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https://www.readbyqxmd.com/read/29758292/novel-truncating-ppm1d-mutation-in-a-patient-with-intellectual-disability
#1
Joseph Porrmann, Andreas Rump, Karl Hackmann, Nataliya Di Donato, Anne-Karin Kahlert, Johannes Wagner, Arne Jahn, Ines Eger, Monika Flury, Evelin Schrock, Andreas Tzschach, Laura Gieldon
Truncating mutations in the last and penultimate exons of the PPM1D gene were recently described as a cause for mild to severe intellectual disability in fourteen patients. Feeding difficulties, periods of fever and vomiting as well as a high pain threshold were described as additional characteristic features and the disorder was subsequently termed "intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (IDDGIP)" in the OMIM database (MIM # 617450). Here we report on an additional patient carrying a novel de novo truncating mutation NM_003620...
May 11, 2018: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/29556286/microrna-499a-5p-inhibits-osteosarcoma-cell-proliferation-and-differentiation-by-targeting-protein-phosphatase-1d-through-protein-kinase-b-glycogen-synthase-kinase-3%C3%AE-signaling
#2
Jun Liu, Lei Huang, Pengxiao Su, Tao Song, Wentao Zhang, Jinzhu Fan, Yang Liu
A number of studies have attempted to elucidate the association between mircoRNAs (miRNAs/miRs) and cancer-associated processes. The aim of the present study was to determine how miR-499a-5p intervenes in human osteosarcoma cell proliferation and differentiation. The cancerous tissues and adjacent non-cancerous tissues of 62 patients with osteosarcoma (OS) were collected. miRNA microarray analysis revealed that 29 miRNAs were upregulated while 26 were downregulated, among which miR-499a-5p expression was the most decreased...
April 2018: Oncology Letters
https://www.readbyqxmd.com/read/29485113/atr-kinase-regulates-its-attenuation-via-ppm1d-phosphatase-recruitment-to-chromatin-during-recovery-from-dna-replication-stress-signalling
#3
Debadrita Bhattacharya, Disha Hiregange, Basuthkar J Rao
In eukaryotes, in response to replication stress, DNA damage response kinase, ATR is activated, whose signalling abrogation leads to cell lethality due to aberrant fork remodelling and excessive origin firing. Here we report that inhibition of ATR kinase activity specifically during replication stress recovery results in persistent ATR signalling, evidenced by the presence of ATR-dependent phosphorylation marks (gamma H2AX, pChk1 and pRad17) and delayed cell cycle re-entry. Further, such disruption of ATR signalling attenuation leads to double-strand breaks, fork collapse and thereby 'replication catastrophe'...
March 2018: Journal of Biosciences
https://www.readbyqxmd.com/read/29386642/cellular-stressors-contribute-to-the-expansion-of-hematopoietic-clones-of-varying-leukemic-potential
#4
Terrence N Wong, Christopher A Miller, Matthew R M Jotte, Nusayba Bagegni, Jack D Baty, Amy P Schmidt, Amanda F Cashen, Eric J Duncavage, Nichole M Helton, Mark Fiala, Robert S Fulton, Sharon E Heath, Megan Janke, Kierstin Luber, Peter Westervelt, Ravi Vij, John F DiPersio, John S Welch, Timothy A Graubert, Matthew J Walter, Timothy J Ley, Daniel C Link
Hematopoietic clones harboring specific mutations may expand over time. However, it remains unclear how different cellular stressors influence this expansion. Here we characterize clonal hematopoiesis after two different cellular stressors: cytotoxic therapy and hematopoietic transplantation. Cytotoxic therapy results in the expansion of clones carrying mutations in DNA damage response genes, including TP53 and PPM1D. Analyses of sorted populations show that these clones are typically multilineage and myeloid-biased...
January 31, 2018: Nature Communications
https://www.readbyqxmd.com/read/29328395/bioinformatic-identification-of-chemoresistance-associated-micrornas-in-breast-cancer-based-on-microarray-data
#5
Ya-Wen Wang, Weiguo Zhang, Rong Ma
Breast cancer is the most commonly diagnosed cancer among females, and chemoresistance constitutes a major clinical obstacle to the treatment of this disease. MicroRNAs (miRNAs) are related to human cancer development, progression and drug resistance. To identify breast cancer chemoresistance-associated miRNAs, miRNA microarray dataset GSE71142, including five chemoresistant breast cancer tissues and five chemosensitive tissues, was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed miRNAs (DE-miRNAs) were obtained by t-test and the potential target genes were predicted by miRWalk2...
