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https://www.readbyqxmd.com/read/28641312/impact-of-novel-mir-145-3p-regulatory-networks-on-survival-in-patients-with-castration-resistant-prostate-cancer
#1
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)...
June 22, 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
#2
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...
June 22, 2017: Cancer
https://www.readbyqxmd.com/read/28636549/p53-independent-p21-induction-by-melk-inhibition
#3
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
#4
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
https://www.readbyqxmd.com/read/28566477/long-term-outcome-of-steroid-resistant-nephrotic-syndrome-in-children
#5
Agnes Trautmann, Sven Schnaidt, Beata S Lipska-Ziętkiewicz, Monica Bodria, Fatih Ozaltin, Francesco Emma, Ali Anarat, Anette Melk, Marta Azocar, Jun Oh, Bassam Saeed, Alaleh Gheisari, Salim Caliskan, Jutta Gellermann, Lina Maria Serna Higuita, Augustina Jankauskiene, Dorota Drozdz, Sevgi Mir, Ayse Balat, Maria Szczepanska, Dusan Paripovic, Alexandra Zurowska, Radovan Bogdanovic, Alev Yilmaz, Bruno Ranchin, Esra Baskin, Ozlem Erdogan, Giuseppe Remuzzi, Agnieszka Firszt-Adamczyk, Elzbieta Kuzma-Mroczkowska, Mieczyslaw Litwin, Luisa Murer, Marcin Tkaczyk, Helena Jardim, Anna Wasilewska, Nikoleta Printza, Kibriya Fidan, Eva Simkova, Halina Borzecka, Hagen Staude, Katharina Hees, Franz Schaefer
We investigated the value of genetic, histopathologic, and early treatment response information in prognosing long-term renal outcome in children with primary steroid-resistant nephrotic syndrome. From the PodoNet Registry, we obtained longitudinal clinical information for 1354 patients (disease onset at >3 months and <20 years of age): 612 had documented responsiveness to intensified immunosuppression (IIS), 1155 had kidney biopsy results, and 212 had an established genetic diagnosis. We assessed risk factors for ESRD using multivariate Cox regression models...
May 31, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28554236/anaplastic-ependymoma-with-ganglionic-differentiation-report-of-a-rare-case-and-implications-in-diagnosis
#6
Shilpa Rao, Niveditha Ravindra, Nishanth Sadashiva, Bhagavatula Indira Devi, Vani Santosh
Ependymomas are glial neoplasms with rare cases exhibiting neuronal differentiation. We describe a case of spinal anaplastic ependymoma with ganglionic differentiation in a 28-year-old woman. The ganglionic component was labeled by synaptophysin, whereas the rest of the tumor showed features of an anaplastic ependymoma. Stem cell marker MELK was noted to stain both the neoplastic ependymal and ganglionic components, possibly suggesting a stem cell/progenitor origin for the tumor with subsequent divergent differentiation...
May 1, 2017: International Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28536141/melk-and-ezh2-cooperate-to-regulate-medulloblastoma-cancer-stem-like-cell-proliferation-and-differentiation
#7
Hailong Liu, Qianwen Sun, Youliang Sun, Junping Zhang, Hongyu Yuan, Shuhuan Pang, Xueling Qi, Haoran Wang, Mingshan Zhang, Hongwei Zhang, Chunjiang Yu, Chunyu Gu
Medulloblastoma is the most common malignant brain tumor in children. Although accumulated research has suggested that cancer stem-like cells play a key role in medulloblastoma tumorigenesis, the specific molecular mechanism regarding proliferation remains elusive. Here, we reported more abundant expression of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) in medulloblastoma stem-like cells than in neural stem cells and the interaction between the two proteins could mediate the self-renewal of sonic hedgehog subtype medulloblastoma...
