Heterogeneity of Adenosine Triphosphate-Based Chemotherapy Response Assay in Colorectal Cancer - Secondary Publication

PURPOSE: Adenosine triphosphate-based chemotherapy response assay (ATP-CRA) is a well-documented and validated technology that can individualize chemotherapy for patients with lung, stomach, or breast cancer. This study explored the feasibility of ATP-CRA as a chemosensitivity test in patients with colorectal cancer. MATERIALS AND METHODS: A total of 118 patients who underwent surgical resection for colorectal adenocarcinoma were analyzed for chemosensitivity to 6 anticancer drugs using ATP-CRA. We calculated the cell death rate (CDR) by measuring intracellular ATP levels of drug-exposed cells and untreated controls. RESULTS: Interpretable results were available for 85.5% (118/138) of patients. The mean coefficient of variation for triplicate ATP measurements was 9.2%. The highest CDR was observed in irinotecan (34.0%) and the lowest CDR in etoposide (21.0%). Paclitaxel had the broadest range of CDR (0-86.7%) and 5-FU had the narrowest range of CDR (0-56.8%). The overall highest responsiveness was seen most prevalently in irinotecan (24.7%, 23/93 patients). Irinotecan had the greatest responsiveness in patients with well differentiated and moderately differentiated carcinoma. CONCLUSION: Our study suggests that ATP-CRA could be used to identify patients with colorectal cancer who might benefit from treatment with a specific chemotherapeutic agent.ope

Calpain-mediated proteolysis of polycystin-1 C-terminus induces JAK2 and ERK signal alterations

AbstractAutosomal dominant polycystic kidney disease (ADPKD), a hereditary renal disease caused by mutations in PKD1 (85%) or PKD2 (15%), is characterized by the development of gradually enlarging multiple renal cysts and progressive renal failure. Polycystin-1 (PC1), PKD1 gene product, is an integral membrane glycoprotein which regulates a number of different biological processes including cell proliferation, apoptosis, cell polarity, and tubulogenesis. PC1 is a target of various proteolytic cleavages and proteosomal degradations, but its role in intracellular signaling pathways remains poorly understood. Herein, we demonstrated that PC1 is a novel substrate for μ- and m-calpains, which are calcium-dependent cysteine proteases. Overexpression of PC1 altered both Janus-activated kinase 2 (JAK2) and extracellular signal-regulated kinase (ERK) signals, which were independently regulated by calpain-mediated PC1 degradation. They suggest that the PC1 function on JAK2 and ERK signaling pathways might be regulated by calpains in response to the changes in intracellular calcium concentration

KIOM-4 Protects against Oxidative Stress-Induced Mitochondrial Damage in Pancreatic β-cells via Its Antioxidant Effects

The protective effect of KIOM-4, a mixture of plant extracts, was examined against streptozotocin (STZ)-induced mitochondrial oxidative stress in rat pancreatic β-cells (RINm5F). KIOM-4 scavenged superoxide and hydroxyl radicals generated by xanthine/xanthine oxidase and Fenton reaction (FeSO4/H2O2), respectively, in a cell-free chemical system. In addition, a marked increase in mitochondrial reactive oxygen species (ROS) was observed in STZ-induced diabetic cells; this increase was attenuated by KIOM-4 treatment. Mitochondrial manganese superoxide dismutase (Mn SOD) activity and protein expression were down-regulated by STZ treatment and up-regulated by KIOM-4 treatment. In addition, NF-E2 related factor 2 (Nrf2), a transcription factor for Mn SOD, was up-regulated by KIOM-4. KIOM-4 prevented STZ-induced mitochondrial lipid peroxidation, protein carbonyl and DNA modification. Moreover, KIOM-4 treatment restored the loss of mitochondrial membrane potential (Δψ) that was induced by STZ treatment, and inhibited the translocation of cytochrome c from the mitochondria to the cytosol. In addition, KIOM-4 treatment elevated the level of ATP, succinate dehydrogenase activity and insulin level, which were reduced by STZ treatment. These results suggest that KIOM-4 exhibits a protective effect through its antioxidant effect and the attenuation of mitochondrial dysfunction in STZ-induced diabetic cells

In-situ analysis of fiber structure development for isotactic polypropylene

Structural development of isotactic polypropylene (iPP) fibers was analyzed in real time through in-situ WAXD/SAXS and fiber temperature measurements during CO(2) laser-heated drawing because the CO(2) laser irradiation can nearly fix the necking position on the running fiber. The in-situ WAXD/SAXS measurements were carried out with a high time-resolution of 0.4 ms. The as-spun iPP fibers of two different initial structures were laser-heat-drawn to a draw ratio of 6.5. For the drawing of PP fiber containing mesophase structure, diffraction from the oriented mesophase remained until an elapsed time of 1.0 ms, when oriented alpha-phase crystal started to form. Meanwhile, for the drawing of PP fiber containing both an alpha-phase and a mesophase structure, fragmented microcrystals were reorganized by orientation-induced crystallization before an elapsed time of 1.0 ms. The long period increased drastically with fragmentation, and decreased with reorganization. The long period was about 16 nm for both drawn fibers.ArticlePOLYMER. 52(9):2044-2050 (2011)journal articl

Effect of drawing stress on mesophase structure formation of poly(ethylene 2,6-naphthalene dicarboxylate) fiber just after the neck-drawing point

