bluuebunny/crossref_metadata_2025 huggingface dataset:
Mammalian PRC1 Complexes: Compositional Complexity and Diverse Molecular Mechanisms
Authors: Geng Zhuangzhuang , Gao Zhonghua
Published: November 2020

Polycomb group (PcG) proteins function as vital epigenetic regulators in various biological processes, including pluripotency, development, and carcinogenesis. PcG proteins form multicomponent complexes, and two major types of protein complexes have been identified in mammals to date, Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2). The PRC1 complexes are composed in a hierarchical manner in which the catalytic core, RING1A/B, exclusively interacts with one of six Polycomb group RING finger (PCGF) proteins. This association with specific PCGF proteins allows for PRC1 to be subdivided into six distinct groups, each with their own unique modes of action arising from the distinct set of associated proteins. Historically, PRC1 was considered to be a transcription repressor that deposited monoubiquitylation of histone H2A at lysine 119 (H2AK119ub1) and compacted local chromatin. More recently, there is increasing evidence that demonstrates the transcription activation role of PRC1. Moreover, studies on the higher-order chromatin structure have revealed a new function for PRC1 in mediating long-range interactions. This provides a different perspective regarding both the transcription activation and repression characteristics of PRC1. This review summarizes new advancements regarding the composition of mammalian PRC1 and accompanying explanations of how diverse PRC1-associated proteins participate in distinct transcription regulation mechanisms.
In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation
Authors: Thappeta Kishore Reddy Venkata , Zhao Li Na , Nge Choy Eng , Crasta Sharon , Leong Chung Yan , Ng Veronica , Kanagasundaram Yoganathan , Fan Hao , Ng Siew Bee
Published: November 2020

Sortase A (SrtA) is a membrane-associated enzyme that anchors surface-exposed proteins to the cell wall envelope of Gram-positive bacteria such as Staphylococcus aureus. As SrtA is essential for Gram-positive bacterial pathogenesis but dispensable for microbial growth or viability, SrtA is considered a favorable target for the enhancement of novel anti-infective drugs that aim to interfere with key bacterial virulence mechanisms, such as biofilm formation, without developing drug resistance. Here, we used virtual screening to search an in-house natural compound library and identified two natural compounds, N1287 (Skyrin) and N2576 ((4,5-dichloro-1H-pyrrol-2-yl)-[2,4-dihydroxy-3-(4-methyl-pentyl)-phenyl]-methanone) that inhibited the enzymatic activity of SrtA. These compounds also significantly reduced the growth of S. aureus but possessed moderate mammalian toxicity. Furthermore, S. aureus strains treated with these compounds exhibited reduction in adherence to host fibrinogen, as well as biofilm formation. Hence, these compounds may represent an anti-infective therapy without the side effects of antibiotics.
IL-18 But Not IL-1 Signaling Is Pivotal for the Initiation of Liver Injury in Murine Non-Alcoholic Fatty Liver Disease
Authors: Hohenester Simon , Kanitz Veronika , Schiergens Tobias , Einer Claudia , Nagel Jutta , Wimmer Ralf , Reiter Florian P. , Gerbes Alexander L. , De Toni Enrico N. , Bauer Christian , Holdt Lesca , Mayr Doris , Rust Christian , Schnurr Max , Zischka Hans , Geier Andreas , Denk Gerald
Published: November 2020

Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life “American lifestyle-induced obesity syndrome” (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, Il-18r−/−- but not Il-1r−/− mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.
Injectable Gel Form of a Decellularized Bladder Induces Adipose-Derived Stem Cell Differentiation into Smooth Muscle Cells In Vitro
Authors: Moreno-Manzano Victoria , Zaytseva-Zotova Daria , López-Mocholí Eric , Briz-Redón Álvaro , Løkensgard Strand Berit , Serrano-Aroca Ángel
Published: November 2020

Biologic scaffolds composed of extracellular matrix components have been proposed to repair and reconstruct a variety of tissues in clinical and pre-clinical studies. Injectable gels can fill and conform any three-dimensional shape and can be delivered to sites of interest by minimally invasive techniques. In this study, a biological gel was produced from a decellularized porcine urinary bladder by enzymatic digestion with pepsin. The enzymatic digestion was confirmed by visual inspection after dissolution in phosphate-buffered saline solution and Fourier-transform infrared spectroscopy. The rheological and biological properties of the gel were characterized and compared to those of the MatrigelTM chosen as a reference material. The storage modulus G’ reached 19.4 ± 3.7 Pa for the 30 mg/mL digested decellularized bladder gels after ca. 3 h at 37 °C. The results show that the gel formed of the porcine urinary bladder favored the spontaneous differentiation of human and rabbit adipose-derived stem cells in vitro into smooth muscle cells to the detriment of cell proliferation. The results support the potential of the developed injectable gel for tissue engineering applications to reconstruct for instance the detrusor muscle part of the human urinary bladder.
A Molecular Perspective on Sirtuin Activity
Authors: Teixeira Carla S. S. , Cerqueira Nuno M. F. S. A. , Gomes Pedro , Sousa Sérgio F.
Published: November 2020

