bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatic Tumor Microenvironments and Effects on NK Cell Phenotype and Function
Authors: Piñeiro Fernández Julián , Luddy Kimberly A. , Harmon Cathal , O’Farrelly Cliona
Published: August 2019

The liver is a complex organ with critical physiological functions including metabolism, glucose storage, and drug detoxification. Its unique immune profile with large numbers of cytotoxic CD8+ T cells and significant innate lymphoid population, including natural killer cells, γ δ T cells, MAIT cells, and iNKTcells, suggests an important anti-tumor surveillance role. Despite significant immune surveillance in the liver, in particular large NK cell populations, hepatic cell carcinoma (HCC) is a relatively common outcome of chronic liver infection or inflammation. The liver is also the second most common site of metastatic disease. This discordance suggests immune suppression by the environments of primary and secondary liver cancers. Classic tumor microenvironments (TME) are poorly perfused, leading to accumulation of tumor cell metabolites, diminished O2, and decreased nutrient levels, all of which impact immune cell phenotype and function. Here, we focus on changes in the liver microenvironment associated with tumor presence and how they affect NK function and phenotype.
Effect of Autophagy Regulated by Sirt1/FoxO1 Pathway on the Release of Factors Promoting Thrombosis from Vascular Endothelial Cells
Authors: Wu Qian , Hu Yuting , Jiang Minrui , Wang Fanglei , Gong Guoqing
Published: August 2019

Factors promoting thrombosis such as von Willebrand factor (vWF) and P-selectin are essential for the development of atherosclerosis (AS) and arterial thrombosis. The processing, maturation and release of vWF are regulated by autophagy of vascular endothelial cells. The Sirt1/FoxO1 pathway is an important pathway to regulate autophagy of endothelial cells, therefore the Sirt1/FoxO1 pathway may be an important target for the prevention of thrombosis. We investigated the role of ox-LDL in the release of vWF and P-selectin and the expression of Sirt1 and FoxO1 by Western Blot, Flow Cytometry, ELISA, and tandem fluorescent mRFP-GFP-LC3. We found that vWF and P-selectin secretion increased and Sirt1/FoxO1 pathway was depressed in human umbilical vein endothelial cells (HUVEC) when treated with ox-LDL. Moreover, the expression of autophagy-related protein LC3-II/I and p62 increased. Then, we explored the relationship between autophagy regulated by the Sirt1/FoxO1 pathway and the secretion of vWF and P-selectin. We found that Sirt1/FoxO1, activated by the Sirt1 activators resveratrol (RSV) and SRT1720, decreased the secretion of vWF and P-selectin, which can be abolished by the autophagy inhibitor 3-MA. The expression of Rab7 increased when Sirt1/FoxO1 pathway was activated, and the accumulation of p62 was decreased. Autophagy flux was inhibited by ox-LDL and Sirt1/FoxO1 pathway might enhance autophagy flux through the promotion of the Rab7 expression. Taken together, our data suggest that by enhancing autophagy flux and decreasing the release of vWF and P-selectin, the Sirt1/FoxO1 pathway may be a promising target to prevent AS and arterial thrombosis.
Identification of Msp1-Induced Signaling Components in Rice Leaves by Integrated Proteomic and Phosphoproteomic Analysis
Authors: Gupta Ravi , Min Cheol Woo , Kim Yu-Jin , Kim Sun Tae
Published: August 2019

MSP1 is a Magnaporthe oryzae secreted protein that elicits defense responses in rice. However, the molecular mechanism of MSP1 action is largely elusive. Moreover, it is yet to be established whether MSP1 functions as a pathogen-associated molecular pattern (PAMP) or an effector. Here, we employed a TMT-based quantitative proteomic analysis of cytosolic as well as plasma membrane proteins to decipher the MSP1 induced signaling in rice. This approach led to the identification of 6691 proteins, of which 3049 were identified in the plasma membrane (PM), while 3642 were identified in the cytosolic fraction. A parallel phosphoproteome analysis led to the identification of 1906 phosphopeptides, while the integration of proteome and phosphoproteome data showed activation of proteins related to the proteolysis, jasmonic acid biosynthesis, redox metabolism, and MAP kinase signaling pathways in response to MSP1 treatment. Further, MSP1 induced phosphorylation of some of the key proteins including respiratory burst oxidase homologue-D (RBOHD), mitogen-activated protein kinase kinase kinase-1 (MEKK1), mitogen-activated protein kinase-3/6 (MPK3/6), calcium-dependent protein kinase (CDPK) and calmodulin (CaM) suggest activation of PAMP-triggered immunity (PTI) in response to MSP1 treatment. In essence, our results further support the functioning of MSP1 as a PAMP and provide an overview of the MSP1 induced signaling in rice leaves.
New Insights into Mechanisms of Cisplatin Resistance: From Tumor Cell to Microenvironment
Authors: Chen Shang-Hung , Chang Jang-Yang
Published: August 2019

Although cisplatin has been a pivotal chemotherapy drug in treating patients with various types of cancer for decades, drug resistance has been a major clinical impediment. In general, cisplatin exerts cytotoxic effects in tumor cells mainly through the generation of DNA-platinum adducts and subsequent DNA damage response. Accordingly, considerable effort has been devoted to clarify the resistance mechanisms inside tumor cells, such as decreased drug accumulation, enhanced detoxification activity, promotion of DNA repair capacity, and inactivated cell death signaling. However, recent advances in high-throughput techniques, cell culture platforms, animal models, and analytic methods have also demonstrated that the tumor microenvironment plays a key role in the development of cisplatin resistance. Recent clinical successes in combination treatments with cisplatin and novel agents targeting components in the tumor microenvironment, such as angiogenesis and immune cells, have also supported the therapeutic value of these components in cisplatin resistance. In this review, we summarize resistance mechanisms with respect to a single tumor cell and crucial components in the tumor microenvironment, particularly focusing on favorable results from clinical studies. By compiling emerging evidence from preclinical and clinical studies, this review may provide insights into the development of a novel approach to overcome cisplatin resistance.
Mutual Enhancement of Opioid and Adrenergic Receptors by Combinations of Opioids and Adrenergic Ligands Is Reflected in Molecular Complementarity of Ligands: Drug Development Possibilities
Authors: Root-Bernstein Robert , Churchill Beth , Turke Miah , Tiruttani Subhramanyam Udaya K. , Labahn Joerg
Published: August 2019

