Pharmacokinetic and pharmacodynamic studies of 9-aminocamptothecin in vitro against human cancer cells.
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Antineoplastic Agents↗
Biomedical subjects
M Li
Publications and source records attributed to M Li.
INDEPTH Wide-Angle Reflection Observation of P-Wave-to-S-Wave Conversion from Crustal Bright Spots in Tibet
Three-component wide-angle seismic data acquired in southern Tibet during Project INDEPTH show strong P-to-S converted reflections from reflectors that are aligned at a depth of approximately 15 kilometers beneath the northern Yadong-Gulu rift. These converted reflections are locally higher in amplitude than the corresponding P-wave reflections. Modeling of reflection mode conversion as a function of incidence angle indicates that this condition obtains for a reflector that is a solid over fluid interface; it is not typical of a solid-solid interface. The likely candidates for a fluid trapped within the crystalline crust of southern Tibet are granitic magma and water (brine).
Journal Article↗
Myelin-associated glycoprotein inhibits neurite/axon growth and causes growth cone collapse.
We have previously shown that myelin-associated glycoprotein (MAG) inhibits neurite growth from a neuronal cell line. In this study we show that 60% of axonal growth cones of postnatal day 1 hippocampal neurons collapsed when they encountered polystyrene beads coated with recombinant MAG (rMAG). Such collapse was not observed with denatured rMAG. Neurite growth from rat embryonic hippocampal and neonatal cerebellar neurons was also inhibited about 80% on tissue culture substrates coated with rMAG. To investigate further the inhibitory activity of MAG in myelin, we purified myelin from MAG-deficient mice and separated octylglucoside extracts of myelin by diethylaminoethyl (DEAE) ion-exchange chromatography. Although there was no significant difference in neurite growth on myelin purified from MAG-/- and MAG+/+ mice, differences were observed in the fractionated material. The major inhibitory peak that is associated with MAG in normal mice was significantly reduced in MAG-deficient mice. These results suggest that although MAG contributes significantly to axon growth inhibition associated with myelin, its lack in MAG-deficient mice is masked by other non-MAG inhibitors. Axon regeneration in these mice was also examined after thoracic lesions of the corticospinal tracts. A very small number of anterogradely labeled axons extended up to 13.2 mm past the lesion in MAG-/- mice. Although there is some enhancement of axon generation, the poor growth after spinal cord injury in MAG-/- mice may be due to the presence of other non-MAG inhibitors. The in vitro studies, however, provide the first evidence that MAG modulates growth cone behavior and inhibits neurite growth by causing growth cone collapse.
Animals↗
Evidence of hexatic phase formation in two-dimensional Lennard-Jones binary arrays.
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Journal Article↗
On the nearest neighbour interchange distance between evolutionary trees.
We present some new results on a well-known distance measure between evolutionary trees. The trees we consider are free 3-trees having n leaves labeled 0,...,n - 1 (representing species), and n - 2 internal nodes of degree 3. The distance between two trees is the minimum number of nearest neighbour interchange (NNI) operations required to transform one into the other. First, we improve an upper bound on the nni-distance between two arbitrary n-node trees from 4n log n (Culik & Wood, 1982, Inf. Pro. Letts. 15, 39-42) to n log n. Second, we present a counterexample disproving several theorems in (Waterman & Smith, 1978, J. theor. Biol. 73, 789-800). Roughly speaking, finding an equal partition between two trees does not imply decomposability of the distance finding problem. Third, we present a polynomial-time approximation algorithm that, given two trees, finds a transformation between them of length O(log n) times their distance. We also present some results of computations we performed on small size trees.
Algorithms↗
Kabuki syndrome is not caused by a microdeletion in the DiGeorge/velocardiofacial chromosomal region within 22q 11.2.
Kabuki syndrome (KS) or Niikawa-Kuroki syndrome is a sporadic disorder characterized by postnatal growth retardation, developmental delay, mild to moderate retardation, and a characteristic facial appearance. Cardiovascular defects, clefts of the lip, palate, or both, and musculoskeletal abnormalities occur in about 50% of patients with KS. The cause of this multiple congenital anomaly syndrome is unknown, and investigators have speculated that KS is a contiguous gene-deletion syndrome. Based on the presence of congenital heart defects in patients with KS, it was suggested that this disorder might share a common cause with the 22q11 deletion syndromes. A preliminary study of 2 patients with KS failed to detect a deletion within 22q11. We report the results of fluorescence in situ hybridization with cosmid probes for loci D22S75 (N25) and D22S259 (R32) within the DiGeorge chromosomal region (DGCR) on metaphase spreads from an additional 5 patients, 2 non-Japanese and 3 Japanese, with KS. None of the 5 had deletions at either locus. It is unlikely that KS is caused by a deletion within 22q11.
