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10.1084/jem.20151778 http://scihub22266oqcxt.onion/10.1084/jem.20151778 C5748843!5748843 !29158376     free     free     free Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\29158376 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       J+Exp+Med 2018 ; 215 (1 ): 197-216 Nephropedia Template TP {{tp|p=29158376 |t=2018. Leukemia-specific delivery of mutant NOTCH1 targeted therapy |pdf=|usr=}}{{29158376 }} gab.com Text Leukemia-specific delivery of mutant NOTCH1 targeted therapy JO: J Exp Med http://www.kidney.de/pget.php?&tw=1&pmid=29158376 #FOAvip On-target drug delivery remains a challenge in cancer precision medicine; it is difficult to deliver a targeted therapy to cancer cells without incurring toxicity to normal tissues. The SERCA (sarco-endoplasmic reticulum Ca(2+) ATPase) inhibitor thapsigargin inhibits mutant NOTCH1 receptors compared with wild type in T cell acute lymphoblastic leukemia (T-ALL), but its administration is predicted to be toxic in humans. Leveraging the addiction of ALL to folic acid, we conjugated folate to an alcohol derivative of thapsigargin via a cleavable ester linkage. JQ-FT is recognized by folate receptors on the plasma membrane and delivered into leukemia cells as a potent antileukemic agent. In mechanistic and translational models of T-ALL, we demonstrate NOTCH1 inhibition in vitro and in vivo. These proof-of-concept studies support the further optimization of this first-in-class NOTCH1 inhibitor with dual selectivity: leukemia over normal cells and NOTCH1 mutants over wild-type receptors. Furthermore, tumor-specific disruption of Notch signaling may overcome legitimate concerns associated with the tumor suppressor function of nontargeted Notch pathway inhibitors. Twit Text FOAVip Leukemia-specific delivery of mutant NOTCH1 targeted therapy ????J Exp Med http://www.kidney.de/pget.php?&tw=1&pmid=29158376 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=29158376 #FOAvip English Wikipedia <ref>{{Cite pmid|29158376 }}</ref> Leukemia-specific delivery of mutant NOTCH1 targeted therapy #MMPMID29158376 Roti G ; Qi J ; Kitara S ; Sanchez-Martin M ; Saur Conway A ; Varca AC ; Su A ; Wu L ; Kung AL ; Ferrando AA ; Bradner JE ; Stegmaier K J Exp Med 2018[Jan]; 215 (1 ): 197-216 PMID29158376 show ga On-target drug delivery remains a challenge in cancer precision medicine; it is difficult to deliver a targeted therapy to cancer cells without incurring toxicity to normal tissues. The SERCA (sarco-endoplasmic reticulum Ca(2+) ATPase) inhibitor thapsigargin inhibits mutant NOTCH1 receptors compared with wild type in T cell acute lymphoblastic leukemia (T-ALL), but its administration is predicted to be toxic in humans. Leveraging the addiction of ALL to folic acid, we conjugated folate to an alcohol derivative of thapsigargin via a cleavable ester linkage. JQ-FT is recognized by folate receptors on the plasma membrane and delivered into leukemia cells as a potent antileukemic agent. In mechanistic and translational models of T-ALL, we demonstrate NOTCH1 inhibition in vitro and in vivo. These proof-of-concept studies support the further optimization of this first-in-class NOTCH1 inhibitor with dual selectivity: leukemia over normal cells and NOTCH1 mutants over wild-type receptors. Furthermore, tumor-specific disruption of Notch signaling may overcome legitimate concerns associated with the tumor suppressor function of nontargeted Notch pathway inhibitors. |*Drug Delivery Systems [MESH] |*Mutation [MESH] |Animals [MESH] |Antineoplastic Agents/*administration & dosage [MESH] |Biological Transport [MESH] |Cell Line, Tumor [MESH] |Disease Models, Animal [MESH] |Endocytosis [MESH] |Folate Receptor 2/genetics/metabolism [MESH] |Folic Acid/chemistry [MESH] |Gene Expression [MESH] |Humans [MESH] |Leukemia/drug therapy/*genetics/metabolism/pathology [MESH] |Mice [MESH] |Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics/metabolism [MESH] |Protein Binding [MESH] |Receptor, Notch1/*antagonists & inhibitors/*genetics/metabolism [MESH] |Signal Transduction/drug effects [MESH] |Thapsigargin/chemistry [MESH]Leukemia-specific delivery of mutant NOTCH1 targeted therapy (epmc).pdf DeepDyve Pubget Overpricing