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Biomedical subjects

L Mao

Publications and source records attributed to L Mao.

At least 19 recordsLinked to original sources
PubMed2006

Incidence and risk factors for urethral and anal gonorrhoea and chlamydia in a cohort of HIV-negative homosexual men: the Health in Men Study.

BACKGROUND: Early detection and treatment of bacterial sexually transmitted infections has been advocated as an HIV prevention strategy. AIM: To inform screening guidelines, the incidence and risk factors for urethral and anal gonorrhoea and chlamydia were studied in a prospective cohort of community-based HIV negative homosexual men in Sydney, New South Wales, Australia. METHODS: All participants were offered annual screening for gonorrhoea and chlamydia (study-visit diagnoses) on urine and anal swabs using nucleic acid amplification. Participants also reported diagnoses of gonorrhoea and chlamydia made elsewhere between interviews (interval diagnoses). All diagnoses were summed to create a combined incidence rate, and detailed data on specific sexual practices with casual and regular partners were collected. RESULTS: Among 1427 men enrolled, the combined incidence rates were 3.49 and 2.96 per 100 person-years for urethral and anal gonorrhoea, respectively; and 7.43 and 4.98 per 100 person-years for urethral and anal chlamydia, respectively. Urethral infections were associated with unprotected anal intercourse (UAI) with HIV-positive partners (hazard ratio (HR) = 2.58, 95% CI 1.10 to 6.05 for urethral gonorrhoea) and with frequent insertive oral sex (p for trend 0.007 for urethral chlamydia). Anal infections were associated with receptive UAI (p for trend 0.001 for both anal gonorrhoea and chlamydia) and other receptive anal sexual practices. Stratified analyses showed the independence of the associations of insertive oral sex with urethral infections and of non-intercourse receptive anal practices with anal infections. CONCLUSION: Incident gonorrhoea and chlamydia were common. Risk behaviours for both urethral and anal infections were not restricted to UAI. Screening that includes tests for anal and urethral infections should be considered for all sexually active homosexual men, not just for those who report UAI.

Adult↗
PubMed2006

Differences between men who report frequent, occasional or no unprotected anal intercourse with casual partners among a cohort of HIV-seronegative gay men in Sydney, Australia.

Past research on unprotected anal intercourse with casual partners (UAIC) contrasts those who report no UAIC with any UAIC. This paper examines differences among three groups of men who had any UAIC on the basis of the number of UAIC acts reported in a six-month period, namely no UAIC (n = 507), occasional UAIC (1-5 acts, n = 251) and frequent UAIC (more than 5 acts, n = 148). The occasional UAIC group had values lying between those of the no- and the frequent-UAIC group. As compared with the frequent-UAIC group, men in the occasional-UAIC group were less likely to have a steady partner, held less favorable attitudes toward condoms and higher levels of HIV treatments optimism and were more likely to report some disclosure of serostatus to or by casual partners and a range of esoteric sexual practice. On the other hand, men in the no-UAIC group had lower levels of 'feeling bad' (distress) and were less likely to use drugs to enhance sexual pleasure in casual encounters. Disclosure of serostatus had a strong association with frequent UAIC and this finding calls for both more research and more community exploration of issues surrounding sexual decision-making.

Adolescent↗
PubMed2006

HIV risk and communication between regular partners in a cohort of HIV-negative gay men.

This paper reports on the breaking of agreements between regular partners among HIV-negative gay men in Sydney. Data were from the 1333 men completing face-to-face interviews through December 2003 for the Health in Men (HIM) open cohort of HIV-negative gay men in Sydney.822 men had a primary regular partner during the six month period before their 2003 interview. Most of these men had entered into agreements with their partners about sex either with each other or with other partners (87.2%). They most commonly agreed not to use condoms with each other (50.6%). Regarding casual sex, they most commonly agreed to always use condoms (34.2%) or to have no sex with men outside their relationships (28.6%). 48.8% reported some discomfort discussing with their partner their sex outside the relationship. Among those with agreements with their partners, 27.7% reported ever breaking those agreements. Those who found it more difficult to discuss issues of HIV serostatus and sexuality were more likely to report having broken their agreements (p<.001; p=.021 at one-year follow-up) and were more likely to have engaged in unprotected anal intercourse with casual partners (p<.001). A third of those men who broke their agreements did not inform their partner. A substantial proportion of gay men with agreements with their regular partners report some discomfort discussing sexuality and HIV serostatus with their partners. Difficulty discussing these issues may place these men at increased risk of breaking their agreements and may place both themselves and their partners at increased risk of infection.

