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Biomedical subjects

J F Zhang

Publications and source records attributed to J F Zhang.

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

Treatment of a human breast cancer xenograft with an adenovirus vector containing an interferon gene results in rapid regression due to viral oncolysis and gene therapy.

Treatment of a human breast cancer cell line (MDA-MB-435) in nude mice with a recombinant adenovirus containing the human interferon (IFN) consensus gene, IFN-con1 (ad5/IFN), resulted in tumor regression in 100% of the animals. Tumor regression occurred when virus was injected either within 24 hr of tumor cell implantation or with established tumors. However, regression of the tumor was also observed in controls in which either the wild-type virus or a recombinant virus containing the luciferase gene was used, although tumor growth was not completely suppressed. Tumor regression was accompanied by a decrease in p53 expression. Two other tumors, the human myelogenous leukemic cell line K562 and the hamster melanoma tumor RPMI 1846, also responded to treatment but only with ad5/IFN. In the case of K562 tumors, there was complete regression of the tumor, and tumors derived from RPMI 1846 showed partial regression. We propose that the complete regression of the breast cancer with the recombinant virus ad5/IFN was the result of two events: viral oncolysis in which tumor cells are being selectively lysed by the replication-competent virus and the enhanced effect of expression of the IFN-con1 gene. K562 and RPMI 1846 tumors regressed only as a result of IFN gene therapy. This was confirmed by in vitro analysis. Our results indicate that a combination of viral oncolysis with a virus of low pathogenicity, itself resistant to the effects of IFN and IFN gene therapy, might be a fruitful approach to the treatment of a variety of different tumors, in particular breast cancers.

Adenoviruses, Human↗
PubMed1996

Multiple structural elements in voltage-dependent Ca2+ channels support their inhibition by G proteins.

Molecular determinants of Ca2+ channel responsiveness to inhibition by receptor-coupled G proteins were investigated in Xenopus oocytes. The inhibitory response of alpha1B (N-type) channels was much larger than alpha1A (P/Q-type) channels, while alpha1C (L-type) channels were unresponsive. Differences in both degree and speed of inhibition were accounted for by variations in inhibitor off-rate. We tested proposals that inhibitory G protein and Ca2+ channel beta subunits compete specifically at the I-II loop. G protein-mediated inhibition remained unaltered in alpha1B subunits containing a point mutation in the I-II loop segment critical for Ca2+ channel beta subunit binding, and in chimeras where the I-II loop of alpha1B was replaced with counterparts from alpha1A or alpha1c. Full interconversion between modulatory behaviors of alpha1B and alpha1A was achieved only by swapping both motif I and the C-terminus in combination. Thus, essential structural elements for G protein modulation reside in multiple Ca2+ channel domains.

Animals↗
PubMed1995

Ca2+ channel selectivity at a single locus for high-affinity Ca2+ interactions.

Ca2+ channels display remarkable selectivity and permeability, traditionally attributed to multiple, discrete Ca2+ binding sites lining the pore. Each of the four pore-forming segments of Ca2+ channel alpha 1 subunits contains a glutamate residue that contributes to high-affinity Ca2+ interactions. Replacement of all four P-region glutamates with glutamine or alanine abolished micromolar Ca2+ block of monovalent current without revealing any additional independent high-affinity Ca2+ binding site. Pairwise replacements of the four glutamates excluded the hypothesis that they form two independent high-affinity sites. Systematic alterations of side-chain length, charge, and polarity by glutamate replacement with aspartate, glutamine, or alanine weakened the Ca2+ interaction, with considerable asymmetry from one repeat to another. The P-region glutamate in repeat I was unusual in its sensitivity to aspartate replacement but not glutamine substitution. While all four glutamates cooperate in supporting high-affinity interactions with single Ca2+ ions, they also influence the interaction between multiple divalent cations.

Alanine↗
PubMed1995

The economic costs of alcohol-related absenteeism and reduced productivity among the working population of New Zealand.

