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Biomedical subjects

T Y Chu

Publications and source records attributed to T Y Chu.

At least 19 recordsLinked to original sources

Favorable clinical outcome of cervical cancers infected with human papilloma virus type 58 and related types.

To determine whether the status of human-papillomavirus (HPV) infection affects the clinical outcome of cervical carcinoma (CC), HPV genotype was prospectively determined in 94 consecutive CC cases subsequently followed for a median duration of 37.5 months. With a consensus PCR-RFLP method of HPV genotyping, 81 (86.2%) cancers were positive for HPV DNA. They were classified, according to the phylogenic similarities, into HPV-16-related (type 16, n = 45; type 31, n = 2), HPV-58-related (type 58, n = 17; type 33, n = 3; type 52, n = 2) and HPV-18-related (type 18, n = 8; type 68, n = 1) groups, and analyzed in relation to clinical outcome. The following results were observed: (i) Type-58-related HPVs were more prevalent in the old age (older than the median age of 52) group than in the young age group (41% vs. 14.6%, p = 0.045); (ii) 63% (5/8) of patients with advanced stages (III and IV) were HPV-negative, a figure much higher than that (9.3%, 8/84) of patients with early stages (stage I and II) (p = 0.002); (iii) the occurrence of adenocarcinoma or adenosquamous carcinoma was higher in the HPV-18-related group (50%) than in the HPV-16-related (33.3%) or the HPV-58-related (16.7%) groups (p = 0.024); (iv) the status of lymph-node metastasis and tumor grade did not correlate with HPV status; (v) 5-year survival rates were 90.2%, 80% and 74% for HPV-58-, HPV-16- and HPV-18-related groups, respectively (p = 0.03, after adjustment for tumor stage); (vi) in comparison with the HPV-16-related group, the relative risk of death in the HPV-58- and the HPV-18-related groups were 0.32 [95% CI, 0.07-1.49] and 1.87 [0.36-14.9] respectively. HPV genotype appears to affect the clinical behavior and outcome of cervical cancer. HPV-58-related types are prevalent in the older population, and appear to confer a favorable prognosis. Int. J. Cancer (Pred. Oncol.) 84:553-557, 1999.

Adult↗

Frequent aberration of the transforming growth factor-beta receptor II gene in cell lines but no apparent mutation in pre-invasive and invasive carcinomas of the uterine cervix.

The type II transforming growth factor-beta (TGF-beta) receptor (RII) gene located at 3p22 plays an important role in regulating growth and differentiation of epithelium, including that of the uterine cervix. Loss-of-function mutations of RII have frequently been found in gastrointestinal cancers, with a replication-error (RER) phenotype characterized by the presence of microsatellite instability (MI). In this study, genomic PCR, SSCP and DNA sequencing were conducted to investigate the coding sequences of the RII gene in cell lines (n = 5) and tissues (n = 15) of squamous carcinomas of the uterine cervix. Intragenic deletions were noted in 2 of 5 cervical-cancer cell lines (ME180 and HeLa cells). However, no mutation, other than DNA polymorphisms, was found in 15 cervical cancers with either alleleic loss at 3p22 (n = 11) or MI (n = 4). Further analysis of squamous intraepithelial lesions (SIL) with (n = 12) or without (n = 4) MI for the (A)10 change, a prototypic mutation found in over 90% of RER-positive colon cancers, also showed no aberration. Our study concludes that the RII gene is frequently disrupted in cervical-cancer cell lines, but is rarely mutated in CC and SIL tissues, including those showing MI or alleleic loss at 3p22. The underlined mechanism of genomic instability in CC and SIL may thus differ from that of colorectal cancer. The allelic loss at 3p22-24 in CC does not involve the coding sequence of the RII gene. The non-coding sequence of RII or an unidentified gene may be responsible for it.

Carcinoma, Squamous Cell↗

Monoclonality and surface lesion-specific microsatellite alterations in premalignant and malignant neoplasia of uterine cervix: a local field effect of genomic instability and clonal evolution.

