FGFR2 amplification in colorectal adenocarcinoma

FGFR2 is recurrently amplified in 5% of gastric cancers and 1%–4% of breast cancers; however, this molecular alteration has never been reported in a primary colorectal cancer specimen. Preclinical studies indicate that several FGFR tyrosine-kinase inhibitors (TKIs), such as AZD4547, have in vitro activity against the FGFR2-amplified colorectal cell line, NCI-H716. The efficacy of these inhibitors is currently under investigation in clinical trials for breast and gastric cancer. Thus, better characterizing colorectal tumors for FGFR2 amplification could identify a subset of patients who may benefit from FGFR TKI therapies. Here, we describe a novel FGFR2 amplification identified by clinical next-generation sequencing in a primary colorectal cancer. Further characterization of the tumor by immunohistochemistry showed neuroendocrine differentiation, similar to the reported properties of the NCI-H716 cell line. These findings demonstrate that the spectrum of potentially clinically actionable mutations detected by targeted clinical sequencing panels is not limited to only single-nucleotide polymorphisms and insertions/deletions but also to copy-number alterations.</jats:p

EFFECT OF INBREEDING ON LOIN AND FAT DEPTH IN HUNGARIAN LANDRACE PIGS

Pedigree and field test data - collected between 1997-2005 - were analyzed in a group of 68062 Hungarian Landrace pigs. The analysed traits were loin depth (LD), fat depth1 (FD1) and fat depth2 (FD2). In the present study inbreeding coefficients, pedigree completeness (complete generation equivalents) and inbreeding depression for LD, FD1 and FD2 were estimated. Increasing number of generations that were considered in the pedigree the estimated inbreeding coefficients did not change after the 5th generation, but pedigree completeness was continuously increasing. The estimated inbreeding depression for LD, FD1 and FD2 were different applying 5 different models but the magnitude of the differences was small. Increasing inbreeding coefficient by 10% caused LD decrease by 0.084 mm, the FD1 by 0.062 mm and did not affect FD2. It can be concluded that the estimated inbreeding depression was low and substantial depression can not be expected in the near future. However, the low level of inbreeding of the studied population can partly be explained by the short pedigrees. This suggests that Hungarian pig breeders may often import breeding animals or carry out herd replacements rather than apply within group selection

EFFECT OF INBREEDING ON LOIN AND FAT DEPTH IN HUNGARIAN LANDRACE PIGS

Pedigree and field test data - collected between 1997-2005 - were analyzed in a group of 68062 Hungarian Landrace pigs. The analysed traits were loin depth (LD), fat depth1 (FD1) and fat depth2 (FD2). In the present study inbreeding coefficients, pedigree completeness (complete generation equivalents) and inbreeding depression for LD, FD1 and FD2 were estimated. Increasing number of generations that were considered in the pedigree the estimated inbreeding coefficients did not change after the 5th generation, but pedigree completeness was continuously increasing. The estimated inbreeding depression for LD, FD1 and FD2 were different applying 5 different models but the magnitude of the differences was small. Increasing inbreeding coefficient by 10% caused LD decrease by 0.084 mm, the FD1 by 0.062 mm and did not affect FD2. It can be concluded that the estimated inbreeding depression was low and substantial depression can not be expected in the near future. However, the low level of inbreeding of the studied population can partly be explained by the short pedigrees. This suggests that Hungarian pig breeders may often import breeding animals or carry out herd replacements rather than apply within group selection

An adjustable law of motion for relativistic spherical shells

A classical and a relativistic law of motion for an advancing shell are deduced applying the thin layer approximation. A new parameter connected with the quantity of absorbed matter in the expansion is introduced; this allows of matching theory and observation.Comment: 15 pages, 10 figures and article in press; Central European Journal of Physics 201