Crosstalk between opioid and adrenergic receptors is well characterized and due to interactions between second messenger systems, formation of receptor heterodimers, and extracellular allosteric binding regions. Both classes of receptors bind both sets of ligands. We propose here that receptor crosstalk may be mirrored in ligand complementarity. We demonstrate that opioids bind to adrenergic compounds with micromolar affinities. Additionally, adrenergic compounds bind with micromolar affinities to extracellular loops of opioid receptors while opioids bind to extracellular loops of adrenergic receptors. Thus, each compound type can bind to the complementary receptor, enhancing the activity of the other compound type through an allosteric mechanism. Screening for ligand complementarity may permit the identification of other mutually-enhancing sets of compounds as well as the design of novel combination drugs or tethered compounds with improved duration and specificity of action.
Phylogenetically Defined Isoforms of Listeria monocytogenes Invasion Factor InlB Differently Activate Intracellular Signaling Pathways and Interact with the Receptor gC1q-R
Authors: Chalenko Yaroslava , Kalinin Egor , Marchenkov Victor , Sysolyatina Elena , Surin Alexey , Sobyanin Konstantin , Ermolaeva Svetlana
Published: August 2019

The pathogenic Gram-positive bacterium Listeria monocytogenes has been evolving into a few phylogenetic lineages. Phylogenetically defined substitutions were described in the L. monocytogenes virulence factor InlB, which mediates active invasion into mammalian cells via interactions with surface receptors c-Met and gC1q-R. InlB internalin domain (idInlB) is central to interactions with c-Met. Here we compared activity of purified recombinant idInlB isoforms characteristic for L. monocytogenes phylogenetic lineage I and II. Size exclusion chromatography and intrinsic fluorescence were used to characterize idInlBs. Western blotting was used to study activation of c-Met-dependent MAPK- and PI3K/Akt-pathways. Solid-phase microplate binding and competition assay was used to quantify interactions with gCq1-R. Isogenic recombinant L. monocytogenes strains were used to elucidate the input of idInlB isoforms in HEp-2 cell invasion. Physicochemical parameters of idInlB isoforms were similar but not identical. Kinetics of Erk1/2 and Akt phosphorylation in response to purified idInlBs was lineage specific. Lineage I but not lineage II idInlB specifically bound gC1q-R. Antibody against gC1q-R amino acids 221–249 inhibited invasion of L. monocytogenes carrying lineage I but not lineage II idInlB. Taken together, obtained results suggested that phylogenetically defined substitutions in idInlB provide functional distinctions and might be involved in phylogenetically determined differences in virulence potential.
Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model
Authors: Sawamoto Kazuki , Tomatsu Shunji
Published: August 2019

Mucopolysaccharidosis IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Conventional enzyme replacement therapy (ERT) is approved for MPS IVA. However, the fact that the infused enzyme cannot penetrate avascular lesions in cartilage leads to minimal impact on the bone lesion. Moreover, short half-life, high cost, instability, and narrow optimal pH range remain unmet challenges in ERT. Thermostable keratanase, endo-β-N-acetylglucosaminidase, has a unique character of a wide optimal pH range of pH 5.0–7.0. We hypothesized that this endoglycosidase degrades keratan sulfate (KS) polymer in circulating blood and, therefore, ameliorates the accumulation of KS in multiple tissues. We propose a novel approach, Substrate Degradation Enzyme Therapy (SDET), to treat bone lesion of MPS IVA. We assessed the effect of thermostable keratanase on blood KS level and bone pathology using Galns knock-out MPS IVA mice. After a single administration of 2 U/kg (= 0.2 mg/kg) of the enzyme at 8 weeks of age via intravenous injection, the level of serum KS was significantly decreased to normal range level, and this suppression was maintained for at least 4 weeks. We administered 2 U/kg of the enzyme to MPS IVA mice every fourth week for 12 weeks (total of 3 times) at newborns or 8 weeks of age. After a third injection, serum mono-sulfated KS levels were kept low for 4 weeks, similar to that in control mice, and at 12 weeks, bone pathology was markedly improved when SDET started at newborns, compared with untreated MPS IVA mice. Overall, thermostable keratanase reduces the level of KS in blood and provides a positive impact on cartilage lesions, demonstrating that SDET is a novel therapeutic approach to MPS IVA.
Radical Stress Is More Cytotoxic in the Nucleus than in Other Organelles
Authors: Paardekooper Laurent M. , van Vroonhoven Ellen , ter Beest Martin , van den Bogaart Geert
Published: August 2019