Adult↗
PubMed2005

Developmentally regulated gene expression of the small heat shock protein Hsp27 in zebrafish embryos.

Mammalian small heat shock proteins including Hsp27 and alpha-B crystallin are constitutively expressed in various adult and embryonic tissues including skeletal and cardiac muscle. However, the function of these proteins during embryonic development is not understood, and information on their expression during the earliest stages of development is limited. We have recently demonstrated constitutive and stress inducible expression of a homologue of human Hsp27 in adult zebrafish, an important experimental model of vertebrate developmental processes. Here, we assessed the temporospatial dynamics of zebrafish Hsp27 (hsp27) and alpha-B crystallin (cryab) gene expression using reverse-transcriptase PCR (RT-PCR) and hsp27 expression by in situ hybridization. Our results reveal that initial upregulation of hsp27 expression occurs during early gastrulation. Expression of hsp27 is detected transiently in developing myotomes, lens and brain, and more persistently in developing heart. The constitutive expression level of hsp27 in embryos at some stages of development is considerably greater than that observed in unstressed adult tissues. Expression of hsp27 was also observed in all tissues examined in embryos recovering from heat stress. The pattern of expression observed for hsp27 overlaps partially, but not completely, with that reported for other heat shock proteins.

Animals↗
PubMed2005

Cardiovascular responses to microinjection of nociceptin and endomorphin-1 into the nucleus tractus solitarii in conscious rats.

Increasing evidence suggests an active participation of nociceptinergic transmission in the central control of cardiovascular activity and reflex. In this study, the role of the classic opioid mu receptor and the nociceptin/orphanin FQ receptor, a novel opioid receptor, in the nucleus tractus solitarii (NTS) in the regulation of cardiovascular activity was investigated and compared in chronically cannulated and freely moving conscious rats. Microinjections of nociceptin, an endogenous ligand for the nociceptin receptor, into the relatively rostral NTS produced dose-related (0.04, 0.2, and 1 nmol) increases in blood pressure and heart rate. Intra-NTS injection of the selective nociceptin receptor antagonist [Nphe(1)]Nociceptin(1-13)NH(2) (NOR-AN) at 1 nmol blocked the increases in blood pressure and heart rate induced by nociceptin. In contrast, pretreatment with the nonselective opioid receptor antagonist naloxone (5 nmol) had no effects on the cardiovascular responses to nociceptin. Like nociceptin, microinjection of endomorphin-1 (EM-1), an endogenous ligand for the opioid mu receptor, into the rostral NTS increased blood pressure and heart rate in a dose-dependent manner (0.04, 0.2, and 1 nmol). Pretreatment with naloxone (5 nmol), but not NOR-AN, blocked cardiovascular responses elicited by EM-1. Neither NOR-AN nor naloxone alone had significant effects on the baseline blood pressure and heart rate. Injection of excitatory amino acid l-glutamate (1 nmol) into the same sites caused the typical depressor and bradycardic responses. In the caudal NTS areas, nociceptin and EM-1 seemed to induce opposite responses: hypotension and bradycardia. These results suggest that the novel nociceptin receptors and traditional opioid receptors in the NTS may be independently involved in the regulation of cardiovascular activity.

Analgesics, Opioid↗
PubMed2005

Contexts for last occasions of unprotected anal intercourse among HIV-negative gay men in Sydney: the health in men cohort.