Invasive squamous carcinoma of the uterine cervix (CC) arises from sequential progression of low-grade (L) and high-grade (H) squamous intraepithelial lesions (SILs). In clinical observations, these lesions are frequently found as synchronous multiple foci. The nature and evolutionary mechanism of these lesions are largely unknown. We have performed allelotyping of three 3p markers (at 3p14, 3p22-24, and 3p25) on 22 LSILs and 15 HSILs microdissected from patients with multiple (n = 21) or uniform (n = 6) cervical lesions. The results were analyzed together with our previous allelotyping of 57 deeply invasive CCs. Loss of heterozygosity at one of the three markers was observed in 23%, 27%, and 31 % of LSILs, HSILs, and CCs, respectively. Frequent and early allelic loss was noted (in 30% of LSILs and 50% of HSILs) at 3p14, which may harbor tumor suppressor genes involved in early stages of cervical carcinogenesis. A high frequency of microsatellite alteration (MA) was found in LSIL (41%) and HSIL (67%) but not in CC (5.3%). In particular, MA was more frequently found in low-grade lesions in association with invasive cancers (75%, 6/8) than in those associated with SILs (29%, 4/14) (P < 0.05). Together with the finding of a monoclonal origin of premalignant and malignant cervical lesions, the present results allow us to propose a model of local field effect of genomic instability that progressively affects the clonal evolution of SIL of uterine cervix.

Carcinoma in Situ↗

Intracervical misoprostol as an effective method of labor induction at term.

OBJECTS: The purpose of this study was to evaluate the safety and effectiveness of intracervical misoprostol for the induction of labor at term. METHODS: Eighty-nine term pregnancies requiring induction of labor were treated intracervically with 50 microg of misoprostol. The dose was repeated every 4 h until adequate uterine contraction and cervical dilatation were achieved. Status of cervical ripening, uterine contraction, cervical dilatation, labor course and side effects were recorded and analyzed. RESULTS: Among the 89 patients, 58 had an unfavorable cervix (Bishop score < or = 4) and 31 had a favorable cervix (Bishop score > 4). Labor was successfully induced in all cases, most (93.3%) of which required a single dose of misoprostol. Seventy-two patients (81%) proceeded to spontaneous vaginal delivery, and 61 (85%) deliveries were achieved within 12 h. The other 17 cases received cesarean delivery with indications of fetopelvic disproportion (six cases), failure of induction (seven cases) and acute fetal distress (four cases). The mean duration from induction to regular uterine contraction and to delivery was 483+/-537 min and 79.2+/-38.2 min, respectively, with no significant difference between the two groups with differing status of cervical ripening. Complications of uterine contraction, including tachysystole (15 cases), hypertonus (one case) and hyperstimulation (10 cases) were more common in the group of unfavorable cervix (45%) than that of favorable cervix (23%) (P < 0.05). CONCLUSION: In addition to the oral and intravaginal routes of administration, intracervical misoprostol at a single dose of 50 microg appears to be an effective method for induction of labor at term, but caution should be taken with cases with unfavorable cervix.

Abortifacient Agents, Nonsteroidal↗

Identification of free deaminated sialic acid (2-keto-3-deoxy-D-glycero-D-galacto-nononic acid) in human red blood cells and its elevated expression in fetal cord red blood cells and ovarian cancer cells.

