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1.
Spatially correlated phenotyping reveals K5-positive luminal progenitor cells and p63-K5/14-positive stem cell-like cells in human breast epithelium.
Boecker, W, van Horn, L, Stenman, G, Stürken, C, Schumacher, U, Loening, T, Liesenfeld, L, Korsching, E, Gläser, D, Tiemann, K, et al
Laboratory investigation; a journal of technical methods and pathology. 2018;(8):1065-1075
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Abstract
Understanding the mechanisms regulating human mammary epithelium requires knowledge of the cellular constituents of this tissue. Different and partially contradictory definitions and concepts describing the cellular hierarchy of mammary epithelium have been proposed, including our studies of keratins K5 and/or K14 as markers of progenitor cells. Furthermore, we and others have suggested that the p53 homolog p63 is a marker of human breast epithelial stem cells. In this investigation, we expand our previous studies by testing whether immunohistochemical staining with monospecific anti-keratin antibodies in combination with an antibody against the stem cell marker p63 might help refine the different morphologic phenotypes in normal breast epithelium. We used in situ multilabel staining for p63, different keratins, the myoepithelial marker smooth muscle actin (SMA), the estrogen receptor (ER), and Ki67 to dissect and quantify the cellular components of 16 normal pre- and postmenopausal human breast epithelial tissue samples at the single-cell level. Importantly, we confirm the existence of K5+ only cells and suggest that they, in contrast to the current view, are key luminal precursor cells from which K8/18+ progeny cells evolve. These cells are further modified by the expression of ER and Ki67. We have also identified a population of p63+K5+ cells that are only found in nipple ducts. Based on our findings, we propose a new concept of the cellular hierarchy of human breast epithelium, including K5 luminal lineage progenitors throughout the ductal-lobular axis and p63+K5+ progenitors confined to the nipple ducts.
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Association of maternal prenatal smoking GFI1-locus and cardio-metabolic phenotypes in 18,212 adults.
Parmar, P, Lowry, E, Cugliari, G, Suderman, M, Wilson, R, Karhunen, V, Andrew, T, Wiklund, P, Wielscher, M, Guarrera, S, et al
EBioMedicine. 2018;:206-216
Abstract
BACKGROUND DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. METHODS We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n = 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). FINDINGS Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0·012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 × 10-7 < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 × 10-8 < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. INTERPRETATION Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. FUND European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595 DynaHEALTH.
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Targeting ZBP-89 for the treatment of hepatocellular carcinoma.
Wang, N, Wang, S, Yang, SL, Liu, LP, Li, MY, Lai, PBS, Chen, GG
Expert opinion on therapeutic targets. 2018;(10):817-822
Abstract
Zinc-binding protein-89 (ZBP-89) is a Krüppel-type zinc-finger transcription factor that regulates target gene expression profiles via directly binding to GC-rich gene promoters, recruiting chromatin modifiers or by interacting with other proteins. The importance of ZBP-89 in the regulation of cell cycle arrest and apoptosis has led to increased interest and investigations for its role in cancer development. Areas covered: We describe ZBP-89 as a candidate therapeutic target for hepatocellular carcinoma (HCC) from several perspectives. ZBP-89 can upregulate apoptosis in HCC in a p53-dependent or - independent manner. In addition, the negative regulation of ZBP-89 on liver cancer stemness sheds light on its possible effect on sensitizing HCC to chemotherapies and the reduction of HCC relapse. The prognostic significance of ZBP-89 in HCC patients further suggests its clinical importance as a potential tumor suppressor. Expert opinion: Given the roles of ZBP-89 in HCC, we believe, ZBP-89 is a promising therapeutic target for enhancing apoptosis and diminishing the liver cancer stemness. At the same time, we also face a series of challenges, especially in the clinical implication of ZBP-89. Resolving the current controversies will advance the development of ZBP-89 for anti-HCC therapy.
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Epithelial mesenchymal transition Transcription Factor (TF): The structure, function and microRNA feedback loop.
Alidadiani, N, Ghaderi, S, Dilaver, N, Bakhshamin, S, Bayat, M
Gene. 2018;:115-120
Abstract
Epithelial to mesenchymal transition (EMT) is a phenomenon in which epithelial cells lose their cell to cell adhesion and detach from the base of the membrane. EMT is a fundamental process which occurs during tumor progression and metastasis. Cancer genomics is a complex network which involves a variety of factors such as transcription factors (TFs), coding genes and microRNAs (miRs). Both TFs and miRs are trans-regulatory elements that crosstalk. Due to a wide range of targets, TF-miR interaction provides a feedback or feedforward loop and cross-gene regulation consequently. In this review, we focused on the structure and function of two TF families involved in EMT, zinc finger and β helix loop helix and p53. Subsequently we analyzed recent findings on TF-miR interaction in EMT.
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Simulation of the Dynamics of Primary Immunodeficiencies in B Cells.
Teku, GN, Vihinen, M
Frontiers in immunology. 2018;:1785
Abstract
Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly rare disorders that affect the immune system. Various aspects of immune system and PID proteins and genes have been investigated and facilitate systems biological studies of effects of PIDs on B cell physiology and response. We reconstructed a B cell network model based on data for the core B cell receptor activation and response processes and performed semi-quantitative dynamic simulations for normal and B cell PID failure modes. The results for several knockout simulations correspond to previously reported molecular studies and reveal novel mechanisms for PIDs. The simulations for CD21, CD40, LYN, MS4A1, ORAI1, PLCG2, PTPRC, and STIM1 indicated profound changes to major transcription factor signaling and to the network. Significant effects were observed also in the BCL10, BLNK, BTK, loss-of-function CARD11, IKKB, MALT1, and NEMO, simulations whereas only minor effects were detected for PIDs that are caused by constitutively active proteins (PI3K, gain-of-function CARD11, KRAS, and NFKBIA). This study revealed the underlying dynamics of PID diseases, confirms previous observations, and identifies novel candidates for PID diagnostics and therapy.
