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https://www.readbyqxmd.com/read/29150397/fragment-based-design-synthesis-biological-evaluation-and-sar-of-1h-benzo-d-imidazol-2-yl-1h-indazol-derivatives-as-potent-pdk1-inhibitors
#1
Ting Chen, Venkataswamy Sorna, Susie Choi, Lee Call, Jared Bearss, Kent Carpenter, Steven L Warner, Sunil Sharma, David J Bearss, Hariprasad Vankayalapati
In this work, we describe the use of the rule of 3 fragment-based strategies from biochemical screening data of 1100 in-house, small, low molecular weight fragments. The sequential combination of in silico fragment hopping and fragment linking based on S160/Y161/A162 hinge residues hydrogen bonding interactions leads to the identification of novel 1H-benzo[d]imidazol-2-yl)-1H-indazol class of Phosphoinositide-Dependent Kinase-1 (PDK1) inhibitors. Consequent SAR and follow-up screening data led to the discovery of two potent PDK1 inhibitors: compound 32 and 35, with an IC50 of 80 nM and 94 nM, respectively...
October 28, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29146772/cre-dependent-cas9-expressing-pigs-enable-efficient-in-vivo-genome-editing
#2
Kepin Wang, Qin Jin, Degong Ruan, Yi Yang, Qishuai Liu, Han Wu, Zhiwei Zhou, Zhen Ouyang, Zhaoming Liu, Yu Zhao, Bentian Zhao, Quanjun Zhang, Jiangyun Peng, Chengdan Lai, Nana Fan, Yanhui Liang, Ting Lan, Nan Li, Xiaoshan Wang, Xinlu Wang, Yong Fan, Pieter A Doevendans, Joost P G Sluijter, Pentao Liu, Xiaoping Li, Liangxue Lai
Despite being time-consuming and costly, generating genome-edited pigs holds great promise for agricultural, biomedical, and pharmaceutical applications. To further facilitate genome editing in pigs, we report here establishment of a pig line with Cre-inducible Cas9 expression that allows a variety of ex vivo genome editing in fibroblast cells including single- and multigene modifications, chromosome rearrangements, and efficient in vivo genetic modifications. As a proof of principle, we were able to simultaneously inactivate five tumor suppressor genes (TP53, PTEN, APC, BRCA1, and BRCA2) and activate one oncogene (KRAS), achieved by delivering Cre recombinase and sgRNAs, which caused rapid lung tumor development...
November 16, 2017: Genome Research
https://www.readbyqxmd.com/read/29145046/genetic-and-clinical-characteristics-of-phyllodes-tumors-of-the-breast
#3
Ji-Yeon Kim, Jong Han Yu, Seok Jin Nam, Seok Won Kim, Se Kyung Lee, Woong-Yang Park, Dong-Young Noh, Do-Hyun Nam, Yeon Hee Park, Wonshik Han, Jeong Eon Lee
PURPOSE: Phyllodes tumors (PTs) of the breast are rare, accounting for less than 1% of all breast tumors. Among PTs, malignant PTs (MPTs) have malignant characteristics and distant metastases occur in about 20% to 30% of MPTs. However, there is no effective treatment for MPTs with distant metastasis, resulting in an abject prognosis. We performed targeted deep sequencing on PTs to identify the associations between genetic alterations and clinical prognosis. METHODS: We performed targeted deep sequencing to evaluate the genetic characteristics of PTs and analyzed the relationships between clinical and genetic characteristics...
November 12, 2017: Translational Oncology
https://www.readbyqxmd.com/read/29143824/pd-1-is-a-haploinsufficient-suppressor-of-t-cell-lymphomagenesis
#4
Tim Wartewig, Zsuzsanna Kurgyis, Selina Keppler, Konstanze Pechloff, Erik Hameister, Rupert Öllinger, Roman Maresch, Thorsten Buch, Katja Steiger, Christof Winter, Roland Rad, Jürgen Ruland
T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes. T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events...
November 15, 2017: Nature
https://www.readbyqxmd.com/read/29143813/ship1-but-not-an-aml-derived-ship1-mutant-suppresses-myeloid-leukemia-growth-in-a-xenotransplantation-mouse-model
#5
M Täger, S Horn, E Latuske, P Ehm, M Schaks, M Nalaskowski, B Fehse, W Fiedler, C Stocking, J Wellbrock, M Jücker
Constitutive activation of the PI3K/AKT signaling pathway is found in ~50-70% of AML patients. The SH2-containing inositol 5-phosphatase 1 (SHIP1) is a negative regulator of PI3K/AKT signaling in hematopoietic cells. SHIP1 knockout mice develop a myeloproliferative syndrome and concomitant deletion of SHIP1 and the tumor suppressor PTEN leads to the development of lethal B-cell lymphomas. In the study presented here, we investigated the role of SHIP1 as a tumor suppressor in myeloid leukemia cells in an in vivo xenograft transplantation model...
