The mtDNA variation of 50 Spanish and 4 Cuban families affected by nonsyndromic sensorineural deafness due to the A1555G mutation in the 12S rRNA gene was studied by high-resolution RFLP analysis and sequencing of the control region. Phylogenetic analyses of haplotypes and detailed survey of population controls revealed that the A1555G mutation can be attributed to >/=30 independent mutational events among the 50 Spanish families and that it occurs on mtDNA haplogroups that are common in all European populations. This indicates that the relatively high detection rate of this mutation in Spain is not due to sampling biases or to a single major founder event. Moreover, the distribution of these mutational events on different haplogroups is compatible with a random occurrence of the A1555G mutation and tends to support the conclusion that mtDNA backgrounds do not play a significant role in the expression of the mutation. Overall, these findings appear to indicate that the rare detection of this mutation in other populations is most likely due to inadequacy in patient ascertainment and molecular screening. This probable lack of identification of the A1555G mutation in subjects affected by sensorineural hearing loss implies that their maternally related relatives are not benefiting from presymptomatic detection and information concerning their increased risk of ototoxicity due to aminoglycoside treatments.
Although activated macrophages destroy cancer cells more effectively than normal cells, the ability to escape activated macrophages is a characteristic of tumor cells. One of the mechanisms responsible for the specific killing of tumor cells by macrophages is the production of the cytokine tumor necrosis factor (TNF) alpha. Therefore, resistance to TNF may provide such cancer cells a selective advantage against host elimination. With the aim of identifying genes with these properties we undertook a large scale genetic screen to identify genes able to bypass TNF-induced G1 arrest. We identified MAP17, a small 17 kDa nonglycosylated membrane protein that localizes to the plasma membrane and the Golgi apparatus. Ectopic expression of MAP17 in tumor cells prevents TNF-induced G1 arrest by impairing p21waf1 induction. However, expression of MAP17 does not inhibit TNF-induced apoptosis in Me180-sensitive tumor cells. The inhibition of TNF is specific since MAP17 does not alter the response to other cytokines such as IFNgamma. As described in the Xenopus oocyte system, MAP17 increases the uptake of mannose in some cells, but this effect is not responsible for TNF bypass. We have also analyzed the expression of MAP17 mRNA in a panel of cell lines. MAP17 is expressed in 30% of cell lines of different origin. However, MAP17 mRNA expression did not correlate with TNF resistance. Our data indicates that although MAP17 expression might bypass TNF-induced growth arrest, it is not the only determinant of this response.
Non-syndromic X-linked deafness is highly heterogeneous. At least five different clinical forms have been described, but only two loci have been mapped. Here we report a Spanish family affected by a previously undescribed X-linked form of hearing impairment. Deafness is non-syndromic, sensorineural, and progressive. In affected males, the auditory impairment is first detected at school age, affecting mainly the high frequencies. Later it evolves to become severe to profound, involving all frequencies for adulthood. Carrier females manifest a moderate hearing impairment in the high frequencies, with the onset delayed to the fourth decade of life. Deafness was assumed to be X-linked dominant, with incomplete penetrance and variable expressivity in carrier females. The family was genotyped for a set of microsatellite markers evenly spaced at intervals of about 10 cM. We found evidence of linkage to markers in the Xp22 region (maximum lod score of 5.30 at theta = 0.000 for DXS8036 and for DXS8022). The position of the novel deafness locus (DFN6) was refined by haplotype analysis. Mapping of the breakpoints in two critical recombinants allowed us to define an interval for DFN6, delimited by DXS7108 on the distal side and by DXS7105 on the proximal side, and spanning a genetic distance of about 15 cM.
Medical imaging techniques play a central role in clinical oncology, helping to obtain important information about the extent of disease, and plan treatment. Advanced imaging modalities such as Positron Emission Tomography–Computed Tomography (PET/CT), may help in the whole-body staging in a single procedure, although the lesions should be carefully interpreted. PET/CT is becoming commonly used in canine cancer patients, but there is still limited information available on specific tumors such as mammary cancer. We evaluated the utility of fluorine-18 fluorodeoxyglucose (
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F-FDG)-PET/CT to detect malignant lesions in eight female dogs with naturally occurring mammary tumors. A whole-body scan was performed prior to surgery, and mammary and non-mammary lesions detected either on PET/CT or during pre-surgical physical exam were resected when possible and submitted for histopathological examination. Multiple mammary lesions involving different mammary glands were detected in 5/8 dogs, for a total of 23 lesions; there were 11 non-mammary-located lesions in 6/8 dogs, three of these were lung or lymph node metastasis. A total of 34 lesions were analyzed: 22 malignant (19 mammary tumors and three metastatic lesions), and 12 benign (four mammary lesions and eight of non-mammary tissues). Glucose uptake by maximum standardized uptake value (SUVmax) was analyzed and correlated with tumor size, and benign vs. malignant pathology. We found that the minimum tumor size needed to distinguish malignant lesions according to the SUVmax was 1.5 cm; benign and malignant lesions <1.5 cm did not differ in glucose uptake (mean SUVmax = 1.1). In addition, a SUVmax value >2 was 100% sensitive for malignancy. Combining these data, lesions >1.5 cm with a SUVmax >2 had a positive predictive value of 100%. Finally, we did not find an association between SUVmax and histologic subtype or grade, which may be present in a larger sample. Thus,
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F-FDG PET/CT is useful for distinguishing malignant from benign lesion but further imaging of dogs with diverse tumors, should establish characteristic SUV value cutoffs for detecting primary and metastatic disease, and distinguishing them from benign lesions.
Apoptotic pathways, including the phosphatidylinositol-3-kinase (PI3K)/AKT survival pathway, are altered in most cancer cells in relation to their normal counterparts and these differences may present an excellent therapeutic window. To gain insight into the relevance of the PI3K pathway as a target for drug discovery we generated tumor cell lines from different tumor samples that we maintained at low passage. The characterization of these cell lines indicates that all of them have constitutively activated the PI3K pathway through different mechanisms. All cell lines were differentially sensitive to the PI3K inhibitor LY294002. Our data also support previous work indicating that PI3K inhibition might help classical chemotherapeutic treatments such as gemcitabine and strengthen suboptimal doses that might be effective for these purposes in decreasing the risk of side-effects. Finally, the analysis of the molecular markers that might be implicated in the synergism between LY294002 and gemcitabine suggests that PI3K inhibition might aid chemotherapeutic treatment, leading to changes in the balance between anti- and pro-apoptotic molecules of the Bcl-2 family, Bcl-XL and Bax. These results facilitate the exploration of potential synergism between chemotherapeutic treatment and the search for others that can account for similar molecular mechanisms of cooperation.
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