimed to evaluate the eicosanoid and pro-resolutive parameters in patients with Post-COVID Syndrome (PCS) during a 12-week supplementation with a marine oil enriched in specialized pro-resolving mediators (SPMs). Patient and methods: This study was conducted on 53 adult patients with PCS. The subjects included must have had a positive COVID-19 test (PCR, fast antigen test, or serologic test) and persistent symptoms related to COVID-19 at least 12 weeks before their enrolment in the study. The following parameters were evaluated: polyunsaturated fatty acids EPA, DHA, ARA, and DPA; specialized pro-resolving mediators (SPMs), 17-HDHA, 18-HEPE, 14-HDHA, resolvins, maresins, protectins, and lipoxins. The eicosanoids group included prostaglandins, thromboxanes, and leukotrienes. The development of the clinical symptoms of fatigue and dyspnea were evaluated using the Fatigue Severity Scale (FSS) and the Modified Medical Research Council (mMRC) Dyspnea Scale. Three groups with different intake amounts were evaluated (daily use of 500 mg, 1500 mg, and 3000 mg) and compared to a control group not using the product. Results: In the serum from patients with PCS, an increase in 17-HDHA, 18-HEPE, and 14-HDHA could be observed, and a decrease in the ratio between the pro-inflammatory and pro-resolutive lipid mediators was detected; both differences were significant (p < 0.05). There were no differences found between the three treatment groups. Fatigue and dyspnea showed a trend of improvement after supplementation in all groups. Conclusions: A clear enrichment in the serum of the three monohydroxylated SPMs could be observed at a dosage of 500 mg per day. Similarly, a clear improvement in fatigue and dyspnea was observed with this dosage.
Nanoscale Surface Metal-Coating Method without Pretreatment for High-Magnification Biological Observation and Applications
Authors: Takemura Kenshin , Motomura Taisei , Takagi Yuko
Published: September 2024

Biospecimen imaging is essential across various fields. In particular, a considerable amount of research has focused on developing pretreatment techniques, ranging from freeze-drying to the use of highly conductive polymers, and on advancements in instrumentation, such as cryogenic electron microscopy. These specialized techniques and equipment have facilitated nanoscale and microscale bioimaging. However, user access to these environments remains limited. This study introduced a novel technique to achieve high conductivity in bioimaging by employing a magnetically controlled sputtering cathode to facilitate low-temperature deposition and low-electron bombardment. This approach allows for the convenient high-magnification observation of highly structured three-dimensional specimens, such as pill bugs and butterfly wings, and fragile specimens, such as single-cell protozoan parasites, using metal deposition only. Furthermore, it is easily accessible in the field of bioimaging because it does not require any pretreatment and enables surface analysis of biospecimens with an electron microscope using only a single pretreatment process. Protozoa, which are microorganisms, were successfully observed at high magnification without structural changes due to thermal denaturation. Furthermore, metallic film deposition and electrochemical signal measurements using these metallic films were achieved in pill bugs.
Effects of Coaxial Nozzle’s Inner Nozzle Diameter on Filament Strength and Gelation in Extrusion-Based 3D Printing with In Situ Ionic Crosslinking
Authors: Rahman Taieba Tuba , Rahman Al Mazedur , Pei Zhijian , Wood Nathan , Qin Hongmin
Published: September 2024

This study systematically investigates the effects of the coaxial nozzle’s inner nozzle diameter on the strength and gelation of filaments produced via extrusion-based 3D printing with in situ ionic crosslinking. In this system, bioink (sodium alginate solution) was extruded through the outer nozzle, and the ionic crosslinking solution (calcium chloride solution) was extruded through the inner nozzle. The outer nozzle diameter was fixed at 2.16 mm, and the inner nozzle diameter was varied among 1.19, 0.84, and 0.584 mm. The results indicate that, as the inner nozzle diameter decreased, filament strength decreased, and filament gelation became poorer. These findings highlight the importance of optimizing inner nozzle diameter for improved filament strength and gelation in extrusion-based 3D printing with in situ ionic crosslinking.
Distinguishing of Histopathological Staging Features of H-E Stained Human cSCC by Microscopical Multispectral Imaging
Authors: Wu Rujuan , Yang Jiayi , Chen Qi , Yang Changxing , Ge Qianqian , Rui Danni , Xiang Huazhong , Zhang Dawei , Wang Cheng , Zhao Xiaoqing
Published: September 2024

