bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteomic Profiling of Archived Tissue of Primary Melanoma Identifies Proteins Associated with Metastasis
Authors: Shapanis Andrew , Lai Chester , Sommerlad Mathew , Parkinson Erika , Healy Eugene , Skipp Paul
Published: November 2020

Formalin-fixed paraffin embedded (FFPE) clinical tissues represent an abundant and unique resource for translational proteomic studies. In the US, melanoma is the 5th and 6th most common cancer in men and women, respectively, affecting over 230,000 people annually and metastasising in 5–15% of cases. Median survival time for distant metastatic melanoma is 6–9 months with a 5-year-survival of < 15%. In this study, 24 primary FFPE tumours which have metastasised (P-M) and 24 primary FFPE tumours which did not metastasise (P-NM) were subjected to proteomic profiling. In total, 2750 proteins were identified, of which 16 were significantly differentially expressed. Analysis of TCGA data demonstrated that expression of the genes encoding for 6 of these 16 proteins had a significant effect on survival in cutaneous melanoma. Pathway analysis of the proteomics data revealed mechanisms likely involved in the process of melanoma metastasis, including cytoskeleton rearrangement, extracellular changes and immune system alterations. A machine learning prediction model scoring an AUC of 0.922, based on these 16 differentially expressed proteins was able to accurately classify samples into P-M and P-NM. This study has identified potential biomarkers and key processes relating to melanoma metastasis using archived clinical samples, providing a basis for future studies in larger cohorts.
Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression
Authors: Yang Guang , Shi Rachel , Zhang Qing
Published: November 2020

Oxygen homeostasis regulation is the most fundamental cellular process for adjusting physiological oxygen variations, and its irregularity leads to various human diseases, including cancer. Hypoxia is closely associated with cancer development, and hypoxia/oxygen-sensing signaling plays critical roles in the modulation of cancer progression. The key molecules of the hypoxia/oxygen-sensing signaling include the transcriptional regulator hypoxia-inducible factor (HIF) which widely controls oxygen responsive genes, the central members of the 2-oxoglutarate (2-OG)-dependent dioxygenases, such as prolyl hydroxylase (PHD or EglN), and an E3 ubiquitin ligase component for HIF degeneration called von Hippel–Lindau (encoding protein pVHL). In this review, we summarize the current knowledge about the canonical hypoxia signaling, HIF transcription factors, and pVHL. In addition, the role of 2-OG-dependent enzymes, such as DNA/RNA-modifying enzymes, JmjC domain-containing enzymes, and prolyl hydroxylases, in gene regulation of cancer progression, is specifically reviewed. We also discuss the therapeutic advancement of targeting hypoxia and oxygen sensing pathways in cancer.
Distinct Molecular Pattern-Induced Calcium Signatures Lead to Different Downstream Transcriptional Regulations via AtSR1/CAMTA3
Authors: Yuan Peiguo , Jewell Jeremy B. , Behera Smrutisanjita , Tanaka Kiwamu , Poovaiah B. W.
Published: November 2020

Plants encrypt the perception of different pathogenic stimuli into specific intracellular calcium (Ca2+) signatures and subsequently decrypt the signatures into appropriate downstream responses through various Ca2+ sensors. Two microbe-associated molecular patterns (MAMPs), bacterial flg22 and fungal chitin, and one damage-associated molecular pattern (DAMP), AtPep1, were used to study the differential Ca2+ signatures in Arabidopsis leaves. The results revealed that flg22, chitin, and AtPep1 induced distinct changes in Ca2+ dynamics in both the cytosol and nucleus. In addition, Flg22 and chitin upregulated the expression of salicylic acid-related genes, ICS1 and EDS1, whereas AtPep1 upregulated the expression of jasmonic acid-related genes, JAZ1 and PDF1.2, in addition to ICS1 and EDS1. These data demonstrated that distinct Ca2+ signatures caused by different molecular patterns in leaf cells lead to specific downstream events. Furthermore, these changes in the expression of defense-related genes were disrupted in a knockout mutant of the AtSR1/CAMTA3 gene, encoding a calmodulin-binding transcription factor, in which a calmodulin-binding domain on AtSR1 was required for deciphering the Ca2+ signatures into downstream transcription events. These observations extend our knowledge regarding unique and intrinsic roles for Ca2+ signaling in launching and fine-tuning plant immune response, which are mediated by the AtSR1/CAMTA3 transcription factor.
Recent Updates of Transarterial Chemoembolilzation in Hepatocellular Carcinoma
Authors: Chang Young , Jeong Soung Won , Young Jang Jae , Jae Kim Yong
Published: November 2020

Transarterial chemoembolization (TACE) is a standard treatment for intermediate-stage hepatocellular carcinoma (HCC). In this review, we summarize recent updates on the use of TACE for HCC. TACE can be performed using two techniques; conventional TACE (cTACE) and drug-eluting beads using TACE (DEB-TACE). The anti-tumor effect of the two has been reported to be similar; however, DEB-TACE carries a higher risk of hepatic artery and biliary injuries and a relatively lower risk of post-procedural pain than cTACE. TACE can be used for early stage HCC if other curative treatments are not feasible or as a neoadjuvant treatment before liver transplantation. TACE can also be considered for selected patients with limited portal vein thrombosis and preserved liver function. When deciding to repeat TACE, the ART (Assessment for Retreatment with TACE) score and ABCR (AFP, BCLC, Child-Pugh, and Response) score can guide the decision process, and TACE refractoriness needs to be considered. Studies on the combination therapy of TACE with other treatment modalities, such as local ablation, radiation therapy, or systemic therapy, have been actively conducted and are still ongoing. Recently, new prognostic models, including analysis of the neutrophil-lymphocyte ratio, radiomics, and deep learning, have been developed to help predict survival after TACE.
Histamine H2-Receptor Antagonists Improve Non-Steroidal Anti-Inflammatory Drug-Induced Intestinal Dysbiosis
Authors: Kawashima Rei , Tamaki Shun , Kawakami Fumitaka , Maekawa Tatsunori , Ichikawa Takafumi
Published: November 2020

