bluuebunny/crossref_metadata_2025 huggingface dataset:
An Experimental Framework for Developing Point-of-Need Biosensors: Connecting Bio-Layer Interferometry and Electrochemical Impedance Spectroscopy
Authors: Ullah Sadia Fida , Moreira Geisianny , Datta Shoumen Palit Austin , McLamore Eric , Vanegas Diana
Published: October 2022

Biolayer interferometry (BLI) is a well-established laboratory technique for studying biomolecular interactions important for applications such as drug development. Currently, there are interesting opportunities for expanding the use of BLI in other fields, including the development of rapid diagnostic tools. To date, there are no detailed frameworks for implementing BLI in target-recognition studies that are pivotal for developing point-of-need biosensors. Here, we attempt to bridge these domains by providing a framework that connects output(s) of molecular interaction studies with key performance indicators used in the development of point-of-need biosensors. First, we briefly review the governing theory for protein-ligand interactions, and we then summarize the approach for real-time kinetic quantification using various techniques. The 2020 PRISMA guideline was used for all governing theory reviews and meta-analyses. Using the information from the meta-analysis, we introduce an experimental framework for connecting outcomes from BLI experiments (KD, kon, koff) with electrochemical (capacitive) biosensor design. As a first step in the development of a larger framework, we specifically focus on mapping BLI outcomes to five biosensor key performance indicators (sensitivity, selectivity, response time, hysteresis, operating range). The applicability of our framework was demonstrated in a study of case based on published literature related to SARS-CoV-2 spike protein to show the development of a capacitive biosensor based on truncated angiotensin-converting enzyme 2 (ACE2) as the receptor. The case study focuses on non-specific binding and selectivity as research goals. The proposed framework proved to be an important first step toward modeling/simulation efforts that map molecular interactions to sensor design.
Sulfonated Starch-Graft-Polyaniline@Graphene Electrically Conductive Nanocomposite: Application for Tyrosinase Immobilization
Authors: Aliya Marzieh , Zare Ehsan Nazarzadeh , Faridnouri Hassan , Ghomi Matineh , Makvandi Pooyan
Published: October 2022

The interaction of tyrosinase with sulfonated starch-graft-polyaniline@graphene (SSt-g-PANI@G) nanocomposite was investigated by electrochemical methods. The activity of the immobilized tyrosinase (Tyase) was proved by the electrochemical detection of three substrates (L-dopa, caffeic acid, and catechol). The SSt-g-PANI@G nanocomposite was characterized by Fourier-transform infrared spectra (FT-IR), X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray analysis (EDX), and thermogravimetric analysis (TGA). To immobilize tyrosinase on the surface of the nanocomposite, a simple drop-casting technique was used. The presence of sulfuric acid and hydroxyl groups in SSt, amine groups in PANI, and high surface-to-volume ratio and electrical conductivity of graphene in the prepared nanocomposite led to good enzyme immobilization on the electrode surface. The modified electrode showed a suitable catalytic effect on the electrochemical redox agent, compared with the bare electrode. The peak current responses for three substrates were studied with a calibration curve derived using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). In addition, the fabricated SSt-g-PANI@G/Tyase/GCE showed a more suitable response to catechol, L-dopa, and caffeic acid substrates, respectively.
Development and Validation of a Practical Model for Transient Biofilter Performance
Authors: Shareefdeen Zarook
Published: October 2022

Biofilters are biological air-phase packed-bed reactors used for the removal of industrial air pollutants such as volatile organic compounds (VOCs) and odors. Because of the economic and environmental benefits, biofilter technology is preferred in applications such as wastewater treatment plants, waste recycling facilities, and several chemical industries over conventional treatment methods such as adsorption, absorption, and thermal oxidation processes. In order to predict the performance of biofilters, mathematical models under steady-state and transient conditions are needed. The transient biofilter models for gas-phase bioreactors are highly complex, as they involve several parameters that are not easily determined for industrial applications. In this work, a practical transient biofilter model is developed and an analytical solution for the transient model is obtained. When this model is compared with the published but more complex model, this new transient model produces almost the same level of prediction with equal comparisons of experimental data for VOCs, benzene, and toluene. This simple model has fewer parameters and will be very useful and practical for industrial applications for the analysis of transient biofilter performance.
Volumetric Variability of the Ventromedial Prefrontal Cortex Reflects the Propensity for Engaging in High-Stakes Gambling Behavior
Authors: Lee Kyuli , Kim Nayoung , Jeong Eun-Joo , Kang Min-Suk , Kim M. Justin
Published: October 2022

The human ventromedial prefrontal cortex (vmPFC) has been traditionally associated with decision-making under risk. Neuroimaging studies of such decision-making processes have largely focused on patients with vmPFC lesions or pathological gambling behavior, leading to a relative paucity of work focusing on the structural variability of the vmPFC in healthy individuals. To address this, we developed a decision-making task that allowed healthy players to choose to participate in either low stakes or high-stakes gambling on a trial-by-trial basis, and computed a metric that indexes the propensity for engaging in gambles with greater potential payoffs. We leveraged voxel-based morphometric analyses to examine the association between prefrontal gray matter volume and individual differences in the propensity for seeking high-risk/high-reward situations. Our analyses showed that vmPFC gray matter volume was inversely correlated with an increased tendency for engaging in high-stakes gambling. These results converge with findings from functional neuroimaging and brain lesion studies of vmPFC, and further extend them to show that normative variability in brain structure could also underpin risk-taking behavior.
Load-Dependent Prefrontal Cortex Activation Assessed by Continuous-Wave Near-Infrared Spectroscopy during Two Executive Tasks with Three Cognitive Loads in Young Adults
Authors: Agbangla Nounagnon Frutueux , Audiffren Michel , Pylouster Jean , Albinet Cédric T.
Published: October 2022

