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Biomedical subjects

C K Lee

Publications and source records attributed to C K Lee.

At least 145 records · Page 8Linked to original sources
PubMed1999

A novel four-drug ablative regimen with hemopoietic stem cell rescue for patients with breast cancer: a phase II study.

High-dose chemotherapy and autologous hemopoietic stem cell transplantation (HSCT) may provide durable progression-free survival in some patients with stage IV breast cancer (S4Brca). We have studied a new four-drug intensive preparative regimen with HSCT in a group of 158 women with S4Brca to define the risk and potential benefit of this regimen in this patient population. From May 1988 through May 1997, 158 women with S4Brca at a single center were treated with cisplatin, etoposide, thiotepa, and cyclophosphamide (PETCy) plus autologous HSCT Eligible patients were also treated with posttransplant involved-field radiation therapy. Patients with estrogen-receptor positive tumors not previously treated with tamoxifen also received this therapy for 5 years following transplantation. All patients experienced significant toxicity requiring blood-product support and parenteral nutrition. Eighteen patients (11%) died of regimen-related toxic events. With a median follow-up of 540 days for surviving patients, a retrospective Kaplan-Meier analysis projects an overall survival of 38+/-8.5% (95% CI) at 890 days with a maximum follow-up of 8.8 years. For 52 patients in sensitive relapse, the median event-free survival time is 767 days, with 46.2+/-15.3% (95% CI) predicted to be alive at 884 days with a maximal follow-up of almost 9 years. Nearly one-half of patients in this study with S4Brca in sensitive relapse have experienced durable remissions following PETCy ablation and HSCT. Although toxicity is significant, the PETCy regimen produces a favorable balance between efficacy (event-free survival) and treatment failure (relapse + regimen-related toxic death) compared with published results. These data suggest that within the high-dose range for preparative therapy, a steep dose-response may exist for breast cancer. Trials comparing the dose intensity of preparative regimens are warranted.

Adult↗
PubMed1999

Human herpes virus 6 fatal encephalitis in a bone marrow recipient.

Human herpes virus 6 (HHV-6) has been implicated as a human pathogen in both normal and immunocompromised hosts. It has been associated with interstitial pneumonitis and bone marrow suppression after transplantation. We report here a case of fatal encephalitis in a bone marrow transplant recipient. This case illustrates the importance of considering HHV6 as an emerging pathogen in immunocompromised hosts.

Bone Marrow Transplantation↗
PubMed1999

Use of embryonic and somatic cells for production of transgenic domestic animals.

In contrast to the highly developed genetic modification systems available for manipulating the mouse genome, at this time only simple gain of function modifications can be undertaken in domestic species. Clearly, the greatest barrier to gene targeting in domestic species has been the unavailability of cell lines that can be modified in vitro and still be used to generate a living organism. In the mouse, the embryonic stem (ES) cells and embryonic germ (EG) cells have fulfilled that role. While the nuclear transfer procedures have solved this problem in sheep and cattle, in swine ES and EG cells are still needed. In addition, targeting in domestic species is affected by the need to develop targeting constructs containing isogenic DNA regions. As a result, it is necessary to isolate the gene of interest, sequence required regions, and develop isogenic targeting constructs by technologies such as long-range PCR. On the positive side, enrichment protocols developed in the mouse can be applied to domestic species, thus facilitating the identification of correctly modified cell lines. Hence, progress in mammalian cloning, the development of EG cell lines, and advances in gene targeting presently allows the introduction of precise genetic modifications into the domestic animal genome.