The protein acetylation of either the α-amino groups of amino-terminal residues or of internal lysine or cysteine residues is one of the major posttranslational protein modifications that occur in the cell with repercussions at the protein as well as at the metabolome level. The lysine acetylation status is determined by the opposing activities of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), which add and remove acetyl groups from proteins, respectively. A special group of KDACs, named sirtuins, that require NAD+ as a substrate have received particular attention in recent years. They play critical roles in metabolism, and their abnormal activity has been implicated in several diseases. Conversely, the modulation of their activity has been associated with protection from age-related cardiovascular and metabolic diseases and with increased longevity. The benefits of either activating or inhibiting these enzymes have turned sirtuins into attractive therapeutic targets, and considerable effort has been directed toward developing specific sirtuin modulators. This review summarizes the protein acylation/deacylation processes with a special focus on the current developments in the sirtuin research field.
The Rationale for Angiotensin Receptor Neprilysin Inhibitors in a Multi-Targeted Therapeutic Approach to COVID-19
Authors: Bellis Alessandro , Mauro Ciro , Barbato Emanuele , Trimarco Bruno , Morisco Carmine
Published: November 2020

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger “cytokine storm” leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on “multi-targeted” therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment.
Breast Cancer and Microcalcifications: An Osteoimmunological Disorder?
Authors: Clemenceau Alisson , Michou Laetitia , Diorio Caroline , Durocher Francine
Published: November 2020

The presence of microcalcifications in the breast microenvironment, combined with the growing evidences of the possible presence of osteoblast-like or osteoclast-like cells in the breast, suggest the existence of active processes of calcification in the breast tissue during a woman’s life. Furthermore, much evidence that osteoimmunological disorders, such as osteoarthritis, rheumatoid arthritis, or periodontitis influence the risk of developing breast cancer in women exists and vice versa. Antiresorptive drugs benefits on breast cancer incidence and progression have been reported in the past decades. More recently, biological agents targeting pro-inflammatory cytokines used against rheumatoid arthritis also demonstrated benefits against breast cancer cell lines proliferation, viability, and migratory abilities, both in vitro and in vivo in xenografted mice. Hence, it is tempting to hypothesize that breast carcinogenesis should be considered as a potential osteoimmunological disorder. In this review, we compare microenvironments and molecular characteristics in the most frequent osteoimmunological disorders with major events occurring in a woman’s breast during her lifetime. We also highlight what the use of bone anabolic drugs, antiresorptive, and biological agents targeting pro-inflammatory cytokines against breast cancer can teach us.
A Matter of Size and Placement: Varying the Patch Size of Anisotropic Patchy Colloids
Authors: Karner Carina , Müller Felix , Bianchi Emanuela
Published: November 2020

Non-spherical colloids provided with well-defined bonding sites—often referred to as patches—are increasingly attracting the attention of materials scientists due to their ability to spontaneously assemble into tunable surface structures. The emergence of two-dimensional patterns with well-defined architectures is often controlled by the properties of the self-assembling building blocks, which can be either colloidal particles at the nano- and micro-scale or even molecules and macromolecules. In particular, the interplay between the particle shape and the patch topology gives rise to a plethora of tilings, from close-packed to porous monolayers with pores of tunable shapes and sizes. The control over the resulting surface structures is provided by the directionality of the bonding mechanism, which mostly relies on the selective nature of the patches. In the present contribution, we investigate the effect of the patch size on the assembly of a class of anisotropic patchy colloids—namely, rhombic platelets with four identical patches placed in different arrangements along the particle edges. Larger patches are expected to enhance the bond flexibility, while simultaneously reducing the bond selectivity as the single bond per patch condition—which would guarantee a straightforward mapping between local bonding arrangements and long-range pattern formation—is not always enforced. We find that the non-trivial interplay between the patch size and the patch position can either promote a parallel particle arrangement with respect to a non-parallel bonding scenario or give rise to a variety a bonded patterns, which destroy the order of the tilings. We rationalize the occurrence of these two different regimes in terms of single versus multiple bonds between pairs of particles and/or patches.
Effects of Rationally Designed Physico-Chemical Variants of the Peptide PuroA on Biocidal Activity towards Bacterial and Mammalian Cells
Authors: Shagaghi Nadin , Clayton Andrew H. A. , Aguilar Marie-Isabel , Lee Tzong-Hsien , Palombo Enzo A. , Bhave Mrinal
Published: November 2020