March 2018: Oncology Reports
https://www.readbyqxmd.com/read/29275106/clinical-significance-of-the-wild-type-p53-induced-phosphatase-1-expression-in-invasive-breast-cancer
#6
Yuka Inoue, Nami Yamashita, Hiroyuki Kitao, Kimihiro Tanaka, Hiroshi Saeki, Eiji Oki, Yoshinao Oda, Eriko Tokunaga, Yoshihiko Maehara
BACKGROUND: Wild type p53-induced phosphatase 1 (Wip1), encoded by the protein phosphatase magnesium dependent 1 delta (PPM1D), inhibits p53. PPM1D amplification has been reported in breast cancer. Breast cancer can sometimes develop without a tumor protein 53 (TP53) mutation. In these cases, the p53 pathway might be disrupted by alternative mechanisms, and Wip1 is reported to be a key molecule involved. MATERIALS AND METHODS: Primary invasive ductal carcinoma specimens were obtained from 201 cases, for which archival tissue samples for immunohistochemistry were available...
November 21, 2017: Clinical Breast Cancer
https://www.readbyqxmd.com/read/29245943/saikosaponin-d-a-calcium-mobilizing-agent-sensitizes-chemoresistant-ovarian-cancer-cells-to-cisplatin-induced-apoptosis-by-facilitating-mitochondrial-fission-and-g2-m-arrest
#7
Hideaki Tsuyoshi, Vincent Kam Wai Wong, Yu Han, Makoto Orisaka, Yoshio Yoshida, Benjamin K Tsang
Cisplatin (CDDP) and its derivatives are first line anti-cancer drugs for ovarian cancer (OVCA). However, chemoresistance due to high incidence of p53 mutations leads to poor clinical prognosis. Saikosaponin-d (Ssd), a saponin from a herbal plant extract, has been shown to induce cell death and sensitize chemoresistant cells to chemotherapeutic agents. Here, we demonstrated that Ssd sensitized chemoresistant OVCA cells with either p53-wt, -mutant and -null to CDDP. The action of Ssd appears to be through induction of mitochondrial fragmentation and G2/M arrest...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29137285/genetic-and-immune-features-of-resectable-malignant-brainstem-gliomas
#8
Yang Zhang, Changcun Pan, Junmei Wang, Jingli Cao, Yuhan Liu, Yajie Wang, Liwei Zhang
We surveyed common genetic mutations (IDH1, H3F3A, PPM1D, and TP53) and immune features (PD-L1 expression and CD8+ T cell tumor infiltration) in a series of 62 malignant brainstem gliomas that were resected via microsurgery. IDH1 mutations were mutually exclusive with H3F3A mutations. IDH1 mutations appeared only in adults and occurred more frequently in tumors larger than 10cm3 (8/29 vs 1/32, Fisher's exact test, p=0.010). H3F3A mutations occurred more frequently in children and adolescent patients (19/24 vs 18/38, chi-square test, p=0...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29046514/protein-phosphatase-magnesium-dependent-1%C3%AE-ppm1d-expression-as-a-prognostic-marker-in-adult-supratentorial-diffuse-astrocytic-and-oligodendroglial-tumors
#9
Hui Jeong Jeong, Chang Gok Woo, Bora Lee, Shin Kwang Khang, Soo Jeong Nam, Jene Choi
BACKGROUND: Protein phosphatase magnesium-dependent 1δ (PPM1D) is a p53-induced serine/threonine phosphatase, which is overexpressed in various human cancers. A recent study reported that a mutation in the PPM1D gene is associated with poor prognosis in brainstem gliomas. In this study, we evaluated the utility of PPM1D as a prognostic biomarker of adult supratentorial diffuse astrocytic and oligodendroglial tumors. METHODS: To investigate PPM1D protein expression, mRNA expression, and copy number changes, immunohistochemistry, RNAscope in situ hybridization, and fluorescence in situ hybridization were performed in 84 adult supratentorial diffuse gliomas...
March 2018: Journal of Pathology and Translational Medicine
https://www.readbyqxmd.com/read/28852847/distinct-molecular-profile-of-diffuse-cerebellar-gliomas
#10
Masashi Nomura, Akitake Mukasa, Genta Nagae, Shogo Yamamoto, Kenji Tatsuno, Hiroki Ueda, Shiro Fukuda, Takayoshi Umeda, Tomonari Suzuki, Ryohei Otani, Keiichi Kobayashi, Takashi Maruyama, Shota Tanaka, Shunsaku Takayanagi, Takahide Nejo, Satoshi Takahashi, Koichi Ichimura, Taishi Nakamura, Yoshihiro Muragaki, Yoshitaka Narita, Motoo Nagane, Keisuke Ueki, Ryo Nishikawa, Junji Shibahara, Hiroyuki Aburatani, Nobuhito Saito
Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions...