November 16, 2017: Gene Therapy
https://www.readbyqxmd.com/read/29142608/upregulation-of-microrna-18b-induces-phosphatase-and-tensin-homolog-to-accelerate-the-migration-and-invasion-abilities-of-ovarian-cancer
#6
Xiaofang Han, Yan Zhang, Dong Wang, Xinyun Fu, Meiqing Li, Aiming Wang
Ovarian cancer (OC) is the most common cause of mortality from malignant gynecological cancers. Its lethality is mainly a result of tumors that are difficult to detect at the early stage and a lack of effective systemic therapy for advanced status cancer. MicroRNAs (miRNAs/miRs) are a category of single-stranded non-coding small RNAs that bind to their target mRNAs, and aberrant expression levels of miRNAs may serve key roles in regulating cell migration and invasion of various types of human cancer. Previous studies have demonstrated that miR-18b may function as an oncogene in numerous types of tumors, but its role and molecular mechanism in OC remained unclear...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29142193/pten-is-a-protein-phosphatase-that-targets-active-ptk6-and-inhibits-ptk6-oncogenic-signaling-in-prostate-cancer
#7
Darren J Wozniak, Andre Kajdacsy-Balla, Virgilia Macias, Susan Ball-Kell, Morgan L Zenner, Wenjun Bie, Angela L Tyner
PTEN activity is often lost in prostate cancer. We show that the tyrosine kinase PTK6 (BRK) is a PTEN substrate. Phosphorylation of PTK6 tyrosine 342 (PY342) promotes activation, while phosphorylation of tyrosine 447 (PY447) regulates auto-inhibition. Introduction of PTEN into a PTEN null prostate cancer cell line leads to dephosphorylation of PY342 but not PY447 and PTK6 inhibition. Conversely, PTEN knockdown promotes PTK6 activation in PTEN positive cells. Using a variety of PTEN mutant constructs, we show that protein phosphatase activity of PTEN targets PTK6, with efficiency similar to PTP1B, a phosphatase that directly dephosphorylates PTK6 Y342...
November 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/29141866/prostate-specific-membrane-antigen-cleavage-of-vitamin-b9-stimulates-oncogenic-signaling-through-metabotropic-glutamate-receptors
#8
Charalambos Kaittanis, Chrysafis Andreou, Haley Hieronymus, Ninghui Mao, Catherine A Foss, Matthias Eiber, Gregor Weirich, Palak Panchal, Anuradha Gopalan, Juan Zurita, Samuel Achilefu, Gabriela Chiosis, Vladimir Ponomarev, Markus Schwaiger, Brett S Carver, Martin G Pomper, Jan Grimm
Prostate-specific membrane antigen (PSMA) or folate hydrolase 1 (FOLH1) is highly expressed on prostate cancer. Its expression correlates inversely with survival and increases with tumor grade. However, the biological role of PSMA has not been explored, and its role in prostate cancer remained elusive. Filling this gap, we demonstrate that in prostate cancer, PSMA initiates signaling upstream of PI3K through G protein-coupled receptors, specifically via the metabotropic glutamate receptor (mGluR). PSMA's carboxypeptidase activity releases glutamate from vitamin B9 and other glutamated substrates, which activate mGluR I...
November 15, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29141684/bioinformatics-prediction-of-mir-30a-targets-and-its-inhibition-of-cell-proliferation-of-osteosarcoma-by-up-regulating-the-expression-of-pten
#9
Biao Zhong, Shang Guo, Wei Zhang, Chi Zhang, Yukai Wang, Changqing Zhang
BACKGROUND: MiRNAs are frequently abnormally expressed in the progression of human osteosarcoma. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is one of the tumor suppressors in various types of human cancer. In the present study, we detected how hsa-miR-30a-3p regulated PTEN and further tested the role of hsa-miR-30a-3p in the cell proliferation of osteosarcoma cells. METHODS: The levels of miR-30a were determined by real time PCR. The expression of PTEN was tested by western blotting analysis...
