bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasmon Resonant Two-Photon Luminescence Inducing Photosensitization and Nonlinear Optical Microscopy In Vivo by Near-Infrared Excitation of Au Nanopeanuts
Authors: Guo Lun-Zhang , Wu Cheng-Ham , Tsai Ming-Fong , Cheng Fong-Yu , Shanmugam Vijayakumar , Tsai Zen-Uong , Zhang Zhiming , Liu Tzu-Ming , Yeh Chen-Sheng
Published: November 2021

Photodynamic therapy (PDT) provides a potential therapeutic approach for killing malignant cell/solid tumors, but currently approved photosensitizers (PSs) are generally excited by visible light, limiting the penetration depth in tissues. It is necessary to develop a near-infrared (NIR) responsive photodynamic platform, providing maximum tissue penetration. Here, we present a gold nanopeanut platform exhibiting dual functions of NIR PDT and two-photon luminescence imaging. The nanopeanut with a size less than 100 nm exhibits two distinct NIR surface plasmon absorption bands at approximately 1110 and 1300 nm. To perform PDT, we conjugated commercial toluidine blue O (TBO) PS on the surface of the nanopeanuts. With spectral overlap, the 1230-nm femtosecond Cr: forsterite laser can excite the surface plasmons of nanopeanuts, transfer energy to TBO, and generate singlet oxygen to kill cells. Moreover, the plasmon resonance-enhanced two-photon luminescence of nanopeanuts can be used to map their delivery in vivo. These results demonstrate that the PS-conjugated gold nanopeanut is an effective theranostic system for NIR PDT.
Pulsed Nanoelectrospray Ionization Boosts Ion Signal in Whole Protein Mass Spectrometry
Authors: Liu Qinwen , Ahmed Ezaz , Kabir K. M. Mohibul , Huang Xiaojing , Xiao Dan , Fletcher John , Donald William A.
Published: November 2021

Electrospray ionisation (ESI) is renowned for its ability to ionise intact proteins for sensitive detection by mass spectrometry (MS). However, the use of a conventional direct current ESI voltage can result in the formation of relatively large initial droplet sizes, which can limit efficient ion desolvation and sensitivity. Here, pulsed nanoESI (nESI) MS using nanoscale emitters with inner diameters of ~250 nm is reported. In this approach, the nESI voltage is rapidly pulsed from 0 to ~1.5 kV with sub-nanosecond rise times, duty cycles from 10 to 90%, and repetition rates of 10 to 350 kHz. Using pulsed nESI, the performance of MS for the detection of intact proteins can be improved in terms of increased ion abundances and decreased noise. The absolute ion abundances and signal-to-noise levels of protonated ubiquitin, cytochrome C, myoglobin, and carbonic anhydrase II formed from standard denaturing solutions can be increased by up to 82% and 154% using an optimal repetition rate of ~200 kHz compared to conventional nESI-MS. Applying pulsed nESI-MS to a mixture of four proteins resulted in the signal for each protein increasing by up to 184% compared to the more conventional nESI-MS. For smaller ions (≤1032 m/z), the signal can also be increased by the use of high repetition rates (200–250 kHz), which is consistent with the enhanced performance depending more on general factors associated with the ESI process (e.g., smaller initial droplet sizes and reduced Coulombic repulsion in the spray plume) rather than analyte-specific effects (e.g., electrophoretic mobility). The enhanced sensitivity of pulsed nESI is anticipated to be beneficial for many different types of tandem mass spectrometry measurements.
Smartphone-Based Colorimetric Detection of Chromium (VI) by Maleic Acid-Functionalized Gold Nanoparticles
Authors: Mohamed Ahmed , Li Xuemeng , Li Chengfei , Li Xuegang , Yuan Chao , Barakat Hassan
Published: November 2021

Because of the significant environmental pollution produced by human activities, there is an ongoing need to develop transportable, simple, and reliable techniques for determining trace contaminants on the spot. This work reported a colorimetric detection method for aqueous Cr(VI) sensing by maleic acid-functionalized gold nanoparticles with high sensitivity and selectivity. The wine-red color of the probe solution can change to gray even in the presence of 1.0 µg L−1 of aqueous Cr(VI). Moreover, with the assistance of a smartphone installed with a commercially available color scan application software, its concentration of could be readily quantified on the spot without the help of UV-Vis spectrometer. The detection limit could reach as low as 0.1 µg L−1 with linear range from 0.2 to 2.0 µg L−1. Most importantly, the coefficient variation of the proposed smartphone-based method was equivalent to that of colorimetry, demonstrating the high accuracy of the proposed method for accurate detection of Cr(VI) in resource-constrained countries. Conclusively, with the help of the smartphone, this nanomaterials-based probe demonstrated the potential in the field of environment monitoring for on-site quantitative detection of any pollutants in resource-constrained countries.
Chronic Effects of Diazinon® Exposures Using Integrated Biomarker Responses in Freshwater Walking Catfish, Clarias batrachus
Authors: Saha Shubhajit , Chukwuka Azubuike V. , Mukherjee Dip , Patnaik Lipika , Nayak Susri , Dhara Kishore , Saha Nimai Chandra , Faggio Caterina
Published: November 2021

