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Biomedical subjects

P W Lee

Publications and source records attributed to P W Lee.

At least 19 recordsLinked to original sources
PubMed1999

Apoptosis is induced by hantaviruses in cultured cells.

Hantaviruses replicate in primary and cultured animal cells with little or no cytopathic effect. We report here that the cultured Vero E6 cells infected by the Hantaan or by the Prospect Hill viruses exhibited characteristic features of apoptosis, including condensation and segmentation of nuclei and internucleosomal cleavage of nuclear DNA. Apoptosis was not seen in the cells adsorbed by UV-inactivated virus, indicating that the viral replication is required for the induction of apoptosis. Furthermore, level of the proto-oncogenic Bcl-2 protein was significantly reduced, whereas its mRNA level remained unchanged in Hantaan virus-infected cells, suggesting possible involvement and posttranscriptional regulation of this antiapoptotic protein in the process.

Animals↗
PubMed1999

p53 DNA binding can be modulated by factors that alter the conformational equilibrium.

The p53 tumor suppressor protein is a dimer of dimers that binds its consensus DNA sequence (containing two half-sites) as a pair of clamps. We show here that after one wild-type dimer of a tetramer binds to a half-site on the DNA, the other (unbound) dimer can be in either the wild-type or the mutant conformation. An equilibrium state between these two conformations exists and can be modulated by two types of regulators. One type modifies p53 biochemically and determines the intrinsic balance of the equilibrium. The other type of regulator binds directly to one or both dimers in a p53 tetramer, trapping each dimer in one or the other conformation. In the wild-type conformation, the second dimer can bind to the second DNA half-site, resulting in drastically enhanced stability of the p53-DNA complex. Importantly, a genotypically mutant p53 can also be in equilibrium with the wild-type conformation, and when trapped in this conformation can bind DNA.

Animals↗
PubMed1999

Indwelling catheter-induced right ventricular rupture.

We describe a case of a 68-year-old man who, because of postoperative mediastinitis, underwent a multiple muscle flap closure of the mediastinum. A chronic indwelling catheter led to erosion and rupture of the anterior wall of the right ventricle. The near exsanguinating hemorrhage was corrected under circulatory arrest. A pericardial patch repair was performed with good results.

Aged↗
PubMed1999

Optimal education techniques for basic surgical trainees: lessons from education theory.

"Calmanisation" of surgical training and the introduction of the "New Deal" on doctor's hours has led to a reduction in "in service" training and a proliferation of training courses. Little research has been done into the optimum design of these courses. Education theory has shown that individuals have optimal learning styles and that these styles tend to be generalised across professional groups. It was decided, therefore, to investigate the optimal learning styles of basic surgical trainees. A learning style inventory was used to assess the preferred learning style of 52 basic surgical trainees. The predominant learning styles (86.5%) were convergent (n = 31) or accommodative (n = 14) whilst only 5 (9.6%) assimilative and 2 (3.9%) divergent styles were detected. Convergent and accommodative learners rely principally on hands on experience and problem solving as their optimal learning technique. Given the shorter hours and duration of Basic Surgical Training, in service practical training and surgical courses should be structured accordingly.

Adult↗
PubMed1998

Reovirus therapy of tumors with activated Ras pathway.

Human reovirus requires an activated Ras signaling pathway for infection of cultured cells. To investigate whether this property can be exploited for cancer therapy, severe combined immune deficient mice bearing tumors established from v-erbB-transformed murine NIH 3T3 cells or human U87 glioblastoma cells were treated with the virus. A single intratumoral injection of virus resulted in regression of tumors in 65 to 80 percent of the mice. Treatment of immune-competent C3H mice bearing tumors established from ras-transformed C3H-10T1/2 cells also resulted in tumor regression, although a series of injections were required. These results suggest that, with further work, reovirus may have applicability in the treatment of cancer.

3T3 Cells↗
PubMed1998

DNA-dependent protein kinase acts upstream of p53 in response to DNA damage.

The tumour suppressor p53 becomes activated as a transcription factor in response to DNA damage, but the mechanism for this activation is unclear. A good candidate for an upstream activator of p53 is the DNA-dependent protein kinase (DNA-PK) that depends on the presence of DNA breaks for its activity. Here we investigate the link between DNA damage and the activation of DNA-PK and of p53. To determine whether DNA-PK is an upstream mediator of the p53 DNA-damage response, we analysed a severe combined-immunodeficiency (SCID) mouse cell line, SCGR11, and the human glioma cell line M059J . Both cell lines lack any detectable DNA-PK activity. We find that p53 is incapable of binding to DNA in the absence of DNA-PK, that DNA-PK is necessary but not sufficient for activation of p53 sequence-specific DNA binding, and that this activation occurs in response to DNA damage. Our results establish DNA-PK as a link between DNA damage and p53 activation, and reveal the existence of a mammalian DNA-damage-response pathway.