Journal Article↗
PubMed1999

The effect of cotinine or cigarette smoke co-administration on the formation of O6-methylguanine adducts in the lung and liver of A/J mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, induces lung adenomas in A/J mice, following a single intraperitoneal (i.p.) injection. However, inhalation of tobacco smoke has not induced or promoted tumors in these mice. NNK-induced lung tumorigenesis is thought to involve O6-methylguanine (O6MeG) formation, leading to GC-->AT transitional mispairing and an activation of the K-ras proto-oncogene in the A/J mouse. NNK can be metabolized by several different cytochromes P450, resulting in a number of metabolites. Formation of the promutagenic DNA adduct O6MeG is believed to require metabolic activation of NNK by cytochrome P450-mediated alpha-hydroxylation of the methylene group adjacent to the N-nitroso nitrogen to yield the unstable intermediate, methanediazohydroxide. Nicotine, cotinine (the major metabolite of nicotine), and aqueous cigarette tar extract (ACTE) have all been shown to effectively inhibit metabolic activation of NNK to its mutagenic form, most likely due to competitive inhibition of the cytochrome P450 enzymes involved in alpha-hydroxylation of NNK. The objective of the current study was to monitor the effects of cotinine and cigarette smoke (CS) on the formation of O6MeG in target tissues of mice during the acute phase of NNK treatment. To test the effect of cotinine, mature female A/J mice received a single intraperitoneal injection of NNK (0, 2.5, 5, 7.5, or 10 mumole/mouse) with cotinine administered at a total dose of 50 mumole/mouse in 3 separate i.p. injections, administered 30 min before, immediately after, and 30 min after NNK treatment. To test the effect of whole smoke exposure on NNK-related O6MeG formation, mice were exposed to smoke generated from Kentucky 1R4F reference cigarettes at 0, 0.4, 0.6, or 0.8 mg wet total particulate matter/liter (WTPM/L) for 2 h, with a single i.p. injection of NNK (0, 3.75, or 7.5 mumole/mouse) midway through the exposure. Cigarette smoke alone failed to yield detectable levels of O6MeG. The number of O6MeG adducts following i.p. injection of NNK was significantly (p < 0.05) reduced in both lung and liver by cotinine and by cigarette smoke exposure. Our results demonstrate that NNK-induced O6MeG DNA adducts in A/J mice are significantly reduced when NNK is administered together with either cotinine, the major metabolite of nicotine, or the parental complex mixture, cigarette smoke.

Animals↗
PubMed1999

Identification and in vivo functional analysis of a virginiamycin S resistance gene (varS) from Streptomyces virginiae.

BarA of Streptomyces virginiae is a specific receptor protein for virginiae butanolide (VB), one of the gamma-butyrolactone autoregulators of the Streptomyces species, and acts as a transcriptional regulator controlling both virginiamycin production and VB biosynthesis. The downstream gene barB, the transcription of which is under the tight control of the VB-BarA system, was found to be transcribed as a polycistronic mRNA with its downstream region, and DNA sequencing revealed a 1,554-bp open reading frame (ORF) beginning at 161 bp downstream of the barB termination codon. The ORF product showed high homology (68 to 73%) to drug efflux proteins having 14 transmembrane segments and was named varS (for S. virginiae antibiotic resistance). Heterologous expression of varS with S. lividans as a host resulted in virginiamycin S-specific resistance, suggesting that varS encoded a virginiamycin S-specific transport protein. Northern blot analysis indicated that the bicistronic transcript of barB-varS appeared 1 to 2 h before the onset of virginiamycin M1 and S production, at which time VB was produced, while exogenously added virginiamycin S apparently induced the monocistronic varS transcript.

4-Butyrolactone↗
PubMed1999

Fatal disseminated Trichoderma longibrachiatum infection in an adult bone marrow transplant patient: species identification and review of the literature.

Trichoderma longibrachiatum was recovered from stool surveillance cultures and a perirectal ulcer biopsy specimen from a 29-year-old male who had received an allogeneic bone marrow transplant for acute lymphoblastic leukemia. The amphotericin B (2.0 microgram/ml) and itraconazole (1.0 microgram/ml) MICs for the organism were elevated. Therapy with these agents was unsuccessful, and the patient died on day 58 posttransplantation. At autopsy, histologic sections from the lungs, liver, brain, and intestinal wall showed infiltration by branching septate hyphae. Cultures were positive for Trichoderma longibrachiatum. While Trichoderma species have been recognized to be pathogenic in profoundly immunosuppressed hosts with increasing frequency, this is the first report of probable acquisition through the gastrointestinal tract. Salient features regarding the identification of molds in the Trichoderma longibrachiatum species aggregate are presented.

