bluuebunny/crossref_metadata_2025 huggingface dataset:
Do Neurotrophins Connect Neurological Disorders and Heart Diseases?
Authors: Fujitani Masashi , Otani Yoshinori , Miyajima Hisao
Published: November 2021

Neurotrophins (NTs) are one of the most characterized neurotrophic factor family members and consist of four members in mammals. Growing evidence suggests that there is a complex inter- and bi-directional relationship between central nervous system (CNS) disorders and cardiac dysfunction, so-called “brain–heart axis”. Recent studies suggest that CNS disorders, including neurodegenerative diseases, stroke, and depression, affect cardiovascular function via various mechanisms, such as hypothalamic–pituitary–adrenal axis augmentation. Although this brain–heart axis has been well studied in humans and mice, the involvement of NT signaling in the axis has not been fully investigated. In the first half of this review, we emphasize the importance of NTs not only in the nervous system, but also in the cardiovascular system from the embryonic stage to the adult state. In the second half, we discuss the involvement of NTs in the pathogenesis of cardiovascular diseases, and then examine whether an alteration in NTs could serve as the mediator between neurological disorders and heart dysfunction. The further investigation we propose herein could contribute to finding direct evidence for the involvement of NTs in the axis and new treatment for cardiovascular diseases.
Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability
Authors: Martín-Campos Jesús Maria
Published: November 2021

Changes in plasma low-density lipoprotein cholesterol (LDL-c) levels relate to a high risk of developing some common and complex diseases. LDL-c, as a quantitative trait, is multifactorial and depends on both genetic and environmental factors. In the pregenomic age, targeted genes were used to detect genetic factors in both hyper- and hypolipidemias, but this approach only explained extreme cases in the population distribution. Subsequently, the genetic basis of the less severe and most common dyslipidemias remained unknown. In the genomic age, performing whole-exome sequencing in families with extreme plasma LDL-c values identified some new candidate genes, but it is unlikely that such genes can explain the majority of inexplicable cases. Genome-wide association studies (GWASs) have identified several single-nucleotide variants (SNVs) associated with plasma LDL-c, introducing the idea of a polygenic origin. Polygenic risk scores (PRSs), including LDL-c-raising alleles, were developed to measure the contribution of the accumulation of small-effect variants to plasma LDL-c. This paper discusses other possibilities for unexplained dyslipidemias associated with LDL-c, such as mosaicism, maternal effect, and induced epigenetic changes. Future studies should consider gene–gene and gene–environment interactions and the development of integrated information about disease-driving networks, including phenotypes, genotypes, transcription, proteins, metabolites, and epigenetics.
Clinical and Radiological Deterioration in a Case of Creutzfeldt–Jakob Disease following SARS-CoV-2 Infection: Hints to Accelerated Age-Dependent Neurodegeneration
Authors: Ciolac Dumitru , Racila Renata , Duarte Carolina , Vasilieva Maria , Manea Diana , Gorincioi Nadejda , Condrea Alexandra , Crivorucica Igor , Zota Eremei , Efremova Daniela , Crivorucica Veaceslav , Ciocanu Mihail , Movila Alexandru , Groppa Stanislav A.
Published: November 2021

Systemic inflammation and the host immune responses associated with certain viral infections may accelerate the rate of neurodegeneration in patients with Creutzfeldt–Jakob disease (CJD), a rare, transmissible neurodegenerative disease. However, the effects of the newly emerged SARS-CoV-2 infection on the pathogenesis of CJD are unknown. In this study, we describe the case of an elderly female patient with sporadic CJD that exhibited clinical deterioration with the emergence of seizures and radiological neurodegenerative progression following an infection with SARS-CoV-2 and severe COVID-19. Despite efforts to control the progression of the disease, a dismal outcome ensued. This report further evidences the age-dependent neurological effects of SARS-CoV-2 infection and proposes a vulnerability to CJD and increased CJD progression following COVID-19.
MiRNAs as New Tools in Lesion Vitality Evaluation: A Systematic Review and Their Forensic Applications
Authors: Manetti Alice Chiara , Maiese Aniello , Baronti Arianna , Mezzetti Eleonora , Frati Paola , Fineschi Vittorio , Turillazzi Emanuela
Published: November 2021

Wound vitality demonstration is one of the most challenging fields in forensic pathology. In recent years, researchers focused on the application of histological and immunohistochemical staining in this sphere of study. It is based on the detection of inflammation, red cell infiltration, and tissue alterations at the histological examination, all of which are supposedly present in antemortem rather than post-mortem wounds. Nevertheless, some doubts about the reliability of those markers have arisen. Furthermore, the lack of a standardized protocol and the operator dependency of this approach make the proper interpretation of its results difficult. Moreover, a differential miRNAs expression has been demonstrated in antemortem and post-mortem wounds. Herein, a systematic review concerning the current knowledge about the use of miRNAs in lesion vitality evaluation is carried out, to encourage researchers to deepen this peculiar study area. A compendium about the potential miRNAs that may be further investigated as vitality markers is also provided. The aim is to collect all available data about this topic to direct further studies on this field and highlight the future applications of miRNAs in forensic pathology. We found 20 articles and a total of 51 miRNAs that are involved in inflammation and wound healing. Further studies are certainly needed to deepen the role of miRNAs in inflammatory processes in lesioned skin and to evaluate their reliability in distinguishing between antemortem and post-mortem lesions.
Acute Respiratory Distress Syndrome: Focus on Viral Origin and Role of Pulmonary Lymphatics
Authors: Fröhlich Eleonore
Published: November 2021