Antimicrobial peptides (AMPs) often exhibit wide-spectrum activities and are considered ideal candidates for effectively controlling persistent and multidrug-resistant wound infections. PuroA, a synthetic peptide based on the tryptophan (Trp)-rich domain of the wheat protein puroindoline A, displays strong antimicrobial activities. In this work, a number of peptides were designed based on PuroA, varying in physico-chemical parameters of length, number of Trp residues, net charge, hydrophobicity or amphipathicity, D-versus L-isomers of amino acids, cyclization or dimerization, and were tested for antimicrobial potency and salt and protease tolerance. Selected peptides were assessed for effects on biofilms of methicillin-resistant Staphylococcus aureus (MRSA) and selected mammalian cells. Peptide P1, with the highest amphipathicity, six Trp and a net charge of +7, showed strong antimicrobial activity and salt stability. Peptides W7, W8 and WW (seven to eight residues) were generally more active than PuroA and all diastereomers were protease-resistant. PuroA and certain variants significantly inhibited initial biomass attachment and eradicated preformed biofilms of MRSA. Further, P1 and dimeric PuroA were cytotoxic to HeLa cells. The work has led to peptides with biocidal effects on common human pathogens and/or anticancer potential, also offering great insights into the relationship between physico-chemical parameters and bioactivities, accelerating progress towards rational design of AMPs for therapeutics.
Combination of Inhibitors of USP7 and PLK1 has a Strong Synergism against Paclitaxel Resistance
Authors: Shin Sol-Bi , Kim Chang-Hyeon , Jang Hay-Ran , Yim Hyungshin
Published: November 2020

USP7 is a promising target for the development of cancer treatments because of its high expression and the critical functions of its substrates in carcinogenesis of several different carcinomas. Here, we demonstrated the effectiveness of targeting USP7 in advanced malignant cells showing high levels of USP7, especially in taxane-resistant cancer. USP7 knockdown effectively induced cell death in several cancer cells of lung, prostate, and cervix. Depletion of USP7 induced multiple spindle pole formation in mitosis, and, consequently, resulted in mitotic catastrophe. When USP7 was blocked in the paclitaxel-resistant lung cancer NCI-H460TXR cells, which has resistance to mitotic catastrophe, NCI-H460TXR cells underwent apoptosis effectively. Furthermore, combination treatment with the mitotic kinase PLK1 inhibitor volasertib and the USP7 inhibitor P22077 showed a strong synergism through down-regulation of MDR1/ABCB1 in paclitaxel-resistant lung cancer. Therefore, we suggest USP7 is a promising target for cancer therapy, and combination therapy with inhibitors of PLK1 and USP7 may be valuable for treating paclitaxel-resistant cancers, because of their strong synergism.
Large-Scale Phosphoproteomic Study of Arabidopsis Membrane Proteins Reveals Early Signaling Events in Response to Cold
Authors: Kamal Md Mostafa , Ishikawa Shinnosuke , Takahashi Fuminori , Suzuki Ko , Kamo Masaharu , Umezawa Taishi , Shinozaki Kazuo , Kawamura Yukio , Uemura Matsuo
Published: November 2020

Cold stress is one of the major factors limiting global crop production. For survival at low temperatures, plants need to sense temperature changes in the surrounding environment. How plants sense and respond to the earliest drop in temperature is still not clearly understood. The plasma membrane and its adjacent extracellular and cytoplasmic sites are the first checkpoints for sensing temperature changes and the subsequent events, such as signal generation and solute transport. To understand how plants respond to early cold exposure, we used a mass spectrometry-based phosphoproteomic method to study the temporal changes in protein phosphorylation events in Arabidopsis membranes during 5 to 60 min of cold exposure. The results revealed that brief cold exposures led to rapid phosphorylation changes in the proteins involved in cellular ion homeostasis, solute and protein transport, cytoskeleton organization, vesical trafficking, protein modification, and signal transduction processes. The phosphorylation motif and kinase–substrate network analysis also revealed that multiple protein kinases, including RLKs, MAPKs, CDPKs, and their substrates, could be involved in early cold signaling. Taken together, our results provide a first look at the cold-responsive phosphoproteome changes of Arabidopsis membrane proteins that can be a significant resource to understand how plants respond to an early temperature drop.
Whole Genome Sequencing and Tn5-Insertion Mutagenesis of Pseudomonas taiwanensis CMS to Probe Its Antagonistic Activity Against Rice Bacterial Blight Disease
Authors: Chen Wen-Jen , Kuo Tzu-Yen , Chen Chun-Yi , Hsieh Feng-Chia , Yang Yu-Liang , Liu Je-Ruei , Shih Ming-Che
Published: November 2020

The Gram-negative bacterium Pseudomonas taiwanensis is a novel bacterium that uses shrimp shell waste as its sole sources of carbon and nitrogen. It is a versatile bacterium with potential for use in biological control, with activities including toxicity toward insects, fungi, and the rice pathogen Xanthomonas oryzae pv.oryzae (Xoo). In this study, the complete 5.08-Mb genome sequence of P. taiwanensis CMS was determined by a combination of NGS/Sanger sequencing and optical mapping. Comparison of optical maps of seven Pseudomonas species showed that P. taiwanensis is most closely related to P. putida KT 2400. We screened a total of 11,646 individual Tn5-transponson tagged strains to identify genes that are involved in the production and regulation of the iron-chelator pyoverdine in P. taiwanensis, which is a key anti-Xoo factor. Our results indicated that the two-component system (TCS) EnvZ/OmpR plays a positive regulatory role in the production of pyoverdine, whereas the sigma factor RpoS functions as a repressor. The knowledge of the molecular basis of the regulation of pyoverdine by P. taiwanensis provided herein will be useful for its development for use in biological control, including as an anti-Xoo agent.
Disease Ionomics: Understanding the Role of Ions in Complex Disease
Authors: Zhang Yan , Xu Yinzhen , Zheng Lin
Published: November 2020

