Biomedical subjects

M C Lin

Publications and source records attributed to M C Lin.

At least 73 records · Page 4Linked to original sources

PubMed2001

Pulmonary function and spinal characteristics: their relationships in persons with idiopathic and postpoliomyelitic scoliosis.

OBJECTIVE: To identify what influence the various features of spinal deformity have on pulmonary function in persons with idiopathic and the postpoliomyelitic scoliosis. DESIGN: Prospective, cohort, observational study with clinical and radiologic evaluations. SETTING: Hospital-based rehabilitation units. PATIENTS: Forty-four patients with idiopathic scoliotis and 16 with postpoliomyelitic scoliotis. Each group was divided into subgroups: normal and abnormal pulmonary function. INTERVENTION: Clinical and radiologic evaluation of spinal deformity, full pulmonary functional test and respiratory muscle strength were performed. Presence of dyspnea on exertion and low back pain (LBP) was recorded. MAIN OUTCOME MEASURES: Pulmonary function: spirometry, lung volume test, and diffusing capacity. Respiratory muscle strength: maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP). Presence of dyspnea on exertion (DOE), and LBP were also recorded. Characteristics of spinal deformity: direction of convexity, uppermost vertebra, number of involved vertebrae, Cobb angle, the apical vertebra, degree of rotation at the apical vertebra, type of scoliotic curve, and presence of balanced spine and pelvic obliquity. Chi-square analyses and Mann-Whitney U test for between-groups comparisons. Spearman's rho correlation coefficient to determine the existence and magnitude of a relationship. RESULTS: We found significant differences between the idiopathic and postpoliomyelitis groups in the degree of rotation at the apical vertebra, MIP, average percentage of predicted vital capacity, residual volume/total lung capacity, presence of double or triple curves, pelvic obliquity, and DOE. Between the idiopathic scoliotis subgroups we found significant differences in the uppermost vertebra and number of vertebrae in the scoliotic curve. Between the subgroups of the postpoliomyelitis group were significant differences in the location of the apical vertebra and the uppermost vertebral body of scoliotic curve. In the idiopathic group, pulmonary function was mostly related to scoliotic angle, number of vertebrae in the scoliotic curve, location of the uppermost vertebra, and the patients' age; MIP and MEP were negatively related to the scoliotic angle and degree of rotation of apical vertebra. In the postpoliomyelitis group, pulmonary function was mostly related to scoliotic angle, kyphotic angle, location of the uppermost vertebra of the scoliotic curve, and age. CONCLUSION: No single factor can predict the severity of impairment in scoliotic patients' pulmonary function. In both groups, severity of pulmonary impairment was related to the combined features of the spinal deformity. However, uppermost vertebra, scoliotic angle, and patient's age may play important roles influencing pulmonary function in both groups.

Adult↗

PubMed2001

A simple modeling approach towards hydroperiod effects on fish dynamics in a northern Taiwan wetland ecosystem.

In this paper we develop a simple dynamic model to describe the seasonality of fish population subjected to the pattern of water level fluctuations (i.e., hydroperiod) in a northern Taiwan wetland ecosystem, Kuandu Natural Reservation. We use a harmonic oscillation to characterize hydroperiod quantitatively by obtaining the amplitude and timing of the dominant periodic component in a time series of water levels. The model illustrates the temporal pattern of fish dynamics through the year that can result in very high density of fish at the end of a hydroperiod as well as the importance of ponds and other depressions that both are refuges and sinks during dry periods. We suggest that a 9-mon effective threshold in the length of the hydroperiod must be exceeded to produce high fish population densities. Our results also indicate that the large, piscivorous fish appear to have a major impact on smaller fish in the marsh habitat. Simulation results reveal that the recovery of small fish populations in the marsh following a major drought requires up to two years. The collective results imply that human activities such as drainage or other alterations of the hydrology can exacerbate natural cycles and results in detrimental stresses on fish production and the higher trophic levels dependent on this production.

Animals↗

PubMed2001

Characterization of activated carbons prepared from sugarcane bagasse by ZnCl2 activation.