3T3 Cells↗
PubMed1998

How p53 binds DNA as a tetramer.

The p53 tumor suppressor protein is a tetramer that binds sequence-specifically to a DNA consensus sequence consisting of two consecutive half-sites, with each half-site being formed by two head-to-head quarter-sites (--><-- --><--). Each p53 subunit binds to one quarter-site, resulting in all four DNA quarter-sites being occupied by one p53 tetramer. The tetramerization domain forms a symmetric dimer of dimers, and two contrasting models have the two DNA-binding domains of each dimer bound to either consecutive or alternating quarter-sites. We show here that the two monomers within a dimer bind to a half-site (two consecutive quarter-sites), but not to separated (alternating) quarter-sites. Tetramers bind similarly, with the two dimers within each tetramer binding to pairs of half-sites. Although one dimer within the tetramer is sufficient for binding to one half-site in DNA, concurrent interaction of the second dimer with a second half-site in DNA drastically enhances binding affinity (at least 50-fold). This cooperative dimer-dimer interaction occurs independently of tetramerization and is a primary mechanism responsible for the stabilization of p53 DNA binding. Based on these findings, we present a model of p53 binding to the consensus sequence, with the tetramer binding DNA as a pair of clamps.

DNA↗
PubMed1998

The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus.

NIH-3T3 cells, which are resistant to reovirus infection, became susceptible when transformed with activated Sos or Ras. Restriction of reovirus proliferation in untransformed NIH-3T3 cells was not at the level of viral gene transcription, but rather at the level of viral protein synthesis. An analysis of cell lysates revealed that a 65 kDa protein was phosphorylated in untransformed NIH-3T3 cells, but only after infection with reovirus. This protein was not phosphorylated in infected or uninfected transformed cells. The 65 kDa protein was determined to be the double-stranded RNA-activated protein kinase (PKR), whose phosphorylation leads to translation inhibition. Inhibition of PKR phosphorylation by 2-aminopurine, or deletion of the Pkr gene, led to drastic enhancement of reovirus protein synthesis in untransformed cells. The emerging picture is one in which early viral transcripts trigger PKR phosphorylation in untransformed cells, which in turn leads to inhibition of translation of viral genes; this phosphorylation event is blocked by an element(s) in the Ras pathway in the transformed cells, allowing viral protein synthesis to ensue. The usurpation of the Ras signaling pathway therefore constitutes the basis of reovirus oncolysis.

3T3 Cells↗
PubMed1998

Active participation of Hsp90 in the biogenesis of the trimeric reovirus cell attachment protein sigma1.

The reovirus cell attachment protein, sigma1, is a lollipop-shaped homotrimer with an N-terminal fibrous tail and a C-terminal globular head. Biogenesis of this protein involves two trimerization events: N-terminal trimerization, which occurs cotranslationally and is Hsp70/ATP-independent, and C-terminal trimerization, which occurs posttranslationally and is Hsp70/ATP-dependent. To determine if Hsp90 also plays a role in sigma1 biogenesis, we analyzed sigma1 synthesized in rabbit reticulocyte lysate. Coprecipitation experiments using anti-Hsp90 antibodies revealed that Hsp90 was associated with immature sigma1 trimers (hydra-like intermediates with assembled N termini and unassembled C termini) but not with mature trimers. The use of truncated sigma1 further demonstrated that only the C-terminal half of sigma1 associated with Hsp90. In the presence of the Hsp90 binding drug geldanamycin, N-terminal trimerization proceeded normally, but C-terminal trimerization was blocked. Geldanamycin did not inhibit the association of Hsp90 with sigma 1 but prevented the subsequent release of Hsp90 from the immature sigma1 complex. We also examined the status of p23, an Hsp90-associated cochaperone. Like Hsp90, p23 only associated with immature sigma1 trimers, and this association was mapped to the C-terminal half of sigma1. However, unlike Hsp90, p23 was released from the sigma1 complex upon the addition of geldanamycin. These results highlight an all-or-none concept of chaperone involvement in different oligomerization domains within a single protein and suggest a possible common usage of chaperones in the regulation of general protein folding and of steroid receptor activation.

Adenosine Triphosphate↗
PubMed1998

Endosonographic evidence of injury to the internal anal sphincter after low anterior resection: long-term follow-up.

