Biomedical subjects
N Zhao
Publications and source records attributed to N Zhao.
Molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases to 1-1.5 Mb and preparation of a PAC-based physical map.
Loss of a whole chromosome 5 or a deletion of the long arm, del(5q), is a recurring abnormality in malignant myeloid diseases. In previous studies, we delineated a commonly deleted segment of approximately 4 Mb within band 5q31 that was flanked by IL9 on the proximal side and D5S166 on the distal side. We have generated a physical map of P1 (PAC), bacterial (BAC), and yeast artificial chromosome (YAC) clones of this interval. The contig consists of 108 clones (78 PACs, 2 BACs, and 28 YACs) to which 125 markers (5 genes, 11 expressed sequence tags, 12 polymorphisms, and 97 sequence-tagged sites) have been mapped. Using PAC clones for fluorescence in situ hybridization analysis of leukemia cells with a del(5q), we have narrowed the commonly deleted segment to 1-1.5 Mb between D5S479 and D5S500. To search for allele loss, we used 7 microsatellite markers within and flanking the commonly deleted segment to examine leukemia cells from 28 patients with loss of 5q, and 14 patients without cytogenetically detectable loss of 5q. In the first group of patients, we detected hemizygous deletions, consistent with the cytogenetically visible loss; no homozygous deletions were detected. No allele loss was detected in patients without abnormalities of chromosome 5, suggesting that allele loss on 5q is the result of visible chromosomal abnormalities. The development of a stable PAC contig and the identification of the smallest commonly deleted segment will facilitate the molecular cloning of a myeloid leukemia suppressor gene on 5q.
dic(5;17): a recurring abnormality in malignant myeloid disorders associated with mutations of TP53.
We have identified three unbalanced translocations involving chromosomes 5 and 17, der(5)t(5;17), der(17)t(5;17), and dic(5;17), in the malignant cells from 17 patients with myeloid neoplasms. Six patients had a primary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) de novo; ten patients had therapy-related MDS and/or AML (t-MDS/t-AML), and one patient had chronic myelogenous leukemia in myeloid blast phase. Two of the six patients with MDS or AML de novo had extensive exposure to industrial solvents, and one patient had Seckel syndrome. The primary diagnoses for the ten patients with t-MDS/t-AML were breast carcinoma and Hodgkin's disease in two patients each, and non-Hodgkin's lymphoma, multiple myeloma, chronic lymphocytic leukemia, ovarian carcinoma, thyroid carcinoma, and rhabdomyosarcoma in one patient each. Four patients had received both prior chemotherapy and radiotherapy, four others received prior chemotherapy only, and the remaining two patients only prior radiotherapy. Fluorescence in situ hybridization of centromere-specific probes for chromosomes 5 and 17 revealed that a dicentric rearrangement was the most common (13/16 patients examined). The genetic consequences of these chromosomal rearrangements are partial monosomy for 5q and 17p. Two of six patients examined had point mutations in TP53, suggesting that loss of function of TP53 in addition to loss of a tumor suppressor gene on 5q may be involved in the pathogenesis of the malignant disease in some of these patients.
AF10 is split by MLL and HEAB, a human homolog to a putative Caenorhabditis elegans ATP/GTP-binding protein in an invins(10;11)(p12;q23q12).