The objective of the paper was to compare encounters involving unprotected anal intercourse (UAI) and protected anal intercourse (PAI) among HIV-negative gay men in Sydney. Data were from those completing baseline face-to-face interviews to end June 2003 for the Health in Men open cohort of HIV-negative gay men in Sydney. The 1,148 participants ranged in age from 18 to 75 years (median = 36). Three hundred and fifty-two (30.7%) reported an occasion of UAI with a casual partner in the previous 6 months and 531 (46.3%) reported an occasion of UAI with a regular partner in that same time. The men's most recent sexual contact with a casual partner involving UAI was distinguished from those involving PAI by a greater likelihood for both partners to disclose HIV serostatus (p = 0.006) and by respondents being more inclined to restrict themselves to the insertive position or to practise withdrawal during occasions involving any UAI than when a condom was used (p = 0.003 and p = 0.001 respectively). Neither location nor recreational drug use differentiated men's most recent sexual contacts involving UAI from those involving PAI. The decision by HIV-negative gay men to use condoms during sexual encounters with either regular or casual partners is guided more by HIV serostatus and risk reduction strategies than by other factors.

Adolescent↗
PubMed2002

Interactions between ionotropic and metabotropic glutamate receptors regulate cAMP response element-binding protein phosphorylation in cultured striatal neurons.

The striatum is a key structure of basal ganglia controlling extrapyramidal motor activity and processing addictive plasticity of abused substances. Glutamatergic transmission that is enriched in the striatum regulates a variety of striatal neuronal activities via selective activation of ionotropic and metabotropic glutamate receptors (mGluRs). In this study, the interaction between N-methyl-D-aspartate (NMDA) receptors and group I mGluRs (mGluR1 and mGluR5 subtypes) in activating a phosphorylation cascade to a transcription factor cAMP response element-binding protein (CREB) was investigated in primary cultures of E18 or postnatal day 1 striatal neurons. We found that activation of NMDA receptors with NMDA rapidly and concentration-dependently increased the number of neurons expressing phosphorylated CREB (pCREB) as revealed by immunocytochemistry. The increased pCREB expression by NMDA was sensitive to an NMDA antagonist MK801. Co-incubation of a subthreshold dose of a group I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) that itself did not alter basal pCREB expression augmented NMDA-induced CREB phosphorylation. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride blocked the DHPG augmentation of NMDA-induced CREB phosphorylation, while the mGluR1 antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester did not. Interestingly, the protein kinase C inhibitors chelerythrine and Gö6983 also prevented DHPG from enhancing CREB phosphorylation induced by NMDA. Whereas a low dose of the protein kinase C activator phorbol 12-myristate 13-acetate mimicked the DHPG potentiation. These results indicate a facilitatory regulation of an NMDA cascade to CREB phosphorylation by concurrent glutamatergic tone on mGluR5, which is probably processed via an intracellular signaling pathway involving protein kinase C.

Animals↗
PubMed2001

Profound astrogenesis in the striatum of adult mice following nigrostriatal dopaminergic lesion by repeated MPTP administration.

Neural progenitor cells are present in the rodent brain throughout adulthood, and can proliferate and differentiate into new neurons and/or glia to repair injury. To explore the repair processes mediated by brain progenitor cells, a selective lesion of the nigrostriatal dopaminergic pathway was induced in young adult mice by repeated administration of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A thymidine analog, bromodeoxyuridine (BrdU), was used as a tracer for DNA synthesis to label the dividing cells and their terminal progeny following injury. Three days after MPTP treatments (25 mg/kg, once daily for 5 days), an 8-fold increase in the number of BrdU-labeled newborn cells was observed in the dorsal striatum. A 5-fold increase was also seen in the substantia nigra (SN). Newborn cells in the striatum survived beyond 60 days after their birth whereas newborn cells in the SN survived for less than 31 days. The vast majority of newborn cells in the striatum differentiated into astroglia according to their radial morphology and co-expression with an astroglial marker, S100beta, within 10 days after birth. In contrast, most BrdU-positive cells in the SN failed to co-express S100beta. Little or none of BrdU-labeled cells in both the striatum and SN were found to co-localize with a neuronal marker, neuronal nuclear antigen, or tyrosine hydroxylase during the full course of survival days surveyed (3 to 60 days). Repeated MPTP also decreased dopamine content and uptake in the striatum, which showed a significant recovery 31 days after MPTP lesion. These results demonstrate a rapid and profound astrogenesis in the striatum of young adult mice in response to toxic dopaminergic insult. The lack of neurogenesis in the two affected brain areas indicates the relative importance of glial cell regeneration in repairing MPTP injury.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice.