Chemical studies have shown the occurrence of the deaminated sialic acid 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (KDN) in paired samples of blood obtained from mothers and newborns of healthy human individuals. Most of the KDN was found in red blood cells, although low levels were detected in mononuclear cells. No N-glycolylneuraminic acid was detected. Unexpectedly, nearly all of the KDN in fetal cord and matched maternal red blood cells was present as the free sugar and comparatively little occurred conjugated or as cytidine 5'-KDN phosphate. The amount of free KDN in fetal newborn red blood cells was 2.4-fold higher than in red blood cells from the mothers or from healthy nonpregnant women. Free KDN was also identified in normal human ovaries, in ovarian tumors, and in ascites cells obtained from ovarian cancer patients. Importantly, as in fetal cord red blood cells, a distinguishing feature of KDN expression in ovarian tumor cells was an elevated level of free KDN compared with normal controls. A positive correlation was found between an increase in the ratio of free KDN/N-acetylneuraminic acid in ovarian adenocarcinomas and the stage of malignancy. This was particularly evident in tumor cells isolated from the ascites fluid. The central importance of these new findings is 2-fold. First, they show that free KDN is a minor but ubiquitous sialic acid in human red blood cells and that its elevated expression in red blood cells from fetal cord blood compared with maternal red blood cells may be developmentally related to blood cell formation during embryogenesis. Second, the enhanced expression of KDN in ovarian cancer cells suggests that this sialic acid, like the alpha2,8-linked polysialic acid glycotope, may be an oncofetal antigen in these tumors and thus could be an "early warning" signal for onset of disease and/or a marker for detection of recurrence of disease. These new findings highlight the importance of elucidating the role that KDN and KDN-containing glycoconjugates may play in normal development and malignancy.

Adenocarcinoma↗

HPV-associated cervical cancers show frequent allelic loss at 3p14 but no apparent aberration of FHIT mRNA.

The genetic aberration involved in the loss of heterozygosity (LOH) at 3p14 has recently been attributed to the disruption of the FHIT gene in many cancers. This study analyzed HPV DNA and allelic status of 5 microsatellite markers spaning 3p13-3p25 in 57 cases of cervical cancer. With no homozygous deletion found in any case, a 39% overall frequency of LOH was noted. The presence of tumorigenic HPV DNA (91%) did not correlate with the allelic loss at any marker, including THRB (3p22-24) and D3S1228 (3p14) which were found with high LOH rates of 43% (12/28) and 37% (11/30), respectively. Further analysis of FHIT mRNA in 29 cancers by reverse transcription (RT)-PCR showed a full-length transcript in all cases. However, additional minor transcripts were occasionally observed in cancer tissues (9/29) as well as in normal tissues (12/31) by nested PCR of the RT products. Sequence analysis of these transcripts showed exclusive internal exon deletions, suggesting a source of minor splicing variants. No apparent mutation of the mRNA sequences was found in 8 transcripts examined, except for a silent polymorphism and a site of alternative splicing. The results suggest that, although frequently reported to be abrogated in several cancers, the mRNA of FHIT remains intact in cervical cancer. Other genes closely linked to FHIT may be responsible for frequent LOH at 3p14 observed in cervical cancer.

Acid Anhydride Hydrolases↗

Second and early third trimester pregnancy termination by extra-amniotic balloon and intracervical PGE2.

OBJECTIVE: The aim of the study was to investigate the efficacy and safety of an alternative modality using extra-amniotic balloon and intracervical prostaglandin (PG) E2 for termination of second and early third trimester pregnancies. METHOD: Thirty-three pregnant women scheduled for legal termination of pregnancy at 15-32 weeks' gestation were included in the study. Each case received extra-amniotic balloon containing 500-800 ml normal saline and two PGE2 tablets inserted into the cervical canal. RESULTS: All 33 patients achieved a successful termination. The mean induction-to-abortion interval was 12.85 h. There was no significant difference in induction-to-abortion interval between second trimester group and third trimester group. However, the mean duration of balloon distention was longer in the second trimester group. There were no severe complications. CONCLUSION: The combined use of extra-amniotic balloon and intracervical PGE2 tablets is effective, safe and convenient for termination of second and early third trimester pregnancy.

Abortion, Legal↗

Thromboxane and prostacyclin in maternal and fetal circulation in pre-eclampsia.

