Lithium-mediated downregulation of PKB/Akt and cyclin E with growth inhibition in hepatocellular carcinoma cells

We studied in vitro effects of glycogen synthase kinase 3β (GSK3β)-inhibitor lithium on the growth of hepatocellular carcinoma (HCC) cells. Lithium induced strong growth inhibition (>70%) in 75% (n = 9 of 12) of cell lines, apparently independent from the status of major genes that are mutated in HCC including p53, p16INK4a, β-catenin and Axin1. Comparative studies with a growth-sensitive Huh7 and growth-resistant Hep40 cell lines showed that lithium induces growth arrest in Huh7 cells but not in Hep40 cells. Lithium induced the accumulation of N-terminally phosphorylated inactive form of GSK3β with concomitant increase in β-catenin and β-catenin/TCF transcriptional activity in both cell lines. This suggests that lithium-mediated HCC growth inhibition is independent of its well-known stimulatory effect on Wnt-β-catenin signaling. The main differences between Huh7 and Hep40 responses to lithium treatment were observed at the levels PKB/Akt and cyclin E proteins. Lithium induced depletion of both proteins in growth-sensitive Huh7, but not in growth-resistant Hep40 cells. PKB/Akt and Cyclin E are 2 major proteins that are known to be constitutively active in HCC. The targeting of both proteins with lithium may be the main reason why most HCC cells are responsive to lithium-mediated growth inhibition, independent of their p53, retinoblastoma and Wnt-β-catenin pathways. The exploration of molecular mechanisms involved in lithium-mediated growth inhibition in relation with PKB/Akt and cyclin E downregulation may provide new insights for therapy of liver tumors. © 2005 Wiley-Liss, Inc

The school bus routing problem: An analysis and algorithm

In this paper we analyse a flexible real world-based model for designing school bus transit systems and note a number of parallels between this and other well-known combinatorial optimisation problems including the vehicle routing problem, the set covering problem, and one-dimensional bin packing. We then describe an iterated local search algorithm for this problem and demonstrate the sort of solutions that we can expect with different types of problem instance

Transmittivity of a Bose-Einstein condensate on a lattice: interference from period doubling and the effect of disorder

We evaluate the particle current flowing in steady state through a Bose-Einstein condensate subject to a constant force in a quasi-onedimensional lattice and to attractive interactions from fermionic atoms that are localized in various configurations inside the lattice wells. The system is treated within a Bose-Hubbard tight binding model by an out-of-equilibrium Green's function approach. A new band gap opens up when the lattice period is doubled by locating the fermions in alternate wells and yields an interference pattern in the transmittivity on varying the intensity of the driving force. The positions of the transmittivity minima are determined by matching the period of Bloch oscillations and the time for tunnelling across the band gap. Massive disorder in the distribution of the fermions will wash out the interference pattern, but the same period doubling of the lattice can be experimentally realized in a four-beam set-up. We report illustrative numerical results for a mixture of 87Rb and 40K atoms in an optical lattice created by laser beams with a wavelength of 763 nm.Comment: 13 pages, 5 figure

TREATMENT, DISEASE CONTROL, QUALITY OF LIFE AND PSYCHOLOGICAL STATUS IN PATIENTS WITH ANKYLOSING SPONDYLITIS DURING THE COVID-19 PANDEMIC

Introduction. The coronavirus disease (COVID-19) pandemic has the potential to impact disease activity and psychological well-being in people with rheumatic diseases. This study aimed to compare ankylosing spondylitis (AS) patients with and without COVID-19 history in terms of treatment, disease control, quality of life and psychological status by providing a cross-sectional look at treatment, disease control, quality of life and psychological status in patients with AS during the COVID-19 pandemic. Methods. The study included 74 AS patients, in two groups based on COVID-19 history. Demographic data and clinical characteristics were recorded. Treatment, disease control, functional status, and quality of life were evaluated using Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index (BASFI), and impact of COVID-19 on quality-of-life scales. Psychological status was assessed using the Beck Depression Inventory, Beck Hopelessness Scale, and COVID-19 anxiety scale. Results. Of the 74 patients diagnosed with AS, 44 were female and 34 were male. The mean age was 47.3 years. In total, 35 patients (47.3%) had COVID-19. We found that the group without COVID-19 had significantly higher levels of hypothyroidism than the other group (p = 0.008). The BASFI value was significantly higher in the COVID-19 group (p = 0.031). The group with COVID-19 had a substantially higher rate of continuing non-anti-rheumatic drug use than the other group (p = 0.02). Conclusion. During COVID-19 pandemic period, the majority of patients continued their medication, so treatment and disease control were not negatively affected. Having COVID-19 did not cause a significant difference psychologically