Diazinon exposures have been linked to the onset of toxic pathways and adverse outcomes in aquatic species, but the ecological implications on model species are not widely emphasized. The objective of this study was to determine how the organophosphate pesticide diazinon affected hematological (hemoglobin, total red blood count, total white blood count, and mean corpuscular hemoglobin), growth (condition factor, hepatosomatic index, specific growth rate), biochemical (total serum glucose, total serum protein), and endocrine (growth hormone, tri-iodothyronine, and thyroxine) parameters in Clarias batrachus after chronic exposure. Diazinon was administered at predefined exposure doses (0.64 and 1.28 mg/L) and monitored at 15, 30, and 45 days into the investigation. Observation for most biomarkers revealed patterns of decreasing values with increasing toxicant concentration and exposure duration. Correlation analysis highlighted a significant inverse relationship between variables (mean corpuscular hemoglobin, condition factor, specific growth rate, tri-iodothyronine, thyroxine, and total serum protein) and elevated chronic diazinon exposure concentrations. The integrated indices (IBR and BRI) indexes were used to provide visual and understandable depictions of toxicity effects and emphasized the relativity of biomarkers in terms of sensitivity and magnitude or severity of responses under graded toxicant exposures. The significant damage reflected by evaluated parameters in diazinon exposure groups compared to control portends risks to the health of local fish populations, including Clarias batrachus in aquatic systems adjacent to agrarian landscapes.
Dual Head and Dual Attention in Deep Learning for End-to-End EEG Motor Imagery Classification
Authors: Xu Meiyan , Yao Junfeng , Ni Hualiang
Published: November 2021

Event-Related Desynchronization (ERD) or Electroencephalogram (EEG) wavelet is essential for motor imagery (MI) classification and BMI (Brain–Machine Interface) application. However, it is difficult to recognize multiple tasks for non-trained subjects that are indispensable for the complexities of the task or the uncertainties in the environment. The subject-independent scenario, where an inter-subject trained model can be directly applied to new users without precalibration, is particularly desired. Therefore, this paper focuses on an effective attention mechanism which can be applied to a subject-independent set to learn EEG motor imagery features. Firstly, a custom form of sequence inputs with spatial and temporal dimensions is adopted for dual headed attention via deep convolution net (DHDANet). Secondly, DHDANet simultaneously learns temporal and spacial features. The features of spacial attention on each input head are divided into two parts for spatial attentional learning subsequently. The proposed model is validated based on the EEG-MI signals collected from 54 subjects in two sessions with 200 trials in each sessions. The classification of left and right hand motor imagery in this paper achieves an average accuracy of 75.52%, a significant improvement compared to state-of-the-art methods. In addition, the visualization of the frequency analysis method demonstrates that the temporal-convolution and spectral-attention is capable of identifying the ERD for EEG-MI. The proposed machine learning structure enables cross-session and cross-subject classification and makes significant progress in the BMI transfer learning problem.
Forecasting the Bearing Capacity of the Driven Piles Using Advanced Machine-Learning Techniques
Authors: Benbouras Mohammed Amin , Petrişor Alexandru-Ionuţ , Zedira Hamma , Ghelani Laala , Lefilef Lina
Published: November 2021

Estimating the bearing capacity of piles is an essential point when seeking for safe and economic geotechnical structures. However, the traditional methods employed in this estimation are time-consuming and costly. The current study aims at elaborating a new alternative model for predicting the pile-bearing capacity based on eleven new advanced machine-learning methods in order to overcome these limitations. The modeling phase used a database of 100 samples collected from different countries. Additionally, eight relevant factors were selected in the input layer based on the literature recommendations. The optimal inputs were modeled using the machine-learning methods and their performance was assessed through six performance measures using a K-fold cross-validation approach. The comparative study proved the effectiveness of the DNN model, which displayed a higher performance in predicting the pile-bearing capacity. This elaborated model provided the optimal prediction, i.e., the closest to the experimental values, compared to the other models and formulae proposed by previous studies. Finally, a reliable and easy-to-use graphical interface was generated, namely “BeaCa2021”. This will be very helpful for researchers and civil engineers when estimating the pile-bearing capacity, with the advantage of saving time and money.
Exploring the Direct and Indirect Use of ICT Measurements in DODME (Dynamic OD Matrix Estimation)
Authors: Ros-Roca Xavier , Montero Lídia , Barceló Jaume
Published: November 2021

The estimation of the network traffic state, its likely short-term evolution, the prediction of the expected travel times in a network, and the role that mobility patterns play in transport modeling is usually based on dynamic traffic models, whose main input is a dynamic origin–destination (OD) matrix that describes the time dependencies of travel patterns; this is one of the reasons that have fostered large amounts of research on the topic of estimating OD matrices from the available traffic information. The complexity of the problem, its underdetermination, and the many alternatives that it offers are other reasons that make it an appealing research topic. The availability of new traffic data measurements that were prompted by the pervasive penetration of information and communications technology (ICT) applications offers new research opportunities. This study focused on GPS tracking data and explored two alternative modeling approaches regarding how to account for this new information to solve the dynamic origin–destination matrix estimation (DODME) problem, either including it as an additional term in the formulation model or using it in a data-driven modeling method to propose new model formulations. Complementarily, independently of the approach used, a key aspect is the quality of the estimated OD, which, as recent research has made evident, is not well measured by the conventional indicators. This study also explored this problem for the proposed approaches by conducting synthetic computational experiments to control and understand the process.
Challenges of Data Refining Process during the Artificial Intelligence Development Projects in the Architecture, Engineering and Construction Industry
Authors: Heo Seokjae , Han Sehee , Shin Yoonsoo , Na Seunguk
Published: November 2021

