Frequent rearrangement of chromosomal bands 1p22 and 11q13 in squamous cell carcinomas of the head and neck

We report the finding of clonal structural chromosome abnormalities in short-term cultures from 15 squamous cell carcinomas of the head and neck region. When the distribution of chromosomal breakpoints in these 15 tumors and in the 16 head and neck carcinomas previously described are assessed, a marked clustering is seen at bands 1p22 and 11q13, which are rearranged in eight and nine tumors, respectively. No other band was involved in aberrations in more than five tumors. Cytogenetic evidence of gene amplification was seen in four tumors, three times in the form of homogeneously staining regions (twice located in 11q13), and in one tumor as double minutes. Among the candidate genes for such amplification are BCLI, INT2, and HSTI, all of which map to 11q13, and NRAS, which maps to 1p22. All these oncogenes have previously been shown to be amplified in subsets of head and neck carcinomas. We conclude that bands 1p22 and 11q13 are nonrandomly involved in chromosomal rearrangements in head and neck carcinomas and suggest that activation of oncogenes located in these bands may proceed via cytogenetic mechanisms.     

Hemodynamic profile of arpromidine and its F2-substituted derivatives in comparison to impromidine in congestive heart failure

There is considerable evidence that congestive heart failure (CHF) is paralleled by a decrease in the number of sarcolemmal β-receptors due to excessive levels of circulating endogenous catecholamines [1, 2]. In contrast, the myocardial H₂-receptor system is not affected. The first clinically available specific H₂-receptor agonist impromidine proved to be a potent inotrope in patients with CHF which were insensitive to catecholamine stimulation [3, 4]. Though the overall results of these initial studies were beneficial, the narrow therapeutic range, high costs of synthesis and the arrhythmogenic potential of impromidine limited its broad clinical application in large scale clinical trials. Recently developed phenylpyridylalkylguanidines [5] were investigated underin vitro andin vivo conditions in the guinea pig under physiologic and pathophysiologic conditions using impromidine as reference. Compounds tested were arpromidine and the difluorinated analogues BU-E-75 and BU-E-76, all guanidine-type H₂-agonists with additional H₁-antagonistic properties due to a pheniramine like moiety. In the isolated perfused heart, all three new compounds were more potent in increasing cardiac contractile force and coronary flow but less effective on heart rate and less arrhythmogenic. The same could be established underin vivo conditions where BU-E-76 was more potent than BU-E-75, arpromidine and impromidine, respectively, in augmenting LV dp/dt, LVP, cardiac output and systemic blood pressure, but all compounds were revealed to have less chronotropic and arrhythmogenic potential. In the vasopressin-induced acute heart failure model, BU-E-76 and BU-E-75 normalized within minutes all contractile parameters in contrast to arpromidine and impromidine. It is thus concluded that these new H₂-receptor agonists may represent a promising therapeutic improvement for treatments of CHF patients, with a cardiovascular profile superior to impromidine and conventional catecholamines.

     

Near-haploid clones in a malignant fibrous histiocytoma

Near-haploid solid tumors are very rare. In a storiform-pleomorphic malignant fibrous histiocytoma (MFH) of bone, we found three cell populations: one with a near-haploid, a second with a near-diploid, and a third with a near-tetraploid chromosome number. The near-haploid cells had few structural rearrangements: i(12p) and t(13q21q) in one clone, and these two and an additional t(19;?)(p11;?) in another clone. One structurally normal copy of all chromosomes was also present, except that the only chromosome 13 was involved in the t(13q21q). There were also two near-diploid clones, one without the t(19;?) and one with a single copy of this derivative chromosome. This is the first MFH reported to have a near-haploid modal chromosome number, and also the first tumor with i(12p) among bone and soft tissue tumors.     

Trisomy 5 and loss of the Y chromosome as the sole cytogenetic anomalies in a cavernous hemangioma/angiosarcoma

Cytogenetic analysis of a cavernous hemangioma with transition to angiosarcoma revealed the mosaic karyotype 47, XY,+5/46, X,-Y,+5/45, X,-Y/46, XY. No cytogenetically analyzed hemangiomas or angiosarcomas have been reported before.     