BACKGROUND: Stimulation of beta(1)- and beta(2)-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the beta(3)AR is also expressed in the human heart and that its stimulation leads to negative inotropic effects. METHODS AND RESULTS: To better understand the role of beta(3)ARs in cardiac function, we generated transgenic mice with cardiac-specific overexpression of 330 fmol/mg protein of the human beta(3)AR (TGbeta(3) mice). Hemodynamic characterization was performed by cardiac catheterization in closed-chest anesthetized mice, by pressure-volume-loop analysis, and by echocardiography in conscious mice. After propranolol blockade of endogenous beta(1)- and beta(2)ARs, isoproterenol resulted in an increase in contractility in the TGbeta(3) mice (30%), with no effect in wild-type mice. Similarly, stimulation with the selective human beta(3)AR agonist L-755,507 significantly increased contractility in the TGbeta(3) mice (160%), with no effect in wild-type mice, as determined by hemodynamic measurements and by end-systolic pressure-volume relations. The underlying mechanism of the positive inotropy incurred with L-755,507 in the TGbeta(3) mice was investigated in terms of beta(3)AR-G-protein coupling and adenylyl cyclase activation. Stimulation of cardiac membranes from TGbeta(3) mice with L-755,507 resulted in a pertussis toxin-insensitive 1.33-fold increase in [(35)S]GTPgammaS loading and a 1.6-fold increase in adenylyl cyclase activity. CONCLUSIONS: Cardiac overexpression of human beta(3)ARs results in positive inotropy only on stimulation with a beta(3)AR agonist. Overexpressed beta(3)ARs couple to G(s) and activate adenylyl cyclase on agonist stimulation.

Adenylyl Cyclases↗
PubMed2001

Activation of melanoma antigen tumor antigens occurs early in lung carcinogenesis.

The melanoma antigen (MAGE)-encoding genes are expressed in various tumor types, including lung, and are thought to be silent in all normal tissues except testis. In search of biomarkers for early lung cancer detection and cancer risk assessment, we investigated frequencies of expressional activation of MAGE-A1, -A3, and -B2 genes in non-small cell lung cancers (NSCLCs). Expression of these genes was evaluated by reverse transcription-PCR (RT-PCR) in 20 primary NSCLC samples and corresponding normal lung tissues as well as in 20 bronchial brush specimens from former smokers without lung cancer. mRNA in situ hybridization was done to confirm the gene expression pattern at the cellular level. Methylation-specific PCR was performed to evaluate the hypomethylation status of CpG sites in the promoter regions of these genes. Among the 20 primary NSCLC samples analyzed, 14 (70%) expressed MAGE-A1 and 17 (85%) each expressed MAGE-A3 and MAGE-B2. A substantial number of normal lung tissues adjacent to NSCLC also had a detectable level of MAGE expression (65, 75, and 80% for MAGE-A1, -A3, and -B2, respectively). We found that 7 (35%), 10 (50%), and 11 (55%) of the adjacent normal lung tissue samples exhibited promoter hypomethylation at MAGE-A1, -A3, and -B2, respectively, compared with 15 (75%), 16 (80%), and 16 (80%) of the NSCLC samples. Among the 20 bronchial epithelium samples from former smokers, 7 (35%), 10 (50%), and 12 (60%) had also detectable -A1, -A3, and -B2 expression, respectively. Activation of MAGE-A1, -A3, and -B2 genes is common not only in NSCLC but also in bronchial epithelium with severe carcinogen insult. These results suggest that MAGE genes may be activated very early in lung carcinogenesis and may be considered as targets for lung cancer prevention.

Aged↗
PubMed2001

Human Rad17 is phosphorylated upon DNA damage and also overexpressed in primary non-small cell lung cancer tissues.

