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Biomedical subjects

K Fan

Publications and source records attributed to K Fan.

At least 37 records · Page 2Linked to original sources
PubMed1999

Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice.

An3 1 KAL I MutL homologue 1 (MLH1) is a member of the family of proteins required for DNA mismatch repair. Germ-line mutations in MLH1 lead to the cancer susceptibility syndrome hereditary nonpolyposis colorectal cancer (HNPCC). We generated mice carrying a null mutation in the Mlh1 gene. We showed that mice heterozygous and homozygous for the Mlh1 gene are predisposed to developing tumors of the gastrointestinal (GI) tract, lymphomas, and a number of other tumor types. We also examined the role of adenomatous polyposis coli gene (Apc) gene mutations in the GI tumors of Mlh1 mutant mice by different methods and showed that the GI tumors in Mlh1 mice express little or no adenomatous polyposis coli protein. When an Apc gene mutation was bred into the Mlh1 mutant mice, the GI tumor incidence increased 40-100-fold. The wild-type Apc allele in these tumors was found to contain mutations. Together, these results show that we have developed two mouse models for human HNPCC and that the mechanisms of tumor development in the GI tract of these mice involve loss of Apc gene function in a manner very similar to that seen in the GI tumors of HNPCC.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Dual chamber implantable cardioverter defibrillator benefits and limitations.

UNLABELLED: Dual chamber ICD capable of providing dual chamber pacing (DDD) and ventricular arrhythmia therapy is now available. We report our experience of clinical performance of dual chamber ICDs amongst Chinese population. METHODS: 9 patients (6 men and 3 women) received dual chamber ICDs, mean age 50 +/- 18.8 years. The indications were ventricular fibrillation (VF) [5], hemodynamic intolerant ventricular tachycardia (VT) [3] and unexplained syncope plus positive induction of VF [1]. The underlying cardiac pathology were congenital LQT syndrome(1), hypertrophic cardiomyopathy [2], coronary artery disease [2], rheumatic valvular disease [1], Brugada syndrome [1], arrhythmogenic right ventricular dysplasia [1] and idiopathic VF [1]. Four patients have documented paroxysmal atrial fibrillation (AF). All patients have defibrillation thresholds (DFT) determined with a binary search protocol starting at 12 joules (J) at implantation. RESULTS: A total of 34 episodes of VF were induced at implantation with mean DFT 13.8 +/- 7 J. The average shocking impedance was 40 +/- 3.6 Omega. The mean acute P wave measured 3.3 +/- 1.3 mV and R wave measured 13.2 +/- 3.2 mV. Atrial and ventricular thresholds, at pulse width 0.5 ms, averaged 0.8 +/- 0.4 V and 0.4 +/- 0.2 V. During follow-up period, 16 episodes of VF were documented and were successfully treated with the first programmed shock. In the patient with LQT syndrome, DDD was initiated to prevent pause-dependant VF. Three episodes of inappropriate therapy (15.8%) were delivered. One patient experienced 2 shocks after exercise. Stored electrograms showed sinus tachycardia with first degree heart block which was misdiagnosed as VT with retrograde 1:1 conduction. Another inappropriate therapy occurred with AF with fast ventricular response within the VF zone and VT therapy inhibitor was disabled. CONCLUSION: Dual chamber ICD allows combined benefits of DDD and VT/VF therapy. Storage of both atrial and ventricular electrograms provide more information in elucidation of nature of dysarrhythmias. Inappropriate shocks, though reduced, are still possible and the rigid algorithms of SVT discrimination from VT will need further published.

Adult↗
PubMed1999

Preclinical mouse models for cancer chemoprevention studies.

To aid in identifying the ability of chemopreventive agents to inhibit tumor development, new preclinical in vivo rodent models have recently been developed. Some of the models contain targeted mutations capable of increasing the incidence and progression of neoplastic lesions, whereas in other models dietary nutrients induce preneoplastic lesions in normal mice. These new preclinical models are assisting the analysis of genetic and environmental factors leading to neoplasia, and clinical studies to evaluate the chemopreventive efficacy of specific nutrients and pharmacological agents.

