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In a series of 81 GEC samples and 19 cell lines, we evaluated KRAS amp+. Using HER2 scoring systems, 81 GEC samples and 19 GEC cell lines were tested for KRAS GCN by fluorescence in situ hybridization. Patient samples with HER2+ status treated with trastuzuamb, as well as a cohort of patients treated with anti-MET therapy were available for pre/post treatment evaluation. A KRAS-amplified cell line was created from ascites fluid and grown in vitro and tested for KRAS mutation using deep next-generation sequencing to determine if KRAS mutant alleles were present. Results: The evaluation of KRAS GCN showed clustered wild type gene amp+ in 16% of FFPE samples, with KRAS mutations present in 7%, while KRAS mutations were found in 7%. Patients treated with anti-HER2 or anti-MET therapy were found to have elevated KRAS in post-treatment biopsies at progressive disease in comparison to pre-treatment biopsy. In vitro, KRAS siRNA significantly reduced KRAS amp+ lines compared to siRNA control. KRAS amp+ growth/proliferation decreased both in vitro and in vivo using combined MEK and AKT pathway inhibitors against either alone or in comparison to various inhibitor controls, and relative to several inhibitor controls compared to various inhibitor controls. Conclusions: We found KRAS wild type gene amp+ in a subset of GEC patients at diagnosis with elevated protein levels in this series. After receiving trastuzumab therapy in HER2+ patients and post anti-MET therapy, the KRAS amp+ was present, as well as after anti-MET therapy.
Source link: https://doi.org/10.1158/1557-3125.rasonc14-a55
In vitro, Knockdown of PAK4 or PAK1 inhibited the proliferation of mutant KRAS or BRAF colon cancer cells. colon cancer cell proliferation was independent of PAK4 or PAK1 protein expression levels, regardless of PAK4 or PAK1 protein expression levels. Mutant KRAS HCT116 colorectal cells were the most sensitive to PAK4 or PAK1 knockdown, leading to potent inhibition of anchorage-dependent and -independence proliferation, as well as the proliferation and propagation of HCT116 colon cancer spheroids. In HCT116 cells, a knockdown of PAK4 or PAK1 may have caused changes to the actin cytoskeleton, leading to reduced basal spread and cell lengthening, as well as increased cell rounding. Cell growth in HCT116 cells was halted by cell death at later time points, which was followed by cell death at later time points. These findings point to a role for the PAKs in the proliferation of mutant KRAS-driven colorectal carcinoma cells by pathways not involving RAF/MEK/ERK and PI3K/AKT signaling.
Source link: https://doi.org/10.1158/1541-7786.mcr-12-0466
Patients with pulmonary graft-versus-host disease have poor prognosis as a result of allogeneic hematopoietic stem cell transplantation. Pathological analysis of lung specimens from 45 allo-HSCT recipients with pGVHD who underwent lung transplantation was done by Pathological Analysis. Cobimetinib reduced bronchiolitis, increased airway resistance, and lung compliance in the mice, and reduced monocyte and TNF- production in vitro, although these characteristics were not limited by trametinib or tacrolimus. cobimetinib delayed the onset of PI3K/AKT signaling, resulting in B cell and monocyte suppression. Using a combination of trametinib and the PI3K inhibitor, taselisib, greatly reduced B cell proliferation in vitro and raised mouse survival rate in comparison to vehicle or monotherapy with trametinib or taselisib, a tertile inhibition of the MEK/ERK and AKT pathways. T cells around bronchioles were positive for phosphorylated ERK, according to phosphorylated ERK, while B cells were positive for phosphorylated AKT.
Source link: https://doi.org/10.1182/bloodadvances.2021006678
In contrast, sIL-1Ra crosses the blood–brain barrier and in turn, can mediate GA anti-inflammatory activities within the CNS by counteracting IL-1Ra's activities. Here we demonstrate intracellular signaling pathways in human monocytes induced by GA that control sIL-1Ra expression. We show that GA promotes sIL-1Ra production by the activation of PI3K, Akt, MEK1/2, and ERK1/2, as demonstrated by both PI3K/Akt and MEK/ERK pathways.