Down-regulation of cell surface CXCR4 by HIV-1

<p>Abstract</p> <p>Background</p> <p>CXC chemokine receptor 4 (CXCR4), a member of the G-protein-coupled chemokine receptor family, can serve as a co-receptor along with CD4 for entry into the cell of T-cell tropic X4 human immunodeficiency virus type 1 (HIV-1) strains. Productive infection of T-lymphoblastoid cells by X4 HIV-1 markedly reduces cell-surface expression of CD4, but whether or not the co-receptor CXCR4 is down-regulated has not been conclusively determined.</p> <p>Results</p> <p>Infection of human T-lymphoblastoid cell line RH9 with HIV-1 resulted in down-regulation of cell surface CXCR4 expression. Down-regulation of surface CXCR4 correlated temporally with the increase in HIV-1 protein expression. CXCR4 was concentrated in intracellular compartments in H9 cells after HIV-1 infection. Immunofluorescence microscopy studies showed that CXCR4 and HIV-1 glycoproteins were co-localized in HIV infected cells. Inducible expression of HIV-1 envelope glycoproteins also resulted in down-regulation of CXCR4 from the cell surface.</p> <p>Conclusion</p> <p>These results indicated that cell surface CXCR4 was reduced in HIV-1 infected cells, whereas expression of another membrane antigen, CD3, was unaffected. CXCR4 down-regulation may be due to intracellular sequestering of HIV glycoprotein/CXCR4 complexes.</p

The significance of lipid composition for membrane activity: new concepts and ways of assessing function

In the last decade or so, it has been realised that membranes do not just have a lipid-bilayer structure in which proteins are embedded or with which they associate. Structures are dynamic and contain areas of heterogeneity which are vital for their formation. In this review, we discuss some of the ways in which these dynamic and heterogeneous structures have implications during stress and in relation to certain human diseases. A particular stress is that of temperature which may instigate adaptation in poikilotherms or appropriate defensive responses during fever in mammals. Recent data emphasise the role of membranes in sensing temperature changes and in controlling a regulatory loop with chaperone proteins. This loop seems to need the existence of specific membrane microdomains and also includes association of chaperone (heat stress) proteins with the membrane. The role of microdomains is then discussed further in relation to various human pathologies such as cardiovascular disease, cancer and neurodegenerative diseases. The concept of modifying membrane lipids (lipid therapy) as a means for treating such pathologies is then introduced. Examples are given when such methods have been shown to have benefit. In order to study membrane microheterogeneity in detail and to elucidate possible molecular mechanisms that account for alteration in membrane function, new methods are needed. In the second part of the review, we discuss ultra-sensitive and ultra-resolution imaging techniques. These include atomic force microscopy, single particle tracking, single particle tracing and various modern fluorescence methods. Finally, we deal with computing simulation of membrane systems. Such methods include coarse-grain techniques and Monte Carlo which offer further advances into molecular dynamics. As computational methods advance they will have more application by revealing the very subtle interactions that take place between the lipid and protein components of membranes – and which are so essential to their function

Membrane fluidity matters: Hyperthermia from the aspects of lipids and membranes

Hyperthermia is a promising treatment modality for cancer in combination both with radio- and chemotherapy. In spite of its great therapeutic potential, the underlying molecular mechanisms still remain to be clarified. Due to lipid imbalances and 'membrane defects' most of the tumour cells possess elevated membrane fluidity. However, further increasing membrane fluidity to sensitise to chemo-or radiotherapy could have some other effects. In fact, hyperfluidisation of cell membrane induced by membrane fluidiser initiates a stress response as the heat shock protein response, which may modulate positively or negatively apoptotic cell death. Overviewing some recent findings based on a technology allowing direct imaging of lipid rafts in live cells and lipidomics, novel aspects of the intimate relationship between the 'membrane stress' of tumour cells and the cellular heat shock response will be highlighted. Our findings lend support to both the importance of membrane remodelling and the release of lipid signals initiating stress protein response, which can operate in tandem to control the extent of the ultimate cellular thermosensitivity. Overall, we suggest that the fluidity variable of membranes should be used as an independent factor for predicting the efficacy of combinational cancer therapies