Comparative chromosome painting discloses homologous Segments in distantly related mammals

Comparative chromosome painting, termed ZOO-FISH, using DNA libraries from flow sorted human chromosomes 1,16,17 and X, and mouse chromosome 11 discloses the presence of syntenic groups in distantly related mammalian Orders ranging from primates (Homo sapiens), rodents (Mus musculus), even-toed ungulates (Muntiacus muntjak vaginalis and Muntiacus reevesi) and whales (Balaenoptera physalus). These mammalian Orders have evolved separately for 55-80 million years (Myr). We conclude that ZOO-FISH can be used to generate comparative chromosome maps of a large number of mammalian species

Genetic variability in CYP3A4 and CYP3A5 in primary liver, gastric and colorectal cancer patients

<p>Abstract</p> <p>Background</p> <p>Drug-metabolizing enzymes play a role in chemical carcinogenesis through enzymatic activation of procarcinogens to biologically reactive metabolites. The role of gene polymorphisms of several cytochrome P450 enzymes in digestive cancer risk has been extensively investigated. However, the drug-metabolizing enzymes with the broader substrate specificity, CYP3A4 and CYP3A5, have not been analyzed so far. This study aims to examine associations between common CYP3A4 and CYP3A5 polymorphisms and digestive cancer risk.</p> <p>Methods</p> <p>CYP3A4 and CYP3A5 genotypes were determined in 574 individuals including 178 patients with primary liver cancer, 82 patients with gastric cancer, 151 patients with colorectal cancer, and 163 healthy individuals.</p> <p>Results</p> <p>The variant allele frequencies for patients with liver cancer, gastric cancer, colorectal cancer and healthy controls, respectively, were: <it>CYP3A4*1B</it>, 4.8 % (95% C.I. 2.6–7.0), 3.7 % (0.8–6.6) 4.3% (2.0–6.6) and 4.3% (2.1–6.5); <it>CYP3A5*3</it>, 91.8 % (93.0–97.4), 95.7% (92.6–98.8), 91.7% (88.6–94.8) and 90.8% (87.7–93.9). The association between <it>CYP3A4*1B </it>and <it>CYP3A5*3 </it>variant alleles did not significantly differ among patients and controls. No differences in genotypes, allele frequencies, or association between variant alleles were observed with regard to gender, age at diagnosis, tumour site or stage.</p> <p>Conclusion</p> <p>Common polymorphisms on <it>CYP3A4 </it>and <it>CYP3A5 </it>genes do not modify the risk of developing digestive cancers in Western Europe.</p

Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy

Cytochrome P450 3A is a drug-metabolising enzyme activity due to CYP3A4 and CYP3A5 gene products, that is involved in the inactivation of anticancer drugs. This study analyses the potential of cytochrome P450 3A enzyme in human colorectal cancer to impact anticancer therapy with drugs that are cytochrome P450 3A substrates. Enzyme activity, variability and properties, and the ability to inactivate paclitaxel (taxol) were analysed in human colorectal cancer and healthy colorectal epithelium. Cytochrome P450 3A enzyme activity is present in healthy and tumoral samples, with a nearly 10-fold interindividual variability. Nifedipine oxidation activity±s.d. for colorectal cancer microsomes was 67.8±36.6 pmol min−1 mg−1. The Km of the tumoral enzyme (42±8 μM) is similar to that in healthy colorectal epithelium (36±8 μM) and the human liver enzyme. Colorectal cancer microsomes metabolised the anticancer drug paclitaxel with a mean activity was 3.1±1.2 pmol min−1 mg−1. The main metabolic pathway is carried out by cytochrome P450 3A, and it is inhibited by the cytochrome P450 3A-specific inhibitor ketoconazole with a KI value of 31 nM. This study demonstrates the occurrence of cytochrome P450 3A-dependent metabolism in colorectal cancer tissue. The metabolic activity confers to cancer cells the ability to inactivate cytochrome P450 3A substrates and may modulate tumour sensitivity to anticancer drugs

Musculoskeletal computed radiography in children: scatter reduction and improvement in bony trabecular sharpness using air gap placement of the imaging plate

The effect of various air gaps on computed radiographic musculoskeletal images was investigated using a knee phantom. Scatter to primary radiation ratios were measured using the beam stop method at air gaps ranging from 0 to 30 in. (0–762-mm). Bony trabecular sharpness, line pair resolution, quantum mottle and visualization of low-contrast beads in the soft tissues were evaluated. A significant reduction of scatter to primary radiation ratio, from a value of almost 1 at table top to about 0.4 at 10-in. (254-mm) air gap and about 0.2 at 25-in. (635-mm) air gap placement of the computed radiography (CR) imaging plate, was obtained. A progressive improvement in bony trabecular sharpness and line pair resolution, compared with the table top and Bucky images was observed on 10-in. (254-mm) through 25-in. (635-mm) air gap images. Sharpness of the bony trabeculae and line pair resolution were best on the 25-in. (635-mm) air gap images. The skin entrance radiation dose does not have to be increased for air gap digital radiography. The radiographic noise or quantum mottle is highest on the Bucky image, higher on air gap images and minimal on the table top images, despite a high scatter to primary radiation ratio at the table top. The lower quantum mottle on the table top images allowed for maximal visualization of low contrast densities in the soft tissues. Air gap radiography further improves musculoskeletal computed imaging by reducing the scatter to primary radiation ratio without an increase in the skin entrance dose. For significant reduction of the scatter to primary radiation ratio and best evaluation of line pair spatial resolution and bony trabeculae, a 25-in. (635-mm) air gap with digital radiography would be optimal. For evaluation of low contrast densities in the soft tissues, table top placement would be the technique of choice.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42044/1/247-27-2-119_70270119.pd

New mutations in the ATM gene and clinical data of 25 AT patients

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, oculocutaneous telangiectasias, chromosomal instability, radiosensitivity, and cancer predisposition. The gene mutated in the patients, ATM, encodes a member of the phosphatidylinositol 3-kinase family proteins. The ATM protein has a key role in the cellular response to DNA damage. Truncating and splice site mutations in ATM have been found in most patients with the classical AT phenotype. Here we report of our extensive ATM mutation screening on 25 AT patients from 19 families of different ethnic origin. Previously unknown mutations were identified in six patients including a new homozygous missense mutation, c.8110T > C (p.Cys2704Arg), in a severely affected patient. Comprehensive clinical data are presented for all patients described here along with data on ATM function generated by analysis of cell lines established from a subset of the patients