Cells are exposed to reactive oxygen species (ROS) as a by-product of mitochondrial metabolism, especially under hypoxia. ROS are also enzymatically generated at the plasma membrane during inflammation. Radicals cause cellular damage leading to cell death, as they react indiscriminately with surrounding lipids, proteins, and nucleotides. However, ROS are also important for many physiological processes, including signaling, pathogen killing and chemotaxis. The sensitivity of cells to ROS therefore likely depends on the subcellular location of ROS production, but how this affects cell viability is poorly understood. As ROS generation consumes oxygen, and hypoxia-mediated signaling upregulates expression of antioxidant transcription factor Nrf2, it is difficult to discern hypoxic from radical stress. In this study, we developed an optogenetic toolbox for organelle-specific generation of ROS using the photosensitizer protein SuperNova which produces superoxide anion upon excitation with 590 nm light. We fused SuperNova to organelle specific localization signals to induce ROS with high precision. Selective ROS production did not affect cell viability in most organelles except for the nucleus. SuperNova is a promising tool to induce locally targeted ROS production, opening up new possibilities to investigate processes and organelles that are affected by localized ROS production.
Robustness of Clonogenic Assays as a Biomarker for Cancer Cell Radiosensitivity
Authors: Matsui Toshiaki , Nuryadi Endang , Komatsu Shuichiro , Hirota Yuka , Shibata Atsushi , Oike Takahiro , Nakano Takashi
Published: August 2019

Photon radiation therapy is a major curative treatment for cancer. However, the lack of robust predictive biomarkers for radiosensitivity precludes personalized radiation therapy. Clonogenic assays are the gold standard method for measuring the radiosensitivity of cancer cells. Although a large number of publications describe the use of clonogenic assays to measure cancer cell radiosensitivity, the robustness of results from different studies is unclear. To address this, we conducted a comprehensive detailed literature search of 256 common cancer cell lines and identified the eight cell lines most-frequently examined for photon sensitivity using clonogenic assays. Survival endpoints and experimental parameters from all 620 relevant experiments were compiled and analyzed. We found that the coefficients of variation for SF2 (surviving fraction after 2 Gy irradiation) and for D10 (dose that yields a surviving fraction of 10%) were below 30% for all cell lines, indicating that SF2 and D10 have acceptable inter-assay precision. These data support further analysis of published data on clonogenic assays using SF2 and D10 as survival endpoints, which facilitates robust identification of biological profiles representative of cancer cell sensitivity to photons.
Vitamin K as a Powerful Micronutrient in Aging and Age-Related Diseases: Pros and Cons from Clinical Studies
Authors: Simes Dina C. , Viegas Carla S. B. , Araújo Nuna , Marreiros Catarina
Published: August 2019

Vitamin K is a multifunctional micronutrient implicated in age-related diseases such as cardiovascular diseases, osteoarthritis and osteoporosis. Although vitamin K-dependent proteins (VKDPs) are described to have a crucial role in the pathogenesis of these diseases, novel roles have emerged for vitamin K, independently of its role in VKDPs carboxylation. Vitamin K has been shown to act as an anti-inflammatory by suppressing nuclear factor κB (NF-κB) signal transduction and to exert a protective effect against oxidative stress by blocking the generation of reactive oxygen species. Available clinical evidences indicate that a high vitamin K status can exert a protective role in the inflammatory and mineralization processes associated with the onset and progression of age-related diseases. Also, vitamin K involvement as a protective super-micronutrient in aging and ‘inflammaging’ is arising, highlighting its future use in clinical practice. In this review we summarize current knowledge regarding clinical data on vitamin K in skeletal and cardiovascular health, and discuss the potential of vitamin K supplementation as a health benefit. We describe the clinical evidence and explore molecular aspects of vitamin K protective role in aging and age-related diseases, and its involvement as a modulator in the interplay between pathological calcification and inflammation processes.
ERK1,2 Signalling Pathway along the Nephron and Its Role in Acid-base and Electrolytes Balance
Authors: Capolongo Giovanna , Suzumoto Yoko , D’Acierno Mariavittoria , Simeoni Mariadelina , Capasso Giovambattista , Zacchia Miriam
Published: August 2019

Mitogen-activated protein kinases (MAPKs) are intracellular molecules regulating a wide range of cellular functions, including proliferation, differentiation, apoptosis, cytoskeleton remodeling and cytokine production. MAPK activity has been shown in normal kidney, and its over-activation has been demonstrated in several renal diseases. The extracellular signal-regulated protein kinases (ERK 1,2) signalling pathway is the first described MAPK signaling. Intensive investigations have demonstrated that it participates in the regulation of ureteric bud branching, a fundamental process in establishing final nephron number; in addition, it is also involved in the differentiation of the nephrogenic mesenchyme, indicating a key role in mammalian kidney embryonic development. In the present manuscript, we show that ERK1,2 signalling mediates several cellular functions also in mature kidney, describing its role along the nephron and demonstrating whether it contributes to the regulation of ion channels and transporters implicated in acid-base and electrolytes homeostasis.
Tumor Metabolism as a Regulator of Tumor–Host Interactions in the B-Cell Lymphoma Microenvironment—Fueling Progression and Novel Brakes for Therapy
Authors: Beielstein Anna C. , Pallasch Christian P.
Published: August 2019

Tumor metabolism and its specific alterations have become an integral part of understanding functional alterations leading to malignant transformation and maintaining cancer progression. Here, we review the metabolic changes in B-cell neoplasia, focusing on the effects of tumor metabolism on the tumor microenvironment (TME). Particularly, innate and adaptive immune responses are regulated by metabolites in the TME such as lactate. With steadily increasing therapeutic options implicating or utilizing the TME, it has become essential to address the metabolic alterations in B-cell malignancy for therapeutic approaches. In this review, we discuss metabolic alterations of B-cell lymphoma, consequences for currently used therapy regimens, and novel approaches specifically targeting metabolism in the TME.
SILAC-Based Quantification of TGFBR2-Regulated Protein Expression in Extracellular Vesicles of Microsatellite Unstable Colorectal Cancers
Authors: Fricke Fabia , Michalak Malwina , Warnken Uwe , Hausser Ingrid , Schnölzer Martina , Kopitz Jürgen , Gebert Johannes
Published: August 2019

