A novel quinoline,MT477: suppresses cell signaling through Ras molecular pathway,inhibits PKC activity,and demonstrates in vivo anti-tumor activity against human carcinoma cell lines

MT477 is a novel thiopyrano[2,3-c]quinoline that has been identified using molecular topology screening as a potential anticancer drug with a high activity against protein kinase C (PKC) isoforms. The objective of the present study was to determine the mechanism of action of MT477 and its activity against human cancer cell lines. MT477 interfered with PKC activity as well as phosphorylation of Ras and ERK1/2 in H226 human lung carcinoma cells. It also induced poly-caspase-dependent apoptosis. MT477 had a dose-dependent (0.006 to 0.2 mM) inhibitory effect on cellular proliferation of H226, MCF-7, U87, LNCaP, A431 and A549 cancer cell lines as determined by in vitro proliferation assays. Two murine xenograft models of human A431 and H226 lung carcinoma were used to evaluate tumor response to intraperitoneal administration of MT477 (33 microg/kg, 100 microg/kg, and 1 mg/kg). Tumor growth was inhibited by 24.5% in A431 and 43.67% in H226 xenografts following MT477 treatment, compared to vehicle controls (p < 0.05). In conclusion, our empirical findings are consistent with molecular modeling of MT477's activity against PKC. We also found, however, that its mechanism of action occurs through suppressing Ras signaling, indicating that its effects on apoptosis and tumor growth in vivo may be mediated by Ras as well as PKC. We propose, therefore, that MT477 warrants further development as an anticancer drug.     

The Influence of Annealing on the Optical Properties and Microstructure Recrystallization of the TiO2 Layers Produced by Means of the E-BEAM Technique

Titanium dioxide films, about 200 nm in thickness, were deposited using the e-BEAM technique at room temperature and at 227 °C (500K) and then annealed in UHV conditions (as well as in the presence of oxygen (at 850 °C). The fabricated dielectric films were examined using X-ray powder diffraction, Raman spectroscopy, X-ray photoelectron spectroscopy, atomic force microscopy, scanning electron microscopy, transmission electron microscopy, and spectroscopic ellipsometry. The applied experimental techniques allowed us to characterize the phase composition and the phase transformation of the fabricated TiO₂ coatings. The films produced at room temperature are amorphous but after annealing consist of anatase crystallites. The layers fabricated at 227 °C contain both anatase and rutile phases. In this case the anatase crystallites are accumulated near the substrate interface whilst the rutile crystallites were formed closer to the surface of the TiO₂ film. It should be emphasized that these two phases of TiO₂ are distinctly separated from each other.     

Rheological Relaxation of OSB Beams Reinforced with CFRP Composites

An experimental and analytical approach to the relaxation problem of wood-based materials—OSB (Oriented Strand Boards—pressed wood-based composite panels) beams, including beams with CFRP (Carbon fiber reinforced polymer) tape composite reinforcement, is presented. It is a relevant engineering and scientific problem due to the fact that wood and wood-based materials, as well as composite reinforcements, are widely used in building constructions. Their rheological properties are very important and complicated to estimate. A 10 day long relaxation test of thick OSB beams without reinforcement and with CFRP tape was performed. A four-point bending test with five different bending levels was performed, during which the reduction of the loading force was measured. A five-parameter rheological model was used to describe the rheology of the beams. The equations of this model were calculated with the use of Laplace transform, whereas the values of the parameters were calculated based on the experimental relaxation curves. A high correlation between experimental and theoretical results was obtained. A beam reinforced with CFRP tape was treated as a system with a viscoelastic element (OSB) and an elastic element (CFRP), joined together without the possibility of slipping. The equations of the mathematical model were calculated based on the assumptions of the linear theory of viscoelasticity and the convolution integral. A good correlation between experimental and theoretical results was obtained. A significant redistribution of stresses was observed during the relaxation of the reinforced beam. The reinforced beams show a higher stiffness of approximately 63% and carry proportionally higher loads than unreinforced beams at the same deflection values.     

Material Model Effect for Simulating a Single-Lap Joint with a Blind Rivet

This paper concerns the influence of the material modeling method on the results of strength analyses. The research object was a single lap joint with a blind rivet (ISO 12996). The results of numerical strength analysis for various configurations of material models with material and contact nonlinearity were compared not only with the experimental results of such a connection but also with the values estimated using classical analytical tools (pressure stress and Hertz stress). The research aimed to determine how the results of numerical analyses (FEMs) were influenced by the method of modeling the material model and how it relates to the experimental results. As part of the analyses, a discrete riveted model and material models were constructed. The analyses took into account various load cases (from 10 to 90% of the connection capacity) to better illustrate the relationship between the numerical and experimental results. As a result of the conducted analyses, it was determined that the linear-elastic model was an acceptable and suggested solution (with a load of up to 90% of the load capacity of the joint connection) for further tests. The work was summarized with general and specific conclusions relating to all cases of numerical modeling. In addition, the summary includes suggestions for future works.     