Lost productivity accounts for a significant proportion of the total cost of alcohol. This study quantifies the costs associated with alcohol consumption using survey data collected from four alcohol surveys conducted in Auckland between November 1990 to May 1992. The total sample size was 4662, of which 2638 were drinkers in paid employment. A computer-assisted telephone interviewing system was used to interview a random sample that closely matched the Auckland population. Respondents gave information about their typical alcohol consumption and frequency of absences from paid employment which were a result of their drinking. They also gave a report of the number of times in the past 12 months when they felt their work had been impaired as a result of their drinking. The cost of absenteeism was recorded as the number of times a respondent reported time away from work multiplied by gross income. Estimates of reduced work efficiency were derived from US figures, which estimated a 25% reduction in work performance among heavy alcohol users; 3.7% of the sample reported alcohol-related absences and 12% reported reduced efficiency days. There was a significant difference in both the number and cost of absentee and reduced efficiency days reported between the top 10% and the bottom 10% drinkers. A conservative estimate of alcohol-related lost productivity among the working population of New Zealand (with a population of 3.4 million and a per capita absolute alcohol consumption of 9.7 litres) was found to be $57 million per year.

Absenteeism↗
PubMed1994

Structural determinants of the blockade of N-type calcium channels by a peptide neurotoxin.

Neurotoxins that selectively block Na+, K+ or Ca2+ channels have provided valuable information about the functional diversity of the voltage-gated channel superfamily. For Ca2+ channels, a variety of toxins have been found to block individual channel types. The best-known example is omega-conotoxin-GVIA, a member of a large family of peptide toxins derived from venomous cone snails, which potently and selectively blocks N-type Ca2+ channels, allowing their purification, cellular localization, and the elucidation of their roles in Ca2+ entry, neurotransmitter release and neuronal migration. In contrast to Na+ and K+ channels, little is known about the molecular features that underlie Ca(2+)-channel susceptibility to toxin block; it is also unknown whether block occurs by direct physical occlusion or an action on channel gating. Here we describe structural determinants of N-type Ca2+ channel's interaction with omega-conotoxin-GVIA. When chimaeras combining individual motifs from the N-type channel and from a channel insensitive to omega-conotoxin-GVIA were expressed in Xenopus oocytes, each of the four motifs appeared to contribute to interaction with the toxin. The most dramatic effects on toxin interactions were seen at a single cluster of residues in the large putative extracellular loop between IIIS5 and IIIH5, consistent with a direct pore-blocking mechanism. These results provide a starting point for delineating the architecture of the outer vestibule of the Ca2+ channel.

Amino Acid Sequence↗
PubMed1994

Molecular determinants of voltage-dependent inactivation in calcium channels.

Voltage-dependent Ca2+ channels respond to membrane depolarization by conformational changes that control channel opening and eventual closing by inactivation. The kinetics of inactivation differ considerably between types of Ca2+ channels and are important in determining the amount of Ca2+ entry during electrical activity and its resulting impact on diverse cellular events. The most intensively characterized forms of inactivation in potassium and sodium channels involve pore block by a tethered plug. In contrast, little is known about the molecular basis of Ca(2+)-channel inactivation. We studied the molecular mechanism of inactivation of voltage-gated calcium channels by making chimaeras from channels with different inactivation rates. We report here that the amino acids responsible for the kinetic differences are localized to membrane-spanning segment S6 of the first repeat of the alpha 1 subunit (IS6), and to putative extracellular and cytoplasmic domains flanking IS6. Involvement of this region in Ca(2+)-channel inactivation was unexpected and raises interesting comparisons with Na+ channels, where the III-IV loop is a critical structural determinant. Ca(2+)-channel inactivation has some features that resemble C-type inactivation of potassium channels.

Amino Acid Sequence↗
PubMed1994

Expression of insulin-like growth factor II in hepatitis B, cirrhosis and hepatocellular carcinoma: its relationship with hepatitis B virus antigen expression.