The spRAD17 gene is an essential component of the DNA damage and replication checkpoints in the fission yeast Schizosaccharomyces pombe. Cloning of the human homologue of spRAD17, hRAD17, indicated that it exhibits structural similarity with the replication accessory protein family, which include subunits of the Replication factor C complex. We have analyzed the phosphorylation status of hRad17 in response to DNA damaging agents. Our results showed that phosphorylation of hRad17 occurred immediately after UV and ionizing radiation treatment and reached peak level at approximately 3 h, suggesting that hRad17 may be a component of the DNA damage checkpoint. When primary tumor samples were analyzed, we observed that the majority (74%) of non-small cell lung carcinoma samples exhibited a significantly higher level of hRad17 expression compared with matched normal tissue controls. In contrast, hRad17 protein levels in a panel of primary colon carcinoma samples did not show an elevated level of expression compared with normal colon tissues. This observation suggests that the function of the hRAD17 gene may be involved in lung cancer development and may serve as a potential tumor marker.

Carcinoma, Non-Small-Cell Lung↗
PubMed2001

Gliogenesis in the striatum of the adult rat: alteration in neural progenitor population after psychostimulant exposure.

Cytogenesis from proliferating progenitor cells is present in the rat brain throughout adulthood, and is regulated by a variety of environmental stimuli. To determine whether adult cytogenesis occurs in the intact rat striatum and to explore the possible regulatory role of psychostimulant exposure on striatal cytogenesis, immunohistochemistry with the thymidine analog bromodeoxyuridine (BrdU), a marker of DNA synthesis that labels dividing cells and their terminal progeny, was performed on the brain sections of normal adult rats and rats treated with a psychostimulant, amphetamine (AMPH). Scattered cells that incorporated BrdU were consistently seen throughout the dorsal (caudate putamen) and ventral (nucleus accumbens) striatum 24 h after BrdU injection. Three to four weeks after BrdU injection, approximately 10-20% of surviving newborn cells differentiated into astroglia according to their radial morphology of glia and co-expression of an astroglial marker, S100beta. However, none of BrdU-positive cells were found to co-localize with a neuronal marker, neuronal nuclear antigen (NeuN). Acute injection of AMPH at a behaviorally active dose (10 mg/kg, i.p.) produced a rapid and transient decrease in the number of BrdU-labeled cells in both the dorsal (70.6% of control) and ventral (66.7% of control) striatum, but not in the subventricular zone and the hippocampal dentate gyrus. However, the fraction of differentiated astrocytes was not altered 3-4 weeks after AMPH treatment. These results indicate an existence of active gliogenesis (both proliferation and differentiation) in the adult rat striatum. Vulnerability of striatal cytogenesis to psychostimulant exposure indicates a new approach to elucidate brain mechanisms responsible for addictive properties of drugs of abuse.

Age Factors↗
PubMed2001

Differentially altered mGluR1 and mGluR5 mRNA expression in rat caudate nucleus and nucleus accumbens in the development and expression of behavioral sensitization to repeated amphetamine administration.

Altered glutamatergic transmission in the striatum may be implicated in behavioral sensitization to repeated amphetamine (AMPH) administration. Quantitative in situ hybridization histochemistry was performed to define the effects of acute and chronic AMPH exposures on mRNA expression of Group I metabotropic glutamate receptors (mGluRs) in the striatum. Behavioral ratings indicated that the motor activity of rats was significantly higher after the final of five daily AMPH injections (4 mg/kg, i.p.) than that after the first of five daily AMPH, indicative of the development of behavioral sensitization. Moreover, the motor activity of rats treated with five daily AMPH was significantly greater than that of rats treated with five daily saline in response to a 2 mg/kg challenge dose of AMPH 7, 14, 28, and 60 days after the discontinuation of drug treatments, indicative of the persistent expression of behavioral sensitization. Three hours after acute administration of AMPH to naive rats, mGluR1 and mGluR5 mRNA expression in the dorsal (caudatoputamen) and ventral (nucleus accumbens) striatum showed no change as compared to acute saline injection. In rats that developed behavioral sensitization to repeated AMPH, mGluR1 levels in the dorsal and ventral striatum were increased by 53% and 43%, respectively, 3 h after the final AMPH treatment. However, this change did not persist during withdrawal since it was not observed 7, 14, and 28 days after the discontinuation of AMPH treatment. Conversely, mGluR5 levels were markedly reduced 3 h after the final of five daily AMPH treatments in the entire striatum of sensitized rats (34% and 77% of controls in the dorsal and ventral striatum, respectively). The reduction persisted at 7, 14, and 28 days of withdrawal. These results reveal a close linkage between striatal Group I mGluR gene expression and behavioral sensitization to AMPH. This may indicate functional implications of the two subtypes of Group I mGluRs in the regulation of behavioral sensitization to the dopamine stimulant.