Ionomics is a novel multidisciplinary field that uses advanced techniques to investigate the composition and distribution of all minerals and trace elements in a living organism and their variations under diverse physiological and pathological conditions. It involves both high-throughput elemental profiling technologies and bioinformatic methods, providing opportunities to study the molecular mechanism underlying the metabolism, homeostasis, and cross-talk of these elements. While much effort has been made in exploring the ionomic traits relating to plant physiology and nutrition, the use of ionomics in the research of serious diseases is still in progress. In recent years, a number of ionomic studies have been carried out for a variety of complex diseases, which offer theoretical and practical insights into the etiology, early diagnosis, prognosis, and therapy of them. This review aims to give an overview of recent applications of ionomics in the study of complex diseases and discuss the latest advances and future trends in this area. Overall, disease ionomics may provide substantial information for systematic understanding of the properties of the elements and the dynamic network of elements involved in the onset and development of diseases.
Abscisic Acid Mediates Drought and Salt Stress Responses in Vitis vinifera—A Review
Authors: Marusig Daniel , Tombesi Sergio
Published: November 2020

The foreseen increase in evaporative demand and reduction in rainfall occurrence are expected to stress the abiotic constrains of drought and salt concentration in soil. The intensification of abiotic stresses coupled with the progressive depletion in water pools is a major concern especially in viticulture, as most vineyards rely on water provided by rainfall. Because its economical relevance and its use as a model species for the study of abiotic stress effect on perennial plants, a significant amount of literature has focused on Vitis vinifera, assessing the physiological mechanisms occurring under stress. Despite the complexity of the stress-resistance strategy of grapevine, the ensemble of phenomena involved seems to be regulated by the key hormone abscisic acid (ABA). This review aims at summarizing our knowledge on the role of ABA in mediating mechanisms whereby grapevine copes with abiotic stresses and to highlight aspects that deserve more attention in future research.
Cannabinoid Type 1 Receptor is Undetectable in Rodent and Primate Cerebral Neural Stem Cells but Participates in Radial Neuronal Migration
Authors: Morozov Yury M. , Mackie Ken , Rakic Pasko
Published: November 2020

Cannabinoid type 1 receptor (CB1R) is expressed and participates in several aspects of cerebral cortex embryonic development as demonstrated with whole-transcriptome mRNA sequencing and other contemporary methods. However, the cellular location of CB1R, which helps to specify molecular mechanisms, remains to be documented. Using three-dimensional (3D) electron microscopic reconstruction, we examined CB1R immunolabeling in proliferating neural stem cells (NSCs) and migrating neurons in the embryonic mouse (Mus musculus) and rhesus macaque (Macaca mulatta) cerebral cortex. We found that the mitotic and postmitotic ventricular and subventricular zone (VZ and SVZ) cells are immunonegative in both species while radially migrating neurons in the intermediate zone (IZ) and cortical plate (CP) contain CB1R-positive intracellular vesicles. CB1R immunolabeling was more numerous and more extensive in monkeys compared to mice. In CB1R-knock out mice, projection neurons in the IZ show migration abnormalities such as an increased number of lateral processes. Thus, in radially migrating neurons CB1R provides a molecular substrate for the regulation of cell movement. Undetectable level of CB1R in VZ/SVZ cells indicates that previously suggested direct CB1R-transmitted regulation of cellular proliferation and fate determination demands rigorous re-examination. More abundant CB1R expression in monkey compared to mouse suggests that therapeutic or recreational cannabis use may be more distressing for immature primate neurons than inferred from experiments with rodents.
Influence of Phosphodiesterase Inhibition on CRE- and EGR1-Dependent Transcription in a Mouse Hippocampal Cell Line
Authors: Maronde Erik
Published: November 2020

Signaling pathways, depending on the second messenger molecule cAMP, modulate hippocampal cell signaling via influencing transcription factors like cAMP-regulated element-binding protein (CREB) or early growth response 1 EGR1/Krox24/zif268/ZENK (EGR1). Here, we investigated two reporter cell lines derived from an immortalized hippocampal neuronal cell line stably expressing a CRE- or EGR1-luciferase reporter gene (HT22CREluc and HT22EGR1luc, respectively). The cells were subjected to phosphodiesterase inhibitors and other cAMP-modulating agents to investigate dose- and time-dependent phosphodiesterase (PDE)-mediated fine-tuning of cAMP-dependent transcriptional signaling. The non-isoform-specific cyclic nucleotide phosphodiesterase (PDE) inhibitor isobutyl-methyl-xanthine (IBMX), as well as selective inhibitors of PDE3 (milrinone) and PDE4 (rolipram), were tested for their ability to elevate CRE- and EGR1-luciferase activity. Pharmacological parameters like onset of activity, maximum activity, and offset of activity were determined. In summary, phosphodiesterase inhibition appeared similarly potent in comparison to adenylate cyclase stimulation or direct activation of protein kinase A (PKA) via specific cAMP agonists and was at least partly mediated by PKA as shown by the selective PKA inhibitor Rp-8-Br-cAMPS. Moreover, transcriptional activation by PDE inhibition was also influenced by organic anion-exchanger action and interacted with fibroblast growth factor (FGF) receptor-mediated pathways.
Clinical Utility of the Pathogenesis-Related Proteins in Alzheimer’s Disease
Authors: Zhou Bin , Fukushima Masanori
Published: November 2020