Activated carbons were prepared from the agricultural waste of sugarcane bagasse by the chemical activation with zinc chloride (ZnCl2) at the activation temperature of 500 degrees C with soaking time of 0.5 hour. The influence of activation parameters on the final carbon products was examined by varying the impregnation ratio (i.e., mass ratio of added ZnCl2 to bagasse) and bagasse size. The physical properties of carbon products were characterized by nitrogen adsorption/desorption isotherms (at 77 K) and helium displacement method. The surface area and pore volume of carbons were thus obtained by the BET equation and t-plot method. Also, the particle density and porosity of carbons were estimated by the total pore volume and true density. The increases of the values of surface area and pore volume are approximately proportional to the impregnation ratio. The microporous carbon product with the BET surface area of 905 m2/g and total pore volume of 0.44 cm3/g was obtained in the present study. Further, the adsorption isotherms of two acid dyes from aqueous solutions onto the carbon products were performed at 30 degrees C. The results show that the adsorption isotherms of acid dyes with high molecular weight or large molecular size on the microporous adsorbents of activated carbons are plateau forms, indicating multilayer adsorptions, which may be attributed to the steric hindrance of the adsorbate molecules.

Adsorption↗

PubMed2001

12-Lipoxygenase inhibition induced apoptosis in human gastric cancer cells.

Arachidonic acid release from membrane phospholipids is essential for tumour cell proliferation. Lipoxygenases constitute a pathway for arachidonate metabolism. The present study investigated the expression of 12-lipoxygenase and its effect on cell proliferation as well as survival in two human gastric cancer cell lines (AGS and MKN-28). RT-PCR and western blots, respectively, showed 12-LOX mRNA and protein expression in both AGS and MKN-28 cell lines. Treatment with a 12-LOX inhibitor, baicalein, significantly inhibited cancer cell proliferation, but a metabolite of 12-LOX activity, 12 hydroxyeicosatetraenoic acid (12-HETE) reversed baicalein-induced growth inhibition. Furthermore, the blockade of the 12-LOX pathway through a 12-LOX inhibitor and antisense induced apoptosis of gastric cancer cell lines. The biochemical characteristics of apoptosis were p53-independent combined with a decrease in bcl-2 expression. Caspase-7 was proteolytically activated and responsible for the apoptosis execution.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed2001

Non-steroidal anti-inflammatory drugs induce apoptosis in gastric cancer cells through up-regulation of bax and bak.

Aspirin- and non-steroidal anti-inflammatory drug (NSAID)-induced apoptosis is one of the important mechanisms for their anti-tumour effect in gastric cancer. We aimed at determining the role of bcl-2 family proteins and caspases in the apoptotic process. Gastric cancer cell lines AGS (wild-type p53) and MKN-28 (mutant p53) were used. Cell proliferation was measured by MTT assay. Apoptosis was determined by acridine orange staining. Protein expressions were determined by western blotting. Aspirin and indomethacin inhibited cell proliferation and induced apoptosis in both cells. AGS cells were more sensitive compared with MKN-28 cells. The pro-apoptotic proteins bax and bak were overexpressed after treatment, while the protein level of bcl-2 remained unchanged. Apoptosis was accompanied by an increase in caspase-3 activity and cleavage of caspase-3 and poly(ADP-ribose) polymerase. Inhibition of caspase-3 rescued aspirin-induced apoptosis. Our results suggest that one of the major pathways which mediates the anti-tumour response of aspirin and indomethacin in gastric cancer cells is through up-regulation of bax and bak and activation of caspase-3. Bax and bak are important in the chemoprevention of gastric cancer.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2001

Gastric intramucosal PCO2 and pH variability in ventilated critically ill patients.

