bluuebunny/crossref_metadata_2025 huggingface dataset:
The Influence of Typhoon-Induced Wave on the Mesoscale Eddy
Authors: Zhao Zeqi , Shi Jian , Shao Weizeng , Yao Ru , Li Huan
Published: December 2023

The strong wind-induced current and sea level have influences on the wave distribution in a tropical cyclone (TC). In particular, the wave–current interaction is significant in the period in which the TC passed the mesoscale eddy. In this study, the wave fields of Typhoon Chan-hom (2015) are hindcastly simulated using a coupled oceanic model that utilizes a nested triangle grid, i.e., the finite-volume community ocean model-simulating waves nearshore (FVCOM-SWAVE) model. The forcing wind field is composited from the European Centre for Medium-Range Weather Forecasts (ECMWF) reanalysis data and the simulation using a parametric Holland model, denoted as H-E. The open boundary fields include tide data from TPOX.5 and the hybrid coordinate ocean model (HYCOM) global datasets, including sea surface temperature (SST), sea surface salinity, sea surface current, and sea level data. The simulated oceanic parameters (e.g., the significant wave height, SWH) are validated against the measurements from the Jason-2 altimeter, yielding a root mean square error (RMSE) of 0.58 m for the SWH, a correlation (COR) coefficient of 0.94, and a scatter index (SI) of 0.23. Similarly, the simulated SSTs are compared with the remote sensing products of the remote sensing system (REMSS) and the measurements from Argos, yielding an RMSE of <0.8 °C, a COR of >0.95, and an SI of <0.04. The significant zonal asymmetry of the wave distribution along the typhoon track is observed. The Stokes drift is calculated from the FVCOM-SWAVE simulation results, and then the contribution of the Stokes transport is estimated using the Ekman–Stokes numbers. It is found that the ratio of the Stokes transport to the total net transport can reach >80% near the typhoon center, and the ratio is reduced to approximately <20% away from the typhoon center, indicating that Stokes transport is an essential aspect in the water mixing during a TC. The mesoscale eddies are detected by the sea level anomalies (SLA) fusion data from AVISO. It is found that the significant wave heights, Stokes drift, and Stokes transport inside the eddy area were higher than those outside the eddy area. These parameters inside the cold mesoscale eddies were higher than t inside the warm mesoscale eddies. Otherwise, the SST mainly increased within the cold mesoscale eddies area, while decreased within the warm mesoscale eddies area. The influence of mesoscale eddies on the SST was in proportion to the eddy radius and eddy EKE.
Describing Conditional Independence Statements Using Undirected Graphs
Authors: Malouche Dhafer
Published: December 2023

This paper investigates the capability of undirected graphs (UGs) to represent a set of Conditional Independence (CI) statements derived from a given probability distribution of a random vector. While it is established that certain axioms can govern this set, providing sufficient conditions for UGs to capture specific CI statements, our focus is on covariance and concentration graphs. These remain the only known families of UGs capable of describing CI statements. We explore the issue of complete representation of CI statements through their corresponding covariance and concentration graphs. Two parameters are defined, one each from the covariance and concentration graphs, to determine the limitations concerning the cardinality of the conditioning subset that the graph can represent. We establish a relationship between these parameters and the cardinality of the separators in each graph, providing a straightforward computational method to evaluate them. In conclusion, we enhance the aforementioned procedure and introduce criteria to ascertain, without additional computations, whether the graphs can fully represent a given set of CI statements. We demonstrate that either the concentration or the covariance graph forms a cycle, and when considered in conjunction, they can represent the entire relation. These criteria also enable us, in specific cases, to deduce the covariance graph from the concentration graph and vice versa.
More Effective Criteria for Testing the Asymptotic and Oscillatory Behavior of Solutions of a Class of Third-Order Functional Differential Equations
Authors: Masood Fahd , Moaaz Osama , AlNemer Ghada , El-Metwally Hamdy
Published: December 2023

This paper delves into the investigation of quasi-linear neutral differential equations in the third-order canonical case. In this study, we refine the relationship between the solution and its corresponding function, leading to improved preliminary results. These enhanced results play a crucial role in excluding the existence of positive solutions to the investigated equation. By building upon the improved preliminary results, we introduce novel criteria that shed light on the nature of these solutions. These criteria help to distinguish whether the solutions exhibit oscillatory behavior or tend toward zero. Moreover, we present oscillation criteria for all solutions. To demonstrate the relevance of our results, we present an illustrative example. This example validates the theoretical framework we have developed and offers practical insights into the behavior of solutions for quasi-linear third-order neutral differential equations.
Understanding the Role of Yes-Associated Protein (YAP) Signaling in the Transformation of Lens Epithelial Cells (EMT) and Fibrosis
Authors: Taiyab Aftab , Belahlou Yasmine , Wong Vanessa , Pandi Saranya , Shekhar Madhu , Chidambaranathan Gowri Priya , West-Mays Judith
Published: December 2023