Research on the Aβ cascade and alternations of biomarkers in neuro-inflammation, synaptic dysfunction, and neuronal injury followed by Aβ have progressed. But the question is how to use the biomarkers. Here, we examine the evidence and pathogenic implications of protein interactions and the time order of alternation. After the deposition of Aβ, the change of tau, neurofilament light chain (NFL), and neurogranin (Ng) is the main alternation and connection to others. Neuro-inflammation, synaptic dysfunction, and neuronal injury function is exhibited prior to the structural and metabolic changes in the brain following Aβ deposition. The time order of such biomarkers compared to the tau protein is not clear. Despite the close relationship between biomarkers and plaque Aβ deposition, several factors favor one or the other. There is an interaction between some proteins that can predict the brain amyloid burden. The Aβ cascade hypothesis could be the pathway, but not all subjects suffer from Alzheimer’s disease (AD) within a long follow-up, even with very elevated Aβ. The interaction of biomarkers and the time order of change require further research to identify the right subjects and right molecular target for precision medicine therapies.
Mesenchymal Stem Cells in Multiple Sclerosis: Recent Evidence from Pre-Clinical to Clinical Studies
Authors: Gugliandolo Agnese , Bramanti Placido , Mazzon Emanuela
Published: November 2020

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. Nowadays, available therapies for MS can help to manage MS course and symptoms, but new therapeutic approaches are required. Stem cell therapy using mesenchymal stem cells (MSCs) appeared promising in different neurodegenerative conditions, thanks to their beneficial capacities, including the immunomodulation ability, and to their secretome. The secretome is represented by growth factors, cytokines, and extracellular vesicles (EVs) released by MSCs. In this review, we focused on studies performed on in vivo MS models involving the administration of MSCs and on clinical trials evaluating MSCs administration. Experimental models of MS evidenced that MSCs were able to reduce inflammatory cell infiltration and disease score. Moreover, MSCs engineered to express different genes, preconditioned with different compounds, differentiated or in combination with other compounds also exerted beneficial actions in MS models, in some cases also superior to native MSCs. Secretome, both conditioned medium and EVs, also showed protective effects in MS models and appeared promising to develop new approaches. Clinical trials highlighted the safety and feasibility of MSC administration and reported some improvements, but other trials using larger cohorts of patients are needed.
New Prognostic and Predictive Markers in Cancer Progression
Authors: Costantini Susan , Budillon Alfredo
Published: November 2020

Biomarkers are a critical medical need for oncologists to predict and detect disease and to determine the best course of action for cancer patient care [...]
Glucose Concentration in Cell Culture Medium Influences the BRCA1-Mediated Regulation of the Lipogenic Action of IGF-I in Breast Cancer Cells
Authors: Koobotse Moses O. , Schmidt Dayane , Holly Jeff M. P. , Perks Claire M.
Published: November 2020

Hyperglycaemia is a common metabolic alteration associated with breast cancer risk and progression. We have previously reported that BRCA1 restrains metabolic activity and proliferative response to IGF-I anabolic actions in breast cancer cells cultured in high glucose. Here, we evaluated the impact of normal physiological glucose on these tumour suppressive roles of BRCA1. Human breast cancer cells cultured in normal physiological and high glucose were treated with IGF-I (0–500 ng/mL). Cellular responses were evaluated using immunoblotting, co-immunoprecipitation, and cell viability assay. As we previously reported, IGF-I induced ACCA dephosphorylation by reducing the association between BRCA1 and phosphorylated ACCA in high glucose, and upregulated FASN abundance downstream of ACCA. However, these effects were not observed in normal glucose. Normal physiological glucose conditions completely blocked IGF-I-induced ACCA dephosphorylation and FASN upregulation. Co-immunoprecipitation studies showed that normal physiological glucose blocked ACCA dephosphorylation by increasing the association between BRCA1 and phosphorylated ACCA. Compared to high glucose, the proliferative response of breast cancer cells to IGF-I was reduced in normal glucose, whereas no difference was observed in normal mammary epithelial cells. Considering these results collectively, we conclude that normal physiological glucose promotes the novel function of BRCA1 as a metabolic restraint of IGF-I actions. These data suggest that maintaining normal glucose levels may improve BRCA1 function in breast cancer and slow down cancer progression.
TULP1 and TUB Are Required for Specific Localization of PRCD to Photoreceptor Outer Segments
Authors: Remez Lital , Cohen Ben , Nevet Mariela J. , Rizel Leah , Ben-Yosef Tamar
Published: November 2020

