bluuebunny/crossref_metadata_2025 huggingface dataset:
Immediate Effects of Anti-Spastic Epidural Cervical Spinal Cord Stimulation on Functional Connectivity of the Central Motor System in Patients with Stroke- and Traumatic Brain Injury-Induced Spasticity: A Pilot Resting-State Functional Magnetic Resonance Imaging Study
Authors: Mayorova Larisa , Radutnaya Margarita , Varyukhina Maria , Vorobyev Alexey , Zhdanov Vasiliy , Petrova Marina , Grechko Andrey
Published: August 2023

Objective: Spinal cord stimulation (SCS) is one approach to the potential improvement of patients with post-stroke or post-traumatic spasticity. However, little is known about whether and how such interventions alter supraspinal neural systems involved in the pathogenesis of spasticity. This pilot study investigated whether epidural spinal cord stimulation at the level of the C3–C5 cervical segments, aimed at reducing spasticity, alters the patterns of functional connectivity of the brain. Methods: Eight patients with spasticity in the right limbs as a result of left cerebral hemisphere damage (due to hemorrhagic and ischemic stroke or traumatic and anoxic brain injury) were assessed with fMRI immediately before and immediately after short-term (1 to 6 days) test cervical epidural SCS therapy. Eight demographically and clinically comparable patients with spasticity in the right extremities due to a left hemisphere ischemic stroke and brain injury who received conventional therapy were examined as a control group. All patients also had paresis of one or two limbs and hyperreflexia. Results: After the SCS therapy, there were three main findings: (1) higher functional connectivity of the brainstem to the right premotor cortex and changes in functional connectivity between cortical motor areas, (2) increased functional connectivity between the right and left lateral nodes of the sensorimotor network, and (3) a positive correlation between decreased spasticity in the right leg and increased functional connectivity within the right hemisphere sensorimotor cortex. All these changes in functional connectivity occurred with a statistically significant decrease in spasticity, as assessed using the modified Ashworth scale. The control group showed no decrease in spasticity or increase in functional connectivity in any of the seeds of interest. On the contrary, a decrease in functional connectivity of the brainstem and right postcentral gyrus was observed in this group during the observation period. Conclusions: We were thus able to detect intrinsic brain connectivity rearrangements that occurred during spasticity mitigation following short epidural SCS therapy. Significance: The clinical results obtained confirmed the efficacy of short-term anti-spastic SCS therapy. The obtained data on functional rearrangements of the central motor system may shed light on the mechanism of antispastic action of this procedure.
Laser Scribing Turns Plastic Waste into a Biosensor via the Restructuration of Nanocarbon Composites for Noninvasive Dopamine Detection
Authors: Suriyaprakash Jagadeesh , Huang Yang , Hu Zhifei , Wang Hao , Zhan Yiyu , Zhou Yangtao , Thangavelu Indumathi , Wu Lijun
Published: August 2023

The development of affordable and compact noninvasive point-of-care (POC) dopamine biosensors for the next generation is currently a major and challenging problem. In this context, a highly sensitive, selective, and low-cost sensing probe is developed by a simple one-step laser-scribing process of plastic waste. A flexible POC device is developed as a prototype and shows a highly specific response to dopamine in the real sample (urine) as low as 100 pmol/L in a broad linear range of 10−10–10−4 mol/L. The 3D topological feature, carrier kinetics, and surface chemistry are found to improve with the formation of high-density metal-embedded graphene-foam composite driven by laser irradiation on the plastic-waste surface. The development of various kinds of flexible and tunable biosensors by plastic waste is now possible thanks to the success of this simple, but effective, laser-scribing technique, which is capable of modifying the matrix’s electronic and chemical composition.
Fluorescent Probes for Mammalian Thioredoxin Reductase: Mechanistic Analysis, Construction Strategies, and Future Perspectives
Authors: Song Zilong , Fan Chengwu , Zhao Jintao , Wang Lei , Duan Dongzhu , Shen Tong , Li Xinming
Published: August 2023

The modulation of numerous signaling pathways is orchestrated by redox regulation of cellular environments. Maintaining dynamic redox homeostasis is of utmost importance for human health, given the common occurrence of altered redox status in various pathological conditions. The cardinal component of the thioredoxin system, mammalian thioredoxin reductase (TrxR) plays a vital role in supporting various physiological functions; however, its malfunction, disrupting redox balance, is intimately associated with the pathogenesis of multiple diseases. Accordingly, the dynamic monitoring of TrxR of live organisms represents a powerful direction to facilitate the comprehensive understanding and exploration of the profound significance of redox biology in cellular processes. A number of classic assays have been developed for the determination of TrxR activity in biological samples, yet their application is constrained when exploring the real-time dynamics of TrxR activity in live organisms. Fluorescent probes offer several advantages for in situ imaging and the quantification of biological targets, such as non-destructiveness, real-time analysis, and high spatiotemporal resolution. These benefits facilitate the transition from a poise to a flux understanding of cellular targets, further advancing scientific studies in related fields. This review aims to introduce the progress in the development and application of TrxR fluorescent probes in the past years, and it mainly focuses on analyzing their reaction mechanisms, construction strategies, and potential drawbacks. Finally, this study discusses the critical challenges and issues encountered during the development of selective TrxR probes and proposes future directions for their advancement. We anticipate the comprehensive analysis of the present TrxR probes will offer some glitters of enlightenment, and we also expect that this review may shed light on the design and development of novel TrxR probes.
Smartphone-Based Rigid Endoscopy Device with Hemodynamic Response Imaging and Laser Speckle Contrast Imaging
Authors: Kim Youngkyu , Choi Woo June , Oh Jeongmin , Lee Kwanhee , Kim Jun Ki
Published: August 2023