Fibrotic cataracts, posterior capsular opacification (PCO), and anterior subcapsular cataracts (ASC) are mainly attributed to the transforming growth factor-β (TGFβ)-induced epithelial-to-mesenchymal transition (EMT) of lens epithelial cells (LECs). Previous investigations from our laboratory have shown the novel role of non-canonical TGFβ signaling in the progression of EMT in LECs. In this study, we have identified YAP as a critical signaling molecule involved in lens fibrosis. The observed increase in nuclear YAP in capsules of human ASC patients points toward the involvement of YAP in lens fibrosis. In addition, the immunohistochemical (IHC) analyses on ocular sections from mice that overexpress TGFβ in the lens (TGFβtg) showed a co-expression of YAP and α-SMA in the fibrotic plaques when compared to wild-type littermate lenses, which do not. The incubation of rat lens explants with verteporfin, a YAP inhibitor, prevented a TGFβ-induced fiber-like phenotype, α-SMA, and fibronectin expression, as well as delocalization of E-cadherin and β-catenin. Finally, LECs co-incubated with TGFβ and YAP inhibitor did not exhibit an induction in matrix metalloproteinase 2 compared to those LECs treated with TGFβ alone. In conclusion, these data demonstrate that YAP is required for TGFβ-mediated lens EMT and fibrosis.
The Role of Glutamine Synthetase (GS) and Glutamate Synthase (GOGAT) in the Improvement of Nitrogen Use Efficiency in Cereals
Authors: Fortunato Stefania , Nigro Domenica , Lasorella Cecilia , Marcotuli Ilaria , Gadaleta Agata , de Pinto Maria Concetta
Published: December 2023

Cereals are the most broadly produced crops and represent the primary source of food worldwide. Nitrogen (N) is a critical mineral nutrient for plant growth and high yield, and the quality of cereal crops greatly depends on a suitable N supply. In the last decades, a massive use of N fertilizers has been achieved in the desire to have high yields of cereal crops, leading to damaging effects for the environment, ecosystems, and human health. To ensure agricultural sustainability and the required food source, many attempts have been made towards developing cereal crops with a more effective nitrogen use efficiency (NUE). NUE depends on N uptake, utilization, and lastly, combining the capability to assimilate N into carbon skeletons and remobilize the N assimilated. The glutamine synthetase (GS)/glutamate synthase (GOGAT) cycle represents a crucial metabolic step of N assimilation, regulating crop yield. In this review, the physiological and genetic studies on GS and GOGAT of the main cereal crops will be examined, giving emphasis on their implications in NUE.
Membrane Proteins and Membrane Curvature: Mutual Interactions and a Perspective on Disease Treatments
Authors: Xie Peng , Zhang Heng , Qin Yatong , Xiong Hehe , Shi Changrong , Zhou Zijian
Published: December 2023

The pathogenesis of various diseases often involves an intricate interplay between membrane proteins and membrane curvature. Understanding the underlying mechanisms of this interaction could offer novel perspectives on disease treatment. In this review, we provide an introduction to membrane curvature and its association with membrane proteins. Furthermore, we delve into the impact and potential implications of this interaction in the context of disease treatment. Lastly, we discuss the prospects and challenges associated with harnessing these interactions for effective disease management, aiming to provide fresh insights into therapeutic strategies.
Anomia: Deciphering Functional Neuroanatomy in Primary Progressive Aphasia Variants
Authors: Akhmadullina Diliara R. , Konovalov Rodion N. , Shpilyukova Yulia A. , Fedotova Ekaterina Yu. , Illarioshkin Sergey N.
Published: December 2023

Naming decline is one of the most common symptoms of primary progressive aphasia (PPA). Most studies on anomia in PPA are performed without taking into account PPA variants, especially for action naming. Only limited data are available for the neuroanatomical basis of anomia considering differences in the pathogenesis of PPAs. The aim of our study is to investigate the associations between anomia severity for both noun and verb naming and gray matter (GM) atrophy, as well as accompanying functional connectivity (FC) changes in three PPA variants. A total of 17 patients with non-fluent (nfvPPA), 11 with semantic (svPPA), and 9 with logopenic (lvPPA) PPA variants were included in the study and underwent cognitive/naming assessments and brain MRIs. Voxel-based morphometry was performed to evaluate GM volume. A resting-state functional MRI was applied to investigate FC changes in the identified GM areas. The study shows that different brain regions are involved in naming decline in each PPA variant with a predominantly temporal lobe involvement in svPPA, parietal lobe involvement in lvPPA, and frontal lobe involvement in nfvPPA. Separate data for object and action naming in PPA variants are provided. The obtained results mainly correspond to the current understanding of language processing and indicate that the evaluation of language impairments is preferable for each PPA variant separately. A further analysis of larger cohorts of patients is necessary to confirm these preliminary results.
Reelin Signaling and Synaptic Plasticity in Schizophrenia
Authors: Markiewicz Renata , Markiewicz-Gospodarek Agnieszka , Borowski Bartosz , Trubalski Mateusz , Łoza Bartosz
Published: December 2023

Recent research emphasizes the significance of studying the quality of life of schizophrenia patients, considering the complex nature of the illness. Identifying neuronal markers for early diagnosis and treatment is crucial. Reelin (RELN) stands out among these markers, with genetic studies highlighting its role in mental health. Suppression of RELN expression may contribute to cognitive deficits by limiting dendritic proliferation, affecting neurogenesis, and leading to improper neuronal circuits. Although the physiological function of reelin is not fully understood, it plays a vital role in hippocampal cell stratification and neuroglia formation. This analysis explores reelin’s importance in the nervous system, shedding light on its impact on mental disorders such as schizophrenia, paving the way for innovative therapeutic approaches, and at the same time, raises the following conclusions: increased methylation levels of the RELN gene in patients with a diagnosis of schizophrenia results in a multiple decrease in the expression of reelin, and monitoring of this indicator, i.e., methylation levels, can be used to monitor the severity of symptoms in the course of schizophrenia.
Validation of the Cognitive Reserve Index Questionnaire (CRIq) in Arabic
Authors: Farran Natali , Darwish Hala
Published: December 2023

