Oral pigmentation in the hard palate associated with imatinib mesylate therapy: a report of three cases.

Imatinib mesylate is a tyrosine kinase inhibitor which targets Bcr-Abl-protein, c-Kit, and platelet-derived growth factor receptor. The drug was originally developed for treatment of chronic myeloid leukemia but is also regarded as first-line treatment of patients with metastatic gastrointestinal stromal tumours (GIST). Dermatologic side effects are common, with superficial edema and rash as the most frequent. In addition, imatinib mesylate treatment is often associated with hypopigmentation. Intraoral side effects are very rare. The present paper demonstrates 1 patient with GIST and 2 patients with chronic myeloid leukemia treated with imatinib mesylate for 5-6 years. All 3 patients presented with diffuse solitary bluish-brown pigmentations in the hard palate. The lesions persisted at follow-ups. There were no other pigmentations in the oral mucosa. The histopathologic examination showed depositions of melanin pigment in the lamina propria. The possible relationship between the observed melanotic maculae and imatinib mesylate treatment is discussed.

Prevalence trends in Sweden for the new variant of Chlamydia trachomatis.

In 2006, a new variant of Chlamydia trachomatis (nvCT) was discovered in Sweden that was not detectable with Abbott m2000 (Abbott) and Amplicor/COBAS Amplicor/TaqMan48 (Roche). The proportion of nvCT was 20-64% of the detected Chlamydia cases in counties using Abbott/Roche test systems. Although the ProbeTec system from Becton Dickinson (BD) could detect nvCT, the proportion of nvCT in counties using BD was 7-19%. The objective of the current study was to follow the nvCT proportions from 2007 to 2009 in two counties that used Roche and had introduced test systems able to detect nvCT in late 2006. The nvCT was also followed in two counties that used BD, and in all four counties the effect of nvCT on the serotype distribution of C. trachomatis wild-type strains was analysed. A total of 2576 specimens positive for C. trachomatis were collected in the four counties at three time points, and analysed for nvCT and serotype E. The proportion of nvCT declined significantly in the two counties using Roche, from 65% and 48% in 2007 to 24% for both counties in 2009 (p <0.001). The nvCT proportion increased in Norrbotten county, which used BD, from 9% in 2007 to 19% in 2009 (p 0.03). In Uppsala county, which also used BD but was surrounded by counties using detection systems from Roche, the proportion of nvCT declined from 24% in 2007 to 18% in 2009 (p <0.03). No major difference in the level of serotype E was seen. The proportion of nvCT seems to rapidly converge in the Swedish counties after the selective diagnostic advantage for nvCT has been lost in the Abbott/Roche counties.

MEKK1 interacts with alpha-actinin and localizes to stress fibers and focal adhesions.

Mitogen-activated protein (MAP) kinases orchestrate the effects of many extracellular stimuli on cells. The serine/threonine protein kinase MEKK1 is an upstream activator of the MAP kinases c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), extracellular signal-regulated kinase (ERK), and p38 as well as NF-kappa B. In a yeast two-hybrid interaction screen to identify proteins that bind to an N-terminal fragment of MEKK1 (amino acids 1-719), the actin-crosslinking protein alpha-actinin was identified as a MEKK1-binding protein. Over-expressed MEKK1 co-immunoprecipitated with alpha-actinin in cell lysates. Both endogenous and over-expressed MEKK1 colocalized with alpha-actinin along actin stress fibers and at focal adhesions. Residues 221-559 of MEKK1 bound to purified alpha-actinin in vitro, indicating that the interaction is direct, and this fragment localized to actin filaments in cells. MEKK1 kinase activity was not required for association with actin filaments, because a catalytically inactive mutant of MEKK1 (MEKK1 D1369A) localized to stress fibers. These results provide strong evidence for the interaction between MEKK1 and alpha-actinin. Thus, restriction of the kinase to the actin cytoskeleton may serve to regulate its specificity towards downstream targets.

Lipopolysaccharide-induced tumor necrosis factor-alpha promoter activity is inhibitor of nuclear factor-kappaB kinase-dependent.

The adverse effects of lipopolysaccharide (LPS) are primarily mediated by tumor necrosis factor-alpha (TNF-alpha). TNF-alpha production by LPS-stimulated macrophages is regulated both transcriptionally and post-transcriptionally. Transcriptional regulation of the TNF-alpha gene is dependent on nuclear factor-kappaB (NF-kappaB). We examined the signaling pathways involved in the regulation of NF-kappaB that lead to TNF-alpha promoter activity. We determined a role for one or both of the recently identified inhibitor of NF-kappaB kinases, IkappaB kinase-1 and IkappaB kinase-2, in LPS induction of an NF-kappaB reporter and of TNF-alpha promoter activity. IkappaB kinase activation is one of the earliest signaling events known to be induced by LPS. Furthermore, our results suggest roles for the IkappaB kinases NF-kappaB-inducing kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 in the regulation of IkappaB kinase-2, as well as in LPS-induced TNF-alpha transcription.

HTLV-I Tax protein binds to MEKK1 to stimulate IkappaB kinase activity and NF-kappaB activation.