Apparent superiority of H2-receptor stimulation and simultaneousβ-blockade over conventional treatment withβ-sympathomimetic drugs in post-acute myocardial infarction: Cardiac effects of impromidine — a new specific H2-receptor agonist — in the surviving catecholamine-insensitive myocardium

Left ventricular infarction (AMI) was produced in experimental animals and the contractile response to -adrenergic and H₂-histaminergic stimulation by isoproterenol and impromidine tested in the isolated perfused heart preparation. Adenylate cyclase activity as well as binding characteristics of [³H]-dihydroalprenolol ([³H]-DHA), [³H]-methyl-tiotidine ([³H]-TIOT) and [³H]-quinuclidinyl benzilate ([³H]-QNB) to cardiac ₁-, H₂- and cholinergic muscarinic receptors were determined in sarcolemmal membrane preparations of the right ventricle of the same hearts. In addition, an attempt was made to elucidate the therapeutic value of post-AMI treatment with impromidine in the presence and absence of-sympathomimetic, in contrast to administration of prenalterol and the conventional therapy with -sympathomimetic drugs, e.g. dobutamine. Three days post-AMI the dose-response curve for isoproterenol of right ventriculardP/dt _max was significantly depressed, while the inotropic effect of impromidine was not impaired. Stimulation of adenylate cyclase activity by isoproterenol was reduced by 80% whereas impromidine and NaF stimulation rates were unaltered. Receptor-binding studies indicated a 90% loss and 10-times lowered affinity (K _D) of the remaining -receptors while specific [³H]-TIOT- and [³H]-QNB-binding was unchanged.Administration of dobutamine increased mortality rates and extension of infarct size, led to a further decrease in contractile response to isoproterenol, induced complete insensitivity of adenylate cyclase to isoproterenol stimulation and caused pronounced additional reduction of number and affinity of [³H]-DHA-binding sites. In contrast, all above alterations were prevented by treatment with either prenalterol or combined administration of impromidine plus metoprolol. It is concluded, that these alterations in the non-ischemic, uninvolved myocardium post-AMI are the result of catecholamine-induced specific damage of sarcolemmal -receptors. Furthermore, treatment with H₂-agonists in combination with -blocking agents may have beneficial effects, whereas conventional therapy with -sympathomimetic drugs tends to worsen the already depressed function of the -adrenergic stimulation mechanism.Supported by grants Ba 666/1 and Ba 666/2-2 from the Deutsche Forschungsgemeinschaft (DFG).Data presented in this paper are part of a doctoral thesis by Dr S.B. Felix.     

β1-Adrenoceptor gene variations: a role in idiopathic dilated cardiomyopathy?

A substantial body of evidence suggests involvement of the human beta1-adrenoceptor (beta1-AR) gene in the pathophysiology of dilated cardiomyopathy (DCM), a severe heart disease of significant public health impact. Beta1-AR-mediated signal transduction is dramatically altered due to downregulation, resulting in an impairment of myocardial response. The important role of genetic factors in idiopathic dilated cardiomyopathy (IDCM) recently recognized, we analyzed this prime candidate gene for genetic variation in carefully selected patients and controls. In this preliminary study, 18 single nucleotide polymorphisms were observed, 17 of which were located in the N-terminal and C-terminal region of the coding exon, resulting in 7 amino acid exchanges: Ser-49-Gly, Ala-59-Ser, Gly-389-Arg, Arg-399-Cys, His-402-Arg, Thr-404-Ala, and Pro-418-Ala. These mutations resulted in 11 different beta1-AR genotypes. Importantly, the genotypes carrying the Ser-49-Gly mutation in the N-terminus of the molecule in a heterozygous or homozygous form were observed significantly more frequently in the group of IDCM patients. The present results may provide a clue on the molecular mechanisms involved in IDCM, and add moreover interesting information on nature, distribution, and evolutionary aspects of sequence variation in human adrenergic receptor genes.     