Amphetamine↗
PubMed2001

Effects of N-(4-hydroxyphenyl)retinamide on hTERT expression in the bronchial epithelium of cigarette smokers.

BACKGROUND: Telomerase activation plays a critical role in tumorigenesis. To determine the role of telomerase in early lung carcinogenesis and as a potential biomarker in chemoprevention trials, we analyzed the expression of the human telomerase reverse transcriptase catalytic subunit (hTERT) in bronchial biopsy specimens from cigarette smokers who were enrolled in a randomized, double-blinded, placebo-controlled chemoprevention trial of N-(4-hydroxyphenyl)retinamide (4-HPR). METHODS: We obtained biopsy specimens from six predetermined sites in the bronchial tree from the 57 participants, before treatment and 6 months after treatment with 4-HPR or placebo. We used in situ hybridization to examine hTERT messenger RNA (mRNA) expression in 266 pretreatment (baseline) and post-treatment site-paired biopsy specimens from 27 patients in the 4-HPR-treated group and from 30 patients in the placebo-treated group. All statistical tests were two-sided. RESULTS: At baseline, 62.4% (95% confidence interval [CI] = 53.9% to 71%) of the biopsy specimens obtained from the group treated with 4-HPR and 65.2% (95% CI = 57.4% to 73.1%) of the biopsy specimens obtained from the placebo-treated group expressed hTERT mRNA. After 6 months, 45.6% (95% CI = 36.9% to 54.3%) of the biopsy specimens obtained from the 4-HPR-treated group and 68.1% (95% CI = 60.4% to 75.8%) of the biopsy specimens obtained from the placebo-treated group expressed hTERT mRNA. The reduction in hTERT expression observed between the two treatment groups over time was statistically significant (P =.01) when we used the biopsy site as the unit of analysis, but not when we used the individual as the unit of analysis (P =.37). CONCLUSIONS: Telomerase is frequently reactivated in the lungs of cigarette smokers. The modulation of hTERT expression in 4-HPR-treated smokers suggests that a novel molecular mechanism underlies the potential chemopreventive properties of 4-HPR. hTERT expression is a promising potential biomarker for risk assessment and for the evaluation of the efficacy of chemopreventive agents in lung carcinogenesis.

Adult↗
PubMed2001

Miniaturized amperometric biosensor based on xanthine oxidase for monitoring hypoxanthine in cell culture media.

Fabrication and characterization of miniaturized amperometric hypoxanthine biosensors are described and demonstrated for monitoring hypoxanthine in myocardial cell culture media. The sensors are based on xanthine oxidase (XO) immobilized on carbon fiber microelectrodes (CFMEs) using a composite film of Nafion and electropolymerized phenol (PPh). Nafion was used for XO immobilization because of its film hydrophobicity, enzyme-favored environment, and electrostatic interaction with XO, which was dispersed in Nafion film by immersing the Nafion-coated CFMEs in XO solution for 5 h. PPh film was formed as an overlay on Nafion and XO-modified CFMEs via electropolymerization. Hypoxanthine was measured with the sensor by the oxidation of enzymatic reaction products, hydrogen peroxide (H(2)O(2)), and uric acid (UA) at +0.60 V (vs Ag/AgCl). The use of Nafion and PPh as a matrix for XO immobilization yields enhanced specificity, sensitivity, and linearity toward hypoxanthine. A dynamic linear range of 5.0 microM to 1.8 mM was achieved with a calculated detection limit of 1.5 microM (S/N = 3) and a sensitivity of 3.144 nA/mM. In addition, the measurement was virtually interference-free from easily oxidizable species such as UA, ascorbic acid, physiological levels of neurotransmitters, and their principal metabolites. The biosensor was used to monitor hypoxanthine accumulation in myocardial cell culture media, in which the level of extracellular hypoxanthine was found to increase with ischemic tolerance.