Dysbiosis, an imbalance of intestinal flora, can cause serious conditions such as obesity, cancer, and psychoneurological disorders. One cause of dysbiosis is inflammation. Ulcerative enteritis is a side effect of non-steroidal anti-inflammatory drugs (NSAIDs). To counteract this side effect, we proposed the concurrent use of histamine H2 receptor antagonists (H2RA), and we examined the effect on the intestinal flora. We generated a murine model of NSAID-induced intestinal mucosal injury, and we administered oral H2RA to the mice. We collected stool samples, compared the composition of intestinal flora using terminal restriction fragment length polymorphism, and performed organic acid analysis using high-performance liquid chromatography. The intestinal flora analysis revealed that NSAID [indomethacin (IDM)] administration increased Erysipelotrichaceae and decreased Clostridiales but that both had improved with the concurrent administration of H2RA. Fecal levels of acetic, propionic, and n-butyric acids increased with IDM administration and decreased with the concurrent administration of H2RA. Although in NSAID-induced gastroenteritis the proportion of intestinal microorganisms changes, leading to the deterioration of the intestinal environment, concurrent administration of H2RA can normalize the intestinal flora.
Prolonged Immobilization Exacerbates the Loss of Muscle Mass and Function Induced by Cancer-Associated Cachexia through Enhanced Proteolysis in Mice
Authors: Mañas-García Laura , Penedo-Vázquez Antonio , López-Postigo Adrián , Deschrevel Jorieke , Durán Xavier , Barreiro Esther
Published: November 2020

We hypothesized that in mice with lung cancer (LC)-induced cachexia, periods of immobilization of the hindlimb (7 and 15 days) may further aggravate the process of muscle mass loss and function. Mice were divided into seven groups (n = 10/group): (1) non-immobilized control mice, (2) 7-day unloaded mice (7-day I), (3) 15-day unloaded mice (15-day I), (4) 21-day LC-cachexia group (LC 21-days), (5) 30-day LC-cachexia group (LC 30-days), (6) 21-day LC-cachexia group besides 7 days of unloading (LC 21-days + 7-day I), (7) 30-day LC-cachexia group besides 15 days of unloading (LC 30-days + 15-day I). Physiological parameters, body weight, muscle and tumor weights, phenotype and morphometry, muscle damage (including troponin I), proteolytic and autophagy markers, and muscle regeneration markers were identified in gastrocnemius muscle. In LC-induced cachexia mice exposed to hindlimb unloading, gastrocnemius weight, limb strength, fast-twitch myofiber cross-sectional area, and muscle regeneration markers significantly decreased, while tumor weight and area, muscle damage (troponin), and proteolytic and autophagy markers increased. In gastrocnemius of cancer-cachectic mice exposed to unloading, severe muscle atrophy and impaired function was observed along with increased muscle proteolysis and autophagy, muscle damage, and impaired muscle regeneration.
Whole-Transcriptome Sequencing-Based Analysis of DAZL and Its Interacting Genes during Germ Cells Specification and Zygotic Genome Activation in Chickens
Authors: Rengaraj Deivendran , Won Sohyoung , Han Jong Won , Yoo DongAhn , Kim Heebal , Han Jae Yong
Published: November 2020

The deleted in azoospermia like (DAZL) is required for germ cells development and maintenance. In chickens, the mRNA and protein of DAZL, a representative maternally inherited germ plasm factor, are detected in the germ plasm of oocyte, zygote, and all stages of the intrauterine embryos. However, it is still insufficient to explain the origin and specification process of chicken germ cells, because the stage at which the zygotic transcription of DAZL occurs and the stage at which the maternal DAZL RNA/protein clears have not yet been fully identified. Moreover, a comprehensive understanding of the expression of DAZL interacting genes during the germ cells specification and development and zygotic genome activation (ZGA) is lacking in chickens. In this study, we identified a set of DAZL interacting genes in chickens using in silico prediction method. Then, we analyzed the whole-transcriptome sequencing (WTS)-based expression of DAZL and its interacting genes in the chicken oocyte, zygote, and Eyal-Giladi and Kochav (EGK) stage embryos (EGK.I to EGK.X). In the results, DAZL transcripts are increased in the zygote (onset of transcription), maintained the increased level until EGK.VI, and decreased from EGK.VIII (possible clearance of maternal RNAs). Among the DAZL interacting genes, most of them are increased either at 1st ZGA or 2nd ZGA, indicating their involvement in germ cells specification and development.
Heme-Induced Oxidation of Cysteine Groups of Myofilament Proteins Leads to Contractile Dysfunction of Permeabilized Human Skeletal Muscle Fibres
Authors: Alvarado Gerardo , Tóth Attila , Csősz Éva , Kalló Gergő , Dankó Katalin , Csernátony Zoltán , Smith Ann , Gram Magnus , Akerström Bo , Édes István , Balla György , Papp Zoltán , Balla József
Published: November 2020

