Lipidomic Profile and Enzymes Activity in Hepatic Microsomes of Rats in Physiological and Pathological Conditions

Among the risk factors affecting the development of cancer, nutritional factors occupy a significant place. Pomegranate seed oil (PSO) and bitter melon extract (BME), used for ages in folk medicine, are nowadays used in the prevention of many diseases and as ingredients of dietary supplements. Despite numerous publications on these raw materials or their active substances, their mechanism of action in various pathological states has not been recognized yet, nor has the safety of their simultaneous use been evaluated. The study aimed to assess how dietary supplementation with either PSO, with BME, or both, affects fatty acids’ profiles and their metabolism in hepatic microsomes, as well as the activity of selected microsomal enzymes (COX-2 and CYP1B1). Experimental animals (Sprague-Dawley rats) were divided into eight parallel experimental groups, differing in applied dietary modifications (control, PSO, BME and both PSO and BME) and introduction of chemical carcinogen—7,12-dimethylbenz[a]nthracene. Obtained results indicated the pronounced effect of the cancerous process on lipid metabolism and demonstrated the antagonistic effect of applied dietary supplements on the content of individual fatty acids and the activity of CYP1B1 and COX-2. The applied broad analytical approach and chemometric data analysis confirmed that raw materials, for which potential cancer prevention has been previously demonstrated, may differ in effects depending on the coexisting pathological state.     

Fourier Transform Infrared Microspectroscopy Combined with Principal Component Analysis and Artificial Neural Networks for the Study of the Effect of β-Hydroxy-β-Methylbutyrate (HMB) Supplementation on Articular Cartilage

The potential of Fourier Transform infrared microspectroscopy (FTIR microspectroscopy) and multivariate analyses were applied for the classification of the frequency ranges responsible for the distribution changes of the main components of articular cartilage (AC) that occur during dietary β-hydroxy-β-methyl butyrate (HMB) supplementation. The FTIR imaging analysis of histological AC sections originating from 35-day old male piglets showed the change in the collagen and proteoglycan contents of the HMB-supplemented group compared to the control. The relative amount of collagen content in the superficial zone increased by more than 23% and in the middle zone by about 17%, while no changes in the deep zone were observed compared to the control group. Considering proteoglycans content, a significant increase was registered in the middle and deep zones, respectively; 62% and 52% compared to the control. AFM nanoindentation measurements collected from animals administered with HMB displayed an increase in AC tissue stiffness by detecting a higher value of Young’s modulus in all investigated AC zones. We demonstrated that principal component analysis and artificial neural networks could be trained with spectral information to distinguish AC histological sections and the group under study accurately. This work may support the use and effectiveness of FTIR imaging combined with multivariate analyses as a quantitative alternative to traditional collagenous tissue-related histology.     

Immunoprofiling: An Encouraging Method for Predictive Factors Examination in Lung Cancer Patients Treated with Immunotherapy

The efficiency of immunotherapy using monoclonal antibodies that inhibit immune checkpoints has been proven in many clinical studies and well documented by numerous registration approaches. To date, PD-L1 expression on tumor and immune cells, tumor mutation burden (TMB), and microsatellite instability (MSI) are the only validated predictive factors used for the qualification of cancer patients for immunotherapy. However, they are not the ideal predictive factors. No response to immunotherapy could be observed in patients with high PD-L1 expression, TMB, or MSI. On the other hand, the effectiveness of this treatment method also may occur in patients without PD-L1 expression or with low TMB and with microsatellite stability. When considering the best predictive factor, we should remember that the effectiveness of immunotherapy relies on an overly complex process depending on many factors. To specifically stimulate lymphocytes, not only should their activity in the tumor microenvironment be unlocked, but above all, they should recognize tumor antigens. The proper functioning of the anticancer immune system requires the proper interaction of many elements of the specific and non-specific responses. For these reasons, a multi-parameter analysis of the immune system at its different activity levels is considered a very future-oriented predictive marker. Such complex immunological analysis is performed using modern molecular biology techniques. Based on the gene expression studies, we can determine the content of individual immune cells within the tumor, its stroma, and beyond. This includes all cell types from active memory cytotoxic T cells, M1 macrophages, to exhausted T cells, regulatory T cells, and M2 macrophages. In this article, we summarize the possibilities of using an immune system analysis to predict immunotherapy efficacy in cancer patients. Moreover, we present the advantages and disadvantages of immunoprofiling as well as a proposed future direction for this new method of immune system analysis in cancer patients who receive immunotherapy.     