Modern smartphones have been employed as key elements in point-of-care (POC) devices due to remarkable advances in their form factor, computing, and display performances. Recently, we reported a combination of the smartphone with a handheld endoscope using laser speckle contrast imaging (LSCI), suggesting potential for functional POC endoscopy. Here, we extended our work to develop a smartphone-combined multifunctional handheld endoscope using dual-wavelength LSCI. Dual-wavelength LSCI is used to monitor the changes in dynamic blood flow as well as changes in the concentration of oxygenated (HbO2), deoxygenated (Hbr), and total hemoglobin (HbT). The smartphone in the device performs fast acquisition and computation of the raw LSCI data to map the blood perfusion parameters. The flow imaging performance of the proposed device was tested with a tissue-like flow phantom, exhibiting a speckle flow index map representing the blood perfusion. Furthermore, the device was employed to assess the blood perfusion status from an exteriorized intestine model of rat in vivo during and after local ischemia, showing that blood flow and HbO2 gradually decreased in the ischemic region whereas hyperemia and excess increases in HbO2 were observed in the same region right after reperfusion. The results indicate that the combination of LSCI with smartphone endoscopy delivers a valuable platform for better understanding of the functional hemodynamic changes in the vasculatures of the internal organs, which may benefit POC testing for diagnosis and treatment of vascular diseases.
The Association between Pesticide Exposure and the Development of Fronto-Temporal Dementia-Cum-Dissociative Disorders: A Review
Authors: Flores-Gutierrez Carlos Alfonso , Torres-Sanchez Erandis Dheni , Reyes-Uribe Emmanuel , Torres-Jasso Juan Heriberto , Reyna-Villela Mireya Zoila , Rojas-Bravo Daniel , Salazar-Flores Joel
Published: August 2023

Pesticides are chemicals used in agricultural fields for the prevention or destruction of pests. Inappropriate use of these substances, as well as handling them without using personal protective equipment, may result in serious health problems such as neurodegenerative diseases and mental disorders. Previous studies have demonstrated the adverse effects of pesticides on brain function. However, some researchers have associated pesticide poisoning with the development of disorders such as dissociative amnesia, multiple personality disorders, and depersonalization disorder. The objective of this work was to perform a bibliographic review of the relationship between pesticide poisoning and the development of dissociative disorders. Previous studies suggest that the duration of pesticide exposure is a major determinant in the development of dissociative diseases and disorders. The information obtained in this review suggests that there is no specific relationship between dissociative disorders and pesticide poisoning. However, these results point to associating the most representative symptoms of dissociative disorder (such as amnesia and memory loss) with pesticide exposure. Based on the bibliographic search, possible mechanisms of action were suggested in an attempt to explain a possible association between exposure to pesticides and the appearance of dissociative disorders.
Is Hearing Loss a Risk Factor for Idiopathic Parkinson’s Disease? An English Longitudinal Study of Ageing Analysis
Authors: Readman Megan Rose , Wan Fang , Fairman Ian , Linkenauger Sally A. , Crawford Trevor J. , Plack Christopher J.
Published: August 2023

Observations that hearing loss is a substantial risk factor for dementia may be accounted for by a common pathology. Mitochondrial oxidative stress and alterations in α-synuclein pathology may be common pathology candidates. Crucially, these candidate pathologies are implicated in Parkinson’s disease (PD). Consequently, hearing loss may be a risk factor for PD. Subsequently, this prospective cohort study of the English Longitudinal Study of Ageing examines whether hearing loss is a risk factor for PD longitudinally. Participants reporting self-reported hearing capabilities and no PD diagnosis prior to entry (n = 14,340) were used. A joint longitudinal and survival model showed that during a median follow up of 10 years (SD = 4.67 years) increased PD risk (p < 0.001), but not self-reported hearing capability (p = 0.402). Additionally, an exploratory binary logistic regression modelling the influence of hearing loss identified using a screening test (n = 4812) on incident PD indicated that neither moderate (p = 0.794), nor moderately severe/severe hearing loss (p = 0.5210), increased PD risk, compared with normal hearing. Whilst discrepancies with prior literature may suggest a neurological link between hearing loss and PD, further large-scale analyses using clinically derived hearing loss are needed.
The Role of Serotonin in Fear Learning and Memory: A Systematic Review of Human Studies
Authors: Tortora Francesco , Hadipour Abed L. , Battaglia Simone , Falzone Alessandra , Avenanti Alessio , Vicario Carmelo M.
Published: August 2023