Microsatellite unstable (MSI) colorectal cancers (CRCs) are characterized by mutational inactivation of Transforming Growth Factor Beta Receptor Type 2 (TGFBR2). TGFBR2-deficient CRCs present altered target gene and protein expression. Such cellular alterations modulate the content of CRC-derived extracellular vesicles (EVs). EVs function as couriers of proteins, nucleic acids, and lipids in intercellular communication. At a qualitative level, we have previously shown that TGFBR2 deficiency causes overall alterations in the EV protein content. To deepen the basic understanding of altered protein dynamics, this work aimed to determine TGFBR2-dependent EV protein signatures in a quantitative manner. Using a stable isotope labeling with amino acids in cell culture (SILAC) approach for mass spectrometry-based quantification, 48 TGFBR2-regulated proteins were identified in MSI CRC-derived EVs. Overall, TGFBR2 deficiency caused upregulation of several EV proteins related to the extracellular matrix and nucleosome as well as downregulation of proteasome-associated proteins. The present study emphasizes the general overlap of proteins between EVs and their parental CRC cells but also highlights the impact of TGFBR2 deficiency on EV protein composition. From a clinical perspective, TGFBR2-regulated quantitative differences of protein expression in EVs might nominate novel biomarkers for liquid biopsy-based MSI typing in the future.
Sex, Age, and Bodyweight as Determinants of Extracellular DNA in the Plasma of Mice: A Cross-Sectional Study
Authors: Janovičová Ľubica , Konečná Barbora , Vokálová Lenka , Lauková Lucia , Vlková Barbora , Celec Peter
Published: August 2019

Extracellular DNA (ecDNA) is studied as a possible biomarker, but also as a trigger of the immune responses important for the pathogenesis of several diseases. Extracellular deoxyribonuclease (DNase) activity cleaves ecDNA. The aim of our study was to describe the interindividual variability of ecDNA and DNase activity in the plasma of healthy mice, and to analyze the potential determinants of the variability, including sex, age, and bodyweight. In this experiment, 58 adult CD1 mice (41 females and 31 males) of a variable age (3 to 16 months old) and bodyweight (females 25.7 to 52.1 g, males 24.6 to 49.6 g) were used. The plasma ecDNA was measured using a fluorometric method. The nuclear ecDNA and mitochondrial ecDNA were quantified using real-time PCR. The deoxyribonuclease activity was assessed using the single radial enzyme diffusion method. The coefficient of variance for plasma ecDNA was 139%, and for DNase 48%. Sex differences were not found in the plasma ecDNA (52.7 ± 73.0 ηg/mL), but in the DNase activity (74.5 ± 33.5 K.u./mL for males, and 47.0 ± 15.4 K.u./mL for females). There were no associations between plasma ecDNA and bodyweight or the age of mice. Our study shows that the variability of plasma ecDNA and DNase in adult healthy mice is very high. Sex, age, and bodyweight seem not to be major determinants of ecDNA variability in healthy mice. As ecDNA gains importance in the research of several diseases, it is of importance to understand its production and cleavage. Further studies should, thus, test other potential determinants, taking into account cleavage mechanisms other than DNase.
Identifying Common Features in the Activation of Melanocortin-2 Receptors: Studies on the Xenopus tropicalis Melanocortin-2 Receptor
Authors: Davis Perry E. , Wilkinson Emily C. , Dores Robert M.
Published: August 2019

The interaction between the pituitary hormone, adrenocorticotropin (ACTH), and melanocortin-2 receptor (MC2R) orthologs involves the H6 F7 R8 W9 and R/K15 K16 R17 R18 motifs in ACTH making contact with corresponding contact sites on MC2R. Earlier studies have localized the common HFRW binding site of all melanocortin receptors to residues in TM2, TM3, and TM6 that are located close to the extracellular space. The current study has identified residues in Xenopus tropicalis (xt) MC2R in TM4 (I158, F161), in EC2 (M166), and in TM5 (V172) that also are involved in activation of xtMC2R, and may be in the R/KKRR contact site of xtMC2R. These results are compared to earlier studies on the corresponding domains of human MC2R and rainbow trout MC2R in an effort to identify common features in the activation of teleost and tetrapod MC2R orthologs following stimulation with ACTH.
Wnt Binding Affinity Prediction for Putative Frizzled-Type Cysteine-Rich Domains
Authors: Agostino Mark , Pohl Sebastian Öther-Gee
Published: August 2019

Several proteins other than the frizzled receptors (Fzd) and the secreted Frizzled-related proteins (sFRP) contain Fzd-type cysteine-rich domains (CRD). We have termed these domains “putative Fzd-type CRDs”, as the relevance of Wnt signalling in the majority of these is unknown; the RORs, an exception to this, are well known for mediating non-canonical Wnt signalling. In this study, we have predicted the likely binding affinity of all Wnts for all putative Fzd-type CRDs. We applied both our previously determined Wnt‒Fzd CRD binding affinity prediction model, as well as a newly devised model wherein the lipid term was forced to contribute favourably to the predicted binding energy. The results obtained from our new model indicate that certain putative Fzd CRDs are much more likely to bind Wnts, in some cases exhibiting selectivity for specific Wnts. The results of this study inform the investigation of Wnt signalling modulation beyond Fzds and sFRPs.
Human IL-23R Cytokine-Binding Homology Region-Fc Fusion Protein Ameliorates Psoriasis via the Decrease of Systemic Th17 and ILC3 Cell Responses
Authors: Gao Yue , Bian Zhengying , Xue Wenyao , Li Qianwen , Zeng Yu , Wang Yimeng , Tang Lei , Tang Tiejun , Gao Xiangdong , Guo Wei
Published: August 2019