Source link: https://doi.org/10.1073/pnas.1009443107
Background: Salivary adenoid cystic carcinoma is one of the most common malignant tumors of the salivary gland, and 32. 4-70% of SACC cases have neural invasion; however, the precise mechanism responsible for SACC's high invasion potential remains uncertain. Methods: The present research examined the role of epidermal growth factor receptor in AKT inhibition- or mitogen-activated protein kinase-induced NI and epithelial-mesenchymal transition in SACC cells using EGFR, PI3K, and MEK inhibitors. Cell viability of SACC 83 cells was assessed using an MTT assay, and cell migration was determined by a wound healing assay to determine cell migration. In a xenograft model in nude mice, the effects of EGFR, PI3K, and MEK inhibitors on tumor formation and NU is investigated. Conclusion: By downregulation of the PI3K/AKT, MEK/ERK, or MEK/ERK pathways, it was discovered that inhibitors of EGFR, PI3K/AKT, MEK/ERK or ERK suppressed SACC-83 cells' proliferation, migration, and NI of SACC-83 cells.
Source link: https://doi.org/10.2174/1568009622666220411112312
rapamycin has been shown to promote hypertrophic growth of the myocardium by two specific systems, mTOR complexed with Raptor and mTOR complicateded to Rictor with downstream activation of S6K1 and AKT respectively, with downstream activation of S6K1 and AKT respectively. For the first time in isolated cardiomyocytes, PKC and AKT can be found a direct link between PKC and AKT by immunoprecipitation of a special signaling complex made up of PKC-bound to mTORC2 and pAKT only during insulin stimulation. These results were published in adult isolated cardiomyocytes for the first time: they demonstrate the need for PKC activation and ii, a signaling complex containing mTOR, Rictor, PKC, and pAKT that occurs during insulin stimulation. These studies show that PKC is a key mediator in AKT activation and survival, and that in isolated cardiomyocytes, there is a clear link between PKC, pAKT, and mTORC2.
Source link: https://doi.org/10.1161/res.109.suppl_1.ap218
Abstract Background: The study sought to determine the clinical origins and clinical significance of A-kinase interacting protein 1 in prostate cancer. Methods: The effect of AKIP1 on cell proliferation, migration, invasion, apoptosis, and stemness in LNCaP and 22Rv1 cells via lentivirus infection was determined by overexpressing and knocking down AKIP1. Figures: AKIP1 expression was up in VCaP, LNCaP, and DU145 cells, but not in 22Rv1 cells compared to RWPE-1 cells. In addition, AKIP1 overexpression accelerated cell proliferation in 22Rv1 and LNCaP cell proliferation, migration, and apoptosis, but not inhibited apoptosis; meanwhile, AKIP1 overexpression increased CD133 + cell rate and improved sphere formation efficiency in 22Rv1 and LNCaP cells, as well as enhanced spheres formation efficiency in 22Rv1 and LNCaP cells; in addition, increased cell proliferation and increased cell proliferation, cell proliferation of AKIP1 was upregulated in prostate tumor tissues in comparison to matched controls, and its tumor high expression was associated with increased pathological T, pathological N stage, and poor prognosis in prostate cancer patients.
Source link: https://doi.org/10.21203/rs.3.rs-568302/v1
ABSTRACT BACTERIAL INFORMATION IS ESSENTIAL for the survival of several cell species. Signals from the extracellular matrix are essential for the survival of several cell species. Two members of Rho family GTPases, Rac1 and Cdc42, lose anchorage in primary mouse fibroblasts and are potent inducers of apoptosis. Both the p53 tumor suppressor and the extracellular signal-regulated mitogen-activated protein kinases must be activated during cell death. Our results show that the Rho family's GTPases control three key components of cell signal transduction, namely, p53, Akt, and Erks, which all participate in the induction of apoptosis due to anchorage loss.
Source link: https://doi.org/10.1128/mcb.21.19.6706-6717.2001
However, the host signaling pathway that promotes host cell entry by sapoviruses is largely unknown. Here we show that porcine sapovirus causes both PI3K/Akt and MEK/ERK cascades at an early stage of infection. This work reveals a new way by which receptor-mediated early onset of both cascades can promote PSaV trafficking from early to late endosomes and late endosomal acidification for PSaV uncoating, which may be a new target for treatment of sapovirus infection.
Source link: https://doi.org/10.1128/jvi.01674-18
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