Adult↗
PubMed1999

[A preliminary report on two distinct tumor-suppressor regions on chromosome 1p36.2-p36.3 in human hepatocellular carcinomas].

OBJECTIVE: Both cytogenetic and molecular genetic analyses have unveiled non-random genomic alterations in the distal short arm of human chromosome 1 associated with a number of human malignancies including heptatocellular carcinoma (HCC). The aim of this investigation is to determine the precise region of deletion that may harbor the putative tumor suppressor genes in HCC. METHODS: For the study of the loss of heterozygosity (LOH), 38 cases of hepatitis B virus (HBV) associated HCC and their corresponding non-tumor liver tissues were detected with 43 microsatellite polymorphic markers particularly focusing on 1p. RESULTS: Twenty-eight of the 38 (74%) tumors showed LOH on at least one locus on 1p36.2-p36.3. Two distinct smallest common deleted regions (SCDRs) with different patterns of deletion were identified. The first SCDR is located on locus D1S2795 at 1p36.3, between loci D1S2145 and D1S2893. The second SCDR is located at 1p36.2, between loci D1S244 and D1S489. Both of the SCDRs have not been previously described in HCC. In addition, a region of possible homozygous deletion (HD) was also detected within the second SCDR between loci D1S1597 and D1S489 by comparative multiplex PCR. This is the first observation of a possible homozygous deletion on the distal short arm of chromosome 1 in HCC as well as in human tumors. CONCLUSIONS: The high-resolution deletion mapping of 1p36.2-p36.3 in HCC in this study confirmed the presence of two distinct regions of deletion. Our data strongly suggest the presence of at least two tumor suppressor regions on 1p36.2-p36.3 and play an important role in the pathogenesis of HBV associated HCC. These results also provide a basis for further studies directed at cloning potential tumor suppressor genes in these regions.

Carcinoma, Hepatocellular↗
PubMed1998

Immunization of mice with urease vaccine affords protection against Helicobacter pylori infection in the absence of antibodies and is mediated by MHC class II-restricted responses.

We examined the roles of cell- and antibody-mediated immunity in urease vaccine-induced protection against Helicobacter pylori infection. Normal and knockout mice deficient in major histocompatibility complex (MHC) class I, MHC class II, or B cell responses were mucosally immunized with urease plus Escherichia coli heat-labile enterotoxin (LT), or parenterally immunized with urease plus aluminum hydroxide or a glycolipid adjuvant, challenged with H. pylori strain X47-2AL, and H. pylori organisms and leukocyte infiltration in the gastric mucosa quantified. In an adjuvant/route study in normal mice, there was a direct correlation between the level of protection and the density of T cells recruited to the gastric mucosa. In knockout studies, oral immunization with urease plus LT protected MHC class I knockout mice [beta2-microglobulin (-/-)] but not MHC class II knockout mice [I-Ab (-/-)]. In B cell knockout mice [microMT (-/-)], vaccine-induced protection was equivalent to that observed in immunized wild-type (+/+) mice; no IgA+ cells were detected in the stomach, but levels of CD4(+) cells equivalent to those in the wild-type strain (+/+) were seen. These studies indicate that protection of mice against H. pylori infection by immunization with the urease antigen is dependent on MHC class II-restricted, cell-mediated mechanisms, and antibody responses to urease are not required for protection.

Adjuvants, Immunologic↗
PubMed1998

CD16 cross-linking blocks rearrangement of the TCR beta locus and development of alpha beta T cells and induces development of NK cells from thymic progenitors.