OBJECTIVE: Gastric intramucosal PCO2 (PiCO2) and pH (pHi) are currently used as indices of the adequacy of splanchnic perfusion and as end points to guide therapeutic intervention. However, little is known about their spontaneous variability over time. The present study was designed to define the magnitude of spontaneous variability of PiCO2 and pHi in sedated medical intensive care unit (ICU) patients using an automated recirculating air tonometer and to test whether high-level positive end-expiratory pressure (PEEP) or inverse inspiratory/expiratory (I:E) ratio ventilation resulted in a greater variability than low PEEP with conventional I:E ratio ventilation. DESIGN: Prospective study. SETTING: Medical ICU in a tertiary medical center. PATIENTS: Twenty-three acute respiratory failure patients. INTERVENTIONS: After being sedated, patients were randomized to undergo pressure control ventilation at the following three settings: A, high PEEP (15 cm H2O) with conventional I:E ratio (1:2), and B, low PEEP (5 cm H2O) with inverse I:E ratio (2:1) alternately, and then C, low PEEP (5 cm H2O) with conventional I:E ratio (1:2). Each ventilation setting period lasted 1 hr. MEASUREMENTS AND MAIN RESULTS: The PiCO2 and pHi were measured at baseline (time 0), and at 15, 30, 45, and 60 mins thereafter. The corresponding coefficients of variation (CVs) of PiCO2 for overall pooled group and settings A, B, and C were 4.0%, 4.4%, 3.4%, and 4.2%, respectively. The corresponding CVs of pHi for overall pooled group and settings A, B, and C were 0.36%, 0.37%, 0.33%, and 0.4%, respectively. Analysis of variance showed no significant difference in the CVs of PiCO2 or pHi between the three settings. The 95% confidence interval is approximately +/-8% variability for PiCO2 and +/-0.7% variability for pHi. CONCLUSIONS: In critically ill medical ICU patients with stable hemodynamics, the spontaneous variability of PiCO2 or pHi are not substantial. High PEEP (15 cm H2O) and inverse ratio ventilation (2:1), which does not change the cardiac output or hemodynamics, does not contribute to increased spontaneous variability in PiCO2 or pHi.

Adult↗

PubMed2001

Evaluation of Etest for direct antifungal susceptibility testing of yeasts in positive blood cultures.

The performance of the Etest (AB BIODISK, Solna, Sweden) for direct antifungal susceptibility testing of yeasts in positive blood cultures was compared with that of the macrodilution method for determining the MICs of five antifungal agents. Culture broths with blood from bottles positive for yeasts were inoculated directly onto plates for susceptibility testing with the Etest, and the MICs were read after 24 and 48 h of incubation. A total of 141 positive blood cultures (72 cultures of Candida albicans, 31 of Candida tropicalis, 14 of Candida glabrata, 11 of Candida parapsilosis, 3 of Candida krusei, and 3 of Cryptococcus neoformans, 4 miscellaneous yeast species, and 3 mixed cultures) were tested, and the rates of MIC agreement (+/-1 log(2) dilution) between the direct Etest (at 24 and 48 h, respectively) and macrodilution methods were as follows: amphotericin B, 81.8 and 93.5%; flucytosine, 84.8 and 87.7%; fluconazole, 89.4 and 85.5%; itraconazole, 69.7 and 63.8%; ketoconazole, 87.9 and 79.0%. By a large-sample t test, the difference in log(2) dilution between the direct Etest and the macrodilution method was found to be small (P < 0.05). The lone exceptions were ketoconazole at 48 h of incubation and itraconazole at both 24 and 48 h of incubation (P > 0.05). By Tukey's multiple comparisons, the difference between the direct Etest (48 h) and reference methods among different species was found to be less than 1 log(2) dilution. When the MICs were translated into interpretive susceptibility, the minor errors caused by the direct Etest (at 24 and 48 h, respectively) were as follows: flucytosine, 2.3 and 1.4%; fluconazole, 3.0 and 3.6%; itraconazole, 21.2 and 21.3%. Itraconazole also produced an additional 3.0 and 3.6% major errors as determined by the direct Etest at 24 and 48 h, respectively. It was concluded that, except for itraconazole, the Etest method was feasible for direct susceptibility testing of blood cultures positive for yeasts. The method is simple, and the results could be read between 24 and 48 h after direct inoculation, whenever the inhibition zones were discernible.

Antifungal Agents↗

PubMed2001

Predicting extended wear complications from overnight corneal swelling.