Heme released from red blood cells targets a number of cell components including the cytoskeleton. The purpose of the present study was to determine the impact of free heme (20–300 µM) on human skeletal muscle fibres made available during orthopedic surgery. Isometric force production and oxidative protein modifications were monitored in permeabilized skeletal muscle fibre segments. A single heme exposure (20 µM) to muscle fibres decreased Ca2+-activated maximal (active) force (Fo) by about 50% and evoked an approximately 3-fold increase in Ca2+-independent (passive) force (Fpassive). Oxidation of sulfhydryl (SH) groups was detected in structural proteins (e.g., nebulin, α-actinin, meromyosin 2) and in contractile proteins (e.g., myosin heavy chain and myosin-binding protein C) as well as in titin in the presence of 300 µM heme. This SH oxidation was not reversed by dithiothreitol (50 mM). Sulfenic acid (SOH) formation was also detected in the structural proteins (nebulin, α-actinin, meromyosin). Heme effects on SH oxidation and SOH formation were prevented by hemopexin (Hpx) and α1-microglobulin (A1M). These data suggest that free heme has a significant impact on human skeletal muscle fibres, whereby oxidative alterations in structural and contractile proteins limit contractile function. This may explain and or contribute to the weakness and increase of skeletal muscle stiffness in chronic heart failure, rhabdomyolysis, and other hemolytic diseases. Therefore, therapeutic use of Hpx and A1M supplementation might be effective in preventing heme-induced skeletal muscle alterations.
The Role of RIPK1 and RIPK3 in Cardiovascular Disease
Authors: DeRoo Elise , Zhou Ting , Liu Bo
Published: November 2020

Cardiovascular diseases, including peripheral arterial and venous disease, myocardial infarction, and stroke, are the number one cause of death worldwide annually. In the last 20 years, the role of necroptosis, a newly identified form of regulated necrotic cell death, in cardiovascular disease has come to light. Specifically, the damaging role of two kinase proteins pivotal in the necroptosis pathway, Receptor Interacting Protein Kinase 1 (RIPK1) and Receptor Interacting Protein Kinase 3 (RIPK3), in cardiovascular disease has become a subject of great interest and importance. In this review, we provide an overview of the current evidence supporting a pathologic role of RIPK1 and RIPK3 in cardiovascular disease. Moreover, we highlight the evidence behind the efficacy of targeted RIPK1 and RIPK3 inhibitors in the prevention and treatment of cardiovascular disease.
Identifying Cancer-Relevant Mutations in the DLC START Domain Using Evolutionary and Structure-Function Analyses
Authors: Holub Ashton S. , Bouley Renee A. , Petreaca Ruben C. , Husbands Aman Y.
Published: November 2020

Rho GTPase signaling promotes proliferation, invasion, and metastasis in a broad spectrum of cancers. Rho GTPase activity is regulated by the deleted in liver cancer (DLC) family of bona fide tumor suppressors which directly inactivate Rho GTPases by stimulating GTP hydrolysis. In addition to a RhoGAP domain, DLC proteins contain a StAR-related lipid transfer (START) domain. START domains in other organisms bind hydrophobic small molecules and can regulate interacting partners or co-occurring domains through a variety of mechanisms. In the case of DLC proteins, their START domain appears to contribute to tumor suppressive activity. However, the nature of this START-directed mechanism, as well as the identities of relevant functional residues, remain virtually unknown. Using the Catalogue of Somatic Mutations in Cancer (COSMIC) dataset and evolutionary and structure-function analyses, we identify several conserved residues likely to be required for START-directed regulation of DLC-1 and DLC-2 tumor-suppressive capabilities. This pan-cancer analysis shows that conserved residues of both START domains are highly overrepresented in cancer cells from a wide range tissues. Interestingly, in DLC-1 and DLC-2, three of these residues form multiple interactions at the tertiary structural level. Furthermore, mutation of any of these residues is predicted to disrupt interactions and thus destabilize the START domain. As such, these mutations would not have emerged from traditional hotspot scans of COSMIC. We propose that evolutionary and structure-function analyses are an underutilized strategy which could be used to unmask cancer-relevant mutations within COSMIC. Our data also suggest DLC-1 and DLC-2 as high-priority candidates for development of novel therapeutics that target their START domain.
The Roles of Host 5-Methylcytosine RNA Methyltransferases during Viral Infections
Authors: Wnuk Maciej , Slipek Piotr , Dziedzic Mateusz , Lewinska Anna
Published: November 2020

Eukaryotic 5-methylcytosine RNA methyltransferases catalyze the transfer of a methyl group to the fifth carbon of a cytosine base in RNA sequences to produce 5-methylcytosine (m5C). m5C RNA methyltransferases play a crucial role in the maintenance of functionality and stability of RNA. Viruses have developed a number of strategies to suppress host innate immunity and ensure efficient transcription and translation for the replication of new virions. One such viral strategy is to use host m5C RNA methyltransferases to modify viral RNA and thus to affect antiviral host responses. Here, we summarize the latest findings concerning the roles of m5C RNA methyltransferases, namely, NOL1/NOP2/SUN domain (NSUN) proteins and DNA methyltransferase 2/tRNA methyltransferase 1 (DNMT2/TRDMT1) during viral infections. Moreover, the use of m5C RNA methyltransferase inhibitors as an antiviral therapy is discussed.
Prevention of Diabetes and Cardiovascular Disease in Obesity
Authors: La Sala Lucia , Pontiroli Antonio E.
Published: November 2020

