bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and Therapeutic Evaluation of the Ten Most Prevalent CRB1 Mutations
Authors: Lopes da Costa Bruna , Kolesnikova Masha , Levi Sarah R. , Cabral Thiago , Tsang Stephen H. , Maumenee Irene H. , Quinn Peter M. J.
Published: January 2023

Mutations in the Crumbs homolog 1 (CRB1) gene lead to severe inherited retinal dystrophies (IRDs), accounting for nearly 80,000 cases worldwide. To date, there is no therapeutic option for patients suffering from CRB1-IRDs. Therefore, it is of great interest to evaluate gene editing strategies capable of correcting CRB1 mutations. A retrospective chart review was conducted on ten patients demonstrating one or two of the top ten most prevalent CRB1 mutations and receiving care at Columbia University Irving Medical Center, New York, NY, USA. Patient phenotypes were consistent with previously published data for individual CRB1 mutations. To identify the optimal gene editing strategy for these ten mutations, base and prime editing designs were evaluated. For base editing, we adopted the use of a near-PAMless Cas9 (SpRY Cas9), whereas for prime editing, we evaluated the canonical NGG and NGA prime editors. We demonstrate that for the correction of c.2843G>A, p.(Cys948Tyr), the most prevalent CRB1 mutation, base editing has the potential to generate harmful bystanders. Prime editing, however, avoids these bystanders, highlighting its future potential to halt CRB1-mediated disease progression. Additional studies investigating prime editing for CRB1-IRDs are needed, as well as a thorough analysis of prime editing’s application, efficiency, and safety in the retina.
Biomimetic Construction of Artificial Selenoenzymes
Authors: Zhao Hanqing , Xu Chengchen , Wang Tingting , Liu Junqiu
Published: January 2023

Selenium exists in the form of selenocysteines in selenoproteins and plays a pivotal role in the catalytic process of the antioxidative enzymes. In order to study the structural and functional properties of selenium in selenoproteins, explore the significance of the role of selenium in the fields of biology and chemistry, scientists conducted a series of artificial simulations on selenoproteins. In this review, we sum up the progress and developed strategies in the construction of artificial selenoenzyme. Using different mechanisms from different catalytic angles, selenium-containing catalytic antibodies, semi-synthetic selenonezyme, and the selenium-containing molecularly imprinted enzymes have been constructed. A variety of synthetic selenoenzyme models have been designed and constructed by selecting host molecules such as cyclodextrins, dendrimers, and hyperbranched polymers as the main scaffolds. Then, a variety of selenoprotein assemblies as well as cascade antioxidant nanoenzymes were built by using electrostatic interaction, metal coordination, and host–guest interaction. The unique redox properties of selenoenzyme glutathione peroxidase (GPx) can be reproduced.
A Feasibility Study of Remote Non-Contact Vital Signs (NCVS) Monitoring in a Clinic Using a Novel Sensor Realized by Software-Defined Radio (SDR)
Authors: Liu Yang , Sweeney Clint , Mayeda Jill C. , Lopez Jerry , Lie Paul E. , Nguyen Tam Q. , Lie Donald Y. C.
Published: January 2023

The COVID-19 outbreak has caused panic around the world as it is highly infectious and has caused about 5 million deaths globally. A robust wireless non-contact vital signs (NCVS) sensor system that can continuously monitor the respiration rate (RR) and heart rate (HR) of patients clinically and remotely with high accuracy can be very attractive to healthcare workers (HCWs), as such a system can not only avoid HCWs’ close contact with people with COVID-19 to reduce the infection rate, but also be used on patients quarantined at home for telemedicine and wireless acute-care. Therefore, we developed a custom Doppler-based NCVS radar sensor system operating at 2.4 GHz using a software-defined radio (SDR) technology, and the novel biosensor system has achieved impressive real-time RR/HR monitoring accuracies within approximately 0.5/3 breath/beat per minute (BPM) on student volunteers tested in our engineering labs. To further test the sensor system’s feasibility for clinical use, we applied and obtained an Internal Review Board (IRB) approval from Texas Tech University Health Sciences Center (TTUHSC) and have used this NCVS monitoring system in a doctor’s clinic at TTUHSC; following testing on 20 actual patients for a small-scale clinical trial, we have found that the system was still able to achieve good NCVS monitoring accuracies within ~0.5/10 BPM across 20 patients of various weight, height and age. These results suggest our custom-designed NCVS monitoring system may be feasible for future clinical use to help combatting COVID-19 and other infectious diseases.
Wider and Stronger Inhibitory Ring of the Attentional Focus in Schizophrenia
Authors: Ronconi Luca , Florio Vincenzo , Bronzoni Silvia , Salvetti Beatrice , Raponi Agnese , Giupponi Giancarlo , Conca Andreas , Basso Demis
Published: January 2023

Anomalies of attentional selection have been repeatedly described in individuals with schizophrenia spectrum disorders. However, a precise analysis of their ability to inhibit irrelevant visual information during attentional selection is not documented. Recent behavioral as well as neurophysiological and computational evidence showed that attentional search among different competing stimuli elicits an area of suppression in the immediate surrounding of the attentional focus. In the present study, the strength and spatial extension of this surround suppression were tested in individuals with schizophrenia and neurotypical controls. Participants were asked to report the orientation of a visual “pop-out” target, which appeared in different positions within a peripheral array of non-target stimuli. In half of the trials, after the target appeared, a probe circle circumscribed a non-target stimulus at various target-to-probe distances; in this case, participants were asked to report the probe orientation instead. Results suggest that, as compared to neurotypical controls, individuals with schizophrenia showed stronger and spatially more extended filtering of visual information in the areas surrounding their attentional focus. This increased filtering of visual information outside the focus of attention might potentially hamper their ability to integrate different elements into coherent percepts and influence higher order behavioral, affective, and cognitive domains.
Current and Future Nano-Carrier-Based Approaches in the Treatment of Alzheimer’s Disease
Authors: Kumar Astik , Sudevan Sachithra Thazhathuveedu , Nair Aathira Sujathan , Singh Ashutosh Kumar , Kumar Sunil , Jose Jobin , Behl Tapan , Mangalathillam Sabitha , Mathew Bijo , Kim Hoon
Published: January 2023

