Posts Tagged ‘Independent’

Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer

Malignant neoplasms evolve in response to changes in oncogenic signalling. Cancer cell plasticity in response to evolutionary pressures is fundamental to tumour progression and the development of therapeutic resistance. Here we determine the molecular and cellular mechanisms of cancer cell plasticity in a conditional oncogenic Kras mouse model of pancreatic ductal adenocarcinoma (PDAC), a malignancy that displays considerable phenotypic diversity and morphological heterogeneity. In this model, stochastic extinction of oncogenic Kras signalling and emergence of Kras-independent escaper populations (cells that acquire oncogenic properties) are associated with de-differentiation and aggressive biological behaviour. Transcriptomic and functional analyses of Kras-independent escapers reveal the presence of Smarcb1–Myc-network-driven mesenchymal reprogramming and independence from MAPK signalling. A somatic mosaic model of PDAC, which allows time-restricted perturbation of cell fate, shows that depletion of Smarcb1 activates the Myc network, driving an anabolic switch that increases protein metabolism and adaptive activation of endoplasmic-reticulum-stress-induced survival pathways. Increased protein turnover renders mesenchymal sub-populations highly susceptible to pharmacological and genetic perturbation of the cellular proteostatic machinery and the IRE1-α–MKK4 arm of the endoplasmic-reticulum-stress-response pathway. Specifically, combination regimens that impair the unfolded protein responses block the emergence of aggressive mesenchymal subpopulations in mouse and patient-derived PDAC models. These molecular and biological insights inform a potential therapeutic strategy for targeting aggressive mesenchymal features of PDAC.

GoodGopher.com rapidly rising as the independent search engine for REAL news… all sites penalized by Google are welcomed to get indexed

(NaturalNews) As the radical, anti-free-speech left has declared all-out war on the independent media, people everywhere are waking up to GoodGopher.com as the alternative search engine for independent news and information.GoodGopher.com, which I creat…

In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration

Targeted genome editing via engineered nucleases is an exciting area of biomedical research and holds potential for clinical applications. Despite rapid advances in the field, in vivo targeted transgene integration is still infeasible because current tools are inefficient, especially for non-dividing cells, which compose most adult tissues. This poses a barrier for uncovering fundamental biological principles and developing treatments for a broad range of genetic disorders. Based on clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9) technology, here we devise a homology-independent targeted integration (HITI) strategy, which allows for robust DNA knock-in in both dividing and non-dividing cells in vitro and, more importantly, in vivo (for example, in neurons of postnatal mammals). As a proof of concept of its therapeutic potential, we demonstrate the efficacy of HITI in improving visual function using a rat model of the retinal degeneration condition retinitis pigmentosa. The HITI method presented here establishes new avenues for basic research and targeted gene therapies.

Automation is coming: 60 percent of today’s students chase jobs that won’t exist in 10 years

Improvements in artificial intelligence and robotic technology will eventually take over so many jobs that the government will need to provide displaced workers with a basic universal income just to ensure their survival, according to one tech industry giant. Elon Musk, the founder and CEO of SpaceX and Tesla, recently told CNBC that computers, AI […]

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RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation

Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammation via kinase-dependent and -independent functions1, 2, 3, 4, 5, 6, 7. RIPK1 kinase activity induces caspase-8-dependent apoptosis and RIPK3/mixed lineage kinase like (MLKL)-dependent necroptosis8, 9, 10, 11, 12, 13. In addition, RIPK1 inhibits apoptosis and necroptosis via kinase-independent functions, which are important for late embryonic development and the prevention of inflammation in epithelial barriers14, 15, 16, 17, 18. The mechanism by which RIPK1 counteracts RIPK3/MLKL-mediated necroptosis has remained enigmatic. Here we show that RIPK1 prevents skin inflammation by inhibiting Z-DNA binding protein 1 (ZBP1, also named DAI or DLM1)-mediated activation of RIPK3/MLKL-dependent necroptosis. ZBP1 deficiency inhibited keratinocyte necroptosis and skin inflammation in mice with epidermis-specific RIPK1 knockout. Moreover, mutation of the conserved RIP homotypic interaction motif (RHIM) of endogenous mouse RIPK1 (RIPK1mRHIM) caused perinatal lethality that was prevented by RIPK3, MLKL or ZBP1 deficiency. Furthermore, mice expressing only RIPK1mRHIM in keratinocytes developed skin inflammation that was abrogated by MLKL or ZBP1 deficiency. Mechanistically, ZBP1 interacted strongly with phosphorylated RIPK3 in cells expressing RIPK1mRHIM, suggesting that the RIPK1 RHIM prevents ZBP1 from binding and activating RIPK3. Collectively, these results show that RIPK1 prevents perinatal death as well as skin inflammation in adult mice by inhibiting ZBP1-induced necroptosis. Furthermore, these findings identify ZBP1 as a critical mediator of inflammation beyond its previously known role in antiviral defence and suggest that ZBP1 might be implicated in the pathogenesis of necroptosis-associated inflammatory diseases.

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