PURPOSE: To examine the hypothesis that the corneal overnight swelling response (ONSR) is a predictor of ocular complications in contact lens extended wear (EW). METHODS: The Berkeley Contact Lens Extended Wear Study (CLEWS) was a randomized, concurrently controlled clinical trial in which more than 200 subjects in EW with rigid gas-permeable (RGP) lenses were observed for 1 year. After adapting to EW, subjects were randomized to either medium or high oxygen-permeable (Dk) RGP lenses and underwent clinical assessments, keratometry, and corneal pachometry at 3-month intervals. RESULTS: The ONSR was directly related to lens Dk (P = 0.01) and exhibited substantial variability across subjects. The probability of remaining free of complications over time was not significantly lower for subjects with a mild ONSR compared with those with greater edema (P = 0.84). The risk of development of keratopathy was not significantly related to the ONSR (relative risk = 1.00). CONCLUSIONS: The corneal ONSR is not a good predictor of ocular complications in 1 year of RGP EW. Lenses that cause little or no corneal edema are not necessarily safer for overnight wear.

Circadian Rhythm↗

PubMed2001

Ruptured cystic teratoma of the testis in a neonate.

Neonatal testicular tumors are extremely rare. We report the case of a full-term male newborn with right hemiscrotal swelling found immediately after birth. The right hemiscrotal skin gradually turned dusky dark and then adhered to the hard scrotal contents. Missed right testicular torsion was suspected and emergency exploration was not attempted. Right hemiscrotal swelling became aggravated, so right orchiectomy and left orchidopexy were performed. During surgery, severe inflammation of the right testis and the right hemiscrotum were observed and diffuse hemorrhage with focal hematomas was noted within the removed right testis. Histopathology of the specimen revealed a ruptured mature cystic teratoma of the testis. The alpha-fetoprotein concentration was 729 x 10(4) micrograms/L 10 days after the operation, and dropped to 185 x 10(4), 25 x 10(4), and less than 20 x 10(4) micrograms/L 2, 5, and 8 months later, respectively. Postoperative abdominal and pelvic computerized tomography scans revealed neither lymphadenopathy nor distant metastasis. During a follow-up of 8 months, no evidence of tumor recurrence was found. Although extremely rare, testicular tumors should be included in the differential diagnosis of an enlarged hard or firm scrotal mass in the male neonate.

Diagnosis, Differential↗

PubMed2000

Maternal cold inducible RNA binding protein is required for embryonic kidney formation in Xenopus laevis.

We cloned a major isoform of Xenopus homologue of cold inducible RNA binding protein (CIRP), XCIRP-1. XCIRP-1 was neither cold inducible nor essential for cell division during early embryonic development. Suppression of XCIRP-1 dose dependently produced tailbuds with deformations of the brain and internal organs. The defects were XCIRP-1 specific as they could be rescued by sense transcript. Suppression of XCIRP-1 also disrupted the morphogenetic migration of the C3 blastomeres (lineaged to become the embryonic kidney, the pronephros). In animal cap explants, depletion of XCIRP-1 inhibited activin/retinoic acid induced expressions of pronephros related Xlim-1 and WT1 genes. These results suggest that XCIRP-1 is required for the specification and morphogenetic lineage migration of the pronephros.

Abnormalities, Multiple↗

PubMed2000

Molecular basis for differing antineurogenic effects of GATA-1a and GATA-1b in Xenopus.

The erythroid transcription factor GATA-1 in Xenopus has been cloned as a pair of presumably duplicated genes designated as xGATA-1a and xGATA-1b. Although both xGATA-1a and xGATA-1b are able to stimulate erythropoiesis, only xGATA-1b is capable of inhibiting neurogenesis in Xenopus embryos. Chimeras of these two genes were constructed by permuting coding and untranslated regions (UTR) on both ends of these two xGATA-1, and their neurogenesis-inhibitory effects were studied. These results reveal that (1) sequence variations between the coding regions alone do not account for the neurogenesis effect; (2) 3' UTR of xGATA-1a causes the loss of the neurogenesis inhibition of xGATA-1b; (3) 3' UTR of xGATA-1b is essential to inhibit neurogenesis. In addition, the presence of either UTR does not affect the stability of the mRNA in vitro. These observations suggest the influence of 3' UTR in xGATA-1 on the inhibition of neurogenesis.

