Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Down syndrome (DS) is a major cause of congenital heart and gut disease and mental retardation. DS individuals also have characteristic facies, hands, and dermatoglyphics, in addition to abnormalities of the immune system, an increased risk of leukemia, and an Alzheimer-like dementia. Although their molecular basis is unknown, recent work on patients with DS and partial duplications of chromosome 21 has suggested small chromosomal regions located in band q22 that are likely to contain the genes for some of these features. We now extend these analyses to define molecular markers for the congenital heart disease, the duodenal stenosis, and an "overlap" region for the facial and some of the skeletal features. We report the clinical, cytogenetic, and molecular analysis of two patients. The first is DUP21JS, who carries both a partial duplication of chromosome 21, including the region 21q21.1-q22.13, or proximal q22.2, and DS features including duodenal stenosis. Using quantitative Southern blot dosage analysis and 15 DNA sequences unique to chromosome 21, we have defined the molecular extent of the duplication. This includes the region defined by DNA sequences for APP (amyloid precursor protein), SOD1 (CuZn superoxide dismutase), D21S47, SF57, D21S17, D21S55, D21S3, and D21S15 and excludes the regions defined by DNA sequences for D21S16, D21S46, D21S1, D21S19, BCE I (breast cancer estrogen-inducible gene), D21S39, and D21S44. Using similar techniques, we have also defined the region duplicated in the second case occurring in a family carrying a translocation associated with DS and congenital heart disease. This region includes DNA sequences for D21S55 and D21S3 and excludes DNA sequences for D21S47 and D21S17.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Down syndrome: molecular mapping of the congenital heart disease and duodenal stenosis. 153 Nov 66

This study was undertaken in an attempt to evaluate the structure-activity relationship of pyrimidinones. Of 20 pyrimidinones tested, only those with a monohalogen substitution at the ortho- or meta-position of the phenyl moiety of the 2-amino-5-halo-6-phenyl-4(3H)-pyrimidinone and ABPP showed statistically significant synergism with cyclophosphamide (CY) against P388 leukemia. Therefore, ABMFPP, AIMFPP, and ABPP were selected for detailed therapeutic evaluation. The pyrimidinone alone had small but significant activity against B16 melanoma with slightly more than a 25% increase in lifespan (ILS); however, when used in combination with CY, ABPP or ABMFPP did not yield an effect greater than treatment with CY alone. Only AIMFPP appeared to produce a more or less additive effect with CY. Although none of these pyrimidinones alone had any significant activity against M5076 tumor, the combination with CY (100 mg/kg) produced a range of 102 to 123% ILS and six to nine of 10 mice per group survived greater than 45 days, whereas the treatment with CY alone yielded only a 48% ILS and none survived greater than 45 days. The synergism of the combination therapy was statistically significant (p less than 0.01). The combination used against L1210 leukemia also appeared to be superior to the treatment with CY alone and produced 25 to 50% long-term survivors (greater than 30 days). The significance of these findings is discussed in terms of its clinical implications.
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PMID:Antitumor activity of pyrimidinones, a class of small-molecule biological response modifiers. 355 28

Bropirimine (ABPP), a pyrimidinone, is currently under clinical trial for its antitumor potential. Bropirimine alone was marginally active against some experimental tumors such as B16 melanoma but was ineffective against others such as P388 or L1210 leukemia. However, it produced statistically significant synergistic activity against P388 leukemia when used in combination with cyclophosphamide (CY). The aim of this investigation was to determine whether the synergism could be achieved with different types of cytotoxic drugs. Actinomycin D (act D), adriamycin, 5-azacytidine, cisplatin, melphalan, mitomycin C, and vincristine were selected. Using an experimental protocol identical to that of CY and bropirimine combination therapy, and using a more or less equally effective dosage of the drug for the initial reduction of tumor burden (i.e., around 100% increase of life span), cisplatin and bropirimine also produced a statistically significant synergism over the treatment with cisplatin alone. The combination of bropirimine with either adriamycin, mitomycin, or vincristine was beneficial but the effect was not as consistent or as striking as that seen with the CY and bropirimine combination. It is clear, however, that the combination of act D and bropirimine was not synergistic under the experimental conditions. Since the antitumor activity of pyrimidinone has been reported to be mediated in part by its stimulation of natural killer cell activity, the effect of these cytotoxic drugs on the immunomodulatory activity of bropirimine was investigated. Like CY, cisplatin did not alter the augmentation of natural killer cell activity by bropirimine. However, adriamycin, mitomycin, or vincristine showed a marked inhibition (25-50%) of the augmentation. Act D completely inhibited the immunomodulating activity of bropirimine 4 days after drug administration and continued to show marked inhibition 18 days later. This may partially explain the reasons for lack of synergism between act D and bropirimine. A prolonged immunosuppressive effect exhibited by act D and the degree of tumor repopulation during this period could render bropirimine ineffective. In addition to the magnitude of initial tumor burden reduction by the chemotherapeutic drugs, the present results indicate that the immunosuppressive property of these drugs may also affect the outcome of chemoimmunotherapy.
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PMID:Relationship between modulation of natural killer cell activity and antitumor activity of bropirimine when used in combination with various types of chemotherapeutic drugs. 366 90

Progressive presenile dementia with lipomembranous polycystic osteodysplasia was first described by Jarvi and Hakola in an isolated region of Finland. We report the occurrence of this disorder in 4 of 10 siblings in an American family of Czechoslovakian ancestry. Characteristics of the disease include multiple bone cysts with pathologic fractures, progressive dementia with seizures and abnormal EEG, calcification of basal ganglia, and death in the fourth to six decades. Autosomal-recessive inheritance is likely. Electronmicroscopy of fat cells reveals peculiar membrane convolutions. Limited neuropathologic material has shown gliosis and demyelination of white matter, senile plaques, and neurofibrillary tangles. Leukemia and a disorder of intestinal motility may be associated findings. Prevalence of the disorder is unknown, partly because it may be confused with Alzheimer disease and fibrous dysplasia of bone. Radiographs of hands and feet should be part of the evaluation of patients with unexplained presenile dementia.
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PMID:Lipomembranous polycystic osteodysplasia (brain, bone, and fat disease): a genetic cause of presenile dementia. 668 64