Cutaneous squamous cell carcinoma (cSCC) is the second most common malignant skin tumor. Early and precise diagnosis of tumor staging is crucial for long-term outcomes. While pathological diagnosis has traditionally served as the gold standard, the assessment of differentiation levels heavily depends on subjective judgments. Therefore, how to improve the diagnosis accuracy and objectivity of pathologists has become an urgent problem to be solved. We used multispectral imaging (MSI) to enhance tumor classification. The hematoxylin and eosin (H&E) stained cSCC slides were from Shanghai Ruijin Hospital. Scale-invariant feature transform was applied to multispectral images for image stitching, while the adaptive threshold segmentation method and random forest segmentation method were used for image segmentation, respectively. Synthetic pseudo-color images effectively highlight tissue differences. Quantitative analysis confirms significant variation in the nuclear area between normal and cSCC tissues (p < 0.001), supported by an AUC of 1 in ROC analysis. The AUC within cSCC tissues is 0.57. Further study shows higher nuclear atypia in poorly differentiated cSCC tissues compared to well-differentiated cSCC (p < 0.001), also with an AUC of 1. Lastly, well differentiated cSCC tissues show more and larger keratin pearls. These results have shown that combined MSI with imaging processing techniques will improve H&E stained human cSCC diagnosis accuracy, and it will be well utilized to distinguish histopathological staging features.
The Cerebrovascular Side of Plasticity: Microvascular Architecture across Health and Neurodegenerative and Vascular Diseases
Authors: Zedde Marialuisa , Pascarella Rosario
Published: September 2024

The delivery of nutrients to the brain is provided by a 600 km network of capillaries and microvessels. Indeed, the brain is highly energy demanding and, among a total amount of 100 billion neurons, each neuron is located just 10–20 μm from a capillary. This vascular network also forms part of the blood–brain barrier (BBB), which maintains the brain’s stable environment by regulating chemical balance, immune cell transport, and blocking toxins. Typically, brain microvascular endothelial cells (BMECs) have low turnover, indicating a stable cerebrovascular structure. However, this structure can adapt significantly due to development, aging, injury, or disease. Temporary neural activity changes are managed by the expansion or contraction of arterioles and capillaries. Hypoxia leads to significant remodeling of the cerebrovascular architecture and pathological changes have been documented in aging and in vascular and neurodegenerative conditions. These changes often involve BMEC proliferation and the remodeling of capillary segments, often linked with local neuronal changes and cognitive function. Cerebrovascular plasticity, especially in arterioles, capillaries, and venules, varies over different time scales in development, health, aging, and diseases. Rapid changes in cerebral blood flow (CBF) occur within seconds due to increased neural activity. Prolonged changes in vascular structure, influenced by consistent environmental factors, take weeks. Development and aging bring changes over months to years, with aging-associated plasticity often improved by exercise. Injuries cause rapid damage but can be repaired over weeks to months, while neurodegenerative diseases cause slow, varied changes over months to years. In addition, if animal models may provide useful and dynamic in vivo information about vascular plasticity, humans are more complex to investigate and the hypothesis of glymphatic system together with Magnetic Resonance Imaging (MRI) techniques could provide useful clues in the future.
Impact of Serial Casting on Autonomic Nervous System Responses during Virtual Reality Tasks in Children with Cerebral Palsy: A Pilot Study Comparing Orthoses and Barefoot Conditions
Authors: de Paula Paro Marisa , de Sousa Raísa Marques , Martinez Juliana Perez , Simcsik Amanda Orasmo , Airoldi Marina Junqueira , Dias Rodrigo Martins , de Moraes Íbis Ariana Peña , Magalhães Fernando Henrique , de Mello Monteiro Carlos Bandeira , da Silva-Magalhães Talita Dias
Published: September 2024

Cerebral palsy (CP) is a group of movement disorders that impair posture and mobility, often leading to spasticity and joint contractures. Interventions like serial casting are commonly used to improve joint mobility and manage spasticity in children with CP. However, its effects on the autonomic nervous system (ANS) remain unclear. This study aimed to evaluate the effects of serial casting and ankle–foot orthoses (AFOs) on ANS responses during a virtual reality (VR) standing task, comparing these interventions with a barefoot condition. Thirty children with CP were randomized into three groups (n = 10 per group): serial casting, AFOs, and barefoot. Heart rate variability (HRV) was used to assess ANS responses across three phases: seated rest, VR task, and recovery. The results showed that the serial casting group exhibited higher sympathetic activity during rest compared to the other groups, but had a reduced sympathetic response during the VR task. Additionally, the serial casting group displayed a more pronounced parasympathetic rebound during recovery, similar to the orthoses and barefoot groups. While serial casting provides essential joint stability, it alters ANS response patterns, leading to heightened sympathetic activation at rest, without providing significant improvements in ANS behavior during physical activity.
Examining the Role of Neuroticism Polygenic Risk in Late Life Cognitive Change: A UK Biobank Study
Authors: Akbarian Niki , Ebrahimi Mahbod , Dos Santos Fernanda C. , Afjeh Sara Sadat , Abdelhack Mohamed , Sanches Marcos , Diaconescu Andreea O. , Rajji Tarek K. , Felsky Daniel , Zai Clement C. , Kennedy James L.
Published: September 2024