Photoreceptor disc component (PRCD) is a small protein which is exclusively localized to photoreceptor outer segments, and is involved in the formation of photoreceptor outer segment discs. Mutations in PRCD are associated with retinal degeneration in humans, mice, and dogs. The purpose of this work was to identify PRCD-binding proteins in the retina. PRCD protein-protein interactions were identified when implementing the Ras recruitment system (RRS), a cytoplasmic-based yeast two-hybrid system, on a bovine retina cDNA library. An interaction between PRCD and tubby-like protein 1 (TULP1) was identified. Co-immunoprecipitation in transfected mammalian cells confirmed that PRCD interacts with TULP1, as well as with its homolog, TUB. These interactions were mediated by TULP1 and TUB highly conserved C-terminal tubby domain. PRCD localization was altered in the retinas of TULP1- and TUB-deficient mice. These results show that TULP1 and TUB, which are involved in the vesicular trafficking of several photoreceptor proteins from the inner segment to the outer segment, are also required for PRCD exclusive localization to photoreceptor outer segment discs.
Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases
Authors: Creeden Justin F. , Alganem Khaled , Imami Ali S. , Brunicardi F. Charles , Liu Shi-He , Shukla Rammohan , Tomar Tushar , Naji Faris , McCullumsmith Robert E.
Published: November 2020

Pancreatic cancer remains one of the most difficult malignancies to treat. Minimal improvements in patient outcomes and persistently abysmal patient survival rates underscore the great need for new treatment strategies. Currently, there is intense interest in therapeutic strategies that target tyrosine protein kinases. Here, we employed kinome arrays and bioinformatic pipelines capable of identifying differentially active protein tyrosine kinases in different patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines and wild-type pancreatic tissue to investigate the unique kinomic networks of PDAC samples and posit novel target kinases for pancreatic cancer therapy. Consistent with previously described reports, the resultant peptide-based kinome array profiles identified increased protein tyrosine kinase activity in pancreatic cancer for the following kinases: epidermal growth factor receptor (EGFR), fms related receptor tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR-3), insulin receptor (INSR), ephrin receptor A2 (EPHA2), platelet derived growth factor receptor alpha (PDGFRA), SRC proto-oncogene kinase (SRC), and tyrosine kinase non receptor 2 (TNK2). Furthermore, this study identified increased activity for protein tyrosine kinases with limited prior evidence of differential activity in pancreatic cancer. These protein tyrosine kinases include B lymphoid kinase (BLK), Fyn-related kinase (FRK), Lck/Yes-related novel kinase (LYN), FYN proto-oncogene kinase (FYN), lymphocyte cell-specific kinase (LCK), tec protein kinase (TEC), hemopoietic cell kinase (HCK), ABL proto-oncogene 2 kinase (ABL2), discoidin domain receptor 1 kinase (DDR1), and ephrin receptor A8 kinase (EPHA8). Together, these results support the utility of peptide array kinomic analyses in the generation of potential candidate kinases for future pancreatic cancer therapeutic development.
Performance of Pheromone-Baited Traps to Monitor the Seasonal Abundance of Tortrix Moths in Chestnut Groves
Authors: Ferracini Chiara , Pogolotti Cristina , Lentini Giada , Saitta Valerio , Busato Enrico , Rama Franco , Alma Alberto
Published: November 2020

(1) Background: Pammene fasciana (L.), Cydia fagiglandana (Zeller), and C. splendana (Hübner) (Lepidoptera: Tortricidae) are considered key moth pests of chestnut in Europe. (2) Methods: Investigations were performed in 2018–2019 in northern Italy. Sticky traps and commercially available pheromones were used for monitoring; moreover, two experimental pheromone blends were tested. All specimens were identified according to male genitalia and molecular analyses. Newly formed chestnut husks and fruits were randomly collected to evaluate the presence of larvae and/or feeding damage, by comparing it to trap catches. (3) Results: P. fasciana was present in all the sites, whereas Cydia species were recorded in three sites of six, with differences in abundance related to pheromone blends studied. Several non-target species, such as Oegoconia novimundi (Busck) and Cydia ilipulana (Walsingham), were present. Data about the seasonal flight activity are provided. (4) Conclusions: This research contributes to ascertaining the presence and abundance of tortrix moths in Italian chestnut groves, and the presence of non-target species highlights the risk of overestimating catches. Fruit damage recorded did not always reflect catches made by pheromone traps, suggesting that monitoring may underestimate the real size of moths’ populations. All of the data acquired are important for planning specific control measures.
Information Recall in Pre-Operative Consultation for Glioma Surgery Using Actual Size Three-Dimensional Models
Authors: Sezer Sümeyye , Piai Vitoria , Kessels Roy P.C. , ter Laan Mark
Published: November 2020