The paper examines that many human resources are needed on the research and development (R&D) process of artificial intelligence (AI) and discusses factors to consider on the current method of development. Labor division of a few managers and numerous ordinary workers as a form of light industry appears to be a plausible method of enhancing the efficiency of AI R&D projects. Thus, the research team regards the development process of AI, which maximizes production efficiency by handling digital resources named ‘data’ with mechanical equipment called ‘computers’, as the digital light industry of the fourth industrial era. As experienced during the previous Industrial Revolution, if human resources are efficiently distributed and utilized, no less progress than that observed in the second Industrial Revolution can be expected in the digital light industry, and human resource development for this is considered urgent. Based on current AI R&D projects, this study conducted a detailed analysis of necessary tasks for each AI learning step and investigated the urgency of R&D human resource training. If human resources are educated and trained, this could lead to specialized development, and new value creation in the AI era can be expected.
Performance Profile among Age Categories in Young Cyclists
Authors: Marín-Pagán Cristian , Dufour Stéphane , Freitas Tomás T. , Alcaraz Pedro E.
Published: November 2021

Endurance profile assessment is of major interest to evaluate the cyclist’s performance potential. In this regard, maximal oxygen uptake and functional threshold power are useful functional parameters to determine metabolic training zones (ventilatory threshold). The aim of this study was to evaluate and compare the physiological profile of different road cyclist age categories (Youth, Junior, and Under-23) to obtain the performance requirements. Sixty-one competitive road cyclists (15–22 years) performed a maximal incremental test on a bike in order to determine functional parameters (maximal fat oxidation zone, ventilatory thresholds, maximal oxygen uptake, and functional threshold power) and metabolic training zones. The results suggest major differences, with the Youth group showing clear changes in all metabolic zones except in fat oxidation. The main differences between Under-23 vs. Junior groups were observed in maximal relative power output (Under-23: 6.70 W·Kg−1; Junior: 6.17 W·Kg−1) and relative functional threshold power (Under-23: 4.91 W·Kg−1; Junior: 4.48 W·Kg−1). The Youth group physiological profile is clearly different to the other age categories. Some parameters normalized to body weight (maximal oxygen consumption, load and functional threshold power) could be interesting to predict a sporting career during the Junior and Under-23 stages.
Identification of Prognostic Gene Biomarkers in Non-Small Cell Lung Cancer Progression by Integrated Bioinformatics Analysis
Authors: Giannos Panagiotis , Kechagias Konstantinos S. , Gal Annamaria
Published: November 2021

The progression of non-small cell lung cancer (NSCLC) is linked to epithelial-mesenchymal transition (EMT), a biologic process that enables tumor cells to acquire a migratory phenotype and resistance to chemo- and immunotherapies. Discovery of novel biomarkers in NSCLC progression is essential for improved prognosis and pharmacological interventions. In the current study, we performed an integrated bioinformatics analysis on gene expression datasets of TGF-β-induced EMT in NSCLC cells to identify novel gene biomarkers and elucidate their regulation in NSCLC progression. The gene expression datasets were extracted from the NCBI Gene Expression Omnibus repository, and differentially expressed genes (DEGs) between TGF-β-treated and untreated NSCLC cells were retrieved. A protein-protein interaction network was constructed and hub genes were identified. Functional and pathway enrichment analyses were conducted on module DEGs, and a correlation between the expression levels of module genes and survival of NSCLC patients was evaluated. Prediction of interactions of the biomarker genes with transcription factors and miRNAs was also carried out. We described four protein clusters in which DEGs were associated with ubiquitination (Module 1), regulation of cell death and cell adhesions (Module 2), oxidation-reduction reactions of aerobic respiration (Module 3) and mitochondrial translation (Module 4). From the module genes, we identified ten prognostic gene biomarkers in NSCLC. Low expression levels of KCTD6, KBTBD7, LMO7, SPSB2, RNF19A, FOXA2, DHTKD1, CDH1 and PDHB and high expression level of KLHL25 were associated with reduced overall survival of NSCLC patients. Most of these biomarker genes were involved in protein ubiquitination. The regulatory network of the gene biomarkers revealed their interaction with tumor suppressor miRNAs and transcription factors involved in the mechanisms of cancer progression. This ten-gene prognostic signature can be useful to improve risk prediction and therapeutic strategies in NSCLC. Our analysis also highlights the importance of deregulation of ubiquitination in EMT-associated NSCLC progression.
D-Amino Acids and D-Amino Acid-Containing Peptides: Potential Disease Biomarkers and Therapeutic Targets?
Authors: Abdulbagi Mohamed , Wang Liya , Siddig Orwa , Di Bin , Li Bo
Published: November 2021

In nature, amino acids are found in two forms, L and D enantiomers, except for glycine which does not have a chiral center. The change of one form to the other will lead to a change in the primary structure of proteins and hence may affect the function and biological activity of proteins. Indeed, several D-amino acid-containing peptides (DAACPs) were isolated from patients with cataracts, Alzheimer’s and other diseases. Additionally, significant levels of free D-amino acids were found in several diseases, reflecting the disease conditions. Studying the molecular mechanisms of the DAACPs formation and the alteration in D-amino acids metabolism will certainly assist in understanding these diseases and finding new biomarkers and drug targets. In this review, the presence of DAACPs and free D-amino acids and their links with disease development and progress are summarized. Similarly, we highlight some recent advances in analytical techniques that led to improvement in the discovery and analysis of DAACPs and D-amino acids.
Implicit Associations between Adverbs of Place and Actions in the Physical and Digital Space
Authors: Craighero Laila , Marini Maddalena
Published: November 2021