Mouse thymocytes normally develop into T lymphocytes, but the embryonic thymus also contains precursor cells capable of developing into NK cells. Here, we describe conditions that induce pro-T cells to develop into NK cells. CD16 is expressed on thymic pro-T cells. We observed that CD16 cross-linking during culture of embryonic thymic organs suppressed rearrangement of the TCR beta locus (but did not inhibit TCR gamma locus rearrangement). Rearrangement of the TCR beta locus is normally required for development to the CD4+CD8+, and this development was also suppressed by CD16 cross-linking. The ability of CD16 cross-linking to block alpha beta T cell development was not attributable to toxic effects, but rather was accompanied by promotion of development into NK cells, identified based on molecular and functional criteria. These results suggest that common lymphoid precursors can respond to environmental signals to commit to the alpha beta T vs NK developmental pathways.

Animals↗
PubMed1998

Takayasu arteritis presented with acute febrile pericardial effusion.

We report the clinical and radiographic findings of Takayasu arteritis (TA) presented with acute febrile pericardial effusion. Our case is unique in that acute pericardial effusion developed in the absence of other intracardiac abnormalities as an initial manifestation of TA. While pericardial effusion is infrequently related with TA, TA should be considered as one of causes of acute febrile pericardial effusion in especially young women.

Acute Disease↗
PubMed1998

The trophic action of IL-7 on pro-T cells: inhibition of apoptosis of pro-T1, -T2, and -T3 cells correlates with Bcl-2 and Bax levels and is independent of Fas and p53 pathways.

Signals from the IL-7R are essential for normal thymocyte development. We isolated thymocytes from early developmental stages and observed that suspensions of pro-T1, -T2, and -T3 cells rapidly died in culture. Addition of IL-7 promoted their survival, but did not induce cell division. Pro-T4 cells did not undergo rapid cell death, and their survival was therefore independent of IL-7. Death in the absence of IL-7 showed the hallmarks of apoptosis, including DNA fragmentation and annexin V binding; however, caspase inhibitors blocked DNA fragmentation, but did not block cell death. The trophic effect of IL-7 was partially inhibited by blocking protein synthesis. The p53 pathway was not involved in this death pathway, since pro-T cells from p53-/- mice also underwent cell death in the absence of IL-7. The Fas/Fas ligand pathway was not involved in cell death, since Fas-deficient pro-T cells died normally in the absence of IL-7, anti-Fas Abs did not protect cells from death in the absence of IL-7, and Fas expression was undetectable on cells at these stages. The IL-7 trophic affect correlated with increased intracellular levels of Bcl-2 and decreased levels of Bax, whereas no Bcl-X(L), Bcl-w, or Bad was detectable. Thus, maintaining a favorable Bcl-2/Bax ratio may account for the trophic action of IL-7.

Animals↗
PubMed1998

The kinetics of bioaccumulation of zinc, copper, lead and cadmium by oysters (Crassostrea iredalei and C. belcheri) under tropical field conditions.

A study on the kinetics of accumulation and depuration of Zn, Cu, Pb and Cd by the oysters (Crassostrea iredalei and Crassostrea belcheri) cultured at two locations in the Merbok Estuary, Malaysia was conducted. A first-order kinetic model was employed to fit the experimental data in order to estimate the rate constants for uptake and elimination processes and to predict the bioconcentration factors (BCF). Among the four metals studied, only the Zn accumulation process could not be modelled using first-order kinetics. The elimination rate constants estimated from depuration data for C. iredalei are found to be much greater than those from accumulation data. The results suggest that the values of kinetic parameters and BCFs derived under conditions of both aqueous and dietary exposure are probably more site- than species-specific.

Animals↗
PubMed1998

Effects of dopamine and estrogen on the regulation of Pit-1 alpha, Pit-1 beta, and PL-II gene expression in the rat placenta.