The present study examined the evolution of the behavioral performance, subjectively perceived difficulty, and hemodynamic activity of the prefrontal cortex as a function of cognitive load during two different cognitive tasks tapping executive functions. Additionally, it investigated the relationships between these behavioral, subjective, and neuroimaging data. Nineteen right-handed young adults (18–22 years) were scanned using continuous-wave functional near-infrared spectroscopy during the performance of n-back and random number generation tasks in three cognitive load conditions. Four emitter and four receptor optodes were fixed bilaterally over the ventrolateral and dorsolateral prefrontal cortices to record the hemodynamic changes. A self-reported scale measured the perceived difficulty. The findings of this study showed that an increasing cognitive load deteriorated the behavioral performance and increased the perceived difficulty. The hemodynamic activity increased parametrically for the three cognitive loads of the random number generation task and in a two-back and three-back compared to a one-back condition. In addition, the hemodynamic activity was specifically greater in the ventrolateral prefrontal cortex than in the dorsolateral prefrontal cortex for both cognitive tasks (random number generation and n-back tasks). Finally, the results highlighted some links between cerebral oxygenation and the behavioral performance, but not the subjectively perceived difficulty. Our results suggest that cognitive load affects the executive performance and perceived difficulty and that fNIRS can be used to specify the prefrontal cortex’s implications for executive tasks involving inhibition and working memory updating.
Irreversible Electroporation Mediates Glioma Apoptosis via Upregulation of AP-1 and Bim: Transcriptome Evidence
Authors: Yu Shuangquan , Chen Lingchao , Song Kun , Shu Ting , Fang Zheng , Ding Lujia , Liu Jilong , Jiang Lei , Zhang Guanqing , Zhang Bing , Qin Zhiyong
Published: October 2022

The heat-sink effect and thermal damage of conventional thermal ablative technologies can be minimized by irreversible electroporation (IRE), which results in clear ablative boundaries and conservation of blood vessels, facilitating maximal safe surgical resection for glioblastoma. Although much comparative data about the death forms in IRE have been published, the comprehensive genetic regulatory mechanism for apoptosis, among other forms of regulatory cell death (RCD), remains elusive. We investigated the electric field intensity threshold for apoptosis/necrosis (YO-PRO-1/PI co-staining) of the U251 human malignant glioma cell line with stepwise increased uniform field intensity. Time course samples (0–6 h) of apoptosis induction and sham treatment were collected for transcriptome sequencing. Sequencing showed that transcription factor AP-1 and its target gene Bim (Bcl2l11), related to the signaling pathway, played a major role in the apoptosis of glioma after IRE. The sequencing results were confirmed by qPCR and Western blot. We also found that the transcription changes also implicated three other forms of RCD: autophagy, necroptosis, and immunogenic cell death (ICD), in addition to apoptosis. These together imply that IRE possibly mediates apoptosis by the AP-1-Bim pathway, causes mixed RCD simultaneously, and has the potential to aid in the generation of a systemic antitumor immune response.
Vortioxetine Improves Depressive Symptoms and Cognition in Parkinson’s Disease Patients with Major Depression: An Open-Label Prospective Study
Authors: Santos García Diego , Alonso Losada Maria Gema , Cimas Hernando Icíar , Cabo López Iria , Yáñez Baña Rosa , Alonso Redondo Ruben , Paz González Jose Manuel , Cores Bartolomé Carlos , Feal Painceiras Maria José , Íñiguez Alvarado Maria Cristina , Labandeira Carmen , García Díaz Iago
Published: October 2022

Depression is frequent in Parkinson’s disease (PD) patients, but the evidence for many antidepressant agents to treat it in PD is insufficient. The aim of the present prospective open-label single-arm study (VOPARK, an open-label study of the effectiveness and safety of VOrtioxetine in PARKinson’s disease patients with depression) was to analyze the effectiveness of vortioxetine on depressive symptoms in PD patients with major depression. The primary efficacy outcome was the change from baseline (VB) at the end of the observational period (12 weeks ± 14 days; V12w) in the 17-item Hamilton Depression Rating Scale (HAM-D17) total score. At VB, all patients had a HAM-D17 total score ≥16. A total of 30 patients (age 66.23 ± 10.27; 73.3% males) were included between February 2021 (first patient, 12/FEB/21) and March 2022 (last patient, 14/MAR/22). At 12 weeks, 27 patients completed the follow-up (90%). The total HAM-D17 total score was reduced by 52.7% (from 21.5 ± 4.75 at VB to 10.44 ± 7.54 at V12w; Cohen’s effect size = −2.5; p < 0.0001) and the response and remission rates were 50% and 43.3%, respectively. Apathy (Apathy Scale; p < 0.0001), cognition (PD-Cognitive Rating Scale; p = 0.007), fatigue (Fatigue Severity Scale; p = 0.014), and quality of life (PDQ-39 (p = 0.001) and EUROHIS-QOL8 (p < 0.0001)) improved at 3 weeks as well. A total of 11 adverse events in 10 patients (33.3%) were reported, one of which was severe (vomiting related to vortioxetine with full recovery after drug withdrawal). Vortioxetine was safe and well tolerated and improved depressive symptoms and other non-motor symptoms in PD patients.
Cannabis-Based Medicinal Products in the Management of Emotionally Unstable Personality Disorder (EUPD): A Narrative Review and Case Series
Authors: Sultan Waseem , Mathew Anup , Brown Matthew R. D. , Gálvez-Flórez Juan F. , Moreno-Sanz Guillermo
Published: October 2022