Neuropsychological, behavioral, and neurophysiological evidence indicates that the coding of space as near and far depends on the involvement of different neuronal circuits. These circuits are recruited on the basis of functional parameters, not of metrical ones, reflecting a general distinction of human behavior, which alternatively attributes to the individual the role of agent or observer. Although much research in cognitive psychology was devoted to demonstrating that language and concepts are rooted in the sensorimotor system, no study has investigated the presence of implicit associations between different adverbs of place (far vs. near) and actions with different functional characteristics. Using a series of Implicit Association Test (IAT) experiments, we tested this possibility for both actions performed in physical space (grasp vs. look at) and those performed when using digital technology (content generation vs. content consumption). For both the physical and digital environments, the results showed an association between the adverb near and actions related to the role of agent, and between the adverb far and actions related to the role of observer. Present findings are the first experimental evidence of an implicit association between different adverbs of place and different actions and of the fact that adverbs of place also apply to the digital environment.
In Time with the Beat: Entrainment in Patients with Phonological Impairment, Apraxia of Speech, and Parkinson’s Disease
Authors: Aichert Ingrid , Lehner Katharina , Falk Simone , Späth Mona , Franke Mona , Ziegler Wolfram
Published: November 2021

In the present study, we investigated if individuals with neurogenic speech sound impairments of three types, Parkinson’s dysarthria, apraxia of speech, and aphasic phonological impairment, accommodate their speech to the natural speech rhythm of an auditory model, and if so, whether the effect is more significant after hearing metrically regular sentences as compared to those with an irregular pattern. This question builds on theories of rhythmic entrainment, assuming that sensorimotor predictions of upcoming events allow humans to synchronize their actions with an external rhythm. To investigate entrainment effects, we conducted a sentence completion task relating participants’ response latencies to the spoken rhythm of the prime heard immediately before. A further research question was if the perceived rhythm interacts with the rhythm of the participants’ own productions, i.e., the trochaic or iambic stress pattern of disyllabic target words. For a control group of healthy speakers, our study revealed evidence for entrainment when trochaic target words were preceded by regularly stressed prime sentences. Persons with Parkinson’s dysarthria showed a pattern similar to that of the healthy individuals. For the patient groups with apraxia of speech and with phonological impairment, considerably longer response latencies with differing patterns were observed. Trochaic target words were initiated with significantly shorter latencies, whereas the metrical regularity of prime sentences had no consistent impact on response latencies and did not interact with the stress pattern of the target words to be produced. The absence of an entrainment in these patients may be explained by the more severe difficulties in initiating speech at all. We discuss the results in terms of clinical implications for diagnostics and therapy in neurogenic speech disorders.
fMRI Evidence for Default Mode Network Deactivation Associated with Rapid Eye Movements in Sleep
Authors: Hong Charles , Fallon James , Friston Karl
Published: November 2021

System-specific brain responses—time-locked to rapid eye movements (REMs) in sleep—are characteristically widespread, with robust and clear activation in the primary visual cortex and other structures involved in multisensory integration. This pattern suggests that REMs underwrite hierarchical processing of visual information in a time-locked manner, where REMs index the generation and scanning of virtual-world models, through multisensory integration in dreaming—as in awake states. Default mode network (DMN) activity increases during rest and reduces during various tasks including visual perception. The implicit anticorrelation between the DMN and task-positive network (TPN)—that persists in REM sleep—prompted us to focus on DMN responses to temporally-precise REM events. We timed REMs during sleep from the video recordings and quantified the neural correlates of REMs—using functional MRI (fMRI)—in 24 independent studies of 11 healthy participants. A reanalysis of these data revealed that the cortical areas exempt from widespread REM-locked brain activation were restricted to the DMN. Furthermore, our analysis revealed a modest temporally-precise REM-locked decrease—phasic deactivation—in key DMN nodes, in a subset of independent studies. These results are consistent with hierarchical predictive coding; namely, permissive deactivation of DMN at the top of the hierarchy (leading to the widespread cortical activation at lower levels; especially the primary visual cortex). Additional findings indicate REM-locked cerebral vasodilation and suggest putative mechanisms for dream forgetting.
The Emerging Role of Scalogram-Based Convolutional Neural Network in the Diagnosis of Epileptic Seizures
Authors: Bernitsas Evanthia
Published: November 2021

Epilepsy, a common disorder affecting 1–2% of the population, can significantly impact a person’s quality of life and can lead to disability or even death [...]
Imaging of Neuroendocrine Prostatic Carcinoma
Authors: Taher Ahmed , Jensen Corey T. , Yedururi Sireesha , Surasi Devaki Shilpa , Faria Silvana C. , Bathala Tharakeshwar K. , Mujtaba Bilal , Bhosale Priya , Wagner-Bartak Nicolaus , Morani Ajaykumar C.
Published: November 2021

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that typically has a high metastatic potential and poor prognosis in comparison to the adenocarcinoma subtype. Although it can arise de novo, NEPC much more commonly occurs as a mechanism of treatment resistance during therapy for conventional prostatic adenocarcinoma, the latter is also termed as castration-resistant prostate cancer (CRPC). The incidence of NEPC increases after hormonal therapy and they represent a challenge, both in the radiological and pathological diagnosis, as well as in the clinical management. This article provides a comprehensive imaging review of prostatic neuroendocrine tumors.
Activation of the Complement System in Patients with Cancer Cachexia
Authors: Deng Min , Vaes Rianne D. W. , van Bijnen Annemarie A. J. H. M. , Olde Damink Steven W. M. , Rensen Sander S.
Published: November 2021

