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1.  Mechanoelectrical feedback regulates the arrhythmogenic activity of pulmonary veins 
Heart  2006;93(1):82-88.
Background
Atrial fibrillation is commonly associated with dilated pulmonary veins. Stretch has been shown to have mechano‐electrical effects.
Objective
To investigate whether stretch can increase the arrhythmogenic activity of the pulmonary veins.
Methods
The transmembrane action potentials were recorded from rabbit pulmonary veins before and after stretch (100 and 300 mg). Gadolinium and streptomycin (stretch‐activated ion channel blockers) were each perfused into the pulmonary veins under a 300‐mg stretch.
Results
Stretch (0, 100 and 300 mg) force dependently increased the incidence of spontaneous activity (22%, 48% and 83%; p<0.05), mean (standard deviation (SD)) firing rates of spontaneous activity (1.7 (0.2), 2.1 (0.3) and 3 (0.2) Hz; p<0.05) and incidence of early post‐depolarisations (9%, 26% and 61%; p<0.05) and delayed post‐depolarisations (0%, 4% and 30%; p<0.05) in 23 pulmonary veins. In the seven preparations with spontaneous activity after the 300‐mg stretch, gadolinium (1, 3 and 10 μmol/l) decreased the incidence of spontaneous activity by 43%, 29% and 14%, respectively (p<0.05), and decreased the firing rate from 2.9 (0.1) Hz to 0.8 (0.4), 0.3 (0.1) and 0.1 (0.1) Hz, respectively (p<0.05). Streptomycin (10 and 40 μmol/l) decreased the incidence of spontaneous activity by 71% and 29%, respectively (p<0.05), and decreased the firing rate from 2.9 (0.1) Hz to 1.6 (0.4) and 0.5 (0.3) Hz, respectively (p<0.05).
Conclusion
Stretch is an important factor in the electrical activity of the pulmonary vein. Stretch‐induced arrhythmogenic activity of the pulmonary vein may contribute to the genesis of atrial fibrillation.
doi:10.1136/hrt.2006.089359
PMCID: PMC1861344  PMID: 16905626
2.  Peptidyl-prolyl cis/trans isomerase Pin1 is critical for the regulation of PKB/Akt stability and activation phosphorylation 
Oncogene  2009;28(26):2436-2445.
The serine/threonine protein kinase B (PKB, also known as Akt) plays a pivotal role in diverse cellular functions. Elevated expression of activated Akt has been detected in a wide variety of human cancers; however, the mechanism of Akt protein stability regulation remains unclear. In this study, we showed a strong correlation between the expression levels of an oncogenic peptidyl-prolyl cis/trans isomerase Pin1 and levels of Akt phosphorylation at S473 in multiple cancer types (P<0.0001). Akt-pS473 status combined with Pin1 expression levels predicted a poorer prognosis than did either one alone in patients with breast cancer (P = 0.0052). We further showed that Pin1 regulated Akt stability and phosphorylation on S473 through the phosphorylated Thr-Pro motifs of Akt. These motifs are conserved evolutionary and are required for the maintenance of Akt stability and its interaction with Pin1. In addition, repressing Pin1 expression through either homologue Pin1 knockout or small interfering RNA-mediated knockingdown compromised its ability to protect Akt from degradation. Our results show how Akt protein stability is regulated by the peptidyl-prolyl cis/trans isomerase Pin1 and highlight the importance of this oncogenic network in human disease pathogenesis.
doi:10.1038/onc.2009.98
PMCID: PMC2748248  PMID: 19448664
PKB/Akt; Pin1; peptidyl-prolyl cis/trans isomerase; breast cancer
3.  hTERT phosphorylation by PKC is essential for telomerase holoprotein integrity and enzyme activity in head neck cancer cells 
British Journal of Cancer  2006;94(6):870-878.
Telomerase activity is suppressed in normal somatic tissues but is activated in most cancer cells. We have previously found that all six telomerase subunit proteins, including hTERT and hsp90 are needed for full enzyme activity. Telomerase activity has been reported to be upregulated by protein kinase C (PKC), but the mechanism is not clear. In this study, we examined how PKC regulates telomerase activity in head and neck cancer cells. PKC inhibitor, bisindolylmaleimide I (BIS), inhibited telomerase activity but had no effect on the expressions of telomerase core subunits. RNA interference (RNAi) and in vitro phosphorylation studies revealed that PKC isoforms α, β, δ, ɛ, ζ specifically involved in telomerase regulation, and the phosphorylation target was on hTERT. Treatment with the hsp-90 inhibitor novobiocin dissociated hsp90 and hTERT as revealed by immunoprecipitation and immunoblot analysis and reduced telomerase activity. Treatment with the PKC activator SC-10 restored the association of hsp90 and hTERT and reactivate telomerase, suggesting that hTERT phosphorylation by PKC is essential for telomerase holoenzyme integrity and function. Analysis on clinical normal and tumour tissues reveal that the expressions of PKC α, β, δ, ɛ, ζ were higher in the tumour tissues, correlated with telomerase activity. Disruption of PKC phosphorylation by BIS significantly increased chemosensitivity to cisplatin. In conclusion, PKC isoenzymes α, β, δ, ɛ, ζ regulate telomerase activity in head and neck cancer cells by phosphorylating hTERT. This phosphorylation is essential for telomerase holoenzyme assembly, leading to telomerase activation and oncogenesis. Manipulation of telomerase activity by PKC inhibitors is worth exploring as an adjuvant therapeutic approach.