NF-kappaB, a key regulator of the cellular inflammatory and immune response, is activated by the HTLV-I transforming and transactivating protein Tax. We show that Tax binds to the amino terminus of the protein kinase MEKK1, a component of an IkappaB kinase complex, and stimulates MEKK1 kinase activity. Tax expression increases the activity of IkappaB kinase beta (IKKbeta) to enhance phosphorylation of serine residues in IkappaB alpha that lead to its degradation. Dominant negative mutants of both IKKbeta and MEKK1 prevent Tax activation of the NF-kappaB pathway. Furthermore, recombinant MEKK1 stimulates IKKbeta phosphorylation of IkappaB alpha. Thus, Tax-mediated increases in NF-kappaB nuclear translocation result from direct interactions of Tax and MEKK1 leading to enhanced IKKbeta phosphorylation of IkappaB alpha.

Cloning of rat MEK kinase 1 cDNA reveals an endogenous membrane-associated 195-kDa protein with a large regulatory domain.

The coding sequence of rat MEK kinase 1 (MEKK1) has been determined from multiple, independent cDNA clones. The cDNA is full-length based on the presence of stop codons in all three reading frames of the 5' untranslated region. Probes from the 5' and the 3' coding sequences both hybridize to a 7-kb mRNA. The open reading frame is 4.5 kb and predicts a protein with molecular mass of 161,225 Da, which is twice the size of the previously published MEKK1 sequence and reveals 801 amino acids of novel coding sequence. The novel sequence contains two putative pH domains, two proline-rich regions, and a cysteine-rich region. Antisera to peptides derived from this new sequence recognize an endogenous protein in human and rodent cells of 195 kDa, consistent with the size of the expressed rat MEKK1 clone. Endogenous and recombinant rat MEKK1 are enriched in membranes; little of either is found in soluble fractions. Expression of recombinant rat MEKK1 leads to activation of three mitogen-activated protein kinase modules in the order c-Jun N-terminal kinase/stress-activated protein kinase > p38 mitogen-activated protein kinase = extracellular signal-regulated kinase 2.

orb is required for anteroposterior and dorsoventral patterning during Drosophila oogenesis.

We describe mutations in the orb gene, identified previously as an ovarian-specific member of a large family of RNA-binding proteins. Strong orb alleles arrest oogenesis prior to egg chamber formation, an early step of oogenesis, whereas females mutant for a maternal-effect lethal orb allele lay eggs with ventralized eggshell structures. Embryos that develop within these mutant eggs display posterior patterning defects and abnormal dorsoventral axis formation. Consistent with such embryonic phenotypes, orb is required for the asymmetric distribution of oskar and gurken mRNAs within the oocyte during the later stages of oogenesis. In addition, double heterozygous combinations of orb and grk or orb and top/DER alleles reveal that mutations in these genes interact genetically, suggesting that they participate in a common pathway. Orb protein, which is localized within the oocyte in wild-type females, is distributed ubiquitously in stage 8-10 orb mutant oocytes. These data will be discussed in the context of a model proposing that Orb is a component of the cellular machinery that delivers mRNA molecules to specific locations within the oocyte and that this function contributes to both D/V and A/P axis specification during oogenesis.

Molecular genetics of the early stages of germ cell differentiation during Drosophila oogenesis.

Germ cells frequently develop in syncytial clusters. We are using molecular genetic approaches to the formation of these clusters in Drosophila as a paradigm for cellular differentiation. The genes described in this paper act during an initial step of cluster formation (bag-of-marbles gene [bam]) and near the end of syncytial divisions (orb gene). The results presented suggest that the bam gene product is required for the four incomplete cytokineses that characterize the initial stages of cluster formation. The orb gene, previously identified as an ovarian-specific cDNA which predicts a new member of the RNA-recognition motif family of RNA-binding proteins, is required for both early and late stages of oogenesis. Strong orb alleles arrest egg development at the time of nurse cell-oocyte cyst formation; weak alleles disrupt formation of the anteroposterior and dorsoventral axes within the oocyte during late oogenesis. We postulate that Orb is a constituent of cytoplasmic multiprotein complexes which deliver RNA molecules to specific addresses within the oocyte.

The human retinal degeneration slow (RDS) gene: chromosome assignment and structure of the mRNA.

Retinal degeneration slow (rds) is a mouse neurological mutation that is characterized phenotypically by abnormal development of rod and cone photoreceptors followed by their slow degeneration. This phenotype resembles the pathologic abnormalities seen in retinitis pigmentosa. The mouse rds gene has recently been cloned. Here we present the sequence of a full-length cDNA clone of the human RDS mRNA. We show that in human retina there are two RDS transcripts of 3.0 and 5.5 kb. By analysis of DNA from a panel of human X hamster somatic cell hybrids, and by direct in situ hybridization, we show that the RDS gene is located on the proximal short arm of human chromosome 6. Finally, we present information on the frequency of several observed restriction fragment length polymorphisms using the RDS cDNA. This information is of potential value for testing linkage of the RDS gene to the disease phenotype in families with retinitis pigmentosa.