Three-dimensional (3D) technologies are being used for patient education. For glioma, a personalized 3D model can show the patient specific tumor and eloquent areas. We aim to compare the amount of information that is understood and can be recalled after a pre-operative consult using a 3D model (physically printed or in Augmented Reality (AR)) versus two-dimensional (2D) MR images. In this explorative study, healthy individuals were eligible to participate. Sixty-one participants were enrolled and assigned to either the 2D (MRI/fMRI), 3D (physical 3D model) or AR groups. After undergoing a mock pre-operative consultation for low-grade glioma surgery, participants completed two assessments (one week apart) testing information recall using a standardized questionnaire. The 3D group obtained the highest recall scores on both assessments (Cohen’s d = 1.76 and Cohen’s d = 0.94, respectively, compared to 2D), followed by AR and 2D, respectively. Thus, real-size 3D models appear to improve information recall as compared to MR images in a pre-operative consultation for glioma cases. Future clinical studies should measure the efficacy of using real-size 3D models in actual neurosurgery patients.
Handwriting Analysis in Children and Adolescents with Hemophilia: A Pilot Study
Authors: Pasta Gianluigi , Mancuso Maria Elisa , De Felice Filomena , Seuser Alexander , Annunziata Salvatore , Peyvandi Flora , Santagostino Elena , Mosconi Mario , Seuser Axel
Published: November 2020

Background: Handwriting is a complex task that requires the integrity of different sensorimotor components to be performed successfully. Patients with hemophilia suffer from recurrent joint bleeds that may occur in the elbow, causing elbow dysfunction with handwriting performance impairment. In our study, we described instrumental dysgraphia that is related to functional disturbances. This pilot study aims to evaluate the handwriting performance in a group of patients with hemophilia. Methods: The study was performed at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan. Boys with severe and moderate hemophilia A and B regularly followed-up at that Center, with age between 6–19 years, were eligible. Patients were invited to the Center for one multidisciplinary evaluation of the upper limbs that included: Clinical examination, surface electromyography, and handwriting assessment. Results: All patients, but one, completed handwriting assessment. Overall, 14/19 (74%) had abnormal handwriting, which was overt instrumental dysgraphia in six (32%). There was no difference in Hemophilia Joint Health Score (HJHS) between dysgraphic and non-dysgraphic boys, while surface electromyography (sEMG) revealed a prevalence of flexor muscles of the upper limb in dysgraphic as compared with non-dysgraphic boys. Conclusions: The rather high prevalence of instrumental dysgraphia found in this pilot study deserves a further development of this preliminary experience by increasing the number of examined patients and comparing them with a control group, including quality of life and psychological assessment.
Validity of Bioimpedance Equations to Evaluate Fat-Free Mass and Muscle Mass in Severely Malnourished Anorectic Patients
Authors: Coëffier Moise , Gâté Mathilde , Rimbert Agnès , Petit André , Folope Vanessa , Grigioni Sébastien , Déchelotte Pierre , Achamrah Najate
Published: November 2020

Background: Bioelectrical impedance analysis (BIA) is a simple and rapid technique to measure body composition (BC). Validity of BIA in patients with low body mass index (BMI) remains controversial. We assessed the validity of several BIA equations to evaluate fat-free mass (FFM), fat mass (FM) and muscle mass in patients with anorexia nervosa (AN) by using dual X ray absorptiometry (DXA) as reference. Methods: Sixteen BIA equations developed for FFM and appendicular lean mass (ALM) were applied on electrical data measured by BIA in AN patients with BMI <16 kg/m². BIA and DXA were done the same day after overnight fasting. Results were compared with the Bland–Altman method, Pearson correlation and a Lin concordance test. Results: Data from 115 female AN patients (14.6 ± 1.2 kg/m²; 32.3 ± 14.5 years) were included. FM and FFM assessed by DXA were, respectively, 4.2 ± 2.4 kg and 35.5 ± 3.8 kg. The best results were obtained with Sun’s equation: respectively for FM and FFM, Bland Altman bias at 0.548 and 0.706 kg, Pearson correlation r at 0.86 and 0.86 and Lin concordance coefficient at 0.81 and 0.84. However, confidence intervals (CI) at 95% were high (−2.73–3.83 kg for FM; −4.55–3.13 kg for FFM). Other equations also showed high 95% CI. Accuracy was acceptable for Sun and Bedogni equations for FFM (approximately 66%) but very low for FM prediction considering all equations (<15%). Concerning ALM evaluated at 14.88 ± 2.04 kg by DXA, only Scafoglieri and Yoshida equations showed acceptable values: bias (−0.2 and 2.8%), Pearson r (0.89 and 0.86), Lin concordance coefficient (0.82 and 0.82) and accuracy (83.5 and 82.6%). Confidence intervals at 95% were high for both equations (−2.1–2.0 for Scafoglieri equation and −1.6–2.4 for Yoshida equation). Conclusion: In AN patients with BMI < 16 kg/m², no BIA equation tested was adapted to evaluate BC at the individual level.
Periostin and Thymic Stromal Lymphopoietin—Potential Crosstalk in Obstructive Airway Diseases
Authors: Nejman-Gryz Patrycja , Górska Katarzyna , Paplińska-Goryca Magdalena , Proboszcz Małgorzata , Krenke Rafał
Published: November 2020