Fear is characterized by distinct behavioral and physiological responses that are essential for the survival of the human species. Fear conditioning (FC) serves as a valuable model for studying the acquisition, extinction, and expression of fear. The serotonin (5-hydroxytryptamine, 5-HT) system is known to play a significant role in emotional and motivational aspects of human behavior, including fear learning and expression. Accumulating evidence from both animal and human studies suggests that brain regions involved in FC, such as the amygdala, hippocampus, and prefrontal cortex, possess a high density of 5-HT receptors, implicating the crucial involvement of serotonin in aversive learning. Additionally, studies exploring serotonin gene polymorphisms have indicated their potential influence on FC. Therefore, the objective of this work was to review the existing evidence linking 5-HT with fear learning and memory in humans. Through a comprehensive screening of the PubMed and Web of Science databases, 29 relevant studies were included in the final review. These studies investigated the relationship between serotonin and fear learning using drug manipulations or by studying 5-HT-related gene polymorphisms. The results suggest that elevated levels of 5-HT enhance aversive learning, indicating that the modulation of serotonin 5-HT2A receptors regulates the expression of fear responses in humans. Understanding the role of this neurochemical messenger in associative aversive learning can provide insights into psychiatric disorders such as anxiety and post-traumatic stress disorder (PTSD), among others.
Investigation of Cross-Language and Stimulus-Dependent Effects on the McGurk Effect with Finnish and Japanese Speakers and Listeners
Authors: Tiippana Kaisa , Ujiie Yuta , Peromaa Tarja , Takahashi Kohske
Published: August 2023

In the McGurk effect, perception of a spoken consonant is altered when an auditory (A) syllable is presented with an incongruent visual (V) syllable (e.g., A/pa/V/ka/ is often heard as /ka/ or /ta/). The McGurk effect provides a measure for visual influence on speech perception, becoming stronger the lower the proportion of auditory correct responses. Cross-language effects are studied to understand processing differences between one’s own and foreign languages. Regarding the McGurk effect, it has sometimes been found to be stronger with foreign speakers. However, other studies have shown the opposite, or no difference between languages. Most studies have compared English with other languages. We investigated cross-language effects with native Finnish and Japanese speakers and listeners. Both groups of listeners had 49 participants. The stimuli (/ka/, /pa/, /ta/) were uttered by two female and male Finnish and Japanese speakers and presented in A, V and AV modality, including a McGurk stimulus A/pa/V/ka/. The McGurk effect was stronger with Japanese stimuli in both groups. Differences in speech perception were prominent between individual speakers but less so between native languages. Unisensory perception correlated with McGurk perception. These findings suggest that stimulus-dependent features contribute to the McGurk effect. This may have a stronger influence on syllable perception than cross-language factors.
Depression and Pseudodementia: Decoding the Intricate Bonds in an Italian Outpatient Setting
Authors: Buccianelli Beatrice , Marazziti Donatella , Arone Alessandro , Palermo Stefania , Simoncini Marly , Carbone Manuel Glauco , Massoni Leonardo , Violi Miriam , Dell’Osso Liliana
Published: August 2023

In spite of the uncertainties of its diagnostic framework, pseudodementia may be conceptualized as a condition characterized by depressive symptoms and cognitive impairment in the absence of dementia. Given the controversies on this topic, the aim of the present study was to assess neurological and cognitive dysfunctions in a sample of elderly depressed subjects, and the eventual relationship between cognitive impairment and depressive symptoms. Fifty-seven elderly depressed outpatients of both sexes were included in the study. A series of rating scales were used to assess diagnoses, depressive and cognitive impairment. Comparisons for continuous variables were performed with the independent-sample Student’s t-test. Comparisons for categorical variables were conducted by the χ2 test (or Fisher’s exact test when appropriate). The correlations between between socio-demographic characteristics and clinical features, as well as between cognitive impairment and depressive symptoms were explored by Pearson’s correlation coefficient or Spearman’s rank correlation. Our data showed the presence of a mild–moderate depression and of a mild cognitive impairment that was only partially related to the severity of depression. These dysfunctions became more evident when analyzing behavioral responses, besides cognitive functions. A high educational qualification seemed to protect against cognitive decline, but not against depression. Single individuals were more prone to cognitive disturbance but were similar to married subjects in terms of the severity of depressive symptoms. Previous depressive episodes had no impact on the severity of depression or cognitive functioning. Although data are needed to draw firm conclusions, our findings strengthen the notion that pseudodementia represents a borderline condition between depression and cognitive decline that should be rapidly identified and adequately treated.
Temporal Feature Extraction and Machine Learning for Classification of Sleep Stages Using Telemetry Polysomnography
Authors: Lal Utkarsh , Mathavu Vasanthsena Suhas , Hoblidar Anitha
Published: August 2023