Obesity is one of the major risk factors for the development of both impaired glucose tolerance (IGT, or prediabetes) and type 2 diabetes (T2D), and its prevalence worldwide drives toward an increased rate of cardiovascular morbidity and mortality. Given the estimations of the World Health Organization (WHO) and the recommendation of the Diabetes Prevention Program (DPP), where IGT and diabetes are considered as risk factors for the development of cardiovascular complications and obesity, the development of diabetes should be treated because of its potential reversibility. In this view, several interventions such as diet, lifestyle changes, and pharmacological treatment are effective, including bariatric metabolic surgery (BMS), which is the most incisive way to efficiently lower body weight. In this review, we sought to summarize some of the major aspects linked to diabetes prevention in overweight/obesity, focusing on the use of surgery; we also attempted to elucidate molecular pathways involved in a variety of obesity-induced processes able to favor the progression of chronic diseases, such as diabetes and its complications.
Idiopathic Osteoporosis and Nephrolithiasis: Two Sides of the Same Coin?
Authors: Rendina Domenico , De Filippo Gianpaolo , Iannuzzo Gabriella , Abate Veronica , Strazzullo Pasquale , Falchetti Alberto
Published: November 2020

Idiopathic osteoporosis and nephrolithiasis are formidable health problems showing a progressive increase in their incidence and prevalence in the last decades. These temporal trends were observed in both pediatric and adult populations worldwide. Epidemiological and experimental studies indicate that both disorders show several common pathogenic environmental and genetic factors. In this review, we analyzed the clinical characteristics common to the two disorders and the state-of-the-art knowledge regarding the genetic predisposition and the environmental factors recognized as triggers in adult and pediatric ages. As a result of this work, we propose to consider idiopathic nephrolithiasis and osteoporosis as two possible expressions of a unique clinical syndrome. Accordingly, the clinical approach to both disorders should be modified in order to program an efficient primary and secondary prevention strategy.
Inhibition of Yes-Associated Protein by Verteporfin Ameliorates Unilateral Ureteral Obstruction-Induced Renal Tubulointerstitial Inflammation and Fibrosis
Authors: Jin Jixiu , Wang Tian , Park Woong , Li Wenjia , Kim Won , Park Sung Kwang , Kang Kyung Pyo
Published: November 2020

Yes-associated protein (YAP) activation after acute ischemic kidney injury might be related to interstitial fibrosis and impaired renal tubular regeneration. Verteporfin (VP) is a photosensitizer used in photodynamic therapy to treat age-related macular degeneration. In cancer cells, VP inhibits TEA domain family member (TEAD)-YAP interactions without light stimulation. The protective role of VP in unilateral ureteral obstruction (UUO)-induced renal fibrosis and related mechanisms remains unclear. In this study, we investigate the protective effects of VP on UUO-induced renal tubulointerstitial inflammation and fibrosis and its regulation of the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. We find that VP decreased the UUO-induced increase in tubular injury, inflammation, and extracellular matrix deposition in mice. VP also decreased myofibroblast activation and proliferation in UUO kidneys and NRK-49F cells by modulating Smad2 and Smad3 phosphorylation. Therefore, YAP inhibition might have beneficial effects on UUO-induced tubulointerstitial inflammation and fibrosis by regulating the TGF-β1/Smad signaling pathway.
Structural Insight on Functional Regulation of Human MINERVA Protein
Authors: Hahn Hyunggu , Lee Dong-Eun , Jang Dong Man , Kim Jiyoun , Lee Yeon , Cheong Heesun , Han Byung Woo , Kim Hyoun Sook
Published: November 2020

MINERVA (melanoma invasion by ERK), also known as FAM129B, is a member of the FAM129 protein family, which is only present in vertebrates. MINERVA is involved in key signaling pathways regulating cell survival, proliferation and apoptosis and found upregulated in many types of cancer promoting invasion. However, the exact function of the protein remains elusive. X-ray crystallographic methods were implemented to determine the crystal structure of MINERVAΔC, lacking C-terminal flexible region. Trypsin digestion was required before crystallization to obtain diffraction-quality crystals. While the N-terminal pleckstrin homology (PH) domain exhibits the typical fold of PH domains, lipid binding assay indicates specific affinity towards phosphatidic acid and inositol 3-phosphate. A helix-rich domain that constitutes the rest of the molecule demonstrates a novel L-shaped fold that encompasses the PH domain. The overall structure of MINERVAΔC with binding assays and cell-based experiments suggest plasma membrane association of MINERVA and its function seem to be tightly regulated by various motifs within the C-terminal flexible region. Elucidation of MINERVAΔC structure presents a novel fold for an α-helix bundle domain that would provide a binding platform for interacting partners.
Molecular Aspects of Mycotoxins—A Serious Problem for Human Health
Authors: Janik Edyta , Niemcewicz Marcin , Ceremuga Michal , Stela Maksymilian , Saluk-Bijak Joanna , Siadkowski Adrian , Bijak Michal
Published: November 2020

