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)

An isolate of Klebsiella oxytoca from the blood culture of a child with leukemia was found to produce two beta-lactamases, at least one of which conferred resistance to ceftazidime. Genes encoding both enzymes were located on a single self-transmissible 100-kb plasmid, pOZ201. This plasmid was introduced into Escherichia coli UB5201 (pACYC184), and the gene encoding one beta-lactamase was transposed onto plasmid pACYC184 by exploiting a gene dosage effect. The transposable gene was found to encode a TEM-12 enzyme as determined by nucleotide sequencing. This gene was subsequently transposed onto plasmid pUB307. The transposable element encoding the TEM-12 enzyme has been designated Tn841. Both plasmids pACYC184::Tn841 and pUB307::Tn841 were shown to encode a beta-lactamase with the same isoelectric point and substrate profile as the TEM-12 beta-lactamase. Transposon Tn841, at approximately 7 kb, is larger than TnA (4.8 kb) and transposes at a lower frequency. Although it produced a resolvase which can complement the resolvase of Tn3, its transposase function was not able to complement the transposition of a TnA element which lacked transposase. The occurrence of a gene encoding an extended-spectrum beta-lactamase on a transposable element in a clinically significant bacterium is potentially a cause for concern for the spread of resistance to the extended-spectrum cephalosporins.
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PMID:Transposition of the gene encoding a TEM-12 extended-spectrum beta-lactamase. 132 36

During a 10-year period, four patients with leukemia were identified who had Branhamella catarrhalis septicemia. Two patients had acute leukemia and the remaining two had chronic myelogenous leukemia with blastic transformation. All patients were febrile and neutropenic at the onset of the septicemia. After appropriate antibiotic therapy, they recovered from their infection despite persistence of neutropenia. Because beta-lactamase-producing bacteria are an increasing cause of nosocomial infections, treatment should be selected to cover them.
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PMID:Branhamella catarrhalis septicemia in patients with leukemia. 313 Jan 77

Three cefoxitin-resistant Escherichia coli isolates from stool specimens of a patient with leukemia were either resistant, intermediate, or sensitive to imipenem. Conjugation experiments showed that cefoxitin resistance, but not imipenem resistance, was transferable. All isolates were shown by isoelectric focusing to produce two beta-lactamases with isoelectric points of 5.4 (TEM-1, confirmed by sequencing of a PCR product) and >8.5 (consistent with a class C beta-lactamase). The gene coding for the unknown beta-lactamase was cloned and sequenced and revealed an enzyme which had 99.9% sequence identity with the plasmid-determined class C beta-lactamase CMY-2. The cloned beta-lactamase gene differed from blaCMY-2 at one nucleotide position that resulted in an amino acid change, tryptophan to arginine at position 221. We propose that this enzyme be designated CMY-4. Both the imipenem-resistant and -intermediate isolates lacked a 38-kDa outer membrane protein (OMP) that was present in the imipenem-sensitive isolate. The lack of an OMP alone did not explain the difference in carbapenem susceptibilities observed. However, measurement of beta-lactamase activities (including measurements under conditions where TEM-1 beta-lactamase was inhibited) indicated that the imipenem-intermediate isolate expressed six- to eightfold less beta-lactamase than did the other isolates. This study illustrates that carbapenem resistance in E. coli can arise from high-level expression of plasmid-mediated class C beta-lactamase combined with an OMP deficiency. Furthermore, in the presence of an OMP deficiency, the level of expression of a plasmid-mediated class C beta-lactamase is an important factor in determining whether E. coli isolates are fully resistant to carbapenems.
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PMID:Carbapenem resistance in Escherichia coli associated with plasmid-determined CMY-4 beta-lactamase production and loss of an outer membrane protein. 1022 37

