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https://www.readbyqxmd.com/read/29140069/dual-functions-of-cyclometalated-iridium-iii-complexes-anti-metastasis-and-lysosome-damaged-photodynamic-therapy
#1
Fang-Xin Wang, Mu-He Chen, Yan-Nan Lin, Hang Zhang, Cai-Ping Tan, Liang-Nian Ji, Zongwan Mao
Four phosphorescent cyclometalated iridium(III) complexes containing benzimidazole moiety have been designed and synthesized. These Ir(III) complexes can inhibit several cancerous processes including cell migration, invasion, colony formation and angiogenesis effectively. Interestingly, they show much higher singlet oxygen quantum yield in acidic solution than in neutral solution. Upon irradiation at 425 nm with low energy (1.2 J·cm(-2)), they can induce apoptosis through lysosomal damage, evaluation of ROS level and activation of caspase-3/7...
November 15, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/29137494/trh-receptor-mobility-in-the-plasma-membrane-is-strongly-affected-by-agonist-binding-and-by-interaction-with-some-cognate-signaling-proteins
#2
Radka Moravcova, Barbora Melkes, Jiri Novotny
OBJECTIVES: Extensive research has been dedicated to elucidating the mechanisms of signal transduction through different G protein-coupled receptors (GPCRs). However, relatively little is known about the regulation of receptor movement within the cell membrane upon ligand binding. In this study we focused our attention on the thyrotropin-releasing hormone (TRH) receptor that typically couples to Gq/11 proteins. METHODS: We monitored receptor diffusion in the plasma membrane of HEK293 cells stably expressing yellow fluorescent protein (YFP)-tagged TRH receptor (TRHR-YFP) by fluorescence recovery after photobleaching (FRAP)...
November 14, 2017: Journal of Receptor and Signal Transduction Research
https://www.readbyqxmd.com/read/29122991/maternal-embryonic-leucine-zipper-kinase-is-a-novel-target-for-proliferation-associated-high-risk-myeloma
#3
Arnold Bolomsky, Roy Heusschen, Karin Schlangen, Kathrin Stangelberger, Joséphine Muller, Wolfgang Schreiner, Niklas Zojer, Jo Caers, Heinz Ludwig
Treatment of high-risk patients is a major challenge in multiple myeloma. This is especially true for patients assigned to the gene-expression-profiling defined proliferation subgroup. Although recent efforts have identified some key players of proliferative myeloma, genetic interactions and players that can be targeted with clinically effective drugs have to be identified to overcome the poor prognosis of these patients. We therefore examined maternal embryonic leucine zipper kinase (MELK) for its implications in hyper-proliferative myeloma and analysed the activity of the MELK inhibitor OTSSP167 in vitro and in vivo...
November 9, 2017: Haematologica
https://www.readbyqxmd.com/read/29100313/g2-m-checkpoint-plays-a-vital-role-at-the-early-stage-of-hcc-by-analysis-of-key-pathways-and-genes
#4
Li Yin, Cuifang Chang, Cunshuan Xu
The present study was designed to explore the molecular mechanism at the early stage of hepatocarcinoma (HCC) and identify the candidate genes and pathways changed significantly. We downloaded the gene expression file dataset GSE6764 from GEO, adopted the Robust Multi-array Average (RMA) algorithm to preprocess the raw file. 797 differentially expressed genes (DEGs) were screened out based on the SAM method using R language. Ingenuity Pathway Analysis (IPA) was used to perform canonical pathway analysis in order to calculate the most significantly changed pathways and predict the upstream regulators...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29025594/gene-expression-profiling-pathway-analysis-and-subtype-classification-reveal-molecular-heterogeneity-in-hepatocellular-carcinoma-and-suggest-subtype-specific-therapeutic-targets
#5
Rahul Agarwal, Jitendra Narayan, Amitava Bhattacharyya, Mayank Saraswat, Anil Kumar Tomar
A very low 5-year survival rate among hepatocellular carcinoma (HCC) patients is mainly due to lack of early stage diagnosis, distant metastasis and high risk of postoperative recurrence. Hence ascertaining novel biomarkers for early diagnosis and patient specific therapeutics is crucial and urgent. Here, we have performed a comprehensive analysis of the expression data of 423 HCC patients (373 tumors and 50 controls) downloaded from The Cancer Genome Atlas (TCGA) followed by pathway enrichment by gene ontology annotations, subtype classification and overall survival analysis...