It is a very alarming situation for the globe because 55 million humans are estimated to be affected by Alzheimer’s disease (AD) worldwide, and still it is increasing at the rapid speed of 10 million cases per year worldwide. This is an urgent reminder for better research and treatment due to the unavailability of a permanent medication for neurodegenerative disorders like AD. The lack of drugs for neurodegenerative disorder treatment is due to the complexity of the structure of the brain, mainly due to blood–brain barrier, because blood–brain drug molecules must enter the brain compartment. There are several novel and conventional formulation approaches that can be employed for the transportation of drug molecules to the target site in the brain, such as oral, intravenous, gene delivery, surgically implanted intraventricular catheter, nasal and liposomal hydrogels, and repurposing old drugs. A drug’s lipophilicity influences metabolic activity in addition to membrane permeability because lipophilic substances have a higher affinity for metabolic enzymes. As a result, the higher a drug’s lipophilicity is, the higher its permeability and metabolic clearance. AD is currently incurable, and the medicines available merely cure the symptoms or slow the illness’s progression. In the next 20 years, the World Health Organization (WHO) predicts that neurodegenerative illnesses affecting motor function will become the second-leading cause of mortality. The current article provides a brief overview of recent advances in brain drug delivery for AD therapy.
Amyloid-PET and White Matter Hyperintensities Have Independent Effects on Baseline Cognitive Function and Synergistic Effects on Longitudinal Executive Function
Authors: Ali Doaa G. , Abner Erin L. , Bahrani Ahmed A. , El Khouli Riham , Gold Brian T. , Jiang Yang , Wilcock Donna M. , Jicha Gregory A.
Published: January 2023

Co-occurrence of beta amyloid (Aβ) and white matter hyperintensities (WMHs) increase the risk of dementia and both are considered biomarkers of preclinical dementia. Moderation and mediation modeling were used to define the interplay between global and regional Aβ and WMHs measures in relation to executive function (EF) and memory composite scores outcomes at baseline and after approximately 2 years across a sample of 714 clinically normal participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI 2). The moderation regression analysis showed additive effects of Aβ and WMHs over baseline memory and EF scores (p = 0.401 and 0.061, respectively) and synergistic effects over follow-up EF (p < 0.05). Through mediation analysis, the data presented demonstrate that WMHs effects, mediated by global and regional amyloid burden, are responsible for baseline cognitive performance deficits in memory and EF. These findings suggest that Aβ and WMHs contribute to baseline cognition independently while WMHs volumes exert effects on baseline cognitive performance directly and through influences on Aβ accumulation.
Electrically Induced Sensory Trick in a Patient with Musician’s Dystonia: A Case Report
Authors: Nishida Daisuke , Mizuno Katsuhiro , Takahashi Osamu , Liu Meigen , Tsuji Tetsuya
Published: January 2023

A sensory trick is a specific maneuver that temporarily improves focal dystonia. We describe a case of musician’s dystonia in the right-hand fingers of a patient, who showed good and immediate improvement after using an electrical stimulation-mimicking sensory trick. A 49-year-old professional guitarist presented with chronic involuntary flexion of the right-hand third and fourth fingers that occurred during guitar performances. Electrical stimulation with a frequency of 40 Hz and an intensity of 1.5 times the sensory threshold was administered on the third and fourth fingernails of the right hand, which facilitated fluent guitar playing. While he played guitar with and without electrical stimulation, we measured the surface electromyograms (sEMG) of the right extensor digitorum and flexor digitorum superficialis muscles to evaluate the sensory-trick-like effects of electrical stimulation. This phenomenon can offer clues for developing electrical stimulation-based treatment devices for focal dystonia. Electrical stimulation has the advantage that it can be turned off to avoid habituation. Moreover, the device is easy to use and portable. These findings warrant further investigation into the use of sensory stimulation for treating focal dystonia.
Effects of Physical Interventions on Subjective Tinnitus, a Systematic Review and Meta-Analysis
Authors: Bousema Eric J. , Koops Elouise A. , van Dijk Pim , Dijkstra Pieter U.
Published: January 2023