Systemic inflammation is thought to underlie many of the metabolic manifestations of cachexia in cancer patients. The complement system is an important component of innate immunity that has been shown to contribute to metabolic inflammation. We hypothesized that systemic inflammation in patients with cancer cachexia was associated with complement activation. Systemic C3a levels were higher in cachectic patients with inflammation (n = 23, C-reactive protein (CRP) ≥ 10 mg/L) as compared to patients without inflammation (n = 26, CRP < 10 mg/L) or without cachexia (n = 13) (medians 102.4 (IQR 89.4–158.0) vs. 81.4 (IQR 47.9–124.0) vs. 61.6 (IQR 46.8–86.8) ng/mL, respectively, p = 0.0186). Accordingly, terminal complement complex (TCC) concentrations gradually increased in these patient groups (medians 2298 (IQR 2022–3058) vs. 1939 (IQR 1725–2311) vs. 1805 (IQR 1552–2569) mAU/mL, respectively, p = 0.0511). C3a and TCC concentrations were strongly correlated (rs = 0.468, p = 0.0005). Although concentrations of C1q and mannose-binding lectin did not differ between groups, C1q levels were correlated with both C3a and TCC concentrations (rs = 0.394, p = 0.0042 and rs = 0.300, p = 0.0188, respectively). In conclusion, systemic inflammation in patients with cancer cachexia is associated with the activation of key effector complement factors. The correlations between C1q and C3a/TCC suggest that the classical complement pathway could play a role in complement activation in patients with pancreatic cancer.
Determination of Additional Surgery after Non-Curative Endoscopic Submucosal Dissection in Patients with Early Gastric Cancer: A Practically Modified Application of the eCura System
Authors: Lee Sejin , Song Jeong Ho , Park Sung Hyun , Cho Minah , Kim Yoo Min , Kim Hyoung-Il , Hyung Woo Jin
Published: November 2021

Background: Additional surgery after non-curative endoscopic submucosal dissection (ESD) may be excessive as few patients have lymph node metastasis (LNM). It is necessary to develop a risk stratification system for LNM after non-curative ESD, such as the eCura system, which was introduced in the Japanese gastric cancer treatment guidelines. However, the eCura system requires venous and lymphatic invasion to be separately assessed, which is difficult to distinguish without special immunostaining. In this study, we practically modified the eCura system by classifying lymphatic and venous invasion as lymphovascular invasion (LVI). Method: We retrospectively reviewed 543 gastric cancer patients who underwent radical gastrectomy after non-curative ESD between 2006 and 2019. LNM was evaluated according to LVI as well as size >30 mm, submucosal invasion ≥500 µm, and vertical margin involvement, which were used in the eCura system. Results: LNM was present in 8.1% of patients; 3.6%, 2.3%, 7.4%, 18.3%, and 61.5% of patients with no, one, two, three, and four risk factors had LNM, respectively. The LNM rate in the patients with no risk factors (3.6%) was not significantly different from that in patients with one risk factor (2.3%, p = 0.523). Among patients with two risk factors, the LNM rate without LVI was significantly lower than with LVI (2.4% vs. 10.7%, p = 0.027). Among patients with three risk factors, the LNM rate without LVI was lower than with LVI (0% vs. 20.8%, p = 0.195), although not statistically significantly. Based on LNM rates according to risk factors, patients with LVI and other factors were assigned to the high-risk group (LNM, 17.4%) while other patients as a low-risk group (LNM, 2.4%). Conclusions: Modifying the eCura system by classifying lymphatic and venous invasion as LVI successfully stratified LNM risk after non-curative ESD. Moreover, the high-risk group can be simply identified based on LVI and the presence of other risk factors.
Landmark Cancer Clinical Trials and Real-World Patient Populations: Examining Race and Age Reporting
Authors: Jayakrishnan Thejus , Aulakh Sonikpreet , Baksh Mizba , Nguyen Kianna , Ailawadhi Meghna , Samreen Ayesha , Parrondo Ricardo , Sher Taimur , Roy Vivek , Manochakian Rami , Paulus Aneel , Chanan-Khan Asher , Ailawadhi Sikander
Published: November 2021

Background: Concern exists that the clinical trial populations differ from respective cancer populations in terms of their age distribution affecting the generalizability of the results, especially in underrepresented minorities. We hypothesized that the clinical trials that do not report race are likely to suffer from a higher degree of age disparity. Methods: Food and Drug Administration (FDA) drug approvals from July 2007 to June 2019 were reviewed to identify oncology approvals, and trials with age details were selected. The outcomes studied were the weighted mean difference in age between the clinical trial population and real-world population for various cancers, the prevalence of race reporting and association of age and race reporting with each other. Results: Of the 261 trials, race was reported in 223 (85.4%) of the trials, while 38 trials (14.6%) had no mention of race. Race reporting improved minimally over time: 29 (85.3%) in 2007–2010 vs. 49 (80.3%) in 2011–2014 vs. 145 (85.4%) during the period 2015–2019 (p-value = 0.41). Age discrepancy between the clinical trial population and the real-world population was higher for studies that did not report race (mean difference −8.8 years (95% CI −12.6 to −5.0 years)) vs. studies that did report it (mean difference −5.1 years, (95% CI −6.4 to −3.7 years), p-value = 0.04). Conclusion: The study demonstrates that a significant number of clinical trials leading to cancer drug approvals suffer from racial and age disparity when compared to real-world populations, and that the two factors may be interrelated. We recommend continued efforts to recruit diverse populations.
Nutritional Status as a Predictive Biomarker for Immunotherapy Outcomes in Advanced Head and Neck Cancer
Authors: Guller Meytal , Herberg Matthew , Amin Neha , Alkhatib Hosam , Maroun Christopher , Wu Evan , Allen Hailey , Zheng Ying , Gourin Christine , Vosler Peter , Tan Marietta , Koch Wayne , Eisele David , Seiwert Tanguy , Fakhry Carole , Pardoll Drew , Zhu Gangcai , Mandal Rajarsi
Published: November 2021