Cognitive decline is a public health concern affecting about 50 million individuals worldwide. Neuroticism, defined as the trait disposition to experience intense and frequent negative emotions, has been associated with an increased risk of late-life cognitive decline. However, the underlying biological mechanisms of this association remain unknown. This study investigated the relationship between genetic predisposition to neuroticism, computed by polygenic risk score (PRS), and performance in cognitive domains of reasoning, processing speed, visual attention, and memory in individuals over age 60. The sample consisted of UK Biobank participants with genetic and cognitive data available (N = 10,737, 4686 females; mean age = 63.4 ± 2.71). The cognitive domains were assessed at baseline for all participants and seven years later for a subset (N = 645, 262 females; mean age = 62.9 ± 2.44). Neuroticism PRS was not associated cross-sectionally with cognitive measures (p > 0.05). However, the trajectory of change for processing speed (β = 0.020; 95% CI = [0.006, 0.035], adjusted p = 0.0148), visual attention (β = −0.077; 95% CI = [−0.0985, −0.0553], adjusted p = 1.412 × 10−11), and memory (β = −0.033; 95% CI = [−0.0535, −0.0131], adjusted p = 0.005) was significantly associated with neuroticism PRS. Specifically, a higher genetic predisposition to neuroticism was associated with less decline in these cognitive domains. This trend persisted after sensitivity analysis using complete cases, although it only remained nominally significant for visual attention.
Why Are Young People Willing to Pay for Health? Chained Mediation Effect of Negative Emotions and Information Seeking on Health Risk Perception and Health Consumption Behavior
Authors: Li Jia , Li Yingyi
Published: September 2024

The perception of health risks can influence people’s health behaviors. However, in the context of modern consumer society, few people delve into in-depth discussions on health consumption as a form of health protection behavior. Inspired by the Health Belief Model and Protection Motivation Theory, this study interprets health consumption behavior as a new form of health protection behavior. A survey was conducted on a sample of Chinese youth (N = 885) to explore the mechanisms of action between health risk perception and health consumption behavior using structural equation modeling. The study found that: (1) health risk perception has a significant positive impact on the health consumption behavior of young people; (2) negative emotions and information seeking play mediating roles respectively in the mechanism of the impact of health risk perception on health consumption behavior; and (3) in addition to their individual mediating roles, negative emotions and information seeking behavior collectively play a chained mediation role in this process. Implications of these results, both theoretical and practical, are further discussed.
An Experimental and Numerical Study on the Lateral Stiffness Limits of Straddle-Type Monorail Tour-Transit Systems
Authors: Zhang Hong , Wang Pengjiao , Li Qin , Jin Junhui , Wei Shiqi , Guo Fengqi , Feng Cheng , Deng Qun
Published: September 2024

The development of the straddle-type monorail tour-transit system (MTTS) has received keen attention. Regarding the unspecified regulations on the lateral stiffness limit of steel substructures, which is essential for the design of MTTSs, this work presents a comprehensive assessment of the issue. Firstly, a wind–vehicle–bridge coupling model was established, integrating multibody dynamics and finite element methods. This model was then validated against field test results, considering measured track irregularities and simulated wind loadings as the excitations. Afterwards, a trend analysis and a variance-based sensitivity analysis was performed to investigate the effect of various factors on the dynamic response of the MTTS. Results indicate that the pier height significantly impacts the lateral displacement of the pier top, accounting for 87% of the first-order sensitivity index and 75% of the total sensitivity index. In comparison, the lateral stiffness of track beams contributes over 70% to the maximum responses at the mid-span. Based on this, two responses, the lateral displacement of the pier top and the lateral deflection–span ratio of the track beam, were utilized as evaluation indicators. With the analysis of indicators in terms of lateral acceleration, Sperling index, and lateral wheel force, the limited values for the two indicators were determined as 8.04 mm and L/4200, respectively. These findings can serve as valuable references for future research and designs in this field.
Multi-Objective Optimisation and Deformation Analysis of Double-System Composite Guideway Based on NSGA-II
Authors: Bai Zhengwei , Zhu Eryu
Published: September 2024

To study the optimal design of the section of the double-system composite guideway under the economic, steel consumption, and carbon emission characteristics, this paper introduced the multi-objective constrained optimisation model, which was established by the non-dominated sorting genetic algorithm II. In addition, the finite element model was established to further analyse the optimised section’s deformation and summarise the rail girder’s deformation law under different loads. The results showed that compared with the original design scheme, the optimised scheme can effectively reduce carbon emission during the construction of the double-system composite guideway, by 23.67% for Scheme I and 42.03% for Scheme II. On the other hand, steel had the largest share in the economic targets of the three design options, accounting for about 75% to 88.5% of the total cost. Concrete had the highest share of carbon emissions, ranging from 90% to 95% of the total carbon emissions. The distribution patterns of horizontal and vertical deformations in the three design options were independent of the load type as well as the load magnitude, but the vertical deformations were related to the load type, especially the self-weight load. The conclusions of this paper aim to fill the gap in the theoretical study of section optimisation of the double-system composite guideway and lay the theoretical foundation for developing the multi-system monorail transportation system.
Seismic Performance of Pile Groups under Liquefaction-Induced Lateral Spreading: Insights from Advanced Numerical Modeling
Authors: Pan Rujiang , Xu Chengshun , Meite Romain , Chen Jilong
Published: September 2024

