No abstract

Tumor suppressor p53 plays a central role in preventing tumorigenesis. Here, we unravel how p53 modulates mitochondrial dynamics to restrain the metastatic properties of cancer cells. p53 inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling to attenuate the protein level of mitochondrial fission process 1 (MTFP1), which fosters the pro-fission dynamin-related protein 1 (Drp1) phosphorylation. This regulatory mechanism allows p53 to restrict cell migration and invasion governed by Drp1-mediated mitochondrial fission. Downregulating p53 expression or elevating the molecular signature of mitochondrial fission correlates with aggressive tumor phenotypes and poor prognosis in cancer patients. Upon p53 loss, exaggerated mitochondrial fragmentation stimulates the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling resulting in epithelial-to-mesenchymal transition (EMT)-like changes in cell morphology, accompanied by accelerated matrix metalloproteinase 9 (MMP9) expression and invasive cell migration. Notably, blocking the activation of mTORC1/MTFP1/Drp1/ERK1/2 axis completely abolishes the p53 deficiency-driven cellular morphological switch, MMP9 expression, and cancer cell dissemination. Our findings unveil a hitherto unrecognized mitochondria-dependent molecular mechanism underlying the metastatic phenotypes of p53-compromised cancers.

No abstract

Arsenic and its compounds are toxic environmental pollutants and known carcinogens.

Pharmacologic intervention to affect the membrane lipid homeostasis of lipid rafts is a potent therapeutic strategy for cancer. Here we showed that gallic acid (GA) caused the complex formation of inactive Ras-related C3 botulinum toxin substrate 1 (Rac1)-phospho (p)-casein kinase 2 α (CK2α) (Tyr 255) in human tongue squamous carcinoma (TSC) cells, which disturbed the lipid raft membrane-targeting of phosphatidylinositol 3-kinase (PI3K)-Rac1-protein kinase B (Akt) signal molecules by inducing the association of p110α-free p85α with unphosphorylated phosphatase tensin homolog deleted on chromosome 10 (PTEN) in lipid rafts. The effects on induction of inactive Rac1-p-CK2α (Tyr 255) complex formation and attenuation of p-Akt (Ser 473), GTP-Rac1, glucose transporter-1 (GLUT-1) lipid raft membrane-targeting, and cell invasive activity by GA were counteracted either by CK2α short hairpin RNA or cellular-Src (c-Src) inhibitor PP1. PP1 treatment, GLUT-1 or constitutively active Rac1 ectopic-expression blocked GA-induced decreases in cellular glucose, sphingolipid and cholesterol of lipid raft membranes, p85α-p110α-GTP-Rac1 complexes, glucosylceramide synthase activity and increase in ceramide and p110α-free p85α-PTEN complex levels of lipid raft membranes, which reversed the inhibition on matrix metalloproteinase (MMP)-2/-9-mediated cell invasion induced by GA. Using transient ectopic expression of nuclear factor-kappa B (NF-κB) p65, MMP-2/-9 promoter-driven luciferase, and NF-κB-dependent luciferase reporter genes and NF-κB specific inhibitors or Rac1 specific inhibitor NSC23766, we confirmed that an attenuation of Rac1 activity by GA confers inhibition of NF-κB-mediated MMP-2/-9 expression and cell invasion. In conclusion, GA-induced c-Src activation is a key inductive event for the formation of inactive Rac1-p-CK2α (Tyr 255) complexes, which disturbed lipid raft compartment of PI3K and PTEN molecules by impairing Akt-regulated GLUT-1-mediated sphingolipid synthesis, and finally resulting in inhibition of TSC cell invasion.

