Differences in PARP Inhibitors for the Treatment of Ovarian Cancer: Mechanisms of Action,Pharmacology, Safety,and Efficacy

Poly(ADP-ribose) polymerases (PARP) are proteins responsible for DNA damage detection and signal transduction. PARP inhibitors (PARPi) are able to interact with the binding site for PARP cofactor (NAD+) and trapping PARP on the DNA. In this way, they inhibit single-strand DNA damage repair. These drugs have been approved in recent years for the treatment of ovarian cancer. Although they share some similarities, from the point of view of the chemical structure and pharmacodynamic, pharmacokinetic properties, these drugs also have some substantial differences. These differences may underlie the different safety profiles and activity of PARPi.     

The Age-Sensitive Efficacy of Calorie Restriction on Mitochondrial Biogenesis and mtDNA Damage in Rat Liver

Calorie restriction (CR) is the most efficacious treatment to delay the onset of age-related changes such as mitochondrial dysfunction. However, the sensitivity of mitochondrial markers to CR and the age-related boundaries of CR efficacy are not fully elucidated. We used liver samples from ad libitum-fed (AL) rats divided in: 18-month-old (AL-18), 28-month-old (AL-28), and 32-month-old (AL-32) groups, and from CR-treated (CR) 28-month-old (CR-28) and 32-month-old (CR-32) counterparts to assay the effect of CR on several mitochondrial markers. The age-related decreases in citrate synthase activity, in TFAM, MFN2, and DRP1 protein amounts and in the mtDNA content in the AL-28 group were prevented in CR-28 counterparts. Accordingly, CR reduced oxidative mtDNA damage assessed through the incidence of oxidized purines at specific mtDNA regions in CR-28 animals. These findings support the anti-aging effect of CR up to 28 months. Conversely, the protein amounts of LonP1, Cyt c, OGG1, and APE1 and the 4.8 Kb mtDNA deletion content were not affected in CR-28 rats. The absence of significant differences between the AL-32 values and the CR-32 counterparts suggests an age-related boundary of CR efficacy at this age. However, this only partially curtails the CR benefits in counteracting the generalized aging decline and the related mitochondrial involvement.     

Expression of RCAS1 Correlates with Urothelial Bladder Cancer Malignancy

RCAS1 is a protein that participates in regulation of the tumor microenvironment and its immune responses, all in order to evade the immune system. The aim of this study was to analyze RCAS1 expression in urothelial bladder cancer cells (and in fibroblasts and macrophages of the tumor stroma) and its relationship with the histological pattern of malignancy. Eighty-three postcystectomy patients were enrolled. We analyzed the histological maturity (grade), progress (pT stage), tissue invasion type (TIT), nonclassic differentiation number (NDN), and the ability to metastasize (pN). The expression of RCAS1 protein was analyzed by immunohistochemistry. Indicators of histological malignancy were observed solely in association with the RCAS1 expression in cells in the border parts (BPs) of the tumor. Histological malignancy of the tumor, indicated by the pT and pN, and metastasis-free survival time, correlated significantly with RCAS1 expression in tumor neoplastic cells, whereas malignancy determined by grade, TIT, and NDN correlated with RCAS1 expression in fibroblasts and macrophages in the tumor microenvironment. These findings suggest that the increased RCAS1 expression depends on its cellular source and that RCAS1 expression itself is a component of various signaling pathways. The immune escape occurs within the tumor BPs, where the increase in the RCAS1 expression occurs within tumor cells and stromal cells in its microenvironment. We conclude that the histological pattern of tumor malignancy, indicated by grade, TIT, NDN, pT, and pN is a morphological indicator of immune escape.     

How Cells Communicate with Each Other in the Tumor Microenvironment: Suggestions to Design Novel Therapeutic Strategies in Cancer Disease

Connexin- and pannexin (Panx)-formed hemichannels (HCs) and gap junctions (GJs) operate an interaction with the extracellular matrix and GJ intercellular communication (GJIC), and on account of this they are involved in cancer onset and progression towards invasiveness and metastatization. When we deal with cancer, it is not correct to omit the immune system, as well as neglecting its role in resisting or succumbing to formation and progression of incipient neoplasia until the formation of micrometastasis, nevertheless what really occurs in the tumor microenvironment (TME), which are the main players and which are the tumor or body allies, is still unclear. The goal of this article is to discuss how the pivotal players act, which can enhance or contrast cancer progression during two important process: “Activating Invasion and Metastasis” and the “Avoiding Immune Destruction”, with a particular emphasis on the interplay among GJIC, Panx-HCs, and the purinergic system in the TME without disregarding the inflammasome and cytokines thereof derived. In particular, the complex and contrasting roles of Panx1/P2X7R signalosome in tumor facilitation and/or inhibition is discussed in regard to the early/late phases of the carcinogenesis. Finally, considering this complex interplay in the TME between cancer cells, stromal cells, immune cells, and focusing on their means of communication, we should be capable of revealing harmful messages that help the cancer growth and transform them in body allies, thus designing novel therapeutic strategies to fight cancer in a personalized manner.     