May 23, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28491859/autophagy-in-kidney-transplants-of-sirolimus-treated-recipients
#8
Sagar Bhayana, Arpita Baisantry, Thomas D Kraemer, Christoph Wrede, Jan Hegermann, Jan-Hinrich Bräsen, Clemens Bockmeyer, Jan Ulrich Becker, Matthias Ochs, Wilfried Gwinner, Hermann Haller, Anette Melk, Roland Schmitt
BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors are increasingly used as immunosuppressive agents in kidney transplantation. In the experimental setting it has been shown that mTOR inhibitors promote autophagy, but the concept that this might also occur in transplant patients has not been addressed. OBJECTIVES: This study was designed to investigate the association between mTOR inhibition and autophagy in renal transplants under routine clinical conditions...
March 2017: Journal of Nephropathology
https://www.readbyqxmd.com/read/28438385/small-molecules-inhibit-stat3-activation-autophagy-and-cancer-cell-anchorage-independent-growth
#9
Donghui Zhou, Maya Z Springer, David Xu, Degang Liu, Andy Hudmon, Kay F Macleod, Samy O Meroueh
Triple-negative breast cancers (TNBCs) lack the signature targets of other breast tumors, such as HER2, estrogen receptor, and progesterone receptor. These aggressive basal-like tumors are driven by a complex array of signaling pathways that are activated by multiple driver mutations. Here we report the discovery of 6 (KIN-281), a small molecule that inhibits multiple kinases including maternal leucine zipper kinase (MELK) and the non-receptor tyrosine kinase bone marrow X-linked (BMX) with single-digit micromolar IC50s...
March 23, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28424560/an-exploratory-study-of-host-polymorphisms-in-genes-that-clinically-characterize-breast-cancer-tumors-and-pretreatment-cognitive-performance-in-breast-cancer-survivors
#10
Theresa A Koleck, Catherine M Bender, Beth Z Clark, Christopher M Ryan, Puja Ghotkar, Adam Brufsky, Priscilla F McAuliffe, Priya Rastogi, Susan M Sereika, Yvette P Conley
PURPOSE: Inspired by the hypothesis that heterogeneity in the biology of breast cancers at the cellular level may account for cognitive dysfunction symptom variability in survivors, the current study explored relationships between host single-nucleotide polymorphisms (SNPs) in 25 breast cancer-related candidate genes (AURKA, BAG1, BCL2, BIRC5, CCNB1, CD68, CENPA, CMC2, CTSL2, DIAPH3, ERBB2, ESR1, GRB7, GSTM1, MELK, MKI67, MMP11, MYBL2, NDC80, ORC6, PGR, RACGAP1, RFC4, RRM2, and SCUBE2), identified from clinically relevant prognostic multigene-expression profiles for breast cancer, and pretreatment cognitive performance...
2017: Breast Cancer: Targets and Therapy
https://www.readbyqxmd.com/read/28396121/antagonism-of-profibrotic-microrna-21-improves%C3%A2-outcome-of-murine-chronic-renal-allograft-dysfunction
#11
Celina Schauerte, Anika Hübner, Song Rong, Shijun Wang, Nelli Shushakova, Michael Mengel, Angela Dettling, Claudia Bang, Kristian Scherf, Malte Koelling, Anette Melk, Hermann Haller, Thomas Thum, Johan M Lorenzen
Chronic renal allograft dysfunction (CAD) is a major limiting factor of long-term graft survival. It is characterized by interstitial fibrosis and tubular atrophy. The underlying pathomechanisms are incompletely understood. MicroRNAs are powerful regulators of gene expression and may have an impact on various diseases by direct mRNA decay or translational inhibition. A murine model of allogenic kidney transplantation was used resulting in CAD at 6 weeks after kidney transplantation. We identified fibrosis-associated miR-21a-5p by whole miRNAome expression analysis to be among the most highly upregulated miRNAs...