Post-earthquake investigations have shown that piles in liquefiable soils are highly susceptible to damage, especially in sloping sites. This study examines the seismic performance of pile groups with lateral spreading through advanced numerical modeling. A three-dimensional finite element model, validated against large-scale shaking table test results, is implemented to capture the key mechanisms driving the dynamic response of pile groups under both inertial and kinematic loading conditions. Parametric seismic response analyses are conducted to compare the behavior of batter and vertical piles under varying ground motion intensities. The results indicate that batter piles experience increased axial compressive and tensile forces compared to vertical piles, up to 70% and 20%, respectively. However, batter piles provide enhanced lateral stiffness and shear resistance compared to vertical piles, reducing horizontal displacements by up to 20% and tilting the cap by 85% under strong ground motion. The results demonstrate that batter piles not only enhance the overall seismic stability of the structure but also mitigate the risk of liquefaction-induced lateral spreading in the near-field through pile-pinning effects. While vertical piles are more commonly used in practice, the distinct advantages of batter piles for seismic stability highlighted in this study may encourage using more advanced numerical modeling in engineering projects.
TBM Advanced Geological Prediction via Ellipsoidal Positioning Velocity Analysis
Authors: Gao Zhen , Rong Xin , Wang Wei , Huang Bin , Liu Junqiang
Published: September 2024

Traditional seismic wave-based tunnel advanced geological forecasting techniques are primarily designed for drill and blast method construction tunnels. However, given the fast excavation speed and limited prediction space in tunnel boring machine (TBM) construction tunnels, traditional methods have significant technical limitations. This study analyzes the characteristics of different types of TBM construction tunnels and, considering the practical construction conditions, identifies an effective observation system and data acquisition method. To address the challenges in advanced forecasting for TBM construction tunnels, a method of ellipsoid positioning velocity analysis, which takes into account the constraints of three-component data directions, is proposed. Based on the characteristics of the advanced forecasting observation system, this method compares the maximum values on the spatial isochronous ellipsoidal surface to determine the average velocity of the geological layer rays, thereby enabling accurate inversion of the spatial distribution ahead. Utilizing numerical simulation, a model for the advanced detection of typical unfavorable geological formations is established by obtaining the wave field response characteristics of seismic waves in three-dimensional space, and the velocity structure of the model is retrieved through this velocity analysis method. In the engineering example, the fracture property, water content, and weathering degree of the surrounding rock are predicted accurately.
A Study of the Optical Properties and Stability of Cs0.33WO3 with Different Particle Sizes for Energy-Efficient Window Films in Building Glazing
Authors: Li Ning , Meng Qinglin , Zhao Lihua , Zhang Nan , Wang Pin , Lu Sumei
Published: September 2024

Cs0.33WO3 (CWO) is a widely used inorganic material in window films and glass coatings, known for its excellent near-infrared radiation (NIR) blocking property and high visible light transmittance (Tvis). However, the stability of NIR blocking and the optical properties of CWO in the process of application is an urgent and important problem, because significant changes in optical results can impact the related products, such as window films, glass coatings, and so on. In this paper, the particle sizes and optical properties of CWO are tested to study the light stability and their relative relations. The results indicate that CWO particle sizes between 130 nm and 100 nm (D90, the point where 90% of the particles have a diameter smaller than the specified value) exhibit high stability in terms of NIR blocking and visible light transmittance (Tvis). CWO particles with D90 < 100 nm experience a greater reduction in NIR blocking, though this ability significantly recovers upon exposure to sunlight, making these coatings particularly suitable for use in tropical and subtropical climates.
Metabolic Reprogramming of Phospholipid Fatty Acids as a Signature of Lung Cancer Type
Authors: Paunovic Marija , Stojanovic Ana , Pokimica Biljana , Martacic Jasmina Debeljak , Cvetkovic Zorica , Ivanovic Nebojsa , Vucic Vesna
Published: September 2024

Background: Lung cancer is one of the leading causes of cancer-related mortality. Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) differ in aggressiveness, proliferation speed, metastasis propensity, and prognosis. Since tumor cells notably change lipid metabolism, especially phospholipids and fatty acids (FA), this study aimed to identify FA alterations in lung cancer tissues. Methods: Our study included patients with newly diagnosed, histologically confirmed SCLC (n = 27) and NSCLC (n = 37). Samples were collected from both malignant and healthy tissues from each patient, providing they were within subject design. Results: In both NSCLC and SCLC tumor tissues, FA contents were shifted toward pro-inflammatory profiles, with increased levels of some individual n-6 polyunsaturated FA (PUFA), particularly arachidonic acid, and elevated activity of Δ6 desaturase. Compared to healthy counterparts, lower levels of alpha-linolenic acid (18:3n-3) and total saturated FA (SFA) were found in NSCLC, while decreased levels of linoleic acid (18:2n-6) and all individual n-3 FA were found in SCLC tissue in comparison to the healthy tissue control. When mutually compared, SCLC tissue had higher levels of total SFA, especially stearic acid, while higher levels of linoleic acid, total PUFA, and n-3 and n-6 PUFA were detected in NSCLC. Estimated activities of Δ6 desaturase and elongase were higher in SCLC than in NSCLC. Conclusions: Our findings indicate a notable impairment of lipid metabolism in two types of lung cancer tissues. These type-specific alterations may be associated with differences in their progression and also point out different therapeutic targets.
Inorganic Polyphosphate Promotes Colorectal Cancer Growth via TRPM8 Receptor Signaling Pathway
Authors: Arrè Valentina , Balestra Francesco , Scialpi Rosanna , Dituri Francesco , Donghia Rossella , Coletta Sergio , Stabile Dolores , Bianco Antonia , Vincenti Leonardo , Fedele Salvatore , Shen Chen , Pettinato Giuseppe , Scavo Maria Principia , Giannelli Gianluigi , Negro Roberto
Published: September 2024