Emotionally unstable personality disorder (EUPD) is a common mental health disorder, manifesting with a range of chronic and debilitating symptoms, including impaired social functioning, unstable mood, and risky impulsive or self-injurious behaviour. Whilst the exact aetiology has not been fully elucidated, implicated factors seem to include genetic factors, environmental causes such as trauma, and neurotransmitter deficits. The literature suggests that impaired functioning of the endocannabinoid system in key brain regions responsible for emotional processing and stress response may underlie the manifestation of EUPD symptoms. The National Institute for Health and Care Excellence (NICE) 2009 guidelines state that “no drugs have established efficacy in treating or managing EUPD”, and yet, patients are commonly prescribed medication which includes antipsychotics, antidepressants, and mood stabilisers. Here we present a case series of seven participants diagnosed with EUPD and treated with cannabis-based medicinal products (CBMPs). Participants were given an initial assessment and followed up one month after CBMPs prescription. Improvement in symptoms was assessed by the completion of ratified rating scales by the participant and psychiatrist. Our results indicate that CBMPs were effective and well tolerated, as six participants reported a noticeable improvement in their symptoms and functioning. Although promising, further research is needed to ascertain the long-term tolerability, efficacy, and dosing strategy for CBMPs in EUPD.
Differentiation of Motor Speech Disorders through the Seven Deviance Scores from MonPaGe-2.0.s
Authors: Fougeron Cécile , Kodrasi Ina , Laganaro Marina
Published: October 2022

For the clinical assessment of motor speech disorders (MSDs) in French, the MonPaGe-2.0.s protocol has been shown to be sensitive enough to diagnose mild MSD based on a combination of acoustic and perceptive scores. Here, we go a step further by investigating whether these scores—which capture deviance on intelligibility, articulation, voice, speech rate, maximum phonation time, prosody, diadochokinetic rate—contribute to the differential diagnosis of MSDs. To this aim, we trained decision trees for two-class automatic classification of different pairs of MSD subtypes based on seven deviance scores that are computed in MonPaGe-2.0.s against matched normative data. We included 60 speakers with mild to moderate MSD from six neuropathologies (amyotrophic lateral sclerosis, Wilson, Parkinson and Kennedy disease, spinocerebellar ataxia, post-stroke apraxia of speech). The two-class classifications relied mainly on deviance scores from four speech dimensions and predicted with over 85% accuracy the patient’s correct clinical category for ataxic, hypokinetic and flaccid dysarthria; classification of the other groups (apraxia of speech and mixed dysarthria) was slightly lower (79% to 82%). Although not perfect and only tested on small cohorts so far, the classification with deviance scores based on clinically informed features seems promising for MSD assessment and classification.
Single-Cell Sequencing Analysis Identified ASTN2 as a Migration Biomarker in Adult Glioblastoma
Authors: Guo Tangjun , Bao Aijun , Xie Yandong , Qiu Jianting , Piao Haozhe
Published: October 2022

Glioblastoma is the most common and aggressive primary central nervous system malignant tumors. With the development of targeted sequencing and proteomic profiling technology, some new tumor types have been established and a series of novel molecular markers have also been identified. The 2021 updated World Health Organization classification of central nervous system tumors first mentioned the classification of adult glioma and pediatric glioma based on the molecular diagnosis. Thus, we used single-cell RNA sequencing analysis to explore the diversity and similarities in the occurrence and development of adult and pediatric types. ASTN2, which primarily encodes astrotactin, has been reported to be dysregulated in various neurodevelopmental disorders. Although some studies have demonstrated that ASTN2 plays an important role in glial-guided neuronal migration, there are no studies about its impact on glioblastoma cell migration. Subsequent single-cell RNA sequencing revealed ASTN2 to be a hub gene of a cell cluster which had a poor effect on clinical prognosis. Eventually, a western blot assay and a wound-healing assay first confirmed that ASTN2 expression in glioblastoma cell lines is higher than that in normal human astrocytes and affects the migration ability of glioblastoma cells, making it a potential therapeutic target.
Responding to Autism in Low and Middle Income Countries (Lmic): What to Do and What Not to Do
Authors: McConkey Roy
Published: October 2022