Periostin and thymic stromal lymphopoietin (TSLP) are newly described markers of obstructive airway diseases and the mechanism by which both markers participate in immune response remains poorly understood. The aim of our study was to determine periostin and TSLP concentration in serum and induced sputum (IS) in patients with atopic asthma, chronic obstructive pulmonary disease (COPD), and controls, as well as to evaluate the potential link between periostin, TSLP, and Th2 immune response. Serum and IS levels of periostin, TSLP, IL-4, and IL-13 were determined in 12 atopic asthmatics, 16 COPD sufferers, and 10 controls. We noticed a significantly higher IS periostin and TSLP concentration at protein and mRNA level in asthmatics compared to the two other groups; additionally, periostin and TSLP were correlated positively with IS eosinophil count. A strong positive correlation between IS periostin and TSLP protein levels (r = 0.96) as well as mRNA expression level (r = 0.95) was found in patients with asthma. The results of our study show that periostin and TSLP are associated with eosinophilic airway inflammation and seem to be important drivers of atopic asthma but not COPD pathobiology. Very strong correlations between local periostin, TSLP, eosinophils, and IL-4 in asthma point to the link between periostin–TSLP and Th2 response.
The Alcohol Hangover Research Group: Ten Years of Progress in Research on the Causes, Consequences, and Treatment of the Alcohol Hangover
Authors: Verster Joris C. , Arnoldy Lizanne , Benson Sarah , Scholey Andrew , Stock Ann-Kathrin
Published: November 2020

The alcohol hangover is defined as the combination of negative mental and physical symptoms, which can be experienced after a single episode of alcohol consumption, starting when blood alcohol concentration (BAC) approaches zero. Here, we present the book “The alcohol hangover: causes, consequences, and treatment”, written to celebrate the 10th anniversary of the Alcohol Hangover Research Group (AHRG), summarizing recent advances in the field of alcohol hangover research.
The New ELN Recommendations for Treating CML
Authors: Hehlmann Rüdiger
Published: November 2020

After normal survival has been achieved in most patients with chronic myeloid leukemia (CML), a new goal for treating CML is survival at good quality of life, with treatment discontinuation in sustained deep molecular response (DMR; MR4 or deeper) and treatment-free remission (TFR). Four tyrosine kinase inhibitors (TKIs) have been approved for first-line therapy: imatinib, dasatinib, nilotinib, bosutinib. Unexpectedly, the outcome of long-term randomized trials has shown that faster response as achieved by higher doses of imatinib, imatinib in combination, or second-generation (2G)-TKIs, does not translate into a survival advantage. Serious and frequent, and in part cumulative long-term toxicities, have led to a reevaluation of the role of 2G-TKIs in first-line therapy. Generic imatinib is the current most cost-effective first-line therapy in the chronic phase. A change of treatment is recommended when intolerance cannot be ameliorated or molecular milestones are not reached. Patient comorbidities and contraindications of all TKIs must be considered. Risk profile at diagnosis should be assessed with the EUTOS score for long-term survival (ELTS). Monitoring of response is by polymerase chain reaction (PCR). Cytogenetics is still required in the case of atypical translocations, atypical transcripts, and additional chromosomal aberrations. TKIs are contraindicated during pregnancy. Since the majority of patients are at risk of lifelong exposure to TKIs, amelioration of chronic low-grade side effects is important.
Artificial Intelligence in Gastroenterology—Walking into the Room of Little Miracles
Authors: Marlicz Wojciech , Koulaouzidis George , Koulaouzidis Anastasios
Published: November 2020

The surge of artificial intelligence (AI) in medicine stands on a lengthy, and frequently reticent, buildout [...]
First Report of Sublingual Gland Ducts: Visualization by Dynamic MR Sialography and Its Clinical Application
Authors: Tanaka Tatsurou , Oda Masafumi , Wakasugi-Sato Nao , Joujima Takaaki , Miyamura Yuichi , Habu Manabu , Kodama Masaaki , Takahashi Osamu , Sago Teppei , Matsumoto-Takeda Shinobu , Nishida Ikuko , Tsurushima Hiroki , Otani Yasushi , Yoshiga Daigo , Sasaguri Masaaki , Morimoto Yasuhiro
Published: November 2020

This study was done to determine whether the sublingual gland ducts could be visualized and/or their function assessed by MR sialography and dynamic MR sialography and to elucidate the clinical significance of the visualization and/or evaluation of the function of sublingual gland ducts by clinical application of these techniques. In 20 adult volunteers, 19 elderly volunteers, and 7 patients with sublingual gland disease, morphological and functional evaluations were done by MR sialography and dynamic MR sialography. Next, four parameters, including the time-dependent changes (change ratio) in the maximum area of the detectable sublingual gland ducts in dynamic MR sialographic images and data were analyzed. Sublingual gland ducts could be accurately visualized in 16 adult volunteers, 12 elderly volunteers, and 5 patients. No significant differences in the four parameters in detectable duct areas of sublingual glands were found among the three groups. In one patient with a ranula, the lesion could be correctly diagnosed as a ranula by MR sialography because the mass was clearly derived from sublingual gland ducts. This is the first report of successful visualization of sublingual gland ducts. In addition, the present study suggests that MR sialography can be more useful in the diagnosis of patients with lesions of sublingual gland ducts.