Cognitive reserve is the adaptability of cognitive processes in the face of brain aging and pathology. This study aimed to validate the Arabic version of the Cognitive Reserve Index Questionnaire (CRIq) in a healthy Lebanese sample. CRIq assesses cognitive reserve through three domains: education, working activity, and leisure time. Statistical measures, including descriptive and regression analysis along with structural equation modeling, were utilized to investigate the convergent and discriminant validity of the CRIq, incorporating fluid intelligence (Gf) and measures of cognitive function, long-term memory encoding and retrieval (Glr), and processing speed (Gs). Results from 174 participants revealed that the activities assessed by the CRIq-Arabic were comparable to the original CRIq study, with slight cultural differences. The internal consistency of the CRIq-Arabic was good (Cronbach’s α = 0.88), indicating reliability. Convergent validity was confirmed, with moderate to high loadings on the cognitive reserve latent construct. Discriminant validity was supported as correlations between cognitive reserve variables and non-target constructs (Gf, Glr, and Gs) were less than 1. The findings provide an initial psychometric validation of the CRIq-Arabic. Further research of clinical samples is needed to enhance its utility in neuropsychological practice.
Asset Resource Optimization Solution for Smart Hospital Facilities and Energy Management through an Interpretive Structural Model
Authors: Chen James K. C. , Ho Han-Hsi
Published: December 2023

An increasing focus has been placed on clean energy, carbon neutrality, carbon footprint monitoring, and adaptation of building information modeling (BIM)-based facility management (FM). Hence, there is also a growing demand to evaluate and prioritize which BIM applications are the most relevant to FM and are the most beneficial in the asset lifecycle, particularly in the operations stage. To inform BIM-FM application on smart hospital management, this research introduces a one-systems method through an interpretive structural model (ISM) to establish a structural contextual interrelationship between BIM uses in the operations stages of the asset. Through a literature review, this research first summarizes facility management functionalities achievable by BIM-FM and establishes their pairwise contextual relationship. A structural self-interaction matrix (SSIM) is then established, followed by partitioning these functionalities into separate levels to form the ISM model, while using driving power and dependence to form a MICMAC analysis matrix. The finding that the BIM uses “Environmental Monitoring and Building Performance” is the foundation that enables the other functionalities whilst validating that ad-hoc operations and maintenance activities enablement has the highest driving power, and automation and robotics have the highest dependency. Among the applications, energy monitoring plays a pivotal and transitional role with a strong dependency between airflow monitoring and solar monitoring, while its performance would directly impact emergency responses.
Strength and Microstructural Changes in Cementitious Composites Containing Waste Oyster Shell Powder
Authors: Kim Min Ook , Lee Myung Kue
Published: December 2023

In this study, the effect of adding waste oyster shell powder (WOSP) on the strength and microstructure of cementitious composites was experimentally investigated. The test variables included the WOSP replacement ratios (0, 25, 50, and 75%) by weight of cement, the type of curing water (tap water and seawater), and the curing period (7, 28, 90, 180, and 365 d). The compressive strength, flexural strength, and initial and secondary sorptivity were measured at specific ages. Moreover, scanning electron microscopy (SEM) and X-ray diffraction (XRD) measurements were conducted, and their results were analyzed. Samples with WOSP replacement ratios greater than 25% exhibited a rapid reduction in measured strength values. The correlation between compressive strength and initial sorptivity tends to be slightly higher than that between flexural strength and initial sorptivity. The one-year investigation revealed that there was no significant effect of using different curing waters on strength development. The effect of the curing period was evident in enhancing the strength only in the early stages, with no significant increase in strength observed after 28 d. The XRD analysis revealed that most samples prepared with WOSP contained CaCO3, and the peak of CaCO3 tended to increase with an increasing WOSP replacement ratio. The SEM results revealed that a high replacement ratio of WOSP can have a negative influence on cement hydration and the pozzolanic effect. The limitations of this study and future work were also discussed.
SOX2-OT Binds with ILF3 to Promote Head and Neck Cancer Progression by Modulating Crosstalk between STAT3 and TGF-β Signaling
Authors: Wang Ru , Yang Yifan , Wang Lingwa , Shi Qian , Ma Hongzhi , He Shizhi , Feng Ling , Fang Jugao
Published: December 2023

Long non-coding RNA (lncRNA) is involved in the progression of head and neck squamous cell carcinoma (HNSCC). The molecular mechanism of lncRNA SOX2-OT in HNSCC remains unclear. Therefore, we aimed to elucidate the oncogenic role of SOX2-OT in HNSCC. QRT-PCR analysis was performed in 61 pairs of HNSCC cancer tissues, adjacent normal tissues, and 68 plasma samples confirmed that lncRNA SOX2-OT was overexpressed in cancer tissues and plasma samples, which served as a poor prognostic factor for HNSCC. The FISH assay demonstrated that SOX2-OT was localized in the nucleus and cytoplasm of HNSCC cell lines. Further, the cell function assay confirmed that SOX2-OT promoted cell proliferation and metastasis in vitro and in vivo. RNA pulldown and RIP assay results revealed that SOX2-OT bonds with ILF3 in HNSCC, and the rescue assay confirmed that SOX2-OT played an oncogenic role depending on ILF3 protein expression. Ingenuity pathway analysis and Western blotting indicated that SOX2-OT regulated HNSCC progression by promoting STAT3 phosphorylation and modulating the crosstalk between STAT3 and TGF-β signaling. These results reveal evidence for the role of SOX2-OT in HNSCC progression and metastasis by binding to ILF3, which may serve as a therapeutic target and prognostic biomarker in HNSCC.
Altered Treg Infiltration after Discoidin Domain Receptor 1 (DDR1) Inhibition and Knockout Promotes Tumor Growth in Lung Adenocarcinoma
Authors: Maitz Kathrin , Valadez-Cosmes Paulina , Raftopoulou Sofia , Kindler Oliver , Kienzl Melanie , Bolouri Hamid , Houghton A. McGarry , Schicho Rudolf , Heinemann Akos , Kargl Julia
Published: December 2023

