Uterine leiomyoma cytogenetics

Uterine leiomyoma--a benign smooth muscle tumor--has recently been found to contain tumor-specific chromosome aberrations. Although only normal karyotypes were detected in 50 to 80% of cytogenetically investigated tumors, 104 leiomyomas with karyotypic aberrations have already been reported. At least four cytogenetically abnormal subgroups have been identified thus far, characterized by rearrangements of 6p, del(7)(q21.2q31.2), +12, and t(12;14)(q14-15;q23-24). The remaining abnormal tumors have had various nonrecurrent anomalies. Secondary karyotypic rearrangements, sometimes including ring chromosomes, have been found in one-third and reflect clonal evolution. Occasional leiomyomas have contained multiple numerical and structural rearrangements. Though benign, these cytogenetically grossly aberrant tumors often displayed more atypical histological features than are usually seen in leiomyoma. Multiple leiomyomas have been investigated from 69 patients, with detection of chromosome anomalies in at least two separate tumors from the same uterus in ten cases. In half of these patients unrelated aberrations were found in different leiomyomas from the same uterus. On other occasions the aberrations were identical, indicating that although some uterine leiomyomas originate independently, others may develop by intra-myometrial spreading from a common neoplastic clone. Some common features are discernible between the karyotypic pictures of uterine leiomyoma and angioleiomyoma; rearrangements of 6p, 13q, and 21q have been described in both tumor types. The cytogenetic similarities so far detected between leiomyoma and the malignant muscle tumors--leiomyosarcoma and rhabdomyosarcoma--are few and may be fortuitous. The cytogenetic profiles of leiomyoma and lipoma are strikingly similar; both tumor types have nonrandom rearrangements of 12q13-15, t(12;14) in leiomyoma and t(3;12) in lipoma, as well as variant rearrangements of the same 12q segment. Both also have cytogenetic subgroups characterized by changes in 6p and ring chromosomes. Finally, karyotypic similarities exists also between leiomyoma and pleomorphic adenoma of the salivary gland, which includes a subset of tumors with anomalies of 12q13-15, and with myxoid liposarcoma, which has t(12;16)(q13;p11) as a tumor-specific rearrangement.     

Attachment of coxsackievirus B3 variants to various cell lines: mapping of phenotypic differences to capsid protein VP1

The coxsackievirus B3 (CVB3) strain Nancy P establishes a persistent carrier-state infection without visible cytopathic effect in primary human fibroblasts (HuFi H), whereas the derivative variant PD induces a complete lysis of the cell monolayer. To define the molecular basis of this exceptional growth property, the complete genomes of both viruses were sequenced and compared to all published sequences of CVB3. As a result, six unique amino acid substitutions in the VP1 capsid protein were observed. Via hybrid virus construction, the lytic phenotype was transferred to a nonlytic cDNA-generated CVB3. Mapping experiments indicate that the presence of amino acid residues K78, A80, A91, and I92 in VP1 is sufficient to induce "lytic" infections in HuFi H cells. Binding assays demonstrate that CVB3 Nancy P preferentially binds to the human coxsackievirus-adenovirus receptor (CAR), while PD exhibits a very weak interaction with CAR but strong binding to the decay accelerating factor (DAF). These results suggest that the mutated amino acid residues in VP1 are involved in receptor recognition/binding. Moreover, the lytic replication of CVB3 PD and the hybrid virus in various nonpermissive rodent cell lines indicates that cell surface molecules other than CAR and DAF may be involved in attachment of this variant to cell surfaces.     

Clonal chromosome aberrations in a keratoacanthoma and a basal cell papilloma

Clonal chromosome abnormalities were found in short-term cultures from two epithelial skin tumors, a basal cell papilloma and a keratoacanthoma. The three-way translocation t(2;6;11)(q21;q27;p13) was the sole clonal rearrangement in the basal cell papilloma. The karyotype of the keratoacanthoma was more complex: 46,XX,der(2)(2pter----2p13::2p11----cen----2q37: :5q33----5qter),der(2) (:2p13----cen----2q37::6q23----6qter),der(5)t(2; 7;5)(q37;q11;q33),der(6) (6pter----cen----6q23::2p13----2pter),der(7)t(2; 7;5)(q37;q11;q33), del(13)(q11q14). In addition, several nonclonal structural changes were seen in both tumors.     

Trisomy 7 in nonneoplastic focal steatosis of the liver.

Cytogenetic analysis of short-term cultures of a nonneoplastic focal steatosis of the liver showed trisomy 7 as the sole chromosomal change. This finding, especially when viewed in light of previous reports describing +7 in nonneoplastic tissues, strongly suggests that trisomy 7 cannot be considered a tumor-specific abnormality when it occurs as the only change. The cell type in which +7 is present is not yet known.     

Chromosomal abnormalities in giant cell tumors of bone.

Cytogenetic analysis of short-term cultures from ten giant cell tumors of bone revealed clonal and nonclonal chromosome abnormalities in three tumors and nonclonal changes only in seven. None of the clonal aberrations, inv(21)(p11q21) in one tumor, +5 in another, and t(15q22q), dic(4;22)(p16;p1?), double minutes, dicentrics, and ring chromosomes present in three separate clones in the third tumor, were identical to previously reported clonal changes in giant cell tumors. Telomeric associations were found in five tumors. The telomeres of chromosome arms 19q and 15p were particularly frequently involved.     