Abnormalities, Multiple↗
Role for Bcl-xL in the regulation of apoptosis by EGF and TGF beta 1 in c-myc overexpressing mammary epithelial cells.
We previously showed that TGF alpha synergizes with c-myc in mammary tumorigenesis through inhibition of Myc-induced apoptosis. We therefore examined the effects of growth factors on apoptosis induction in several cell lines from MMTV-myc mammary tumors. When EGF was withdrawn or TGF beta 1 was added, cells became apoptotic after 15 h (by ELISA and morphology). Northern and Western analysis revealed high levels of Bax and p53, and low or undetectable levels of Bcl-2 and Bcl-xS under all treatment condition. In contrast, Bcl-xL expression was highest in the presence of EGF or TGF alpha, with a significant reduction upon removal of EGF or exposure to TGF beta. In mouse mammary tumors, the relative Bcl-xL/Bax ratio was higher in TGF alpha/Myc double transgenics than in Myc single transgenics, in agreement with the in vitro data. Our results suggest a role for Bcl-xL in the regulation of apoptosis by EGF and TGF beta in mammary epithelial cells.
Animals↗
Inhibition of melanoma-associated antigen expression and ecotropic retrovirus production in B16BL6 melanoma cells transfected with major histocompatibility complex class I genes.
We have previously reported that expression of the melanoma-associated antigen (MAA) recognized by MM2-9B6 monoclonal antibody in B16 melanoma was closely associated with C-type ecotropic retroviral particle production. Our present data show that this MAA is encoded by the env gene of an ecotropic retrovirus produced by B16 melanoma cells. Transfection of H-2Kb or H-2Kd genes into two individual clones isolated from B16BL6 melanoma, BL6-8 (H-2Kb-, H-2Db+) and BL6-2 (H-2Kb-, H-2Db-), resulted in a loss of MAA expression. Electron immunohistochemical analysis of melanoma cells and reverse transcriptase assay revealed that the loss of MAA expression in the H-2K gene-transfected cells paralleled the elimination of retroviral particles. In contrast, expression of the endogenous H-2Db gene or transfection with the H-2Dd or H-2Ld gene had no effect on MAA expression or retrovirus production. Northern blot analysis showed equivalent retroviral messages in retrovirus-producing and -nonproducing BL6 melanoma clones. Southern blot analysis revealed that H-2Kb-negative BL6 melanoma cells contain at least four different ecotropic retroviruses with different insertion sites that somatically emerged during malignant transformation or progression. Restriction enzyme analysis showed various changes in proviral DNAs from the H-2Kb- and H2Kd-transfected cells that failed to produce retroviral particles. The observed alterations in the patterns of PstI- and HindIII-digested proviral DNA were found to be due to the appearance of PstI and loss of HindIII restriction sites in the pol region as a result of several nucleotide substitutions. Thus, BL6 melanoma cells produce melanoma-specific ecotropic murine leukemia viruses that encode serologically detectable cell surface MAA. The transfection of BL6 melanoma cells with H-2Kb or H2Kd genes but not H-2Dd or H-2Ld genes resulted in a loss of MAA expression that was attributed to the changes in proviral DNA and loss of melanoma-specific ecotropic retrovirus particle production.
Animals↗
Time-sensitive reversal of hyperplasia in transgenic mice expressing SV40 T antigen.
The role of viral oncoprotein expression in the maintenance of cellular transformation was examined as a function of time through controlled expression of simian virus 40 T antigen (TAg). Expression of TAg in the submandibular gland of transgenic mice from the time of birth induced cellular transformation and extensive ductal hyperplasia by 4 months of age. The hyperplasia was reversed when TAg expression was silenced for 3 weeks. When TAg expression was silenced after 7 months, however, the hyperplasia persisted even though TAg was absent. Although the polyploidy of ductal cells could be reversed at 4 months of age, cells at 7 months of age remained polyploid even in the absence of TAg. These results support a model of time-dependent multistep tumorigenesis, in which virally transformed cells eventually lose their dependence on the viral oncoprotein for maintenance of the transformed state.
Animals↗
Dirichlet boundary state in a linear dilaton background.
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Journal Article↗
Crystal structure of the catalytic domain of Pseudomonas exotoxin A complexed with a nicotinamide adenine dinucleotide analog: implications for the activation process and for ADP ribosylation.