Increasingly, patients suffering from subjective tinnitus seek help from physical therapists. Numerous randomised controlled trials (RCTs) have investigated the effect of physical interventions commonly used in physical therapy practice on subjective tinnitus. This systematic review and meta-analysis aimed to analyse the effects of physical interventions on tinnitus loudness, tinnitus annoyance, and scores on the Tinnitus Handicap Index (THI). Four databases were searched from inception up to March 2022. A total of 39 RCTs were included in the systematic review, and 23 studies were appropriate for meta-analyses. Risk of bias assessments were also performed. Interventions analysed in at least five studies were summarised, including transcutaneous electrical nerve stimulation (TENS), laser therapy, and acupuncture. Random-effects meta-analysis models were used, and effect sizes were expressed as Hedge’s standardised mean differences (SMD) with 95%CI’s. The quality of three-quarters of the studies was limited due to insufficient allocation concealment, lack of adequate blinding, and small sample sizes. Large, pooled effects sizes were found for acupuncture (SMD: 1.34; 95%CI: 0.79, 1.88) and TENS (SMD: 1.17; 95%CI: 0.48, 1.87) on THI as well as for acupuncture on tinnitus loudness (VAS Loudness (SMD: 0.84; 95%CI: 0.33, 1.36) and tinnitus annoyance (SMD: 1.18; 95%CI: 0.00, 2.35). There is some evidence that physical interventions (TENS and acupuncture, but not laser therapy) may be effective for tinnitus. However, the lack of high-quality studies and the risk of bias in many studies prohibits stronger conclusions.
Time Pressure Weakens Social Norm Maintenance in Third-Party Punishment
Authors: Zhou Xing , Wang Yanqing , He Weiqi , Li Shuaixia , Jia Shuxin , Feng Chunliang , Gu Ruolei , Luo Wenbo
Published: January 2023

Decision-making under time pressure may better reflect an individual’s response preference, but few studies have examined whether individuals choose to be more selfish or altruistic in a scenario where third-party punishment is essential for maintaining social norms. This study used a third-party punishment paradigm to investigate how time pressure impacts on individuals’ maintenance of behavior that follows social norms. Thirty-one participants observed a Dictator Game and had to decide whether to punish someone who made what was categorized as a high unfair offer by spending their own Monetary units to reduce that person’s payoff. The experiment was conducted across different offer conditions. The study results demonstrated that reaction times were faster under time pressure compared with no time pressure. Time pressure was also correlated with less severe punishment. Specifically, participants were less likely to punish the dictator under time pressure compared with no time pressure when the offer was categorized as a high unfair. The findings suggested that individuals in these game conditions and under time pressure do not overcome their pro-selves and that time pressure weakens an individual’s willingness to punish high unfair offers.
Effective Intracerebral Connectivity in Acute Stroke: A TMS–EEG Study
Authors: Tecchio Franca , Giambattistelli Federica , Porcaro Camillo , Cottone Carlo , Mutanen Tuomas P. , Pizzella Vittorio , Marzetti Laura , Ilmoniemi Risto J. , Vernieri Fabrizio , Rossini Paolo Maria
Published: January 2023

Stroke is a major cause of disability because of its motor and cognitive sequelae even when the acute phase of stabilization of vital parameters is overcome. The most important improvements occur in the first 8–12 weeks after stroke, indicating that it is crucial to improve our understanding of the dynamics of phenomena occurring in this time window to prospectively target rehabilitation procedures from the earliest stages after the event. Here, we studied the intracortical excitability properties of delivering transcranial magnetic stimulation (TMS) to the primary motor cortex (M1) of left and right hemispheres in 17 stroke patients who suffered a mono-lateral left hemispheric stroke, excluding pure cortical damage. All patients were studied within 10 days of symptom onset. TMS-evoked potentials (TEPs) were collected via a TMS-compatible electroencephalogram system (TMS–EEG) concurrently with motor-evoked responses (MEPs) induced in the contralateral first dorsal interosseous muscle. Comparison with age-matched healthy volunteers was made by collecting the same bilateral-stimulation data in nine healthy volunteers as controls. Excitability in the acute phase revealed relevant changes in the relationship between left lesioned and contralesionally right hemispheric homologous areas both for TEPs and MEPs. While the paretic hand displayed reduced MEPs compared to the non-paretic hand and to healthy volunteers, TEPs revealed an overexcitable lesioned hemisphere with respect to both healthy volunteers and the contra-lesion side. Our quantitative results advance the understanding of the impairment of intracortical inhibitory networks. The neuronal dysfunction most probably changes the excitatory/inhibitory on-center off-surround organization that supports already acquired learning and reorganization phenomena that support recovery from stroke sequelae.
An Automated Space-Based Graph Generation Framework for Building Energy Consumption Estimation
Authors: Kiavarz Hamid , Jadidi Mojgan , Rajabifard Abbas , Sohn Gunho
Published: January 2023

The 3D information in Building Information Modeling (BIM) has received significant interest for smart city applications. Recently, employing Industry Foundation Classes (IFC) for BIM in data-driven methods for Building Energy Consumption Estimation (BECE) has gained momentum because of the enriched geometric and semantic information. However, despite extensive studies on applying the IFC data in BECE analysis, employing the full potential of the BIM remains poor due to its complex data model and incompatibility with data-driven algorithms. This paper proposes a framework to extract accurate semantic, geometry, and topology information from the room-level (space) IFC schema by introducing new geo-computation algorithms to deal with these challenges. Additionally, we define a new topological weighted relationship between spaces in different stories by combining common geometry area with energy resistance value. Eventually, the proposed weighted space-based graph will be constructed to decrease the original complexity of the IFC model, and it is compatible with graph-based machine learning algorithms. The results are promising, with more than 90% accuracy in extracting the geometry information for the convex and non-convex polyhedron rooms and 100% accuracy in detecting vertical and horizontal adjacent rooms. This study confirms the proposed approach’s efficiency, accuracy, and feasibility for space-based BECE analysis.
Automatic Construction Hazard Identification Integrating On-Site Scene Graphs with Information Extraction in Outfield Test
Authors: Liu Xuan , Jing Xiaochuan , Zhu Quan , Du Wanru , Wang Xiaoyin
Published: January 2023