Expression of insulin-like growth factor II in two human hepatocellular carcinoma cell lines and in hepatitis B, cirrhosis and hepatocellular carcinoma in 419 cases were investigated, and its relationship with the expression of hepatitis B virus X gene was studied by means of immunohistochemical and electron microscopic techniques. The results demonstrated that hepatocellular carcinoma cells (SMMC 7721 and QGY 7703) in culture could express insulin-like growth factor II. Expression seemed to be regulated by cell density, which was suggested as the molecular basis of the contact inhibition of cell proliferation. In tissue sections, cells with high expression of insulin-like growth factor II were observed not only in hepatocellular carcinoma (93%) but also in 95% of the pericancerous liver tissues, 72% of cirrhotic livers, 64% of chronic active hepatitis and 37% of chronic persistent hepatitis. In most cases of hepatocellular carcinoma, insulin-like growth factor II was localized in the cytoplasm of the cancer cells. In the benign liver disorders, four types of cells that highly expressed insulin-like growth factor II were observed: (a) a kind of small liver cell we named the small polygonal liver cell; (b) multinuclear giant hepatocytes; (c) hepatocytes in most of hyperplastic and neoplastic nodules, small hepatocyte nodules and some of regenerative nodules; and (d) some proliferating ductular cells. Even more interestingly, insulin-like growth factor II expression was shown to be closely related to the expression of hepatitis B virus X gene product. We suggest that the activation of insulin-like growth factor II gene and its overexpression may be a crucial step in the processes of hepatitis B virus-associated hepatocarcinogenesis and that the X gene product may activate the insulin-like growth factor II gene through a transactivation mechanism. In addition, we studied the characteristics of small polygonal liver cells, and the roles they may play in the regeneration and carcinogenesis of hepatitis B virus-infected liver are discussed.

Carcinoma, Hepatocellular↗
PubMed1994

The effect of calcitonin gene-related peptide on ischemic reperfusion-induced arrhythmias in rats.

Thirty-six wistar rats (150-250 g body weight) were randomly divided into two groups. There were equal numbers of male and female rats in each group. Each group of rats was given either 0.5 ml normal saline or calcitonin gene-related peptide (CGRP, 20 micrograms/kg dissolved in 0.5 ml normal saline) intravenously within 5 min. Coronary arteries of these rats were occluded 5 min after administration. The coronary artery was then released from ligation 5 min later. The heart beat of all rats was monitored for 30 min. An electrocardiogram was recorded using limb leads and below-xiphoid leads. There was no ischemic reperfusion-induced arrhythmia in the first minute of reperfusion in CGRP group, while 13 rats occurred ischemic reperfusion-induced arrhythmia (ventricular tachycardia and fibrillation) in the normal saline group (P < 0.05). Average onset time of ischemic reperfusion-induced arrhythmia was 377.5 +/- 141.0 s/sim. In the CGRP group, compared with 42.7 +/- 55.4 s/sim. for the normal saline group (P < 0.01). The duration of ischemic reperfusion-induced arrhythmia was 15.0 +/- 30.6 s/sim. In the CGRP group compared with 104.4 +/- 143.8 s/sim. in the normal group (P < 0.05). There was no death in the CGRP group, but six rats in the normal saline group died (P < 0.05). The results showed that CGRP could reduce and delay the occurrence of ischemic reperfusion-induced arrhythmia such as ventricular tachycardia and fibrillation, especially in the early period, and decrease the mortality. The mechanism is not clear and needs to be studied further.

Animals↗
PubMed1994

Comparison of six alcohol consumption measures from survey data.

Data were collected from a national sample of 1680 New Zealanders that allowed comparison of six different alcohol consumption measures. A measure based on reports of typical frequency and the amount typically consumed in 15 specified drinking locations produced the highest estimate of consumption. This measure and three others showed a particularly high degree of correlation, these being: a measure based on typical frequency and typical occasion amount; a variation of the Finnish period estimate; and a New Zealand variation of the period estimate that incorporated a typical frequency measure. The four measures just described, together with a last 7 days measure, showed generally consistent results when data were examined at the level of the total population and age, gender and socio-economic sub-groups. A measure based on the last two drinking occasions showed the least consistency with the other measures. The high degree of consistency found in the present study is similar to that found in a previous Finnish study and gives confidence that different ways of obtaining information about alcohol consumption, including relatively quick methods, can lead to similar conclusions about the comparative drinking of population sub-groups.