Interleukin (IL)-23 is considered an effective therapeutic target for the treatment of psoriasis because of the crucial role of the IL-23/IL-17 axis in the pathogenesis of psoriasis, and it has recently been reported to be involved in ILC3 cell differentiation. In this study, we report that eukaryotically expressed rhIL23R-CHR/Fc, as an endogenous extracellular receptor analogue, could be a natural antagonist in an imiquimod (IMQ)-induced psoriasis-like mouse model, including the antagonizing effect of suppressed inflammation in the skin lesion, decreased production of pro-inflammatory cells, and reduced the expression of pro-inflammatory factors. The rhIL23R-CHR/Fc fusion protein inhibits both innate immune and adaptive immune-mediated inflammatory responses. These findings shed light on rhIL23R-CHR/Fc as a promising candidate therapy for the treatment of psoriasis.
Correction: Huang, H.-M., et al. Effects of Sapindus mukorossi Seed Oil on Skin Wound Healing: In Vivo and In Vitro Testing. Int. J. Mol. Sci. 2019, 20, 2579
Authors: Chen Chang-Chih , Nien Chia-Jen , Chen Lih-Geeng , Huang Kuen-Yu , Chang Wei-Jen , Huang Haw-Ming
Published: August 2019

The authors are sorry to report that some of the HPLC data reported in their recently published paper [...]
L1 Cell Adhesion Molecule in Cancer, a Systematic Review on Domain-Specific Functions
Authors: van der Maten Miriam , Reijnen Casper , Pijnenborg Johanna M.A. , Zegers Mirjam M.
Published: August 2019

L1 cell adhesion molecule (L1CAM) is a glycoprotein involved in cancer development and is associated with metastases and poor prognosis. Cellular processing of L1CAM results in expression of either full-length or cleaved forms of the protein. The different forms of L1CAM may localize at the plasma membrane as a transmembrane protein, or in the intra- or extracellular environment as cleaved or exosomal forms. Here, we systematically analyze available literature that directly relates to L1CAM domains and associated signaling pathways in cancer. Specifically, we chart its domain-specific functions in relation to cancer progression, and outline pre-clinical assays used to assess L1CAM. It is found that full-length L1CAM has both intracellular and extracellular targets, including interactions with integrins, and linkage with ezrin. Cellular processing leading to proteolytic cleavage and/or exosome formation results in extracellular soluble forms of L1CAM that may act through similar mechanisms as compared to full-length L1CAM, such as integrin-dependent signals, but also through distinct mechanisms. We provide an algorithm to guide a step-wise analysis on L1CAM in clinical samples, to promote interpretation of domain-specific expression. This systematic review infers that L1CAM has an important role in cancer progression that can be attributed to domain-specific forms. Most studies focus on the full-length plasma membrane L1CAM, yet knowledge on the domain-specific forms is a prerequisite for selective targeting treatment.
Positive Effects of Ger-Gen-Chyn-Lian-Tang on Cholestatic Liver Fibrosis in Bile Duct Ligation-Challenged Mice
Authors: Chang Zi-Yu , Chen Chin-Chang , Liu Hsuan-Miao , Yeh Yuan-Chieh , Lin Tung-Yi , Lee Tzung-Yan , Huang Tse-Hung
Published: August 2019

The purpose of this study was to investigate whether Ger-Gen-Chyn-Lian-Tang (GGCLT) suppresses oxidative stress, inflammation, and angiogenesis during experimental liver fibrosis through the hypoxia-inducible factor-1α (HIF-1α)-mediated pathway. Male C57BL/6 mice were randomly assigned to a sham-control or bile duct ligation (BDL) group with or without treatment with GGCLT at 30, 100, and 300 mg/kg. Plasma alanine aminotransferase (ALT) levels were analyzed using a diagnostic kit. Liver histopathology and hepatic status parameters were measured. Compared to control mice, the BDL mice exhibited an enlargement in liver HIF-1α levels, which was suppressed by 100 and 300 mg/kg GGCLT treatments (control: BDL: BDL + GGCLT-100: BDL + GGCLT-300 = 0.95 ± 0.07: 1.95 ± 0.12: 1.43 ± 0.05: 1.12 ± 0.10 fold; p < 0.05). GGCLT restrained the induction of hepatic hydroxyproline and malondialdehyde levels in the mice challenged with BDL, further increasing the hepatic glutathione levels. Furthermore, in response to increased hepatic inflammation and fibrogenesis, significant levels of ALT, nuclear factor kappa B, transforming growth factor-β, α-smooth muscle actin, matrix metalloproteinase-2 (MMP-2), MMP-9, and procollagen-III were found in BDL mice, which were attenuated with GGCLT. In addition, GGCLT reduced the induction of angiogenesis in the liver after BDL by inhibiting vascular endothelial growth factor (VEGF) and VEGF receptors 1 and 2. In conclusion, the anti-liver fibrosis effect of GGCLT, which suppresses hepatic oxidative stress and angiogenesis, may be dependent on an HIF-1α-mediated pathway.
Investigating the Role of VDR and Megalin in Semi-Selectivity of Side-Chain Modified 19-nor Analogs of Vitamin D
Authors: Berkowska Klaudia , Corcoran Aoife , Grudzień Małgorzata , Jakuszak Agnieszka , Chodyński Michał , Kutner Andrzej , Marcinkowska Ewa
Published: August 2019