OBJECTIVES: A major pathophysiologic change of pre-eclampsia has been attributed to the overproduction of thromboxane A2 (TXA2) mainly from activated platelets. On the other hand, increased biosynthesis of TXA2 has also been reported from preeclamptic placentas. The systemic role of these different sources of TXA2 has not been clarified. The purpose of this study is to define the changes of TXA2 and the antagonizing prostacyclin (PC) in maternal and fetal circulations. METHODS: The stable metabolites of TXA2 and PC [Thromboxine B2 (TXB2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), respectively] in the cord and maternal blood of nine patients with pre-eclampsia and nine normal parturients were measured by radioimmunoassay. RESULT: In normal pregnancy, the cord blood contained much higher TXB2 (1697+/-898 vs. 267+/-128 ng/ml, P < 0.01) and 6-keto-PGF1alpha (266+/-263 vs. 12.5+/-3.9 ng/ml, P < 0.05) levels than the maternal blood. In the preeclamptic state, a marked increase of TXB2 was noted in both maternal and cord blood, reaching levels which were significantly higher than during normal pregnancy (2995+/-1103 vs. 267+/-128 ng/ml in maternal blood, P < 0.0001, and 3197+/-1288 vs. 1697+/-898 ng/ml in cord blood, P < 0.005). A less significant increase in 6-keto-PGF1alpha (134+/-10.8 vs. 12.5+/-3.9 ng/ml, P < 0.05) was also noted in the maternal blood. Moreover, the level of TXB2 correlated with the diastolic blood pressure of preeclamptic patients before and after delivery. CONCLUSION: The results suggest an abundant source of eicosanoids in the feto-placental circulation, which does not readily cross the placental barrier. In pregnancy complicated with pre-eclampsia, thromboxane level of both fetal and maternal circulations are markedly increased, which may be responsible for the pathophysiologic changes. The lack of adverse systemic effects on the fetus highlights a placental source of TXA2 of transient bioactivity which is rapidly hydrolyzed to non-active TXB2. Federation of Gynecology and Obstetrics

Adult↗

Extra-amniotic balloon with PGE2 versus extra-ovular Foley catheter with PGF2alpha in mid-trimester pregnancy termination.

OBJECTIVE: The objective of this study was to compare the efficacy and side effects of two methods of mid-trimester labor induction, extra-amniotic balloon with intracervical prostaglandin (PG) E2 (0.5 mg x 2) vs. extra-ovular Foley catheter with intrauterine PGF2alpha (1 mg/h x6). METHODS: A cohort of 32 and 36 cases indicated for mid-trimester termination was enrolled and managed with extra-amniotic balloon and extra-ovular Foley catheter methods, respectively. Outcomes of induction-to-delivery interval, induction failure, and occurrence of side effects were assessed. RESULTS: There were no statistical differences in maternal age, parity, gestational age or fetal birth weight between the two groups. Compared with the extra-ovular Foley catheter with PGF2alpha group, the induction-to-delivery interval was significantly shorter in the extra-amniotic balloon plus PGE2 group. There was no significant difference in side effects and major complications developed in either groups. CONCLUSIONS: The extra-amniotic balloon with intracervical PGE2 is more efficient in reducing the induction-to-delivery interval for termination of mid-trimester pregnancies than the extra-ovular Foley catheter with intrauterine PGF2alpha.

Abortion, Induced↗

Extensive thrombophlebitis with reactive thrombocytosis in a high risk Chinese parturient associated with retained placenta increta: a case report.

Postpartum thrombophlebitis is an infrequent disorder in Chinese women. A case is reported of extensive postpartum thrombophlebitis involving 23 cm of the femoral and pelvic veins. This 25-year-old splenectomized victim of beta-thalassemia was bedridden for 12 weeks because of threatened premature labor before Cesarean delivery. During the operation, placenta increta with massive bleeding was encountered. To save the uterus, ten percent of the placenta was retained. Duplex color Doppler imaging was performed for the diagnosis and follow-up of the thrombosis and vigorous anticoagulation therapy successfully cured this patient.

Adult↗

Overexpression of the proto-oncogene c-jun in association with low-risk type specific human papillomavirus infection in condyloma acuminata.