Construction hazards occur at any time in outfield test sites and frequently result from improper interactions between objects. The majority of casualties might be avoided by following on-site regulations. However, workers may be unable to comply with the safety regulations fully because of stress, fatigue, or negligence. The development of deep-learning-based computer vision and on-site video surveillance facilitates safety inspections, but automatic hazard identification is often limited due to the semantic gap. This paper proposes an automatic hazard identification method that integrates on-site scene graph generation and domain-specific knowledge extraction. A BERT-based information extraction model is presented to automatically extract the key regulatory information from outfield work safety requirements. Subsequently, an on-site scene parsing model is introduced for detecting interaction between objects in images. An automatic safety checking approach is also established to perform PPE compliance checks by integrating detected textual and visual relational information. Experimental results show that our proposed method achieves strong performance in various metrics on self-built and widely used public datasets. The proposed method can precisely extract relational information from visual and text modalities to facilitate on-site hazard identification.
Study on the Applicable Room Size Dimension of Stratum Ventilation for Heating Based on Multi-Criteria Analytic Hierarchy Process-Entropy Weight Model
Authors: Mao Yanhui , Xie Honglei , Zhang Xinlu , Hou Fumin , Wang Miantong
Published: January 2023

With the implementation of clean heating and the outbreak of COVID-19, stratum ventilation with both energy-saving and healthy indoor environments has become a research hotspot. Room size dimension is one of the critical factors affecting the air distribution, thermal comfort, and ventilation performance of space heating, which is still a research blank at present. This study determined the applicable room size dimension of stratum ventilation for space heating by using a multi-criteria analytic hierarchy process-entropy weight (AHP-EW) model. A computational fluid dynamics (CFD) simulation verified by experiments was conducted. To investigate the ventilation performance of different room sizes in energy utilization and thermal comfort, airflow distribution, ventilation efficiency (Et), dimensionless temperature, effective ventilation temperature (EDT), air distribution performance index (ADPI), and predicted mean vote (PMV) were calculated. The multi-criteria AHP-EW method is used to evaluate every case comprehensively. The results show that the maximum room size obtained by multi-criteria APH-EW is 6 m, and considering the single criteria, the suitable height for stratum ventilation for heating is below 5.7 m. The data obtained in this paper can be used as a reference for further study on the application of stratum ventilation and heating in the future.
Follicular Lymphoma in the 5th Edition of the WHO-Classification of Haematolymphoid Neoplasms—Updated Classification and New Biological Data
Authors: Kurz Katrin S. , Kalmbach Sabrina , Ott Michaela , Staiger Annette M. , Ott German , Horn Heike
Published: January 2023

The conceptual description of Follicular lymphoma (FL) in the 5th edition of the World Health Organization (WHO) classification of haematolymphoid tumors (WHO-HAEM5) has undergone significant revision. The vast majority of FL (85%) with a follicular growth pattern are composed of centrocytes and centroblasts, harbor the t(14;18)(q32;q21) translocation and are now termed classic FL (cFL). They are set apart from three related subtypes, FL with predominantly follicular growth pattern, FL with unusual cytological features (uFL) and follicular large B-cell lymphoma (FLBCL). In contrast to the revised 4th edition of the WHO classification of haematolymphoid tumors (WHO-HAEM4R), grading of cFL is no longer mandatory. FL with a predominantly diffuse growth pattern had been previously recognized in WHO-HAEM4R. It frequently occurs as a large tumor in the inguinal region and is associated with CD23 expression. An absence of the IGH::BCL2 fusion and frequent STAT6 mutations along with 1p36 deletion or TNFRSF14 mutation is typical. The newly introduced subtype of uFL includes two subsets that significantly diverge from cFL: one with “blastoid” and one with “large centrocyte” variant cytological features. uFL more frequently displays variant immunophenotypic and genotypic features. FLBCL is largely identical to WHO-HAEM4R FL grade 3B and renaming was done for reasons of consistency throughout the classification. In-situ follicular B-cell neoplasm, pediatric-type FL, duodenal-type FL and primary cutaneous follicle center lymphoma are categorized as discrete entities. In addition, novel findings concerning underlying biological mechanisms in the pathogenesis of early and systemic follicular lymphoma will be presented.
Is There a Role for Molecular Testing for Low-Risk Differentiated Thyroid Cancer? A Cost-Effectiveness Analysis
Authors: Tessler Idit , Leshno Moshe , Feinmesser Gilad , Alon Eran E. , Avior Galit
Published: January 2023

Molecular testing for thyroid nodules has been rapidly developed in recent years, aiming to predict the presence of malignancy and aggressive features. While commonly utilized to predict malignancy, its role in guiding the management approach is still developing. The high cost of genetic tests and long-term sequences of thyroid cancer is limiting to real-life studies. Objective: To evaluate the cost effectiveness of molecular testing for low-risk differentiated thyroid cancer (lrDTC). Methods: We developed a Markovian decision tree model of a simulated lrDTC cohort, comparing two management strategies: (I) Conducting genetic tests (GT)—patients are stratified into three risk groups for distant metastasis by the identified molecular markers: low-, intermediate- and high-risk molecular profile; followed by management accordingly: patients with low-risk will undergo hemithyroidectomy (HT), patients with intermediate-risk will undergo total thyroidectomy (TT), and high-risk patients will undergo TT with central neck dissection; (II) Without genetic tests (wGT)—all patients will undergo HT according to the ATA recommendations for lrDTC. Outcomes were measured as quality-adjusted life years (QALYs) and costs of each strategy. Results: GT was found as cost effective, leading to a gain of 1.7 QALYs with an additional cost of $327 per patient compared to wGT strategy. This yielded an incremental cost-effectiveness ratio of $190 per QALY. Sensitivity analysis demonstrated robust results across the variables’ ranges. The most impactful variable was the benefit from performing TT rather than HT for intermediate to high-risk patients. Conclusions: Our model found that molecular testing for lrDTC is cost-effective, allowing tailored management according to the patient’s personal risk level reflected in the genetic profile, hence improving outcomes.
Unusual Suspects: Bone and Cartilage ECM Proteins as Carcinoma Facilitators
Authors: Sorvina Alexandra , Antoniou Michael , Esmaeili Zahra , Kochetkova Marina
Published: January 2023