1,25-dihydroxyvitamin D3 (1,25D3) is implicated in many cellular functions, including cell proliferation and differentiation, thus exerting potential antitumor effects. A major limitation for therapeutic use of 1,25D3 are potent calcemic activities. Therefore, synthetic analogs of 1,25D3 for use in anticancer therapy should retain cell differentiating potential, with calcemic activity being reduced. To obtain this goal, the analogs should effectively activate transcription of genes responsible for cell differentiation, leaving the genes responsible for calcium homeostasis less active. In order to better understand this phenomenon, we selected a series of structurally related 19-nor analogs of 1,25D (PRI-5100, PRI-5101, PRI-5105, and PRI-5106) and tested their activities in blood cells and in cells connected to calcium homeostasis. Affinities of analogs to recombinant vitamin D receptor (VDR) protein were not correlated to their pro-differentiating activities. Moreover, the pattern of transcriptional activities of the analogs was different in cell lines originating from various vitamin D-responsive tissues. We thus hypothesized that receptors which participate in transport of the analogs to the cells might contribute to the observed differences. In order to study this hypothesis, we produced renal cells with knock-out of the megalin gene. Our results indicate that megalin has a minor effect on semi-selective activities of vitamin D analogs.
Performance of Three Isolates of Metarhizium anisopliae and Their Virulence against Zeugodacus cucurbitae under Different Temperature Regimes, with Global Extrapolation of Their Efficiency
Authors: Onsongo Susan , Gichimu Bernard , Akutse Komivi , Dubois Thomas , Mohamed Samira
Published: August 2019

The performance of entomopathogenic fungi in pest control is usually affected by both biotic and abiotic factors. This study aimed to determine the effects of various temperatures (15, 20, 25 and 30 °C) on conidial germination, mycelial growth and conidial density and virulence to the melon fly Zeugodacus cucurbitae of three selected isolates of Metarhizium anisopliae. The three isolates, ICIPE 18, ICIPE 30 and ICIPE 69, had previously been selected in laboratory bioassays. Percentage mortality by the three isolates ranged between 16.25% and 100.0% across the different temperatures. The isolates ICIPE 69 and ICIPE 18 recorded the highest percentage mortality of 96.25% and 100% and the shortest LT50 values of 2.61 and 2.63 days, respectively, at 30 °C. However, at 30 °C, ICIPE 69 produced the highest number of conidia of 90.5 × 107 /mL and was therefore selected for global mapping to predict its efficacy against Z. cucurbitae using the geospatial temperature data layer and the best fitted quadratic model. The map showed that the isolate would be more effective in the tropics than in temperate climates.
Right Heart Remodeling in Patients with End-Stage Alcoholic Liver Cirrhosis: Speckle Tracking Point of View
Authors: Zhang Kun , Braun Alexander , von Koeckritz Francisca , Schmuck Rosa B. , Teegen Eva M. , Cuspidi Cesare , Heinzel Frank , Pieske Burkert , Tadic Marijana
Published: August 2019

Background: Data regarding cardiac remodeling in patients with alcoholic liver cirrhosis are scarce. We sought to investigate right atrial (RA) and right ventricular (RV) structure, function, and mechanics in patients with alcoholic liver cirrhosis. Methods: This retrospective cross-sectional investigation included 67 end-stage cirrhotic patients, who were referred for evaluation for liver transplantation and 36 healthy controls. All participants underwent echocardiographic examination including strain analysis, which was performed offline. Results: RV basal diameter and RV thickness were significantly higher in patients with cirrhosis. Conventional parameters of the RV systolic function were similar between the observed groups. Global, endocardial, and epicardial RV longitudinal strains were significantly lower in patients with cirrhosis. Active RA function was significantly higher in cirrhotic patients than in controls. The RA reservoir and conduit strains were significantly lower in cirrhotic patients, while there was no difference in the RA contractile strain. Early diastolic and systolic RA strain rates were significantly lower in cirrhotic patients than in controls, whereas there was no difference in the RA late diastolic strain rate between the two groups. Transaminases and bilirubin correlated negatively with RV global longitudinal strain and RV-free wall strain in patients with end-stage liver cirrhosis. The Model for End-stage Liver Disease (MELD) score, predictor of 3-month mortality, correlated with parameters of RV structure and systolic function, and RA active function in patients with end-stage liver cirrhosis. Conclusions: RA and RV remodeling is present in patients with end-stage liver cirrhosis even though RV systolic function is preserved. Liver enzymes, bilirubin, and the MELD score correlated with RV and RA remodeling.
Use of the General Movements Assessment for the Early Detection of Cerebral Palsy in Infants with Congenital Anomalies Requiring Surgery
Authors: Crowle Cathryn , Loughran Fowlds Alison , Novak Iona , Badawi Nadia
Published: August 2019

The general movements (GMs) assessment is recognised as one of the most important tools in the early detection of cerebral palsy (CP). However, there remains a paucity of data on its application to infants with congenital anomalies requiring surgery. This was a prospective study of 202 infants (mean gestation 38 weeks, SD 2.2) who had undergone major surgery for congenital anomalies in the neonatal period. Infants were assessed at three months of age (mean 12 weeks, SD 1.6) and GMs videos were independently rated by three clinicians, two blinded to clinical details. Developmental follow-up was at three years of age. Of the twenty-five infants (9%) rated as having an absence of fidgety movements, 22 were seen at 3 years, and 17 had an abnormal outcome: 11 with CP, and 6 with a developmental disability. Infants with absent fidgety movements were 21.5 (95% CI 7.3–63.8) times more likely to have an abnormal outcome including CP. None of the infants with normal fidgety movements had a diagnosis of CP and 86% were assessed to be developing normally. The GMs assessment has predictive value for cerebral palsy and neurodevelopment for infants with congenital anomalies, and should be incorporated into routine follow-up to facilitate early referral.
Periprosthetic Joint Infection Caused by Gram-Positive Versus Gram-Negative Bacteria: Lipopolysaccharide, but not Lipoteichoic Acid, Exerts Adverse Osteoclast-Mediated Effects on the Bone
Authors: Chen Mei-Feng , Chang Chih-Hsiang , Hu Chih-Chien , Wu Ying-Yu , Chang Yuhan , Ueng Steve W. N.
Published: August 2019