November 15, 2017: BMC Medical Genomics
https://www.readbyqxmd.com/read/29141221/chemotherapy-induced-depletion-of-oct4-positive-cancer-stem-cells-in-a-mouse-model-of-malignant-testicular-cancer
#10
Timothy M Pierpont, Amy M Lyndaker, Claire M Anderson, Qiming Jin, Elizabeth S Moore, Jamie L Roden, Alicia Braxton, Lina Bagepalli, Nandita Kataria, Hilary Zhaoxu Hu, Jason Garness, Matthew S Cook, Blanche Capel, Donald H Schlafer, Teresa Southard, Robert S Weiss
Testicular germ cell tumors (TGCTs) are among the most responsive solid cancers to conventional chemotherapy. To elucidate the underlying mechanisms, we developed a mouse TGCT model featuring germ cell-specific Kras activation and Pten inactivation. The resulting mice developed malignant, metastatic TGCTs composed of teratoma and embryonal carcinoma, the latter of which exhibited stem cell characteristics, including expression of the pluripotency factor OCT4. Consistent with epidemiological data linking human testicular cancer risk to in utero exposures, embryonic germ cells were susceptible to malignant transformation, whereas adult germ cells underwent apoptosis in response to the same oncogenic events...
November 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/29141219/preventive-inhibition-of-liver-tumorigenesis-by-systemic-activation-of-innate-immune-functions
#11
Jin Lee, Rui Liao, Gaowei Wang, Bi-Huei Yang, Xiaolin Luo, Nissi M Varki, Shuang-Jian Qiu, Bing Ren, Wenxian Fu, Gen-Sheng Feng
Liver cancer has become the second most deadly malignant disease, with no efficient targeted or immune therapeutic agents available yet. While dissecting the roles of cytoplasmic signaling molecules in hepatocarcinogenesis using an inducible mouse gene targeting system, Mx1-cre, we identified a potent liver tumor-inhibitory effect of synthetic double-stranded RNA (dsRNA), polyinosinic-polycytidylic acid (pIC), an inducer of the Mx1-cre system. Injection of pIC at the pre-cancer stage robustly suppressed liver tumorigenesis either induced by chemical carcinogens or by Pten loss and associated hepatosteatosis...
November 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/29138751/expression-of-microrna-29a-regulated-by-yes-associated-protein-modulates-the-neurite-outgrowth-in-n2a-cells
#12
Chunye Tan, Changlin Yu, Zhiwen Song, Hongjun Zou, Xu Xu, Jinbo Liu
Yes-associated protein (YAP) is proved to increase miR-29a in the present study, but the relevant molecular mechanism is not clear. Also, growing evidence indicates that the high-level miR-29a promotes the neurite outgrowth by decreasing PTEN (phosphatase and tensin homologue deleted on chromosome 10). Results show that the expression of miR-29a increases but the PTEN decreases during transfecting the N2a cells with the YAP plasmid. Meanwhile, the advancement of neurite outgrowth is presented via using multiple methods to detect the expression of GAP-43 and NF-200, which have a strong association with neurite outgrowth...
2017: BioMed Research International
https://www.readbyqxmd.com/read/29138323/reply-to-liu-et-al-yin-and-yang-of-pten-regulation
#13
Per Johnsson, Nicholas Lister, Galina Shevchenko, James Walshe, Sandro F Ataide, Kevin V Morris
No abstract text is available yet for this article.
November 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29138265/targeted-delivery-of-stat-3-modulator-to-breast-cancer-stem-like-cells-down-regulates-a-series-of-stem-ness-genes
#14
Santosh K Misra, Arun De, Dipanjan Pan
Cancer stem cells are known to be controlled by pathways that are dormant in normal adult cells, e.g. PTEN, which is a negative regulator of transcription factor STAT3. STAT3 regulates genes that are involved in stem cell self-renewal and thus represents a novel therapeutic target of enormous clinical significance. Studies on breast cancer stem cells (BCSCs) have been also significantly correlated with STATs. We describe here for the first time a novel strategy to selectively target CSCs and to induce downregulation of STAT3 downstream target genes reducing expression of series of 'stem-ness genes' in treated tumors...