Accurate sleep stage detection is crucial for diagnosing sleep disorders and tailoring treatment plans. Polysomnography (PSG) is considered the gold standard for sleep assessment since it captures a diverse set of physiological signals. While various studies have employed complex neural networks for sleep staging using PSG, our research emphasises the efficacy of a simpler and more efficient architecture. We aimed to integrate a diverse set of feature extraction measures with straightforward machine learning, potentially offering a more efficient avenue for sleep staging. We also aimed to conduct a comprehensive comparative analysis of feature extraction measures, including the power spectral density, Higuchi fractal dimension, singular value decomposition entropy, permutation entropy, and detrended fluctuation analysis, coupled with several machine-learning models, including XGBoost, Extra Trees, Random Forest, and LightGBM. Furthermore, data augmentation methods like the Synthetic Minority Oversampling Technique were also employed to rectify the inherent class imbalance in sleep data. The subsequent results highlighted that the XGBoost classifier, when used with a combination of all feature extraction measures as an ensemble, achieved the highest performance, with accuracies of 87%, 90%, 93%, 96%, and 97% and average F1-scores of 84.6%, 89%, 90.33%, 93.5%, and 93.5% for distinguishing between five-stage, four-stage, three-stage, and two distinct two-stage sleep configurations, respectively. This combined feature extraction technique represents a novel addition to the body of research since it achieves higher performance than many recently developed deep neural networks by utilising simpler machine-learning models.
Active Parental Mediation and Adolescent Problematic Internet Use: The Mediating Role of Parent–Child Relationships and Hiding Online Behavior
Authors: Liu Jingjing , Wu Li , Sun Xiaojun , Bai Xuqing , Duan Changying
Published: August 2023

In today’s information society, with the growing integration of the Internet into individuals’ lives, problematic Internet use (PIU) among adolescents has become more prevalent. Therefore, we conducted this study to investigate the correlation between active parental mediation and PIU in adolescents, as well as the potential mediating roles of parent–child relationship and adolescents’ hiding online behavior. A total of 539 middle school students (mean age = 13.384) were recruited for this study and participated by completing a series of paper-and-pencil questionnaires. The findings indicated a significant negative relationship between active parental mediation and PIU. Furthermore, both the mediating role of the parent–child relationship and the role of hiding online behavior were found to be significant. Specifically, the mediating role is comprised of two paths: the independent mediating role of the parent–child relationship, and the sequential mediating role involving both the parent–child relationship and hiding online behavior. The study contributes an innovative theoretical perspective to deepen the understanding of the formation mechanism of PIU. Moreover, it offers practical empirical insights for the prevention and intervention of PIU among adolescents.
Bimanual Movement Characteristics and Real-World Performance Following Hand–Arm Bimanual Intensive Therapy in Children with Unilateral Cerebral Palsy
Authors: Gardas Shailesh S. , Lysaght Christine , McMillan Amy Gross , Kantak Shailesh , Willson John D. , Patterson Charity G. , Surkar Swati M.
Published: August 2023

The purpose of this study was to quantify characteristics of bimanual movement intensity during 30 h of hand–arm bimanual intensive therapy (HABIT) and bimanual performance (activities and participation) in real-world settings using accelerometers in children with unilateral cerebral palsy (UCP). Twenty-five children with UCP participated in a 30 h HABIT program. Data were collected from bilateral wrist-worn accelerometers during 30 h of HABIT to quantify the movement intensity and three days pre- and post-HABIT to assess real-world performance gains. Movement intensity and performance gains were measured using six standard accelerometer-derived variables. Bimanual capacity (body function and activities) was assessed using standardized hand function tests. We found that accelerometer variables increased significantly during HABIT, indicating increased bimanual symmetry and intensity. Post-HABIT, children demonstrated significant improvements in all accelerometer metrics, reflecting real-world performance gains. Children also achieved significant and clinically relevant changes in hand capacity following HABIT. Therefore, our findings suggest that accelerometers can objectively quantify bimanual movement intensity during HABIT. Moreover, HABIT enhances hand function as well as activities and participation in real-world situations in children with UCP.
The Sensitivity of Global Structural Parameters for Unreinforced Masonry Buildings Subjected to Simulated Ground Motions
Authors: Koc Ahmet Bahadir , Erberik Murat Altug , Askan Aysegul , Karimzadeh Shaghayegh
Published: August 2023

This research performs a parametric study based on Equivalent Single Degree of Freedom (ESDOF) models for simplified seismic analysis of unreinforced masonry (URM) structures. This is a necessary action due to the fact that it is not affordable to model and analyze populations of masonry buildings by using detailed continuum-based models during regional seismic damage and loss estimation studies. Hence, this study focuses on the sensitivity of major structural parameters of a selected idealized hysteretic model for URM buildings. The numerical models are subjected to region-specific simulated ground motion time histories generated using validated seismological parameters. The variations in dynamic analysis results are evaluated using statistical tools for major structural and seismological parameters. The results reveal that the strength factor is the most influential structural parameter, whereas magnitude and distance have a significant impact on the response of idealized URM models as seismological parameters. Furthermore, the specific seismic performance exhibiting limited ductility capacity and the narrow margin of safety between the initial state of inelastic behavior and the ultimate (collapse) state for URM buildings is verified by the statistical approaches employed in this study.
Effect of Cu on Performance of Self-Dispersing Ni-Catalyst in Production of Carbon Nanofibers from Ethylene
Authors: Afonnikova Sofya D. , Bauman Yury I. , Stoyanovskii Vladimir O. , Volochaev Mikhail N. , Mishakov Ilya V. , Vedyagin Aleksey A.
Published: August 2023