3' Untranslated Regions↗

PubMed2000

Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers.

BACKGROUND: PTEN tumor suppressor gene mutations are the most frequent genetic lesions in endometrial adenocarcinomas of the endometrioid subtype. Testing the hypothesis that altered PTEN function precedes the appearance of endometrial adenocarcinoma has been difficult, however, partly because of uncertainties in precancer diagnosis. METHODS: Two series of endometrial cancer and precancer (endometrial intraepithelial neoplasia, as diagnosed by computerized morphometric analysis) tissue samples were studied, one for PTEN mutations by the use of denaturing gradient gel electrophoresis and another for PTEN protein expression by immunohistochemistry. Endometria altered by high estrogen levels that are unopposed by progestins-conditions known to increase cancer risk-were also studied by immunohistochemistry. Fisher's exact test was used for statistical analysis. RESULTS: The PTEN mutation rate was 83% (25 of 30) in endometrioid endometrial adenocarcinomas and 55% (16 of 29) in precancers, and the difference in number of mutations was statistically significant (two-sided P =.025). No normal endometria showed PTEN mutations. Although most precancers and cancers had a mutation in only one PTEN allele, endometrioid endometrial adenocarcinomas showed complete loss of PTEN protein expression in 61% (20 of 33) of cases, and 97% (32 of 33) showed at least some diminution in expression. Cancers and most precancers exhibited contiguous groups of PTEN-negative glands, while endometria altered by unopposed estrogens showed isolated PTEN-negative glands. CONCLUSIONS: Loss of PTEN function by mutational or other mechanisms is an early event in endometrial tumorigenesis that may occur in response to known endocrine risk factors and offers an informative immunohistochemical biomarker for premalignant disease. Individual PTEN-negative glands in estrogen-exposed endometria are the earliest recognizable stage of endometrial carcinogenesis. Proliferation into dense clusters that form discrete premalignant lesions follows.

Biomarkers, Tumor↗

PubMed2000

Calcium and magnesium in drinking water and risk of death from prostate cancer.

The possible association between the increased risk of prostate cancer and the levels of calcium and magnesium in drinking water from municipal supplies was investigated in a matched cancer case-control study in Taiwan. All eligible prostate-cancer deaths (682 cases) of Taiwan residents from 1987 through 1993 were compared with deaths from other causes (682 controls). The levels of calcium and magnesium in the drinking water of these residents were also determined. Data on calcium and magnesium levels in drinking water throughout Taiwan were obtained from the Taiwan Water Supply Corporation (TWSC). The control group consisted of people who died from other causes, and the controls were pair-matched to the cases by year of birth and death. The adjusted odds ratios for prostate cancer death for those with higher magnesium levels in their drinking water, as compared to the lowest tertile, were 0.73 (95% CI = 0.51-1.03) and 0.64 (95% CI = 0.43-0.96), respectively. The adjusted odd ratios for the relationship between calcium levels in drinking water and prostate cancer were not statistically significant. The results of the present study show that there may be a significant protective effect of magnesium intake from drinking water and other dietary sources against the risk of prostate cancer development.

Aged↗

PubMed2000

Novel effects of gossypol, a chemical contraceptive in man: mobilization of internal Ca(2+) and activation of external Ca(2+) entry in intact cells.