The association between pretreatment nutritional status and immunotherapy response in patients with advanced head and neck cancer is unclear. We retrospectively analyzed a cohort of 99 patients who underwent treatment with anti-PD-1 or anti-CTLA-4 antibodies (or both) for stage IV HNSCC between 2014 and 2020 at the Johns Hopkins Hospital. Patient demographics and clinical characteristics were retrieved from electronic medical records. Baseline prognostic nutritional index (PNI) scores and pretreatment body mass index (BMI) trends were calculated. Associations between PNI and BMI were correlated with overall survival (OS), progression-free survival (PFS), and immunotherapy response. In univariate analysis, there was a significant correlation between OS and PFS with baseline PNI (OS: HR: 0.464; 95% CI: 0.265–0.814; PFS: p = 0.007 and HR: 0.525; 95% CI: 0.341–0.808; p = 0.003). Poor OS was also associated with a greater decrease in pretreatment BMI trend (HR: 0.42; 95% CI: 0.229–0.77; p = 0.005). In multivariate analysis, baseline PNI but not BMI trend was significantly associated with OS and PFS (OS: log (HR) = −0.79, CI: −1.6, −0.03, p = 0.041; PFS: log (HR) = −0.78, CI: −1.4, −0.18, p = 0.011). In conclusion, poor pretreatment nutritional status is associated with negative post-immunotherapy outcomes.
A Simple Preoperative Blood Count to Stratify Prognosis in Isocitrate Dehydrogenase-Wildtype Glioblastoma Patients Treated with Radiotherapy plus Concomitant and Adjuvant Temozolomide
Authors: Clavreul Anne , Lemée Jean-Michel , Soulard Gwénaëlle , Rousseau Audrey , Menei Philippe
Published: November 2021

Purpose: The survival times of glioblastoma (GB) patients after the standard therapy including safe maximal resection followed by radiotherapy plus concomitant and adjuvant temozolomide are heterogeneous. In order to define a simple, reliable method for predicting whether patients with isocitrate dehydrogenase (IDH)-wildtype GB treated with the standard therapy will be short- or long-term survivors, we analyzed the correlation of preoperative blood counts and their combined forms with progression-free survival (PFS) and overall survival (OS) in these patients. Methods: Eighty-five patients with primary IDH-wildtype GB treated with the standard therapy between 2012 and 2019 were analyzed retrospectively. Cox proportional hazards models and Kaplan–Meier analysis were used to investigate the survival function of preoperative hematological parameters. Results: Preoperative high neutrophil-to-lymphocyte ratio (NLR, >2.42), high platelet count (>236 × 109/L), and low red blood cell (RBC) count (≤4.59 × 1012/L) were independent prognostic factors for poorer OS (p = 0.030, p = 0.030, and p = 0.004, respectively). Moreover, a high NLR was an independent prognostic factor for shorter PFS (p = 0.010). We also found that, like NLR, preoperative high derived NLR (dNLR, >1.89) was of poor prognostic value for both PFS (p = 0.002) and OS (p = 0.033). A significant correlation was observed between NLR and dNLR (r = 0.88, p < 0.001), which had a similar prognostic power for OS (NLR: AUC = 0.58; 95% CI: [0.48; 0.68]; dNLR: AUC = 0.62; 95% CI: [0.51; 0.72]). Two scores, one based on preoperative platelet and RBC counts plus NLR and the other on preoperative platelet and RBC counts plus dNLR, were found to be independent prognostic factors for PFS (p = 0.006 and p = 0.002, respectively) and OS (p < 0.001 for both scores). Conclusion: Cheap, routinely ordered, preoperative assessments of blood markers, such as NLR, dNLR, RBC, and platelet counts, can predict the survival outcomes of patients with IDH-wildtype GB treated with the standard therapy.
Kinome-Wide siRNA Screening Identifies DYRK1B as a Potential Therapeutic Target for Triple-Negative Breast Cancer Cells
Authors: Chang Chia-Che , Chiu Chien-Chih , Liu Pei-Feng , Wu Chih-Hsuan , Tseng Yen-Chiang , Lee Cheng-Hsin , Shu Chih-Wen
Published: November 2021