Acute respiratory distress syndrome (ARDS) is a serious affection of the lung caused by a variety of pathologies. Great interest is currently focused on ARDS induced by viruses (pandemic influenza and corona viruses). The review describes pulmonary changes in ARDS and specific effects of the pandemic viruses in ARDS, and summarizes treatment options. Because the known pathogenic mechanisms cannot explain all aspects of the syndrome, the contribution of pulmonary lymphatics to the pathology is discussed. Organization and function of lymphatics in a healthy lung and in resorption of pulmonary edema are described. A future clinical trial may provide more insight into the role of hyaluronan in ARDS but the development of promising pharmacological treatments is unlikely because drugs play no important role in lymphedema therapy.
Deep Learning for Human Disease Detection, Subtype Classification, and Treatment Response Prediction Using Epigenomic Data
Authors: Nguyen Thi Mai , Kim Nackhyoung , Kim Da Hae , Le Hoang Long , Piran Md Jalil , Um Soo-Jong , Kim Jin Hee
Published: November 2021

Deep learning (DL) is a distinct class of machine learning that has achieved first-class performance in many fields of study. For epigenomics, the application of DL to assist physicians and scientists in human disease-relevant prediction tasks has been relatively unexplored until very recently. In this article, we critically review published studies that employed DL models to predict disease detection, subtype classification, and treatment responses, using epigenomic data. A comprehensive search on PubMed, Scopus, Web of Science, Google Scholar, and arXiv.org was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Among 1140 initially identified publications, we included 22 articles in our review. DNA methylation and RNA-sequencing data are most frequently used to train the predictive models. The reviewed models achieved a high accuracy ranged from 88.3% to 100.0% for disease detection tasks, from 69.5% to 97.8% for subtype classification tasks, and from 80.0% to 93.0% for treatment response prediction tasks. We generated a workflow to develop a predictive model that encompasses all steps from first defining human disease-related tasks to finally evaluating model performance. DL holds promise for transforming epigenomic big data into valuable knowledge that will enhance the development of translational epigenomics.
Acne Syndromes and Mosaicism
Authors: Baroud Sumer , Wu Jim , Zouboulis Christos C.
Published: November 2021

Abnormal mosaicism is the coexistence of cells with at least two genotypes, by the time of birth, in an individual derived from a single zygote, which leads to a disease phenotype. Somatic mosaicism can be further categorized into segmental mosaicism and nonsegmental somatic mosaicism. Acne is a chronic illness characterized by inflammatory changes around and in the pilosebaceous units, commonly due to hormone- and inflammatory signaling-mediated factors. Several systemic disorders, such as congenital adrenal hyperplasia, polycystic ovarian syndrome, and seborrhoea-acne-hirsutism-androgenetic alopecia syndrome have classically been associated with acne. Autoinflammatory syndromes, including PAPA, PASH, PAPASH, PsAPASH, PsaPSASH, PASS, and SAPHO syndromes include acneiform lesions as a key manifestation. Mosaic germline mutations in the FGFR2 gene have been associated with Apert syndrome and nevus comedonicus, two illnesses that are accompanied by acneiform lesions. In this review, we summarize the concept of cutaneous mosaicism and elaborate on acne syndromes, as well as acneiform mosaicism.
Pattern of Repetitive Element Transcription Segregate Cell Lineages during the Embryogenesis of Sea Urchin Strongylocentrotus purpuratus
Authors: Panyushev Nick , Okorokova Larisa , Danilov Lavrentii , Adonin Leonid
Published: November 2021

Repetitive elements (REs) occupy a significant part of eukaryotic genomes and are shown to play diverse roles in genome regulation. During embryogenesis of the sea urchin, a large number of REs are expressed, but the role of these elements in the regulation of biological processes remains unknown. The aim of this study was to identify the RE expression at different stages of embryogenesis. REs occupied 44% of genomic DNA of Strongylocentrotus purpuratus. The most prevalent among these elements were the unknown elements—in total, they contributed 78.5% of REs (35% in total genome occupancy). It was revealed that the transcription pattern of genes and REs changes significantly during gastrulation. Using the de novo transcriptome assembly, we showed that the expression of RE is independent of its copy number in the genome. We also identified copies that are expressed. Only active RE copies were used for mapping and quantification of RE expression in the single-cell RNA sequencing data. REs expression was observed in all cell lineages and they were detected as population markers. Moreover, the primary mesenchyme cell (PMC) line had the greatest diversity of REs among the markers. Our data suggest a role for RE in the organization of developmental domains during the sea urchin embryogenesis at the single-cell resolution level.
Dynamic Effective Elasticity of Melanoma Cells under Shear and Elongational Flow Confirms Estimation from Force Spectroscopy
Authors: Jötten Anna Martina , Neidinger Simon V. , Tietze Julia K. , Welzel Julia , Westerhausen Christoph
Published: November 2021