The catalytic, or third domain of Pseudomonas exotoxin A (PEIII) catalyzes the transfer of ADP ribose from nicotinamide adenine dinucleotide (NAD) to elongation factor-2 in eukaryotic cells, inhibiting protein synthesis. We have determined the structure of PEIII crystallized in the presence of NAD to define the site of binding and mechanism of activation. However, NAD undergoes a slow hydrolysis and the crystal structure revealed only the hydrolysis products, AMP and nicotinamide, bound to the enzyme. To better define the site of NAD binding, we have now crystallized PEIII in the presence of a less hydrolyzable NAD analog, beta-methylene-thiazole-4-carboxamide adenine dinucleotide (beta-TAD), and refined the complex structure at 2.3 angstroms resolution. There are two independent molecules of PEIII in the crystal, and the conformations of beta-TAD show some differences in the two binding sites. The beta-TAD attached to molecule 2 appears to have been hydrolyzed between the pyrophosphate and the nicotinamide ribose. However molecule 1 binds to an intact beta-TAD and has no crystal packing contacts in the vicinity of the binding site, so that the observed conformation and interaction with the PEIII most likely resembles that of NAD bound to PEIII in solution. We have compared this complex with the catalytic domains of diphtheria toxin, heat labile enterotoxin, and pertussis toxin, all three of which it closely resembles.
ADP Ribose Transferases↗
Molecular identification of I1PP2A, a novel potent heat-stable inhibitor protein of protein phosphatase 2A.
The amino acid sequences of two tryptic peptides derived from purified preparations of I1PP2A indicated that this potent heat-stable protein inhibitor of protein phosphatase 2A (PP2A) may be equivalent to putative histocompatibility leukocyte antigens class II-associated protein I (PHAP-I). Experiments using purified preparations of recombinant human PHAP-I confirmed that this protein inhibited PP2A. Half-maximal inhibition of the phosphatase occurred at about 4 nM PHAP-I, similar to the half-maximal inhibition obtained with purified preparations of bovine kidney I1PP2A. In addition, PHAP-I did not affect the activities of protein phosphatase 1, 2B, and 2C in a manner analogous to that of I1PP2A. Together, the results establish the identity of I1PP2A on a firm basis.
Amino Acid Sequence↗
The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A.
Two potent heat-stable protein phosphatase 2A (PP2A) inhibitor proteins designated I1PP2A and I2PP2A have been purified to apparent homogeneity from extracts of bovine kidney (Li, M., Guo, H., and Damuni, Z. (1995) Biochemistry 34, 1988-1996). N-terminal and internal amino acid sequencing indicated that I2PP2A was a truncated form of SET, a largely nuclear protein that is fused to nucleoporin Nup214 in acute non-lymphocytic myeloid leukemia. Experiments using purified preparations of recombinant human SET confirmed that this protein inhibited PP2A. Half-maximal inhibition of the phosphatase occurred at about 2 nM SET. By contrast, SET (up to 20 nM) did not affect the activities of purified preparations of protein phosphatases 1, 2B, and 2C. The results indicate that SET is a potent and specific inhibitor of PP2A and suggest that impaired regulation of PP2A may contribute to acute myeloid leukemogenesis.
Amino Acid Sequence↗
Brain sigma receptors labelled by [3H]nemonapride.
Binding of [3H]nemonapride and [3H]raclopride was examined in the brain areas of three species (rat, cow and human). The results indicated that [3H]nemonapride binding is inhibited by selective sigma receptor ligands in frontal cortex, striatum and cerebellum. Only the striatum showed significant dopaminergic sites as defined by sulpiride. Use of the subtraction method of [3H]nemonapride minus [3H]raclopride binding as a measure of D4 dopamine receptor binding may, therefore, also include a sigma receptor component.
Animals↗
Cisplatin-DNA binding specificity of calf high-mobility group 1 protein.
We have identified a series of proteins with an affinity for cisplatin -damaged DNA using damaged DNA affinity chromatography. We have purified one of these proteins to homogeneity on the basis of a mobility shift assay detecting binding to cisplatin-damaged DNA. The protein was identified as high-mobility group 1 protein (HMG-1) by N-terminal protein sequence analysis. Analysis of a variety of DNA structures revealed that fully duplex DNAs were the best substrates for HMG-1 binding, while partial duplexes were less avidly bound. The decreased levels of binding are attributed to the length of the duplex region of the DNA substrates. A 3-fold increase in binding was observed when a cisplatin-damaged DNA substrate containing a single break in the phosphodiester backbone was joined by DNA ligase. The strict DNA size dependence of binding was also assessed, and a 10-fold increase in binding was observed when the length of the DNA duplex was increased from 44 to 180 base pairs (bp) at the same level of cisplatin damage. HMG-1 binding also was correlated with the degree of cisplatin-DNA damage, suggesting a higher affinity for DNA containing multiple cisplatin adducts. Nuclease degradation of the cisplatin-damaged DNA demonstrated that at the lowest levels of cisplatin damage all of the substrates contained at least one cisplatin adduct. The potential role of HMG-1 in the repair of cisplatin-DNA adducts is discussed.