Lung cancer is the leading cause of cancer-related death worldwide. Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor, has been associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). However, its role in tumorigenesis remains poorly understood. This work aimed to explore the impact of DDR1 expression on immune cell infiltration in lung adenocarcinoma. Pharmacological inhibition and knockout of DDR1 were used in an immunocompetent mouse model of KRAS/p53-driven lung adenocarcinoma (LUAD). Tumor cells were engrafted subcutaneously, after which tumors were harvested for investigation of immune cell composition via flow cytometry. The Cancer Genome Atlas (TCGA) cohort was used to perform gene expression analysis of 509 patients with LUAD. Pharmacological inhibition and knockout of DDR1 increased the tumor burden, with DDR1 knockout tumors showing a decrease in CD8+ cytotoxic T cells and an increase in CD4+ helper T cells and regulatory T cells. TCGA analysis revealed that low-DDR1-expressing tumors showed higher FoxP3 (regulatory T-cell marker) expression than high-DDR1-expressing tumors. Our study showed that under certain conditions, the inhibition of DDR1, a potential therapeutic target in cancer treatment, might have negative effects, such as inducing a pro-tumorigenic tumor microenvironment. As such, further investigations are necessary.
TRPV6 Channel Is Involved in Pancreatic Ductal Adenocarcinoma Aggressiveness and Resistance to Chemotherapeutics
Authors: Mesquita Gonçalo , Haustrate Aurélien , Mihalache Adriana , Soret Benjamin , Cordier Clément , Desruelles Emilie , Duval Erika , Pethö Zoltan , Prevarskaya Natalia , Schwab Albrecht , Lehen’kyi V’yacheslav
Published: December 2023

Pancreatic ductal adenocarcinoma (PDAC) stands as a highly aggressive and lethal cancer, characterized by a grim prognosis and scarce treatment alternatives. Within this context, TRPV6, a calcium-permeable channel, emerges as a noteworthy candidate due to its overexpression in various cancers, capable of influencing the cell behavior in different cancer entities. Nonetheless, the exact expression pattern and functional significance of TRPV6 in the context of PDAC remains enigmatic. This study scrutinizes the expression of TRPV6 in tissue specimens obtained from 46 PDAC patients across distinct stages and grades. We manipulated TRPV6 expression (knockdown, overexpression) in the human PDAC cell lines Panc-1 and Capan-1. Subsequently, we analyzed its impact on multiple facets, encompassing Ca2+ influx, proliferation, apoptosis, migration, chemoresistance, and tumor growth, both in vitro and in vivo. Notably, the data indicate a direct correlation between TRPV6 expression levels, tumor stage, and grade, establishing a link between TRPV6 and PDAC proliferation in tissue samples. Decreasing TRPV6 expression via knockdown hampered Ca2+ influx, resulting in diminished proliferation and viability in both cell lines, and cell cycle progression in Panc-1. The knockdown simultaneously led to an increase in apoptotic rates and increased the susceptibility of cells to 5-FU and gemcitabine treatments. Moreover, it accelerated migration and promoted collective movement among Panc-1 cells. Conversely, TRPV6 overexpression yielded opposing outcomes in terms of proliferation in Panc-1 and Capan-1, and the migration of Panc-1 cells. Intriguingly, both TRPV6 knockdown and overexpression diminished the process of tumor formation in vivo. This intricate interplay suggests that PDAC aggressiveness relies on a fine-tuned TRPV6 expression, raising its profile as a putative therapeutic target.
Charlson–Deyo Comorbidity Index as a Novel Predictor for Recurrence in Non-Muscle-Invasive Bladder Cancer
Authors: Scheipner Lukas , Zurl Hanna , Altziebler Julia V. , Pichler Georg P. , Schöpfer-Schwab Stephanie , Jasarevic Samra , Gaisl Michael , Pohl Klara C. , Pemberger Karl , Andlar Stefan , Hutterer Georg C. , Bele Uros , Leitsmann Conrad , Leitsmann Marianne , Augustin Herbert , Zigeuner Richard , Ahyai Sascha , Mischinger Johannes
Published: December 2023