Immunological consequence of renal transplantation and immunosuppression. I. Alterations in human natural killer-cell activity

The role and activity of natural killer (NK) cells following renal transplantation remain unknown. To monitor NK activity, a⁵¹Cr release of K-562 targets in prednisone-and azathioprine-treated patients receiving renal allografts was utilized. In 18 patients in whom NK activity was measured prior to and after transplantation, a significant diminution in NK activity within 3 weeks following transplantation was demonstrated compared to pretransplant values (34.71 vs 12.20%, respectively;P<0.001). In 11 subjects who had NK activity assayed at various intervals after transplantation but not prior to allografting, mean NK values were markedly lower (mean, 14.2%) than those of normal volunteers or patients maintained on hemodialysis (P<0.001). The latter two control groups demonstrated no difference (P = NS) in mean NK activity (39.46 vs 35.82%, respectively). In 5 of the 29 patients evaluated with good long-term graft function (mean, 2.7 years), restitution of normal NK activity was demonstrated. In two patients with bacterial infections, NK activity increased from 39.29 to 51.7% and from 13.54 to 20.00%. After infection, these values were 35.3% in the former and 3.39% in the latter. Viral infection did not appear to affect NK activity significantly. NK activity was increased in only one of seven patients with documented rejection episodes. In three of such patients, NK activity declined significantly following pulse methylprednisolone therapy. These results indicate that (1) NK-cell activity significantly decreases immediately after transplantation, probably as a result of immunosuppressive therapy; (2) NK activity does not appear to be stimulated by the alloreactive rejection process; (3) NK activity may be augmented in the course of bacterial but not viral infections; and (4) long-term allograft survival may be associated with a restoration of NK-cell levels in certain recipients.     

Molecular adjuvants for mucosal immunity

Summary: Mucosal surfaces represent the entry route of a multitude of viral pathogens. For many of these viruses, such as the herpes simplex viruses and human immunodeficiency virus, no effective vaccine exists. Hence, it is important that prospective vaccines engender maximal immunity at these susceptible sites. Genetic vaccines encoding adjuvant molecules represent one approach to optimize mucosal as well as systemic immunity. Promising candidates include various inflammatory cytokines and chemokines that might be used to enhance the primary response to a level sufficient for protection. Encouraging studies involving cytokines such as granulocyte/macrophage colony‐stimulating factor, interleukin‐2 (IL‐2), IL‐12, IL‐18, and many others are examined. Notable chemokines that may offer hope in such efforts include IL‐8, RANTES, CCL19, CCL21, and a few others. Combinatorial approaches utilizing several cytokines and chemokines will most likely yield the greatest success. In addition, as more is discovered regarding the requirements for memory development of T cells, boosters involving key cytokines such as IL‐15 and IL‐23 may prove beneficial to long‐term maintenance of the memory pool. This review summarizes the progress in the use of genetic vaccines to achieve mucosal immunity and discusses the needed strategies to maximize long‐term prospective immunity at this vulnerable entry site.     

The adaptational strategies of the hindlimb muscles in the Tenrecidae species including the aquatic web-footed tenrec (Limnogale mergulus).

The hindlimb muscles in four species of Tenrecidae (Oryzoryctinae: Talazac long-tailed tenrec and web-footed tenrec, Tenrecinae: lesser hedgehog tenrec, and streaked tenrec), were examined macroscopically. The weight ratios of the muscles to the body in the oryzoryctinid species are larger than those in Tenrecinae, since the Oryzoryctinae species have an obviously smaller body from the evolutionary point of view. It can be primarily pointed out that the adaptation of the body size is different between the two subfamilies, and secondarily, that functional adaptation to locomotion is complete within each subfamily. The weight data and the morphological findings demonstrate that the web-footed tenrec possesses an extraordinary large M. semimembranosus in comparison to the Talazac long-tailed tenrec in their weight ratios. This muscle may act as a strong flexor motor in the knee joint during the aquatic locomotion of the web-footed tenrec. Since the other muscles of the web-footed tenrec are similar to those of the Talazac long-tailed tenrec regards weight ratio data, we think that the web-footed tenrec may have derived from a terrestrial ancestor such as the long-tailed tenrecs. In Tenrecinae the streaked tenrec is equipped with larger Mm. adductores, M. semimembranosus and M. triceps surae than the lesser hedgehog tenrec. This species is adapted to fossorial life derived from non-specialized ancestors within the evolutionary lines of the spiny tenrecs.