Background: Colorectal cancer (CRC) is characterized by a pro-inflammatory microenvironment and features high-energy-supply molecules that assure tumor growth. A still less studied macromolecule is inorganic polyphosphate (iPolyP), a high-energy linear polymer that is ubiquitous in all forms of life. Made up of hundreds of repeated orthophosphate units, iPolyP is essential for a wide variety of functions in mammalian cells, including the regulation of proliferative signaling pathways. Some evidence has suggested its involvement in carcinogenesis, although more studies need to be pursued. Moreover, iPolyP regulates several homeostatic processes in animals, spanning from energy metabolism to blood coagulation and tissue regeneration. Results: In this study, we tested the role of iPolyP on CRC proliferation, using in vitro and ex vivo approaches, in order to evaluate its effect on tumor growth. We found that iPolyP is significantly increased in tumor tissues, derived from affected individuals enrolled in this study, compared to the corresponding peritumoral counterparts. In addition, iPolyP signaling occurs through the TRPM8 receptor, a well-characterized Na+ and Ca2+ ion channel often overexpressed in CRC and linked with poor prognosis, thus promoting CRC cell proliferation. The pharmacological inhibition of TRPM8 or RNA interference experiments performed in established CRC cell lines, such as Caco-2 and SW620, showed that the involvement of TRPM8 is essential, greater than that of the other two known iPolyP receptors, P2Y1 and RAGE. The presence of iPolyP drives cancer cells towards the mitotic phase of the cell cycle by enhancing the expression of ccnb1, which encodes the Cyclin B protein. In vitro 2D and 3D data reflected the ex vivo results, obtained by the generation of CRC-derived organoids, which increased in size. Conclusions: These results indicate that iPolyP may be considered a novel and unexpected early biomarker supporting colorectal cancer cell proliferation.
Fractionated Stereotactic Intensity-Modulated Radiotherapy for Large Brain Metastases: Comprehensive Analyses of Dose–Volume Predictors of Radiation-Induced Brain Necrosis
Authors: Murai Taro , Kasai Yuki , Eguchi Yuta , Takano Seiya , Kita Nozomi , Torii Akira , Takaoka Taiki , Tomita Natsuo , Shibamoto Yuta , Hiwatashi Akio
Published: September 2024

Background: The objective was to explore dosimetric predictors of brain necrosis (BN) in fractionated stereotactic radiotherapy (SRT). Methods: After excluding collinearities carefully, multivariate logistic models were developed for comprehensive analyses of dosimetric predictors in patients who received first-line fractionated SRT for brain metastases (BMs). The normal brain volume receiving an xx Gy biological dose in 2 Gy fractions (VxxEQD2) was calculated from the retrieved dose–volume parameters. Results: Thirty Gy/3 fractions (fr) SRT was delivered to 34 patients with 75 BMs (median target volume, 3.2 cc), 35 Gy/5 fr to 30 patients with 57 BMs (6.4 cc), 37.5 Gy/5 fr to 28 patients with 47 BMs (20.2 cc), and 40 Gy/10 fr to 20 patients with 37 BMs (24.3 cc), according to protocols, depending on the total target volume (p < 0.001). After excluding the three-fraction groups, the incidence of symptomatic BN was significantly higher in patients with a larger V50EQD2 (adjusted odds ratio: 1.07, p < 0.02), V55EQD2 (1.08, p < 0.01), or V60EQD2 (1.09, p < 0.01) in the remaining five- and ten-fraction groups. The incidence of BN was also significantly higher in cases with V55EQD2 > 30 cc or V60EQD2 > 20 cc (p < 0.05). These doses correspond to 28 or 30 Gy/5 fr and 37 or 40 Gy/10 fr, respectively. Conclusions: In five- or ten-fraction SRT, larger V55EQD2 or V60EQD2 are BN risk predictors. These biologically high doses may affect BN incidence. Thus, the planning target volume margin should be minimized as much as possible.
Demographic and Clinical Characteristics of Malignant Solitary Fibrous Tumors: A SEER Database Analysis
Authors: Piccinelli Mattia Luca , Law Kyle , Incesu Reha-Baris , Tappero Stefano , Cano Garcia Cristina , Barletta Francesco , Morra Simone , Scheipner Lukas , Baudo Andrea , Tian Zhe , Luzzago Stefano , Mistretta Francesco Alessandro , Ferro Matteo , Saad Fred , Shariat Shahrokh F. , Carmignani Luca , Ahyai Sascha , Longo Nicola , Briganti Alberto , Chun Felix K. H. , Terrone Carlo , Tilki Derya , de Cobelli Ottavio , Musi Gennaro , Karakiewicz Pierre I.
Published: September 2024

