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Inhibition of the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) increases the sensitivity of cancer cells to DNA damage by ionizing radiation (IR). We have developed a novel inhibitor of PNKP, i.e., A83B4C63, as a potential radio-sensitizer for the treatment of solid tumors. Systemic delivery of A83B4C63, however, may sensitize both cancer and normal cells to DNA damaging therapeutics. Preferential delivery of A83B4C63 to solid tumors by nanoparticles (NP) was proposed to reduce potential side effects of this PNKP inhibitor to normal tissue, particularly when combined with DNA damaging therapies. Here, we investigated the radio-sensitizing activity of A83B4C63 encapsulated in NPs (NP/A83) based on methoxy poly(ethylene oxide)-b-poly(α-benzyl carboxylate-ε-caprolactone) (mPEO-b-PBCL) or solubilized with the aid of Cremophor EL: Ethanol (CE/A83) in human HCT116 colorectal cancer (CRC) models. Levels of γ-H2AX were measured and the biodistribution of CE/A83 and NP/A83 administered intravenously was determined in subcutaneous HCT116 CRC xenografts. The radio-sensitization effect of A83B4C63 was measured following fractionated tumor irradiation using an image-guided Small Animal Radiation Research Platform (SARRP), with 24 h pre-administration of CE/A83 and NP/A83 to Luc+/HCT116 bearing mice. Therapeutic effects were analyzed by monitoring tumor growth and functional imaging using Positron Emission Tomography (PET) and [18F]-fluoro-3’-deoxy-3’-L:-fluorothymidine ([18F]FLT) as a radiotracer for cell proliferation. The results showed an increased persistence of DNA damage in cells treated with a combination of CE/A83 or NP/A83 and IR compared to those only exposed to IR. Significantly higher tumor growth delay in mice treated with a combination of IR and NP/A83 than those treated with IR plus CE/A83 was observed. [18F]FLT PET displayed significant functional changes for tumor proliferation for the drug-loaded NP. This observation was attributed to the higher A83B4C63 levels in the tumors for NP/A83-treated mice compared to those treated with CE/A83. Overall, the results demonstrated a potential for A83B4C63-loaded NP as a novel radio-sensitizer for the treatment of CRC.

The clinical use of 7-ethyl-10-hydroxy-camptothecin (SN-38), which is the active metabolite of irinotecan, has been hampered because of its practical water-insolubility. In this study, we successfully synthesized two self-associating SN-38-polymer drug conjugates to improve the water-solubility of SN-38, while retaining its anticancer activity. The polymeric micellar SN-38 conjugates were composed of either methoxy-poly(ethylene oxide)-block-poly(α-benzyl carboxylate-ε-caprolactone) conjugated to SN-38 at the PBCL end (mPEO-b-PBCL/SN-38) or mPEO-block-poly(α-carboxyl-ε-caprolactone) attached to SN-38 from the pendent-free carboxyl site (mPEO-b-PCCL/SN-38). The chemical structure of block copolymers was confirmed by 1H NMR. The physicochemical characterizations of their self-assembled structures including size, surface charge, polydispersity, critical micellar concentration, conjugation content and efficiency, morphology, kinetic stability, and in vitro release of SN-38 were compared between the two formulations. In vitro anticancer activities were evaluated by measuring cellular cytotoxicity and caspase activation by MTS and Caspase-Glo 3/7 assays, respectively. The hemolytic activity of both micellar structures against rat red blood cells was also measured. The results showed the formation of SN-38-polymeric micellar conjugates at diameters < 50 nm with a narrow size distribution and sustained release of SN-38 for both structures. The loading content of SN-38 in mPEO-b-PBCL and mPEO-b-PCCL were 11.47 ± 0.10 and 12.03 ± 0.17 (% w/w), respectively. The mPEO-b-PBCL/SN-38, end-capped micelles were kinetically more stable than mPEO-b-PCCL/SN-38. The self-assembled mPEO-b-PBCL/SN-38 and mPEO-b-PCCL/SN-38 micelles resulted in significantly higher cytotoxic effects than irinotecan against human colorectal cancer cell lines HCT116, HT-29, and SW20. The CRC cells were found to be 70-fold to 330-fold more sensitive to micellar SN-38 than irinotecan, on average. Both SN-38-incorporated micelles showed two-fold higher caspase-3/7 activation levels than irinotecan. The mPEO-b-PBCL/SN-38 micelles were not hemolytic, but mPEO-b-PCCL/SN-38 showed some hemolysis. The overall results from this study uphold mPEO-b-PBCL/SN-38 over mPEO-b-PCCL/SN-38 micellar formulation as an effective delivery system of SN-38 that warrants further preclinical investigation.

Many offline studies have explored the feasibility of EEG potentials related to single limb movements for a brain-computer interface (BCI) control signal. However, only few functional online single-trial BCI systems have been reported. We investigated whether inexperienced subjects could control a BCI accurately by means of visually-cued left versus right index finger movements, performed every 2 s, after only a 20-min training period. Ten subjects tried to move a circle from the center to a target location at the left or right side of the computer screen by moving their left or right index finger. The classifier was updated after each trial using the correct class labels, enabling up-to-date feedback to the subjects throughout the training. Therefore, a separate data collection session for optimizing the classification algorithm was not needed. When the performance of the BCI was tested, the classifier was not updated. Seven of the ten subjects were able to control the BCI well. They could choose the correct target in 84 %-100 % of the cases, 3.5-7.7 times a minute. Their mean single trial classification rate was 80% and bit rate 10 bits/min. These results encourage the development of BCIs for paralyzed persons based on detection of single-trial movement attempts. Index Terms--Brain-computer interface (BCI), electroencephalography, online training, single-trial classification.

An analysis of picture learning using whole-head magnetoencephalography technique reveals that the change from visual to symbolic representation proceeds bilaterally from the occipital visual cortex to the temporal and frontal lobes. The active naming process causes the most extensive cortical activation. Covert naming and passive viewing induce reactions from some language-related sites.

Sustainable management and conservation of the world's oceans requires effective monitoring, evaluation, and reporting (MER). Despite the growing political and social imperative for these activities, there are some persistent and emerging challenges that marine practitioners face in undertaking these activities. In 2015, a diverse group of marine practitioners came together to discuss the emerging challenges associated with marine MER, and potential solutions to address these challenges. Three emerging challenges were identified: (i) the need to incorporate environmental, social and economic dimensions in evaluation and reporting; (ii) the implications of big data, creating challenges in data management and interpretation; and (iii) dealing with uncertainty throughout MER activities. We point to key solutions to address these challenges across MER activities: (i) integrating models into marine management systems to help understand, interpret, and manage the environmental and socio-economic dimensions of uncertain and complex marine systems; (ii) utilizing big data sources and new technologies to collect, process, store, and analyze data; and (iii) applying approaches to evaluate, account for, and report on the multiple sources and types of uncertainty. These solutions point towards a potential for a new wave of evidence-based marine management, through more innovative monitoring, rigorous evaluation and transparent reporting. Effective collaboration and institutional support across the science- management-policy interface will be crucial to deal with emerging challenges, and implement the tools and approaches embedded within these solutions. [ABSTRACT FROM AUTHOR]