Pituitary-specific transcription factor Pit-1 regulates growth hormone and prolactin gene expression in the pituitary. Recently, Pit-1 was shown to be locally synthesized in the rat placenta and is involved in the regulation of rat placental lactogen (PL) gene expression. Pit-1 has three different splicing variants. They are well known as being biologically active. In the present study, we found that Pit-1 beta is also synthesized in the rat placenta and we tried to examine the effects of dopamine and estrogen on the regulation of Pit-1 alpha, beta and PL-II genes expression using the reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot hybridization. A dopamine receptor agonist, bromocriptine, significantly decreased placental Pit-1 alpha, beta, and PL-II mRNA levels. To examine the effect of estrogen on the gene expression of Pit-1 beta, pregnant female rats were ovariectomized (OVX) and injected daily with 17 beta-estradiol. OVX markedly lowered the amount of Pit-1 beta mRNA. Estrogen injection recovered the OVX-induced inhibition of Pit-1 beta mRNA level. Finally, we investigated the site-specific transcription of Pit-1 alpha and beta mRNA in the labyrinth zone and junctional zone of the placental in 15 and 20 days of gestation. The main site of Pit-1 alpha and beta synthesis was shifted from the junctional zone to the labyrinth zone from 15 to 20 days of gestation. Together, these data presume that Pit-1 beta may play a more important role in the placenta than in the pituitary and that Pit-1 may be involved in the regulation of the PL and prolactin-like peptide by estrogen and dopamine in the rat placenta.

Animals↗
PubMed1998

A novel mutation of Arg306 of factor V gene in Hong Kong Chinese.

We have analyzed 83 unrelated Hong Kong Chinese for the presence of genetic variants of factor V gene. Forty-three of them had a history of deep vein thrombosis. The DNA sequence variations of exons 7, 10, and 13, where the codons for Arg306, Arg506, and Arg679 are located, respectively, were studied by denaturing gradient gel electrophoresis. The G1691-->A (Arg 506-->Gln) mutation in exon 10 was not detectable in any of the 83 subjects. However, a high allelic frequency for the G1628-->A (Arg 485-->Lys) substitution was detectable in the same exon. We have also identified a novel DNA sequence mutation (A1090-->G) in exon 7 that resulted in Arg 306-->Gly substitution in 2 thrombotic patients and 1 nonthrombotic subject. Fresh blood samples were available from one of them for analysis of activated protein C resistance and the result was negative. Variation of DNA sequence was not found in exon 13 in any of our 83 subjects. The results of this study showed that, although the Arg 506-->Gln mutation was rarely found in the Hong Kong Chinese population, a different mutation site such as A 1090-->G in exon 7 of the factor V gene (Arg 306) may be of clinical importance.

Arginine↗
PubMed1998

Allogeneic bone marrow transplantation for severe aplastic anemia: the Hong Kong scenario.

Severe aplastic anemia (SAA) is a disease associated with high mortality. For young patients with HLA identical siblings, allogeneic bone marrow transplantation (BMT) offers the best chance of cure. Favourable results have also been reported using immunosuppressive therapy (IST). Transplantation is usually favoured for patients below 45 years of age. We report our experience of 11 allogeneic and one syngeneic BMT for adult Chinese patients with SAA, over a 4-year period from 1991 to 1995. Ten of the 12 (83 per cent) patients had received and failed prior IST including anti-thymocyte globulin (ATG) before being referred for BMT. Neutrophil and platelet engraftment was successful in 11 of them (92 per cent) and nine were completely transfusion independent after transplantation. Their overall 3-year survival was 67 per cent. The compromised overall result was due to a number of cases transplanted after a long time delay. No patient transplanted beyond 3 years from the initial time of diagnosis of SAA achieved long-term marrow engraftment, and they all eventually succumbed. On univariate analysis, a longer time delay and hence a larger amount of blood products exposure, were highly significantly statistically associated with inferior marrow engraftment and patient survival. Other factors including age, iron status, infused cell dose and the conditioning protocol were not found to significantly affect engraftment and survival. Graft versus host disease was clinically mild or absent in most patients. This may be related to ethnicity or previous ATG exposure. In conclusion, early allogeneic BMT was a safe and effective treatment in our small series of patients with SAA failing IST.