An adult man presented with loss of weight and this progressed over several months before the appearance of signs of neurologic disease. Autopsy showed histiocytic lymphoma with extensive meningeal spread and dense infiltration of the hypothalamus. This diencephalic syndrome has been reported with cerebral tumor, leukemia, encephalitis lethargica, multiple sclerosis, and Alzheimer disease, CT of the brain and examination of the CSF may be helpful in diagnosis.
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PMID:Cerebral histiocytic lymphoma presenting with loss of weight. 704 29

The central nervous system deposition by neurons and glia of beta A4 amyloid protein is an important contributing factor to the development of Alzheimer's disease. Amyloidogenic cells overexpress amyloid precursor protein (APP) mRNAs suggesting a transcriptional or post-transcriptional defect may contribute to this process. We have previously shown that APP mRNAs display regulated stability which is dependent on a 29-base element within the 3'-untranslated region (UTR). This domain specifically interacted with several cytoplasmic RNA-binding proteins. We have purified these APP RNA-binding proteins from a human T-cell leukemia and demonstrate that five cytoplasmic proteins of 70, 48, 47, 39, and 38 kDa form the previously observed APP RNA protein complexes. Amino acid sequence analyses showed that the 70-, 48-, and 47-kDa proteins were fragments of nucleolin and that the 39- and 38-kDa proteins were heterogeneous nuclear ribonucleoprotein (hnRNP) C protein. Northwestern and Western blot analyses of purified material further confirmed these data. Nucleolin protein is known to shuttle between the nucleus and cytoplasm but hnRNP C has not been reported within the cytoplasm. This report of sequence specific, mRNA binding by nucleolin and hnRNP C suggests that these proteins participate in the post-transcriptional regulation of APP mRNA through 3'-UTR, site-specific interactions.
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PMID:Nucleolin and heterogeneous nuclear ribonucleoprotein C proteins specifically interact with the 3'-untranslated region of amyloid protein precursor mRNA. 761 29

This review discusses the research published in the last five years on the behavioral, genetic, medical, and neuroscience aspects of Down syndrome. The subject areas that have experienced the most active research include Alzheimer disease, language development, leukemia, and pregnancy screening and diagnosis. These and other areas are reviewed.
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PMID:Down syndrome: progress in research. 1124 81

We describe a 64-year-old woman with biphenotypic leukemia involving the meninges who received 2 doses of intrathecal methotrexate. Soon after treatment, the patient developed postural rigidity and a marked decline in mental status. The patient died of respiratory failure 1 month after methotrexate treatment was initiated. At autopsy, the brain was grossly normal. Routine microscopy showed no evidence of leukemic infiltrates or necrotizing lesions. However, when stained with beta-amyloid precursor protein, multifocal axonal injury was evident in the brain, spinal cord, and nerve roots. Our findings show that immunohistochemical staining for beta-amyloid precursor protein can effectively demonstrate axonal injury associated with methotrexate neurotoxicity, even when conventional staining procedures are negative. This technique may therefore reveal a possible pathologic substrate for some of the neurological complications seen in patients with methotrexate neurotoxicity.
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PMID:Methotrexate-related nonnecrotizing multifocal axonopathy detected by beta-amyloid precursor protein immunohistochemistry. 1224 Jun 24

Cytonectin is a novel 35,000 molecular weight protein that displays remarkable ion-independent adherence properties. This consigns it to a family of well-known adherence molecules essential for cell communication and the development of 3-dimensional tissue structures. Cytonectin is expressed in a variety of organs and tissues, being evolutionarily conserved from human to avian species. It is hypothesized to serve as a key structural component of the body, and as a "do not attack" signal molecule that prevents tissue destruction by cells of monocyte lineage. This paper describes the properties of cytonectin and its proposed role in normal and disease states. The protein is overexpressed in Alzheimer disease entorhinal cortex as compared to normal age-matched controls. It is also detected in tissues from patients with Down syndrome and leukemia. Its presence in all 3 of these related conditions may prove important to their etiopathogenesis.
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PMID:Cytonectin expression in Alzheimer disease. 1189 37

Alzheimer's disease is characterized by deposition of beta-amyloid peptide (Abeta) into plaques in the brain, leading to neuronal toxicity and dementia. Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system can also cause a dementia, and amyloid deposition in the central nervous system is significantly higher in HIV-1-infected individuals compared with uninfected controls. Here we report that Abeta fibrils stimulated, by 5-20-fold, infection of target cells expressing CD4 and an appropriate coreceptor by multiple HIV-1 isolates but did not permit infection of cells lacking these receptors. Abeta enhanced infection at the stage of virus attachment or entry into the cell. Abeta fibrils also stimulated infection by amphotrophic Moloney leukemia virus, herpes simplex virus, and viruses pseudotyped with the envelope glycoprotein of vesicular stomatitis virus. Other synthetic fibril-forming peptides similarly enhanced viral infection and may be useful in gene delivery applications utilizing retroviral vectors. These data suggest that Abeta deposition may increase the vulnerability of the central nervous system to enveloped viral infection and that amyloidogenic peptides could be useful in enhancing gene transfer by enveloped viral vectors.
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PMID:Stimulation of enveloped virus infection by beta-amyloid fibrils. 1211 88


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