PURPOSE: Transanal stapled anastomosis has been associated with continence disturbances and reduced postoperative anal sphincter function. The aim of the present work was to study the effect of transanal stapling on anal sphincter morphology by endoanal ultrasound. METHODS: Thirty-nine consecutive patients undergoing stapled low anterior resection for rectal carcinoma were assessed. Each patient was assessed by endoluminal ultrasound before surgery, immediately after surgery, and at 3, 6, 9, 12, and 24 months after surgery. RESULTS: There were no preoperative internal anal sphincter defects observed. Three female patients were observed to have preoperative evidence of external anal sphincter defects. After low anterior resection, seven patients were found to have internal anal sphincter defects, which persisted after the two-year follow-up. There were no additional external anal sphincter injuries. Three patients with internal anal sphincter injuries required the use of pads for poor bowel function. CONCLUSIONS: Up to 18 percent of patients who underwent stapled low anterior resection had long-term evidence of internal anal sphincter injury. The external sphincter does not appear to be affected by the procedure.

Anal Canal↗
PubMed1998

Impaired interleukin-12 production is associated with a defective anti-tumor response in colorectal cancer.

INTRODUCTION: Despite development of many chemotherapeutic regimens, colorectal cancer continues to have a high mortality. One of the major new potential therapies is interleukin-12, a heterodimeric cytokine produced by antigen presenting cells. In vitro and in vivo studies have demonstrated the role of interleukin-12 in stimulating a cell-mediated anti-tumor response against a number of colon adenocarcinoma tumor models. However, it is unknown whether patients with colorectal cancer have impaired interleukin-12 production. A study was performed to investigate production of interleukin-12 preoperatively and the relationship between these levels and disease stage at surgery. METHODS: Preoperative peripheral blood mononuclear cells from colorectal cancer patients and age-matched controls were stimulated by Staphylococcus aureus Cowan's Strain 1 (0.0075 percent wt/vol) in vitro for 24 hours. Expression of interleukin-12 was then assessed by enzyme-linked immunosorbent assay. A single pathologist assessed the tumors for stage according to TNM and Dukes classifications. RESULTS: Twenty-eight patients with colorectal cancer and 14 controls were recruited for the study. Interleukin-12 production was significantly impaired in patients with colorectal cancer compared with controls (P = 0.014), especially those with advanced disease: Dukes C, P = 0.001 and T4, P < 0.05. CONCLUSION: Interleukin-12 production is impaired in patients with colorectal cancer, especially those with advanced disease, suggesting a defective Thl-mediated anti-tumor response. These patients may well benefit from exogenous interleukin-12 treatment.

Adenocarcinoma↗
PubMed1998

Nonoxidative pentose phosphate pathways and their direct role in ribose synthesis in tumors: is cancer a disease of cellular glucose metabolism?

Pentose phosphate pathways (PPP) are considered important in tumor proliferation processes because of their role in supplying tumor cells with reduced NADP and carbons for intracellular anabolic processes. Direct involvement of PPP in tumor DNA/RNA synthesis is not considered as significant as in lipid and protein syntheses. Currently, PPP activity in tumor cells is measured by lactate production, which shows a moderate activity: about 4% to 7% compared with glycolysis. Recent data generated in our laboratory indicate that PPP are directly involved in ribose synthesis in pancreatic adenocarcinoma cells, through oxidative steps (< 31%) and transketolase reactions (69%). These findings raise serious questions about the adequacy of lactate in measuring PPP activity in tumors. We hypothesize that ribose, not lactate, is the major product of PPP in tumor cells. Control of both oxidative and nonoxidative PPP may be critical in the treatment of cancer. PPP are substantially involved in the proliferation of human tumors, which raises the prospect of new treatment strategies targeting specific biochemical reactions of PPP by hormones related to glucose metabolism, controlling thiamine intake, the cofactor of the nonoxidative transketolase PPP reaction, or treating cancer patients with antithiamine analogues.

Adenocarcinoma↗
PubMed1998

Transcatheter coil embolotherapy: a safe and effective option for major colonic haemorrhage.

BACKGROUND: The management of major colonic bleeding is problematic. A proportion of patients require emergency surgery which is associated with high morbidity and mortality. Percutaneous embolotherapy, previously considered a high risk procedure in the colon, may provide an alternative treatment in this group of patients. AIMS: To assess the safety and efficacy of embolotherapy in the treatment of life threatening colonic haemorrhage. PATIENTS AND METHODS: Thirty eight patients with fresh haemorrhage per rectum were referred for surgery because of failed conservative treatment. All underwent angiography; in 14 a bleeding site or vascular abnormality was detected. A coaxial catheter was directed to the most distal bleeding artery and this was embolised with platinum coils. RESULTS: Detection of a bleeding site correlated with haemodynamic stability at the time of angiography (r = 1 for a systolic blood pressure less than 100 mm Hg). Bleeding sites or vascular abnormalities were detected and embolised in 14 patients (37%). In 12/14 there was immediate and sustained haemodynamic improvement; two continued to bleed and required emergency hemicolectomy (14%). Three developed ischaemic complications (21.4%); these were managed conservatively and required no intervention. The 30 day mortality was 7.1% in the embolotherapy group and 10.5% in the overall group of 38 patients. CONCLUSION: Colonic embolotherapy for life threatening haemorrhage is an effective, relatively safe procedure with a low incidence of major complications. Its use depends on the identification of a focal bleeding point or vascular abnormality, which in turn depends on the haemodynamic stability of the patient at the time of angiography.