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The role of zinc and its compounds in leukemia.
Orlov, AP, Orlova, MA, Trofimova, TP, Kalmykov, SN, Kuznetsov, DA
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry. 2018;(3):347-362
Abstract
Zinc is one of the most important microelements necessary for normal body functioning. Zinc is marked in numerous diseases and, hence, its properties and behavior in the body have long been a subject of extensive study. This review considers trends in the assessment of the role of zinc and its compounds in the past decade. It becomes evident that redox-inactive zinc is the main supervisor in the conformation of the most important molecules in all body organs and tissues. We placed emphasis on the variety of zinc-binding sites and the role of zinc in the genesis and progress of different forms of leukemia. The importance of some families of transcription factors in the development and prognosis of treatment of various leukemia forms is examined; new directions of these studies are shown.
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Mutations outside the N-terminal part of RBCK1 may cause polyglucosan body myopathy with immunological dysfunction: expanding the genotype-phenotype spectrum.
Krenn, M, Salzer, E, Simonitsch-Klupp, I, Rath, J, Wagner, M, Haack, TB, Strom, TM, Schänzer, A, Kilimann, MW, Schmidt, RLJ, et al
Journal of neurology. 2018;(2):394-401
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Abstract
A subset of patients with polyglucosan body myopathy was found to have underlying mutations in the RBCK1 gene. Affected patients may display diverse symptoms ranging from skeletal muscular weakness, cardiomyopathy to chronic autoinflammation and immunodeficiency. It was suggested that the exact localization of the mutation within the gene might be responsible for the specific phenotype, with N-terminal mutations causing severe immunological dysfunction and mutations in the middle or C-terminal part leading to a myopathy phenotype. We report the clinical, immunological and genetic findings of two unrelated individuals suffering from a childhood-onset RBCK1-asscociated disease caused by the same homozygous truncating mutation (NM_031229.2:c.896_899del, p.Glu299Valfs*46) in the middle part of the RBCK1 gene. Our patients suffered from a myopathy with cardiac involvement, but in contrast to previous reports on mutations in this part of the gene, also displayed signs of autoinflammation and immunodeficiency. Our report suggests that RBCK1 mutations at locations that were previously thought to lack immunological features may also present with immunological dysfunction later in the disease course. This notably broadens the genotype-phenotype correlation of RBCK1-related polyglucosan body myopathy.
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Expression of the three components of linear ubiquitin assembly complex in breast cancer.
Kharman-Biz, A, Gao, H, Ghiasvand, R, Haldosen, LA, Zendehdel, K
PloS one. 2018;(5):e0197183
Abstract
Proteins belonging to the linear ubiquitin assembly complex (LUBAC) are believed to be important in tumorigenesis. LUBAC has been demonstrated to be composed of RBCK1, RNF31 and SHARPIN. The aim of this study was to explore all members of the LUBAC complex as novel biomarkers in breast cancer. We have already reported that RNF31 mRNA levels are higher in breast cancer samples compared to adjacent non-tumor tissue. In this study we extend these findings by demonstrating that the mRNA levels of RBCK1 and SHARPIN are also higher in tumors compared to adjacent non-tumor tissue in the same cross sectional study of samples (p < 0.001). In addition, up-regulated mRNA expression of all three members of the LUBAC complex displayed high predictive value in distinguishing tumor tissues from adjacent non-tumor tissue as determined by ROC curve analysis. Furthermore, we investigated whether there is an association between the mRNA and protein expression levels of RBCK1, RNF31 and SHARPIN and clinicopathological parameters including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2) status and found that RNF31 protein is significantly higher in ERalpha-negative tumors than ERalpha-positive tumors (p = 0.034). Collectively, our findings indicate that up-regulated mRNA expression of RNF31, RBCK1 and SHARPIN could potentially be diagnostic biomarkers of breast cancer and RNF31 might be a drug target for ERalpha-negative breast cancers.
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Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.
Chen, H, Cade, BE, Gleason, KJ, Bjonnes, AC, Stilp, AM, Sofer, T, Conomos, MP, Ancoli-Israel, S, Arens, R, Azarbarzin, A, et al
American journal of respiratory cell and molecular biology. 2018;(3):391-401
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Abstract
Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10-8) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.
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Regulation of carbohydrate degradation pathways in Pseudomonas involves a versatile set of transcriptional regulators.
Udaondo, Z, Ramos, JL, Segura, A, Krell, T, Daddaoua, A
Microbial biotechnology. 2018;(3):442-454
Abstract
Bacteria of the genus Pseudomonas are widespread in nature. In the last decades, members of this genus, especially Pseudomonas aeruginosa and Pseudomonas putida, have acquired great interest because of their interactions with higher organisms. Pseudomonas aeruginosa is an opportunistic pathogen that colonizes the lung of cystic fibrosis patients, while P. putida is a soil bacterium able to establish a positive interaction with the plant rhizosphere. Members of Pseudomonas genus have a robust metabolism for amino acids and organic acids as well as aromatic compounds; however, these microbes metabolize a very limited number of sugars. Interestingly, they have three-pronged metabolic system to generate 6-phosphogluconate from glucose suggesting an adaptation to efficiently consume this sugar. This review focuses on the description of the regulatory network of glucose utilization in Pseudomonas, highlighting the differences between P. putida and P. aeruginosa. Most interestingly, It is highlighted a functional link between glucose assimilation and exotoxin A production in P. aeruginosa. The physiological relevance of this connection remains unclear, and it needs to be established whether a similar relationship is also found in other bacteria.