The extracellular matrix (ECM) is the complex three-dimensional network of fibrous proteins and proteoglycans that constitutes an essential part of every tissue to provide support for normal tissue homeostasis. Tissue specificity of the ECM in its topology and structure supports unique biochemical and mechanical properties of each organ. Cancers, like normal tissues, require the ECM to maintain multiple processes governing tumor development, progression and spread. A large body of experimental and clinical evidence has now accumulated to demonstrate essential roles of numerous ECM components in all cancer types. Latest findings also suggest that multiple tumor types express, and use to their advantage, atypical ECM components that are not found in the cancer tissue of origin. However, the understanding of cancer-specific expression patterns of these ECM proteins and their exact roles in selected tumor types is still sketchy. In this review, we summarize the latest data on the aberrant expression of bone and cartilage ECM proteins in epithelial cancers and their specific functions in the pathogenesis of carcinomas and discuss future directions in exploring the utility of this selective group of ECM components as future drug targets.
Associations between Lifestyle Factors and Neurocognitive Impairment among Chinese Adolescent and Young Adult (AYA) Survivors of Sarcoma
Authors: Cheung Yin Ting , Ma Chung Tin , Li Michael Can Heng , Zhou Keary Rui , Loong Herbert Ho Fung , Chan Agnes Sui Yin , Wong Kwok Chuen , Li Chi Kong
Published: January 2023

Background: The effect of lifestyle on neurocognitive impairment among cancer survivors remain an understudied area. This study explored the association between lifestyle factors and neurocognitive outcomes (specifically, attention, memory, processing speed and cognitive flexibility) in AYA survivors (aged 15–39 years) of sarcoma. Methods: This study recruited 116 AYA survivors (age 28.2 (SD = 8.2) years), who were diagnosed with osteosarcoma (49%) or soft-tissue sarcoma (51%) at age 13.3 (SD = 7.2) years. The neurocognitive battery included measures of attention, memory, motor-processing speed, and cognitive flexibility. Survivors reported health-damaging practices, which included: physical inactivity, smoking, alcohol intake, inadequate sleep (<7 h of actual sleep/day), sleep-related fatigue (Multidimensional Fatigue Scale) and long working hours (>9 h/day). General linear modeling was conducted to examine the association between lifestyle factors and neurocognitive outcomes, adjusting for age at diagnosis, sex, education attainment and clinical/treatment variables. Results: At 14.9 (SD = 7.6) years post-diagnosis, survivors demonstrated impairment in attentiveness (4.3–13.0%), processing speed (34.5%) and cognitive flexibility (18.1%). Nearly half (45.7%) had developed a chronic health condition (CHC). Low physical activity (estimate = −0.97, p = 0.003) and sleep-related fatigue (estimate = −0.08, p = 0.005) were associated with inattention. Survivors who worked >9 h/day (n = 15) demonstrated worse attention (estimate = 5.42, p = 0.023) and cognitive flexibility (estimate = 5.22, p = 0.005) than survivors who worked ≤9 h/day (n = 66). Interaction analysis (CHCs*physical activity) showed that survivors who developed CHCs and reported low physical activity had worse attention (p = 0.032) and cognitive-flexibility (p = 0.019) scores than other subgroups. Conclusion: Treatment-related CHCs, coupled with continued physical inactivity, may exacerbate inattention and executive dysfunction among survivors. Long working hours and sleep-related fatigue are associated with worse functioning; this finding should be validated with prospective assessment of work-related stressors and objective sleep measures.
The Efficacy of Using Patient-Derived Organoids to Predict Treatment Response in Colorectal Cancer
Authors: Su Chang , Olsen Kelly A. , Bond Catherine E. , Whitehall Vicki L. J.
Published: January 2023

Colorectal cancer is an important cause of morbidity and mortality worldwide. The current treatment landscape includes chemotherapy, targeted therapy, immunotherapy, radiotherapy, and surgery. A key challenge to improving patient outcomes is the significant inter-patient heterogeneity in treatment response. Tumour organoids derived from the patients’ tumours via surgically resected or endoscopically biopsied tissue, have emerged as promising models for personalised medicine. This review synthesises the findings, to date, of studies which have explored the efficacy of ex vivo organoid sensitivity testing for predicting treatment response. Most studies have focused on predicting the response to standard-of-care radiotherapy and chemotherapy options. There is strong evidence to support organoid sensitivity testing of ionising radiation, 5-fluorouracil, and irinotecan, and to a lesser extent, oxaliplatin and TAS-102. Fewer studies have used organoids to identify patients who are likely to benefit from novel treatment options that otherwise remain in clinical trials. This review also summarises recent advancements in organoid culture to include non-epithelial components of the tumour microenvironment, to allow testing of immunotherapy and certain targeted therapy options. Overall, further prospective trials will support the implementation of organoid-based personalised medicine for colorectal cancer patients in the future.
Prevalence and Characteristics of Human Papillomavirus Infection in Oropharyngeal Squamous Cell Papilloma
Authors: Ahn Dongbin , Kwak Ji-Hye , Lee Gil-Joon , Sohn Jin-Ho
Published: January 2023