Autism is a spectrum disorder that occurs globally with increasing numbers of children and adults being identified with this condition. Although rates are higher in more affluent nations, the bulk of people with autism reside in Low and Middle Income Countries (LMICs). However, most do not have access to timely and appropriate support. The types of services delivered in high income countries are often ill-suited to the needs and resources of LMICs. Rather alternative forms of provision need to be devised. In common with other public health initiatives, these should be family-focused and community based, with suitably qualified and experienced leaders who in turn train and supervise a cadre of knowledgeable support workers drawn from local communities and cultures. As well as providing personalized, home-based guidance to people with autism and to their primary carers, regular group-based advocacy and training activities are undertaken in partnership with available mainstream services such as schools and social services. The principles and operations of these new forms of services are described in this paper albeit with an acknowledgment of their limitations. In recent decades, the cost-effectiveness of these approaches have been demonstrated with other chronic illnesses and disabling conditions in LMICs but their extension to autism has barely begun. More affluent countries are being forced to adopt similar strategies in response to the increased numbers of people identified with autism. A transformation in research strategies is essential to building better international support for persons with autism.
Psychopathology Changes in Alzheimer’s Disease
Authors: Henriques-Calado Joana
Published: October 2022

The advances in knowledge about the association between personality and neuropathology in Alzheimer’s disease have been highlighted. This research is oriented to the evaluation of personality changes in the screening of axis II personality disorders in Alzheimer’s disease. The investigation was managed with four groups to whom were applied the PDQ-4+ in individual interviews. Some results are in line with the state-of-the-art review and we also provide new research data. A higher global personality disorder index and greater incidence of clusters C (anxious) and A (odd/eccentric) are confirmed as personality changes. Interpretive possibilities of the data and their implications for the study of psychopathology changes in Alzheimer’s disease are discussed.
Examining the Mediating Effect of Customer Experience on the Emotions–Behavioral Intentions Relationship: Evidence from the Passenger Transport Sector
Authors: Gerou Anastasia
Published: October 2022

The aim of this research is to examine the influence of customer experience on the customers’ emotions–customers’ behavioral intentions relationship. Moreover, this study seeks to obtain data that will help to address this research gap in the passenger transportation industry. A large-scale survey on the coastal line shipping industry was conducted. The random sampling methodology was employed, and the target respondents were ferry passengers. The anonymized questionnaires were completed by 840 passengers. The data were analyzed through exploratory and confirmatory factor analyses and regression analysis. The findings verified application of the adopted (customer experience, emotions) and adapted (behavioral intentions) measurement instruments in the examined customer journey in the passenger shipping sector and indicated the mediating role of customer experience in the relationship between customers’ emotions and customers’ behavioral intentions. A distinguishing feature of this work is that it measures and assesses emotions during the customer journey and not afterward based on recall journeys. Additionally, although academics have carried out extensive research on the emotions–behavioral intentions relationship, very little is known about the role of customer experience in this relationship. Thus, what is not yet clear is the impact of customer experience on the emotions–behavioral intentions relationship. Additionally, the measurement instruments used to test this research hypothesis were empirically tested for the first time in the passenger shipping service environment.
Development of Daylight Glare Analysis Method Using an Integrated Parametric Modelling Approach: A Comparative Study of Glare Evaluation Standards
Authors: Wang Tsung-Hsien , Huang Yichun , Park Jihyun
Published: October 2022

Conducting lighting simulations to investigate lighting performance, such as glare, is widely accepted and of particular interest in the design development stage. However, the main challenge remains in integrating lighting performance metrics into a streamlined modelling and evaluation workflow. With the advancement in digital and modelling technologies, an automatic workflow of modelling parametric design studies with lighting performance evaluation becomes feasible. This study investigates a parametric modelling approach to facilitate glare evaluation using China Green Building Standard as an example. Their glare evaluation adopted the known daylight glare index (DGI) with a revised glare source definition in the calculation. An evaluation toolkit is presented, demonstrating its applications with the sky model. Compared with DGI, the results articulate how a parametric modelling workflow can automate lighting performance evaluation and facilitate technical investigation and clarifications for glare evaluation. Through the parametric simulation studies, the differences in the limited metric scale and the sensitivity of capturing window sizes on the glare evaluation suggest future evaluation protocols for the environmental standard development.
Traditional Passive Design Solutions as a Key Factor for Sustainable Modern Urban Designs in the Hot, Arid Climate of the United Arab Emirates
Authors: Salameh Muna , Touqan Basim
Published: October 2022

Sustainable architecture is a key approach for creating sustainable cities and reducing the impact of climate change. In hot, arid regions, the passive design traditional architecture is known for its ability to provide comfortable indoor environments and outdoor shaded areas, in contrast to the use of energy-intensive air conditioners in a great deal of modern architecture. Thus, this research used a qualitative methodology based on ENVI-met software to study, investigate, and compare the thermal performance of two urban fabrics as case studies (traditional and modern districts) in the hot, arid climate of the United Arab Emirates. The thermal performance of the old urban districts was better than the new ones, with a lower maximum potential air temperature and an improvement in the level of thermal comfort, measured by a predicted mean vote. Moreover, it was found that enhancing the shade in the outdoor open areas in the modern district, mimicking the traditional passive design solutions, resulted in lower air temperature and PMVs. This research is expected to be one step among many towards creating sustainable, innovative modern architecture.
Prediction of Ballistic Limit of Strengthened Reinforced Concrete Slabs Using Quasi-Static Punching Test
Authors: Abbas Husain , Siddiqui Nadeem , Almusallam Tarek , Abadel Aref , Al-Salloum Yousef
Published: October 2022