October 2017: Cancer Genetics
https://www.readbyqxmd.com/read/28938528/p53-independent-p21-induction-by-melk-inhibition
#6
Tatsuo Matsuda, Taigo Kato, Kazuma Kiyotani, Yunus Emre Tarhan, Vassiliki Saloura, Suyoun Chung, Koji Ueda, Yusuke Nakamura, Jae-Hyun Park
MELK play critical roles in human carcinogenesis through activation of cell proliferation, inhibition of apoptosis and maintenance of stemness. Therefore, MELK is a promising therapeutic target for a wide range of cancers. Although p21 is a well-known p53-downstream gene, we found that treatment with a potent MELK inhibitor, OTS167, could induce p21 protein expression in cancer cell lines harboring loss-of-function TP53 mutations. We also confirmed that MELK knockdown by siRNA induced the p21 expression in p53-deficient cancer cell lines and caused the cell cycle arrest at G1 phase...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28926375/early-effects-of-renal-replacement-therapy-on-cardiovascular-comorbidity-in-children-with-end-stage-kidney-disease-findings-from-the-4c-t-study
#7
Bernhard M W Schmidt, Rizky I Sugianto, Daniela Thurn, Karolis Azukaitis, Aysun K Bayazit, Nur Canpolat, Ayse Guler Eroglu, Salim Caliskan, Anke Doyon, Ali Duzova, Tevfik Karagoz, Ali Anarat, Murat Deveci, Sevgi Mir, Bruno Ranchin, Rukshana Shroff, Esra Baskin, Mieczyslaw Litwin, Z Birsin Özcakar, Rainer Büscher, Oguz Soylemezoglu, Jiri Dusek, Markus Kemper, Maria C Matteucci, Sandra Habbig, Guido Laube, Elke Wühl, Uwe Querfeld, Anja Sander, Franz Schaefer, Anette Melk
BACKGROUND: The early impact of renal transplantation on subclinical cardiovascular measures in pediatric patients has not been widely investigated. This analysis is performed for pediatric patients participating in the prospective 4C study and focuses on the early effects of RRT modality on cardiovascular comorbidity in patients receiving a preemptive transplant or started on dialysis. METHODS: We compared measures indicating subclinical cardiovascular organ damage (aortal pulse wave velocity, carotid intima media thickness, left ventricular mass index) and evaluated cardiovascular risk factors in 166 pediatric patients before and 6 to 18 months after start of RRT (n=76 transplantation, n=90 dialysis)...
September 18, 2017: Transplantation
https://www.readbyqxmd.com/read/28926338/melk-is-not-necessary-for-the-proliferation-of-basal-like-breast-cancer-cells
#8
Hai-Tsang Huang, Hyuk-Soo Seo, Tinghu Zhang, Yubao Wang, Baishan Jiang, Qing Li, Dennis L Buckley, Behnam Nabet, Justin M Roberts, Joshiawa Paulk, Shiva Dastjerdi, Georg E Winter, Hilary McLauchlan, Jennifer Moran, James E Bradner, Michael J Eck, Sirano Dhe-Paganon, Jean J Zhao, Nathanael S Gray
Thorough preclinical target validation is essential for the success of drug discovery efforts. In this study, we combined chemical and genetic perturbants, including the development of a novel selective maternal embryonic leucine zipper kinase (MELK) inhibitor HTH-01-091, CRISPR/Cas9-mediated MELK knockout, a novel chemical-induced protein degradation strategy, RNA interference and CRISPR interference to validate MELK as a therapeutic target in basal-like breast cancers (BBC). In common culture conditions, we found that small molecule inhibition, genetic deletion, or acute depletion of MELK did not significantly affect cellular growth...