An Investigation into the Effect of Electro-Contact Heating in the Machining of Low-Rigidity Thin-Walled Micro-Machine Parts

Low-rigidity thin-walled parts are components of many machines and devices, including high precision electric micro-machines used in control and tracking systems. Unfortunately, traditional machining methods used for machining such types of parts cause a significant reduction in efficiency and in many cases do not allow obtaining the required accuracy parameters. Moreover, they also fail to meet modern automation requirements and are uneconomical and inefficient. Therefore, the aim of provided studies was to investigate the dependency of cutting forces on cutting parameters and flank wear, as well as changes in cutting forces induced by changes in heating current density and machining parameters during the turning of thin-walled parts. The tests were carried out on a specially designed and constructed turning test stand for measuring cutting forces and temperature at specific cutting speed, feed rate, and depth of cut values. As part of the experiments, the effect of cutting parameters and flank wear on cutting forces, and the effect of heating current density and turning parameters on changes in cutting forces were analyzed. Moreover, the effect of cutting parameters (depth of cut, feed rate, and cutting speed) on temperature has been determined. Additionally, a system for controlling electro-contact heating and investigated the relationship between changes in cutting forces and machining time in the operations of turning micro-machine casings with and without the use of the control system was developed. The obtained results show that the application of an electro-contact heating control system allows to machine conical parts and semi-finished products at lower cutting forces and it leads to an increase in the deformation of the thin-walled casings caused by runout of the workpiece.     

Hepatitis and the polyglandular autoimmune syndrome,type 1

Autoimmune polyglandular syndrome, type 1 (APS-1) is a rare syndrome. Here we present a case report of a 24-year-old female patient who complained of progressive weakness. While autoimmune hepatitis was diagnosed, no improvement of biochemical parameters was obtained after immunosuppressive treatment. Hypoparathyroidism and adrenocortical failure were identified. Her health status clearly improved once proper control of the calcium-phosphate metabolism was obtained and after the administration of substitution hydrocortisone doses, leading to full normalization of biochemical liver tests. The reported case illustrates a rare form of APS-1 failure, in which the diagnosed autoimmune hepatitis was only the first symptom.     

17β-estradiol and tamoxifen prevent gastric cancer by modulating leukocyte recruitment and oncogenic pathways in Helicobacter pylori-infected INS-GAS male mice

Helicobacter pylori infection promotes male predominant gastric adenocarcinoma in humans. Estrogens reduce gastric cancer risk and previous studies showed that prophylactic 17β-estradiol (E2) in INS-GAS mice decreases H. pylori-induced carcinogenesis. We examined the effect of E2 and tamoxifen (TAM) on H. pylori-induced gastric cancer in male and female INS-GAS mice. After confirming robust gastric pathology at 16 weeks postinfection (WPI), mice were implanted with E2, TAM, both E2 and TAM, or placebo pellets for 12 weeks. At 28 WPI, gastric histopathology, gene expression, and immune cell infiltration were evaluated and serum inflammatory cytokines measured. After treatment, no gastric cancer was observed in H. pylori-infected males receiving E2 and/or TAM, whereas 40% of infected untreated males developed gastric cancer. E2, TAM, and their combination significantly reduced gastric precancerous lesions in infected males compared with infected untreated males (P < 0.001, 0.01, and 0.01, respectively). However, TAM did not alter female pathology regardless of infection status. Differentially expressed genes from males treated with E2 or TAM (n = 363 and n = 144, Q < 0.05) associated highly with cancer and cellular movement, indicating overlapping pathways in the reduction of gastric lesions. E2 or TAM deregulated genes associated with metastasis (PLAUR and MMP10) and Wnt inhibition (FZD6 and SFRP2). Compared with controls, E2 decreased gastric mRNA (Q < 0.05) and serum levels (P < 0.05) of CXCL1, a neutrophil chemokine, leading to decreased neutrophil infiltration (P < 0.01). Prevention of H. pylori-induced gastric cancer by E2 and TAM may be mediated by estrogen signaling and is associated with decreased CXCL1, decreased neutrophil counts, and downregulation of oncogenic pathways.     

TRAIL protein expression in breast cancer cells correlates with nuclear grade

Introduction

TRAIL protein may serve as an escape mechanism for cancer cells from the immune response. The aim of the study was to assess whether the presence of TRAIL protein correlates with unfavourable prognostic factors in breast carcinoma.

Material and methods

The study group was composed of breast cancer patients treated surgically in the Department of Surgical Oncology, Medical University of Lodz, Poland, from January to December 2003. Inclusion criteria for the study were fulfilled by 117 women. The immunohistochemical study of TRAIL protein expression was performed in 118 breast carcinomas diagnosed in the study group. TRAIL protein expression was correlated with other variables: tumour size, lymph node status, grade, histological type of carcinoma, oestrogen and progesterone receptor status, HER2 expression, presence of lymphovascular invasion and age of the patient.

Results

Expression of TRAIL protein was present in 73% of breast carcinomas. The percentage of TRAIL-expressing breast carcinoma cells correlated with the nuclear grade (τ = 0.26, p < 0.05; Tau Kendall test). The intensity of TRAIL expression (intensity of staining) in breast carcinoma cells correlated with the nuclear grade (τ = 0.15, p < 0.05; Tau Kendall test). TRAIL expression in breast carcinoma did not correlate with other studied variables.

Conclusions

Our analysis revealed that expression of TRAIL protein in breast carcinoma cells correlates with nuclear grade of carcinoma.