The detection and enrichment of circulating melanoma cells is a challenge, as the cells are very heterogeneous in terms of their biomechanical properties and surface markers. In addition, there is a lack of valid and reliable biomarkers predicting progress and therapeutic response. In this study, we analyze the elasticity of A375 melanoma cells by applying force spectroscopy and a microfluidic method. To identify and eventually separate freely circulating tumor cells, it is crucial to know their physical properties precisely. First, we use standard AFM force spectroscopy, where the elasticity of the cells is calculated from indentation with a pyramidal tip. To extend the limits of the measurements with a tip, we then use cantilevers without a tip to apply force over a larger area of the cells. The resulting Young’s moduli are slightly lower and vary less without the tip, presumably because of the spatial inhomogeneity of the cells. Finally, we implement our microfluidic method: we measure single cell elasticity by analyzing their deformation in high-speed micrographs while passing a stenosis. Combining the force field and the change in shape provides the basis for a stress–strain diagram. The results from the microfluidic deformation analysis were well in accordance with the results from force spectroscopy. The microfluidic method, however, provides advantages over conventional methods, as it is less invasive and less likely to harm the cell during the measurement. The whole cell is measured as one entity without having contact to a stiff substrate, while force spectroscopy is limited to the contact area of the tip, and in some cases dependent of the cell substrate interaction. Consequently, microfluidic deformation analysis allows us to predict the overall elastic behavior of the whole, inhomogeneous cell in three-dimensional force fields. This method may contribute to improve the detection of circulating melanoma cells in the clinical practice.
An Exploratory Study on Resting-State Functional Connectivity in Individuals with Disorganized Attachment: Evidence for Key Regions in Amygdala and Hippocampus
Authors: Cruciani Gianluca , Boccia Maddalena , Lingiardi Vittorio , Giovanardi Guido , Zingaretti Pietro , Spitoni Grazia Fernanda
Published: November 2021

Studies comparing organized (O) and unresolved/disorganized (UD) attachment have consistently shown structural and functional brain abnormalities, although whether and how attachment patterns may affect resting state functional connectivity (RSFC) is still little characterized. Here, we investigated RSFC of temporal and limbic regions of interest for UD attachment. Participants’ attachment was classified via the Adult Attachment Interview, and all participants underwent clinical assessment. Functional magnetic resonance imaging data were collected from 11 UD individuals and seven matched O participants during rest. A seed-to-voxel analysis was performed, including the anterior and the posterior cingulate cortex, the bilateral insula, amygdala and hippocampus as seed regions. No group differences in the clinical scales emerged. Compared to O, the UD group showed lower RSFC between the left amygdala and the left cerebellum (lobules VIII), and lower functional coupling between the right hippocampus and the posterior portion of the right middle temporal gyrus. Moreover, UD participants showed higher RSFC between the right amygdala and the anterior cingulate cortex. Our findings suggest RSFC alterations in regions associated with encoding of salient events, emotion processing, memories retrieval and self-referential processing in UD participants, highlighting the potential role of attachment experiences in shaping brain abnormalities also in non-clinical UD individuals.
Blockchain-Based Trusted Property Transactions in the Built Environment: Development of an Incubation-Ready Prototype
Authors: Perera Srinath , Hijazi Amer A. , Weerasuriya Geeganage Thilini , Nanayakkara Samudaya , Rodrigo Muhandiramge Nimashi Navodana
Published: November 2021

Blockchain can be introduced to use cases in the built environment where reliability of transaction records is paramount. Blockchain facilitates decentralised, cryptographically secure, trustworthy, and immutable recordkeeping of transactions. However, more research is urgently required to understand the process and complications in implementing blockchain solutions in the built environment. This paper demonstrates a methodology for developing a blockchain system starting from problem analysis, selection of blockchain platform, system modelling, prototype development, and evaluation. The evolutionary prototyping model was selected as the software development methodology for the use case of property transactions. A systematic process protocol involving the multi-criteria decision-making method, Simple Multi Attribute Rating Technique (SMART), was used to select Hyperledger Fabric as the most suitable blockchain platform for the prototype. The system architecture facilitates a simplified, lean property transaction process implemented through chaincode (smart contract) algorithms and graphical user interfaces. System evaluation through test cases allowed iterative improvements, leading to an incubation-ready software prototype. The contribution to knowledge of this paper is in the demonstration of the process to follow to implement a blockchain solution for a specific domain. The findings provide the foundation for developing proofs of concept for other potential applications of blockchain in the built environment.
Interception of Signaling Circuits of Esophageal Adenocarcinoma Cells by Resveratrol Reveals Molecular and Immunomodulatory Signatures
Authors: Dhir Hardika , Choudhury Monica , Patil Ketki , Cheung Candice , Bodlak Adriana , Pardo Danny , Adams Asana , Travaglino Stefano , Rojas Jose Araque , Pai S. Balakrishna
Published: November 2021

Deregulation of signaling pathways due to mutations sets the cell on a path to neoplasia. Therefore, recent reports of increased mutations observed in esophageal tissue reflects the enhanced risk of tumor formation. In fact, adenocarcinoma of the esophagus has been on the rise lately. Increase in mortality due to a paucity of efficacious drugs for this cancer prompted us to discover molecular signatures to combat this malady. To this end, we chose resveratrol—a polyphenol with anticancer property—and studied its impact on three esophageal adenocarcinoma cell lines (OE33, OE19 and FLO-1) by multilevel profiling. Here, we show the impact of resveratrol on the viability of the three adenocarcinoma esophageal cell systems studied, at the cellular level. Furthermore, an analysis at the molecular level revealed that the action was through the programmed cell death pathway, resulting in an increase in apoptotic and caspase-positive cells. The impact on reactive oxygen species (ROS) and a decrease in Bcl2 levels were also observed. Moreover, proteomic profiling highlighted pivotal differentially regulated signaling molecules. The phenotypic effect observed in resveratrol-treated esophageal cells could be due to the stoichiometry per se of the fold changes observed in entities of key signaling pathways. Notably, the downregulation of Ku80 and other pivotal entities by resveratrol could be harnessed for chemo-radiation therapy to prevent DNA break repair after radiation therapy. Additionally, multilevel profiling has shed light on molecular and immune-modulatory signatures with implications for discovering novel treatments, including chemo-immunotherapy, for esophageal adenocarcinomas which are known to be aggressive cancers.
A Polygenic Risk Score Predicts Incident Prostate Cancer Risk in Older Men but Does Not Select for Clinically Significant Disease
Authors: Bakshi Andrew , Riaz Moeen , Orchard Suzanne G. , Carr Prudence R. , Joshi Amit D. , Cao Yin , Rebello Richard , Nguyen-Dumont Tú , Southey Melissa C. , Millar Jeremy L. , Gately Lucy , Gibbs Peter , Ford Leslie G. , Parnes Howard L. , Chan Andrew T. , McNeil John J. , Lacaze Paul
Published: November 2021