September 19, 2017: ELife
https://www.readbyqxmd.com/read/28804814/factors-associated-with-cardiovascular-target-organ-damage-in-children-after-renal-transplantation
#9
Bianca Borchert-Mörlins, Daniela Thurn, Bernhard M W Schmidt, Anja K Büscher, Jun Oh, Tanja Kier, Elena Bauer, Sabrina Baig, Nele Kanzelmeyer, Markus J Kemper, Rainer Büscher, Anette Melk
BACKGROUND: Cardiovascular disease is the second-most common cause of death in pediatric renal transplant recipients. The aim of this study was to evaluate subclinical cardiovascular target organ damage defined as the presence of arterio- and atherosclerotic lesions and cardiac remodeling and to analyze contributing risk factors in a large cohort of children after renal transplantation (RT). METHODS: A total of 109 children aged 13.1 ± 3.3 years who had undergone RT at one of three German transplant centers were enrolled in this study...
November 2017: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
https://www.readbyqxmd.com/read/28796785/low-renal-but-high-extrarenal-phenotype-variability-in-schimke-immuno-osseous-dysplasia
#10
Beata S Lipska-Ziętkiewicz, Jutta Gellermann, Olivia Boyer, Olivier Gribouval, Szymon Ziętkiewicz, Jameela A Kari, Mohamed A Shalaby, Fatih Ozaltin, Jiri Dusek, Anette Melk, Aysun K Bayazit, Laura Massella, Lidia Hyla-Klekot, Sandra Habbig, Astrid Godron, Maria Szczepańska, Beata Bieniaś, Dorota Drożdż, Rasha Odeh, Wioletta Jarmużek, Katarzyna Zachwieja, Agnes Trautmann, Corinne Antignac, Franz Schaefer
Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date. In 11 patients the diagnosis was made unsuspectedly through SRNS gene panel testing...
2017: PloS One
https://www.readbyqxmd.com/read/28764577/melk-a-potential-novel-therapeutic-target-for-tnbc-and-other-aggressive-malignancies
#11
REVIEW
Mary Kathryn Pitner, Juliana M Taliaferro, Kevin N Dalby, Chandra Bartholomeusz
There is an unmet need in triple-negative breast cancer (TNBC) patients for targeted therapies. Maternal embryonic leucine zipper kinase (MELK) is a promising target for inhibition based on the abundance of correlative and functional data supporting its role in various cancer types. Areas covered: This review endeavors to outline the role of MELK in cancer. Studies covering a range of biological functions including proliferation, apoptosis, cancer stem cell phenotypes, epithelial-to-mesenchymal transition, metastasis, and therapy resistance are discussed here in order to understand the potential of MELK as a clinically significant target for TNBC patients...
September 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28729036/molecular-mechanisms-of-renal-aging
#12
REVIEW
Roland Schmitt, Anette Melk
Epidemiologic, clinical, and molecular evidence suggest that aging is a major contributor to the increasing incidence of acute kidney injury and chronic kidney disease. The aging kidney undergoes complex changes that predispose to renal pathology. The underlying molecular mechanisms could be the target of therapeutic strategies in the future. Here, we summarize recent insight into cellular and molecular processes that have been shown to contribute to the renal aging phenotype.The main clinical finding of renal aging is the decrease in glomerular filtration rate, and its structural correlate is the loss of functioning nephrons...
