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H Alder

Publications and source records attributed to H Alder.

At least 37 records · Page 2Linked to original sources
PubMed1996

Aberrant FHIT transcripts in Merkel cell carcinoma.

Merkel cell carcinoma is a rare neuroendocrine carcinoma of the skin which shares several features with small cell lung carcinoma. In a previous study, we reported a high frequency of abnormalities of the FHIT gene, located at 3p14.2, in small cell lung tumors. To determine the role of the FHIT gene in small cell neuroendocrine malignancies, 14 cases of Merkel cell carcinoma were analyzed by reverse transcription of FHIT mRNA followed by PCR amplification and sequencing of products. Eight of 14 tumors (57%) displayed abnormal FHIT products that lacked three or more exons of the FHIT gene. The pattern of abnormal transcripts was similar to that observed in small cell lung tumors, suggesting that FHIT abnormalities might be a common genetic marker of these two types of neuroendocrine tumors.

Acid Anhydride Hydrolases↗
PubMed1996

The evolutionary relationship among Caucasian MS patients and controls.

Previous observations suggest that the mitochondrial (mt)DNA may confer susceptibility to multiple sclerosis (MS). However, the proportion of affected individuals and the range of contributing mtDNA abnormalities are unknown. To help clarify this question, we analyzed the first hypervariable D-loop sequences of the mtDNA in a group of randomly selected Caucasian MS patients, in MS patients with prominent optic neuritis (PON) and in controls. Phylogenetic analysis of these D-loop sequences revealed that individuals in both groups of patients are generally scattered in the Caucasian phylogeny. However, a small cluster of unrelated MS patients identified by this analysis suggests that a maternal lineage with MS relevant mtDNA sequences may exist, and merits a more comprehensive study.

Base Sequence↗
PubMed1995

A novel t(9;11)(p22;q23) with ALL-1 gene rearrangement associated with progression of a myeloproliferative disorder to acute myeloid leukemia.

We have analyzed genomic DNAs from a patient who developed acute myeloid leukemia 1 year after a myeloproliferative disorder was diagnosed. The development of the acute leukemia was associated with the acquisition of a t(9;11)(p22;q23) chromosome translocation. ALL-1 gene rearrangement, on chromosome 11, was present at the onset of the acute phase, but not during the chronic phase of the myeloproliferative disorder. The genomic rearrangement on chromosome 9 was within an unidentified region. By the use of polymerase chain reaction, we were able to determine that the chromosomal rearrangement was completely absent during the chronic phase of the myeloproliferative disorder, indicating that the ALL-1 gene rearrangement was causally related to the development of the acute phase. The rapid progression into the acute phase suggests that this case might be therapy related. This work provides a clear example of association of a molecular defect with the development of a specific clinical leukemic stage, and supports the indication that ALL-1 gene rearrangement is associated with poor clinical outcome in adult leukemias.

Adult↗
PubMed1995

Junctional region of the myelin basic protein-specific T cell receptor beta chain in mice.

Evidence for the existence of both conserved and diverse amino acid sequences in the junctional regions of the myelin basic protein (MBP)-specific T cell receptors (TCR) in mice is presented. The junctional region of the Nac1-11 MBP peptide-specific, H-2u-restricted TCR beta-chains is characterized by the utilization of similar amino acid sequences. In contrast, diverse junctional sequences within the TCR beta-chains of the p89-101 MBP peptide and H-2s-restricted T cell clones are reported. These findings demonstrate that a limited heterogeneity of the MBP-specific T cell clones does exist. However, it may not be universal even in inbred mouse strains.

Amino Acid Sequence↗
PubMed1995

Characteristics of the T lymphocytes involved in experimental allergic encephalomyelitis.

Both heterogeneity and restricted heterogeneity of the encephalitogenic myelin basic protein (MBP) peptide-specific T cell receptors (TCRs) were demonstrated in inbred animals depending on the strain-specific genetic characteristics, the stage of the disease, the compartment of the lymphocytes obtained and the methodology used. Nevertheless, the similar features of some MBP-specific TCRs demonstrated across species suggest that conservation of these autoantigen-specific molecules undoubtedly exists, even though the degree of this conservation is controversial. However, the unequivocal heterogeneity of the immune response directed at one of the most important myelin constituents, proteolipid lipoprotein (PLP), which occurs either as a primary or a secondary event during experimental allergic encephalomyelitis (EAE), indicates the complexity of the in vivo situation. Intramolecular and intermolecular spreading of antigen specificity during the course of the disease indicates that a TCR directed therapy may not be the choice of intervention in established disease even in individual strains of laboratory animals with restricted heterogeneity of the primary MBP-specific response. Studying the sequence of events, the recruited regulatory cells and cytokines, and the stromal factors controlling persistence or death of activated, memory cells in the tissue lesion, may reveal new therapeutic modalities with more universal applicabilities.

