CONTEXT For patients with cancer-related pain and their physicians, routine oncology visits are an opportunity to adjust the analgesic regimen and secure better pain control. However, treatment intensification occurs haphazardly in practice. OBJECTIVES To estimate the effect of patient-centered tailored education and coaching (TEC) on the likelihood of analgesic treatment adjustment during oncology visits, and in turn, the influence of treatment adjustment on subsequent cancer pain control, we studied patients enrolled in a randomized trial of TEC. METHODS Just before a scheduled oncology visit, 258 patients with at least moderate baseline pain received TEC or control; just after the same visit, they reported on whether the physician recommended a new pain medicine or a change in dose of an existing medicine. Pain severity and pain-related impairment were measured two, six, and 12 weeks later. RESULTS Patients assigned to TEC were more likely than controls to report a change in the analgesic treatment regimen (60% vs. 36%, P<0.01); significant effects persisted after adjustment for baseline pain, study site, and physician (adjusted odds ratio 2.61, 95% confidence interval 1.55, 4.40, P<0.01). In a mixed-effects repeated measures regression, analgesic change (but not TEC itself) was associated with a sustained decrease in pain severity (P<0.05). CONCLUSION TEC increases the likelihood of self-reported, physician-directed adjustments in analgesic prescribing, and treatment intensification is associated with better cancer pain outcomes.

Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, non-selective kinase inhibitor discovered in our previous screening study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1, but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a cellular study, 14 potently inhibited the growth of human leukemia cell line MV4-11, but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14.

Tissue infiltration of activated lymphocytes is a hallmark of transplant rejection and organ-specific autoimmune diseases. Migration and activation of lymphocytes depend on DOCK2, an atypical Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 does not contain Dbl homology domain typically found in guanine nucleotide exchange factors, DOCK2 mediates the GTP-GDP exchange reaction for Rac through its DHR-2 domain. Here, we have identified 4-[3'-(2″-chlorophenyl)-2'-propen-1'-ylidene]-1-phenyl-3,5-pyrazolidinedione (CPYPP) as a small-molecule inhibitor of DOCK2. CPYPP bound to DOCK2 DHR-2 domain in a reversible manner and inhibited its catalytic activity in vitro. When lymphocytes were treated with CPYPP, both chemokine receptor- and antigen receptor-mediated Rac activation were blocked, resulting in marked reduction of chemotactic response and T cell activation. These results provide a rational of and a chemical scaffold for development of the DOCK2-targeting immunosuppressant.

ABSTRACT: BACKGROUND: Glioblastoma is the most aggressive form of brain tumors showing resistance to treatment with various chemotherapeutic agents. The most effective way to eradicate glioblastoma requires the concurrent inhibition of multiple signaling pathways and target molecules involved in the progression of glioblastoma. Recently, we obtained a series of 1,2,3,4-tetrahydroisoquinoline alkaloids with potent anti-cancer activities, including ecteinascidin-770 (ET-770; the compound 1a) and renieramycin M (RM; the compound 2a) from Thai marine invertebrates, together with a 2'-N-4"-pyridinecarbonyl derivative of ET-770 (the compound 3). We attempted to characterize the molecular pathways responsible for cytotoxic effects of these compounds on a human glioblastoma cell line U373MG. METHODS: We studied the genome-wide gene expression profile on microarrays and molecular networks by using pathway analysis tools of bioinformatics. RESULTS: All of these compounds induced apoptosis of U373MG cells at nanomolar concentrations. The compound 3 reduced the expression of 417 genes and elevated the levels of 84 genes, while ET-770 downregulated 426 genes and upregulated 45 genes. RM decreased the expression of 274 genes and increased the expression of 9 genes. The set of 196 downregulated genes and 6 upregulated genes showed an overlap among all the compounds, suggesting an existence of the common pathways involved in induction of apoptosis. We identified the ErbB (EGFR) signaling pathway as one of the common pathways enriched in the set of downregulated genes, composed of PTK2, AKT3, and GSK3B serving as key molecules that regulate cell movement and the nervous system development. Furthermore, a GSK3B-specific inhibitor induced apoptosis of U373MG cells, supporting an anti-apoptotic role of GSK3B. CONCLUSION: Molecular network analysis is a useful approach not only to characterize the glioma-relevant pathways but also to identify the network-based effective drug targets.

Bunch-shaped ZnO nanowires film was successfully fabricated by the forced-hydrolysis-initiated-nucleation of anhydrous zinc acetate in an aqueous solution of zinc acetate and sodium hydroxide at low temperature. X-ray diffraction and a field emission scanning electron microscope clarified their formation mechanism and morphology development. The morphology was controllable by adjusting the solution temperature and deposition time. ZnO nanowires obtained at 65 degrees C for 6 h have a high aspect ratio of about 106. The smaller diameter with higher aspect ratio of ZnO nanowires, the easier the formation of bunch shapes by the capillary force during the drying process. This fabrication technique indicated that bunched ZnO film was prepared at low cost, and fittable to low heat-resistance substrates such as a polymer substarte.

We have developed a series of novel near-infrared (NIR) wavelength-excitable fluorescent dyes, SiR-NIRs, based on the Si-rhodamine scaffold. Among them, SiR680 and SiR700 showed sufficiently high quantum efficiency in aqueous media for in vivo fluorescence imaging. Both antibody-bound and free dye exhibited high tolerance to photobleaching in aqueous solution. Subcutaneous xenograft tumors were successfully visualized in a mouse tumor model using SiR700-labeled anti-tenascin-C (TN-C) antibody, SiR700-RCB1. SiR-NIRs are expected to be useful as labelling agents for in vivo imaging studies including multi-color imaging, and also as scaffolds for NIR fluorescence probes.

BACKGROUND Chaperone-mediated autophagy (CMA) is a selective autophagy-lysosome protein degradation pathway. The role of CMA in normal neuronal functions and in neural disease pathogenesis remains unclear, in part because there is no available method to monitor CMA activity at the single-cell level. METHODOLOGY/PRINCIPAL FINDINGS We sought to establish a single-cell monitoring method by visualizing translocation of CMA substrates from the cytosol to lysosomes using the HaloTag (HT) system. GAPDH, a CMA substrate, was fused to HT (GAPDH-HT); this protein accumulated in the lysosomes of HeLa cells and cultured cerebellar Purkinje cells (PCs) after labeling with fluorescent dye-conjugated HT ligand. Lysosomal accumulation was enhanced by treatments that activate CMA and prevented by siRNA-mediated knockdown of LAMP2A, a lysosomal receptor for CMA, and by treatments that inactivate CMA. These results suggest that lysosomal accumulation of GAPDH-HT reflects CMA activity. Using this method, we revealed that mutant γPKC, which causes spinocerebellar ataxia type 14, decreased CMA activity in cultured PCs. CONCLUSION/SIGNIFICANCE In the present study, we established a novel fluorescent-based method to evaluate CMA activity in a single neuron. This novel method should be useful and valuable for evaluating the role of CMA in various neuronal functions and neural disease pathogenesis.

Venous malformations are the most common cerebral vascular malformation, frequently associated with cavernous malformation, and rarely accompanied by a varix. We report the case of a 67-year-old woman with tinnitus, whose cranial magnetic resonance images and selective catheter angiograms showed extensive cerebellar venous malformation with cavernous malformations and varix. Injury of vessel walls by increased blood flow in the draining vein of the malformation may have led to the development of cavernous malformations and a varix. To our knowledge, such association with an extensive cerebellar venous malformation has not been reported.