Adult↗
PubMed1994

Alcohol in the mass media and drinking by adolescents: a longitudinal study.

Data from a longitudinal study carried out in Dunedin, New Zealand, were used to investigate associations between alcohol consumption at age 18 years and alcohol-related mass media communications recalled at ages 13 and 15 years. The respondents' recall of alcohol-related mass media material were categorized as: commercial alcohol advertising, alcohol moderation messages or the portrayal of alcohol in entertainment. An additional media variable was the number of hours spent watching television. Non-media variables, such as peer approval of drinking, living situation and occupation (all at age 18 years) were also included in the analyses. The period between the interviews at ages 13 and 15 years saw an increase in the broadcast of commercial alcohol advertisements on television in New Zealand and this was reflected in an increase in the proportion of the mass media material recalled which was categorized as commercial advertising. At age 15 years television advertising, mostly for beer companies, was the predominant material recalled. No relationships were found between the commercial advertising and wine and spirits consumption, among either men or women, but young women who had watched more hours of television drank more wine/spirits. Among women there were two unexpected negative relationships between recall of alcohol in the media at age 13 years and beer consumption. However, among men there was a consistent positive relationship such that those who had recalled more alcohol advertisements at age 15 years drank larger quantities of beer at age 18 years.

Adolescent↗
PubMed1994

[Semiquantitative detection and application about the expression of nitric oxide synthase gene].

Using the Reverse Transcription (RT)-Polymerase Chain Reaction (PCR) method of Martin (1993) for semiquantitation determinating of NOS gene, it was found that NOS mRNA is not only existed in brain, but also distributed extensively in heart, kidney, lung and liver. Among of them, NOS mRNA levels were highest in the brain, followed in descending order by kidney, heart. In addition to endothelial cell, NOS gene was also highly expressed in smooth muscle cells, suggesting that they may be an important site of NOS in organism. Furthermore, NOS mRNA levels were found to decrease significantly in brain, kidney, liver and smooth muscle cell in spontaneous hypertensive rat. These data suggest that pathogeny of hypertension may be related to low expression of NOS gene in these tissues.

Amino Acid Oxidoreductases↗
PubMed1994

[Follow-up study of porcine bioprosthetic valve replacement in 15 children].

GD-I porcine bioprosthetic valve replacement were performed in 15 cases from Jul. 1978 to Nov. 1982. Pathology: RHD 11, CHD 4, 13 with MVR, 1 AVR, 1 TVR. One patient died during operation (operative mortality 6.7%). 13 cases were followed up for 3-10 years: in the early years the symptoms and cardiac function were greatly improved and the size reduced. However dysfunction of bioprosthetic valve was detected 2-8 years after operation in 12 patients (19.37%/patient year). The main cause of damage and dysfunction of porcine valve is calcification of the leaflet. As compared with the adult group(dysfunction rate 3.6%/patient year) in this institute, more calcification of the porcine valve in children is considered because of: (1) stronger metabolism of calcium in children, (2) less mobility of the leaflet due to lower cardiac output in children, and (3) stronger immunoreaction to porcine valve in children.

Adolescent↗
PubMed1994

[Comparative study of the expression of IGF-2 and HBxAg in human hepatocellular carcinoma and liver cirrhosis].