Animals↗
Scavenging effect of Chinonin on NO and oxygen free radicals and its protective effect on the myocardium from the injury of ischemia-reperfusion.
The scavenging effect of Chinonin on NO and oxygen free radicals and its protective effect on myocardium from the ischemia-reperfusion injury was studied with electron spin resonance (ESR) and chemiluminescence techniques. Chinonin can effectively inhibit the oxidative activity of ONOO-, (the IC50 = 7 x 10 (-5) mmol/L) and scavenge oxygen free radicals generated from the reaction of xanthine and xanthine oxidase (the IC50 = 2/5 x 10(-4) mmol/l). It is difficult to find another antioxidant which can scavenge so effectively both ONOO- and oxygen free radicals simultaneously. In the system of ischemia-reperfusion injury of myocardium, Chinonin can, in parallel, scavenge the NO and oxygen free radicals generated from the ischemia-reperfused myocardium, and decrease the activities of lactate dehydrogenase (LDH) and creatine kinase (CK) in the coronary artery effluent of ischemia-reperfused heart and therefore protect the heart from ischemia-reperfusion injury. The protective effect of 0.1 mmol/l Chinonin is similar to that of 1500 U/ml SOD and catalase.
Animals↗
Reconstitution of human Fc gamma RIII cell type specificity in transgenic mice.
The human low affinity receptors for the Fc domain of immunoglobulin G, Fc gamma RIII, are encoded by two genes (IIIA and IIIB) which share >95% sequence identity in both coding and flanking sequences. Despite this extraordinary sequence conservation, IIIA is expressed in natural killer (NK) cells and macrophages and is absent in neutrophils, whereas IIIB is expressed only in neutrophils. To determine the molecular basis for this differential expression, we have generated transgenic mice using the genomic sequences of IIIA and IIIB. IIIA and IIIB transgenic mice show faithful reconstitution of this human pattern of cell type specificity. To determine the cis acting sequence elements that confer this specificity, we constructed chimeric genes in which 5.8 kb of 5' sequences of the IIIB gene has been replaced with a homologous region from the IIIA gene, and conversely, IIIA 5' sequences have been substituted for the analogous region of the IIIB gene. Promoter swap transgenic mice that carry IIIA 5' flanking sequences express Fc gamma RIII in macrophages and NK cells. In contrast, promoter swap transgenic mice that contain IIIB 5' sequences express Fc gamma RIII in neutrophils only. These studies define the elements conferring the cell type-specific expression of the human Fc gamma RIII genes within the 5' flanking sequences and first intron of the human Fc gamma RIIIA and Fc gamma RIIIB genes.
Animals↗
Comparative study of skeletal response to estrogen depletion at red and yellow marrow sites in rats.
BACKGROUND: Skeletal sites with red and yellow marrow may respond differently to estrogen depletion. To investigate this possibility, bone histomorphometric changes were compared at skeletal sites with different marrow composition in ovariectomized (OVX) rats, an animal model for postmenopausal bone loss. METHODS: Female rats were OVX or sham-operated at 3 months of age and sacrificed at 1 month or 1 year postsurgery. Eight rats were sacrificed at the beginning of the study as baseline controls. The proximal tibial metaphysis (PTM) and first lumbar vertebra (LV), bone sites with red marrow, as well as the distal tibial metaphysis (DTM) and fifth caudal vertebra (CV), bone sites with yellow marrow, were processed undecalcified for quantitative bone histomorphometry. RESULTS: In control rats, an age-related decrease in bone turnover was observed at all bone sites. Indices of bone turnover, such as osteoclast surface, mineral apposition rate, and bone formation rate, were lower in the DTM and CV compared to the PTM and LV. At 1 month postovariectomy, most bone resorption and formation indices at all bone sites were increased in OVX rats relative to control rats, but decreased cancellous bone volume was found only in the PTM. At 1 year postovariectomy, OVX rats exhibited severe cancellous osteopenia in the PTM and moderate cancellous osteopenia in the LV. In contrast, cancellous osteopenia did not develop in the DTM and CV even at 1 year postovariectomy, despite the fact that OVX rats still exhibited a trend for increased bone turnover at these yellow marrow sites. CONCLUSIONS: The results indicate that unlike skeletal sites with red marrow, estrogen depletion does not induce cancellous osteopenia at skeletal sites with yellow marrow in rats. Since increased bone turnover occurred at the various skeletal sites in OVX rats regardless of marrow composition, this skeletal alteration does not by itself induce cancellous bone loss. An imbalance between bone resorption and formation appears to be the major factor that determines the magnitude of bone loss at a given skeletal site in OVX rats. Differences in the anatomical characteristics of red and yellow marrow that may form a basis for these findings are discussed.
Age Factors↗