Animals↗
PubMed1999

Inverse relationship between Leydig cell density and metastatic potential of prostatic adenocarcinoma.

PURPOSE: Evaluate the relationship between metastatic potential of prostatic adenocarcinoma (PC) and testicular Leydig cell density. MATERIALS AND METHODS: Tissue samples from 111 men, age 52-85, with PC and bilateral orchiectomy were evaluated for Leydig cell density. The patients were divided into two groups: Group A were patients with metastasis (n = 36) and Group B were patients without metastasis (n = 75). Leydig cell density was determined by direct manual microscopic cell count on the tissue sections. The means of cell counts by four pathologists, expressed as cell/0.78 mm2 were used for analysis. The normally distributed data were analyzed by two-tail Student's t-test. Thirty-eight age-compatible autopsy cases who died of unrelated causes served as normal controls. RESULTS: The mean of Leydig cell count in group A patients was 14.43 (14.43+/-1.19 SE). Mean of Group B was 47.05 (47.05+/-4.05 SE) whereas normal controls displayed a mean of 48.66 (48.66+/-2.94 SE). Group A was significantly different from control (p < 0.00001). Group A and Group B were also significant different (p < 0.001) whereas control was not significantly different from Group B (p > 0.75). CONCLUSIONS: Patients with metastatic adenocarcinoma of prostate, as a group, have a significantly lower Leydig cell density than patients without metastasis or patients without PC in compatible age groups. The hormonal relationship between this observation is however unknown. One possible explanation is that PC subpopulation with metastatic potential may require different level of endogenous androgen or are androgen-independent.

Adenocarcinoma↗
PubMed1999

Determination of benzodiazepines in clinical serum samples: comparative evaluation of REMEDi system, aca analyzer, and conventional HPLC performance.

Emergency toxicology or drug screening in clinical settings requires rapid qualitative and quantitative analysis with acceptable levels of sensitivity and specificity. The aim of this study was to comparatively evaluate the performance of the multi-column HPLC-based REMEDi drug profiling system (Bio-Rad), the aca analyzer (Du Pont), and the bench standard conventional HPLC method in the identification of 12 clinically important benzodiazepines. In this study, the presence of benzodiazepines in 133 patients' serum samples were qualitatively and comparatively analyzed by these three procedures. Among these methods, 120 of 133 samples were identified as benzodiazepine-positive by conventional HPLC (90%); 127 by aca analyzer (95%); and 84 by REMEDi (63%). Detection sensitivity of REMEDi for most of the benzodiazepines was found satisfactory when concentrations were greater than 1.0 microg/mL. When benzodiazepine concentrations were in the ranges of 0.3-1.0 microg/mL, detection sensitivity became varied among the benzodiazepine family of drugs by REMEDi method. REMEDi procedure should not be considered as the method of choice for detection of benzodiazepines if expected concentration levels are below 0.3 microg/mL, with the exception of bromazepam. Conventional HPLC displayed the highest sensitivity and specificity for the detection of benzodiazepines. In our studies, 36 REMEDi-negative samples were positive by HPLC, although in 16 of the 36 REMEDi negative samples (13.3%), the presence of benzodiazepines was detected but only listed as candidates without positive identification of the individual compounds by REMEDi. In our series, however, there were no false positives by the REMEDi method whereas aca procedure showed 13 false positive results (9%) and 6 cases of false negative (4%). Our data indicate that the REMEDi procedure can be used on serum samples for rapid qualitative screening of clinically important high levels of benzodiazepines with high specificity. However, due to the relatively low sensitivity of REMEDi in samples with low benzodiazepine levels and relatively low specificity by aca, all samples should be further confirmed by conventional HPLC procedure.

Autoanalysis↗
PubMed1998

Dietary modulation of carcinoma development in a mouse model for human familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is caused by a dominant mutation in the adenomatous polyposis coli (APC) gene. Individuals with FAP progressively develop adenomas and carcinomas of the colon and rectum. We developed a mouse model for this disorder by genetically modifying the Apc gene. The resulting mice Apc1638 progressively develop neoplasms in the colon and remainder of the gastrointestinal tract. In this study when Apc1638 mice were fed a Western-style diet, they developed an increased incidence of the end point of carcinomas and number of invasive tumors. The findings therefore demonstrated dietary modulation of carcinoma incidence in mice with a targeted mutation providing a model for the study of gene-environment interactions in cancer.