The formulas available in the literature for predicting the projectile impact response of reinforced concrete (RC) targets are generally developed based on the results of impact tests. Recently, however, in order to avoid performing involved and challenging projectile impact tests, the impact response of RC targets was predicted using the quasi-static punching response of RC slabs. In this paper, the concept is extended to concrete slabs strengthened with textile-reinforced mortar (TRM) or carbon fiber-reinforced polymer (CFRP) sheets externally bonded to the concrete surface. In 16 groups, 96 slabs of 600 × 600 × 90 mm size were cast and tested under quasi-static and impact loads. The slabs were reinforced with two types of reinforcement: ϕ8@100 mm and ϕ4@25 mm. The singly and doubly reinforced concrete slabs with rebar spacing of 100 mm were strengthened using externally bonded CFRP and TRM on the back side of the slab specimens. Two mixes of concrete, representing normal and high-strength concretes, were used. The results of the present study reveal that the CFRP and TRM strengthening of RC slabs enhanced the energy absorption in punching by 57–130% and 20–59%, respectively. The use of WWM in singly and doubly reinforced slabs also resulted in a 30–42% and 41–63% increase in energy absorption in punching, respectively. An earlier proposed model was modified to incorporate the influence of strengthening (CFRP and TRM) in the estimation of the projectile perforation energy of the strengthened RC slabs with the help of energy absorbed in their quasi-static punching. This perforation energy was then employed for predicting the ballistic limit of CFRP- and TRM-strengthened slabs. The predictions show good agreement with the experimentally observed ballistic limits.
Subclass Analysis of Malignant, Inflammatory and Degenerative Pathologies Based on Multiple Timepoint FAPI-PET Acquisitions Using FAPI-02, FAPI-46 and FAPI-74
Authors: Glatting Frederik M. , Hoppner Jorge , Kauczor Hans-Ulrich , Huber Peter E. , Kratochwil Clemens , Giesel Frederik L. , Haberkorn Uwe , Röhrich Manuel
Published: October 2022

Purpose: FAPI-PET is a promising imaging technique for various malignant as well as non-malignant pathologies. In a recent retrospective analysis, we evaluated the diagnostic value of repetitive early FAPI-PET-imaging with FAPI-02, FAPI-46 and FAPI-74 for malignant, inflammatory/reactive and degenerative pathologies. Here, we apply a subgroup analysis to that dataset and describe the tracer-wise uptake kinetic behavior of multiple types of FAPI-positive lesions, which are encountered frequently during clinical routine. Methods: A total of 24 cancer patients underwent whole-body FAPI-PET scans, and images were acquired at 10, 22, 34, 46 and 58 min after the administration of 150–250 MBq of 68Ga-FAPI tracer molecules (eight patients each regarding FAPI-02, FAPI-46 and FAPI-74). Standardized uptake values (SUVmax and SUVmean) of healthy tissues, cancer manifestations and non-malignant lesions were measured and target-to-background ratios (TBR) versus blood and fat were calculated for all acquisition timepoints. Results: Differential uptake behavior over time was observed in several subclasses of malignant lesions, inflammatory/reactive lesions and degenerative lesions. These differences over time were particularly manifested in the direct comparison between the uptakes associated with pancreatic carcinoma (stable or increasing over time) and inflammatory lesions of the pancreas (markedly decreasing over time). Furthermore, marked differences were found between the three tracer variants regarding their time-dependent uptake and TBRs within different subclasses of malignant, inflammatory/reactive and degenerative pathologies. Conclusion: Multiple timepoint FAPI-PET/CT is a promising innovative imaging technique that provides additional imaging information compared to single timepoint imaging. Differences in the kinetic behavior of malignant and benign pathologies can facilitate the interpretation of FAPI-positive lesions.
Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer
Authors: Bryce Adam S. , Dreyer Stephan B. , Froeling Fieke E. M. , Chang David K.
Published: October 2022

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterised by a stubbornly low 5-year survival which is essentially unchanged in the past 5 decades. Despite recent advances in chemotherapy and surgical outcomes, progress continues to lag behind that of other cancers. The PDAC microenvironment is characterised by a dense, fibrotic stroma of which cancer-associated fibroblasts (CAFs) are key players. CAFs and fibrosis were initially thought to be uniformly tumour-promoting, however this doctrine is now being challenged by a wealth of evidence demonstrating CAF phenotypic and functional heterogeneity. Recent technological advances have allowed for the molecular profiling of the PDAC tumour microenvironment at exceptional detail, and these technologies are being leveraged at pace to improve our understanding of this previously elusive cell population. In this review we discuss CAF heterogeneity and recent developments in CAF biology. We explore the complex relationship between CAFs and other cell types within the PDAC microenvironment. We discuss the potential for therapeutic targeting of CAFs, and we finally provide an overview of future directions for the field and the possibility of improving outcomes for patients with this devastating disease.
Interplay between Immune Cell Infiltration and Tumor Histological Subtype: A Case of Adrenocortical Cancer
Authors: Bogolyubova Apollinariya V. , Pachuashvili Nano V. , Tkachuk Arina V. , Mokrysheva Natalia G. , Urusova Liliya S.
Published: October 2022