A novel cephalosporin derivative of monohydroguaiaretic acid (cephem-M(3)N, 7) was synthesized and found to possess anticancer activity against human leukemia (K562), breast carcinoma (MCF7), human lung cancer (A549), human colon cancer (Colo205) and pancreatic cancer cells (Capan2 and MiaPaCa2). A tumor targeting fusion protein (dsFv3-beta-lactamase) was also used in conjunction with cephem-based M(3)N 7 and its potency toward K562, MCF7, A549, Colo205, Capan2, and MiaPaCa2 was found to approach that of the free M(3)N (4). In the presence of dsFv3-beta-lactamase, tumor cells were found to be much more susceptible to conjugate 7 than normal human embryonic lung (HEL) cells and normal fibroblasts (Hef522). These notions provide a new approach to the use of nordihydroguaiaretic acid (NDGA) and its derivatives for antitumor therapy.
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PMID:Design, synthesis, and biological evaluation of a cephalosporin-monohydroguaiaretic acid prodrug activated by a monoclonal antibody-beta-lactamase conjugate. 1211 Mar 14

Although nonhuman primates are genetically close to humans, their T cells do not support productive replication of HIV-1. In contrast, HIV-1 replicates in activated human CD4(+) T cells, monocytes, and metabolically active human cells of a variety of cell types become permissive for HIV-1 replication when transduced to express CD4 and CCR5 or CXCR4. The molecular basis of this species restriction to HIV-1 replication was investigated by using African green monkey and rhesus macaque cell lines that were stably transduced to express human CD4 and CCR5. The cells supported replication of cognate viruses [simian immunodeficiency virus from African green monkeys (SIV-AGM) and macaques (SIVmac239)] but did not support replication of an R5-tropic cytopathic HIV-1. A beta-lactamase-based HIV-1 entry assay was used to show that the virus efficiently entered the nonhuman primate cells. Provirus formation was reduced 50-fold compared with similarly infected human cells. Real-time PCR quantitation demonstrated that reverse transcription failed to initiate efficiently in the simian cells. The block to reverse transcription was overridden at multiplicity of infection >1 or by preincubation of the nonhuman primate cells with virus, a feature reminiscent of the Friend virus resistance gene-1 (FV-1), restriction to murine leukemia virus replication in mouse cells. Heterokaryon analysis in which human and simian cells were fused demonstrated that the block was dominant. These findings suggested that the primate cells contain a dominant inhibitor that prevents HIV-1 reverse transcription.
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PMID:A dominant block to HIV-1 replication at reverse transcription in simian cells. 1236 68

One of the most important steps in a productive viral infection is when the virus fuses to a cell membrane and delivers its genome into the cell cytosol. This dynamic event is mediated by interactions between specific virus envelope proteins with their cell-bound receptors. This process is exemplified by Moloney murine leukemia virus (Mo-MLV) where envelope protein interaction with its receptor, mCAT-1, leads to virus-cell membrane fusion and infection of cells. Here, fluorescent nanoparticles (NPs) were coated with Mo-MLV derived membranes (Mo-NPs) by extrusion. Electron microscopy and biochemical analysis showed tight association of the virus membranes and NPs. The coated NPs mimic native virus by binding and entering only cells expressing the virus receptor. Confocal microscopy revealed that the coated NPs were taken up into endocytic compartments containing receptor and were also seen associated with caveolin, a marker of caveolae. To demonstrate that the Mo-NPs could escape endosomes and deliver a protein cargo into the cell cytosol, beta-lactamase (betalac) was covalently coupled to the Mo-NP cores and incubated with cells. betalac activity was only detected in the cytosol of mCAT-1-expressing cells. This is the first time that virus proteins have been used to specifically target NPs to receptor-bearing cells as well as penetration into the cell cytosol. Extrusion provides a rapid, detergent-free method to couple virus membranes to NPs and should be readily applicable for many other virus and NP types.
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PMID:Targeting and penetration of virus receptor bearing cells by nanoparticles coated with envelope proteins of Moloney murine leukemia virus. 1709 66