The development of effective catalysts for the pyrolysis of light hydrocarbons with the production of carbon nanomaterials represents a relevant direction. In the present work, the influence of copper addition on performance of a self-dispersed Ni-catalyst and structural features of the obtained carbon nanofibers (CNFs) was studied. The precursors of Ni and Ni-Cu catalysts were prepared by activation of metal powders in a planetary mill. During contact with the C2H4/H2 reaction mixture, a rapid disintegration of the catalysts with the formation of active particles catalyzing the growth of CNFs has occurred. The kinetics of CNF accumulation during ethylene decomposition on Ni- and Ni-Cu catalysts was studied. The effect of temperature on catalytic performance was explored and it was shown that introduction of copper promotes 1.5–2-fold increase in CNFs yield in the range of 525–600 °C; the maximum CNFs yield (100 g/gcat and above, for 30-min reaction) is reached on Ni-Cu-catalyst at 575–600 °C. A comparative analysis of the morphology and structure of CNF was carried out using electron microscopy methods. The growth mechanism of carbon filaments in the shape of “railway crossties” on large nickel crystals (d > 250 nm) was proposed. It was found that the addition of copper leads to a decrease in the bulk density of the carbon product from 40–60 to 25–30 g/L (at T = 550–600 °C). According to the low-temperature nitrogen adsorption data, specific surface area (SSA) of CNF samples (at T < 600 °C) lies in the range of 110–140 m2/g, regardless of the catalyst composition; at T = 600 °C the introduction of copper contributed to an increase in the specific surface of CNF by 100 m2/g.
Understanding Breast-Cancer-Associated Fibroblasts and Their Epigenetic Activation to Unveil Novel Targets for Breast Cancer Therapy
Authors: Ahmad Aamir
Published: August 2023

The review article ‘Cancer-Associated Fibroblasts: Epigenetic Regulation and Therapeutic Intervention in Breast Cancer’ by Lee et al [...]
Elevated Glycated Haemoglobin (HbA1c) Is Associated with an Increased Risk of Pancreatic Ductal Adenocarcinoma: A UK Biobank Cohort Study
Authors: McDonnell Declan , Cheang Adrian W. E. , Wilding Sam , Wild Sarah H. , Frampton Adam E. , Byrne Christopher D. , Hamady Zaed Z.
Published: August 2023

Background: The role of dysglycaemia as a risk marker for Pancreatic Ductal Adenocarcinoma (PDAC) is uncertain. We investigated the relationship between glycated haemoglobin (HbA1c) and incident PDAC using a retrospective cohort study within the UK Biobank. Methods: A study involving 499,804 participants from the UK Biobank study was undertaken. Participants were stratified by diabetes mellitus (DM) status, and then by HbA1c values < 42 mmol/mol, 42–47 mmol/mol, or ≥48 mmol/mol. Cox proportional hazard models were used to describe the association between HbA1c category (with time-varying interactions) and incident PDAC. Results: PDAC occurred in 1157 participants during 11.6 (10.9–12.3) years follow up [(median (interquartile range)]. In subjects without known DM at baseline, 12 months after recruitment, the adjusted hazard ratios (aHR, 95% CI) for incident PDAC for HbA1c 42–47 mmol/mol compared to HbA1c < 42 mmol/mol (reference group) was 2.10 (1.31–3.37, p = 0.002); and was 8.55 (4.58–15.99, p < 0.001) for HbA1c ≥ 48 mmol/mol. The association between baseline HbA1c and incident PDAC attenuated with increasing duration of time of follow-up to PDAC diagnosis. Conclusions: Dysglycaemia detected by elevated HbA1c is associated with an increased risk of PDAC. The strength of the association between elevated HbA1c and incident PDAC is inversely proportional to the time from detecting dysglycaemia but remains significant for at least 60 months following HbA1c testing.
No Excess Cancer Risk among Veterinarians in Denmark, Finland, Iceland, Norway, and Sweden after the 1980s
Authors: Laakso Laura , Jokelainen Pikka , Houe Hans , Skjerve Eystein , Hansen Johnni , Lynge Elsebeth , Martinsen Jan-Ivar , Mehlum Ingrid Sivesind , Selander Jenny , Torfadóttir Jóhanna Eyrún , Weiderpass Elisabete , Heikkinen Sanna , Pukkala Eero
Published: August 2023

The cancer profile of veterinarians has received little research attention, despite the profession potentially being exposed to a wide range of known and suspected carcinogens. In this large-scale cohort study, we assessed cancer incidence in veterinarians in Denmark, Finland, Iceland, Norway, and Sweden, across more than 40 years (1961–2005). The cohort comprised 4708 veterinarians and 119,503 person-years at follow-up. The overall cancer incidence in veterinarians was close to the incidence in the total population in all countries and in all age groups. In male veterinarians, the standardized incidence ratios (SIR) in 1961–1990 were elevated for colon cancer (1.86, 95% confidence interval (CI) 1.39–2.44), prostate cancer (1.35, 95% CI 1.07–1.67), and especially skin melanoma (3.62, 95% CI 2.78–2.84), while there was no longer any statistically significant excess in the more recent follow-up period. Decreased SIRs were observed for lip cancer (0.11, 95% CI 0.00–0.62), laryngeal cancer (0.38, 95% CI 0.12–0.89), lung cancer (0.59, 95% CI 0.47–0.74), and stomach cancer (0.58, 95% CI 0.38–0.86), without a marked change in SIR over time. Non-significant excesses among male veterinarians were also observed in Hodgkin lymphoma (1961–1990 only), and leukaemia. This multi-country study indicates that there was an elevated incidence of several cancer types among male veterinarians before the 1990s but not after that. Some of the findings might rather be attributed to lifestyle factors and not directly to work conditions, but the excess risk of cancers of kidney and bladder, for example, might be related to work exposures.
Human Papillomavirus-Associated Oropharyngeal Cancer: Global Epidemiology and Public Policy Implications
Authors: Ndon Sifon , Singh Amritpal , Ha Patrick K. , Aswani Joyce , Chan Jason Ying-Kuen , Xu Mary Jue
Published: August 2023