Acceptance sampling is a useful tool for determining whether submitted lots should be accepted or rejected. With the current increase in outsourcing production processes and the high-quality levels required, it is very desirable to have an efficient and economic sampling scheme. This paper develops a variables repetitive group sampling (RGS) plan that accounts for the process yield (meeting the manufacturing specifications) and the quality loss (variation from the target). The plan parameters are determined by solving a nonlinear optimisation problem. This implies that the plan parameters minimise the average sample number required for inspection and fulfil the classical two-point conditions on the operating characteristic (OC) curve. Besides, this paper investigates the efficiency of the proposed plan and compares it with the existing variables single sampling plan. Tables of the plan parameters for the proposed variables RGS plan are provided and an application example is presented for illustration. IntroductionAcceptance sampling is one of the most practical tools in classical quality control and assurance applications, which deal with quality contracts for product orders between factories and their customers. Acceptance sampling plans provide the producer and the consumer with a general criterion for lot sentencing. A well-designed sampling plan can substantially reduce the difference between the required and the actual supplied product quality Wu 2006, 2007). Unfortunately, it cannot avoid the risk of accepting unwanted poor product lots, nor can it avoid the risk of rejecting good product lots without implementing 100% inspection (e.g. Montgomery 2009). The criteria used to measure the performance in an acceptance sampling plan are usually based on the operating characteristic (OC) curve, which quantifies the risks of producers and consumers. The OC curve plots the probability of accepting a lot against the actual quality level of the submitted lots. In other words, the OC curve shows the discriminatory power of the sampling plan, which provides the producer and the buyer with a common base for judging whether the sampling plan is appropriate. Sherman (1965) developed a new type of sampling plan, called the repetitive group sampling (RGS) plan, for attributes. The operating procedure of this RGS plan is similar to that of the sequential sampling plan. Balamurali and Jun (2006) extended the RGS concept to variables inspection for a normally distributed quality characteristic. They also compared the efficiency of the variables RGS plan with the variables single and double sampling plans. Their results indicate that the variables RGS plan gives the desired protection with the minimum average sample number (ASN) for inspection. It is highly desirable to have an efficient and economic acceptance sampling scheme, especially when the required quality level is very high (Montgomery 2009). Therefore, the main purpose of this paper is to develop a variables RGS plan for product acceptance determination based on the ...

Tumor suppressor p53 plays a central role in preventing tumorigenesis. Here, we unravel how p53 modulates mitochondrial dynamics to restrain the metastatic properties of cancer cells. p53 inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling to attenuate the protein level of mitochondrial fission process 1 (MTFP1), which fosters the pro-fission dynamin-related protein 1 (Drp1) phosphorylation. This regulatory mechanism allows p53 to restrict cell migration and invasion governed by Drp1-mediated mitochondrial fission. Downregulating p53 or elevating the molecular signature of mitochondrial fission correlates with aggressive tumor phenotypes and poor prognosis in cancer patients. Upon p53 loss, exaggerated mitochondrial fragmentation stimulates the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling resulting in epithelial-to-mesenchymal transition (EMT)-like changes in cell morphology, accompanied by accelerated matrix metalloproteinase-9 (MMP9) expression and invasive cell migration. Notably, blocking the p53 deficiency-induced activation of mTORC1/MTFP1/Drp1/ERK axis completely abolishes the morphological switch, MMP9 expression, and cancer cell dissemination. Our findings unveil a hitherto unrecognized molecular mechanism underlying the metastatic phenotypes of p53-compromised cancers.

This paper deals with a scheduling problem at a bottleneck common facility lorn subsequent production lines, each of which is dedicated to produce a family of products. The common facility represents the bottleneck, since its capacity is less than the sum of the capacities of then production lines. The components supplied by the bottleneck lor the n lines are not exactly the same, and hence a non-productivechange-over (or setup) time for the bottleneck is incurred when jobs switch between families. As such, it is desirable to make as few change-overs as possible to save the expensive setup time. However, if the bottleneck continues processingjobs for a given line, not only will the inventory at the line build up but also other lines will become idle. Thus, a scheduling scheme must be developed for finding a schedule that keeps all the production lines busy with few change-overs for the bottleneck. This objective can be appropriately measured by minimizationofthe total production time. For thecaseoln = 2,a solutionprocedureisdevelopedin this paper to find the optimal schedule.