Purpose: To test the association between the Charlson–Deyo Comorbidity Index (CCI) and the recurrence of non-muscle-invasive bladder cancer (NMIBC). Methods: NMIBC (Ta, T1, TIS) patients who underwent transurethral resection of bladder tumor (TURB) between 2010 and 2018 were identified within a retrospective data repository of a large university hospital. Kaplan–Meier estimates and uni- and multivariable Cox regression models tested for differences in risk of recurrence according to low vs. high comorbidity burden (CCI ≤ 4 vs. >4) and continuously coded CCI. Results: A total of 1072 NMIBC patients were identified. The median follow-up time of the study population was 55 months (IQR 29.6–79.0). Of all 1072 NMIBC patients, 423 (39%) harbored a low comorbidity burden vs. 649 (61%) with a high comorbidity burden. Overall, the rate of recurrence was 10% at the 12-month follow-up vs. 22% at the 72-month follow-up. In low vs. high comorbidity burden groups, rates of recurrence were 6 vs. 12% at 12 months and 18 vs. 25% at 72 months of follow-up (p = 0.02). After multivariable adjustment, a high comorbidity burden (CCI > 4) independently predicted a higher risk of recurrence (HR 1.42, 95% confidence interval (CI) 1.06–1.92, p = 0.018). After multivariable adjustment, the hazard of recurrence increased by 5% per each one-unit increase on the CCI scale (HR 1.05, 95% CI 1.00–1.10, p = 0.04). Conclusions: Comorbidities in NMIBC patients are common. Our data suggest that patients with higher CCI have an increased risk of BC recurrence. As a consequence, patients with a high comorbidity burden should be particularly encouraged to adhere to NMIBC guidelines and conform to follow-up protocols.
Defining an Abnormal Geriatric Assessment: Which Deficits Matter Most?
Authors: Carrozzi Anthony , Jin Rana , Monginot Susie , Puts Martine , Alibhai Shabbir M. H.
Published: December 2023

At present, there is no clear definition of what constitutes an abnormal geriatric assessment (GA) in geriatric oncology. Various threshold numbers of abnormal GA domains are often used, but how well these are associated with treatment plan modification (TPM) and whether specific GA domains are more important in this context remains uncertain. A retrospective review of the geriatric oncology clinic database at Princess Margaret Cancer Centre in Toronto, Canada, including new patients seen for treatment decision making from May 2015 to June 2022, was conducted. Logistic regression modelling was performed to determine the association between various predictor variables (including the GA domains and numerical thresholds) and TPM. The study cohort (n = 736) had a mean age of 80.7 years, 46.1% was female, and 78.3% had a VES-13 score indicating vulnerability (≥3). In the univariable analysis, the best-performing threshold number of abnormal domains based on area under the curve (AUC) was 4 (AUC 0.628). The best-performing multivariable model (AUC 0.704) included cognition, comorbidities, and falls risk. In comparison, the multivariable model with the sole addition of the threshold of 4 had an AUC of 0.689. Overall, an abnormal GA may be best defined as one with abnormalities in the domains of cognition, comorbidities, and falls risk. The optimal numerical threshold to predict TPM is 4.
The Role of γδ T-Lymphocytes in Glioblastoma: Current Trends and Future Directions
Authors: Ahmedna Taha , Khela Harmon , Weber-Levine Carly , Azad Tej D. , Jackson Christopher M. , Gabrielson Kathleen , Bettegowda Chetan , Rincon-Torroella Jordina
Published: December 2023

Cell-based immunotherapy for glioblastoma (GBM) encounters major challenges due to the infiltration-resistant and immunosuppressive tumor microenvironment (TME). γδ T cells, unconventional T cells expressing the characteristic γδ T cell receptor, have demonstrated promise in overcoming these challenges, suggesting great immunotherapeutic potential. This review presents the role of γδ T cells in GBM and proposes several research avenues for future studies. Using the PubMed, ScienceDirect, and JSTOR databases, we performed a review of the literature studying the biology of γδ T cells and their role in GBM treatment. We identified 15 studies focused on γδ T cells in human GBM. Infiltrative γδ T cells can incite antitumor immune responses in certain TMEs, though rapid tumor progression and TME hypoxia may impact the extent of tumor suppression. In the studies, available findings have shown both the potential for robust antitumor activity and the risk of protumor activity. While γδ T cells have potential as a therapeutic agent against GBM, the technical challenges of extracting, isolating, and expanding γδ T cells, and the activation of antitumoral versus protumoral cascades, remain barriers to their application. Overcoming these limitations may transform γδ T cells into a promising immunotherapy in GBM.
Life-Threatening Endocrinological Immune-Related Adverse Events of Immune Checkpoint Inhibitor Therapy
Authors: Basek Aleksandra , Jakubiak Grzegorz K. , Cieślar Grzegorz , Stanek Agata
Published: December 2023

Malignant neoplasms are currently one of the leading causes of morbidity and mortality worldwide, posing a major public health challenge. However, recent advances in research in cancer biology and immunity have led to the development of immunotherapy, which is now used on an everyday basis in cancer treatment in addition to surgical treatment, classical cytostatics, and radiotherapy. The efficacy of immunotherapy has promoted the great popularity of this treatment among patients, as well as significant research interest. The increasing number of patients being treated with immunotherapy not only reassures physicians of the efficacy of this technique but also shows the wide spectrum of side effects of this therapy, which has not been considered before. Immune-related adverse events may affect many systems and organs, such as digestive, cardiovascular, respiratory, skin, or endocrine organs. Most complications have a mild or moderate course, but there are life-threatening manifestations that are essential to be aware of because if they are not properly diagnosed and treated on time, they can have fatal consequences. The purpose of this paper was to present the results of a literature review on the current state of knowledge on life-threatening endocrine side effects (such as adrenal crisis, thyroid storm, myxoedema crisis, diabetic ketoacidosis, and severe hypocalcaemia) of immune checkpoint inhibitors to provide information on symptoms, diagnostics, and management strategies.
Susceptibility Genes Associated with Multiple Primary Cancers
Authors: Lu Mengyao , Zhang Xuemei , Chu Qian , Chen Yuan , Zhang Peng
Published: December 2023