Despite the high prevalence of prostate cancer in older men, the predictive value of a polygenic risk score (PRS) remains uncertain in men aged ≥70 years. We used a 6.6 million-variant PRS to predict the risk of incident prostate cancer in a prospective study of 5701 men of European descent aged ≥70 years (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial. The study endpoint was prostate cancer, including metastatic or non-metastatic disease, confirmed by an expert panel. After excluding participants with a history of prostate cancer at enrolment, we used a multivariable Cox proportional hazards model to assess the association between the PRS and incident prostate cancer risk, adjusting for covariates. Additionally, we examined the distribution of Gleason grade groups by PRS group to determine if a higher PRS was associated with higher grade disease. We tested for interaction between the PRS and aspirin treatment. Logistic regression was used to independently assess the association of the PRS with prevalent (pre-trial) prostate cancer, reported in medical histories. During a median follow-up time of 4.6 years, 218 of the 5701 participants (3.8%) were diagnosed with prostate cancer. The PRS predicted incident risk with a hazard ratio (HR) of 1.52 per standard deviation (SD) (95% confidence interval (CI) 1.33–1.74, p < 0.001). Men in the top quintile of the PRS distribution had an almost three times higher risk of prostate cancer than men in the lowest quintile (HR = 2.99 (95% CI 1.90–4.27), p < 0.001). However, a higher PRS was not associated with a higher Gleason grade groups. We found no interaction between aspirin treatment and the PRS for prostate cancer risk. The PRS was also associated with prevalent prostate cancer (odds ratio = 1.80 per SD (95% CI 1.65–1.96), p < 0.001).While a PRS for prostate cancer is strongly associated with incident risk in men aged ≥70 years, the clinical utility of the PRS as a biomarker is currently limited by its inability to select for clinically significant disease.
Photothermal Therapy as Adjuvant to Surgery in an Orthotopic Mouse Model of Human Fibrosarcoma
Authors: Simón Marina , Jørgensen Jesper Tranekjær , Melander Fredrik , Andresen Thomas Lars , Christensen Anders , Kjaer Andreas
Published: November 2021

Surgery is still the first-line treatment for multiple solid cancers. However, recurrence is a common issue, especially when dealing with aggressive tumors or tumors that are difficult to completely remove due to their location. Getting clear surgical margins can be challenging, but treatment strategies combining surgery with other anti-cancer therapies can potentially improve the outcome. Photothermal therapy (PTT) is a technique that relies on photoabsorbing agents, such as gold nanoparticles, to transform light into local hyperthermia. This technique can be used to ablate tumor tissue where the photoabsorbing agent accumulates, sparing healthy surrounding tissue. In this study, we examined the potential of gold nanoparticle-based PTT as an adjuvant treatment to surgery in a mouse model of human fibrosarcoma. For this we performed subtotal tumor resection to mimic a clinical situation where total tumor removal is not achieved, and subsequent PTT was applied on the surgical field. Our results showed that animals undergoing adjuvant PTT after surgery presented sustained delayed tumor growth and improved survival when compared to animals that only underwent surgery. We believe that these findings show the potential of PTT as an adjuvant method to traditional tumor surgery and could pave way to more personalized treatment options.
Magnetometer-Guided Sentinel Lymph Node Dissection in Prostate Cancer: Rate of Lymph Node Involvement Compared with Radioisotope Marking
Authors: Engels Svenja , Michalik Bianca , Meyer Luca-Marie , Nemitz Lena , Wawroschek Friedhelm , Winter Alexander
Published: November 2021

Sentinel pelvic lymph node dissection (sPLND) enables the targeted removal of lymph nodes (LNs) bearing the highest metastasis risk. In prostate cancer (PCa), sPLND alone or combined with extended PLND (ePLND) reveals more LN metastases along with detecting sentinel LNs (SLNs) outside the conventional ePLND template. To overcome the disadvantages of radioisotope-guided sPLND in PCa treatment, magnetometer-guided sPLND applying superparamagnetic iron oxide nanoparticles as a tracer was established. This retrospective study compared the nodal staging ability between magnetometer- and radioisotope-guided sPLNDs. We analyzed data of PCa patients undergoing radical prostatectomy and magnetometer- (848 patients, 2015–2021) or radioisotope-guided (2092 patients, 2006–2015) sPLND. To reduce heterogeneity among cohorts, we performed propensity score matching and compared data considering sentinel nomogram-based probabilities for LN involvement (LNI). Magnetometer- and radioisotope-guided sPLNDs had SLN detection rates of 98.12% and 98.09%, respectively; the former detected more SLNs per patient. The LNI rates matched nomogram-based predictions in both techniques equally well. Approximately 7% of LN metastases were detected outside the conventional ePLND template. Thus, we confirmed the reliability of magnetometer-guided sPLND in nodal staging, with results comparable with or better than radioisotope-guided sPLND. Our findings highlight the importance of the sentinel technique for detecting LN metastases in PCa.
Leukemia Stem Cells as a Potential Target to Achieve Therapy-Free Remission in Chronic Myeloid Leukemia
Authors: Ito Kyoko , Ito Keisuke
Published: November 2021