April 8, 2017: Kidney International
https://www.readbyqxmd.com/read/28351607/discovery-of-a-potent-inhibitor-of-melk-that-inhibits-expression-of-the-anti-apoptotic-protein-mcl-1-and-tnbc-cell-growth
#12
Ramakrishna Edupuganti, Juliana M Taliaferro, Qiantao Wang, Xuemei Xie, Eun Jeong Cho, Fnu Vidhu, Pengyu Ren, Eric V Anslyn, Chandra Bartholomeusz, Kevin N Dalby
Despite recent advances in molecularly directed therapy, triple negative breast cancer (TNBC) remains one of the most aggressive forms of breast cancer, still without a suitable target for specific inhibitors. Maternal embryonic leucine zipper kinase (MELK) is highly expressed in TNBC, where level of overexpression correlates with poor prognosis and an aggressive disease course. Herein, we describe the discovery through targeted kinase inhibitor library screening, and structure-guided design of a series of ATP-competitive indolinone derivatives with subnanomolar inhibition constants towards MELK...
May 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28337968/crispr-cas9-mutagenesis-invalidates-a-putative-cancer-dependency-targeted-in-on-going-clinical-trials
#13
Ann Lin, Christopher J Giuliano, Nicole M Sayles, Jason M Sheltzer
The Maternal Embryonic Leucine Zipper Kinase (MELK) has been reported to be a genetic dependency in several cancer types. MELK RNAi and small-molecule inhibitors of MELK block the proliferation of various cancer cell lines, and MELK knockdown has been described as particularly effective against the highly-aggressive basal/triple-negative subtype of breast cancer. Based on these preclinical results, the MELK inhibitor OTS167 is currently being tested as a novel chemotherapy agent in several clinical trials. Here, we report that mutagenizing MELK with CRISPR/Cas9 has no effect on the fitness of basal breast cancer cell lines or cell lines from six other cancer types...
March 24, 2017: ELife
https://www.readbyqxmd.com/read/28323497/potential-mechanisms-underlying-cdk5-related-osteosarcoma-progression
#14
Hang-Xing Bao, Qing Bi, Yong Han, Chen Zhao, Hai Zou
OBJECTIVES: Identification of new prognostic biomarkers and therapeutic targets is of crucial importance for patients with osteosarcoma. Cyclin-dependent kinase 5 (CDK5) is overexpressed in several tumor types. However, the exact role CDK5 plays in osteosarcoma is still unknown. METHODS: In this study, we explored the association between CDK5 expression and the prognosis of osteosarcoma patients using publicly available gene expression datasets. Potential molecular mechanisms underlying its pro-malignant role in cancer progression were also discussed...
May 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28319600/early-and-late-factors-impacting-patient-and-graft-outcome-in-pediatric-liver-transplantation-summary-of-an-espghan-monothematic-conference
#15
Valérie A McLin, Upton Allen, Olivia Boyer, John Bucuvalas, Michele Colledan, Maria-Cristina Cuturi, Lorenzo d'Antiga, Dominique Debray, Antal Dezsofi, Jean de Ville de Goyet, Anil Dhawan, Ozlem Durmaz, Christine Falk, Sandy Feng, Björn Fischler, Stéphanie Franchi-Abella, Esteban Frauca, Rainer Ganschow, Stephen Gottschalk, Nedim Hadzic, Loreto Hierro, Simon Horslen, Stefan Hubscher, Vincent Karam, Deirdre Kelly, Britta Maecker-Kolhoff, George Mazariegos, Patrick McKiernan, Anette Melk, Valerio Nobili, Funda Ozgenç, Raymond Reding, Marco Sciveres, Khalid Sharif, Piotr Socha, Christian Toso, Pietro Vajro, Anita Verma, Barbara E Wildhaber, Ulrich Baumann
As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications...
March 17, 2017: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/28275243/the-microrna-expression-signature-of-small-cell-lung-cancer-tumor-suppressors-of-mir-27a-5p-and-mir-34b-3p-and-their-targeted-oncogenes
#16
Keiko Mizuno, Hiroko Mataki, Takayuki Arai, Atsushi Okato, Kazuto Kamikawaji, Tomohiro Kumamoto, Tsubasa Hiraki, Kazuhito Hatanaka, Hiromasa Inoue, Naohiko Seki
Small cell lung cancer (SCLC) constitutes approximately 15% of all diagnosed lung cancers. SCLC is a particularly lethal malignancy, as the 2-year survival rate after appropriate treatment is less than 5%. The patients with SCLC have not been received a benefit of the recently developed molecular targeted treatment. Therefore, a new treatment strategy is necessary for the patients. The molecular mechanisms underlying the aggressiveness of SCLC cells and their development of treatment-resistance are still ambiguous...