Global trends in human papillomavirus (HPV)-associated head and neck cancers (HNC), specifically in the oropharynx subsite, have been dynamically changing, leading to new staging and treatment paradigms. Epidemiologic studies have noted regional variations in HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). While HPV vaccination remains the main preventative approach, vaccination policy in relation to gender neutrality is heterogeneous and particularly sparse in low- and middle-income countries, where the burden of global cancer cases and HPV-associated HNC are not well-characterized in certain regions. This review summarizes the existing literature on regional variations of HPV-associated OPSCC and gender-neutral vaccine policies. Based on available data, the incidence of HPV-associated OPSCC is highest in North America, Europe, and Oceania. As of 2022, 122 of 195 (63%) World Health Organization (WHO) member states had incorporated HPV vaccinations nationally; of these, 41 of 122 (34%) member states have introduced gender-neutral vaccine coverage. Future research is needed to describe continued evolving trends in HPV-associated OPSCC, understand underlying risk factors leading to regional variation in disease, and implement gender-neutral policy more broadly.
Evaluation of Systemic Treatment Options for Gastrointestinal Stromal Tumours
Authors: Golčić Marin , Jones Robin L. , Huang Paul , Napolitano Andrea
Published: August 2023

Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract. Surgical treatment is recommended for the majority of localised GIST, while systemic treatment is the cornerstone of management for metastatic or unresectable disease. While a three-year regimen of imatinib is the standard of care in the adjuvant setting, there is no precise recommendation for the duration of neoadjuvant treatment, where imatinib is usually given between 4 and 12 months. Continuous treatment with imatinib at a dose of 400 mg once per day is recommended for most patients with unresectable or metastatic GIST in the first line. An exception is represented by patients with tumours harbouring the imatinib-insensitive PDGFRA D842V mutation who would be better treated with avapritinib. Targeted therapies are also recommended in the presence of NTRK rearrangements and BRAF mutations, although limited data are available. While an increase in the dose of imatinib to 800 mg is an option for the second line, sunitinib is usually considered the standard of care. Similar outcomes were reported for ripretinib in patients with tumours harbouring KIT exon 11 mutation, with significantly fewer side effects. Regorafenib and ripretinib are the standards of care in the third and fourth lines, respectively. The recent development of various systemic treatment options allows for a more personalised approach based on the molecular profile of the GIST, patient characteristics, and the profile of medications’ adverse events. A multidisciplinary approach is paramount since combining systemic treatment with locoregional treatment options and supportive care is vital for long-term survival.
Development and Validation of a Predictive Model for Metastatic Melanoma Patients Treated with Pembrolizumab Based on Automated Analysis of Whole-Body [18F]FDG PET/CT Imaging and Clinical Features
Authors: Dirks Ine , Keyaerts Marleen , Dirven Iris , Neyns Bart , Vandemeulebroucke Jef
Published: August 2023

Background: Antibodies that inhibit the programmed cell death protein 1 (PD-1) receptor offer a significant survival benefit, potentially cure (i.e., durable disease-free survival following treatment discontinuation), a substantial proportion of patients with advanced melanoma. Most patients however fail to respond to such treatment or acquire resistance. Previously, we reported that baseline total metabolic tumour volume (TMTV) determined by whole-body [18F]FDG PET/CT was independently correlated with survival and able to predict the futility of treatment. Manual delineation of [18F]FDG-avid lesions is however labour intensive and not suitable for routine use. A predictive survival model is proposed based on automated analysis of baseline, whole-body [18F]FDG images. Methods: Lesions were segmented on [18F]FDG PET/CT using a deep-learning approach and derived features were investigated through Kaplan–Meier survival estimates with univariate logrank test and Cox regression analyses. Selected parameters were evaluated in multivariate Cox survival regressors. Results: In the development set of 69 patients, overall survival prediction based on TMTV, lactate dehydrogenase levels and presence of brain metastases achieved an area under the curve of 0.78 at one year, 0.70 at two years. No statistically significant difference was observed with respect to using manually segmented lesions. Internal validation on 31 patients yielded scores of 0.76 for one year and 0.74 for two years. Conclusions: Automatically extracted TMTV based on whole-body [18F]FDG PET/CT can aid in building predictive models that can support therapeutic decisions in patients treated with immune-checkpoint blockade.
Selecting Optimal Proton Pencil Beam Scanning Plan Parameters to Reduce Dose Discrepancy between Discrete Spot Plan and Continuous Scanning: A Proof-of-Concept Study
Authors: Liang Xiaoying , Beltran Chris J. , Liu Chunbo , Park Chunjoo , Lu Bo , Yaddanapudi Sridhar , Tan Jun , Furutani Keith M.
Published: August 2023