Leukemia stem cells (LSCs, also known as leukemia-initiating cells) not only drive leukemia initiation and progression, but also contribute to drug resistance and/or disease relapse. Therefore, eradication of every last LSC is critical for a patient’s long-term cure. Chronic myeloid leukemia (CML) is a myeloproliferative disorder that arises from multipotent hematopoietic stem and progenitor cells. Tyrosine kinase inhibitors (TKIs) have dramatically improved long-term outcomes and quality of life for patients with CML in the chronic phase. Point mutations of the kinase domain of BCR-ABL1 lead to TKI resistance through a reduction in drug binding, and as a result, several new generations of TKIs have been introduced to the clinic. Some patients develop TKI resistance without known mutations, however, and the presence of LSCs is believed to be at least partially associated with resistance development and CML relapse. We previously proposed targeting quiescent LSCs as a therapeutic approach to CML, and a number of potential strategies for targeting insensitive LSCs have been presented over the last decade. The identification of specific markers distinguishing CML-LSCs from healthy HSCs, and the potential contributions of the bone marrow microenvironment to CML pathogenesis, have also been explored. Nonetheless, 25% of CML patients are still expected to switch TKIs at least once, and various TKI discontinuation studies have shown a wide range in the incidence of molecular relapse (from 30% to 60%). In this review, we revisit the current knowledge regarding the role(s) of LSCs in CML leukemogenesis and response to pharmacological treatment and explore how durable treatment-free remission may be achieved and maintained after discontinuing TKI treatment.
Identification of Gene Co-Expression Networks Associated with Consensus Molecular Subtype-1 of Colorectal Cancer
Authors: Nunez Sha’Kayla K. , Young Corey D. , Griffen Ti’ara L. , Ohandjo Adaugo Q. , McKinney Lawrence P. , Kopetz Scott , Lillard James W.
Published: November 2021

Colorectal cancer (CRC) is driven in part by dysregulated Wnt, Ras-Raf-MAPK, TGF-β, and PI3K-Akt signaling. The progression of CRC is also promoted by molecular alterations and heterogeneous—yet interconnected—gene mutations, chromosomal instability, transcriptomic subtypes, and immune signatures. Genomic alterations of CRC progression lead to changes in RNA expression, which support CRC metastasis. An RNA-based classification system used for CRC, known as consensus molecular subtyping (CMS), has four classes. CMS1 has the lowest survival after relapse of the four CRC CMS phenotypes. Here, we identify gene signatures and associated coding mRNAs that are co-expressed during CMS1 CRC progression. Using RNA-seq data from CRC primary tumor samples, acquired from The Cancer Genome Atlas (TCGA), we identified co-expression gene networks significantly correlated with CMS1 CRC progression. CXCL13, CXCR5, IL10, PIK3R5, PIK3AP1, CCL19, and other co-expressed genes were identified to be positively correlated with CMS1. The co-expressed eigengene networks for CMS1 were significantly and positively correlated with the TNF, WNT, and ERK1 and ERK2 signaling pathways, which together promote cell proliferation and survival. This network was also aligned with biological characteristics of CMS1 CRC, being positively correlated to right-sided tumors, microsatellite instability, chemokine-mediated signaling pathways, and immune responses. CMS1 also differentially expressed genes involved in PI3K-Akt signaling. Our findings reveal CRC gene networks related to oncogenic signaling cascades, cell activation, and positive regulation of immune responses distinguishing CMS1 from other CRC subtypes.
Rational Development of Liquid Biopsy Analysis in Renal Cell Carcinoma
Authors: Glennon Kate I. , Maralani Mahafarin , Abdian Narges , Paccard Antoine , Montermini Laura , Nam Alice Jisoo , Arseneault Madeleine , Staffa Alfredo , Jandaghi Pouria , Meehan Brian , Brimo Fadi , Tanguay Simon , Rak Janusz , Riazalhosseini Yasser
Published: November 2021

Renal cell carcinoma (RCC) is known for its variable clinical behavior and outcome, including heterogeneity in developing relapse or metastasis. Recent data highlighted the potential of somatic mutations as promising biomarkers for risk stratification in RCC. Likewise, the analysis of circulating tumor DNA (ctDNA) for such informative somatic mutations (liquid biopsy) is considered an important advance for precision oncology in RCC, allowing to monitor molecular disease evolution in real time. However, our knowledge about the utility of ctDNA analysis in RCC is limited, in part due to the lack of RCC-appropriate assays for ctDNA analysis. Here, by interrogating different blood compartments in xenograft models, we identified plasma cell-free (cf) DNA and extracellular vesicles (ev) DNA enriched for RCC-associated ctDNA. Additionally, we developed sensitive targeted sequencing and bioinformatics workflows capable of detecting somatic mutations in RCC-relevant genes with allele frequencies ≥ 0.5%. Applying this assay to patient-matched tumor and liquid biopsies, we captured tumor mutations in cf- and ev-DNA fractions isolated from the blood, highlighting the potentials of both fractions for ctDNA analysis. Overall, our study presents an RCC-appropriate sequencing assay and workflow for ctDNA analysis and provides a proof of principle as to the feasibility of detecting tumor-specific mutations in liquid biopsy in RCC patients.
Remote Skin Cancer Diagnosis: Adding Images to Electronic Referrals Is More Efficient Than Wait-Listing for a Nurse-Led Imaging Clinic
Authors: Jones Leah , Jameson Michael , Oakley Amanda
Published: November 2021