Aims: The selective molecules for targeted therapy of triple-negative breast cancer (TNBC) are limited. Several kinases play pivotal roles in cancer development and malignancy. The study aims to determine if any kinases confer to malignancy of TNBC cells, which could serve as a theranostic target for TNBC. Methods: Kinome siRNA library was used to screen selective genes required for the proliferation of TNBC cells. The involvement of DYRK1B in cancer malignancy was evaluated with migration, invasion assays, and spheroid culture. The expression of DYRK1B was confirmed with quantitative PCR and immunoblotting. The clinical correlation of DYRK1B in TNBC patients was examined with tissue microarray and The Cancer Genome Atlas (TCGA) database. Results: Our results showed that silencing DYRK1B significantly suppressed cell viability in DYRK1B-high expressed TNBC cells, likely by arresting the cell cycle at the G1 phase. Nevertheless, silencing DYRK1B had marginal effects on DYRK1B-low expressed TNBC cells. Similarly, the knockdown of DYRK1B decreased tumorsphere formation and increased cell death of the tumorsphere. Moreover, inactivation of DYRK1B by either specific inhibitor or ectopic expressing catalytic mutant of DYRK1B inhibited cell viability and metastatic characteristics, including migration and invasion. In addition, DYRK1B protein expression was elevated in tumor tissues compared to that in adjacent normal tissues of TNBC patients. Further, DYRK1B gene expression was highly correlated with CCDC97 or ZNF581 genes in TNBC cells and patients. High co-expression of DYRK1B with CCDC97 or ZNF581 was significantly associated with unfavorable overall survival and disease-free survival of TNBC patients. Conclusions: our results suggest DYRK1B might be essential for promoting tumor progression and could be a theranostic target for TNBC. Silencing or inactivation of DYRK1B might be a potential targeted therapy for TNBC.
Intra-Tumoral Pharmacokinetics of Pazopanib in Combination with Radiotherapy in Patients with Non-Metastatic Soft-Tissue Sarcoma
Authors: Molenaar-Kuijsten Laura , van Meekeren Milan , Verheijen Remy B. , Bovée Judith V. M. G. , Fiocco Marta , Thijssen Bas , Rosing Hilde , Huitema Alwin D. R. , Miah Aisha B. , Gelderblom Hans , Haas Rick L. M. , Steeghs Neeltje
Published: November 2021

There is a lack of understanding whether plasma levels of anticancer drugs (such as pazopanib) correlate with intra-tumoral levels and whether the plasma compartment is the best surrogate for pharmacokinetic and pharmacodynamic evaluation. Therefore, we aimed to quantify pazopanib concentrations in tumor tissue, to assess the correlation between tumor concentrations and plasma concentrations and between tumor concentrations and efficacy. In this clinical trial, non-metastatic STS patients were treated with neo-adjuvant concurrent radiotherapy and pazopanib. Plasma samples and tumor biopsies were collected, and pazopanib concentrations were measured using liquid chromatography-tandem mass spectrometry. Twenty-four evaluable patients were included. The median pazopanib tumor concentration was 19.2 µg/g (range 0.149–200 µg/g). A modest correlation was found between tumor concentrations and plasma levels of pazopanib (ρ = 0.41, p = 0.049). No correlation was found between tumor concentrations and percentage of viable tumor cells (p > 0.05); however, a trend towards less viable tumor cells in patients with high pazopanib concentrations in tumor tissue was observed in a categorical analysis. Possible explanations for the lack of correlation might be heterogeneity of the tumors and timing of the biopsy procedure.
Prognostic Value of Prospective Longitudinal CRP to Albumin Ratio among Older Outpatients with Cancer
Authors: Burgassi Fiamma , Paillaud Elena , Poisson Johanne , Bousquet Guilhem , Pamoukdjian Frédéric
Published: November 2021

The prognostic value of the CRP to albumin ratio (CAR) among older adults with cancer is not known. Six hundred and three older outpatients with cancer and undergoing geriatric assessment before therapeutic decisions were prospectively recruited from the PF-EC cohort study. Serum albumin levels, serum CRP levels and the CAR were prospectively recorded at baseline, and at each consultation thereafter, as follows: 1, 3, 6, 9, 12, 18, 24 and 36 months. Frailty was defined as a G8-index ≤ 14. The primary endpoint was longitudinal variation in the CAR during the study follow-up. Two clusters in the longitudinal trajectories of the CAR were identified, one favourable, with lower values and better overall survival (cluster A), and the second with higher values and less favourable overall survival (cluster B). The median CAR [95% CI] for clusters A and B were respectively: 0.17 [0.04–0.48] and 0.26 [0.04–0.79] at baseline (p = 0.01), and 0.18 [0.02–3.17] and 0.76 [0.03–6.87] during the study follow-up (p < 0.0001). Cluster B was associated with the frailest patients with metastatic disease, mainly driven by a high CRP level at baseline, and low albumin during the study follow-up. Our study results suggest that the most risk-prone patients have a cancer-cachexia trajectory.
High Density of CD16+ Tumor-Infiltrating Immune Cells in Recurrent Ovarian Cancer Is Associated with Enhanced Responsiveness to Chemotherapy and Prolonged Overall Survival
Authors: Lalos Alexandros , Neri Ornella , Ercan Caner , Wilhelm Alexander , Staubli Sebastian , Posabella Alberto , Weixler Benjamin , Terracciano Luigi , Piscuoglio Salvatore , Stadlmann Sylvia , Spagnoli Giulio C. , Droeser Raoul A. , Singer Gad
Published: November 2021