Animals↗
PubMed1995

Mitochondrial DNA mutations in multiple sclerosis.

The presence of mitochondrial DNA mutations, including eight of those frequently associated with Leber's hereditary optic neuropathy (LHON), was investigated by sequencing and restriction endonuclease analysis in randomly selected patients with MS. Class I LHON mutations with primary pathogenic significance for blindness were not detected in any of the MS patients studied. A trend was observed for higher frequency of class II LHON mutations with unknown pathogenic significance in the MS patients than in the controls. Specifically, the mutation at position 4216 and its associated simultaneous mutations occurred with a higher frequency. Eleven of the 53 patients (20.8%) were positive for at least two (4216 and 4917 or 13,708) or three (4216, 13,708, 15,257) simultaneous class II LHON mutations, while 7 of the 74 controls (9.5%) carried simultaneous mutations (P = 0.036). Earlier studies reported the occurrence of either the 11,778 or 3460 LHON type mutations in MS patients with a positive LHON pedigree and/or with a disease course predominantly involving the optic nerves. The mutations we detected did not correlate with the severity of visual loss in either LHON or MS, rather they seemed to be present in randomly selected MS patients. We conclude that the mutations with primary pathogenic significance for blindness are not shared between LHON and randomly selected MS. However, the presence of further mitochondrial mutations cannot be excluded in MS. The increased incidence of the simultaneous class II LHON mutations in MS patients (and LHON) vs controls may indicate that certain sets of mitochrondrial DNA mutations/variants are associated with and predispose to MS, a possibility which needs to be investigated further. Alternatively, a biological disadvantage may be associated with the coexistence of the mutations detected.

DNA, Mitochondrial↗
PubMed1994

Leucine-zipper dimerization motif encoded by the AF17 gene fused to ALL-1 (MLL) in acute leukemia.

Chromosome region 11q23 is involved in reciprocal chromosome translocations associated with human acute leukemias. These aberrations fuse the ALL-1 gene located at 11q23 to a series of partner genes positioned on a variety of human chromosomes. The fused genes encode chimeric proteins. Here we report the cloning and characterization of the ALL-1 partner at 17q21, the AF17 gene. The AF17 gene encodes a protein of 1093 amino acids, containing a leucine-zipper dimerization motif located 3' of the fusion point and a cysteine-rich domain at the N terminus. The latter can be arranged in three zinc fingers and shows homology to a domain within the protein Br140 (peregrin). AF17 contains stretches of amino acids previously associated with domains involved in transcriptional repression or activation. Based on features of AF17 and of the proteins encoded by the other partner genes analyzed and in conjunction with other recent studies, we propose a model in which ALL-1 rearrangements result in loss of function of the gene. In this model, the partner polypeptide plays an accessory role either by repressing activity of the truncated ALL-1 protein or by blocking the function of the normal protein presumably present in the leukemic cells.

Amino Acid Sequence↗
PubMed1994

Sequence analysis of the breakpoint cluster region in the ALL-1 gene involved in acute leukemia.

DNA rearrangements caused by chromosome translocations between band 11q23 and various chromosomes can be detected by a single probe, B859, an 859-base pair complementary DNA fragment derived from the human ALL-1 gene. To try to understand why band 11q23 becomes a frequent target of the translocations, we have sequenced the entire breakpoint cluster region, a 8342-base pair BamHI genomic fragment delineated by B859. We found eight Alu repeats located within this region in the same orientation as the ALL-1 gene. We have also analyzed the sequences of the breakpoints in 10 patients with 6 different types of 11q23 aberration. In five patients the breaks coincided with Alu sequences on chromosome 11, but not on the partner chromosomes. Also, seven of the breaks occurred in the region delineated by exons 6 and 7, which is composed mainly of Alu sequences. In three patients topoisomerase II recognition site-like sequences, at different stringency levels, were identified at the breakpoints on chromosome 11. We conclude that while there is no specific sequence element present at all the breakpoints, the high density of Alu sequences in the breakpoint cluster region possibly makes the latter more prone to recombination events.