July 17, 2017: Kidney International
https://www.readbyqxmd.com/read/28729033/metabolic-acidosis-is-common-and-associates-with-disease-progression-in-children-with-chronic-kidney-disease
#13
Jérôme Harambat, Kevin Kunzmann, Karolis Azukaitis, Aysun K Bayazit, Nur Canpolat, Anke Doyon, Ali Duzova, Anna Niemirska, Betul Sözeri, Daniela Thurn-Valsassina, Ali Anarat, Lucie Bessenay, Cengiz Candan, Amira Peco-Antic, Alev Yilmaz, Sibylle Tschumi, Sara Testa, Augustina Jankauskiene, Hakan Erdogan, Alejandra Rosales, Harika Alpay, Francesca Lugani, Klaus Arbeiter, Francesca Mencarelli, Aysel Kiyak, Osman Dönmez, Dorota Drozdz, Anette Melk, Uwe Querfeld, Franz Schaefer
Recent studies in adult chronic kidney disease (CKD) suggest that metabolic acidosis is associated with faster decline in estimated glomerular filtration rate (eGFR). Alkali therapies improve the course of kidney disease. Here we investigated the prevalence and determinants of abnormal serum bicarbonate values and whether metabolic acidosis may be deleterious to children with CKD. Associations between follow-up serum bicarbonate levels categorized as under 18, 18 to under 22, and 22 or more mmol/l and CKD outcomes in 704 children in the Cardiovascular Comorbidity in Children with CKD Study, a prospective cohort of pediatric patients with CKD stages 3-5, were studied...
July 17, 2017: Kidney International
https://www.readbyqxmd.com/read/28683086/phosphorylation-of-the-hiv-1-capsid-by-melk-triggers-uncoating-to-promote-viral-cdna-synthesis
#14
Hiroaki Takeuchi, Hideki Saito, Takeshi Noda, Tadashi Miyamoto, Tomokazu Yoshinaga, Kazutaka Terahara, Hiroshi Ishii, Yasuko Tsunetsugu-Yokota, Shoji Yamaoka
Regulation of capsid disassembly is crucial for efficient HIV-1 cDNA synthesis after entry, yet host factors involved in this process remain largely unknown. Here, we employ genetic screening of human T-cells to identify maternal embryonic leucine zipper kinase (MELK) as a host factor required for optimal uncoating of the HIV-1 core to promote viral cDNA synthesis. Depletion of MELK inhibited HIV-1 cDNA synthesis with a concomitant delay of capsid disassembly. MELK phosphorylated Ser-149 of the capsid in the multimerized HIV-1 core, and a mutant virus carrying a phosphorylation-mimetic amino-acid substitution of Ser-149 underwent premature capsid disassembly and earlier HIV-1 cDNA synthesis, and eventually failed to enter the nucleus...
July 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28659600/comparative-genetic-proteomic-and-phosphoproteomic-analysis-of-c-elegans-embryos-with-a-focus-on-ham-1-stox-and-pig-1-melk-in-dopaminergic-neuron-development
#15
Sarah-Lena Offenburger, Dalila Bensaddek, Alejandro Brenes Murillo, Angus I Lamond, Anton Gartner
Asymmetric cell divisions are required for cellular diversity and defects can lead to altered daughter cell fates and numbers. In a genetic screen for C. elegans mutants with defects in dopaminergic head neuron specification or differentiation, we isolated a new allele of the transcription factor HAM-1 [HSN (Hermaphrodite-Specific Neurons) Abnormal Migration]. Loss of both HAM-1 and its target, the kinase PIG-1 [PAR-1(I)-like Gene], leads to abnormal dopaminergic head neuron numbers. We identified discrete genetic relationships between ham-1, pig-1 and apoptosis pathway genes in dopaminergic head neurons...
June 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28652378/caenorhabditis-elegans-ces-1-snail-represses-pig-1-melk-expression-to-control-asymmetric-cell-division
#16
Hai Wei, Bo Yan, Julien Gagneur, Barbara Conradt
Snail-like transcription factors affect stem cell function through mechanisms that are incompletely understood. In the Caenorhabditis elegans neurosecretory motor neuron (NSM) neuroblast lineage, CES-1 Snail coordinates cell cycle progression and cell polarity to ensure the asymmetric division of the NSM neuroblast and the generation of two daughter cells of different sizes and fates. We have previously shown that CES-1 Snail controls cell cycle progression by repressing the expression of cdc-25.2 CDC25. However, the mechanism through which CES-1 Snail affects cell polarity has been elusive...