The analysis of the tumor microenvironment, especially tumor-infiltrated immune cells, is essential for predicting tumor prognosis, clinical outcomes, and therapy strategies. Adrenocortical cancer is a rare nonimmunogenic malignancy in which the importance of the presence of immune cells is not well understood. In our study, we made the first attempt to understand the interplay between the histology of adrenocortical cancer and its immune landscape using cases from The Cancer Genome Atlas database and the Endocrinology Research Centre collection (Moscow, Russia). We showed that the oncocytic variant of adrenocortical cancer is characterized by intensive immune infiltration and better survival, and it is crucial to analyze the effect of immune infiltration independently for each histological variant.
The Predictive and Prognostic Role of RAS–RAF–MEK–ERK Pathway Alterations in Breast Cancer: Revision of the Literature and Comparison with the Analysis of Cancer Genomic Datasets
Authors: Rocca Andrea , Braga Luca , Volpe Maria Concetta , Maiocchi Serena , Generali Daniele
Published: October 2022

Although gene alterations of the RAS/RAF/MEK/ERK pathway are uncommon in breast cancer, this pathway is frequently activated in breast tumors, implying its role in tumor progression. We describe, after a revision of the literature, the frequency and types of gene alterations affecting this pathway in breast cancer by analyzing some public datasets from cBioPortal. Moreover, we consider their prognostic and predictive impact on treatment response, along with the role of transcriptomic predictors of RAS pathway activation. Our analysis shows that the driver alterations in RAS/RAF/MEK/ERK pathway-related genes are detected in 11% of primary breast cancers. The most frequently mutated genes are NF1 and KRAS, while copy number alterations mainly affect KRAS and BRAF, especially in basal-like tumors. The subgroup of patients carrying these alterations shows a worse prognosis; alterations in NF1 and RAF1 are associated with significantly reduced breast-cancer-specific survival in multivariate analysis. The literature review shows that the pathway is implicated, either by genetic or epigenetic alterations or by signaling network adaptations, in the mechanisms of sensitivity and resistance to a wide range of drugs used in the treatment of breast cancer. A thorough understanding of these alterations is critical for developing combination therapies that can delay or overcome drug resistance.
Afatinib and Dacomitinib Efficacy, Safety, Progression Patterns, and Resistance Mechanisms in Patients with Non-Small Cell Lung Cancer Carrying Uncommon EGFR Mutations: A Comparative Cohort Study in China (AFANDA Study)
Authors: Li Hong-Shuai , Wang Shou-Zheng , Xu Hai-Yan , Yan Xiang , Zhang Jin-Yao , Lei Si-Yu , Li Teng , Hao Xue-Zhi , Zhang Tao , Yang Guang-Jian , Zhou Li-Qiang , Liu Peng , Wang Yu-Ying , Hu Xing-Sheng , Xing Pu-Yuan , Wang Yan
Published: October 2022

(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene (EGFR) mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon EGFR mutations. However, no comparative study has been conducted. (2) Methods: Two cohorts were employed: the AFANDA cohort, an ambispective cohort including 121 patients with uncommon EGFR mutations admitted to two tertiary hospitals in China, and an external validation afatinib cohort (ex-AC), extracted from the Afatinib Uncommon EGFR Mutations Database (N = 1140). The AFANDA cohort was divided into an afatinib cohort (AC) and a dacomitinib cohort (DC) for internal exploration. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed for comparison. Progression patterns and resistance mechanisms were explored. (3) Results: In total, 286 patients with advanced NSCLC carrying uncommon EGFR mutations treated with afatinib or dacomitinib were enrolled, including 79 in the AFANDA cohort (44 in the DC, 35 in the AC) and 207 in the ex-AC. In internal exploration, the ORR of the DC was significantly higher than that of the AC (60.5 vs. 26.7%, p = 0.008), but there was no significant difference in median PFS between the DC and the AC (12.0 months vs. 10.0 months, p = 0.305). Multivariate analysis confirmed an independent favorable effect of dacomitinib on PFS (hazard ratio (HR), 1.909; p = 0.047). In external validation, multivariate analysis confirmed the independent prognostic role of dacomitinib in PFS (HR, 1.953; p = 0.029). Propensity score matching analysis confirmed the superiority of dacomitinib over afatinib in terms of PFS in both univariate and multivariate analyses. Toxicity profiling analysis suggested more G1 (p = 0.006), but fewer G3 (p = 0.036) AEs in the DC than in the AC. Progression patterns revealed that the incidence of intracranial progression in the AC was significantly higher than that in the DC (50 vs. 21.1%, p = 0.002). Drug resistance analysis indicated no significant difference in the occurrence of T790M between the AC and the DC (11.8 vs. 15.4%, p = 0.772). (4) Conclusions: Compared with afatinib, dacomitinib demonstrated a more favorable activity with manageable toxicity and different progression patterns in patients with NSCLC carrying uncommon EGFR mutations.
The Riddle of Cetuximab-Related Skin Toxicity: 1H-NMR Sebum Analysis Revealed Dynamic Lipid Alterations Associated with Skin Toxicity Development in Metastatic Colorectal Cancer Patients
Authors: Saorin Asia , Di Gregorio Emanuela , Buonadonna Angela , Miolo Gianmaria , Corona Giuseppe
Published: October 2022