doi:10.1038/sj.bjc.6603008
PMCID: PMC2361368  PMID: 16508638
hTERT; PKC isoenzymes; phosphorylation; telomerase
4.  Aberrant FHIT transcripts in hepatocellular carcinomas. 
British Journal of Cancer  1998;77(3):417-420.
To study abnormalities of the FHIT gene in human hepatocellular carcinoma (HCC), eight liver cancer cell lines, 18 matched tumorous and non-tumorous tissues from patients with HCC and three normal liver tissues were analysed by microsatellite polymorphism analysis and reverse transcription of FHIT mRNA followed by polymerase chain reaction (PCR) amplification and sequencing of the products. No loss of heterozygosity at chromosome 3p14.2 as defined by markers D3S1300 and D3S1312 was detected in any of the specimens. In addition, a normal transcript of the gene without any sequence change was found to be expressed in all the cell lines, 17 of the 18 tumorous and all 21 non-tumorous liver tissues tested. Although five out of eight liver cancer cell lines (62.5%), 12 out of 18 HCC tissues (66.7%) and 8 out of 18 paired non-tumorous liver tissues (44.4%) displayed abnormal faint bands of smaller size, sequence analysis revealed that they were aberrant FHIT transcripts lacking three or more exons and might represent alternatively spliced transcripts only. In conclusion, these studies indicate that abnormalities of the FHIT gene transcripts occur in a fairly high frequency of tumorous and non-tumorous liver tissues. However, it might not be causally related to the hepatocarcinogenesis.
PMCID: PMC2151291  PMID: 9472637
5.  A retrospective cohort study of leukemia and other cancers in benzene workers 
A retrospective cohort study was carried out in 1982–1983 among 28,460 benzene-exposed workers (15,643 males, 12,817 females) from 233 factories and 28,257 control workers (16,621 males, 12,366 females) from 83 factories in 12 large cities in China. All-cause mortality was significantly higher among the exposed (265.46/100,000 person-years) than among the unexposed (139.06/100,000 person-years), as was mortality from all malignant neoplasms (123.21/100,000 versus 54.7/100,000, respectively). For certain cancers, increased mortality was noted among benzene-exposed males in comparison with that among unexposed males; the standardized mortality ratios (SMR) were elevated for leukemia (SMR = 5.74), lung cancer (SMR = 2.31), primary hepatocarcinoma (SMR = 1.12), and stomach cancer (SMR = 1.22). For females only leukemia occurred in excess among the exposed. Risk of leukemia rose as duration to exposure to benzene increased up to 15 years, and then declined with additional years of exposure. Leukemia occurred among some workers with as little as 6 to 10 ppm average exposure and 50 ppm-years (or possibly less) cumulative lifetime exposure (based on all available measurements for the exposed work units). Among the 30 leukemia cases identified in the exposed cohort, the proportion of subjects with acute lymphocytic leukemia was substantially lower and the proportion with acute nonlymphocytic leukemias was higher than in the general population. During 1972 to 1981, the annual incidence of leukemia ranged from 5.83 to 28.33 per 100,000 with higher rates occurring in the interval 1977 to 1981 than in the earlier years of the study period. Future studies should evaluate more precisely the relationship between exposure levels, job title, and development of leukemia among cases and noncases within the exposed cohort.
PMCID: PMC1568128  PMID: 2792042
6.  Leukaemia in benzene workers: a retrospective cohort study. 
A retrospective cohort study was conducted in 233 benzene factories and 83 control factories in 12 cities in China. The benzene cohort and the control cohort consisted of 28,460 benzene exposed workers (178,556 person-years in 1972-81) and 28,257 control workers (199,201 person-years). Thirty cases of leukaemia (25 dead and 5 alive) were detected in the former and four cases (all dead) in the latter. The leukaemia mortality rate was 14/100,000 person-years in the benzene cohort and 2/100,000 person-years in the control cohort; the standardized mortality ratio was 5.74 (p less than 0.01 by U test). The average latency of benzene leukaemia was 11.4 years. Most (76.6%) cases of benzene leukaemia were of the acute type. The mortality due to benzene leukaemia was high in organic synthesis plants followed by painting and rubber synthesis industries. The concentration of benzene to which patients with a leukaemia were exposed ranged from 10 to 1000 mg/m3 (mostly from 50 to 500 mg/m3). Of the 25 cases of leukaemia, seven had a history of chronic benzene poisoning before the leukaemia developed.