March 9, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28260099/identification-of-prognostic-genes-in-kidney-renal-clear-cell-carcinoma-by-rna%C3%A2-seq-data-analysis
#17
Yanqin Gu, Linfeng Lu, Lingfeng Wu, Hao Chen, Wei Zhu, Yi He
The present study aimed to analyze RNA-seq data of kidney renal clear cell carcinoma (KIRC) to identify prognostic genes. RNA‑seq data were downloaded from The Cancer Genome Atlas. Feature genes with a coefficient of variation (CV) >0.5 were selected using the genefilter package in R. Gene co‑expression networks were constructed with the WGCNA package. Cox regression analysis was performed using the survive package. Furthermore, a functional enrichment analysis was conducted using Database for Annotation, Visualization and Integrated Discovery tools...
April 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28237943/kinome-profiling-identifies-druggable-targets-for-novel-human-cytomegalovirus-hcmv-antivirals
#18
Kyle C Arend, Erik M Lenarcic, Heather A Vincent, Naim Rashid, Eric Lazear, Ian M McDonald, Thomas S K Gilbert, Michael P East, Laura E Herring, Gary L Johnson, Lee M Graves, Nathaniel J Moorman
Human cytomegalovirus (HCMV) is a significant cause of disease in immune-compromised adults and immune naïve newborns. No vaccine exists to prevent HCMV infection, and current antiviral therapies have toxic side effects that limit the duration and intensity of their use. There is thus an urgent need for new strategies to treat HCMV infection. Repurposing existing drugs as antivirals is an attractive approach to limit the time and cost of new antiviral drug development. Virus-induced changes in infected cells are often driven by changes in cellular kinase activity, which led us to hypothesize that defining the complement of kinases (the kinome), whose abundance or expression is altered during infection would identify existing kinase inhibitors that could be repurposed as new antivirals...
April 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28214016/melk-expression-in-ovarian-cancer-correlates-with-poor-outcome-and-its-inhibition-by-otssp167-abrogates-proliferation-and-viability-of-ovarian-cancer-cells
#19
Reto S Kohler, Henriette Kettelhack, Alexandra M Knipprath-Mészaros, André Fedier, Andreas Schoetzau, Francis Jacob, Viola Heinzelmann-Schwarz
OBJECTIVE: Maternal embryonic leucine-zipper kinase (MELK) shows oncogenic properties in basal-like breast cancer, a cancer subtype sharing common molecular features with high-grade serous ovarian cancer. We examined the potential of MELK as a molecular and pharmacological target for treatment of epithelial ovarian cancer (EOC). METHODS/MATERIALS: Bioinformatic analysis was performed on nine OC transcriptomic data sets totaling 1241 patients. Effects of MELK depletion by shRNA or inhibition by OTSSP167 in cell lines were assessed by colony formation and MTT (proliferation) assays, Western blotting (apoptosis), and flow cytometry (cell cycle analysis)...
April 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28195154/zinc-finger-protein-zpr9-functions-as-an-activator-of-ampk-related-serine-threonine-kinase-mpk38-melk-involved-in-ask1-tgf-%C3%AE-p53-signaling-pathways
#20
Hyun-A Seong, Ravi Manoharan, Hyunjung Ha
Murine protein serine-threonine kinase 38 (MPK38), an AMP-activated protein kinase (AMPK)-related kinase, has been implicated in the induction of apoptosis signal-regulating kinase 1 (ASK1)-, transforming growth factor-β (TGF-β)-, and p53-mediated activity involved in metabolic homeostasis. Here, zinc finger protein ZPR9 was found to be an activator of MPK38. The association of MPK38 and ZPR9 was mediated by cysteine residues present in each of these two proteins, Cys(269) and Cys(286) of MPK38 and Cys(305) and Cys(308) of ZPR9...
February 14, 2017: Scientific Reports
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