Adenoma↗
PubMed1997

Mutation in the mismatch repair gene Msh6 causes cancer susceptibility.

Mice carrying a null mutation in the mismatch repair gene Msh6 were generated by gene targeting. Cells that were homozygous for the mutation did not produce any detectable MSH6 protein, and extracts prepared from these cells were defective for repair of single nucleotide mismatches. Repair of 1, 2, and 4 nucleotide insertion/deletion mismatches was unaffected. Mice that were homozygous for the mutation had a reduced life span. The mice developed a spectrum of tumors, the most predominant of which were gastrointestinal tumors and B- as well as T-cell lymphomas. The tumors did not show any microsatellite instability. We conclude that MSH6 mutations, like those in some other members of the family of mismatch repair genes, lead to cancer susceptibility, and germline mutations in this gene may be associated with a cancer predisposition syndrome that does not show microsatellite instability.

Adenomatous Polyposis Coli Protein↗
PubMed1997

A mouse model of human familial adenomatous polyposis.

In an effort to generate a good mouse model for human colorectal cancer, we generated mice which carry a mutation in the adenomatous polyposis coli (Apc) gene. Mice which are heterozygous for the mutation, designated Apc1638, develop colonic polyps and tumors of the small intestine. Neoplasms were found in 96% of animals studied, and they included adenomas, adenocarcinomas, and polypoid hyperplasias. The mice developed an average of 3.3 tumors, with the highest number in duodenum, followed by jejunum, stomach, ileum, and colon. Focal areas of dysplasias were observed in the colonic mucosa in 50% of mice which were 10 months old or older. These results suggest that mice carrying the Apc1638 mutation can serve as a good model to study the initiation, progression, and inhibition of gastrointestinal tumors.

Adenomatous Polyposis Coli↗
PubMed1997

Use of low molecular weight heparin in postangioplasty management.

The results of using low molecular weight heparin (LMWH) in postangioplasty management are examined. In comparison to intravenous unfractionated heparin, subcutaneous LMWH caused less groin complications and was simpler and cheaper to be administered by the medical personnel. The incidence of ischaemic complications after angioplasty including acute closure and myocardial infarction, however, remained similar and was not excessive. Subcutaneous administration of LMWH provides and alternative simple and cost-effective strategy for postangioplasty management.

Aged↗
PubMed1997

Significance of p53 overexpression in urinary bladder transitional cell carcinoma in situ before and after bacillus Calmette-Guérin treatment.

OBJECTIVES: Overexpression of p53, normally secondary to gene mutation, in invasive uroepithelial neoplasms (transitional cell carcinoma) and a high percentage of transitional cell carcinoma in situ (CIS) has been described; however, the role of p53 before and after bacillus Calmette-Guérin (BCG) treatment of CIS needs to be defined. METHODS: Immunohistochemical reaction for p53 overexpression was performed on 12 patients with CIS before and after BCG treatment. Thirty cystectomy specimens with invasive TCC were also evaluated for the presence of CIS, hyperplasia, and dysplasia. RESULTS: Twenty-three cases of CIS were identified. Approximately 90% of CIS cases (21 of 23) were positive for p53 overexpression, whereas transitional cell hyperplasia was uniformly negative. Less than 5% of the cells in morphologically dysplastic lesions were positively stained. Ten of 12 CIS patients displayed p53 overexpression before BCG treatment. After BCG treatment, 4 patients displayed residual CIS with p53 overexpression, and 8 patients showed no residual CIS or p53 overexpression. Three of the 4 patients with residual CIS and overexpression rapidly developed invasive transitional cell carcinoma requiring cystectomy. The 1 remaining patient was treated with a second course of BCG; further biopsies displayed the development of grade 1 papillary transitional cell carcinoma without invasion, and the patient is currently being followed CONCLUSIONS: Our data suggest that follow-up biopsy procedures are essential in all patients with CIS treated with BCG. The biopsy specimens should be evaluated for p53 overexpression, because our data indicate that persistent p53 overexpression in uroepithelial lesions after BCG treatment is an ominous finding for probable tumor progression.