December 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28803919/therapy-related-clonal-hematopoiesis-in-patients-with-non-hematologic-cancers-is-common-and-associated-with-adverse-clinical-outcomes
#11
Catherine C Coombs, Ahmet Zehir, Sean M Devlin, Ashwin Kishtagari, Aijazuddin Syed, Philip Jonsson, David M Hyman, David B Solit, Mark E Robson, José Baselga, Maria E Arcila, Marc Ladanyi, Martin S Tallman, Ross L Levine, Michael F Berger
Clonal hematopoiesis (CH), as evidenced by recurrent somatic mutations in leukemia-associated genes, commonly occurs among aging human hematopoietic stem cells. We analyzed deep-coverage, targeted, next-generation sequencing (NGS) data of paired tumor and blood samples from 8,810 individuals to assess the frequency and clinical relevance of CH in patients with non-hematologic malignancies. We identified CH in 25% of cancer patients, with 4.5% harboring presumptive leukemia driver mutations (CH-PD). CH was associated with increased age, prior radiation therapy, and tobacco use...
September 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28775233/genetic-and-immune-features-of-resectable-malignant-brainstem-gliomas
#12
Yang Zhang, Changcun Pan, Junmei Wang, Jingli Cao, Yuhan Liu, Yajie Wang, Liwei Zhang
We surveyed common genetic mutations (IDH1, H3F3A, PPM1D, and TP53) and immune features (PD-L1 expression and CD8+ T cell tumor infiltration) in a series of 62 malignant brainstem gliomas that were resected via microsurgery. IDH1 mutations were mutually exclusive with H3F3A mutations. IDH1 mutations appeared only in adults and occurred more frequently in tumors larger than 10cm3 (8/29 vs 1/32, Fisher's exact test, p=0.010). H3F3A mutations occurred more frequently in children and adolescent patients (19/24 vs 18/38, chi-square test, p=0...
July 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28486685/inhibition-of-ser-thr-phosphatase-ppm1d-induces-neutrophil-differentiation-in-hl-60-cells
#13
Rui Kamada, Fuki Kudoh, Fumihiko Yoshimura, Keiji Tanino, Kazuyasu Sakaguchi
Protein phosphatase Magnesium-dependent 1, Delta (PPM1D) is a wild-type p53-inducible Ser/Thr phosphatase that acts as a negative regulator of the p53 tumor suppressor. Gene amplification and overexpression of PPM1D have been reported in various cancers including leukemia and neuroblastoma. Therefore, PPM1D is a promising target in cancer therapy. It has been reported that PPM1D knockout mice exhibit neutrophilia in blood and show a defective immune response. Here, we found that inhibition of PPM1D induced neutrophil differentiation of human promyelocytic leukemia cell line HL-60...
October 1, 2017: Journal of Biochemistry
https://www.readbyqxmd.com/read/28483762/clonal-hematopoiesis-with-and-without-candidate-driver-mutations-is-common-in-the-elderly
#14
Florian Zink, Simon N Stacey, Gudmundur L Norddahl, Michael L Frigge, Olafur T Magnusson, Ingileif Jonsdottir, Thorgeir E Thorgeirsson, Asgeir Sigurdsson, Sigurjon A Gudjonsson, Julius Gudmundsson, Jon G Jonasson, Laufey Tryggvadottir, Thorvaldur Jonsson, Agnar Helgason, Arnaldur Gylfason, Patrick Sulem, Thorunn Rafnar, Unnur Thorsteinsdottir, Daniel F Gudbjartsson, Gisli Masson, Augustine Kong, Kari Stefansson
Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single dominant hematopoietic stem cell lineage. Somatic mutations in candidate driver (CD) genes are thought to be responsible for at least some cases of CH. Using whole-genome sequencing of 11 262 Icelanders, we found 1403 cases of CH by using barcodes of mosaic somatic mutations in peripheral blood, whether or not they have a mutation in a CD gene. We find that CH is very common in the elderly, trending toward inevitability...
August 10, 2017: Blood
https://www.readbyqxmd.com/read/28423363/multiple-gene-panel-analysis-in-a-case-series-of-255-women-with-hereditary-breast-and-ovarian-cancer
#15
Gianluca Tedaldi, Michela Tebaldi, Valentina Zampiga, Rita Danesi, Valentina Arcangeli, Mila Ravegnani, Ilaria Cangini, Francesca Pirini, Elisabetta Petracci, Andrea Rocca, Fabio Falcini, Dino Amadori, Daniele Calistri
As new genes predisposing to breast (BC) and ovarian cancer (OC) are constantly emerging, the use of panels of genes analyzed by Next-Generation Sequencing (NGS) is increasing in clinical diagnostics. The identification of a large number of new germline mutations allows for deeper knowledge of cancer predisposition, although raising many questions about patient management.BC and OC patients recruited by our counseling service between 2012-2015 were included in this study. DNA was extracted from peripheral blood and a panel of 94 genes involved in hereditary tumors was analyzed by NGS...