Mycotoxins are toxic fungal secondary metabolities formed by a variety of fungi (moulds) species. Hundreds of potentially toxic mycotoxins have been already identified and are considered a serious problem in agriculture, animal husbandry, and public health. A large number of food-related products and beverages are yearly contaminated by mycotoxins, resulting in economic welfare losses. Mycotoxin indoor environment contamination is a global problem especially in less technologically developed countries. There is an ongoing effort in prevention of mould growth in the field and decontamination of contaminated food and feed in order to protect human and animal health. It should be emphasized that the mycotoxins production by fungi (moulds) species is unavoidable and that they are more toxic than pesticides. Human and animals are exposed to mycotoxin via food, inhalation, or contact which can result in many building-related illnesses including kidney and neurological diseases and cancer. In this review, we described in detail the molecular aspects of main representatives of mycotoxins, which are serious problems for global health, such as aflatoxins, ochratoxin A, T-2 toxin, deoxynivalenol, patulin, and zearalenone.
An Affective and Cognitive Toy to Support Mood Disorders
Authors: Johnson Esperanza , González Iván , Mondéjar Tania , Cabañero-Gómez Luis , Fontecha Jesús , Hervás Ramón
Published: November 2020

Affective computing is a branch of artificial intelligence that aims at processing and interpreting emotions. In this study, we implemented sensors/actuators into a stuffed toy mammoth, which allows the toy to have an affective and cognitive basis to its communication. The goal is for therapists to use this as a tool during their therapy sessions that work with patients with mood disorders. The toy detects emotion and provides a dialogue that would guide a session aimed at working with emotional regulation and perception. These technical capabilities are possible by employing IBM Watson’s services, implemented into a Raspberry Pi Zero. In this paper, we delve into its evaluation with neurotypical adolescents, a panel of experts, and other professionals. The evaluation aims were to perform a technical and application validation for use in therapy sessions. The results of the evaluations are generally positive, with an 87% accuracy for emotion recognition, and an average usability score of 77.5 for experts (n = 5), and 64.35 for professionals (n = 23). We add to that information some of the issues encountered, its effects on applicability, and future work to be done.
Strengthening of Low-Strength Concrete Columns with Fibre Reinforced Polymers. Full-Scale Tests
Authors: Martínez Sonia , de Diego Ana , Castro Viviana J. , Echevarría Luis , Barroso Francisco J. , Rentero Gabriel , Soldado Rafael P. , Gutiérrez José Pedro
Published: November 2020

Confinement of columns with externally bonded fibre reinforced polymers (FRP) sheets is an easy and effective way of enhancing the load carrying and strain capacity of reinforced concrete (RC) columns. Many experimental studies have been conducted on cylindrical small-scale un-reinforced concrete specimens externally confined with FRP. It is widely accepted that confinement of square or rectangular columns is less efficient than the confinement of circular columns. The theoretical models for rectangular sections are mostly based on approaches for circular columns modified by a shape factor, but the different models do not give similar results. This paper presents an experimental program on large-scale square and rectangular RC columns externally strengthened with carbon FRP sheets and subjected to axial load. The main variables were the side-aspect ratio of the cross-section, the radius of curvature of the corners and the amount of FRP reinforcement. The results show that the FRP confinement can increase the strength and strain capacity of rectangular concrete columns with low strength concrete. The FRP hoop ultimate strain was much lower than the material ultimate tensile strain obtained from flat coupon tests and the strain efficiency factor achieved in the tests was less than the value usually recommended by design guides.
Modelling Drosophila suzukii Adult Male Populations: A Physiologically Based Approach with Validation
Authors: Rossini Luca , Contarini Mario , Giarruzzo Federica , Assennato Matteo , Speranza Stefano
Published: November 2020

The Spotted Wing Drosophila (SWD), Drosophila suzukii (Matsumura), is a harmful insect pest for soft fruit cultivations. Even though its main hosts belong to the genera Prunus and Rubus, its high polyphagy and adaptability to new environments makes it a serious problem for farmers worldwide, who have reported several economic losses because of this pest. A wide series of proposals to control SWD are available and operate in line with the mechanisms of integrated pest management, demonstrating their high efficiency when applied at the opportune moment. This work aims to apply and validate a physiologically based model which summarises all the available information about D. suzukii biology, such as the relationship between environmental temperature and its development, fertility and mortality rates. The model provided, as a result, a description of a population of SWD females taking into consideration the multiple generations that occurred during the year. Simulations were then compared with field data collected in a three-year survey in two experimental fields located in the Sabina Romana area (Lazio, Italy). More specifically, D. suzukii males were monitored with traps in fields cultivated with mixed varieties of cherries and they were selected because of their clearer identification in comparison to females. Results showed a high level of reliability of simulations in representing the field data, highlighting at the same time that there is no discrepancy in simulating D. suzukii females in order to represent male populations.
Polyethylene Identification in Ocean Water Samples by Means of 50 keV Energy Electron Beam
Authors: Adlish John I. , Costa Davide , Mainardi Enrico , Neuhold Piero , Surrente Riccardo , Tagliapietra Luca J.
Published: November 2020