We undertook a retrospective comparison of two teledermatology pathways that provide diagnostic and management advice for suspected skin cancers, to evaluate the time from referral to diagnosis and its concordance with histology. Primary Care doctors could refer patients to either the Virtual Lesion Clinic (VLC), a nurse-led community teledermoscopy clinic or, more recently, to the Suspected Skin Cancer (SSC) pathway, which requires them to attach regional, close-up, and dermoscopic images. The primary objective of this study was to determine the comparative time course between the SSC pathway and VLC. Secondary objectives included comparative diagnostic concordance, skin lesion classification, and evaluation of missed skin lesions during subsequent follow-up. VLC referrals from July to December 2016 and 2020 were compared to SSC referrals from July to December 2020. 408 patients with 682 lesions in the VLC cohort were compared with 480 patients with 548 lesions from the 2020 SSC cohort, matched for age, sex, and ethnicity, including histology where available. Median time (SD) from referral to receipt of teledermatology advice was four (2.8) days and 50 (43.0) days for the SSC and VLC cohorts, respectively (p < 0.001). Diagnostic concordance between teledermatologist and histopathologist for benign versus malignant lesions was 70% for 114 lesions in the SSC cohort, comparable to the VLC cohort (71% of 122 lesions). Referrals from primary care, where skin lesions were imaged with variable devices and quality resulted in faster specialist advice with similar diagnostic performance compared to high-quality imaging at nurse-led specialist dermoscopy clinics.
Safety of COVID-19 mRNA Vaccines in Patients with Cancer Enrolled in Early-Phase Clinical Trials
Authors: Trillo Aliaga Pamela , Trapani Dario , Sandoval José Luis , Crimini Edoardo , Antonarelli Gabriele , Vivanet Grazia , Morganti Stefania , Corti Chiara , Tarantino Paolo , Friedlaender Alex , Belli Carmen , Minchella Ida , Locatelli Marzia , Esposito Angela , Criscitiello Carmen , Curigliano Giuseppe
Published: November 2021

Pivotal trials of COVID-19 vaccines did not include cancer patients, with questions remaining about their safety and efficacy in this population. Patients enrolled in early-phase clinical trials receive novel treatments with unknown efficacy and safety profiles. Studies on the safety of COVID-19 vaccines in these patients are urgently required. This is a retrospective, real-world, cohort study of patients receiving anticancer treatments and COVID-19 vaccines between 1 February and 25 June 2021 at the Division of New Drugs Development for Innovative Therapies of the European Institute of Oncology. One hundred thirteen patients were enrolled, 40 in early-phase clinical trials, and 20 under novel immunotherapy agents. Nearly three-quarters of the patients experienced at least one adverse event (AE) after the first dose (1D) (74.3%) and second dose (2D) (72.6%). Most of the AEs were local (67.3% 1D and 61.9% after 2D), while 31.8% (1D) and 38.1% (2D) of the patients had systemic AEs. No AEs above grade 2 were observed. Therefore, COVID-19 vaccines appear to be safe in patients enrolled in early-phase clinical trials, including patients receiving novel immunotherapy compounds. All cancer patients should be prioritized for COVID-19 vaccination, regardless of ongoing treatments or enrollment in early-phase trials.
A Multicenter Epidemiological Study on Second Malignancy in Non-Syndromic Pheochromocytoma/Paraganglioma Patients in Italy
Authors: Canu Letizia , Puglisi Soraya , Berchialla Paola , De Filpo Giuseppina , Brignardello Francesca , Schiavi Francesca , Ferrara Alfonso Massimiliano , Zovato Stefania , Luconi Michaela , Pia Anna , Appetecchia Marialuisa , Arvat Emanuela , Letizia Claudio , Maccario Mauro , Parasiliti-Caprino Mirko , Altieri Barbara , Faggiano Antongiulio , Modica Roberta , Morelli Valentina , Arosio Maura , Verga Uberta , Pellegrino Micaela , Petramala Luigi , Concistrè Antonio , Razzore Paola , Ercolino Tonino , Rapizzi Elena , Maggi Mario , Stigliano Antonio , Burrello Jacopo , Terzolo Massimo , Opocher Giuseppe , Mannelli Massimo , Reimondo Giuseppe
Published: November 2021

No studies have carried out an extensive analysis of the possible association between non-syndromic pheochromocytomas and paragangliomas (PPGLs) and other malignancies. To assess >the risk of additional malignancy in PPGL, we retrospectively evaluated 741 patients with PPGLs followed-up in twelve referral centers in Italy. Incidence of second malignant tumors was compared between this cohort and Italian patients with two subsequent malignancies. Among our patients, 95 (12.8%) developed a second malignant tumor, which were mainly prostate, colorectal and lung/bronchial cancers in males, breast cancer, differentiated thyroid cancer and melanoma in females. The standardized incidence ratio was 9.59 (95% CI 5.46–15.71) in males and 13.21 (95% CI 7.52–21.63) in females. At multivariable analysis, the risk of developing a second malignant tumor increased with age at diagnosis (HR 2.50, 95% CI 1.15–5.44, p = 0.021 for 50–59 vs. <50-year category; HR 3.46, 95% CI 1.67–7.15, p < 0.001 for >60- vs. <50-year). In patients with available genetic evaluation, a positive genetic test was inversely associated with the risk of developing a second tumor (HR 0.25, 95% CI 0.10–0.63, p = 0.003). In conclusion, PPGLs patients have higher incidence of additional malignant tumors compared to the general population who had a first malignancy, which could have an impact on the surveillance strategy.
Soluble PD-L1 in Serum and Urine in Urinary Bladder Cancer Patients
Authors: Vikerfors Anders , Davidsson Sabina , Frey Janusz , Jerlström Tomas , Carlsson Jessica
Published: November 2021