The epidermal growth factor receptor inhibitor (EGFRIs) treatments are commonly associated with the development of adverse skin effects. This study aims to investigate the lipid composition change in sebum during cetuximab-based treatment in an attempt to identify specific metabolic signatures useful in predicting the occurrence of severe skin toxicity. Sebum from 30 metastatic colorectal cancer (mCRC) patients was collected at three time points during the targeted therapy by the application of Sebutape® on the forehead, and the major lipid classes were analyzed and quantified by 1H-NMR. Univariate analysis was performed to reveal significant alterations among patients in sebum production as well as lipid composition and over the course of cetuximab therapy. A transient but significant decrease in sebum production associated with a reduction in the relative content of triglycerides (TG) and squalene (SQ) was found to be induced by cetuximab administration. The reduction of these two lipid classes was also found to be associated with the severity of skin rash experienced by patients. The results of this study indicate that cetuximab-based treatment can reduce sebum gland activity, leading to an overall decrease in sebum production and the induction of specific modifications to its composition. The extent of the loss of skin barrier function may be important for determining the severity of skin toxicity development.
A Novel apaQTL-SNP for the Modification of Non-Small-Cell Lung Cancer Susceptibility across Histological Subtypes
Authors: Qiu Anni , Xu Huiwen , Mao Liping , Xu Buyun , Fu Xiaoyu , Cheng Jingwen , Zhao Rongrong , Cheng Zhounan , Liu Xiaoxuan , Xu Jingsheng , Zhou Yan , Dong Yang , Tian Tian , Tian Guangyu , Chu Minjie
Published: October 2022

Background: Alternative polyadenylation (APA) events may be modulated by single nucleotide polymorphisms (SNPs). Therefore, this study aims to evaluate the association between APA quantitative trait loci (apaQTLs)-related SNPs (apaQTL-SNPs) and non-small-cell lung cancer (NSCLC) risk. Methods: APA-related genes associated with NSCLC (LUAD and LUSC) were first identified, and the respective apaQTL-SNPs of those genes were selected. Then, a two-phase case-control study was performed to evaluate the association between candidate apaQTL-SNPs and NSCLC risk. Results: A total of 7 LUAD- and 21 LUSC-associated apaQTL-SNPs were selected. In the first phase, the apaQTL-SNP rs10138506 was significantly associated with LUAD risk (p < 0.05), whereas the other two apaQTL-SNPs (rs1130698 and rs1130719) were significantly associated with LUSC risk (p < 0.05). In the second phase, the variant G allele of rs10138506 was still significantly associated with an increased risk of LUAD (OR = 1.42, 95%CI = 1.02–1.98, p = 0.038). Functional annotation indicated that the variant G allele of rs10138506 was significantly associated with a higher PDUI value of CHURC1. Meanwhile, 3′RACE experiments verified the presence of two poly(A) sites (proximal and distal) in CHURC1, while qRT-PCR results indicated that different genotypes of rs1127968 which, in perfect LD with rs10138506, can mediate changes in the lengths of the 3′UTR of CHURC1 isoforms. Conclusion: The variant G allele of rs10138506 in CHURC1 was correlated with a longer 3′UTR of CHURC1 mRNA and an increased LUAD risk. Further studies should evaluate the interaction between rs10138506 and different 3′UTR lengths of CHURC1 that regulate LUAD development.
Quality of Life (QoL) of Children and Adolescents Participating in a Precision Medicine Trial for High-Risk Childhood Cancer
Authors: Hetherington Kate , Wakefield Claire E. , Kunalan Kavitha P. K. , Donoghoe Mark W. , McGill Brittany C. , Fardell Joanna E. , Daly Rebecca , Deyell Rebecca J. , Ziegler David S.
Published: October 2022

Precision medicine is changing the treatment of childhood cancer globally, however little is known about quality of life (QoL) in children and adolescents participating in precision medicine trials. We examined QoL among patients enrolled in PRISM, the Zero Childhood Cancer Program’s precision medicine trial for high-risk childhood cancer. We assessed patient QoL via self-report (aged 12–17 years) and parent-proxy (aged 4–17 years) completion of the EQ-5D-Y. We analysed data using descriptive statistics and regression models. Patients (n = 23) and parents (n = 136) provided data after trial enrolment and following receipt of trial results and treatment recommendations (n = 8 patients, n = 84 parents). At enrolment, most patients were experiencing at least some difficulty across more than one QoL domain (81% patient self-report, 83% parent report). We did not find strong evidence of a change in QoL between timepoints, or of demographic or disease factors that predicted parent-reported patient QoL (EQ-VAS) at enrolment. There was strong evidence that receiving a treatment recommendation but not a change in cancer therapy was associated with poorer parent-reported patient QoL (EQ-VAS; Mdiff = −22.5, 95% CI: −36.5 to −8.5, p = 0.006). Future research needs to better understand the relationship between treatment decisions and QoL and would benefit from integrating assessment of QoL into routine clinical care.
Safety of Anti-Angiogenic Drugs in Pediatric Patients with Solid Tumors: A Systematic Review and Meta-Analysis
Authors: Spini Andrea , Ciccone Valerio , Rosellini Pietro , Ziche Marina , Lucenteforte Ersilia , Salvo Francesco , Donnini Sandra
Published: October 2022