Infection with different types of human papillomavirus (HPV) is associated with neoplasia at different anatomic sites. The "low-risk" HPVs (LR-HPV) are responsible for benign genital lesions such as condyloma acuminata. In order to clarify the tumorigenic mechanism of LR-HPV, the HPV infection status was investigated and the expression of the c-jun proto-oncogene in different HPV-related skin and genital lesions analyzed. Of the 17 condyloma specimens analyzed by Western blotting, 13 cases (76.5%) exhibited overexpression of the c-jun gene. All 13 cases harbored high copy numbers of the LR-HPV genome with an average of 926 copies per cell, whereas the other four cases had an average of 12 copies of LR-HPV per cell (P < 0.001). Further typing of HPV by Southern blotting revealed that HPV-6 and HPV-11 infections predominated in c-jun positive cases. The c-jun protein was detected much less frequently in cervical cancers (three of 29, or 10.3%) and skin warts (one of 10), and was not detected in five genital polyps or in five normal cervical tissues. These findings suggest a type 6/11-specific induction of c-jun gene expression in HPV-related neoplastic lesions.

Animals↗

Postcoital hemoperitoneum without identifiable bleeding source: a case report.

Spontaneous intra-abdominal bleeding has been called abdominal apoplexy. It has been so named because its nature and spontaneity closely resemble those of its more common cerebral counterpart. The bleeding source commonly came from a ruptured branch of celiac axis or superior mesenteric artery. Rarely, hemoperitoneum occurs spontaneously post coitus without evident vaginal injury. There were only twelve cases reported in the medical literature to date. Nearly, all of them showed injury of pelvic organs including round or broad ligaments, ovarian cysts or adhesion bands. A case of massive hemoperitoneum after coitus, with no definite bleeding source, is reported.

Adult↗

The Wsh and Ph mutations affect the c-kit expression profile: c-kit misexpression in embryogenesis impairs melanogenesis in Wsh and Ph mutant mice.

The receptor tyrosine kinases (RTKs) c-kit and platelet-derived growth factor receptor alpha chain (PDG-FRa) are encoded at the white spotting (W) and patch (Ph) loci on mouse chromosome 5. While W mutations affect melanogenesis, gametogenesis, and hematopoiesis, the Ph mutation affects melanogenesis and causes early lethality in homozygotes. W-sash (Wsh) is an expression mutation and blocks c-kit expression in certain cell types and enhances c-kit expression in others, including at sites important for early melanogenesis. We have determined the effect of Ph on c-kit expression during embryogenesis in Ph heterozygotes. Immunohistochemical analysis revealed enhanced c-kit expression in several cell types, including sites important for early melanogenesis. We propose that in both Wsh and Ph mutant mice c-kit misexpression affects early melanogenesis and is responsible for the pigment deficiency. Moreover, we have defined the organization of the RTKs in the W/Ph region on chromosome 5 and characterized the Wsh mutation by using pulsed-field gel electrophoresis. Whereas the order of the RTK genes was determined as Pdgfra-c-kit-flk1, analysis of the Wsh mutation revealed that the c-kit and Pdgfra genes are unlinked in Wsh, presumably because of an inversion of a small segment of chromosome 5. The Ph mutation consists of a deletion including Pdgfra and the 3' deletion endpoint of Ph lies between Pdgfra and c-kit. Therefore, positive 5' upstream elements controlling c-kit expression in mast cells and some other cell types are affected by the Wsh mutation and negative elements are affected by both the Wsh and the Ph mutation.

Animals↗

Characterization of the promoter of the proto-oncogene c-kit.