The effect of gossypol on Ca(2+) signaling in Madin Darby canine kidney (MDCK) cells was investigated by using fura-2 as a Ca(2+) probe. Gossypol evoked a rise in cytosolic free Ca(2+) levels ([Ca(2+)](i)) concentration-dependently between 2 and 20 microM. The response was decreased by external Ca(2+) removal. In Ca(2+)-free medium pretreatment with gossypol nearly abolished the [Ca(2+)](i) increase induced by carbonylcyanide m-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler, and thapsigargin, an inhibitor of the endoplasmic reticulum Ca(2+) pump; but pretreatment with CCCP and thapsigargin only partly inhibited gossypol-induced Ca(2+) release. Addition of 3 mM Ca(2+) induced a [Ca(2+)](i) increase after pretreatment with 5 microM gossypol in Ca(2+)-free medium. This Ca(2+) entry was decreased by 25 microM econazole, 50 microM SKF96365 and 40 microM aristolochic acid (a phospholipase A(2) inhibitor). Pretreatment with aristolochic acid inhibited 5 microM gossypol-induced internal Ca(2+) release by 55%, but suppression of phospholipase C with 2 microM 1-(6-((17beta-3-methoxyestra-1,3, 5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione) had no effect. Gossypol (5 microM) also increased [Ca(2+)](i) in human bladder cancer cells and neutrophils. Collectively, we have found that gossypol increased [Ca(2+)](i) in MDCK cells by releasing Ca(2+) from multiple Ca(2+) stores in a manner independent of the production of inositol-1,4,5-trisphosphate, followed by Ca(2+) influx from external space.

Animals↗

PubMed2000

Mouse peroxiredoxin V is a thioredoxin peroxidase that inhibits p53-induced apoptosis.

We have identified human and mouse peroxiredoxin V (Prx-V) by virtue of the sequence homologies to yeast peroxisomal antioxidant enzyme PMP20. Prx-V represents the fifth of the six currently known subfamilies of mammalian peroxiredoxins. It is a novel organellar enzyme that has orthologs in bacteria. Biochemically, Prx-V is a thioredoxin peroxidase. One important aspect of p53 function in mammalian cells involves induction of apoptosis likely mediated by redox. We show that overexpression of Prx-V prevented the p53-dependent generation of reactive oxygen species. Likewise, Prx-V inhibited p53-induced apoptosis. Thus, Prx-V is critically involved in intracellular redox signaling.

Amino Acid Sequence↗

PubMed2000

An appraisal of liver and portal vein resection for hepatocellular carcinoma with tumor thrombi extending to portal bifurcation.

BACKGROUND: The role of surgical resection for hepatocellular carcinoma with tumor thrombi involving the major portal vein is controversial because of a high operative risk and poor prognosis. Previously, a resection was performed only when the tumor thrombi were limited to the first branch of the portal vein without extension to the portal bifurcation. HYPOTHESIS: Concomitant liver and portal vein resection may be beneficial in patients with hepatocellular carcinoma with tumor thrombi extending to portal bifurcation. DESIGN: Retrospective review. SETTING: University hospital, tertiary referral center. PATIENTS: Among 368 patients with hepatocellular carcinoma who underwent a curative resection, portal vein involvement occurred in 112 patients. Fifteen of the 112 patients underwent a concomitant liver and portal vein resection owing to extension of tumor thrombi to the portal bifurcation (group 1). The remaining 97 patients did not need portal vein resection (group 2). INTERVENTION: Surgical indications, procedures, and results of pathological examination of resected specimens were assessed in patients in group 1. The clinicopathological characteristics, operative morbidity and mortality, and operative results were compared between the 2 groups. MAIN OUTCOME MEASURES: Disease-free and actuarial survival rates. RESULTS: Intramural tumor infiltration was found at the site of thrombi adhesion to the portal vein cuff in 11 of 15 patients in group 1. Owing to patient selection bias, patients in group 1 were significantly younger and had better liver function and greater resected liver weight. The operative time, postoperative hospitalization, operative blood loss, amount of blood transfusion, and operative morbidity and mortality did not differ significantly between the 2 groups. The 5-year disease-free survival rates of groups 1 and 2 were 21.6% and 20.4% (P =.19), respectively, while the actuarial survival rates were 26. 4% and 28.5% (P =.33), respectively. CONCLUSION: Liver resection with partial resection of the portal vein is justified in selected patients with hepatocellular carcinoma with tumor thrombi extending to portal bifurcation.

Carcinoma, Hepatocellular↗

PubMed2000

Allelic imbalance in lichen sclerosus, hyperplasia, and intraepithelial neoplasia of the vulva.