August 2017: Genetics
https://www.readbyqxmd.com/read/28641312/impact-of-novel-mir-145-3p-regulatory-networks-on-survival-in-patients-with-castration-resistant-prostate-cancer
#17
Yusuke Goto, Akira Kurozumi, Takayuki Arai, Nijiro Nohata, Satoko Kojima, Atsushi Okato, Mayuko Kato, Kazuto Yamazaki, Yasuo Ishida, Yukio Naya, Tomohiko Ichikawa, Naohiko Seki
BACKGROUND: Despite recent advancements, metastatic castration-resistant prostate cancer (CRPC) is not considered curative. Novel approaches for identification of therapeutic targets of CRPC are needed. METHODS: Next-generation sequencing revealed 945-1248 miRNAs from each lethal mCRPC sample. We constructed miRNA expression signatures of CRPC by comparing the expression of miRNAs between CRPC and normal prostate tissue or hormone-sensitive prostate cancer (HSPC)...
July 25, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28640357/rna-sequencing-of-esophageal-adenocarcinomas-identifies-novel-fusion-transcripts-including-npc1-melk-arising-from-a-complex-chromosomal-rearrangement
#18
Zhixiong Wang, Yulan Cheng, John M Abraham, Rong Yan, Xi Liu, Wei Chen, Sariat Ibrahim, Gary P Schroth, Xiquan Ke, Yulong He, Stephen J Meltzer
BACKGROUND: Studies of chromosomal rearrangements and fusion transcripts have elucidated mechanisms of tumorigenesis and led to targeted cancer therapies. This study was aimed at identifying novel fusion transcripts in esophageal adenocarcinoma (EAC). METHODS: To identify new fusion transcripts associated with EAC, targeted RNA sequencing and polymerase chain reaction (PCR) verification were performed in 40 EACs and matched nonmalignant specimens from the same patients...
October 15, 2017: Cancer
https://www.readbyqxmd.com/read/28636549/p53-independent-p21-induction-by-melk-inhibition
#19
Tatsuo Matsuda, Taigo Kato, Kazuma Kiyotani, Yunus Emre Tarhan, Vassiliki Saloura, Suyoun Chung, Koji Ueda, Yusuke Nakamura, Jae-Hyun Park
MELK play critical roles in human carcinogenesis through activation of cell proliferation, inhibition of apoptosis and maintenance of stemness. Therefore, MELK is a promising therapeutic target for a wide range of cancers. Although p21 is a well-known p53-downstream gene, we found that treatment with a potent MELK inhibitor, OTS167, could induce p21 protein expression in cancer cell lines harboring loss-of-function TP53 mutations. We also confirmed that MELK knockdown by siRNA induced the p21 expression in p53-deficient cancer cell lines and caused the cell cycle arrest at G1 phase...
June 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28588728/maternal-embryonic-leucine-zipper-kinase-inhibits-epithelial-mesenchymal-transition-by-regulating-transforming-growth-factor-%C3%AE-signaling
#20
Jianjian Cheng, Binyu Qin, Bao Liu, Taibo Huang, Yuguang Li, Lijun Ma
Maternal embryonic leucine zipper kinase (MELK) performs an important role in self-renewal and proliferation of progenitor cells or tumor stem cells, and is expressed in aggressive cancers, contributing to tumorigenesis. However, the function of MELK in metastasis is unknown. In the present study, the lung cancer A549 cell line was utilized in order to study the role of MELK in epithelial-mesenchymal transitions (EMTs), the initial step of tumor metastasis. It was identified that transforming growth factor-β (TGF-β) could downregulate the expression of MELK, and that MELK could inhibit EMT by regulating TGF-β signaling...
June 2017: Oncology Letters
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