60 Cases of hepatocellular carcinoma (HCC) and 47 cases of liver cirrhosis (LC) were examined with immunocytochemistry methods using antibodies against IGF-2 and HBxAg on paraffin embedded sections. 32 HCC and 37 LC were found to be positive to HBxAg, in which the positive rates of IGF-2 were 100% (32/32) and 94.6% (35/37) respectively. 28 HCC and 10 LC were found to be HBxAg negative, IGF-2 was positive in 23 HCC (82.1%) and 6 LC (60%). The positive expression rates of IGF-2 in the HBxAg positive tissues were significantly higher than those in the HBxAg negative tissues (P < 0.05). There were three types of IGF-2 distribution in HCC and LC: (1) perinucleus; (2) diffuse in cytoplasm; (3) in nucleus. Small polygonal liver cells (SPLC) were found in the liver tissue surrounding the tumor or cirrhosis, the SPLC were positive to both IGF-2 and HBxAg. The positive rates of IGF-2 in SPLC were 86.4% (38/44) in HBxAg positive group and 40.5% (15/37) in the HBxAg negative group. The above findings suggest that IGF-2 plays an important role in abnormal proliferation of HCC and SPLC. The relation of IGF-2 and HBxAg and the nature of SPLC were also discussed.

Carcinoma, Hepatocellular↗
PubMed1993

Molecular determinants of Ca2+ selectivity and ion permeation in L-type Ca2+ channels.

Voltage-gated Ca2+ channels link changes in membrane potential to the delivery of Ca2+, a key second messenger for many cellular responses. Ca2+ channels show selectivity for Ca2+ over more plentiful ions such as Na+ or K+ by virtue of their high-affinity binding of Ca2+ within the pore. It has been suggested that this binding involves four conserved glutamate residues in equivalent positions in the putative pore-lining regions of repeats I-IV in the Ca2+ channel a1 subunit. We have carried out a systematic series of single amino-acid substitutions in each of these positions and find that all four glutamates participate in high-affinity binding of Ca2+ or Cd2+. Each glutamate carboxylate makes a distinct contribution to ion binding, with the carboxylate in repeat III having the strongest effect. Some single glutamate-to-lysine mutations completely abolish micromolar Ca2+ block, indicating that the pore does not possess any high-affinity binding site that acts independently of the four glutamate residues. The prevailing model of Ca2+ permeation must thus be modified to allow binding of two Ca2+ ions in close proximity, within the sphere of influence of the four glutamates. The functional inequality of the glutamates may be advantageous in allowing simultaneous interactions with multiple Ca2+ ions moving single-file within the pore. Competition among Ca2+ ions for individual glutamates, together with repulsive ion-ion electrostatic interaction, may help achieve rapid flux rates through the channel.

Amino Acid Sequence↗
PubMed1993

Functional expression of a rapidly inactivating neuronal calcium channel.

Diverse types of calcium channels in vertebrate neurons are important in linking electrical activity to transmitter release, gene expression and modulation of membrane excitability. Four classes of Ca2+ channels (T, N, L and P-type) have been distinguished on the basis of their electrophysiological and pharmacological properties. Most of the recently cloned Ca2+ channels fit within this functional classification. But one major branch of the Ca2+ channel gene family, including BII (ref. 15) and doe-1 (ref. 16), has not been functionally characterized. We report here the expression of doe-1 and show that it is a high-voltage-activated (HVA) Ca2+ channel that inactivates more rapidly than previously expressed calcium channels. Unlike L-type or P-type channels, doe-1 is not blocked by dihydropyridine antagonists or the peptide toxin omega-Aga-IVA, respectively. In contrast to a previously cloned N-type channel, doe-1 block by omega-CTx-GVIA requires micromolar toxin and is readily reversible. Unlike most HVA channels, doe-1 also shows unusual sensitivity to block by Ni2+. Thus, doe-1 is an HVA Ca2+ channel with novel functional properties. We have identified a Ca2+ channel current in rat cerebellar granule neurons that resembles doe-1 in many kinetic and pharmacological features.

Animals↗
PubMed1993

Distinctive pharmacology and kinetics of cloned neuronal Ca2+ channels and their possible counterparts in mammalian CNS neurons.