BACKGROUND: Few studies have addressed in detail the genetic alterations that occur in vulvar squamous carcinomas (VSCC) and their precursor lesions. In a previous study, we determined the most common chromosomal loci for allelic imbalance (AI) in HPV-positive and -negative VSCCs. The present study was designed to determine whether AI and the microsatellite instability phenotype (MIN) were present in epithelial lesions known to be associated with VSCC. DESIGN: Fifty-seven epithelial loci were analyzed, including HPV-positive (classic) and -negative (differentiated) vulvar intraepithelial neoplasms (VINs), lichen sclerosus (LS), and nonatypical hyperplasias. Thirty-one epithelial loci (55%) were obtained from patients with associated invasive vulvar carcinoma. HPV status was determined by polymerase chain reaction analysis. AI and MIN were determined by comparisons of microdissected target tissues with stromal controls, targeting 11 chromosomal loci. RESULTS: AI was identified in all epithelial categories, involving at least one chromosomal locus in 67, 53, 50, and 43% of classic VIN, differentiated VIN, hyperplasia, and LS. MIN was infrequent (10-13%), but confined to HPV-negative epithelial changes. HPV-positive lesions generally scored for AI more frequently, but certain loci scored nearly equally in both HPV-positive and -negative lesions, including 8p, 11q, and 17p. There were no differences in frequency of AI between epithelia with and without associated invasive carcinoma. CONCLUSIONS: The presence of allelic imbalance in vulvar hyperplasia and LS supports the hypothesis that these alterations are at greater risk for neoplasia despite the absence of conspicuous cellular atypia. A model is proposed in which these changes represent monoclonal expansion and are at empirically greater risk for subsequent "critical events" leading to morphologic atypia (VIN). The possibility that these early genetic changes influence both HPV-positive and -negative pathways merits further study.

Carcinoma in Situ↗

PubMed2000

Induction of oocyte maturation by jun-N-terminal kinase (JNK) on the oncogenic ras-p21 pathway is dependent on the raf-MEK signal transduction pathway.

PURPOSE: We have previously found that microinjection of activated MEK (mitogen activated kinase kinase) and ERK (mitogen-activated protein; MAP kinase) fails to induce oocyte maturation, but that maturation, induced by oncogenic ras-p21 and insulin-activated cell ras-p21, is blocked by peptides from the ras-binding domain of raf. We also found that jun kinase (JNK), on the stress-activated protein (SAP) pathway, which is critical to the oncogenic ras-p21 signal transduction pathway, is a strong inducer of oocyte maturation. Our purpose in this study was to determine the role of the raf-MEK-MAP kinase pathway in oocyte maturation and how it interacts with JNK from the SAP pathway. METHODS: We microinjected raf dominant negative mutant mRNA (DN-raf) and the MEK-specific phosphatase, MKP-T4, either together with oncogenic p21 or c-raf mRNA, into oocytes or into oocytes incubated with insulin to determine the effects of these raf-MEK-MAP kinase pathway inhibitors. RESULTS: We found that oocyte maturation induced by both oncogenic and activated normal p21 is inhibited by both DN-raf and by MKP-T4. The latter more strongly blocks the oncogenic pathway. Also an mRNA encoding a constitutively activated MEK strongly induces oocyte maturation that is not inhibited by DN-raf or by MKP-T4. Surprisingly, we found that oocyte maturation induced by JNK is blocked both by DN-raf and MKP-T4. Furthermore, we discovered that c-raf induces oocyte maturation that is inhibited by glutathione-S-transferase (GST), which we have found to be a potent and selective inhibitor of JNK. CONCLUSION: We conclude that there is a strong reciprocal interaction between the SAP pathway involving JNK and the raf-MEK-MAP kinase pathway and that oncogenic ras-p21 can be preferentially inhibited by MEK inhibitors. The results imply that blockade of both MEK and JNK-oncogenic ras-p21 interactions may constitute selective synergistic combination chemotherapy against oncogenic ras-induced tumors.

Animals↗