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IMAGE: Regulation of spine molecules in HL-60 wt versus Fgr KO cells by RA. HL-60 wt and FGR KO cells were cultured for 72 h in the absence or presence of. view more
Credit: Correspondence to - Andrew Yen - ay13@cornell.edu
Using a leukemic patient-derived in vitro model of a non-APL AML, these authors previously found that RA evokes activation of a macromolecular signaling complex, a signalosome, built of numerous MAPK-pathway-related signaling molecules; and this signaling enabled Retinoic-Acid-Response-Elements to regulate gene expression that results in cell differentiation/cell cycle arrest. Toward mechanistic insight into the nature of this novel signaling, they now find that the NUMB cell fate determinant protein is an apparent scaffold for the signalosome.
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IMAGE: Candidate therapeutics tested for TH4 subtype in IU-TAB-1 cell line. Experimental dose-response curves assessing relative growth (Hoechst staining of DNA), proliferation (Ki67), viability (DRAQ7 assay), and apoptosis (caspase) for (A). view more
Credit: Correspondence to - Sukhmani K. Padda - sukhmani.padda@cshs.org
Six novel molecular subtypes of TETs from the TCGA were identified, and there was no association with WHO histologic subtype.
The IU-TAB-1 cell line clustered into the TH4 molecular subtype and in vitro testing of candidate therapeutics was performed.
Sensitivity to nelfinavir was due to the IU-TAB-1 cell line s gain-of function mutation in PIK3CA and amplification of genes observed from array comparative genomic hybridization, including AURKA, ERBB2, KIT, PDGFRA and PDGFB, that are known upregulate AKT, while resistance to everolimus was primarily driven by upregulation of downstream signaling of KIT, PDGFRA and PDGFB in the presence of mT
As PALB2 exhibits functions in the BRCA1/2-RAD51-dependent homologous DNA recombination repair pathway, we sought to use
ex vivo functional screening to explore sensitivity of the tumor cells to therapeutic targeting of DNA repair.
Drug screening suggested sensitivity of the PALB2 deficient cells to BET-bromodomain inhibition, and modest sensitivity to DNA-PKi, ATRi, WEE1i and PARPi.
A phenotypic RNAi screen of 300 DNA repair genes was undertaken to assess DNA repair targeting in more detail.
RNAi inhibition of RAD52-dependent HR on the other hand potentiated the efficacy of a novel BETi ODM-207.
Together these
Oncotarget results describe the first ever CAC case with a BRCAness genetic background, evaluate combinatorial DNA repair targeting, and provide a data resource for further analyses of DNA repair targeting in PALB2 deficient cancers.
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IMAGE: Alteration in biomechanical properties of PANC-1 cells exposed to 5 μM cytochalasin D (CytD) in normoxia and hypoxia. (A) Time trace of Young s modulus E in normoxia (n = 5). view more
Credit: Correspondence to - Yongki Choi - yongki.choi@ndsu.edu
Oncotarget published Dynamic cellular biomechanics in responses to chemotherapeutic drug in hypoxia probed by atomic force spectroscopy which reported that by exploiting single-cell, force spectroscopy methods, the authors probed biophysical and biomechanical kinetics of brain, breast, prostate, and pancreatic cancer cells with standard chemotherapeutic drugs in normoxia and hypoxia over 12-24 hours.
After exposure to the drugs, they found that brain, breast, and pancreatic cancer cells became approximately 55-75% less stiff, while prostate cancer cells became more stiff, due to either drug-induced disruption or reinforcement of cytoskeletal structure.
Epidemiologically, COPD patients are 6.35 times more likely to develop lung cancer.
To mimic COPD, the authors exposed mice to nose-only cigarette smoke and used human samples of lung adenocarcinoma patients according to the smoking and COPD status.
Interestingly, higher expression of AIM2 in non-cancerous tissue of smoking COPD adenocarcinoma patients was correlated to a higher hazard ratio of poor survival rate than in patients who presented lower levels of AIM2.
The
Oncotarget authors found that AIM2 inflammasome is at the crossroad between COPD and lung cancer in that its higher presence is correlated to lower survival rate of smoking COPD adenocarcinoma patients.