Periprosthetic joint infection (PJI)—the most common cause of knee arthroplasty failure—may result from Gram-positive (GP) or Gram-negative (GN) bacterial infections. The question as to whether PJI due to GP or GN bacteria can lead to different rates of aseptic loosening after reimplantation remains open. We have investigated this issue through a retrospective review of clinical records obtained from 320 patients with bacterial PJI. The results revealed that, compared with GP infections, GN infections were associated with an increased risk of aseptic loosening. In animal studies, mice underwent intrafemoral injection of lipopolysaccharide (LPS) from GN bacteria or lipoteichoic acid (LTA) from GP bacteria. We demonstrate that LPS—but not LTA—reduced both the number of trabeculae and the bone mineral density in mice. In addition, LPS-treated mice exhibited a reduced body weight, higher serum osteocalcin levels, and an increased number of osteoclasts. LPS accelerated monocyte differentiation into osteoclast-like cells, whereas LTA did not. Finally, ibudilast—a toll-like receptor (TLR)-4 antagonist—was found to inhibit LPS-induced bone loss and osteoclast activation in mice. Taken together, our data indicate that PJI caused by GN bacteria portends a higher risk of aseptic loosening after reimplantation, mainly because of LPS-mediated effects on osteoclast differentiation.
Use of Central Nervous System (CNS) Medicines in Aged Care Homes: A Systematic Review and Meta-Analysis
Authors: Hasan Syed Shahzad , Zaidi Syed Tabish Razi , Nirwan Jorabar Singh , Ghori Muhammad Usman , Javid Farideh , Ahmadi Keivan , Babar Zaheer- Ud-Din
Published: August 2019

Background: Both old age and institutionalization in aged care homes come with a significant risk of developing several long-term mental and neurological disorders, but there has been no definitive meta-analysis of data from studies to determine the pooled estimate of central nervous system (CNS) medicines use in aged care homes. We conducted this systematic review to summarize the use of CNS drugs among aged care home residents. Methods: MEDLINE, EMBASE, CINAHL, Scopus, and International Pharmaceutical Abstracts (IPA) databases were searched (between 1 January 2000 and 31 December 2018) to identify population-based studies that reported the use of CNS medicines in aged care homes. Pooled proportions (with 95% confidence interval), according to study location were calculated. Results: A total of 89 studies reported the use of CNS medicines use in aged care. The pooled estimate of CNS drug use varied according to country (from 20.3% in Ireland to 49.0% in Belgium) and region (from 31.7% in North America to 42.5% in Scandinavia). The overall pooled estimate of psychotropic medicines use was highest in Europe (72.2%, 95% CI, 67.1–77.1%) and lowest in the ANZ region (56.9%, 95% CI, 52.2–61.4%). The pooled estimate of benzodiazepines use varied widely, from 18.9% in North America to 44.8% in Europe. The pooled estimate of antidepressant use from 47 studies was 38.3% (95% CI 35.1% to 41.6%), with the highest proportion in North America (44.9%, 95% CI, 35.3–54.5%). Conclusion: The overall use of CNS drugs varied among countries, with studies from Australia New Zealand reporting the lowest use of CNS drugs. The criteria for prescribing CNS drugs in clinical practice should be evidence-based. The criteria should be used not to prohibit the use of the listed medications but to support the clinical judgement as well as patient safety.
Impact of an Infectious Disease Specialist on an Antimicrobial Stewardship Program at a Resource-Limited, Non-Academic Community Hospital in Korea
Authors: Kim Yong Chan , Kim Eun Jin , Heo Jung Yeon , Choi Young Hwa , Ahn Jin Young , Jeong Su Jin , Ku Nam Su , Choi Jun Yong , Yeom Joon-sup , Kim Ha Yan
Published: August 2019

Background: Implementing a successful antimicrobial stewardship program (ASP) is difficult for non-academic community (NAC) hospitals due to insufficient infrastructure. Aim: We evaluated the impact of an infectious disease specialist (IDS) on implementing an ASP in a resource-limited setting in Korea. Methods: A retrospective study was performed at a NAC hospital between June 2015 and August 2018. An IDS has led an ASP at the hospital since June 2017. We used an interrupted time series analysis to evaluate longitudinal effects of the IDS-led ASP on the amount of antibiotic use and incidence of multidrug-resistant organism (MDRO) acquisition. Findings: Total antibiotic use changed from 698.82 ± 74.41 to 602.09 ± 69.94 defined daily dose/1000 patient-days (PDs) after intervention. An immediate reduction in the use of carbapenems, glycopeptides, penicillins, and other antibiotics followed the IDS-led ASP. The 3rd/4th generation cephalosporins and carbapenems prescription rates decreased in slope after the intervention. Incidence of MDRO acquisition changed from 1.38, 0.78, and 0.21/1000 PDs to 1.06, 0.15, and 0.32/1000 PDs in methicillin-resistant Staphylococcus aureus, multidrug-resistant Acinetobacter baumannii, and multidrug-resistant Pseudomonas aeruginosa, respectively. The incidence of methicillin-resistant Staphylococcus aureus and multidrug-resistant Acinetobacter baumannii acquisition immediately decreased following intervention. Conclusion: An IDS can implement a successful ASP by reducing antibiotic consumption and MDRO acquisition at resource-limited NAC hospitals.
Potential Protective Effect of Oleanolic Acid on the Components of Metabolic Syndrome: A Systematic Review
Authors: Fernández-Aparicio Ángel , Schmidt-RioValle Jacqueline , Perona Javier S. , Correa-Rodríguez María , Castellano Jose M. , González-Jiménez Emilio
Published: August 2019