Background/Objectives: Solitary fibrous tumors (SFTs) represent a rare mesenchymal malignancy that can occur anywhere in the body. Due to the low prevalence of the disease, there is a lack of contemporary data regarding patient demographics and cancer-control outcomes. Methods: Within the SEER database (2000–2019), we identified 1134 patients diagnosed with malignant SFTs. The distributions of patient demographics and tumor characteristics were tabulated. Cumulative incidence plots and competing risks analyses were used to estimate cancer-specific mortality (CSM) after adjustment for other-cause mortality. Results: Of 1134 SFT patients, 87% underwent surgical resection. Most of the tumors were in the chest (28%), central nervous system (22%), head and neck (11%), pelvis (11%), extremities (10%), abdomen (10%) and retroperitoneum (6%), in that order. Stage was distributed as follows: localized (42%) vs. locally advanced (35%) vs. metastatic (13%). In multivariable competing risks models, independent predictors of higher CSM were stage (locally advanced HR: 1.6; metastatic HR: 2.9), non-surgical management (HR: 3.6) and tumor size (9–15.9 cm HR: 1.6; ≥16 cm HR: 1.9). Conclusions: We validated the importance of stage and surgical resection as independent predictors of CSM in malignant SFTs. Moreover, we provide novel observations regarding the independent importance of tumor size, regardless of the site of origin, stage and/or surgical resection status.
Survival after Lung Metastasectomy from Urothelial Carcinoma: A Multi-Institutional Database Study
Authors: Yamauchi Yoshikane , Sato Masaaki , Iwata Takekazu , Endo Makoto , Ikeda Norihiko , Hashimoto Hiroshi , Hato Tai , Suzuki Hidemi , Matsuguma Haruhisa , Shintani Yasushi , Kondo Haruhiko , Oyama Takahiko , Azuma Yoko , Iida Tomohiko , Sakakura Noriaki , Mun Mingyon , Asakura Keisuke , Ohtsuka Takashi , Uehara Hirofumi , Sakao Yukinori
Published: September 2024

Background/objectives: The efficacy of lung metastasectomy in patients with urothelial carcinoma remains inconclusive, as there is only limited evidence from small studies. In this study, we aimed to assess the prognostic outcomes of excising pulmonary metastases from urothelial carcinoma. Methods: In this study, we utilized data from the Metastatic Lung Tumor Study Group of Japan database, a multi-institutional prospective database of pulmonary metastasectomies. We examined the data of patients who had undergone pulmonary metastasectomy for urothelial carcinoma between 1985 and 2021. Exclusion criteria included insufficient clinical information and follow-up of <3 months. Results: The study cohort comprised 100 patients (63 bladder cancer, 37 renal pelvic and ureteral cancer), with a median follow-up of 34 months. There were 70 male and 30 female patients of average age 66.5 ± 10.4 years at lung metastasectomy. The median interval from treatment of the primary lesion to metastasectomy was 19 months and the maximum tumor diameter was 21 ± 15 mm. Three- and five-year overall survival rates were 69% and 59%, respectively. Three- and five-year disease-free survival rates were 56% and 46%, respectively. Multivariate analysis identified larger tumor diameter (hazard ratio: 1.62, 95% confidence interval: 1.21–2.17) and distant metastases at the time of treatment of the primary cancer (hazard ratio: 4.23; 95% confidence interval: 1.54–11.6) as significant adverse prognostic factors for overall survival. Conclusions: To our knowledge, this is the largest published case series of pulmonary resection for metastatic urothelial carcinoma, providing benchmark data for the assessment of long-term outcomes of this rare entity.
Drug Interactions between Androgen Receptor Axis-Targeted Therapies and Antithrombotic Therapies in Prostate Cancer: Delphi Consensus
Authors: Leblanc Kori , Edwards Scott J. , Dranitsaris George , Leong Darryl P. , Carrier Marc , Malone Shawn , Rendon Ricardo A. , Bond Alison M. , Sitland Troy D. , Zalewski Pawel , Wang Michelle , Emmenegger Urban
Published: September 2024

