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Oncotarget published "PIP3-binding proteins promote age-dependent protein aggregation and limit survival in C. elegans" which reported that Class-I phosphatidylinositol 3-kinase converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-triphosphate. Proteins with domains that specifically bind that head-group are thus tethered to the inner plasma-membrane surface where they have an enhanced likelihood of interaction with other PIP3-bound proteins, in particular other components of their signaling pathways. Null alleles of the C. elegans age-1 gene, encoding the catalytic subunit of PI3KI, lack any detectable class-I PI3K activity and so cannot form PIP3. These mutant worms survive almost 10-fold longer than the longest-lived normal control, and are highly resistant to a variety of stresses including oxidative and electrophilic challenges. The authors used ligand-affinity capture to identify membrane-bound proteins downstream of PI3KI that preferentially bind PIP3. Computer modeling supports a subset of candidate proteins predicted to directly bind PIP3 in preference to PIP2, and functional testing by RNAi knockdown confirmed candidates that partially mediate the stress-survival, aggregation-reducing and longevity benefits of PI3KI disruption. In this Oncotarget study, PIP3-specific candidate sets are highly enriched for proteins previously reported to affect translation, stress responses, lifespan, proteostasis, and lipid transport.

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Oncotarget: Targeted lymphodepletion with a CD45-directed antibody radioconjugate

  Oncotarget   recently published " Targeted lymphodepletion with a CD45-directed antibody radioconjugate as a novel conditioning regimen prior to adoptive cell therapy " which reported that Chimeric antigen receptor T cell therapies, and adoptive cell therapy in general, represent one of the most promising anti-cancer strategies. In contrast to relatively non-specific chemotherapy-derived lymphodepletion, targeted lymphodepletion with radioimmunotherapy directed to CD45 may be a safer and more effective alternative to target and deplete immune cells. Here the authors describe the results of preclinical studies with an anti-mouse CD45 antibody 30F11, labeled with two different beta-emitters 131Iodine and 177Lutetium, to investigate the effect of anti-CD45 RIT lymphodepletion on immune cell types and on tumor control in a model of adoptive cell therapy. Treatment of mice with 3.7 MBq 131I-30F11 or 1.48 MBq 177Lu-30F11 safely depleted immune cells such as spleen CD4 and CD8 T C
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Oncotarget: Survival after resection of brain metastases: A matched cohort analysis

 The cover for issue 32 of Oncotarget features Figure 2, "This figure depicts overall survival and local in-brain recurrence-free survival in the study's subgroups," by Hussein, et al. which reported that the aim of the present study is to assess whether the use of 5-ALA has an impact on local recurrence or survival compared to conventional white light microscopic tumor resection. Two groups were compared:      In the “white light” group, resection was performed with conventional microscopy.      In the 5-ALA group, fluorescence guided peritumoral resection was additionally performed after standard microscopic resection. Local in-brain recurrence occurred in 21/175 patients with a rate of 15/119 in the white light and 6/56 in the 5-ALA group. The use of 5-ALA did not result in lower in-brain recurrence or mortality compared to the use of white light microscopy. Dr. Bawarjan Schatlo from the Department of Neurosurgery at The University of Medicine Goettingen said, "
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Combination of copanlisib with cetuximab improves tumor response

Oncotarget published "Combination of copanlisib with cetuximab improves tumor response in cetuximab-resistant patient-derived xenografts of head and neck cancer" which reported that HNSCC is frequently associated with either amplification or mutational changes in the PI3K pathway, making PI3K an attractive target, particularly in cetuximab-resistant tumors. Here, the authors explored the antitumor activity of the selective, pan-class I PI3K inhibitor copanlisib with predominant activity towards PI3Kα and δ in monotherapy and in combination with cetuximab using a mouse clinical trial set-up with 33 patient-derived xenograft models with known HPV and PI3K mutational status and available data on cetuximab sensitivity. Combination treatment with copanlisib and cetuximab was superior to either of the monotherapies alone in the majority of the models, and the effect was particularly pronounced in cetuximab-resistant tumors. While no correlation was observed between PI3K mutatio
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