In previous studies, we have characterized the nature and function of the proto-oncogene c-kit, which encodes a receptor tyrosine kinase. This receptor together with its ligand, a stem cell growth factor, constitutes a cell signaling system which is crucial for the development of hematopoietic, melanocytic and germ cells. The expression of the gene correlates with its protein functions in specific cell lineages and is temporally and spatially regulated during fetal and adult life. As a start point to study the gene regulation, we have characterized the promoter of the c-kit gene. A single transcription initiation site located 58 bases upstream of the ATG start codon has been identified. The sequence upstream to the initiation site reveals a TATA-less, non-GC rich promoter. Several potential binding sites for transcription factors pertinent to c-kit expression, such as Sp-1, GATA-1, myb and Oct-4, have been identified. Promoter activities of different lengths of the 5' sequence have been analyzed in transient expression assay. The 2.7 kb of the 5' sequence facilitates the expression of the CAT gene in several cell lines while the sequence further upstream from 2.7 to 5.0 kb shows a negative regulatory activity. This study reveals a unique promoter of the c-kit gene and provides a basis for further elucidation of the regulatory mechanism of c-kit gene expression.

Animals↗

Inactivation of constitutive hepatic cytochromes P450 by phencyclidine in the rat.

The purpose of this study was to determine whether phencyclidine (PCP) inhibits constitutive hepatic cytochrome P450 (CYP) isozymes when administered to naive adult male Sprague-Dawley rats. Animals were pretreated with PCP (25 mg/kg/day for 2 days), killed 3 and 16 hr after the last dose, and liver microsomes prepared. The washed microsomes were then assayed for benzphetamine, methamphetamine (MA), and methylenedioxymethamphetamine (MDMA) N-demethylation together with MDMA demethylenation and MA 4-hydroxylation activities. MDMA demethylenation (low substrate concentration), MA 4-hydroxylation, and metoprolol alpha-hydroxylation reactions, which are catalyzed by CYP2D isozymes, were reduced > 74% 3 hr after the last PCP dose and were only partially restored 13 hr later. Benzphetamine and (-)-MDMA N-demethylation activities were restored to control values 16 hr after the last dose. These results indicate that PCP suppresses constitutive isozymes, including CYP2C11 and members of the CYP2D subfamily. The suppression of cytochromes P450 activity by PCP in vivo is consistent with its in vitro actions found in this and other studies, and demonstrates that alteration of CYP activity is another pharmacological effect of this compound.

Amphetamines↗

The demethylenation of methylenedioxymethamphetamine ("ecstasy") by debrisoquine hydroxylase (CYP2D6).

The metabolism of methylenedioxymethamphetamine (MDMA, "ecstasy") was examined in a microsomal preparation of the yeast Saccharomyces cerevisiae expressing human debrisoquine hydroxylase, CYP2D6. Only one product, dihydroxymethylamphetamine (DHMA), was detected in the incubation mixture, and this product accounted for all of the substrate consumption at low concentration (10 microM). Mean +/- SD values of apparent Km(microM) and Vmax (nmol/min per nmol P450) for the demethylenation of (+) and (-)-MDMA at low concentrations (1-100 microM) were 1.72, 0.12 and 6.45, 0.10 and 2.90, 0.10 and 7.61, 0.06, respectively. At high concentrations (> 1000 microM) substrate inhibition was noted, with Ki values of 14.2 and 28.2 mM, respectively, for the (+) and (-) enantiomers. Incubation of MDMA isomers with human liver microsomes indicated that their demethylenation is deficient in the poor metabolizer phenotype. Thus, MDMA is converted to the catecholamine DHMA by CYP2D6, and this may give rise to genetically-determined differences in toxicity.

3,4-Methylenedioxyamphetamine↗

Effects of E5a and E7 genes of human papillomavirus type 11 on immortalized human epidermal keratinocytes and NIH 3T3 cells.

The E5a gene of HPV-11 expressed in NIH 3T3 cells led to tumorigenesis in nude mice; whereas when expressed in keratinocytes, E5a induced anchorage independent growth, but was nontumorigenic in nude mice. The E7 gene of HPV-11 expressed NIH 3T3 cells led to tumors in nude mice and morphological transformation, but not anchorage independent growth. Keratinocytes expressing the E7 gene induced colony formation in soft agarose, but not tumorigenesis in nude mice. Comparison of transforming activities of HPV-11 E5a and E7 genes of HPV-11 showed that the efficiency of cell transformation by E7 was weaker than that of E5a.

3T3 Cells↗