Soluble PD-L1 (sPD-L1) levels have been identified as a potential biomarker for various cancers, but its diagnostic and prognostic value in urinary bladder cancer (BC) remains to be fully elucidated. In this study, we investigated sPD-L1 levels in serum and urine samples from 132 patients with BC and compared them to 51 patients with hematuria (controls). The levels of sPD-L1 in serum and urine were determined using ELISA. Soluble PD-L1 could be detected in 99.5% of the serum samples and 34.4% of the urine samples. Patients diagnosed with BC had significantly higher urinary levels of sPD-L1, compared to controls, however no difference were found in serum sPD-L1 levels (p = 0.038 and p = 0.61, respectively). Significantly higher serum sPD-L1 levels were found in patients with muscle invasive disease and metastatic disease, compared to patients with non-muscle invasive BC and non-metastatic disease (p < 0.05). There was also a trend for higher urine sPD-L1 levels in patients with metastatic disease, compared to patients with non-metastatic disease (p = 0.05). The results from this study suggest that sPD-L1 in serum, but not in urine, could be a potential prognostic biomarker for patients with BC.
Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: From Epidemiology to Diagnostic Approach
Authors: Grgurevic Ivica , Bozin Tonci , Mikus Mislav , Kukla Michal , O’Beirne James
Published: November 2021

Non-alcoholic fatty liver disease (NAFLD) is becoming the leading cause of liver morbidity worldwide and, as such, represents the pathogenic background for the increasing incidence of hepatocellular carcinoma (HCC). The annual incidence of NAFLD-related HCC is expected to increase by 45–130% by 2030. Diabetes mellitus is the most important risk factor for HCC development in NAFLD, with the risk further increased when associated with other metabolic traits, such as obesity, arterial hypertension and dyslipidemia. The highest risk of HCC exists in patients with advanced fibrosis or cirrhosis, although 20–50% of HCC cases arise in NAFLD patients with an absence of cirrhosis. This calls for further investigation of the pathogenic mechanisms that are involved in hepatocarcinogenesis, including genetics, metabolomics, the influence of the gut microbiota and immunological responses. Early identification of patients with or at risk of NAFLD is of utmost importance to improve outcomes. As NAFLD is highly prevalent in the community, the identification of cases should rely upon simple demographic and clinical characteristics. Once identified, these patients should then be evaluated for the presence of advanced fibrosis or cirrhosis and subsequently enter HCC surveillance programs if appropriate. A significant problem is the early recognition of non-cirrhotic NAFLD patients who will develop HCC, where new biomarkers and scores are potential solutions to tackle this issue.
1H-NMR Plasma Lipoproteins Profile Analysis Reveals Lipid Metabolism Alterations in HER2-Positive Breast Cancer Patients
Authors: Corona Giuseppe , Di Gregorio Emanuela , Vignoli Alessia , Muraro Elena , Steffan Agostino , Miolo Gianmaria
Published: November 2021

The lipid tumour demand may shape the host metabolism adapting the circulating lipids composition to its growth and progression needs. This study aims to exploit the straightforward 1H-NMR lipoproteins analysis to investigate the alterations of the circulating lipoproteins’ fractions in HER2-positive breast cancer and their modulations induced by treatments. The baseline 1H-NMR plasma lipoproteins profiles were measured in 43 HER2-positive breast cancer patients and compared with those of 28 healthy women. In a subset of 32 patients, longitudinal measurements were also performed along neoadjuvant chemotherapy, after surgery, adjuvant treatment, and during the two-year follow-up. Differences between groups were assessed by multivariate PLS-DA and by univariate analyses. The diagnostic power of lipoproteins subfractions was assessed by ROC curve, while lipoproteins time changes along interventions were investigated by ANOVA analysis. The PLS-DA model distinguished HER2-positive breast cancer patients from the control group with a sensitivity of 96.4% and specificity of 90.7%, mainly due to the differential levels of VLDLs subfractions that were significantly higher in the patients’ group. Neoadjuvant chemotherapy-induced a significant drop in the HDLs after the first three months of treatment and a specific decrease in the HDL-3 and HDL-4 subfractions were found significantly associated with the pathological complete response achievement. These results indicate that HER2-positive breast cancer is characterized by a significant host lipid mobilization that could be useful for diagnostic purposes. Moreover, the lipoproteins profiles alterations induced by the therapeutic interventions could predict the clinical outcome supporting the application of 1H-NMR lipoproteins profiles analysis for longitudinal monitoring of HER2-positive breast cancer in large clinical studies.
A 5-(2-Pyridyl)tetrazolate Complex of Molybdenum(VI), Its Structure, and Transformation to a Molybdenum Oxide-Based Hybrid Heterogeneous Catalyst for the Epoxidation of Olefins
Authors: Nunes Martinique S. , Gomes Diana M. , Gomes Ana C. , Neves Patrícia , Mendes Ricardo F. , Paz Filipe A. Almeida , Lopes André D. , Valente Anabela A. , Gonçalves Isabel S. , Pillinger Martyn
Published: November 2021