Acute Disease↗
PubMed1993

Cloning of the ALL-1 fusion partner, the AF-6 gene, involved in acute myeloid leukemias with the t(6;11) chromosome translocation.

Reciprocal chromosome translocations involving 11q23 are frequently associated with acute leukemias, with the t(4;11) translocation predominating among acute lymphoblastic leukemias, and the t(9;11), t(11;19) and t(6;11) translocations most common among acute myeloid leukemias. In each of these translocations the ALL-1 gene, located at 11q23 and constituting the human homologue of Drosophila trithorax, fuses to a specific gene on the partner chromosome to produce a chimeric protein. Here we report the cloning and the characterization of the partner gene from chromosome 6 (AF-6). AF-6 is expressed in a variety of cell types and encodes a protein of 1612 amino acids. The protein contains short stretches rich in prolines, charged amino acids, serines, or glutamines. In addition, the AF-6 protein contains the GLGF motif shared with several proteins of vertebrates and invertebrates thought to be involved in signal transduction at special cell-cell junctions.

Amino Acid Sequence↗
PubMed1993

Analysis of the murine All-1 gene reveals conserved domains with human ALL-1 and identifies a motif shared with DNA methyltransferases.

A series of translocation break points found in a subset of human acute leukemias have one of the breaks on human chromosome 11q23. This region has recently been cloned and a large gene, ALL-1, with homology to the Drosophila trithorax gene has been identified. This paper describes the cloning, sequencing, and mapping of the mouse homolog of ALL-1. We have found a motif present in All-1 that shows homology to the zinc-binding domain of DNA (cytosine-5) methyltransferases (EC 2.1.1.63). Sequence analysis of the murine All-1 gene has identified distinct regions of homology with the human ALL-1 gene; these highly conserved domains may define regions of functional significance in mammals. In addition, we have identified alternatively spliced forms of All-1 within one of the zinc-finger domains, suggesting that there may be different targets and/or functions for All-1 proteins. Finally, we report that All-1 resides in the proximal portion of mouse chromosome 9 and is a candidate for a mutation that results in skeletal transformations during embryonic development.

Alternative Splicing↗
PubMed1993

Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs.

Chromosome translocations involving band 11q23 are associated with human acute leukemias. These translocations fuse the ALL-1 gene, homolog of Drosophila trithorax and located at chromosome band 11q23, to genes from a variety of chromosomes. We cloned and sequenced cDNAs derived from transcripts of the AF-4 and AF-9 genes involved in the most common chromosome abnormalities, t(4:11)(q21:q23) and t(9:11)(p22:q23), respectively. Sequence analysis indicates high homology between the AF-9 gene protein product and the protein encoded by the ENL gene fused to ALL-1 in (11:19) chromosome translocations. AF-4, AF-9, and ENL proteins contain nuclear targeting sequences as well as serine-rich and proline-rich regions. Stretches abundant in basic amino acids are also present in the three proteins. These results suggest that the different proteins fused to ALL-1 polypeptide(s) provide similar functional domains.

Acute Disease↗
PubMed1993

Safe Medical Devices Act of 1990: current hospital requirements and recommended actions.

Since the Safe Medical Devices Act of 1990 was signed into law, a great deal of confusion has surrounded it. This document reviews the current status of user reporting and device tracing--including the MEDWatch program--and the status of the final regulations. In addition, readers will learn what it all really means for hospitals and what incidents must now be reported to the FDA.

Equipment Safety↗
PubMed1992

The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene.

The ALL-1 gene located at human chromosome 11 band q23 is rearranged in acute leukemias with interstitial deletions or reciprocal translocations between this region and chromosomes 1, 4, 6, 9, 10, or 19. The gene spans approximately 100 kb of DNA and contains at least 21 exons. It encodes a protein of more than 3910 amino acids containing three regions with homology to sequences within the Drosophila trithorax gene, including cysteine-rich regions that can be folded into six zinc finger-like domains. The breakpoint cluster region within ALL-1 spans 8 kb and encompasses several small exons, most of which begin in the same phase of the open reading frame. The t(4;11) chromosome translocation results in two reciprocal fusion products coding for chimeric proteins derived from ALL-1 and from a gene on chromosome 4. This suggests that each 11q23 abnormality gives rise to a specific oncogenic fusion protein.