Characterization of HCV Interactions with Toll-Like Receptors and RIG-I in Liver Cells

The aim of this study was to examine the mechanisms of IFN induction and viral escape. In order to accomplish the goal we compared our new hepatoma cell line LH86, which has intact TLR3 and RIG-I expression and responds to HCV by inducing IFN, with Huh7.5 cells which lack those features.The initial interaction of LH86 cells, Huh7.5 cells or their transfected counter parts (LH86 siRIG-I, siTLR3 or siTLR7 and Huh7.5 RIG-I, TLR3 or TLR7) after infection with HCV (strain JFH-1) was studied by measuring the expression levels of IFNβ, TRAIL, DR4, DR5 and their correlation to viral replication.HCV replicating RNA induces IFN in LH86 cells. The IFN induction system is functional in LH86, and the expression of the RIG-I and TLR3 in LH86 is comparable to the primary hepatocytes. Both proteins appear to play important roles in suppression of viral replication. We found that innate immunity against HCV is associated with the induction of apoptosis by RIG-I through the TRAIL pathway and the establishment of an antiviral state by TLR3. HCV envelope proteins interfere with the expression of TLR3 and RIG-I.These findings correlate with the lower expression level of PRRs in HCV chronic patients and highlight the importance of the PRRs in the initial interaction of the virus and its host cells. This work represents a novel mechanism of viral pathogenesis for HCV and demonstrates the role of PRRs in viral infection

Bone Marrow Mononuclear Cells Up-Regulate Toll-Like Receptor Expression and Produce Inflammatory Mediators in Response to Cigarette Smoke Extract

Several reports link cigarette smoking with leukemia. However, the effects of cigarette smoke extract (CSE) on bone marrow hematopoiesis remain unknown. The objective of this study was to elucidate the direct effects of cigarette smoke on human bone marrow hematopoiesis and characterize the inflammatory process known to result from cigarette smoking. Bone marrow mononuclear cells (BMCs) from healthy individuals when exposed to CSE had significantly diminished CFU-E, BFU-E and CFU-GM. We found increased nuclear translocation of the NF-κB p65 subunit and, independently, enhanced activation of AKT and ERK1/2. Exposure of BMCs to CSE induced IL-8 and TGF-β1 production, which was dependent on NF-κB and ERK1/2, but not on AKT. CSE treatment had no effect on the release of TNF-α, IL-10, or VEGF. Finally, CSE also had a significant induction of TLR2, TLR3 and TLR4, out of which, the up-regulation of TLR2 and TLR3 was found to be dependent on ERK1/2 and NF-κB activation, but not AKT. These results indicate that CSE profoundly inhibits the growth of erythroid and granulocyte-macrophage progenitors in the bone marrow. Further, CSE modulates NF-κB- and ERK1/2-dependent responses, suggesting that cigarette smoking may impair bone marrow hematopoiesis in vivo as well as induce inflammation, two processes that proceed malignant transformation

Lagrangian relaxation bounds for a production-inventory-routing problem

We consider a single item Production-Inventory-Routing problem with a single producer/supplier and multiple retailers. Inventory management constraints are considered both at the producer and at the retailers, following a vendor managed inventory approach, where the supplier monitors the inventory at retailers and decides on the replenishment policy for each retailer. We assume a constant production capacity. Based on the mathematical formulation we discuss a classical Lagrangian relaxation which allows to decompose the problem into four subproblems, and a new Lagrangian decomposition which decomposes the problem into just a production-inventory subproblem and a routing subproblem. The new decomposition is enhanced with valid inequalities. A computational study is reported to compare the bounds from the two approaches