Aged↗
PubMed1998

Primary inguinal hernia repair: how audit changed a surgeon's practice.

Over 10 years one senior consultant surgeon performed 114 standard plication darn herniorraphies on 92 patients with primary inguinal hernias. These patients were contacted and were reviewed if there was any suspicion of recurrence. Four recurrences were detected, giving an overall recurrence rate of about 3.5%. According to actuarial life-table analysis the risks of recurrence at 1 year, 5 years and 10 years were 0.94%, 3.02% and 9%. This level of recurrence is unacceptable in modern practice and, as a result of the audit, the surgeon changed his technique of primary inguinal hernia repair.

Female↗
PubMed1998

The 15-year outcome of Chinese patients with schizophrenia in Hong Kong.

OBJECTIVE: To explore the differential outcome of schizophrenia in developed and developing countries. The 15-year outcome of patients with schizophrenia in Hong Kong is reported. METHOD: In a 15-year retrospective outcome study, 100 patients with first-onset schizophrenia in 1977-1978 were randomly selected for outcome assessment from a pool of 797 patient files. The patterns of outcome were assessed by the same set of instruments and methodology as in other centres, since Hong Kong is 1 of the World Health Organization (WHO) centres for the International Study of Schizophrenia (ISoS). RESULTS: Nineteen subjects were untraceable, and 10 subjects committed suicide. More than one-half of the subjects had a good symptomatic outcome, while about 20% of the subjects were rated as having a good psychosocial adjustment. Over the entire 15-year period, 96% of the subjects were maintained on medications, and 79% were living with family members. CONCLUSION: Despite Hong Kong's developed economy, its schizophrenia outcome is similar to that in developing countries. The existence of good family support and active follow-up treatment may be important contributory factors to better outcome.

Adult↗
PubMed1998

Multiple cell populations in colorectal carcinomas: analysis by 3-colour fluorescence in situ hybridization.

A three-colour FISH approach using centromere-specific DNA probes was used to analyse the number of chromosomes 7, 17 and 18 found within individual tumour cells and the results were correlated with total DNA ploidy determined by image analysis. FISH analysis showed a high level of heterogeneity in the majority of tumour samples with only 7 out of 44 samples having a single chromosome profile occurring in greater than 40% of the cells. Analysis of the modal chromosome number showed that a diploid 2/2/2 profile for chromosome 7, 17 and 18 respectively occurred most commonly. The DNA ploidy index for biopsies with a 2/2/2 profile varied between 0.93-2.06. No gain of chromosome was observed in the adenoma samples or Dukes A tumours but a loss of chromosome 18 was seen in 50% of these early carcinomas. A modal chromosome profile of 4/2/2 was commonly found in Dukes B and C tumours suggesting that endoreduplication with the relative loss of chromosome 17 and 18 is common in advanced cancers. The DNA ploidy index for the more advanced tumours was also variable but significantly higher than that found in the early tumours and non-tumour controls. In conclusion, this work shows that tumours are highly heterogeneous and that the majority of tumours consist of a large number of cell sub-populations with respect to the expression of chromosomes 7, 17 and 18.

Adenocarcinoma↗
PubMed1998

Psychological interventions in general hospitals: background, current status and clinical guidelines.

PURPOSE: To promote the systematic development, interests, practice, research and clinical applications of health psychology in general hospitals in Hong Kong and the mainland of China. DATA SOURCES: The targets and aims of therapeutic work with patients in pain, cancer patients, child and adolescent patients, patients with chronic illnesses, the elderly, and patients requiring organ transplantation are highlighted. STUDY SELECTION: The psychological interventions described are experiences derived from routine clinical services carried out in the Clinical Health Psychology Unit where the authors are affiliated, and can be seen as an example of a more comprehensive psychological intervention program for physically ill patients in Hong Kong. RESULTS: Psychological interventions have intrinsic values in reducing patients' distress and sufferings. The services are also an integral part of modem day comprehensive patient care with positive effects on treatment effectiveness and eventual illness outcome. CONCLUSIONS: Physical illnesses affect a person physically as well as psychologically. Psychological care in general hospitals is cost effective and beneficial in reducing undue psychological complications precipitated by physical afflictions as well as in promoting better overall outcomes.

Chronic Disease↗