Elitist clonal selection algorithm for optimal choice of free knots in B-spline data fitting

Data fitting with B-splines is a challenging problem in reverse engineering for CAD/CAM, virtual reality, data visualization, and many other fields. It is well-known that the fitting improves greatly if knots are considered as free variables. This leads, however, to a very difficult multimodal and multivariate continuous nonlinear optimization problem, the so-called knot adjustment problem. In this context, the present paper introduces an adapted elitist clonal selection algorithm for automatic knot adjustment of B-spline curves. Given a set of noisy data points, our method determines the number and location of knots automatically in order to obtain an extremely accurate fitting of data. In addition, our method minimizes the number of parameters required for this task. Our approach performs very well and in a fully automatic way even for the cases of underlying functions requiring identical multiple knots, such as functions with discontinuities and cusps. To evaluate its performance, it has been applied to three challenging test functions, and results have been compared with those from other alternative methods based on AIS and genetic algorithms. Our experimental results show that our proposal outperforms previous approaches in terms of accuracy and flexibility. Some other issues such as the parameter tuning, the complexity of the algorithm, and the CPU runtime are also discussed.     

Efficacy of alpha-cypermethrin and thiamethoxam against Trogoderma granarium Everts (Coleoptera: Dermestidae) and Tenebrio molitor L. (Coleoptera: Tenebrionidae) on concrete

Laboratory bioassays were conducted to evaluate alpha-cypermethrin and thiamethoxam for the control of adults, small larvae and large larvae of the khapra beetle Trogoderma granarium, and the yellow mealworm beetle Tenebrio molitor, on concrete. Factors such as dose (0.025 and 0.1 mg alpha-cypermethrin or thiamethoxam/cm²), exposure interval (1, 3 and 7 d), and formulation (alpha-cypermethrin SC and thiamethoxam WG) were evaluated. Apart from immediate assessment at end of exposure, an assessment of delayed mortality was performed with the survivors of the 7-d exposure by removing them from the treated substrate and keeping them on untreated surfaces for 7 more days. After the 7-d exposure, more T. granarium adults were dead on dishes treated with alpha-cypermethrin than with thiamethoxam. Small larvae were generally less susceptible than adults. After 7 d, small larval mortality reached 64.4% for alpha-cypermethrin, while for thiamethoxam it was <6%. Large T. granarium larvae were more tolerant than the small ones. Delayed mortality of T. granarium adults was generally high for both insecticides and doses, and ranged between 43.3 and 63.3% of those that were still alive immediately after the 7-d treatment. For both larval categories, delayed mortality was higher for larvae that had been previously exposed to alpha-cypermethrin, than with thiamethoxam. For T. molitor, after the 7-d exposure, significantly more adults were dead on dishes treated with alpha-cypermethrin than with thiamethoxam. For small larvae mortality was 38.9% at the lowest thiamethoxam dose, but in the other cases ranged between 88.9 and 95.6%. In the case of large larvae, the overall mortality was low in all tested combinations. Regarding delayed mortality of this species, it remained at low levels, for both adults and small larvae. Our results indicate that T. molitor was more susceptible than T. granarium in both insecticides tested, but alpha-cypermethrin was more effective than thiamethoxam.     

化妆品功效评价(Ⅵ)——化妆品人体功效评价的实验设计

概述了化妆品人体功效评价实验设计的概念、基本要素和基本原则,介绍了常用实验设计类型和实验设计要点,提供了人体功效评价实验方案设计的思路,有助于提高研究者制定实验设计方案的水平。     

Change detection in synthetic aperture radar images based on unsupervised artificial immune systems

In this paper, we propose a novel change detection method for synthetic aperture radar images based on unsupervised artificial immune systems. After generating the difference image from the multitemporal images, we take each pixel as an antigen and build an immune model to deal with the antigens. By continuously stimulating the immune model, the antigens are classified into two groups, changed and unchanged. Firstly, the proposed method incorporates the local information in order to restrain the impact of speckle noise. Secondly, the proposed method simulates the immune response process in a fuzzy way to get an accurate result by retaining more image details. We introduce a fuzzy membership of the antigen and then update the antibodies and memory cells according to the membership. Compared with the clustering algorithms we have proposed in our previous works, the new method inherits immunological properties from immune systems and is robust to speckle noise due to the use of local information as well as fuzzy strategy. Experiments on real synthetic aperture radar images show that the proposed method performs well on several kinds of difference images and engenders more robust result than the other compared methods.