Invins(10;11)(p12;q23q12) is one of the rare but recurring chromosome rearrangements seen in acute monoblastic leukemia. We cloned the proximal 10p breakpoint from one patient and showed that the MLL gene at 11q23 was fused to the 3' portion of AF10 at 10p12. In addition, we cloned the telomeric 10p junction and we found that the 5' portion of AF10 was juxtaposed to a previously unidentified gene at 11q12, which we call HEAB (a human homolog to a hypothetical Caenorhabditis elegans ATP/GTP-binding protein). These results indicate that the AF10 gene is split into a 5' AF10 and a 3' AF10 portion by the 11q23q12 chromosome segment and that both breakpoint junctions result in fusion transcripts of 5' AF10/HEAB and MLL/3' AF10. Only the MLL/3' AF10 fusion mRNA results in an in-frame fusion. Northern blot analysis of HEAB expression shows that a 2.0-kb major transcript is expressed ubiquitously in human tissues and is especially abundant in testis and skeletal muscle, whereas a 3.2-kb minor transcript is noted with the highest level of expression in thymus and peripheral blood leukocytes. The HEAB gene encodes a 425-amino acid protein that is rich in valine and leucine. HEAB protein shows high homology in its entire amino acid sequence to a putative C elegans protein and contains an adenosine triphosphate (ATP)/guanosine triphosphate (GTP)-binding motif that has homology to the ATP-binding transporter superfamily or to GTP-binding proteins. Our results could explain the high frequency of complex insertion and other rearrangement events that involve 10p12 and 11q12 and 11q23. The finding that different portions of a single gene are involved in fusions with two independent genes in the same leukemic cell is unique in the analysis of chromosome translocations.
Search for an endogenous mammalian cardiotonic factor.
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Combined analysis of case-control studies of smoking and lung cancer in China.
Fifteen case-control studies on the relationship between smoking and lung cancers in China were analyzed and evaluated by the method of meta-analysis, using both the fixed-effect and the random-effect models. The cumulative cases and controls were 5703 and 5669, respectively. Calculations based on the fixed-effect model resulted in a combined odds ratio (OR) of 2.19, 95% CI, 2.03-2.73, with a population attributable risk (PAR) of 33.64%. A dose-response relationship between the amount of smoking, the duration of smoking (years), the age at which smoking started and the OR for developing lung cancer was found. The pooled OR for squamous cell carcinoma was 4.79, 95% CI, 4.02-5.70, with a PAR of 65.44%. The combined OR for adenocarcinoma was 1.02, 95% CI, 0.87-1.20, with a PAR of 0.99%. To further investigate the relationship between smoking and lung cancer in Chinese women, twelve case-control studies were analyzed by meta-analysis, using the fixed-effect model. The cumulative cases and controls were 2168 and 2496, respectively. The combined OR was 2.19, 95% CI, 1.93-2.48, and the PAR was 30.34%. The combined OR for female squamous cell carcinoma was 7.45, 95% CI, 5.21-10.67, with a PAR of 53.97%. The combined OR for female adenocarcinoma was 1.09, 95% CI, 0.82-1.94, with a PAR of 1.65%. The combined OR for exposure to environmental tobacco smoke (ETS) was 1.004, 95% CI, 0.74-1.35 and the PAR was only 0.16%. The possible bias and confounding factors for this analysis are also discussed.
[Studies on the characteristics of leukotriene B4 receptor with radio-ligand binding assay].
Leukotriene B4 (LTB4), one of the metabolites of arachidonic acid via 5-lipoxygenase (5-LO), plays important role in some inflammatory diseases as one of the most potent chemotaxis factor. A radio-ligand binding assay was set up and the characteristics of LTB4 receptor on guinea-pig splenocytes membrane were studied. At 25 degrees C, the Kd was found to be 1.55 x 10(-9) mol.L-1 and the Bmax was 2.59 x 10(-13) mol.mg-1 protein. The assay established was evaluated by nordihydroguaiaretic acid (NDGA) as positive control.
High-density cDNA filter analysis of the expression profiles of the genes preferentially expressed in human brain.
We previously established a method, called high-density cDNA filter analysis (HDCFA), for analyzing the expression profiles of a large number of genes in a systematic manner. In the present study, we constructed a cDNA filter of about 8300 cDNAs from a human cerebral cortex cDNA library and quantitatively analyzed their expression in human adult brain, fetal brain, kidney and liver using HDCFA. Using a comparison of the relative amount of expression of each clone in different tissues and following (partial) sequence analysis, about 200 clones were selected as those preferentially expressed in adult or fetal brain, one half of which may be unknown. Their expression was further analyzed in human neuroblastoma cell lines, a human glioma cell line, human cerebral cortex, cerebellum and kidney. Finally, eight clones were selected and sequenced as characteristically expressed genes (cDNAs). A homology search revealed that three clones were human homologues of the rat genes preferentially expressed in brain and five clones were unknown. The full-length cDNA sequence of one of the unknown clones was determined.