Individual- and trial-level surrogacy in colorectal cancer

Two conditions must be fulfilled for an intermediate endpoint to be an acceptable surrogate for a true clinical endpoint: (1) there must be a strong association between the surrogate and the true endpoint, and (2) there must be a strong association between the effects of treatment on the surrogate and the true endpoint. We test whether these conditions are fulfilled for disease-free survival (DFS) and progression-free survival (PFS) on data from 20 clinical trials comparing experimental treatments with standard treatments for early and advanced colorectal cancer. The effects of treatment on DFS (or PFS in advanced disease) and OS were quantified through log hazard ratios (log HR), estimated through a Weibull model stratified for trial. The rank correlation coefficients between DFS and OS, and trial-specific treatment effects, were estimated using a bivariate copula distribution for these endpoints. A linear regression model between the estimated log hazard ratios was used to compute the "surrogate threshold effect", which is the minimum treatment effect on DFS required to predict a non-zero treatment effect on OS in a future trial. In early disease, the rank correlation coefficient between DFS and OS was equal to 0.96 (CI 0.95-0.97). The correlation coefficient between the log hazard ratios was equal to 0.94 (CI 0.87-1.01). The risk reductions were approximately 3% smaller on OS than on DFS, and the surrogate threshold effect corresponded to a DFS hazard ratio of 0.93. In advanced disease, the rank correlation coefficient between PFS and OS was equal to 0.82 (CI 0.82-0.83). The correlation coefficient between the log hazard ratios was equal to 0.99 (CI 0.94-1.04). The risk reductions were approximately 19% smaller on OS than on PFS, and the surrogate threshold effect corresponded to a PFS hazard ratio of 0.86. One trial with a large treatment effect on PFS and OS had a strong influence on the results in advanced disease. DFS (and PFS in advanced disease) are acceptable surrogates for OS in colorectal cancer.     

Prototype sodium polybutadiene and poly(butadiene-styrene) batteries

The conductive properties of butadiene polymer (BR) and styrene-butadiene polymer (SBR) with sodium chlorate (VII) can be used at industrial scale as miniature batteries. Polymer material modified with sodium chlorate (VII) was used to produce sodium polybutadiene and poly(styrene-butadiene) batteries. The conductivity of such polymer composites for temperatures ranging 243–313 K is at a similar level and amounts to 10⁻⁴ S cm⁻¹ for butadiene polymer and to 10⁻³ S cm⁻¹ for styrene-butadiene polymer at 100 kHz. The conductive battery made of butadiene polymer shows a open circuit voltage of 0.9 V with a short-circuit current of 40 mA, whereas that made of styrene-butadiene polymer shows a open circuit voltage of 1.2 V with a short-circuit current of 38 mA. The lightness, commonly found material (sodium), and environment-friendly energy are main advantages of sodium polybutadiene and poly(styrene-butadiene) batteries.     

Epoxy compositions cured with aluminosilsesquioxanes: Thermomechanical properties

The aim of this study was to verify the influence of bis(heptaphenylaluminosilsesquioxane) (AlPOSS), used as a curing agent, on the thermomechanical properties of epoxy resin. Moreover, various curing conditions were taken into account. Epoxy casts were prepared from epoxy resin based on bisphenol A cured with different amounts of bis(heptaphenylaluminosilsesquioxane). The thermomechanical properties were investigated during dynamical mechanical thermal analysis (DMTA) in two cycles of heating. The storage modulus G′ of the epoxy casts was found to be higher in comparison to the reference epoxy sample and significantly dependent on the POSS content. A correlation between the glass transition temperatures (T_g), the curing conditions and the amount of curing agents were closely related. The occurrence of the crosslinking process in epoxy matrix was proved by the FTIR spectroscopy. The structure of the epoxy casts was investigated using scanning electron microscopy (SEM). © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40672.     

UV Differentially Induces Oxidative Stress,DNA Damage and Apoptosis in BCR-ABL1-Positive Cells Sensitive and Resistant to Imatinib

Chronic myeloid leukemia (CML) cells express the active BCR-ABL1 protein, which has been targeted by imatinib in CML therapy, but resistance to this drug is an emerging problem. BCR-ABL1 induces endogenous oxidative stress promoting genomic instability and imatinib resistance. In the present work, we investigated the extent of oxidative stress, DNA damage, apoptosis and expression of apoptosis-related genes in BCR-ABL1 cells sensitive and resistant to imatinib. The resistance resulted either from the Y253H mutation in the BCR-ABL1 gene or incubation in increasing concentrations of imatinib (AR). UV irradiation at a dose rate of 0.12 J/(m²·s) induced more DNA damage detected by the T4 pyrimidine dimers glycosylase and hOGG1, recognizing oxidative modifications to DNA bases in imatinib-resistant than -sensitive cells. The resistant cells displayed also higher susceptibility to UV-induced apoptosis. These cells had lower native mitochondrial membrane potential than imatinib-sensitive cells, but UV-irradiation reversed that relationship. We observed a significant lowering of the expression of the succinate dehydrogenase (SDHB) gene, encoding a component of the complex II of the mitochondrial respiratory chain, which is involved in apoptosis sensing. Although detailed mechanism of imatinib resistance in AR cells in unknown, we detected the presence of the Y253H mutation in a fraction of these cells. In conclusion, imatinib-resistant cells may display a different extent of genome instability than their imatinib-sensitive counterparts, which may follow their different reactions to both endogenous and exogenous DNA-damaging factors, including DNA repair and apoptosis.