Clonality and genetic divergence in multifocal low-grade superficial urothelial carcinoma as determined by chromosome 9 and p53 deletion analysis

Multifocality and recurrence are clinically important features of urothelial carcinomas of the urinary bladder. Recent molecular genetic studies have suggested that multifocal urothelial carcinomas are monoclonally derived from an identical transformed progenitor cell. However, most of these studies investigated advanced and poorly differentiated tumors. The study presented focuses on early papillary tumors, including 52 superficial well-differentiated multifocal and recurrent bladder carcinomas from 10 patients. Microdissection separating urothelium from stromal cells was considered essential to obtain pure tumor cell populations. Genetic analysis was carried out by applying two different methods. Dual color fluorescence in situ hybridization (FISH) with centromeric probes for chromosomes 9 and 17 and gene-specific probes for chromosome loci 9q22, 9p21, and 17p13 was carried out in parallel to loss of heterozygosity (LOH) analyses applying 5 microsatellite markers on these chromosomes. Overall, deletions on chromosome 9p were found in 47 tumors (90%), at chromosome 9q in 36 tumors (69%) and at chromosome 17p in 3 tumors (6%). There was a very high correlation of the results between FISH and LOH analysis. Ten early superficial papillary tumors showed deletion of chromosome 9p without deletion of 9q, suggesting 9p deletions as a very early event in the development of papillary urothelial carcinoma. Although in four patients, all investigated tumors showed identical genetic alterations and one patient showed no genetic alterations at the loci investigated, in five patients, two or more clones with different deletions were found. In four of these patients, the results are compatible with clonal divergence and selection of different cell subpopulations derived from a common progenitor cell. However, in one patient different alleles in two markers at chromosome 9 were deleted, favoring an independent evolution of two recurring tumor cell clones. In summary, we could show that there is considerable genetic heterogeneity in early multifocal and recurring urothelial carcinoma and demonstrated the occurrence of two independent clones in at least one patient as an indicator of possible initial oligoclonality of bladder cancer.     

Inactivation determined by a single site in K+ pores

An N-terminus peptide or a C-terminus mechanism involving a single residue in transmembrane segment 6 produces inactivation in voltage-dependent K⁺ channels. Here we show that a single position in the pore of K⁺ channels can produce inactivation having characteristics distinct from either N- or C-type inactivation. In a chimeric K⁺ channel (CHM), the point reversion CHM V 369I produced fast inactivation and CHM V 369S had the additional effect of halving K⁺ conductance consistent with a position in the pore. The result was not restricted to CHM; mutating position 369 in the naturally occurring channel Kv2.1 also produced fast inactivation. Like N- and C-types of inactivation, pore or P-type inactivation was characterized by short bursts terminated by rapid entry into the inactivated state. Unlike C-type inactivation, in which external tetraethylammonium (TEA) produced a simple blockade that slowed inactivation and reduced currents, in P-type inactivation external TEA increased currents. Unlike N-type inactivation, internal TEA produced a simple reduction in current and K⁺ occupancy of the pore had no effect. External TEA was not the only cation to increase current; external K⁺ enhanced channel availability and recovery from inactivation. Additional features of P-type inactivation were residue-specific effects on the extent of inactivation and removal of inactivation by a point reversion at position 374, which also regulates conductance. The demonstration of P-type inactivation indicates that pore residues in K⁺ channels may be part of the inactivation gating machinery.     

Welche Medikamente sind in der Stillzeit erlaubt?

Wiener Medizinische Wochenschrift - Oft liegen abweichende oder keine pharmakokinetischen Daten für Medikamente zur Anwendung in der Stillzeit vor. Fachinformationen empfehlen eine Stillpause...     

Fatal outcome of nevirapine-associated toxic epidermal necrolysis

The irregular use of antiretroviral therapy (ART) can result in ART-resistance but can also lead to a sensitization between agents with a cross-sensitivity. We report a case of nevirapine-associated toxic epidermal necrolysis resulting in death in an HIV-infected man.     

Rare occurrence of IgVH gene translocations and restricted IgVH gene repertoire in ocular MALT-type lymphoma

FISH studies on 37 ocular MALT-type lymphomas yielded chromosomal translocations affecting MAL andT1 BCL10 in 1 case each, no evidence for a break in the FOXP1 locus, and trisomy 3 in 14 out of 34 cases (41%). Three out of 8 cases analyzed used the highly mutated VH3-23 gene and showed ongoing somatic hypermutations.     

Toxicity and bioaccumulation of xenobiotic organic compounds in the presence of aqueous suspensions of aggregates of nano-C(60)

The potential of C(60)-nanoparticles (Buckminster fullerenes) as contaminant carriers in aqueous systems was studied in a series of toxicity tests with algae (Pseudokirchneriella subcapitata) and crustaceans (Daphnia magna). Four common environmental contaminants (atrazine, methyl parathion, pentachlorophenol (PCP), and phenanthrene) were used as model compounds, representing different physico-chemical properties and toxic modes of action. The aggregates of nano-C(60) formed over 2 months of stirring in water were mixed with model compounds 5 days prior to testing. Uptake and excretion of phenanthrene in 4-days-old D. magna was studied with and without addition of C(60) in aqueous suspensions. It was found that 85% of the added phenanthrene sorbed to C(60)-aggregates >200 nm whereas about 10% sorption was found for atrazine, methyl parathion, and pentachlorophenol. In algal tests, the presence of C(60)-aggregates increased the toxicity of phenanthrene with 60% and decreased toxicity of PCP about 1.9 times. Addition of C(60)-aggregates reduced the toxicity of PCP with 25% in tests with D. magna, whereas a more than 10 times increase in toxicity was observed for phenanthrene when results were expressed as water phase concentrations. Thus, results from both toxicity tests show that phenanthrene sorbed to C(60)-aggregates is available for the organisms. For atrazine and methyl parathion no statistically significant differences in toxicities could be observed in algal and daphnid tests as a result of the presence of C(60)-aggregates. In bioaccumulation studies with phenanthrene in D. magna it was found that the uptake of phenanthrene was faster when C(60) was present in suspension and that a 1.7 times higher steady-state concentration was reached in the animals. However, a very fast clearance took place when animals were transferred to clean water resulting in no accumulation of phenanthrene. This study is the first to demonstrate the influence of C(60)-aggregates on aquatic toxicity and bioaccumulation of other environmentally relevant contaminants. The data provided underline that not only the inherent toxicity of manufactured nanoparticles, but also interactions with other compounds and characterisation of nanoparticles in aqueous suspension are of importance for risk assessment of nanomaterials.