Studies on human papillomavirus (HPV) infection in oropharyngeal squamous papilloma (OPSP) are lacking, although HPV infection has been recognized as the primary cause of oropharyngeal cancer for several decades. This study aimed to evaluate the prevalence and characteristics of HPV infections in patients with OPSP. We retrospectively enrolled patients with histologically confirmed OPSP in whom the presence of HPV infections and p16 expression were evaluated. The results of HPV infection in OPSP were analyzed according to the clinicodemographic profiles. Of the 83 patients included in this study, HPV test results were positive in 12 patients, with an overall prevalence of 14.5%. HPV genotypes involved low-risk and high-risk HPV types in three (3.6%) and nine (10.8%) patients, respectively. The most prevalent genotype was HPV16, accounting for 58.3% of all HPV infections. None of the OPSPs showed p16 IHC positivity. There were trends toward a higher prevalence of high-risk HPV infection in patients with OPSP aged ≤45 years, never-smokers, and those with multifocal diseases. These findings could enhance our understanding of HPV infection in OPSP and be used as valuable epidemiological data for the management of HPV-associated OPSP and regarding the possible efficacy of HPV vaccinations in OPSP.
Kynureninase Upregulation Is a Prominent Feature of NFR2-Activated Cancers and Is Associated with Tumor Immunosuppression and Poor Prognosis
Authors: León-Letelier Ricardo A. , Abdel Sater Ali H. , Chen Yihui , Park Soyoung , Wu Ranran , Irajizad Ehsan , Dennison Jennifer B. , Katayama Hiroyuki , Vykoukal Jody V. , Hanash Samir , Ostrin Edwin J. , Fahrmann Johannes F.
Published: January 2023

The nuclear factor erythroid 2-related factor 2 (NRF2) pathway is frequently activated in various cancer types. Aberrant activation of NRF2 in cancer is attributed to gain-of-function mutations in the NRF2-encoding gene NFE2L2 or a loss of function of its suppressor, Kelch-like ECH-associated protein 1 (KEAP1). NRF2 activation exerts pro-tumoral effects in part by altering cancer cell metabolism. Previously, we reported a novel mechanism of NRF2 tumoral immune suppression through the selective upregulation of the tryptophan-metabolizing enzyme kynureninase (KYNU) in lung adenocarcinoma. In the current study, we explored the relevance of NRF2-mediated KYNU upregulation across multiple cancer types. Specifically, using a gene expression dataset for 9801 tumors representing 32 cancer types from The Cancer Genome Atlas (TCGA), we demonstrated that elevated KYNU parallels increased gene-based signatures of NRF2-activation and that elevated tumoral KYNU mRNA expression is strongly associated with an immunosuppressive tumor microenvironment, marked by high expression of gene-based signatures of Tregs as well as the immune checkpoint blockade-related genes CD274 (PDL-1), PDCD1 (PD-1), and CTLA4, regardless of the cancer type. Cox proportional hazard models further revealed that increased tumoral KYNU gene expression was prognostic for poor overall survival in several cancer types, including thymoma, acute myeloid leukemia, low-grade glioma, kidney renal papillary cell carcinoma, stomach adenocarcinoma, and pancreatic ductal adenocarcinoma (PDAC). Using PDAC as a model system, we confirmed that siRNA-mediated knockdown of NRF2 reduced KYNU mRNA expression, whereas activation of NFE2L2 (the coding gene for NRF2) through either small-molecule agonists or siRNA-mediated knockdown of KEAP1 upregulated KYNU in PDAC cells. Metabolomic analyses of the conditioned medium from PDAC cell lines revealed elevated levels of KYNU-derived anthranilate, confirming that KYNU was enzymatically functional. Collectively, our study highlights the activation of the NRF2–KYNU axis as a multi-cancer phenomenon and supports the relevance of tumoral KYNU as a marker of tumor immunosuppression and as a prognostic marker for poor overall survival.
Endocrine Tumor Classification via Machine-Learning-Based Elastography: A Systematic Scoping Review
Authors: Mao Ye-Jiao , Zha Li-Wen , Tam Andy Yiu-Chau , Lim Hyo-Jung , Cheung Alyssa Ka-Yan , Zhang Ying-Qi , Ni Ming , Cheung James Chung-Wai , Wong Duo Wai-Chi
Published: January 2023

Elastography complements traditional medical imaging modalities by mapping tissue stiffness to identify tumors in the endocrine system, and machine learning models can further improve diagnostic accuracy and reliability. Our objective in this review was to summarize the applications and performance of machine-learning-based elastography on the classification of endocrine tumors. Two authors independently searched electronic databases, including PubMed, Scopus, Web of Science, IEEEXpress, CINAHL, and EMBASE. Eleven (n = 11) articles were eligible for the review, of which eight (n = 8) focused on thyroid tumors and three (n = 3) considered pancreatic tumors. In all thyroid studies, the researchers used shear-wave ultrasound elastography, whereas the pancreas researchers applied strain elastography with endoscopy. Traditional machine learning approaches or the deep feature extractors were used to extract the predetermined features, followed by classifiers. The applied deep learning approaches included the convolutional neural network (CNN) and multilayer perceptron (MLP). Some researchers considered the mixed or sequential training of B-mode and elastographic ultrasound data or fusing data from different image segmentation techniques in machine learning models. All reviewed methods achieved an accuracy of ≥80%, but only three were ≥90% accurate. The most accurate thyroid classification (94.70%) was achieved by applying sequential training CNN; the most accurate pancreas classification (98.26%) was achieved using a CNN–long short-term memory (LSTM) model integrating elastography with B-mode and Doppler images.
Advances in the Management of Central Nervous System Metastases in Non-Small Cell Lung Cancer
Authors: D’Aiello Angelica , Miao Emily , Cheng Haiying
Published: January 2023