Pencil beam scanning delivered with continuous scanning has several advantages over conventional discrete spot scanning. Such advantages include improved beam delivery efficiency and reduced beam delivery time. However, a move dose is delivered between consecutive spots with continuous scanning, and current treatment planning systems do not take this into account. Therefore, continuous scanning and discrete spot plans have an inherent dose discrepancy. Using the operating parameters of the state-of-the-art particle therapy system, we conducted a proof-of-concept study in which we systematically generated 28 plans for cubic targets with different combinations of plan parameters and simulated the dose discrepancies between continuous scanning and a planned one. A nomograph to guide the selection of plan parameters was developed to reduce the dose discrepancy. The effectiveness of the nomograph was evaluated with two clinical cases (one prostate and one liver). Plans with parameters guided by the nomograph decreased dose discrepancy than those used standard plan parameters. Specifically, the 2%/2 mm gamma passing rate increased from 96.3% to 100% for the prostate case and from 97.8% to 99.7% for the liver case. The CTV DVH root mean square error decreased from 2.2% to 0.2% for the prostate case and from 1.8% to 0.9% for the liver case. The decreased dose discrepancy may allow the relaxing of the delivery constraint for some cases, leading to greater benefits in continuous scanning. Further investigation is warranted.
Identifying Significantly Perturbed Subnetworks in Cancer Using Multiple Protein–Protein Interaction Networks
Authors: Yang Le , Chen Runpu , Melendy Thomas , Goodison Steve , Sun Yijun
Published: August 2023

Background: The identification of cancer driver genes and key molecular pathways has been the focus of large-scale cancer genome studies. Network-based methods detect significantly perturbed subnetworks as putative cancer pathways by incorporating genomics data with the topological information of PPI networks. However, commonly used PPI networks have distinct topological structures, making the results of the same method vary widely when applied to different networks. Furthermore, emerging context-specific PPI networks often have incomplete topological structures, which pose serious challenges for existing subnetwork detection algorithms. Methods: In this paper, we propose a novel method, referred to as MultiFDRnet, to address the above issues. The basic idea is to model a set of PPI networks as a multiplex network to preserve the topological structure of individual networks, while introducing dependencies among them, and, then, to detect significantly perturbed subnetworks on the modeled multiplex network using all the structural information simultaneously. Results: To illustrate the effectiveness of the proposed approach, an extensive benchmark analysis was conducted on both simulated and real cancer data. The experimental results showed that the proposed method is able to detect significantly perturbed subnetworks jointly supported by multiple PPI networks and to identify novel modular structures in context-specific PPI networks.
Optimizing Boron Neutron Capture Therapy (BNCT) to Treat Cancer: An Updated Review on the Latest Developments on Boron Compounds and Strategies
Authors: Monti Hughes Andrea , Hu Naonori
Published: August 2023

Boron neutron capture therapy (BNCT) is a tumor-selective particle radiotherapy. It combines preferential boron accumulation in tumors and neutron irradiation. The recent initiation of BNCT clinical trials employing hospital-based accelerators rather than nuclear reactors as the neutron source will conceivably pave the way for new and more numerous clinical trials, leading up to much-needed randomized trials. In this context, it would be interesting to consider the implementation of new boron compounds and strategies that will significantly optimize BNCT. With this aim in mind, we analyzed, in this review, those articles published between 2020 and 2023 reporting new boron compounds and strategies that were proved therapeutically useful in in vitro and/or in vivo radiobiological studies, a critical step for translation to a clinical setting. We also explored new pathologies that could potentially be treated with BNCT and newly developed theranostic boron agents. All these radiobiological advances intend to solve those limitations and questions that arise during patient treatment in the clinical field, with BNCT and other therapies. In this sense, active communication between clinicians, radiobiologists, and all disciplines will improve BNCT for cancer patients, in a cost- and time-effective way.
Metastases of OSCC Based on Oral Lichen Ruber Planus
Authors: Obermeier Katharina Theresa , Wuersching Sabina Noreen , Liokatis Paris , Smolka Wenko , Poxleitner Philipp , Kleye Christin , Ehrenfeld Michael , Kollmuss Maximilian , Otto Sven
Published: August 2023

Oral lichen ruber planus (OLP) is a poorly understood chronically inflammatory disease of the oral mucosa. Malignant transformation into oral squamous cell carcinoma (OSCC) is reported in between 1–2% of cases in the literature. After malignant transformation, surgical treatment—meaning tumor resection combined with neck dissection—is recommended. The recommended extent of treatment is controversial in the literature because this kind of OSCC is often a highly differentiated tumor with a lower risk for lymph nodal spreading. This study aims to overview 103 patients treated in our department due to OLP. The primary outcome parameter was the development of metastases in OLP patients compared to a group of OSCC patients without OLP and the comparison of survival in between both groups. Statistical analysis showed a significantly lower risk for patients with OSCC and with OLP for lymph nodal spreading (p = 0.013). Patients with OSCC and without OLP had a 4.76-higher risk for lymph nodal spreading. On the other hand, second metachronous tumor occurred more often in patients with OSCC and OLP. Overall, OSCC based on OLP occurs more often in female patients, is more highly differentiated and comes with a lower risk for metastases but has a higher risk for second metachronous tumors. Therefore, special attention should be paid to patients with OSCC based on OLP when planning adjuvant therapy and clinical follow-up. The indication for postoperative radiation should be made cautiously in this case, and clinical controls should be performed more closely due to the risk of recurrent disease or tumors at different locations.
A Comprehensive Benchmark of Transcriptomic Biomarkers for Immune Checkpoint Blockades
Authors: Kang Hongen , Zhu Xiuli , Cui Ying , Xiong Zhuang , Zong Wenting , Bao Yiming , Jia Peilin
Published: August 2023