Na,K-ATPase inhibitors from bovine hypothalamus and human plasma are different from ouabain: nanogram scale CD structural analysis.
The specific, high affinity binding of plant-derived digitalis glycosides by the mammalian sodium and potassium transporting adenosine triphosphatase (Na,K-ATPase, or sodium pump), a plasma membrane enzyme with critical physiological importance in mammalian tissues, has raised the possibility that a mammalian analog of digitalis might exist. We previously isolated and structurally characterized from bovine hypothalamus a novel isomer of the plant glycoside, ouabain, which differs structurally only in the attachment site and/or the stereochemistry of the steroid moiety [Tymiak et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 8189-8193]. Hamlyn and co-workers reported a molecule purified from human plasma which by mass spectrometry could not be distinguished from plant ouabain [Hamlyn et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 6259-6263]. Since rhamnoside cardiotonic steroids are not known as natural products from mammalian sources, it became important to compare these two pure isolates to determine if the same or structurally distinct compounds has been found. Our results indicate that the human and bovine Na,K-ATPase-inhibitors are identical, but different from plant ouabain. This supports the notion that the human sodium pump may be under specific physiological regulation by a mammalian analog of the digitalis glycosides.
High-density cDNA filter analysis: a novel approach for large-scale, quantitative analysis of gene expression.
In order to analyze the expression profiles of a large number of genes in the tissues (or cells) of interest, and to identify the genes preferentially expressed in the tissues, we have developed a large-scale gene expression analysis system. It is based on the hybridization of the mRNAs from the tissues with a high-density cDNA filter followed by the quantitative measurement of the amount of the hybridized mRNA on each cDNA spot. By employing a high-performance bioimaging analyzer, the system allowed us to compare the expression profiles of thousands of genes (cDNAs) simultaneously with a sensitivity comparable to conventional Northern blotting analysis. By this system (called high-density cDNA filter analysis or HDCFA), the expression profiles of 2505 cloned human brain cDNAs (genes) were monitored. Through the comparison of the expression profiles of these cDNAs in the adult brain, fetal brain and adult liver, about one half of these brain cDNAs (1239 clones) were identified as the candidates which were expressed preferentially in the brain. Among these, 408 and 288 clones were found to be preferentially expressed in the adult and fetal brain, respectively. The results have shown that the system may be widely applicable for analysis of the gene expression profiles of various tissues on a large scale.
Combined synthetic/CD strategy for the preparation and configurational assignments of model acyclic 1,3-polyols with a 1,2-diol terminal.
Acyclic 1,3-polyols or skipped polyols are widely distributed in nature. Particularly skipped 1,3-polyols with a terminal 1,2-diol group are present in numerous antifungal polyene macrolides in various masked forms. Although over 200 polyene macrolides are known, the planar structures of only about 40 have been determined, while those for which the full stereochemistry has been elucidated is less than ten. No simple method exists for configurational assignments of the 1,3-polyols moieties; moreover, this class of compounds are difficult to crystallize. In order to develop a general chiroptical method for structure determination of acyclic 1,3-polyols, we have combined a divergent synthetic approach with CD to prepare all possible stereoisomers of 1,2,4-triols, 1,2,4,6-tetrols and 1,2,4,6,8-pentols. The current set of reference polyols should be useful for setting up reference CD libraries and for model studies leading to a general method for configurational assignment of acyclic polyols. This strategy can be used to synthesize further extended members of acyclic 1,3-polyols and mixed 1,2/1,3-polyols which can be used for structural investigations of polyene macrolides and related compounds.
Phylogenetic evidence for the transfer of Pseudomonas cocovenenans (van Damme et al. 1960) to the genus Burkholderia as Burkholderia cocovenenans (van Damme et al. 1960) comb. nov.