Cyclic GMP and acid production in isolated gastric cells of the rat

Summary Just as cAMP is regarded as an intracellular mediator of histamine, so has cGMP been connected with cholinergic stimulation of gastric acid secretion. The object of the present investigation was to study the possible role of cellular cGMP on ¹⁴C-aminopyrine uptake, an indirect measure of parietal cell H⁺-production, by using mixtures of isolated rat gastric cells and fractions with different parietal cell content. Cellular cAMP and cGMP. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) enhanced the cAMP and cGMP of gastric cells in a time- and concentration-dependent manner, by 98 and 124% (1 mmol/l) and was included in all further studies. In parietal cell enriched fractions, histamine elevated cAMP by 109% (100 mol/l) without changing cGMP while carbachol did not influence either nucleotide. Various thiols and nitrogen compounds strongly enhanced cellular cGMP, e. g. hydroxylamine and l-cysteine (1 mmol/l) by 527 and 656%, whereas changes in cAMP were minimal. The hydroxylamine response occurred in parietal cell depleted and enriched fractions. ¹⁴ C-aminopyrine (AP) uptake. IBMX alone reduced the basal AP uptake, potentiated the effect of histamine and inhibited the effect of carbachol, which alone stimulated basal accumulation by 302%. The most efficacious stimulant of parietal cell H⁺-production was dibutyryl cAMP (582%, 100 mol/l), whereas dibutyryl cGMP was without effect. However, this latter compound (1 mmol/l) reduced AP accumulation due to dibutyryl cAMP almost completely. Thiols and nitrogen compounds all more or less reduced AP uptake.The data contraindicate the theory of a second messenger function for cGMP in cholinergic acid stimulation of the rat stomach. They show, that an increase in cGMP is associated with low H⁺-production, even if cAMP levels are raised above their resting state. Thus, the results suggest that cGMP rather mediates inhibition of acid secretion, possibly by counteracting the messenger function of cAMP.This study was supported by the Deutsche Forschungsgemeinschaft     

Karyotypic abnormalities in adenocarcinomas of the lung

Cytogenetic analysis of 114 adenocarcinomas of the lung revealed clonal abnormalities in 67 tumors. The chromosome numbers ranged from near-diploid to hypertetraploid. Clonal abnormalities seen as the sole anomaly were loss of the Y chromosome (21 tumors), trisomy 7 (2 tumors), and trisomy 12 (1 tumor). A supernumerary ring chromosome was the only clonal change in 4 tumors. The bands most often affected were 17p11-13 (13 cases), 1q10-12 and 1p22 (10 cases each), 1p11-13 and 1q21 (9 cases each), and 11p11, 11p15 and 15p11-13 (6 cases each). The chromosomes most frequently involved in structural rearrangements were chromosomes 1 (30 cases), 11 (20 cases), 3 (17 cases), 17 and 7 (16 cases each). Repeated loss of material from chromosome arms 1p, 3p, 6q, 11p, and 17p and gains of 1q were found. Recurrent structural changes were del(1)(p22) and i(5)(p10) (5 cases each) i(1)(q10), i(13)(q10), i(14)(q10) and del(17)(p11) (3 cases each). We found no abnormalities that seemed to be specifically associated with pulmonary adenocarcinomas, but isochromosomes i(1)(q10), i(5)(p10) and i(13)(q10) and changes of 6q were present in our series at frequencies higher than those generally seen in the other main types of lung cancer.     

Cytogenetic findings in primary and secondary MDS.

More than 1300 MDS cases with clonal cytogenetic abnormalities, 200 of them secondary MDS, have been reported. The most common aberrations in primary MDS are del(5q) (27%), trisomy 8 (19%), monosomy 7 (15%), der(11q) (7%), -5, der(12p) and -Y (5%), del(7q) (4%), and t(1;7), der(3q), del(13q), i(17q) and del(20q) in 2% or less. The 5q- is mostly, but not always, a del(5)(q13q33); it is the cytogenetic hall-mark of the "5q- syndrome" and is frequently found as the sole abnormality. The frequency of the aberrations varies among MDS subgroups: 5q- is most frequent in RA, -5, -7, and der(12p) are more common in CMML and especially in RAEB, and +8 and der(11q) are more often found in RARS. The most common aberrations in secondary MDS are -7 (41%), del(5q) (28%), -5 (11%), der(21q) (9%), 7q-, +8 and der(12p) (8%), t(1;7) and -12 (7%), der(17p) (6%), der(3p) and der(6p) (5%), and der(3q), der(11q), -17, -18 and der(19q) (4%). The average number of abnormalities per case is 5.3, compared with 2.9 in unspecified MDS. The frequency of cytogenetically unrelated clones is 5.7% in secondary and 4.3% in primary MDS. When the literature data are broken down by type of genotoxic exposure, it turns out that -5, -7, and der(17p) are over-represented in patients who have received chemotherapy, whereas 5q- is associated with no exposure or preceding radiotherapy only. The karyotypic profile is prognostically important: patients with -7 or complex karyotypes have a higher risk of progression to acute leukemia and shorter survival.     

Atypical organisation of the auditory cortex in dyslexia as revealed by MEG

Neuroanatomical and -radiological studies have converged to suggest an atypical organisation in the temporal bank of the left-hemispheric Sylvian fissure for dyslexia. Against the background of this finding, we applied high temporal resolution magnetoencephalography (MEG) to investigate functional aspects of the left-hemispheric auditory cortex in 11 right-handed dyslexic children (aged 8–13 years) and nine matched normal subjects (aged 8–14 years). Event-related field components during a passive oddball paradigm with pure tones and consonant–vowel syllables were evaluated. The first major peak of the auditory evoked response, the M80, showed identical topographical distributions in both groups. In contrast, the generating brain structures of the later M210 component were located more anterior to the earlier response in children with dyslexia only. Control children exhibited the expected activation of more posterior source locations of the component that appeared later in the processing stream. Since the group difference in the relative location of the M210 source seemed to be independent of stimulus category, it is concluded that dyslexics and normally literate children differ as to the organisation of their left-hemispheric auditory cortex.