The high prevalence of obesity is a serious public health problem in today’s world. Both obesity and insulin resistance favor the development of metabolic syndrome (MetS), which is associated with a number of pathologies, especially type 2 diabetes mellitus, and cardiovascular diseases. This serious problem highlights the need to search for new natural compounds to be employed in therapeutic and preventive strategies, such as oleanolic acid (OA). This research aimed to systematically review the effects of OA on the main components of MetS as well as oxidative stress in clinical trials and experimental animal studies. Databases searched included PubMed, Medline, Web of Science, Scopus, EMBASE, Cochrane, and CINAHL from 2013 to 2019. Thus, both animal studies (n = 23) and human clinical trials (n = 1) were included in our review to assess the effects of OA formulations on parameters concerning insulin resistance and the MetS components. The methodological quality assessment was performed through using the SYRCLE’s Risk of Bias for animal studies and the Jadad scale. According to the studies in our review, OA improves blood pressure levels, hypertriglyceridemia, hyperglycemia, oxidative stress, and insulin resistance. Although there is scientific evidence that OA has beneficial effects in the prevention and treatment of MetS and insulin resistance, more experimental studies and randomized clinical trials are needed to guarantee its effectiveness.
SEPT14 Mutations and Teratozoospermia: Genetic Effects on Sperm Head Morphology and DNA Integrity
Authors: Wang Ya-Yun , Lai Tsung-Hsuan , Chen Mei-Feng , Lee Hui-Ling , Kuo Pao-Lin , Lin Ying-Hung
Published: August 2019

The main objective of this study was to evaluate the potential genetic effects of SEPT14 on male infertility through sequencing the SEPT14 coding region. To address this research gap, 254 men with sperm abnormalities and 116 normozoospermic men were recruited, and the whole-coding regions of SEPT14 were sequenced. Two heterozygous mutations, p.Ala123Thr (3/254 vs. 0/116) and p.Ile333Thr (3/254 vs. 0/116), were identified in these cases. A high percentage of defective sperm heads was found in sperm with mutated SEPT14. Both mutations are highly evolutionarily conserved among vertebrates. The results of a fine morphological and chromatin structural analysis indicated severely malformed sperm heads with abnormal chromatin packaging through transmission electron microscopy and Toluidine blue staining. Compared with controls, high DNA fragmentation was demonstrated in sperm from cases carrying SEPT14 mutations using the comet assay. In addition, these two mutations in SEPT14 affected its polymerization ability in vitro. These data revels that the two SEPT14 missense mutations impaired sperm head morphology and induced DNA damage. Our study suggests that genetic variant of SEPT14 is one of the effects for human sperm formation and male fertility.
Evaluation of the Intraoperative Perfusion Index for Correlation with Acute Postoperative Pain in Patients Undergoing Laparoscopic Colorectal Cancer Surgery
Authors: Kwon Ji Hye , Park Hue Jung , Sim Woo Seog , Park Joo Hyun , Jung Kang Ha , Oh Min Seok , Seon Heui Jin , Lee Jin Young
Published: August 2019

Despite technical advancements in the perioperative management of cancer surgery, postoperative pain remains a significant clinical issue. We examined the diagnostic value of the intraoperative perfusion index for predicting acute postoperative pain in patients undergoing laparoscopic colorectal cancer surgery. We retrospectively analyzed data for 105 patients who had undergone laparoscopic colorectal cancer surgery. Patients with pain scores <7 and ≥7 on a 10-point scale upon arrival in the postoperative anesthesia care unit (PACU) were categorized into the N and P groups, respectively. The perfusion index value was extracted prior to intubation, at the start and end of surgery, and after extubation. To minimize individual variance in the absolute value of the perfusion index, we calculated the perfusion index change ratio. A total of 98 patients were examined. Among them, 50 (51.0%) and 48 (49.0%) patients reported pain scores of <7 and ≥7 upon arrival at the PACU, respectively. Fentanyl consumption during the intraoperative and PACU periods was significantly higher in Group P than in Group N (p < 0.001). The perfusion index change ratios did not significantly differ between the groups. The intraoperative perfusion index change ratios do not correlate with acute postoperative pain following laparoscopic colorectal cancer surgery.
Nutritional Challenges in Metabolic Syndrome
Authors: Hoyas Irene , Leon-Sanz Miguel
Published: August 2019

Metabolic Syndrome (MetS) is a combination of risk factors for the development of cardiovascular disease (CVD) and type 2 diabetes. Different diagnostic criteria were proposed, but a consensus was reached in 2009 based on values of waist circumference, blood pressure, fasting glycemia, triglycerides, and high-density lipoprotein (HDL)-cholesterol levels. The main underlying etiologic factor is insulin resistance. The quality and quantity of individual macronutrients have an influence on the development and resolution of this syndrome. However, the main treatment goal is weight loss and a decrease in insulin resistance. A controlled energy dietary recommendation, together with moderate levels of physical activity, may positively change the parameters of MetS. However, there is no single dietary or exercise prescription that works for all patients. Dietary patterns such as Mediterranean-style, dietary approaches to stop hypertension (DASH), low-carbohydrate, and low-fat diets can ameliorate insulin resistance and MetS. Long-term adherence to a healthy lifestyle is key in assuring that individuals significantly reduce the risk of CVD and diabetes mellitus.