Adjuvants, Immunologic↗
PubMed1996

Cytokeratin, lectin, and acidic mucin modulation in differentiating colonic epithelial cells of mice after feeding Western-style diets.

Several studies have recently reported the development of colonic epithelial cell hyperproliferation in rodents following the ingestion of Western-style diets. In this study, additional measurements related to differentiation and maturation of the colonic epithelial cells were made after feeding this type of diet. Two Western-style diets high in fat and phosphate content and low in calcium and vitamin D were fed to C57BL/6J mice for 12, 24, and 52 weeks. Diet A contained American Blend fat as a source of lipids, diet B contained corn oil, and control diet C was a standard AIN-76A semisynthetic diet which is lower in fat content and higher in calcium and vitamin D. Colonic epithelial cells were studied for three biomarkers: cytokeratin catalogue no. 18 (clone LE64) expression, soybean agglutinin carbohydrate lectin binding, and acidic mucins including sialo- and sulfomucins. Feeding of diets A and B revealed that colonic epithelial cells had increased expression of cytokeratin catalogue 18 and SBA carbohydrate lectin binding compared to controls (P = 0.0001 for diet A versus C and diet B versus C). Significant differences were found between diets B and C (P = 0.0001) and diets A and C (P = 0.0001) in total acidic mucins and in the ratio of sialomucin:sulfomucin (P = 0.0001). These findings demonstrate that both functional and structural modifications occurred in colonic epithelial cells under these dietary conditions, and further defined this rodent model for preclinical evaluation of nutritional and chemopreventive interventions.

Animals↗
PubMed1996

[A novel RNA capture method for the extraction of HCV-RNA].

A novel method for the extraction of HCV-RNA by using DNA probe coated-latex microparticle (AmpliTex) was developed. This high density particle, with a large surface area, could be dispersed uniformly in a guanidium lysate of the serum. The DNA probe on the particles could hybridize with a few copies of HCV-RNA in the lysate. The RNA thus extracted on the particle can be subjected to the reverse-transcription and PCR reaction. Analytical sensitivity to detect HCV in serum was approximately 20 copies per ml. AmpliTex and the conventional organic extraction gave the same sensitivity and specificity (both 100%) to detect the HCV-RNA from fifty clinical specimens. It was also possible to extract the HCV-RNA from heparinated plasma.

DNA Probes↗
PubMed1996

Increased phospholipid fatty acid remodeling in human and rat prostatic adenocarcinoma tissues.

PURPOSE: To study the mechanism of diminished arachidonic acid levels in malignant prostatic tissues. MATERIALS AND METHODS: Benign and malignant prostate tissues were obtained from human radical prostatectomy specimens and from rats using Pollard's Lobund/Wistar rat prostate cancer model. Fatty acid composition and a variety of enzyme activities involved in maintaining phospholipid fatty acid composition were compared in malignant and benign prostatic tissues. RESULTS: Decreased arachidonic acid levels, previously reported in human prostate cancer, were present in malignant rat as well as in human tissues. There were 21% and 26% decreases of arachidonic acid levels in the rat and human malignant tissues compared with benign tissues. Fatty acid desaturase activity was undetectable. Fatty acyl-CoA hydrolase and synthetase activities were not altered in the malignant tissues. However, there was a 2-fold increase in phospholipase A2 activity and a 4- to 12-fold increase in fatty acyl-CoA lysophosphatidylcholine acyltransferase activity in malignant rat and human prostatic tissues. CONCLUSIONS: These data indicate that, in malignant prostate tissues, the fatty acid remodeling mechanism is activated through the deacylation-reacylation cycle. This process may be a result of increased use of arachidonic acid for the formation of prostaglandins that may be crucial for the further development and growth of the malignant tissues.

Adenocarcinoma↗