PMCID: PMC1007793  PMID: 3814544
7.  Highly potent and specific siRNAs against E6 or E7 genes of HPV16- or HPV18-infected cervical cancers 
Cancer Gene Therapy  2010;17(12):827-836.
Infection with high-risk types (type 16 or type 18) of human papillomaviruses (HPVs) increases a patient's risk of cervical cancer. Given the importance of the cervix and the severe side effects resulting from traditional cancer therapies, this study aimed to achieve targeted inhibition of viral oncogenes in tumor cells using small interfering RNAs (siRNA). To accomplish this, we developed nine siRNAs against either the E6 or E7 genes of HPV-16 or HPV-18 in several combinations, yielding siRNAs targeting 16E6, 16E7, 18E6 and 18E7. We measured the effectiveness of the siRNAs by examining E6 or E7 mRNA expression after transfection of the siRNAs into HPV-positive CaSki (HPV-16) or HeLa (HPV-18) cell lines. We found that the HPV-siRNAs significantly reduced cell growth and colony formation in both cell lines. Flow cytometry analysis revealed a significant increase in apoptosis. The siRNAs had no effect on cell growth, colony formation or apoptosis in HPV-negative C33A cells, demonstrating a lack of off-target effects. In addition, an in vivo xenograft study showed that intra-tumoral injection of the siRNAs reduced tumor growth in BALB/c nude mice. In conclusion, we have developed highly specific and potent HPV-siRNAs that successfully suppress tumor growth and induce apoptosis in HPV-positive cervical cancer cells. siRNA treatment has potential for further development as an adjuvant therapy for cervical cancer.
doi:10.1038/cgt.2010.38
PMCID: PMC2994641  PMID: 20885450
HPV; E6; E7; cervical cancer; siRNA silencing
8.  The prevalence and spectrum of α and β thalassaemia in Guangdong Province: implications for the future health burden and population screening 
Journal of Clinical Pathology  2004;57(5):517-522.
Aim: Thalassaemia is a good candidate disease for control by preventive genetic programmes in developing countries. Accurate population frequency data are needed for planning the control of thalassaemia in the high risk Guangdong Province of southern China.
Methods: In total, 13 397 consecutive samples from five geographical areas of Guangdong Province were analysed for both haematological and molecular parameters.
Results: There was a high prevalence of carriers of α thalassaemia (8.53%), β thalassaemia (2.54%), and both α and β thalassaemia (0.26%). Overall, 11.07% of the population in this area were heterozygous carriers of α and β thalassaemia. The mutation spectrum of α and β thalassaemia and its constitution were fully described in this area. This study reports the true prevalence of silent α thalassaemia in the southern China population for the first time. In addition, two novel mutations that give rise to α thalassaemia, one deletion resulting in β thalassaemia, and a rare deletion (−−THAI allele) previously unreported in mainland China were detected. The frequency of the most common mutation, the Southeast Asian type of deletion (−−SEA, accounting for 48.54% of all α thalassaemias) was similar to the total of two α+ thalassaemia deletions (−α3.7 and −α4.2, accounting for 47.49% of α thalassaemia).
Conclusion: Both α and β thalassaemia are widely distributed in Guangdong Province of China. The knowledge gained in this study will enable the projected number of pregnancies at risk to be estimated and a screening strategy for control of thalassaemia to be designed in this area.
doi:10.1136/jcp.2003.014456
PMCID: PMC1770296  PMID: 15113860
thalassaemia; epidemiology; mutations; Hb H disease; genetic screening
9.  Effect of aminophylline on brain stem auditory evoked potentials in preterm infants. 
To determine the neurophysiological effects of aminophylline on apnoea of prematurity, the brain stem auditory evoked potentials (BAEPs) of 30 apnoeic infants and 34 age matched controls were evaluated and compared. After six days of treatment with aminophylline, the brain stem conduction time (interpeak latency of I-V) in apnoeic infants decreased compared with controls of a similar postconceptional age. The mean latencies of the peaks and interpeaks of all waves except wave I were significantly lower in the apnoeic infants after than before receiving aminophylline. No significant differences were found in the latencies of BAEPs between the apnoeic infants who responded and those who did not respond to aminophylline treatment, however. These results suggest that aminophylline may enhance conduction along central auditory pathways and stimulate the regulatory effect on the respiratory centre of the brain stem.
PMCID: PMC1061062  PMID: 8092864

Results 1-9 (9)