Animals↗
PubMed2001

Multiple oral squamous epithelial lesions: are they genetically related?

The development of second primary tumors (SPTs) in patients with head and neck squamous cell carcinoma (HNSCC) has become an increasingly important factor in clinical treatment decisions. Currently, clinical and histologic parameters are used to determine whether or not SPT is present. Recent studies suggest that many SPTs in the upper aerodigestive tract have a common clonal origin, challenging the longstanding multiclonal origin concept. To determine genetic relationships among multiple oral cancerous and precancerous lesions (MOCP), we analysed 100 lesions from 26 Japanese patients. Lesion development was synchronous and metachronous. We looked for patterns of microsatellite alterations (MA) using seven markers at chromosomes 3p14, 9p21, and 17p13, where MA occurs early in oral carcinogenesis. Loss of heterozygosity (LOH) was found in 52.6% (41/78), 62.5% (60/96), and 59.3% (32/54) of informative MOCP at 3p14, 9p21, and 17p13, respectively. Microsatellite instability (MI) was observed in 11, 26 and 13% of the samples at 3p14, 9p21, and 17p13 markers, respectively. Patterns of MA were concordant in only nine (14%) of 63 lesions from four (18%) of 22 patients who initially presented with noninvasive lesions. However, two of four patients with invasive cancer as indexed lesion showed 16 (43%) clonally related MOCP among 37 lesions (P=0.003). The results suggest that the majority of MOCP arise from clonally independent cells affected by field cancerization. However, the probability of mucosal spread of clonal malignant or premalignant cells may increase along with malignant progression.

Carcinoma, Squamous Cell↗
PubMed2001

Cardiac overexpression of a G(q) inhibitor blocks induction of extracellular signal-regulated kinase and c-Jun NH(2)-terminal kinase activity in in vivo pressure overload.

BACKGROUND: Understanding the cellular signals that initiate cardiac hypertrophy is of critical importance in identifying the pathways that mediate heart failure. The family of mitogen-activated protein kinases (MAPKs), including the extracellular signal-regulated kinases (ERKs), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPKs, may play specific roles in myocardial growth and function. METHODS AND RESULTS: To determine the mechanism of activation of MAPK pathways during the development of cardiac hypertrophy, we evaluated the induction of MAPK activity after aortic constriction in wild-type and in 2 types of cardiac gene-targeted mice: one overexpressing a carboxyl-terminal peptide of Galpha(q) that inhibits G(q)-mediated signaling (TG GqI mouse) and another overexpressing a carboxyl-terminal peptide of beta-adrenergic receptor kinase-1 that inhibits Gbetagamma signaling (TG betaARKct mouse). Wild-type mice with pressure overload showed an acute induction of JNK, followed by the induction of p38/p38beta at 3 days and ERK at 7 days. Both JNK and p38 activity remained elevated at 7 days after banding. In TG GqI mice, hypertrophy was significantly attenuated, and induction of ERK and JNK activity was abolished, whereas the induction of p38 and p38beta was robust, but delayed. By contrast, all 3 MAPK pathways were activated by aortic constriction in the TG betaARKct hearts, suggesting a role for Galpha(q), but not Gbetagamma. CONCLUSIONS: Taken together, these data show that the induction of ERK and JNK activity in in vivo pressure-overload hypertrophy is mediated through the stimulation of G(q)-coupled receptors and that non-G(q)-mediated pathways are recruited to activate p38 and p38beta.

Animals↗