Background/Objectives: Abiraterone acetate, apalutamide, darolutamide, and enzalutamide, which make up the androgen receptor axis-targeted therapies (ARATs) drug class, are commonly used in the management of prostate cancer. Many patients on ARATs also receive oral antithrombotic therapy (i.e., anticoagulants or antiplatelets). The concomitant use of ARATs and antithrombotic therapies creates the potential for clinically relevant drug–drug interactions, but the literature regarding the actual consequences of these interactions, and guidance for co-prescribing, is limited. We assembled a multidisciplinary panel of experts and provided them with clinical information derived from a comprehensive literature review regarding the drug–drug interactions between ARATs and antithrombotic therapies. Methods: A three-stage modified electronic Delphi process was used to gather and consolidate opinions from the panel. Each stage consisted of up to three rounds of voting to achieve consensus on which ARAT/antithrombotic therapy drug pairs warrant attention, the possible clinical consequences of drug–drug interactions, and suggested actions for management. Results: The panel achieved consensus to avoid 11 ARAT/antithrombotic therapy drug pairs and modify therapy for eight pairs. Assessments relied heavily on pharmacokinetic data and extrapolation from drug–drug interaction studies of similarly metabolized drugs. Conclusions: This e-Delphi process highlights the need for further research into the clinical impact of ARAT/antithrombotic drug interactions. Nonetheless, the suggested actions aim to provide clinicians with a practical framework for therapeutic decision making.
Accurate Co-Localization of Luciferase Expression and Fluorescent Anti-CEA Antibody Targeting of Liver Metastases in an Orthotopic Mouse Model of Colon Cancer
Authors: Lee Kyung-Ha , Cox Kristin E. , Amirfakhri Siamak , Jaiswal Sunidhi , Liu Shanglei , Hosseini Mojgan , Lwin Thinzar M. , Yazaki Paul J. , Hoffman Robert M. , Bouvet Michael
Published: September 2024

Background: The present study aimed to validate the accuracy of a tumor-specific antibody to target liver metastases of colorectal cancer. Methods: A humanized anti-CEA antibody conjugated to a fluorescent dye (M5A-IR800) was tested for targeting human colorectal cancer liver metastases (CRLMs) expressing luciferase in an orthotopic mouse model. Orthotopic mouse models of CRLMs were established by implanting fragments of a luciferase-expressing human colorectal cancer cell line, LS174T, in the liver of nude mice. Mice received 50 µg M5A-IR800 72 h prior to imaging. To test co-localization, bioluminescence imaging was performed using D-luciferin, which was given via intraperitoneal injection just prior to imaging. Results: Tumors were able to be visualized non-invasively through the skin with the luciferase–luciferin signal. Intra-abdominal imaging showed accurate labeling of CRLMs with M5A-IR800, which co-localized with the luciferase–luciferin signal. Conclusions: The present results validate the accuracy of a tumor-specific anti-CEA antibody in targeting liver metastases of colorectal cancer.
Rare Oncogenic Fusions in Pediatric Central Nervous System Tumors: A Case Series and Literature Review
Authors: Ahmed Melek , Sieben Anne , Van Genechten Toon , Libbrecht Sasha , Gilis Nathalie , De Praeter Mania , Fricx Christophe , Calò Pierluigi , Van Campenhout Claude , D’Haene Nicky , Witte Olivier De , Kempen Léon C. Van , Lammens Martin , Salmon Isabelle , Lebrun Laetitia
Published: September 2024

Background and Objectives: Central Nervous System (CNS) pediatric tumors represent the most common solid tumors in children with a wide variability in terms of survival and therapeutic response. By contrast to their adult counterpart, the mutational landscape of pediatric CNS tumors is characterized by oncogenic fusions rather than multiple mutated genes. CNS pediatric tumors associated with oncogenic fusions represent a complex landscape of tumors with wide radiological, morphological and clinical heterogeneity. In the fifth CNS WHO classification, there are few pediatric CNS tumors for which diagnosis is based on a single oncogenic fusion. This work aims to provide an overview of the impact of rare oncogenic fusions (NTRK, ROS, ALK, MET, FGFR, RAF, MN1, BCOR and CIC genes) on pathogenesis, histological phenotype, diagnostics and theranostics in pediatric CNS tumors. We report four cases of pediatric CNS tumors associated with NTRK (n = 2), ROS (n = 1) and FGFR3 (n = 1) oncogenic fusion genes as a proof of concept. Cases presentation and literature review: The literature review and the cohort that we described here underline that most of these rare oncogenic fusions are not specific to a single morpho-molecular entity. Even within tumors harboring the same oncogenic fusions, a wide range of morphological, molecular and epigenetic entities can be observed. Conclusions: These findings highlight the need for caution when applying the fifth CNS WHO classification, as the vast majority of these fusions are not yet incorporated in the diagnosis, including grade evaluation and DNA methylation classification.
Reproducible and Interpretable Machine Learning-Based Radiomic Analysis for Overall Survival Prediction in Glioblastoma Multiforme
Authors: Duman Abdulkerim , Sun Xianfang , Thomas Solly , Powell James R. , Spezi Emiliano
Published: September 2024

