Palladin Mutation Causes Familial Pancreatic Cancer and Suggests a New Cancer Mechanism

BACKGROUND: Pancreatic cancer is a deadly disease. Discovery of the mutated genes that cause the inherited form(s) of the disease may shed light on the mechanism(s) of oncogenesis. Previously we isolated a susceptibility locus for familial pancreatic cancer to chromosome location 4q32–34. In this study, our goal was to discover the identity of the familial pancreatic cancer gene on 4q32 and determine the function of that gene. METHODS AND FINDINGS: A customized microarray of the candidate chromosomal region affecting pancreatic cancer susceptibility revealed the greatest expression change in palladin (PALLD), a gene that encodes a component of the cytoskeleton that controls cell shape and motility. A mutation causing a proline (hydrophobic) to serine (hydrophilic) amino acid change (P239S) in a highly conserved region tracked with all affected family members and was absent in the non-affected members. The mutational change is not a known single nucleotide polymorphism. Palladin RNA, measured by quantitative RT-PCR, was overexpressed in the tissues from precancerous dysplasia and pancreatic adenocarcinoma in both familial and sporadic disease. Transfection of wild-type and P239S mutant palladin gene constructs into HeLa cells revealed a clear phenotypic effect: cells expressing P239S palladin exhibited cytoskeletal changes, abnormal actin bundle assembly, and an increased ability to migrate. CONCLUSIONS: These observations suggest that the presence of an abnormal palladin gene in familial pancreatic cancer and the overexpression of palladin protein in sporadic pancreatic cancer cause cytoskeletal changes in pancreatic cancer and may be responsible for or contribute to the tumor's strong invasive and migratory abilities

Epigenetic Drugs Can Stimulate Metastasis through Enhanced Expression of the Pro-Metastatic Ezrin Gene

Ezrin has been reported to be upregulated in many tumors and to participate in metastatic progression. No study has addressed epigenetic modification in the regulation of Ezrin gene expression, the importance of which is unknown. Here, we report that highly metastatic rhabdomyosarcoma (RMS) cells with high levels of Ezrin have elevated acetyl-H3-K9 and tri-methyl-H3-K4 as well as reduced DNA methylation at the Ezrin gene promoter. Conversely, poorly metastatic RMS cells with low levels of Ezrin have reduced acetyl-H3-K9 and elevated methylation. Thus epigenetic covalent modifications to histones within nucleosomes of the Ezrin gene promoter are linked to Ezrin expression, which in fact can be regulated by epigenetic mechanisms. Notably, treatment with histone deacetylase (HDAC) inhibitors or DNA demethylating agents could restore Ezrin expression and stimulate the metastatic potential of poorly metastatic RMS cells characterized by low Ezrin levels. However, the ability of epigenetic drugs to stimulate metastasis in RMS cells was inhibited by expression of an Ezrin-specific shRNA. Our data demonstrate the potential risk associated with clinical application of broadly acting covalent epigenetic modifiers, and highlight the value of combination therapies that include agents specifically targeting potent pro-metastatic genes

Experimental Correlation of Combined Heat and Mass Transfer for NH 3 -H 2 0 falling film absorption

vection. The main conclusion from this study is that the negative concentration gradient of the surface tension is a trigger for inducement of Marangoni convection before the additive solubility, while the imbalance of the surface tension and the interfacial tension is a trigger after the solubility limit. Acknowledgment The authors thank Mr. K. Iizuka, Tokyo University of Agriculture and Technology, for his experimental assistance. The authors acknowledge that this work has been partially funded by the Japan Science and Technology Corporation (JST). References Beutler, A., Greiter, I., Wagner, A., Hohhmann, L., Schreier, S., and Alefeld, G., 1996, "Surfactants and Fluid Properties," Int. J. Refrigeration, Vol. 19, No. 5, pp. 342-346. Chavepeyer, G" Salajan, M., Platten, J. K., and Smet, P., 1995, "InterfacialTension and Surface Adsorption in j-Heptanol/Water Systems," Journal of Colloid and Interface Science, Vol. 174, Daiguji, H,, Hihara, E., and Saito, T., 1997, "Mechanism of Absorption Enhancement by Surfactant," Int. J. Heat and Mass Transfer, Vol. 40, No. 8, pp. 1743-1752. Fujita, T., 1993, "Falling Liquid Films in Absorption Machines," Int. J. Refrigeration, Vol. 16, No. 4, pp. 282-294. Hihara, E" and Saito, T., 1993 Journal of Heat Transfer TL = temperature of the fluid far away from the plate t' = time t R = reference time u = velocity of the fluid UD = reference velocity at' = frequency X,, = distance of the transition point from the leading edge |3 = coefficient of volume expansion p = density e = amplitude (constant) 9 = nondimensional temperature u = nondimensional velocity i = y-i Introduction Transient laminar-free convection flow past an infinite vertical plate under different plate conditions was studied by many researchers. The first closed-form solutions for Prandtl number Pr = 1.0 in case of a step change in wall temperature with time was derived by Illingworth (1950) and for Pr # 1.0, he derived the solution in integral form. Siegel (1958) studied the unsteady freeconvection flow past a semi-infinite vertical plate under stepchange in wall temperature or surface heat flux by employing the momentum integral method. Experimental evidence for such a situation was presented by Goldstein and Eckert (1960). For a semi-infinite vertical plate, unsteady free-convection flow was studied analytically b

ABCB4 missense mutations D243A, K435T, G535D, I490T, R545C, and S978P significantly impair the lipid floppase and likely predispose to secondary pathologies in the human population

EJA was funded by Barts and the London Charity (award 458/1495). MN was funded by a Medical Research Council Centenary Award

TRNSYS Modelling of Solar Cooling Systems with Air-conditioning with Separated Sensible and Latent Heat Treatment

The objective of this study is to develop a simulation model for designing and evaluating solar cooling systems based on TRNSYS, a modelling tool for building equipment. The system is assumed to consist of solar collectors, an adsorption chiller, an absorption chiller, a desiccant air-conditioner and a boiler. The feature of the modelling in this study is that the air conditioning load in summer is separated into sensible cooling and latent cooling, where the dehumidification by desiccant air-conditioning is explicitly expressed. The desiccant air-conditioning system is operated with hot water from the solar collectors and chilled water from the adsorption chiller driven with solar thermal. The system consists of a total heat exchanging rotor and a desiccant rotor. A supercooling process with chilled water from the chillers is also incorporated to control the dehumidification. The operation of the solar cooling system was analysed by TRNSYS simulation taking into account the air conditioning load of a hospital in Japan. The system works to supply cooling and hot water in summer season while heating and hot water in winter season. The total contribution of solar thermal energy was evaluated from the viewpoint of reducing primary energy consumption

The performance analysis of a novel dual evaporator type three-bed adsorption chiller

10.1016/j.ijrefrig.2009.10.005International Journal of Refrigeration332276-285IJRF

Multi-bed regenerative adsorption chiller - improving the utilization of waste heat and reducing the chilled water outlet temperature fluctuation

10.1016/S0140-7007(99)00078-XInternational Journal of Refrigeration242124-136IJRF

Entropy generation analysis of two-bed, silica gel-water, non-regenerative adsorption chillers

10.1088/0022-3727/31/12/011Journal of Physics D: Applied Physics31121471-1477JPAP