Immune checkpoint blockades (ICBs) have revolutionized cancer therapy by inducing durable clinical responses, but only a small percentage of patients can benefit from ICB treatments. Many studies have established various biomarkers to predict ICB responses. However, different biomarkers were found with diverse performances in practice, and a timely and unbiased assessment has yet to be conducted due to the complexity of ICB-related studies and trials. In this study, we manually curated 29 published datasets with matched transcriptome and clinical data from more than 1400 patients, and uniformly preprocessed these datasets for further analyses. In addition, we collected 39 sets of transcriptomic biomarkers, and based on the nature of the corresponding computational methods, we categorized them into the gene-set-like group (with the self-contained design and the competitive design, respectively) and the deconvolution-like group. Next, we investigated the correlations and patterns of these biomarkers and utilized a standardized workflow to systematically evaluate their performance in predicting ICB responses and survival statuses across different datasets, cancer types, antibodies, biopsy times, and combinatory treatments. In our benchmark, most biomarkers showed poor performance in terms of stability and robustness across different datasets. Two scores (TIDE and CYT) had a competitive performance for ICB response prediction, and two others (PASS-ON and EIGS_ssGSEA) showed the best association with clinical outcome. Finally, we developed ICB-Portal to host the datasets, biomarkers, and benchmark results and to implement the computational methods for researchers to test their custom biomarkers. Our work provided valuable resources and a one-stop solution to facilitate ICB-related research.
Expression of Claudins in Preneoplastic Conditions of the Gastrointestinal Tract: A Review
Authors: Ouban Abderrahman , Arabi Tarek Ziad
Published: August 2023

Premalignant lesions of the gastrointestinal tract are a group of disorders which act as the harbinger of malignant tumors. They are the ground-zero of neoplastic transformation, and their identification and management offer patients the best opportunity of blocking the progress of cancer. However, diagnoses of some of these conditions are hard to make, and their clinical importance is difficult to assess. Recent reports indicated that several claudin proteins have altered expressions in many cancers, including esophageal, gastric, colon, liver, and pancreatic cancers. The early identification of the aberrant expression of these proteins could lead to the early diagnosis and management of gastrointestinal tumors. Specifically, claudins -1, -2, -3, -4, and -18 are frequently overexpressed in gastrointestinal preneoplastic lesions. These altered expressions have shown clinical value in several tumors, providing diagnostic and prognostic information. In this article, we review the literature on the aberrant expression of claudins in preneoplastic lesions of the gastrointestinal tract. Additionally, we summarize their diagnostic and prognostic implications.
Effects of Difluorophenyl Substituents on Structural, Redox, and Magnetic Properties of Blatter Radicals
Authors: Gulyaev Dmitry , Serykh Andrey , Tretyakov Evgeny , Akyeva Anna , Syroeshkin Mikhail , Gorbunov Dmitry E. , Maltseva Svetlana V. , Gritsan Nina P. , Romanenko Galina , Bogomyakov Artem
Published: August 2023

Blatter radicals 1-(3,4-difluorophenyl)-(1a) and 1-(2,4-difluorophenyl)-3-phenyl-1,4-dihydrobenzo[e][1,2,4]triazin-4-yl (1b) were prepared in good yields through oxidation of the corresponding amidrazones using MnO2 in dry CH2Cl2. Cyclic voltammetry showed that both radicals are oxidized and reduced chemically and electrochemically reversibly in accordance with −1/0 and 0/+1 processes. EPR spectroscopy indicated that spin density is mainly delocalized on the triazinyl moiety of the heterocycle. The structure of all paramagnets was unambiguously confirmed by single-crystal X-ray diffraction, and two different 1D chains of alternating radicals were identified. 3,4-difluorophenyl-derivatives 1a are packed into columns composed of two kinds of alternating centrosymmetric dimers, having comparatively short intermolecular distances. In crystals of 2,4-difluorophenyl-derivative 1b, the parallel arrangement of bicyclic moieties and phenyl rings favors the formation of 1D regular chains wherein the radicals are related by translation parallel to the crystallographic stacking axis. Magnetic susceptibility measurements in the 2–300 K region showed that in crystals of the radicals, strong antiferromagnetic interactions are dominant. Subsequent fitting of the dependence of χT on T with 12-membered looped stacks gave the following best-fit parameters: for 1a, g = 2.01 ± 0.05, J1/kB = −292 ± 10 K (according to BS-DFT calculations J2 = 0.12 × J1 and J3 = 0.61 × J1); for 1b, g = 2.04 ± 0.01 J1/kB = −222 ± 17 K. For comparison, in a nonfluorinated related radical, there are only very weak intermolecular interactions along the columns (J/kB = −2.2 ± 0.2 K). These results illustrate the magnitude of the influence of the difluorophenyl substituents introduced into Blatter radicals on their structure and magnetic properties.