With advancements in treatment and screening techniques, we have been witnessing an era where more cancer survivors harbor multiple primary cancers (MPCs), affecting approximately one in six patients. Identifying MPCs is crucial for tumor staging and subsequent treatment choices. However, the current clinicopathological criteria for clinical application are limited and insufficient, making it challenging to differentiate them from recurrences or metastases. The emergence of next-generation sequencing (NGS) technology has provided a genetic perspective for defining multiple primary cancers. Researchers have found that, when considering multiple tumor pairs, it is crucial not only to examine well-known essential mutations like MLH1/MSH2, EGFR, PTEN, BRCA1/2, CHEK2, and TP53 mutations but also to explore certain pleiotropic loci. Moreover, specific deleterious mutations may serve as regulatory factors in second cancer development following treatment. This review aims to discuss these susceptibility genes and provide an explanation of their functions based on the signaling pathway background. Additionally, the association network between genetic signatures and different tumor pairs will be summarized.
AI-Based Risk Score from Tumour-Infiltrating Lymphocyte Predicts Locoregional-Free Survival in Nasopharyngeal Carcinoma
Authors: Wibawa Made Satria , Zhou Jia-Yu , Wang Ruoyu , Huang Ying-Ying , Zhan Zejiang , Chen Xi , Lv Xing , Young Lawrence S. , Rajpoot Nasir
Published: December 2023

Background: Locoregional recurrence of nasopharyngeal carcinoma (NPC) occurs in 10% to 50% of cases following primary treatment. However, the current main prognostic markers for NPC, both stage and plasma Epstein–Barr virus DNA, are not sensitive to locoregional recurrence. Methods: We gathered 385 whole-slide images (WSIs) from haematoxylin and eosin (H&E)-stained NPC sections (n = 367 cases), which were collected from Sun Yat-sen University Cancer Centre. We developed a deep learning algorithm to detect tumour nuclei and lymphocyte nuclei in WSIs, followed by density-based clustering to quantify the tumour-infiltrating lymphocytes (TILs) into 12 scores. The Random Survival Forest model was then trained on the TILs to generate risk score. Results: Based on Kaplan–Meier analysis, the proposed methods were able to stratify low- and high-risk NPC cases in a validation set of locoregional recurrence with a statically significant result (p < 0.001). This finding was also found in distant metastasis-free survival (p < 0.001), progression-free survival (p < 0.001), and regional recurrence-free survival (p < 0.05). Furthermore, in both univariate analysis (HR: 1.58, CI: 1.13–2.19, p < 0.05) and multivariate analysis (HR:1.59, CI: 1.11–2.28, p < 0.05), we also found that our methods demonstrated a strong prognostic value for locoregional recurrence. Conclusion: The proposed novel digital markers could potentially be utilised to assist treatment decisions in cases of NPC.
Therapeutic Targeting of Glioblastoma and the Interactions with Its Microenvironment
Authors: Genoud Vassilis , Kinnersley Ben , Brown Nicholas F. , Ottaviani Diego , Mulholland Paul
Published: December 2023

Glioblastoma (GBM) is the most common primary malignant brain tumour, and it confers a dismal prognosis despite intensive multimodal treatments. Whilst historically, research has focussed on the evolution of GBM tumour cells themselves, there is growing recognition of the importance of studying the tumour microenvironment (TME). Improved characterisation of the interaction between GBM cells and the TME has led to a better understanding of therapeutic resistance and the identification of potential targets to block these escape mechanisms. This review describes the network of cells within the TME and proposes treatment strategies for simultaneously targeting GBM cells, the surrounding immune cells, and the crosstalk between them.
A Novel LncRNA MASCC1 Regulates the Progression and Metastasis of Head and Neck Squamous Cell Carcinoma by Sponging miR-195
Authors: Wang Yujia , Qin Zhen , Chen Yiwen , Zheng Yunfei , Jia Lingfei
Published: December 2023

The altered expression of long noncoding RNAs (lncRNAs) is associated with human carcinogenesis. We performed a high-throughput analysis of lncRNA expression in strictly selected pairs of metastatic head and neck squamous cell carcinoma (HNSCC) and non-metastatic HNSCC samples. We identified a novel lncRNA, which was highly expressed in metastatic HNSCC, named Metastasis Associated Squamous Cell Carcinoma 1 (MASCC1), for further study. Using qRT-PCR, we further compared MASCC1 expression in 60 HNSCC samples. The results show that high expression of MASCC1 in patients with HNSCC was related to poor prognosis. In vitro, MASCC1 knockdown (KD) inhibited HNSCC proliferation, migration, invasion, and tumor sphere formation, while promoting apoptosis. In vivo, MASCC1 KD inhibited HNSCC growth and lymph node metastasis. Mechanistically, MASCC1 acted as a competing endogenous RNA (ceRNA) by binding to miR-195, subsequently regulating the expression of Cyclin D1, BCL-2, and YAP1. Moreover, miR-195 overexpression rescued the effects of MASCC1 on the biological behaviors of HNSCC. Taken together, our results suggest that MASCC1 is a novel oncogene that can predict the prognosis of patients with HNSCC and is a potential therapeutic target for HNSCC intervention.
Neutralization of p40 Homodimer and p40 Monomer Leads to Tumor Regression in Patient-Derived Xenograft Mice with Pancreatic Cancer
Authors: Sheinin Monica , Mondal Susanta , Pahan Kalipada
Published: December 2023