Central nervous system (CNS) metastases are common among patients with non-small cell lung cancer (NSCLC). While the presence of brain metastases has historically portended poor prognosis, recent advances in local and systemic therapies have greatly improved outcomes for NSCLC patients with CNS involvement. Stereotactic radiology surgery (SRS) has emerged as an effective radiotherapy technique with fewer toxicities compared to whole brain radiotherapy (WBRT). Furthermore, multi-generation tyrosine kinase inhibitors (TKIs) with CNS overall response rates (ORR) of up to 70–80% are now an accepted first-line approach for a subset of advanced NSCLC patients with targetable molecular alterations. In addition, while the CNS was once considered an immunologic sanctuary site, growing evidence shows that immune checkpoint inhibitors (ICIs) can induce durable responses in brain metastases as well. Ongoing efforts to optimize CNS metastases management are necessary to refine multimodal treatment approaches and develop new therapeutics with better CNS penetrance.
Head and Neck Cancer Immunotherapy: Molecular Biological Aspects of Preclinical and Clinical Research
Authors: Chakraborty Rajdeep , Darido Charbel , Liu Fei , Maselko Maciej , Ranganathan Shoba
Published: January 2023

Breakthrough research in the field of immune checkpoint inhibitors and the development of a human papilloma virus vaccine triggered a plethora of research in the field of cancer immunotherapy. Both had significant effects on the treatment of head and neck squamous cell carcinoma. The advent of preclinical models and multidisciplinary approaches including bioinformatics, genetic engineering, clinical oncology, and immunology helped in the development of tumour-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T-cell therapy. Here, we discuss different immunotherapies such as adoptive T-cell transfer, immune checkpoint inhibitors, interleukins, and cancer vaccines for the treatment of head and neck cancer. This review showcases the intrinsic relation between the understanding and implementation of basic biology and clinical practice. We also address potential limitations of each immunotherapy approach and the advantages of personalized immunotherapy. Overall, the aim of this review is to encourage further research in the field of immunotherapy for head and neck cancer.
Evaluation of Exposure Doses of Elective Nodal Irradiation in Chemoradiotherapy for Advanced Esophageal Cancer
Authors: Tamamura Hiroyasu , Hasatani Kenkei , Matsumoto Sae , Asahi Satoko , Tatebe Hitoshi , Sato Yoshitaka , Matsusita Keiichiro , Tameshige Yuji , Maeda Yoshikazu , Sasaki Makoto , Takamatsu Shigeyuki , Yamamoto Kazutaka
Published: January 2023

We evaluated elective nodal irradiation (ENI) doses during radical chemoradiotherapy (CRT) for esophageal cancer (EC). A total of 79 patients (65 men and 14 women) aged 52–80 years with T1-3, N0-3, and M0 (including M1ly) who underwent CRT for EC during November 2012–September 2019 were eligible for this retrospective analysis. Patients were divided into two groups: the high-dose group (HG), including 38 patients who received ≥40 Gy as ENI; and the low-dose group (LG), including 41 patients who received <40 Gy. The median doses were 40.0 and 36.0 Gy in HG and LG, respectively. During the follow-up (median: 36.7 months), no lymph node recurrence was observed in the ENI field in all patients. Lymph node recurrence near the ENI field was observed in six patients. No significant differences were observed between the two groups in median overall survival, progression-free survival, and local control. Grade 3–4 acute and late adverse events were observed in five patients of HG and six patients of LG, respectively. No ulceration or stricture was observed in the ENI field on endoscopy examined with 58 Gy irradiation. In conclusion, an ENI dose of 36 Gy could be considered to control the elective nodes of EC.
P38 MAPK and Radiotherapy: Foes or Friends?
Authors: García-Flores Natalia , Jiménez-Suárez Jaime , Garnés-García Cristina , Fernández-Aroca Diego M. , Sabater Sebastia , Andrés Ignacio , Fernández-Aramburo Antonio , Ruiz-Hidalgo María José , Belandia Borja , Sanchez-Prieto Ricardo , Cimas Francisco J.
Published: January 2023

Over the last 30 years, the study of the cellular response to ionizing radiation (IR) has increased exponentially. Among the various signaling pathways affected by IR, p38 MAPK has been shown to be activated both in vitro and in vivo, with involvement in key processes triggered by IR-mediated genotoxic insult, such as the cell cycle, apoptosis or senescence. However, we do not yet have a definitive clue about the role of p38 MAPK in terms of radioresistance/sensitivity and its potential use to improve current radiotherapy. In this review, we summarize the current knowledge on this family of MAPKs in response to IR as well as in different aspects related to radiotherapy, such as their role in the control of REDOX, fibrosis, and in the radiosensitizing effect of several compounds.
Current Landscape and Potential Challenges of Immune Checkpoint Inhibitors in Microsatellite Stable Metastatic Colorectal Carcinoma
Authors: San-Román-Gil María , Torres-Jiménez Javier , Pozas Javier , Esteban-Villarrubia Jorge , Albarrán-Fernández Víctor , Álvarez-Ballesteros Pablo , Chamorro-Pérez Jesús , Rosero-Rodríguez Diana , Orejana-Martín Inmaculada , Martínez-Delfrade Íñigo , Reguera-Puertas Pablo , Fuentes-Mateos Raquel , Ferreiro-Monteagudo Reyes
Published: January 2023