Background: Ovarian cancer (OC) is the most aggressive and fatal malignancy of the female reproductive system. Debulking surgery with adjuvant chemotherapy represents the standard treatment, but recurrence rates are particularly high. Over the past decades, the association between the immune system and cancer progression has been extensively investigated. However, the interaction between chemotherapy and cancer immune infiltration is still unclear. In this study, we examined the prognostic role of CD16 expression in OC, as related to the effectiveness of standard adjuvant chemotherapy treatment. Methods: We analyzed the infiltration by immune cells expressing CD16, a well-characterized natural killer (NK) and myeloid cell marker, in a tissue microarray (TMA) of 47 patient specimens of primary OCs and their matching recurrences by immunohistochemistry (IHC). We analyzed our data first in the whole cohort, then in the primary tumors, and finally in recurrences. We focused on recurrence-free survival (RFS), overall survival (OS), and chemosensitivity. Chemosensitivity was defined as RFS of more than 6 months. Results: There was no significant correlation between CD16 expression and prognosis in primary carcinomas. However, interestingly, a high density of CD16-expressing tumor-infiltrating immune cells (TICs) in recurrent carcinoma was associated with better RFS (p = 0.008) and OS (p = 0.029). Moreover, high CD16 cell density in recurrent ovarian carcinoma showed a significant association with chemosensitivity (p = 0.034). Univariate Cox regression analysis revealed that the high expression of CD16+ TIC in recurrent cancer biopsies is significantly associated with an increased RFS (HR = 0.49; 95% CI 0.24–0.99; p = 0.047) and OS (HR = 0.28; 95% CI 0.10–0.77; p = 0.013). However, this was not independent of known prognostic factors such as age, FIGO stage, resection status, and the number of chemotherapy cycles. Conclusions: The high density of CD16-expressing TICs in recurrent ovarian cancer is associated with a better RFS and OS, thereby suggesting a previously unsuspected interaction between standard OC chemotherapy and immune cell infiltration.
Charting the Unknown Association of COVID-19 with Thyroid Cancer, Focusing on Differentiated Thyroid Cancer: A Call for Caution
Authors: Deligiorgi Maria V. , Siasos Gerasimos , Vakkas Lampros , Trafalis Dimitrios T.
Published: November 2021

Background: Conceived of as the “silver lining” of the dark cloud of the coronavirus disease 2019 (COVID-19) pandemic, lessons taught by this catastrophe should be leveraged by medical authorities and policy makers to optimize health care globally. A major lesson is that resilient health systems should absorb sudden shocks incited by overwhelming health emergencies without compromising the continuum of care of chronic diseases, especially of cancer. Methods: The present review dissects the association between COVID-19 and thyroid cancer (TC), especially with differentiated TC (DTC), focusing on available data, knowledge gaps, current challenges, and future perspectives. Results: Obesity has been incriminated in terms of both COVID-19 severity and a rising incidence of TC, especially of DTC. The current conceptualization of the pathophysiological landscape of COVID-19–(D)TC association implicates an interplay between obesity, inflammation, immunity, and oxidative stress. Whether COVID-19 could aggravate the health burden posed by (D)TC or vice versa has yet to be clarified. Improved understanding and harnessing of the pathophysiological landscape of the COVID-19–(D)TC association will empower a mechanism-guided, safe, evidence-based, and risk-stratified management of (D)TC in the COVID-19 era and beyond. Conclusion: A multidisciplinary patient-centered decision-making will ensure high-quality (D)TC care for patients, with or without COVID-19.
Theoretical Study on Ethylene Polymerization Catalyzed by Half-Titanocenes Bearing Different Ancillary Groups
Authors: Li Yang , Lai Xiaoling , Xu Xiaowei , So Yat-Ming , Du Yijing , Zhang Zhengze , Pan Yu
Published: November 2021

Half-titanocenes are well known to show high activity for ethylene polymerization and good capability for copolymerization of ethylene with other olefins, and the ancillary ligands can crucially affect the catalytic performance. In this paper, the mechanisms of ethylene polymerization catalyzed by three half-metallocenes, (η5-C5Me5)TiCl2(O-2,6-iPr2C6H3) (1), (η5-C5Me5)TiCl2(N=CtBu2) (2) and [Me2Si(η5-C5Me4)(NtBu)]TiCl2 (3), have been investigated by density functional theory (DFT) method. At the initiation stage, a higher free energy barrier was determined for complex 1, probably due to the presence of electronegative O atom in phenoxy ligand. At the propagation stage, front-side insertion of the second ethylene is kinetically more favorable than back-side insertion for complexes 1 and 2, while both side insertion orientations are comparable for complex 3. The energy decomposition showed that the bridged cyclopentadienyl amide ligand could enhance the rigidity of the active species as suggested by the lowest deformation energy derived from 3. At the chain termination stage, β-H transfer was calculated to be a dominant chain termination route over β-H elimination, presumably owing to the thermodynamic perspective.
Signaling through the S1P−S1PR Axis in the Gut, the Immune and the Central Nervous System in Multiple Sclerosis: Implication for Pathogenesis and Treatment
Authors: Chatzikonstantinou Simela , Poulidou Vasiliki , Arnaoutoglou Marianthi , Kazis Dimitrios , Heliopoulos Ioannis , Grigoriadis Nikolaos , Boziki Marina
Published: November 2021

Sphingosine 1-phosphate (S1P) is a signaling molecule with complex biological functions that are exerted through the activation of sphingosine 1-phosphate receptors 1–5 (S1PR1–5). S1PR expression is necessary for cell proliferation, angiogenesis, neurogenesis and, importantly, for the egress of lymphocytes from secondary lymphoid organs. Since the inflammatory process is a key element of immune-mediated diseases, including multiple sclerosis (MS), S1PR modulators are currently used to ameliorate systemic immune responses. The ubiquitous expression of S1PRs by immune, intestinal and neural cells has significant implications for the regulation of the gut–brain axis. The dysfunction of this bidirectional communication system may be a significant factor contributing to MS pathogenesis, since an impaired intestinal barrier could lead to interaction between immune cells and microbiota with a potential to initiate abnormal local and systemic immune responses towards the central nervous system (CNS). It appears that the secondary mechanisms of S1PR modulators affecting the gut immune system, the intestinal barrier and directly the CNS, are coordinated to promote therapeutic effects. The scope of this review is to focus on S1P−S1PR functions in the cells of the CNS, the gut and the immune system with particular emphasis on the immunologic effects of S1PR modulation and its implication in MS.