This paper provides a brief overview of the diversity of voltage-gated Ca2+ channels and our recent work on neuronal Ca2+ channels with novel pharmacological and biophysical properties that distinguish them from L, N, P or T-type channels. The Ca2+ channel alpha 1 subunit known as alpha 1A or BI [Mori Y., Friedrich T., Kim M.-S., Mikami A., Nakai J., Ruth P., Bosse E., Hofmann F., Flockerzi V., Furuichi T., Mikoshiba K., Imoto K., Tanabe T. and Numa S. (1991) Nature 350, 398-402] is generally assumed to encode the P-type Ca2+ channel. However, we find that alpha 1A expressed in Xenopus oocytes differs from P-type channels in its kinetics of inactivation and its degree of sensitivity to block by the peptide toxins omega-Aga-IVA and omega-CTx-MVIIC [Sather W. A., Tanabe T., Zhang J.-F., Mori Y., Adams M. E. and Tsien R. W. (1993) Neuron 11, 291-303]. Thus, alpha 1A is capable of generating a Ca2+ channel with characteristics quite distinct from P-type channels. Doe-1, recently cloned from the forebrain of a marine ray, is another alpha 1 subunit which exemplifies a different branch of the Ca2+ channel family tree [Horne W. A., Ellinor P. T., Inman I., Zhou M., Tsien R. W. and Schwarz T. L. (1993) Proc. Natn. Acad. Sci. U.S.A. 90, 3787-3791]. When expressed in Xenopus oocytes, doe-1 forms a high voltage-activated (HVA) Ca2+ channel [Ellinor P. T., Zhang J.-F., Randall A. D., Zhou M., Schwarz T. L., Tsien R. W. and Horne W. (1993) Nature 363, 455-458]. It inactivates more rapidly than any previously expressed calcium channel and is not blocked by dihydropyridine antagonists or omega-Aga-IVA. Doe-1 current is reduced by omega-CTx-GVIA, but the inhibition is readily reversible and requires micromolar toxin, in contrast to this toxin's potent and irreversible block of N-type channels. Doe-1 shows considerable sensitivity to block by Ni2+ or Cd2+. We have identified components of Ca2+ channel current in rat cerebellar granule neurons with kinetic and pharmacological features similar to alpha 1A and doe-1 in oocytes [Randall A. D., Wendland B., Schweizer F., Miljanich G., Adams M. E. and Tsien R. W. (1993) Soc. Neurosci. Abstr. 19, 1478]. The doe-1-like component (R-type current) inactivates much more quickly than L, N or P-type channels, and also differs significantly in its pharmacology.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Distinctive biophysical and pharmacological properties of class A (BI) calcium channel alpha 1 subunits.

Transcripts for the class A Ca2+ channel alpha 1 subunit (also known as BI) are present at high levels in many parts of the mammalian CNS and are widely assumed to encode the P-type Ca2+ channel. To characterize the biophysical and pharmacological properties of alpha 1A channels, macroscopic and single-channel recordings were made in Xenopus oocytes injected with alpha 1A cRNA. alpha 1-specific properties were identified by making systematic comparisons with the more familiar class C alpha 1 subunit under the condition of a standard ancillary subunit (alpha 2/delta + beta) makeup. alpha 1A currents activate and inactivate more rapidly and display steeper voltage dependence of gating than alpha 1C currents. Unlike alpha 1C, alpha 1A channels are largely insensitive to dihydropyridines and FPL 64176, but respond to the cone snail peptide omega-CTx-MVIIC(SNX-230), a potent and fairly selective inhibitor. In comparison with P-type Ca2+ channels in rat cerebellar Purkinje cells, alpha 1A channels in oocytes are approximately 10(2)-fold less sensitive to omega-Aga-IVA and approximately 10-fold more sensitive to omega-CTx-MVIIC. alpha 1A channels are not inhibited by Bay K 8644 and inactivate much more rapidly than P-type Ca2+ channels. Thus, alpha 1A is capable of generating a Ca2+ channel phenotype quite different from P-type current.

Animals↗