July 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28417018/dna-damage-induced-phosphatase-wip1-in-regulation-of-hematopoiesis-immune-system-and-inflammation
#16
REVIEW
B Uyanik, B B Grigorash, A R Goloudina, O N Demidov
PP2C serine-threonine phosphatase, Wip1, is an important regulator of stress response. Wip1 controls a number of critical cellular functions: proliferation, cell cycle arrest, senescence and programmed cell death, apoptosis or autophagy. Ppm1d, the gene encoding Wip1 phosphatase, is expressed in hematopoietic progenitors, stem cells, neutrophils, macrophages B and T lymphocytes in bone marrow and peripheral blood. The Wip1-/- mice display immunodeficiency, abnormal lymphoid histopathology in thymus and spleen, defects in B- and T-cell differentiation, as well as susceptibility to viral infection...
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/28343630/de-novo-truncating-mutations-in-the-last-and-penultimate-exons-of-ppm1d-cause-an-intellectual-disability-syndrome
#17
Sandra Jansen, Sinje Geuer, Rolph Pfundt, Rachel Brough, Priyanka Ghongane, Johanna C Herkert, Elysa J Marco, Marjolein H Willemsen, Tjitske Kleefstra, Mark Hannibal, Joseph T Shieh, Sally Ann Lynch, Frances Flinter, David R FitzPatrick, Alice Gardham, Birgitta Bernhard, Nicola Ragge, Ruth Newbury-Ecob, Raphael Bernier, Malin Kvarnung, E A Helena Magnusson, Marja W Wessels, Marjon A van Slegtenhorst, Kristin G Monaghan, Petra de Vries, Joris A Veltman, Christopher J Lord, Lisenka E L M Vissers, Bert B A de Vries
Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis...
April 6, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28248986/cellular-responses-and-gene-expression-profile-changes-due-to-bleomycin-induced-dna-damage-in-human-fibroblasts-in-space
#18
Tao Lu, Ye Zhang, Yared Kidane, Alan Feiveson, Louis Stodieck, Fathi Karouia, Govindarajan Ramesh, Larry Rohde, Honglu Wu
Living organisms in space are constantly exposed to radiation, toxic chemicals or reactive oxygen species generated due to increased levels of environmental and psychological stresses. Understanding the impact of spaceflight factors, microgravity in particular, on cellular responses to DNA damage is essential for assessing the radiation risk for astronauts and the mutation rate in microorganisms. In a study conducted on the International Space Station, confluent human fibroblasts in culture were treated with bleomycin for three hours in the true microgravity environment...
2017: PloS One
https://www.readbyqxmd.com/read/28177873/prognostic-mutations-in-myelodysplastic-syndrome-after-stem-cell-transplantation
#19
R Coleman Lindsley, Wael Saber, Brenton G Mar, Robert Redd, Tao Wang, Michael D Haagenson, Peter V Grauman, Zhen-Huan Hu, Stephen R Spellman, Stephanie J Lee, Michael R Verneris, Katharine Hsu, Katharina Fleischhauer, Corey Cutler, Joseph H Antin, Donna Neuberg, Benjamin L Ebert
BACKGROUND: Genetic mutations drive the pathogenesis of the myelodysplastic syndrome (MDS) and are closely associated with clinical phenotype. Therefore, genetic mutations may predict clinical outcomes after allogeneic hematopoietic stem-cell transplantation. METHODS: We performed targeted mutational analysis on samples obtained before transplantation from 1514 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research Repository between 2005 and 2014...
February 9, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28105167/cisplatin-induces-hepg2-cell-cycle-arrest-through-targeting-specific-long-noncoding-rnas-and-the-p53-signaling-pathway
#20
Ping Wang, Jiayue Cui, Jihong Wen, Yunhui Guo, Liangzi Zhang, Xia Chen
Cisplatin has been used effectively in the treatment of hepatocellular carcinoma (HCC). Long noncoding RNAs (lncRNAs) were recently reported to contribute to the pathogenesis and progression of HCC. Their molecular mechanism related to cisplatin treatment remains unclear. The purpose of this study is to identify specific lncRNAs and to clarify their functions in HCC after cisplatin exposure. Reannotation and identification of differentially expressed lncRNAs were performed using the microarray data set GSE38122 in the Gene Expression Omnibus database...
December 2016: Oncology Letters
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