This study presents a new methodology to reveal traces of polyethylene (the most common microplastic particles, known as a structure of C2H4) in a sample of ocean water by the irradiation of a 50 keV, 1 µA electron beam. This is performed by analyzing the photon (produced by the electrons in water) fluxes and spectra (i.e., fluxes as a function of photon energy) with different types of contaminated water using an adequate device and in particular looking at the peculiar interactions of electrons/photons with the potential abnormal atomic hydrogen (H), oxygen (O), carbon (C), and phosphorus (P) compositions present in the water, as a function of living and nonliving organic organisms with PO4 group RNA/DNA strands in a cluster configuration through a volumetric cells grid.
Microglial Expression of Hdac1 and Hdac2 is Dispensable for Experimental Autoimmune Encephalomyelitis (EAE) Progression
Authors: Datta Moumita , Hansen Stefanie M. , Staszewski Ori
Published: November 2020

Previously, we reported that microglial expression of histone deacetylases 1 and 2 (Hdac1 and Hdac2) is required for microglial maturation and modulates disease progression in a mouse model of Alzheimer’s disease. Here, we analyze the role of microglial expression of Hdac1 and Hdac2 in another disease paradigm, namely experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. The aim of this study was to ascertain whether microglial expression of these two epigenetic regulators modulates disease progression in the context of autoimmune disease. Hdac1 and Hdac2 were knocked out either individually or in combination using a microglia-specific, tamoxifen-inducible Cre-deleter line (Cx3cr1-CreERT2). The clinical course as well as histopathological changes during EAE were assessed in adult mice lacking microglial expression of these genes. Overall, no differences in disease onset, progression or severity could be detected in mice lacking microglial expression of either one or both of Hdac1 and Hdac2 genes. Similarly, the histopathology showed no differences in lymphocyte or macrophage infiltration or demyelination in either of the analyzed groups. As such, we conclude that unlike in neurodegenerative disease, microglial expression of Hdac1 and Hdac2 does not play a role in EAE.
Saint Peter’s First Burial Site According to Maria Valtorta’s Mystical Writings, Checked against the Archeology of Rome in the I Century
Authors: De Caro Liberato , La Greca Fernando , Matricciani Emilio
Published: November 2020

The discovery of the mortal remains of the apostle Peter in the Vatican caves, in the 1940s, has aroused several doubts among scholars. In any case, there is consensus on this not being Peter’s first burial site on the Vatican Hill. The recent studies on Maria Valtorta’s mystical writings have shown that they contain a lot of data open to check through disparate scientific disciplines. Every time this check has been done, unexpected results have been found, as if her writings contain data not ascribable to her skills and awareness. Maria Valtorta describes also Peter’s first burial site, which, she writes, was not on the Vatican Hill. The analysis of these particular texts, checked against the archeology of Rome in the I century and its catacombs, has allowed us to locate Peter’s first burial site in a hypogeum discovered in 1864 but not yet fully explored, near the beginning of Via Nomentana, in Rome. A mathematical estimate of the probability that Maria Valtorta, by chance, invented the data that lead to this particular site shows that it is very small and reinforces the conclusion, already reached with archeology, that casualness is very doubtful. The full exploration of this hypogeum would assess the reliability of this alleged Peter’s first burial site.
Role of Imaging in the Evaluation of Minimal Residual Disease in Multiple Myeloma Patients
Authors: Zamagni Elena , Tacchetti Paola , Barbato Simona , Cavo Michele
Published: November 2020

The International Myeloma Working Group (IMWG) recently introduced the evaluation of minimal residual disease (MRD) within the multiple myeloma (MM) response criteria, and MRD negativity assessed inside and outside the bone marrow is currently considered the most powerful predictor of favorable long-term outcomes. However, MRD evaluation has thus far relied on flow-cytometry or molecular-based methods, despite the limitations associated with the patchy infiltration of bone marrow (BM) plasma cells and the presence of extra-medullary (EMD). On the contrary, imaging-based sensitive response assessment through the use of functional rather than morphological whole-body (WB) imaging techniques, such as positron emission tomography with computed tomography (PET/CT) and magnetic resonance imaging (MRI), likely is a promising strategy to overcome these limitations in evaluating response to therapy and in the assessment of the MRD status in MM patients. However, despite the significant advances in the development and availability of novel functional imaging techniques for MRD evaluation, a worldwide standardization of imaging criteria for acquisition, interpretation, and reporting is yet to be determined and will be object of future investigations.
Current Treatments of Metastatic Colorectal Cancer with Immune Checkpoint Inhibitors—2020 Update
Authors: Jung Gerhard , Benítez-Ribas Daniel , Sánchez Ariadna , Balaguer Francesc
Published: November 2020

During the last 20 years, chemotherapy has improved survival rates of colorectal cancer (CRC). However, the majority of metastatic cases do not respond to or progress after first line conventional chemotherapy and contribute to the fatalities of patients with CRC. Insights into the immune contexture of the tumor microenvironment (TME) have enabled the development of new systemic treatments that boost the host immune system against the tumor—the immune checkpoint inhibitors (ICI). These promising drugs have already shown astonishing efficacies in other cancer types and have raised new hope for the treatment of metastatic CRC (mCRC). In this review, we will summarize the results of the clinical trials that led to their accelerated approval by the U.S. Food and Drug Administration (FDA) in 2017, as well as all relevant recent studies conducted since then—some of which are not published yet. We will focus on therapeutic efficacy, but also discuss the available data for drug safety and security, changes in quality of life indicators and predictive biomarkers for treatment response. The burgeoning evidence for a potential use of ICIs in other settings than mCRC will also be mentioned. For each trial, we have made a preliminary assessment of the quality of clinical trial design and of the “European Society of Medical Oncology (ESMO) magnitude of clinical benefit” (ESMO-MCBS) in order to provide the first evidence-based recommendation to the reader.
Reversed Neurovascular Coupling on Optical Coherence Tomography Angiography Is the Earliest Detectable Abnormality before Clinical Diabetic Retinopathy
Authors: Zhang Yi Stephanie , Mucollari Ilda , Kwan Changyow C. , Dingillo Gianna , Amar Jaspreet , Schwartz Gregory W. , Fawzi Amani A.
Published: November 2020