November 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29137436/tumor-biopsy-stratification-based-on-mtor-pathway-activity-and-functional-mutations-in-the-upstream-genes-pik3ca-and-pten
#15
Jean-François Laes, Sebastien Sauvage, Gregori Ghitti
The mechanistic target of the rapamycin (mTOR) pathway is frequently activated in human cancers. Our objective was to evaluate relationships between mTOR-pathway activity and functional mutations in the upstream genes PIK3CA and PTEN in solid-tumor biopsies from a broad selection of cancer types. Formalin-fixed paraffin-embedded (FFPE) tumor samples were analyzed by immunohistochemistry (IHC) and next-generation sequencing (NGS). TOR-pathway activation was identified by expression (by IHC) of the downstream effector p-4E-BP1...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29137428/pten-loss-is-associated-with-prostate-cancer-recurrence-and-alterations-in-tumor-dna-methylation-profiles
#16
Milan S Geybels, Min Fang, Jonathan L Wright, Xiaoyu Qu, Marina Bibikova, Brandy Klotzle, Jian-Bing Fan, Ziding Feng, Elaine A Ostrander, Peter S Nelson, Janet L Stanford
Background: Prostate cancer (PCa) with loss of the tumor suppressor gene PTEN has an unfavorable prognosis. DNA methylation profiles associated with PTEN loss may provide further insights into the mechanisms underlying these more aggressive, clinically relevant tumors. Methods: The cohort included patients with clinically localized PCa. Samples taken from the primary tumor were used to determine PTEN genomic deletions using FISH, and to analyze epigenome-wide DNA methylation profiles...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29137351/microrna-200-associated-with-metastatic-breast-cancer-promotes-traits-of-mammary-luminal-progenitor-cells
#17
Lourdes Sánchez-Cid, Mònica Pons, Juan José Lozano, Nuria Rubio, Marta Guerra-Rebollo, Aroa Soriano, Laia Paris-Coderch, Miquel F Segura, Raquel Fueyo, Judit Arguimbau, Erika Zodda, Raquel Bermudo, Immaculada Alonso, Xavier Caparrós, Marta Cascante, Arash Rafii, Yibin Kang, Marian Martínez-Balbás, Stephen J Weiss, Jerónimo Blanco, Montserrat Muñoz, Pedro L Fernández, Timothy M Thomson
MicroRNAs are critical regulators of gene networks in normal and abnormal biological processes. Focusing on invasive ductal breast cancer (IDC), we have found dysregulated expression in tumor samples of several microRNAs, including the miR-200 family, along progression from primary tumors to distant metastases, further reflected in higher blood levels of miR-200b and miR-7 in IDC patients with regional or distant metastases relative to patients with primary node-negative tumors. Forced expression of miR-200s in MCF10CA1h mammary cells induced an enhanced epithelial program, aldehyde dehydrogenase (ALDH) activity, mammosphere growth and ability to form branched tubuloalveolar structures while promoting orthotopic tumor growth and lung colonization in vivo...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29136769/lncrna-p21-inhibited-the-proliferation-of-osteosarcoma-cells-via-the-mir-130b-pten-akt-signaling-pathway
#18
Weifeng Han, Junpeng Liu
Osteosarcoma (OS) is the most common type of malignant bone tumor in children and adolescents. However, the molecular mechanism underlying OS development is unclear. Here, we investigated the contribution of lncRNA-p21, a novel long non-coding RNA, on OS cell proliferation. Our results demonstrated that the expression of lncRNA-p21 was repressed in OS tissue. Growth curves and the cell colony formation assay showed that lncRNA-p21 significantly inhibited the proliferation of OS cell lines. In addition, the expression of lncRNA-p21 increased the protein levels of proliferation markers, such as Ki-67 and cyclin D1...
November 7, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29136761/galangin-inhibits-the-cell-progression-and-induces-cell-apoptosis-through-activating-pten-and-caspase-3-pathways-in-retinoblastoma
#19
Wen-Wei Zou, Su-Ping Xu
Retinoblastoma is reported as a rare cancer that occurs during childhood. Although several treatments are available for retinoblastoma, there is a need for alternative new treatment modalities for retinoblastoma with better safety and efficacy profile. Galangin (3,5,7-trihydroxyflavone), is a flavonoid compound, which is found in high concentration in lesser galangal. Galangin has been reported to have various bioactivities, including anti-inflammation, anti-oxidative stress and anti-cancer through various pathways...
November 6, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29136733/-exploratory-study-of-circulating-tumor-dna-detection-in-early-breast-cancer-an-analysis-of-75-next-generation-sequencing-results
#20
B Zhou, L Xin, L Xu, Y H Liu, M M Zhang, R L Jing, X Y Liang, S B Cao
Objective: To explore the utility of circulating tumor DNA detection in early breast cancer by using next-generation sequencing. Methods: This exploratory study of circulating tumor DNA detection is for early invasive breast cancer patients treated in Breast Disease Center, Peking University First Hospital from December 2015 to July 2016. Plasma samples were collected and were used to isolate plasma cell-free DNA.Exons or hotspots of 247 cancer related genes were sequenced by next-generation sequencing. Mutations and their correlation with clinic-pathological factors were analyzed...
November 1, 2017: Zhonghua Wai Ke za Zhi [Chinese Journal of Surgery]
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