Amino Acid Sequence↗
PubMed1992

The (4;11)(q21;q23) chromosome translocations in acute leukemias involve the VDJ recombinase.

Chromosomal region 11q23 is frequently rearranged in acute lymphocytic leukemias (ALLs) and in acute myeloid leukemias (AMLs), mostly in reciprocal exchanges with various translocation partners. The most common of these translocations is t(4;11)(q21;q23). It is present in approximately 10% of ALL patients, most frequently in very young children. We have recently cloned a region of chromosome 11, the ALL-1 locus, found to be rearranged in malignant cells from patients with the t(4;11), t(9;11), t(11;19), t(1;11), t(6;11), t(10;11), and del(11q23) chromosomal abnormalities. Here we report the cloning and characterization of chromosomal breakpoints from leukemic cells with t(4;11) aberrations. The breakpoints cluster in regions of 7-8 kilobases on both chromosomes 4 and 11. The presence of heptamer- and nonamer-like sequences at the sites of breakage suggests that the VDJ recombinase utilized for immunoglobulin gene rearrangement is also directly involved in these translocations. We also show that leukemic cells with t(4;11) express altered RNAs transcribed from the derivative chromosomes 11 and 4.

Acute Disease↗
PubMed1992

Inhibition of cell cycle progression by antisense oligodeoxynucleotides.

We have used the antisense strategy to study the role of certain genes in cell cycle progression. In particular, we used antisense oligodeoxynucleotides to study: (1) the role of the IGF-1 receptor in the control of cell proliferation; and (2) the sequence of gene expression during the cell cycle. Our results can be summarized as follows: (1) the activation of the IGF-1 receptor by its ligand, IGF-1, is an obligatory step in the proliferation of fibroblasts and hemopoietic cells; and (2) the expression of DNA synthesis genes, such as PCNA, DNA polymerase alpha, and cdc2, is dependent on the expression of previous genes. A tentative temporal order is: c-myc > c-myb > IGF-1 receptor > DNA synthesis genes.

Animals↗
PubMed1992

Cell cycle effects of microinjected antisense oligodeoxynucleotides to p34cdc2 kinase.

In this study the effect of antisense oligomers targeted against the mRNA transcripts of p34cdc2 kinase on G1 progression into S-phase was examined. For this purpose, antisense, sense, or nonsense oligomers were introduced directly into the cytoplasm of T98G cells grown in monolayer cultures by glass-capillary microinjection. The microinjection of antisense oligomers (but not sense or nonsense oligomers) into growth-arrested cells before serum stimulation inhibited G1 progression into S-phase. This inhibition was correlated with a reduction in the steady-state levels of nuclear p34cdc2 protein. Microinjection of antisense oligomers into cells at 2 and 6 hours after serum stimulation also resulted in a marked inhibition in the ability of cells to enter S-phase. The inhibitory effect decreased when cells were microinjected at 12 hours after serum stimulation. When cells were microinjected at 18 and 24 hours after serum stimulation, only a slight inhibition was observed. As the antisense oligomers were introduced directly into the cytoplasm of cells at each of the time points examined, the observed differences in the inhibitory effects of the antisense oligomers at later times after serum stimulation cannot be explained by differences in uptake. An alternative explanation is that after a certain threshold level of nuclear p34cdc2 protein is reached in late G1 phase; no further increase is necessary, because the cells become committed to enter S-phase. In yeast, p34cdc2 appears to play an important role in the G1/S-phase transition at a control point in late G1 phase called START (reviewed by Lewin). In mammalian cells a control point that could be equivalent to START is the "restriction point" which is defined as the time after which inhibition of protein synthesis fails to block entry into S-phase (reviewed by Pardee). The effects observed with antisense oligomers to p34cdc2 kinase are strikingly similar to what is observed when low concentrations of the drug cycloheximide are added to these cells at different times after serum stimulation; entry into S-phase is significantly inhibited when cycloheximide is added up to 12 hours postimulation. Thus, the results reported in this study are in agreement with the idea that p34cdc2 kinase plays a role in the G1/S phase transition in mammalian cells. Finally, introduction of antisense oligomers directly into the cytoplasm of cells grown in monolayer cultures by glass-capillary microinjection appears to be a viable alternative to simply adding the oligomers to the culture medium.(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