Pancreatic cancer is a highly aggressive cancer with a high mortality rate and limited treatment options. It is the fourth leading cause of cancer in the US, and mortality is rising rapidly, with a 12% relative 5-year survival rate. Early diagnosis remains a challenge due to vague symptoms, lack of specific biomarkers, and rapid tumor progression. Interleukin-12 (IL-12) is a central cytokine that regulates innate (natural killer cells) and adaptive (cytokine T-lymphocytes) immunity in cancer. We demonstrated that serum levels of IL-12p40 homodimer (p402) and p40 monomer (p40) were elevated and that of IL-12 and IL-23 were lowered in pancreatic cancer patients compared to healthy controls. Comparably, human PDAC cells produced greater levels of p402 and p40 and lower levels of IL-12 and IL-23 compared to normal pancreatic cells. Notably, neutralization of p402 by mAb a3-1d and p40 by mAb a3-3a induced the death of human PDAC cells, but not normal human pancreatic cells. Furthermore, we demonstrated that treatment of PDX mice with p402 mAb and p40 mAb resulted in apoptosis and tumor shrinkage. This study illustrates a new role of p402 and p40 monomer in pancreatic cancer, highlighting possible approaches against this deadly form of cancer with p402 and p40 monomer immunotherapies.
Increased Thyroidal Activity on Routine FDG-PET/CT after Combination Immune Checkpoint Inhibition: Temporal Associations with Clinical and Biochemical Thyroiditis
Authors: Galligan Anna , Wallace Roslyn , Krishnamurthy Balasubramanian , Kay Thomas W. H. , Sachithanandan Nirupa , Chiang Cherie , Sandhu Shahneen , Hicks Rodney J. , Iravani Amir
Published: December 2023

Background: FDG-PET/CT used for immune checkpoint inhibitor (ICI) response assessment can incidentally identify immune-related adverse events (irAEs), including thyroiditis. This study aimed to correlate the time course of FDG-PET/CT evidence of thyroiditis with clinical and biochemical evolution of thyroid dysfunction. Methods: A retrospective review was performed by two independent blinded nuclear medicine physicians (NMPs) of thyroidal FDG uptake in 127 patients who underwent PET/CT between January 2016 and January 2019 at baseline and during treatment monitoring of combination ICI therapy for advanced melanoma. Interobserver agreement was assessed and FDG-PET/CT performance defined by a receiver-operating characteristic (ROC) curve using thyroid function tests (TFTs) as the standard of truth. Thyroid maximum standardized uptake value (SUVmax) and its temporal changes with respect to the longitudinal biochemistry were serially recorded. Results: At a median of 3 weeks after commencing ICI, 43/127 (34%) had a diagnosis of thyroiditis established by abnormal TFTs. FDG-PET/CT was performed at baseline and at a median of 11 weeks (range 3–32) following the start of therapy. ROC analysis showed an area under the curve of 0.87 (95% CI 0.80, 0.94) for FDG-PET/CT for detection of thyroiditis with a positive predictive value of 93%. Among patients with biochemical evidence of thyroiditis, those with a positive FDG-PET/CT were more likely to develop overt hypothyroidism (77% versus 35%, p < 0.01). In the evaluation of the index test, there was an almost perfect interobserver agreement between NMPs of 93.7% (95% CI 89.4–98.0), kappa 0.83. Conclusion: Increased metabolic activity of the thyroid on routine FDG-PET/CT performed for tumoral response of patients undergoing ICI therapy is generally detected well after routine biochemical diagnosis. Elevation of FDG uptake in the thyroid is predictive of overt clinical hypothyroidism and suggests that an ongoing robust inflammatory response beyond the initial thyrotoxic phase may be indicative of thyroid destruction.
The Complex Role of the Microbiome in Non-Small Cell Lung Cancer Development and Progression
Authors: Souza Vanessa G. P. , Forder Aisling , Pewarchuk Michelle E. , Telkar Nikita , de Araujo Rachel Paes , Stewart Greg L. , Vieira Juliana , Reis Patricia P. , Lam Wan L.
Published: December 2023

In recent years, there has been a growing interest in the relationship between microorganisms in the surrounding environment and cancer cells. While the tumor microenvironment predominantly comprises cancer cells, stromal cells, and immune cells, emerging research highlights the significant contributions of microbial cells to tumor development and progression. Although the impact of the gut microbiome on treatment response in lung cancer is well established, recent investigations indicate complex roles of lung microbiota in lung cancer. This article focuses on recent findings on the human lung microbiome and its impacts in cancer development and progression. We delve into the characteristics of the lung microbiome and its influence on lung cancer development. Additionally, we explore the characteristics of the intratumoral microbiome, the metabolic interactions between lung tumor cells, and how microorganism-produced metabolites can contribute to cancer progression. Furthermore, we provide a comprehensive review of the current literature on the lung microbiome and its implications for the metastatic potential of tumor cells. Additionally, this review discusses the potential for therapeutic modulation of the microbiome to establish lung cancer prevention strategies and optimize lung cancer treatment.
Potentially Pathogenic SORL1 Mutations Observed in Autosomal-Dominant Cases of Alzheimer’s Disease Do Not Modulate APP Physiopathological Processing
Authors: Bauer Charlotte , Duplan Eric , Saint-George-Hyslop Peter , Checler Frédéric
Published: December 2023