Adolescent↗
PubMed1998

CEOP treatment results and validity of the International Prognostic Index in Chinese patients with aggressive non-Hodgkin's lymphoma.

From 1991 to 1997, we have treated 78 newly diagnosed patients with aggressive non-Hodgkin's lymphoma with a modified CHOP regimen in which epirubicin (60 mg/m2) was used in place of doxorubicin (50 mg/m2), i.e. CEOP (cyclophosphamide, epirubicin, vincristine and prednisolone). The median age was 41 years (range: 17 to 67). Sixty-four (82 per cent) had diffuse large cell (Working Formulation category G) histology. The median LDH level was 453 u/l. Thirty-three (42.3 per cent) and 45 (57.7 per cent) had stage I/II and stage III/IV disease, respectively. Fifty-five of 78 (71 per cent) CEOP-treated patients achieved CR, and the projected DFS and OS were both 65 per cent. In an earlier cohort of patients (from 1985-1991) treated with second or third-generation chemotherapy regimens (m-BACOD, MACOP-B, ProMACE-CytaBOM), CR was achieved in 95/123 (77 per cent) patients and the projected DFS and OS were 62 per cent and 55 per cent. There was no significant difference in the clinical characteristics, CR rates (p = 0.26), DFS (p = 0.38) or OS (p = 0.68) between patients who received CEOP or second/third-generation chemotherapy regimens. Of the patients treated with CEOP, 37.9 per cent, 28.8 per cent, 24.2 per cent and 9.1 per cent were in the age-adjusted International Index L, LI, HI and H risk groups, with CR rates of 82 per cent and 57 per cent in the L/LI and HI/H risk groups (p = 0.03). Moreover, patients in the L, LI and HI/H risk groups had significantly different projected DFS (87 per cent, 62 per cent and 39 per cent, p = 0.02) and OS (85 per cent, 80 per cent and 36 per cent, p = 0.006). In conclusion, CEOP is an effective regimen and the age-adjusted International Index is valid for Chinese patients with aggressive NHL.

Adolescent↗
PubMed1998

Allogeneic bone marrow transplantation for adult acute lymphoblastic leukemia: a single-centre experience.

Between 1990 and 1997, we performed 29 allogeneic BMTs for acute lymphoblastic leukemia (ALL) patients with HLA-identical sibs. Their median age was 31 years (range 15 to 43); there were 15 males and 14 females. The conditioning protocol was Cy-TBI (n = 15), VP16-Cy-TBI(n = 12), CBV (n = 1) and Bu-Cy (n = 1). Cyclosporin and methotrexate were used for GVHD prophylaxis. The median disease-free survival (DFS) was 12 months (range 1 to 92) with an actuarial 4-years DFS of 42.3 per cent. Three patients died of transplant-related complications before 100 days. Relapse occurred in 11 cases at a median time of 5 months (range 3 to 14). All nine patients relapsing within one year died form resistant leukemia. Three patients died of late treatment-related complications. There were 13 survivors (median follow-up 38 months, range 12-98), with 12 in remission. Only four had limited cGVHD, and all had 100 per cent performance scores. One patient also cleared her chronic hepatitis B carrier status due to acquired immunity. The DFS rates amongst CR1 cases and R1/CR2 cases were comparable (p = 0.39). No long-term DFS is obtained from patients with resistant disease (n = 4). The survival results for BMT at CR1 were superior to those using intensive chemotherapy consolidation (p = 0.29), mainly due to poor late results in the chemotherapy arm. For young ALL patients with HLA-matched siblings, the option of BMT should be considered in light of local consolidation survival results.

Adolescent↗