Purpose: To develop and validate an MRI-based radiomic model for predicting overall survival (OS) in patients diagnosed with glioblastoma multiforme (GBM), utilizing a retrospective dataset from multiple institutions. Materials and Methods: Pre-treatment MRI images of 289 GBM patients were collected. From each patient’s tumor volume, 660 radiomic features (RFs) were extracted and subjected to robustness analysis. The initial prognostic model with minimum RFs was subsequently enhanced by including clinical variables. The final clinical–radiomic model was derived through repeated three-fold cross-validation on the training dataset. Performance evaluation included assessment of concordance index (C-Index), integrated area under curve (iAUC) alongside patient stratification into low and high-risk groups for overall survival (OS). Results: The final prognostic model, which has the highest level of interpretability, utilized primary gross tumor volume (GTV) and one MRI modality (T2-FLAIR) as a predictor and integrated the age variable with two independent, robust RFs, achieving moderately good discriminatory performance (C-Index [95% confidence interval]: 0.69 [0.62–0.75]) with significant patient stratification (p = 7 × 10−5) on the validation cohort. Furthermore, the trained model exhibited the highest iAUC at 11 months (0.81) in the literature. Conclusion: We identified and validated a clinical–radiomic model for stratification of patients into low and high-risk groups based on OS in patients with GBM using a multicenter retrospective dataset. Future work will focus on the use of deep learning-based features, with recently standardized convolutional filters on OS tasks.
Nerve-Sparing Laparoscopic Radical Hysterectomy (nsLRH) without Adjuvant Therapy in FIGO Stage IB3 Cervical Cancer Patients: Surgical Technique and Survival Outcomes
Authors: Tozzi Roberto , Bigardi Sofia , Spagnol Giulia , Ferrari Federico , Saccardi Carlo , Noventa Marco , Marchetti Matteo
Published: September 2024

(1) Background: In 2018 FIGO reclassified tumors confined to the cervix larger than 4 cm as stage IB3. Although concurrent CTRT has been the standard of care and surgery the alternative, optimal management remains controversial due to the lack of direct comparison between surgery and CTRT. (2) Methods: This prospective observational study investigated the efficacy, safety and oncologic outcomes of nerve-sparing laparoscopic radical hysterectomy (nsLRH) for FIGO stage IB3 cervical cancer patients (IB3). From 2009 to 2023, IB3 patients underwent laparoscopic pelvic lymphadenectomies with frozen section analysis, followed by a nsLRH if the lymph nodes were tumor-free. No uterine manipulator was used and the vaginal cuff was sealed before retrieving the specimen. Intermediate-risk patients were under close observation without adjuvant therapy. Outcomes were monitored until 2023. (3) Results: During the study period, 74 IB3 patients were treated. Sixty-eight (91.9%) underwent a nsLRH. A complete resection with negative margins was achieved in all cases. At a median of 68 months of follow-up, the disease-free survival (DFS) rate was 89.7% and the overall survival (OS) rate was 93.1%. The overall complication rate was 23.5% and there were no grade 4–5 complications. (4) Conclusions: In patients with IB3 cervical cancer, a nsLRH is safe and effective. While awaiting the results from ongoing randomized trials, these findings support nsLRH as a viable treatment.
Tolerability and Safety Assessment of Adjuvant Chemoradiotherapy with S-1 after Limited Surgery for T1 or T2 Lower Rectal Cancer
Authors: Miyoshi Norikatsu , Uemura Mamoru , Noura Shingo , Yasui Masayoshi , Nishimura Junichi , Tei Mitsuyoshi , Matsuda Chu , Morita Shunji , Inoue Akira , Tamagawa Hiroki , Mokutani Yukako , Yoshioka Shinichi , Fujii Makoto , Kato Shinya , Sekido Yuki , Ogino Takayuki , Yamamoto Hirofumi , Murata Kohei , Doki Yuichiro , Eguchi Hidetoshi
Published: September 2024

Background: The short-term outcomes of chemoradiotherapy (CRT) with S-1 (a combination of tegafur, gimeracil, and oteracil) following limited surgery for patients with T1 or T2 lower rectal cancer have shown encouraging results. Objectives: This study was designed to delve deeper into the long-term outcomes of CRT with S-1 after limited surgery, with the goal of evaluating both the long-term efficacy and potential risks associated with this treatment approach in patients diagnosed with T1 or T2 lower rectal cancer. Methods: This was conducted as a multicenter, single-arm, prospective phase II trial. The patient population consisted of individuals clinically diagnosed with either T1 or T2 lower rectal or anal canal cancer, with a maximum tumor diameter of 30 mm and classified as N0 or M0. Patients underwent local excision or endoscopic resection. After surgery, CRT with S-1 was administered to patients meeting several criteria, including the confirmation of well-differentiated or moderately differentiated adenocarcinoma, negative surgical margins, submucosal invasion depth of ≥1000 µm, and high tumor-budding grade (2/3). The primary endpoint of this study was relapse-free survival, while secondary endpoints included local recurrence-free survival, overall survival, anal sphincter preservation rate, and safety. Results: A total of 52 patients were included, with pathological diagnoses revealing T1 in 36 patients and T2 in 16 patients. The 3-year and 5-year relapse-free survival rates were 90.17% and 85.87%, respectively. The 3-year and 5-year local recurrence-free survival rates were 90.17% and 88.07%, respectively, while the 3-year and 5-year overall survival rates were 94.03% and 91.94%, respectively. Conclusions: CRT with S-1 after limited surgery for T1 lower rectal cancer demonstrated favorable outcomes in terms of recurrence, survival, and local control rates while effectively maintaining anal function in patients. However, further treatment approaches may be necessary to improve outcomes for patients diagnosed with stage T2 lower rectal cancer