The SORL1 gene encodes LR11/SorLA, a protein that binds β-amyloid precursor protein (APP) and drives its intracellular trafficking. SORL1 mutations, occurring frequently in a subset of familial cases of Alzheimer’s disease (AD), have been documented, but their pathogenic potential is not yet clear and questions remain concerning their putative influence on the physiopathological processing of APP. We have assessed the influence of two SORL1 mutations that were described as likely disease-causing and that were associated with either benign (SorLA924) or severe (SorLA511) AD phenotypes. We examined the influence of wild-type and mutants SorLA in transiently transfected HEK293 cells expressing either wild-type or Swedish mutated APP on APP expression, secreted Aβ and sAPPα levels, intracellular Aβ 40 and Aβ42 peptides, APP-CTFs (C99 and C83) expressions, α-, β- and γ-secretases expressions and activities as well as Aβ and CTFs-degrading enzymes. These paradigms were studied in control conditions or after pharmacological proteasomal modulation. We also established stably transfected CHO cells expressing wild-type SorLA and established the colocalization of APP and either wild-type or mutant SorLA. SorLA mutations partially disrupt co-localization of wild-type sorLA with APP. Overall, although we mostly confirmed previous data concerning the influence of wild-type SorLA on APP processing, we were unable to evidence significant alterations triggered by our set of SorLA mutants, whatever the cells or pharmacological conditions examined. Our study , however, does not rule out the possibility that other AD-linked SORL1 mutations could indeed affect APP processing, and that pathogenic mutations examined in the present study could interfere with other cellular pathways/triggers in AD.
Mapping Chromatin Occupancy of Ppp1r1b-lncRNA Genome-Wide Using Chromatin Isolation by RNA Purification (ChIRP)-seq
Authors: Hwang John , Kang Xuedong , Wolf Charlotte , Touma Marlin
Published: December 2023

Long non-coding RNA (lncRNA) mediated transcriptional regulation is increasingly recognized as an important gene regulatory mechanism during development and disease. LncRNAs are emerging as critical regulators of chromatin state; yet the nature and the extent of their interactions with chromatin remain to be fully revealed. We have previously identified Ppp1r1b-lncRNA as an essential epigenetic regulator of myogenic differentiation in cardiac and skeletal myocytes in mice and humans. We further demonstrated that Ppp1r1b-lncRNA function is mediated by the interaction with the chromatin-modifying complex polycomb repressive complex 2 (PRC2) at the promoter of myogenic differentiation transcription factors, TBX5 and MyoD1. Herein, we employed unbiased chromatin isolation by RNA purification (ChIRP) and high throughput sequencing to map the repertoire of Ppp1r1b-lncRNA chromatin occupancy genome-wide in the mouse muscle myoblast cell line. We uncovered a total of 99732 true peaks corresponding to Ppp1r1b-lncRNA binding sites at high confidence (p-value < 1E-5) and enrichment score ≥ 10). The Ppp1r1b-lncRNA-binding sites averaged 558 bp in length and were distributed widely within the coding and non-coding regions of the genome. Approximately 46% of these true peaks were mapped to gene elements, of which 1180 were mapped to experimentally validated promoter sequences. Importantly, the promoter-mapped binding sites were enriched in myogenic transcription factors and heart development while exhibiting focal interactions with known motifs of proximal promoters and transcription initiation by RNA Pol-II, including TATA-box, transcription initiator motif, CCAAT-box, and GC-box, supporting Ppp1r1b-lncRNA role in transcription initiation of myogenic regulators. Remarkably, nearly 40% of Ppp1r1b-lncRNA-binding sites mapped to gene introns were enriched with the Homeobox family of transcription factors and exhibited TA-rich motif sequences, suggesting potential motif-specific Ppp1r1b-lncRNA-bound introns. Lastly, more than 136521 enhancer sequences were detected in Ppp1r1b-lncRNA-occupancy sites at high confidence. Among these enhancers, 3390 (12%) exhibited cell type/tissue-specific enrichment in fetal heart and muscles. Together, our findings provide further insights into the genome-wide Ppp1r1b-lncRNA: Chromatin interactome that may dictate its function in myogenic differentiation and potentially other cellular and biological processes.
The Identification of Nuclear FMRP Isoform Iso6 Partners
Authors: Ledoux Nassim , Lelong Emeline I. J. , Simard Alexandre , Hussein Samer , Adjibade Pauline , Lambert Jean-Philippe , Mazroui Rachid
Published: December 2023

A deficiency of FMRP, a canonical RNA-binding protein, causes the development of Fragile X Syndrome (FXS), which is characterised by multiple phenotypes, including neurodevelopmental disorders, intellectual disability, and autism. Due to the alternative splicing of the encoding FMR1 gene, multiple FMRP isoforms are produced consisting of full-length predominantly cytoplasmic (i.e., iso1) isoforms involved in translation and truncated nuclear (i.e., iso6) isoforms with orphan functions. However, we recently implicated nuclear FMRP isoforms in DNA damage response, showing that they negatively regulate the accumulation of anaphase DNA genomic instability bridges. This finding provided evidence that the cytoplasmic and nuclear functions of FMRP are uncoupled played by respective cytoplasmic and nuclear isoforms, potentially involving specific interactions. While interaction partners of cytoplasmic FMRP have been reported, the identity of nuclear FMRP isoform partners remains to be established. Using affinity purification coupled with mass spectrometry, we mapped the nuclear interactome of the FMRP isoform iso6 in U2OS. In doing so, we found FMRP nuclear interaction partners to be involved in RNA processing, pre-mRNA splicing, ribosome biogenesis, DNA replication and damage response, chromatin remodeling and chromosome segregation. By comparing interactions between nuclear iso6 and cytoplasmic iso1, we report a set of partners that bind specifically to the nuclear isoforms, mainly proteins involved in DNA-associated processes and proteasomal proteins, which is consistent with our finding that proteasome targets the nuclear FMRP iso6. The specific interactions with the nuclear isoform 6 are regulated by replication stress, while those with the cytoplasmic isoform 1 are largely insensitive to such stress, further supporting a specific role of nuclear isoforms in DNA damage response induced by replicative stress, potentially regulated by the proteasome.