Cancer is a clinical condition that can benefit from anti-angiogenic drugs (AADs). Given the low prevalence and the heterogeneity of childhood cancers, information about the safety of these drugs in pediatric patients is partially assessed. The aim of this study was to evaluate the safety of AADs in pediatric patients with solid tumors. Clinical trials and observational studies were searched in PubMed, ISI Web of Science, and ClinicalTrials database For each included study, adverse events (AEs) were extracted. A meta-analysis was conducted by pooling proportions of AEs using a random intercept logistic regression model. Seventy studies were retrieved. Most part were clinical trials (55 out of 70), and only fifteen observational studies were found. Overall, proportion of serious and non-serious AEs of AADs used as monotherapy was 46% and 89%, respectively. Proportions of serious AEs varied among drugs: sunitinib, 79%; lenvatinib, 64%; sorafenib, 48%; ramucirumab, 41%; pazopanib, 30%; and vandetanib, 27%. A higher proportion of non-serious hematological AEs was found in the patients receiving pazopanib with respect to sunitinib and lenvatinib. The safety profile of AADs has been extensively investigated for mostly drugs in phase I and II trials and is limited to acute toxicities. Overall, one out of two patients using AAD drugs in monotherapy experienced a serious AE despite proportions varied per single drugs. When AADs were combined with standard chemotherapy, the proportion of AEs varied in relation to the single combinations.
Urinary Zinc Loss Identifies Prostate Cancer Patients
Authors: Maddalone Maria Grazia , Oderda Marco , Mengozzi Giulio , Gesmundo Iacopo , Novelli Francesco , Giovarelli Mirella , Gontero Paolo , Occhipinti Sergio
Published: October 2022

Prostate Cancer (PCa) is one of the most common malignancies in men worldwide, with 1.4 million diagnoses and 310,000 deaths in 2020. Currently, there is an intense debate regarding the serum prostatic specific antigen (PSA) test as a diagnostic tool in PCa due to the lack of specificity and high prevalence of over-diagnosis and over-treatments. One of the most consistent characteristics of PCa is the marked decrease in zinc; hence the lost ability to accumulate and secrete zinc represents a potential parameter for early detection of the disease. We quantified zinc levels in urine samples collected after a standardized prostatic massage from 633 male subjects that received an indication for prostate biopsy from 2015 and 2019 at AOU Città della Salute e della Scienza di Torino Hospital. We observed that the mean zinc levels were lower in the urine of cancer patients than in healthy subjects, with a decreasing trend in correlation with the progression of the disease. The combination of zinc with standard parameters, such as PSA, age, digital rectal exploration results, and magnetic resonance findings, displayed high diagnostic performance. These results suggest that urinary zinc may represent an early and non-invasive diagnostic biomarker for prostate cancer.
Gut Microbiota and Tumor Immune Escape: A New Perspective for Improving Tumor Immunotherapy
Authors: He Yunbo , Huang Jinliang , Li Qiaorong , Xia Weiping , Zhang Chunyu , Liu Zhi , Xiao Jiatong , Yi Zhenglin , Deng Hao , Xiao Zicheng , Hu Jiao , Li Huihuang , Zu Xiongbing , Quan Chao , Chen Jinbo
Published: October 2022

The gut microbiota is a large symbiotic community of anaerobic and facultative aerobic bacteria inhabiting the human intestinal tract, and its activities significantly affect human health. Increasing evidence has suggested that the gut microbiome plays an important role in tumor-related immune regulation. In the tumor microenvironment (TME), the gut microbiome and its metabolites affect the differentiation and function of immune cells regulating the immune evasion of tumors. The gut microbiome can indirectly influence individual responses to various classical tumor immunotherapies, including immune checkpoint inhibitor therapy and adoptive immunotherapy. Microbial regulation through antibiotics, prebiotics, and fecal microbiota transplantation (FMT) optimize the composition of the gut microbiome, improving the efficacy of immunotherapy and bringing a new perspective and hope for tumor treatment.
Range-Bounded Adaptive Therapy in Metastatic Prostate Cancer
Authors: Brady-Nicholls Renee , Enderling Heiko
Published: October 2022

Adaptive therapy with abiraterone acetate (AA), whereby treatment is cycled on and off, has been presented as an alternative to continuous therapy for metastatic castration resistant prostate cancer (mCRPC). It is hypothesized that cycling through treatment allows sensitive cells to competitively suppress resistant cells, thereby increasing the amount of time that treatment is effective. It has been proposed that there exists a subset of patients for whom this competition can be enhanced through slight modifications. Here, we investigate how adaptive AA can be modified to extend time to progression using a simple mathematical model of stem cell, non-stem cell, and prostate-specific antigen (PSA) dynamics. The model is calibrated to longitudinal PSA data from 16 mCRPC patients undergoing adaptive AA in a pilot clinical study at Moffitt Cancer Center. Model parameters are then used to simulate range-bounded adaptive therapy (RBAT) whereby treatment is modulated to maintain PSA levels between pre-determined patient-specific bounds. Model simulations of RBAT are compared to the clinically applied adaptive therapy and show that RBAT can further extend time to progression, while reducing the cumulative dose patients received in 11/16 patients. Simulations also show that the cumulative dose can be reduced by up to 40% under RBAT. Through small modifications to the conventional adaptive therapy design, our study demonstrates that RBAT offers the opportunity to improve patient care, particularly in those patients who do not respond well to conventional adaptive therapy.