Colorectal cancer (CRC) is the third most frequent cancer and the second most common cause of cancer-related death in Europe. High microsatellite instability (MSI-H) due to a deficient DNA mismatch repair (dMMR) system can be found in 5% of metastatic CRC (mCRC) and has been established as a biomarker of response to immunotherapy in these tumors. Therefore, immune checkpoint inhibitors (ICIs) in mCRC with these characteristics were evaluated with results showing remarkable response rates and durations of response. The majority of mCRC cases have high levels of DNA mismatch repair proteins (pMMR) with consequent microsatellite stability or low instability (MSS or MSI-low), associated with an inherent resistance to ICIs. This review aims to provide a comprehensive analysis of the possible approaches to overcome the mechanisms of resistance and evaluates potential biomarkers to establish the role of ICIs in pMMR/MSS/MSI-L (MSS) mCRC.
Circulating HPV16 DNA in Blood Plasma as Prognosticator and Early Indicator of Cancer Recurrence in Radio-Chemotherapy for Anal Cancer
Authors: Mazurek Agnieszka M. , Małusecka Ewa , Jabłońska Iwona , Vydra Natalia , Rutkowski Tomasz W. , Giglok Monika , Suwiński Rafał
Published: January 2023

Background: Implementation of anal squamous cell carcinoma (ASCC) treatment modifications requires reliable patient risk stratification. The circulating tumor–related human papillomavirus type 16 (ctHPV16) may play a role in predicting survival or assessing treatment response. Methods: The study included 62 ASCC patients treated with chemoradiotherapy. A threshold of 2.5 was used to determine the maximum standardized uptake value (SUVmax). The ctHPV16 viral load (VL) was quantified by qPCR. Results: In the multivariate Cox analysis, lower SUVmax (p = 0.047) and ctHPV16–positive (p = 0.054) proved to be independent prognostic factors for favorable overall survival (OS). In the subgroup with the higher SUVmax, ctHPV16 and nodal (N) status were independent prognostic factors with p = 0.022 for ctHPV16 and p = 0.053 for N. The best survival rate (95%) presented ctHPV16–positive/N–negative patients. High ctHPV16 VL tended to be slightly specific for patients younger than 63 years (p = 0.152). The decrease in ctHPV16 VL to undetectable level after the end of treatment correlated with the overall clinical response. Conclusions: A prognostic stratification by SUVmax, ctHPV16 and N–positive status allows consideration of more aggressive treatment in high–risk patients (those with high SUVmax, ctHPV16–negative, and N–positive) or de–intensification of therapy in low–risk patients (those with low SUVmax, ctHPV16–positive and N–negative). However, prospective clinical trials on a large group are needed.
Synthesis of Phenol-Tagged Ruthenium Alkylidene Olefin Metathesis Catalysts for Robust Immobilisation Inside Metal–Organic Framework Support
Authors: Nadirova Maryana , Cejas-Sánchez Joel , Sebastián Rosa María , Wiszniewski Marcin , Chmielewski Michał J. , Kajetanowicz Anna , Grela Karol
Published: January 2023

Two new unsymmetrical N-heterocyclic carbene ligand (uNHC)-based ruthenium complexes featuring phenolic OH function were obtained and fully characterised. The more active one was then immobilised on the metal–organic framework (MOF) solid support (Al)MIL-101-NH2. The catalytic activity of such a heterogeneous system was tested, showing that, while the heterogeneous catalyst is less active than the corresponding homogeneous catalyst in solution, it can catalyse selected olefin metathesis reactions, serving as the proof-of-concept for the immobilisation of catalytically active complexes in MOFs using a phenolic tag.
A One-Pot Hydrothermal Preparation of High Loading Ni/La2O3 Catalyst for Efficient Hydrogenation of Cinnamaldehyde
Authors: Yan Haoting , Ren Yongwang , Zhang Renkun , Chang Feixiang , Wei Qinhong , Xu Jing
Published: January 2023

It is a challenging task for selective hydrogenation of cinnamaldehyde (CAL) to hydrocinnamaldehyde (HCAL) without additional by-product formation. In this work, a La2O3 supported high Ni content nanoparticle catalyst was prepared for CAL selective hydrogenation. Meanwhile, Co-La2O3 catalysts were used as a reference catalyst. XRD, TEM, STEM-HAADF, XPS, and H2-TPR measurements were used to investigate the physicochemical properties of Ni-La2O3 catalysts. The experimental results confirmed that the CAL conversion and HCAL selectivity were effectively promoted with the increase of Ni loading amounts. At a Ni/La molar ratio of four, a high HCAL selectivity of 87.4% was obtained at a CAL conversion of 88.1% under mild reaction conditions. The catalyst was recycled five times without activity loss. Combined with various characterizations, it could be inferred that the good hydrogen adsorption and dissociation capacity of Ni and the presence of a certain amount of oxygen vacancies on the La2O3 support have a positive effect on the improvement of HCAL selectivity. This work provided an effective path to design transition-metal-based supported oxide catalyst for the cinnamaldehyde hydrogenation to hydrocinnamaldehyde.