Bacteremia due to Capnocytophaga sputigena occurred in a 4-year and 9-month-old Japanese girl patient with acute erythroblastic leukemia in Shinshu University Hospital, Japan. On her admission to the hospital, she had a temperature of 38.2 degrees C with canker sore. Prior to the commencement of chemotherapy, peripheral blood culture was carried out with the BacT/Alert 3D System ver. 4.00D (bioMerieux Japan Ltd., Tokyo, Japan) using both the PF and the SN bottles. At 48 hrs of incubation, the System showed the positive sign only in the anaerobic SN bottle for bacterial growth. The strain isolated from the SN bottle was morphologically, biochemically, and genetically characterized, and finally identified as Capnocytophaga sputigena. The causative Capnocytophaga sputigena isolate was found to be a beta-lactamase-producer demonstrating to possess cfxA3 gene. The gene responsible for the production of CfxA3-beta-lactamase was proved to be chromosome-encoded, by means of southern hybridization analysis. This was the first case of bacteremia caused by chromosome-encoded CfxA3-beta-lactamase-producing Capnocytophaga sputigena.
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PMID:First case of bacteremia due to chromosome-encoded CfxA3-beta-lactamase-producing Capnocytophaga sputigena in a pediatric patient with acute erythroblastic leukemia. 1849 60

Signaling pathways and their protein target constituents (e.g. kinases) have become important therapeutic targets in many disease areas. Traditional selectivity profiling for kinase inhibitors has relied upon screening panels of recombinant enzymes in biochemical assay formats. Recent studies have highlighted the importance of using cellular assays to better approximate true biological selectivity. We have developed a portfolio of CellSensor beta-lactamase transcriptional reporter gene assays that can be used to screen for perturbagens of various endogenous signaling pathways. Here we describe a multi-pathway profiling approach for generating compound-pathway selectivity maps. To demonstrate the utility of this approach, we have screened 32 known compounds across a diverse panel of 12 key signaling pathways and generated the first comprehensive cellular pathway selectivity profiles of several clinically approved kinase and other well-known bioactive inhibitors. Selectivity score comparisons identified several kinase inhibitors that were more promiscuous than predicted by traditional biochemical profiling methods. For example, we identified effects of sorafenib on the JAK/STAT pathway and demonstrated the potential therapeutic indication of sorafenib in treating leukemia/myeloproliferative disorder patients harboring TEL-JAK2 or JAK2V617F mutations. Our results indicate that multi-pathway profiling can efficiently characterize both on and off-pathway compound activities, revealing potential novel pathways and opportunities for drug repositioning purposes and/or safety liabilities in one profiling campaign.
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PMID:Multi-pathway cellular analysis of compound selectivity. 2059 73

Acute leukemias are a group of aggressive malignant diseases associated with a high degree of morbidity and mortality. An important cause of both the latter is infectious complications. Patients with acute leukemia are highly susceptible to infectious diseases due to factors related to the disease itself, factors attributed to treatment, and specific individual risk factors in each patient. Patients with chemotherapy-induced neutropenia are at particularly high risk, and microbiological agents include viral, bacterial, and fungal agents. The etiology is often unknown in infectious complications, although adequate patient evaluation and sampling have diagnostic, prognostic and treatment-related consequences. Bacterial infections include a wide range of potential microbes, both Gram-negative and Gram-positive species, while fungal infections include both mold and yeast. A recurring problem is increasing resistance to antimicrobial agents, and in particular, this applies to extended-spectrum beta-lactamase resistance (ESBL), Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and even carbapenemase-producing Enterobacteriaceae (CPE). International guidelines for the treatment of sepsis in leukemia patients include the use of broad-spectrum Pseudomonas-acting antibiotics. However, one should implant the knowledge of local microbiological epidemiology and resistance conditions in treatment decisions. In this review, we discuss infectious diseases in acute leukemia with a major focus on febrile neutropenia and sepsis, and we problematize the diagnostic, prognostic, and therapeutic aspects of infectious complications in this patient group. Meticulously and thorough clinical and radiological examination combined with adequate microbiology samples are cornerstones of the examination. Diagnostic and prognostic evaluation includes patient review according to the multinational association for supportive care in cancer (MASCC) and sequential organ failure assessment (SOFA) scoring system. Antimicrobial treatments for important etiological agents are presented. The main challenge for reducing the spread of resistant microbes is to avoid unnecessary antibiotic treatment, but without giving to narrow treatment to the febrile neutropenic patient that reduce the prognosis.
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PMID:Febrile Neutropenia in Acute Leukemia. Epidemiology, Etiology, Pathophysiology and Treatment. 3193 19