Radium-223 dichloride (radium-223, Xofigo), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study ...examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models.
Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized into groups (
= 12-17) based on lesion grade and/or serum PSA level and administered radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals. X-rays and serum samples were obtained biweekly. Soft tissue tumors were observed macroscopically at sacrifice. Tibiae were analyzed by gamma counter, micro-CT, autoradiography and histology.
Radium-223 inhibited tumor-induced osteoblastic bone growth and protected normal bone architecture, leading to reduced bone volume in LNCaP and abiraterone-resistant LuCaP 58 models. Furthermore, radium-223 resulted in lower PSA values and reduced total tissue and tumor areas, indicating that treatment constrains prostate cancer growth in bone. In addition, radium-223 suppressed abnormal bone metabolic activity as evidenced by decreased number of osteoblasts and osteoclasts and reduced level of the bone formation marker PINP. Mode-of-action studies revealed that radium-223 was deposited in the intratumoral bone matrix. DNA double-strand breaks were induced in cancer cells within 24 hours after radium-223 treatment, and PSA levels were significantly lower 72 hours after treatment, providing further evidence of the antitumor effects.
Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathologic bone formation in tumor microenvironment of osseous CRPC growth in mice.
.
Prebiotics, probiotics and synbiotics are dietary ingredients with the potential to influence health and mucosal and systemic immune function by altering the composition of the gut microbiota. In the ...present study, a candidate prebiotic (xylo-oligosaccharide, XOS, 8 g/d), probiotic (Bifidobacterium animalis subsp. lactis Bi-07, 109 colony-forming units (CFU)/d) or synbiotic (8 g XOS+109 CFU Bi-07/d) was given to healthy adults (25-65 years) for 21 d. The aim was to identify the effect of the supplements on bowel habits, self-reported mood, composition of the gut microbiota, blood lipid concentrations and immune function. XOS supplementation increased mean bowel movements per d (P= 0·009), but did not alter the symptoms of bloating, abdominal pain or flatulence or the incidence of any reported adverse events compared with maltodextrin supplementation. XOS supplementation significantly increased participant-reported vitality (P= 0·003) and happiness (P= 0·034). Lowest reported use of analgesics was observed during the XOS+Bi-07 supplementation period (P= 0·004). XOS supplementation significantly increased faecal bifidobacterial counts (P= 0·008) and fasting plasma HDL concentrations (P= 0·005). Bi-07 supplementation significantly increased faecal B. lactis content (P= 0·007), lowered lipopolysaccharide-stimulated IL-4 secretion in whole-blood cultures (P= 0·035) and salivary IgA content (P= 0·040) and increased IL-6 secretion (P= 0·009). XOS supplementation resulted in lower expression of CD16/56 on natural killer T cells (P= 0·027) and lower IL-10 secretion (P= 0·049), while XOS and Bi-07 supplementation reduced the expression of CD19 on B cells (XOS × Bi-07, P= 0·009). The present study demonstrates that XOS induce bifidogenesis, improve aspects of the plasma lipid profile and modulate the markers of immune function in healthy adults. The provision of XOS+Bi-07 as a synbiotic may confer further benefits due to the discrete effects of Bi-07 on the gut microbiota and markers of immune function.
Elderly adults have alterations in their gut microbiota and immune functions that are associated with higher susceptibility to infections and metabolic disorders. Probiotics and prebiotics, and their ...synbiotic combinations are food supplements that have been shown to improve both gut and immune function. The objective of this randomised, double-blind, placebo-controlled, cross-over human clinical trial was to study immune function and the gut microbiota in healthy elderly adults. Volunteers (n 37) consumed prebiotic galacto-oligosaccharides (GOS; 8 g/d), probiotic Bifidobacterium lactis Bi-07 (Bi-07; 109 colony-forming units/d), their combination (Bi-07 + GOS) and maltodextrin control (8 g/d) in four 3-week periods separated by 4-week wash-out periods. Immune function was analysed by determining the phagocytic and oxidative burst activity of monocytes and granulocytes, whole-blood response to lipopolysaccharide, plasma chemokine concentrations and salivary IgA levels. Gut microbiota composition and faecal SCFA content were determined using 16S ribosomal RNA fluorescence in situ hybridisation and HPLC, respectively. Primary statistical analyses indicated the presence of carry-over effects and thus measurements from only the first supplementation period were considered valid. Subsequent statistical analysis showed that consumption of Bi-07 improved the phagocytic activity of monocytes (P < 0·001) and granulocytes (P = 0·02). Other parameters were unchanged. We have for the first time shown that the probiotic Bi-07 may provide health benefits to elderly individuals by improving the phagocytic activity of monocytes and granulocytes. The present results also suggest that in the elderly, the effects of some probiotics and prebiotics may last longer than in adults.
The Self-Organizing Map (SOM) is a powerful neural network method for analysis and visualization of high-dimensional data. It maps nonlinear statistical dependencies between high-dimensional ...measurement data into simple geometric relationships on a usually two-dimensional grid. The mapping roughly preserves the most important topological and metric relationships of the original data elements and, thus, inherently clusters the data. The need for visualization and clustering occurs, for instance, in the analysis of various engineering problems. In this paper, the SOM has been applied in monitoring and modeling of complex industrial processes. Case studies, including pulp process, steel production, and paper industry axe described.
In this paper, we introduce a modeling approach called independent variable group analysis (IVGA) which can be used for finding an efficient structural representation for a given data set. The basic ...idea is to determine such a grouping for the variables of the data set that mutually dependent variables are grouped together whereas mutually independent or weakly dependent variables end up in separate groups. Computation of an IVGA model requires a combinatorial algorithm for grouping of the variables and a modeling algorithm for the groups. In order to be able to compare different groupings, a cost function which reflects the quality of a grouping is also required. Such a cost function can be derived, for example, using the variational Bayesian approach, which is employed in our study. This approach is also shown to be approximately equivalent to minimizing the mutual information between the groups. The modeling task is computationally demanding. We describe an efficient heuristic grouping algorithm for the variables and derive a computationally light nonlinear mixture model for modeling of the dependencies within the groups. Finally, we carry out a set of experiments which indicate that IVGA may turn out to be beneficial in many different applications.
Clustering of the self-organizing map Vesanto, J.; Alhoniemi, E.
IEEE transactions on neural networks,
05/2000, Letnik:
11, Številka:
3
Journal Article
The self-organizing map (SOM) is an excellent tool in exploratory phase of data mining. It projects input space on prototypes of a low-dimensional regular grid that can be effectively utilized to ...visualize and explore properties of the data. When the number of SOM units is large, to facilitate quantitative analysis of the map and the data, similar units need to be grouped, i.e., clustered. In this paper, different approaches to clustering of the SOM are considered. In particular, the use of hierarchical agglomerative clustering and partitive clustering using K-means are investigated. The two-stage procedure-first using SOM to produce the prototypes that are then clustered in the second stage-is found to perform well when compared with direct clustering of the data and to reduce the computation time.
Monitoring industrial processes using the self-organizing map Ahola, J.; Alhoniemi, E.; Simula, O.
SMCia/99 Proceedings of the 1999 IEEE Midnight - Sun Workshop on Soft Computing Methods in Industrial Applications (Cat. No.99EX269),
1999
Conference Proceeding
In this paper, three process monitoring methods based on the self-organizing map (SOM) are presented: trajectory display, fuzzy response and probabilistic response. These approaches are compared with ...each other and also demonstrated in two case studies: continuous pulping and hot rolling of steel strips.
PDF