Diabetic retinopathy (DR) has traditionally been viewed as either a microvasculopathy or a neuropathy, though neurovascular coupling deficits have also been reported and could potentially be the earliest derangement in DR. To better understand neurovascular coupling in the diabetic retina, we investigated retinal hemodynamics by optical coherence tomography angiography (OCTA) in individuals with diabetes mellitus (DM) but without DR (DM no DR) and mild non-proliferative DR (mild NPDR) compared to healthy eyes. Using an experimental design to monitor the capillary responses during transition from dark adaptation to light, we examined 19 healthy, 14 DM no DR and 11 mild NPDR individuals. We found that the only structural vascular abnormality in the DM no DR group was increased superficial capillary plexus (SCP) vessel density (VD) compared to healthy eyes, while mild NPDR eyes showed significant vessel loss in the SCP at baseline. There was no significant difference in inner retinal thickness between the groups. During dark adaptation, the deep capillary plexus (DCP) VD was lower in mild NPDR individuals compared to the other two groups, which may leave the photoreceptors more susceptible to ischemia in the dark. When transitioning from dark to ambient light, both diabetic groups showed a qualitative reversal of VD trends in the SCP and middle capillary plexus (MCP), with significantly decreased SCP at 5 min and increased MCP VD at 50 s compared to healthy eyes, which may impede metabolic supply to the inner retina during light adaptation. Mild NPDR eyes also demonstrated DCP dilation at 50 s and 5 min and decreased adjusted flow index at 5 min in light. Our results show altered neurovascular responses in all three macular vascular plexuses in diabetic subjects in the absence of structural neuronal changes on high resolution imaging, suggesting that neurovascular uncoupling may be a key mechanism in the early pathogenesis of DR, well before the clinical appearance of vascular or neuronal loss.
The Use of Diaphragm Ultrasonography in Pulmonary Physiotherapy of COPD Patients: A Literature Review
Authors: Lewińska Agnieszka , Shahnazaryan Karen
Published: November 2020

There is potentially a broad range of patient populations in which ultrasound imaging (US) might be beneficial form of physiotherapy process support. Among them, the group of patients with chronic obstructive pulmonary disease (COPD) is of great importance, as in this individuals the diaphragm dysfunction is frequently observed. Pulmonary physiotherapy often includes techniques which are intended to influence the diaphragm muscle but its anatomy does not allow for variety of techniques to assess function. Lack of easily available and reliable measures complicates outcomes interpretation and makes decision-making process difficult. A review of the electronic literature was conducted to identify studies related to the US assessment of physiotherapy process and its outcome in COPD patients. As a consequence, seven papers were identified. Based on the results obtained, it can be concluded that the diaphragm excursion is US measure that is most often described in context of diaphragm-related physiotherapy in COPD patients. The methodology applied, however, varies greatly making it difficult to compare results. Thus, developing standards of outcome assessment methods and therapy monitoring systems which are supported by evidence should be of paramount importance. Future studies could also focus on identifying which components of physiotherapeutic diaphragm-targeted approach provide acceptable level of evidence.
Evidence of Mitochondrial Dysfunction in Fibromyalgia: Deviating Muscle Energy Metabolism Detected Using Microdialysis and Magnetic Resonance
Authors: Gerdle Björn , Ghafouri Bijar , Lund Eva , Bengtsson Ann , Lundberg Peter , Ettinger-Veenstra Helene van , Leinhard Olof Dahlqvist , Forsgren Mikael Fredrik
Published: November 2020

In fibromyalgia (FM) muscle metabolism, studies are sparse and conflicting associations have been found between muscle metabolism and pain aspects. This study compared alterations in metabolic substances and blood flow in erector spinae and trapezius of FM patients and healthy controls. FM patients (n = 33) and healthy controls (n = 31) underwent a clinical examination that included pressure pain thresholds and physical tests, completion of a health questionnaire, participation in microdialysis investigations of the etrapezius and erector spinae muscles, and also underwent phosphorus-31 magnetic resonance spectroscopy of the erector spinae muscle. At the baseline, FM had significantly higher levels of pyruvate in both muscles. Significantly lower concentrations of phosphocreatine (PCr) and nucleotide triphosphate (mainly adenosine triphosphate) in erector spinae were found in FM. Blood flow in erector spinae was significantly lower in FM. Significant associations between metabolic variables and pain aspects (pain intensity and pressure pain threshold PPT) were found in FM. Our results suggest that FM has mitochondrial dysfunction, although it is unclear whether inactivity, obesity, aging, and pain are causes of, the results of, or coincidental to the mitochondrial dysfunction. The significant regressions of pain intensity and PPT in FM agree with other studies reporting associations between peripheral biological factors and pain aspects.
Impact on Prognosis of the Surgical Route, Laparoscopy or Laparotomy, for the Surgical Staging of Early Stage Ovarian Cancer—A Study from the FRANCOGYN Group
Authors: Merlier Margaux , Kerbage Yohan , Pierache Adeline , Ramdane Nassima , Canlorbe Geoffroy , Bolze Pierre-Adrien , Ballester Marcos , Bendifallah Sofiane , Ouldamer Lobna , Touboul Cyril , Huchon Cyrille , Lavoue Vincent , Dabi Yohann , Akladios Cherik , Coutant Charles , Raimond Emilie , Bricou Alexandre , Phalippou Jerôme , Collinet Pierre , Azaïs Henri
Published: November 2020