There is a considerable practical interest in discovering new ways to obtain organomolybdenum heterogeneous catalysts for olefin epoxidation that are easier to recover and reuse and display enhanced productivity. In this study, the complex salt (H2pytz)[MoO2Cl2(pytz)] (1) (Hpytz = 5-(2-pyridyl)tetrazole) has been prepared, structurally characterized, and employed as a precursor for the hydrolysis-based synthesis of a microcrystalline molybdenum oxide/organic hybrid material formulated as [MoO3(Hpytz)] (2). In addition to single-crystal X-ray diffraction (for 1), compounds 1 and 2 were characterized by FT-IR and Raman spectroscopies, solid-state 13C{1H} cross-polarization (CP) magic-angle spinning (MAS) NMR, and scanning electron microscopy (SEM). Compounds 1 and 2 were evaluated as olefin epoxidation catalysts using the model reaction of cis-cyclooctene (Cy8) with tert-butyl hydroperoxide (TBHP), at 70 °C, which gave 100% epoxide selectivity up to 100% conversion. While 1 behaved as a homogeneous catalyst, hybrid 2 behaved as a heterogeneous catalyst and could be recovered for recycling without showing structural degradation or loss of catalytic performance over consecutive reaction cycles. The substrate scope was broadened to monoterpene DL-limonene (Lim) and biobased unsaturated fatty acid methyl esters, methyl oleate (MeOle), and methyl linoleate (MeLin), which gave predominantly epoxide products.
Development of Antimicrobial Cotton Fabric Impregnating AgNPs Utilizing Contemporary Practice
Authors: Repon Md. Reazuddin , Islam Tarikul , Sadia Halima Tus , Mikučionienė Daiva , Hossain Shakhawat , Kibria Golam , Kaseem Mosab
Published: November 2021

Multifunctional fabrics using conventional processes have piqued increasing global interest. The focus of this experiment was to assess the modification of the cotton fabric surface by utilizing silver nanoparticles (AgNPs) and introducing functional properties along with sustainable dyeing performance. A single-jersey knitted fabric composed of cellulose-enriched 100% natural fiber (cotton) with an areal density of 172 GSM was used in this study. The standard recipe and test methods were employed. FTIR-ATR spectra were used to determine the fixing of AgNPs onto the fiber surface. A comparative assessment was conducted in response to the distribution of color, color fastness to wash, water, perspiration, rubbing, and light. Scanning electron microscopy (SEM) was used to characterize the surface of nano-Ag-deposited specimens. In terms of functional properties, antimicrobial activity was scrutinized. Our findings reveal that the nanoparticles impart remarkable antibacterial effects to cellulose-enriched fabric against S. aureus (Gram-positive) and E. coli (Gram-negative). Direct dyes were used for dyeing the proposed samples, resulting in enhanced dyeing performance. Except for light fastness, the samples dipped with AgNPs showed outstanding color levelness and color durability characteristics. The developed fabrics can be applied in a wide range of functions, including protective clothing, packaging materials, and healthcare, among others.
Degradation Mechanisms Occurring in PTFE-Based Coatings Employed in Food-Processing Applications
Authors: Rondinella Alfredo , Andreatta Francesco , Turrin Daniele , Fedrizzi Lorenzo
Published: November 2021

The application of polytetrafluoroethylene (PTFE) coatings to metal surfaces is a well-known procedure carried out to avoid fouling phenomena on food-processing surfaces. Fluorine-based polymers are generally chemically and thermally stable, thus allowing them to be the preferred choice when designing anti-stick coatings in the food service industry. Their lifespan, however, depends on the environmental conditions. It is well known that thermal ageing can affect the properties of PTFE polymers and reduce their mechanical, thermal, and chemical properties causing failures and contaminating food. The main goal of the study is to identify the different failure mechanisms occurring in PTFE-based coatings, using both SEM/EDXS and ATR FT-IR data to reveal the starting point of degradation phenomena in food processing applications. The results from this research reveal that the preferential points for failures are mainly the polymer/substrate interfaces, the polymer/filler interfaces, or the polymer matrix itself.
Data Analysis of Two-Phase Flow Simulation Experiment of Array Optical Fiber and Array Resistance Probe
Authors: Cui Shuaifei , Liu Junfeng , Li Kui , Li Qinze
Published: November 2021

To solve the problem that traditional single-probe instruments cannot accurately measure the gas and water holdup, the domestic design of the array holdup measuring instrument Array of Optical and Resistance Tool (AORT), composed of five sets of optical fiber probes and five sets of resistance probes, is carried out in both gas–water and oil–water. Simulated measurement experiments were conducted under different water cut in phase flow. Through the analysis of the experimental data, the response relationship between the optical fiber probe and the resistance probe of the AORT instrument in different fluids was obtained. Then, the data under different conditions of fluid, flowrate and water cut in the experiment were compared by drawing. Interpolation algorithm was used to perform two-maintenance holdup imaging, and finally the holdup image was compared with the pictures of the flow in the pipe recorded during the experiment. The results show that the resistance probe has a better response under low water cut conditions, and the optical fiber probe has a better response under high gas cut conditions, which is consistent with the theoretical analysis. The imaging diagram and the flow pattern in the pipe during the experiment are in good agreement. It can be seen that the accuracy of the holdup measured by the AORT instrument under the test conditions is verified, and can provide technical support for further carrying out the measurement and interpretation of the holdup in future, as well as the improvement of the instrument and on-site testing.