The structural development of poly(ethylene 2,6-naphthalene dicarboxylate) (PEN) fibers was analyzed by in situ X-ray diffraction and fiber temperature measurements. The PEN fiber was drawn continuously under three drawing stresses, where the neck-drawing point was fixed accurately by CO2 laser irradiation heating. The developed crystal structures of the drawn fibers depended on the drawing stresses, that is, only the alpha-crystal was obtained under a drawing stress of 148 MPa, an alpha-rich mixed crystal was obtained for 54 MPa, and a beta-rich mixed crystal was obtained under 23 MPa stress. Fiber containing over 70% beta-crystal was obtained in the third case. Orientation-induced crystallization rates (K) and crystallization induction times (t(0)) were estimated for the three drawing stresses: K = 2210 s(-1) and t(0) = 0.5 ms for 148 MPa, K = 940 s(-1) and t(0) = 1.0 ms for 54 MPa, and K= 655 s(-1) and t(0) = 4.0 ms for 23 MPa. In addition, the drawing stress acted as a definitive influence not only on the resulting crystal form but also on the chain conformation of the mesophase structure. The d-spacing of the (001') diffraction increased with drawing stress, and the longer (001') spacing generated the alpha-crystal while the comparatively shorter (001') spacing yielded the beta-crystal. The d-spacings of 1.27 and 1.23 nm for the drawing stresses of 148 and 23 MPa, respectively, were somewhat shorter than the c-axis lengths of the alpha- and beta-crystals of 1.32 and 1.27 nm, respectively.ArticlePOLYMER. 53(19):4272-4279 (2012)journal articl

Experimental Study on the Acellular Demal Matrix Graft for the Root Coverage in Dog

Mucogingival surgery is a plastic surgical procedure designed to correct defects in the morphology, position, and dimensions of the gingiva surrounding the teeth. Many surgical techniques have been reported in mucogingival surgery. Since these procedures also include the soft tissue esthetic approach, the term periodontal plastic surgery has been proposed to be more appropriate.1 Root coverage is a procedure that falls with this definition, and it has attracted more interest than others

Retrospective Analysis of Peripheral Blood Stem Cell Transplantation for the Treatment of High-Risk Neuroblastoma

Disease relapse after autologous peripheral blood stem cell transplantation (APBSCT) is the main cause of treatment failure in high-risk neuroblastoma (NBL). To reduce relapse, various efforts have been made such as CD34+ selection and double APBSCT. Here the authors reviewed the clinical features and outcomes of high-risk NBL patients and analyzed their survival. The medical records of 36 patients with stage III or IV NBL who underwent APBSCT at Seoul National University Children's Hospital between May 1996 and May 2004 were reviewed. Total 46 APBSCTs were performed in 36 patients. Disease free survival (DFS) and overall survival of all patients were 47.7% and 68.8%, respectively. The patients were allocated to three groups according to the APBSCT type. The DFS of CD34+ non-selected single APBSCT patients (N=13), CD34+ selected single APBSCT patients (N=14), and CD34+ selected double APBSCT patients (N=9) were 55.6%, 40.6%, and 50.0%, respectively, which were not significantly different. Thus the survival was not found to be affected by CD34+ selection or transplantation number. To improve long-term survival, various efforts should be made such as chemotherapy dose intensification, more effective tumor purging, and control of minimal residual disease via the use of differentiating and immune-modulating agents

Development of a fiber structure in poly(vinylidene fluoride) by a CO(2) laser-heated drawing process

Rapid and uniform heating by CO(2) laser radiation can fix the position where necking occurs. Therefore, this study investigated the development of a fiber structure in poly(vinylidene fluoride) in continuous drawing by in situ measurement using synchrotron X-ray radiation with a time resolution of several hundred microseconds. Two neck-deformation behaviors were observed in the laser drawing: a moderate neck deformation under low drawing stress and a steep neck deformation under high drawing stress. The low drawing stress resulted in a mixture of alpha- and beta-crystals in which the beta-crystal was formed within 1ms after the necking, earlier than the alpha-crystal. The development of the fiber structure under high drawing stress was almost complete in less than 1 ms, and the developed structure contained only beta-crystals. Small-angle X-ray scattering images showed meridional streaks at low drawing stress, whereas a four-pointed pattern occurred under high drawing stress. Low drawing stress generated a long periodic structure that was defective in the periodic regularity of crystalline and amorphous regions, although the molecular chains were nearly oriented along the fiber axis. The high drawing stress resulted in a well-packed structure of adjacent fibrils with alternating amorphous and crystalline regions. Polymer Journal (2010) 42, 657-662; doi: 10.1038/pj.2010.53; published online 23 June 2010ArticlePOLYMER JOURNAL. 42(8):657-662 (2010)journal articl

Radionuclide Labeling and Evaluation of Candidate Radioligands for PET Imaging of Histone Deacetylase in the Brain

Histone deacetylases (HDACs) regulate gene expression by inducing conformational changes in chromatin. Ever since the discovery of a naturally occurring HDAC inhibitor, trichostatin A (TSA) stimulated the recent development of suberoylanilide (SAHA, Zolinza®), HDAC has become an important molecular target for drug development. This has created the need to develop specific in vivo radioligands to study epigenetic regulation and HDAC engagement for drug development for diseases including cancer and psychiatric disorders. 6-([18F]Fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) was recently developed as a HDAC substrate and shows moderate blood–brain barrier (BBB) permeability and specific signal (by metabolic trapping/or deacetylation) but rapid metabolism. Here, we report the radiosynthesis of two carbon-11 labeled candidate radiotracers (substrate- and inhibitor-based radioligand) for HDAC and their evaluation in non-human primate brain. PET studies showed very low brain uptake and rapid metabolism of both labeled compounds but revealed a surprising enhancement of brain penetration by F for H substitution when comparing one of these to [18F]FAHA. Further structural refinement is needed for the development of brain-penetrant, metabolically stable HDAC radiotracers and to understand the role of fluorine substitution on brain penetration.Chemistry and Chemical Biolog