Background and objective: according to the latest ESMO−ESGO recommendations, laparotomy is the standard surgical approach to treat and stage patients with presumed early stage epithelial ovarian cancer (EOC). A few studies have investigated the efficacy and the safety of laparoscopy for the staging of early stage EOC, and this question is still in the center of debates. Recurrence-free survival (RFS) and overall survival (OS) benefits of the minimally invasive surgery (MIS) have still to be specified. The aim of this multicenter and retrospective study is to assess the survival outcomes of laparoscopic staging in comparison with laparotomic staging for patients presenting with an early stage EOC. Methods: data of patients with early stage EOC (FIGO I-IIA) who underwent primary surgery between 2000 and 2018 were extracted from the FRANCOGYN database. OS and RFS of these two groups, constituted according to the surgical route, were compared using Log rank test. Results: of the 144 patients included, 107 patients underwent laparotomy and 37 underwent laparoscopy for a staging purpose. The median follow-up was 36.0 months (18.0 to 58.0). For the laparoscopy and the laparotomy group, the median follow-up period was 24 (11.0 to 50.0) and 42.0 (24.0 to 66.0) months, respectively, (p < 0.001). Tumor recurrence occurred in 33 (23%) patients: 2 (5.4%) in the laparoscopy group and 31 (29%) in the laparotomy group (p = 0.08). The OS rate at 5 years was 97.3% after laparoscopy and 79.8% after laparotomy (p = 0.19). Conclusions: there is no difference associated with the laparoscopic approach for the staging of early stage EOC on RFS and OS in comparison with laparotomy. MIS may be proposed as a safe and adequate alternative to laparotomy when performed by well-trained surgeons.
A Holistic Perspective: Exosomes Shuttle between Nerves and Immune Cells in the Tumor Microenvironment
Authors: Dragomir Mihnea P. , Moisoiu Vlad , Manaila Roxana , Pardini Barbara , Knutsen Erik , Anfossi Simone , Amit Moran , Calin George A.
Published: November 2020

One of the limitations of cancer research has been the restricted focus on tumor cells and the omission of other non-malignant cells that are constitutive elements of this systemic disease. Current research is focused on the bidirectional communication between tumor cells and other components of the tumor microenvironment (TME), such as immune and endothelial cells, and nerves. A major success of this bidirectional approach has been the development of immunotherapy. Recently, a more complex landscape involving a multi-lateral communication between the non-malignant components of the TME started to emerge. A prime example is the interplay between immune and endothelial cells, which led to the approval of anti-vascular endothelial growth factor-therapy combined with immune checkpoint inhibitors and classical chemotherapy in non-small cell lung cancer. Hence, a paradigm shift approach is to characterize the crosstalk between different non-malignant components of the TME and understand their role in tumorigenesis. In this perspective, we discuss the interplay between nerves and immune cells within the TME. In particular, we focus on exosomes and microRNAs as a systemic, rapid and dynamic communication channel between tumor cells, nerves and immune cells contributing to cancer progression. Finally, we discuss how combinatorial therapies blocking this tumorigenic cross-talk could lead to improved outcomes for cancer patients.
Editorial: Cardiomyopathies: Current Treatment and Future Options
Authors: Peters Stefan
Published: November 2020

Cardiomyopathies are an essential component in clinical cardiology. The number of different cardiomyopathies have increased a lot due to genetics and newer insights in pathomechanism. The current treatment and future options are demonstrated in advance.
Effectiveness of Heel-Raise-Lower Exercise after Transcutaneous Electrical Nerve Stimulation in Patients with Stroke: A Randomized Controlled Study
Authors: Jung Kyoung-sim , Jung Jin-hwa , In Tae-sung , Cho Hwi-young
Published: November 2020

Objective: This study was conducted to investigate the effect of the heel-raise-lower exercise on spasticity, strength, and gait speed after the application of 30 min of transcutaneous electrical nerve stimulation (TENS) in patients with stroke. Methods: The participants were randomly divided into the TENS group and the placebo group, with 20 participants assigned to each group. In the TENS group, heel-raise-lower exercise was performed after applying TENS for six weeks. The placebo group was trained in the same manner for the same amount of time but without electrical stimulation. The spasticity of the ankle plantar flexors was measured using the composite spasticity score. A handheld dynamometer and a 10-m walk test were used to evaluate muscle strength and gait speed, respectively. Results: Spasticity was significantly more improved in the TENS group (mean change −2.0 ± 1.1) than in the placebo group (mean change −0.4 ± 0.9) (p < 0.05). Similarly, muscle strength was significantly more improved in the TENS group (6.4 ± 3.3 kg) than in the placebo group (4.5 ± 1.6 kg) (p < 0.05). Moreover, participants assigned to the TENS group showed a significant greater improvement in gait speed than those in the placebo group (mean change −5.3 ± 1.4 s vs. −2.7 ± 1.2 s). Conclusions: These findings show the benefits of heel-raise-lower exercise after TENS for functional recovery in patients with stroke.