Pseudomonas cocovenenans, the producer of bongkrekic acid and toxoflavin, has been described previously by us (N.-X. Zhao, M.-S. Ma, Y.-P. Zhang, and D.-C. Xu, Int. J. Syst. Bacteriol. 40:452-455, 1990) in terms of more than 180 phenotypic traits, G+C content, and DNA relatedness. The bacterium conformed to section II of the genus Pseudomonas. Here, its partial 16S rRNA gene sequence was compared with those of Burkholderia spp., and the results verified that P. cocovenenans is a Burkholderia species. On the basis of the phenotype and genetic characteristics, P. cocovenenans is transferred to the genus Burkholderia as Burkholderia cocovenenans comb. nov.
Cloning and sequence analysis of the human SNAP25 cDNA.
During the screening of human brain-specific cDNAs by a modified differential hybridization analysis, we found a clone which was highly and specifically expressed in the (adult) brain. This clone was subjected to nucleotide sequence analysis and proven to be a nearly full-length cDNA of a human homologue of the previously reported mouse synaptosomal-associated protein 25 (mSNAP25). The human SNAP25 (hSNAP25) and mSNAP25 showed perfect amino-acid sequence conservation.
Absolute stereochemistry of natural 3,4-dihydroxy-beta-ionone glycosides by the CD exciton chirality method.
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Characterization of the interaction of the glp repressor of Escherichia coli K-12 with single and tandem glp operator variants.
The glp operons of Escherichia coli are negatively controlled by the glp repressor. Comparison of the repressor-binding affinities for consensus and altered consensus operators in vivo showed that all base substitutions at positions 3, 4, 5, and 8 from the center of the palindromic operator caused a striking decrease in repressor binding. Substitutions at other positions had a severe to no effect on repressor binding, depending on the base substitution. The results obtained indicate that the repressor binds with highest affinity to operators with the half-site WATKYTCGWW, where W is A or T, K is G or T, and Y is C or T. Strong cooperative binding of the repressor to tandem operators was demonstrated in vivo. Cooperativity was maximal when two 20-bp operators were directly repeated or when 2 bp separated the two operators. Cooperativity decreased with the deletion of 2 bp or the addition of 4 bp between the individual operators. Cooperativity was eliminated with a 6-bp insertion between the operators.
[Risk analysis of combination effects of risk factors for primary liver cancer].
Combination effects of major risk factors for primary liver cancer (PLC) was evaluated by generalized relative risk model to examine the adequacy of the multiplicative structure for describing the effects of them and to estimate their relative risk (RR) and population attributable risk (PAR). The results suggested combination effects of hepatitis B virus (HBV) infection and drinking pond-ditch water tended to be multiplicative, and that of aflatoxin B1 (AFB1) contamination and HBV infection and drinking pond-ditch water to be additive. The relative importance of these factors of PLC based on their RR and PAR was HBV infection, drinking pond-ditch water, and AFB1 contamination in proper order. Recognition of the mode of the combination effects of relevant risk factors was important for the causal explanation and public health practice.
[Modelling the general relative risk models in case-control studies of primary hepatocellular carcinoma].
This paper was to analyse the effect of risk factors of primary hepatocellular carcinoma (PHC). The analysis was carried on using the family of relative risk functions to asses which scale could better explain the risk structure underlying the data. The results showed that the risk factors of PHC in south area of China were HBV infection, family history of PHC, drank pond-ditch water, while the risk factors of PHC in north area were HBV infection, family history of PHC, history of hepatitis, drank alcohol. The results suggested that the combined effect of risk factors was near to multiplicative. Being able to discriminate between risk structures has important implications on causal interpretation and public health practice.
[Interaction among the relative risk factors of primary liver cancer in a case-control study].
This paper evaluates the combined effect of HBsAg, drinking water and aflatoxin B1 (AFB1) on the primary hepatocellular carcinoma (PHC) in a case-control study which was carried out in Fusui, Guangxi. We used relative risk model (from subadditive to supermultiplicative) to fit the relationship. The results showed that the combined effect of HBsAg infection and drinking pond-ditch water is nearly multiplicative, and the combined effect of HBsAg infection and AFB1 intake as well as drinking pond-ditch water and AFB1 intake were nearly additive.