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E Leung

Publications and source records attributed to E Leung.

At least 19 recordsLinked to original sources
PubMed2006

A complex fistula caused by an eroding pelvic mesh sling.

Pelvic mesh slings are increasingly used to create abdomino-pelvic partitions. This procedure is usually safe and carries low morbidity and mortality rates. However, we report a case of a 60-year-old male with a history of an abdomino-perineal resection for a low rectal carcinoma followed by adjuvant radiotherapy, who presented with an entero-vesicle-cutaneous fistula as a result of the polypropylene mesh eroding into his small bowel. He had to have a total cystectomy, small bowel resection and mesh removal in order to alleviate his symptoms.

Adenocarcinoma↗
PubMed2006

Ileostomy rod--is it a bridge too far?

OBJECTIVE: Defunctioning loop ileostomies are used commonly to protect low colorectal anastomoses and thereby reducing the serious complications of leakage. However, they are associated with specific complications such as retraction. Traditionally, a supporting rod is placed as a bridge to support both limbs of the stoma in the hope of reducing the incidence of stomal retraction. There is little evidence in the published literature to support this practice. The aim of this study was to determine whether using an ileostomy rod would reduce the incidence of stomal retraction. METHOD: A prospective, randomised controlled trial was performed in 60 consecutive patients who required a defunctioning loop ileostomy. Patients were allocated to either a 'bridge' or 'bridge-less' protocol. All the patients were assessed by dedicated stoma nurses for at least 3 months and until their stomas were closed. Their postoperative symptoms, including stoma activity and retraction rate, were recorded. RESULTS: Between May 2001 and June 2004, 57 patients completed the study (28 bridge; 29 bridge-less). There were no significant differences in the retraction rate between the groups. No clinical anastomotic leakage was recorded and none of the patients required early closure. CONCLUSIONS: If a loop ileostomy is constructed properly, stomal retraction is uncommon and routine use of a bridge is unnecessary.

Aged↗
PubMed2005

MRL/Mp CD4+,CD25- T cells show reduced sensitivity to suppression by CD4+,CD25+ regulatory T cells in vitro: a novel defect of T cell regulation in systemic lupus erythematosus.

OBJECTIVE: To investigate the hypothesis that loss of suppression mediated by peripheral CD4+,CD25+ regulatory T cells is a hallmark of systemic lupus erythematosus (SLE). METHODS: Mice of the MRL/Mp strain were studied as a polygenic model of SLE. Following immunomagnetic selection, peripheral lymphoid CD25+ and CD25- CD4+ T cells were cultured independently or together in the presence of anti-CD3/CD28 monoclonal antibody-coated beads. Proliferation was assessed by measuring the incorporation of tritiated thymidine. RESULTS: While MRL/Mp CD4+,CD25+ regulatory T cells showed only subtle abnormalities of regulatory function in vitro, syngeneic CD4+,CD25- T cells showed significantly reduced sensitivity to suppression, as determined by crossover experiments in which MRL/Mp CD4+,CD25- T cells were cultured with H-2-matched CBA/Ca CD4+,CD25+ regulatory T cells in the presence of a polyclonal stimulus. CONCLUSION: Our findings highlight a novel defect of peripheral tolerance in SLE. Identification of this defect could open new opportunities for therapeutic intervention.

Animals↗
PubMed2005

Prospective analysis of stoma-related complications.

BACKGROUND: Stoma-related complication rates vary between 10% and 70%, possibly because of varying lengths of follow-up. It is thought that most of the complications improve with time. Furthermore, little is known about the commonly neglected but potentially quite distressing complications such as leakage, soiling and night-time emptying. The aim of this audit was to examine prospectively whether there was any difference in the complication rates at different time-points during the postoperative follow up period. METHOD: A prospective study on 408 consecutive patients with either colostomy or ileostomy was conducted over a period of at least 2 years. Both emergency and elective procedures were included. Stoma related complications were analysed at 10 days, 3 months, 6 months, 1 year and 2 years postoperatively. RESULTS: Both elective and emergency stomas had similar complication rates. The percentage of patients who had stenosis (1-2%), retraction (8-22%), prolapse (1-3%) or odour (6-9%) did not significantly change with time. The complication rates for skin excoriation, leakage, soiling or night-time emptying were higher amongst the ileostomy patients, and these rates did not improve with time. The proportion of patients who had parastomal hernias increased with time (from 0 to 40% in the colostomy and 0 to 22% in the ileostomy group). Daytime leakage, night-time leakage, soiling and night-time emptying were more problematic in the ileostomy group. CONCLUSIONS: The proportion of patients who had postoperative stoma-related complications did not improve with time, but the rate of parastomal hernias in both groups and night-time emptying in the ileostomy group was worse with time. Ileostomy patients had a higher incidence of skin excoriation, leakage, soiling, and night-time emptying, and they should receive additional support.

Colorectal Neoplasms↗
PubMed2004

Dynamic EBV gene loads in renal, hepatic, and cardiothoracic transplant recipients as determined by real-time PCR light cycler.

BACKGROUND: Epstein-Barr virus (EBV) is recognised as one of the causative agents for most cases of post-transplant lymphoproliferative disease (PTLD). Elevated levels of EBV DNA are known to be associated with the onset of PTLD, but little information is available regarding how EBV loads change with time in asymptomatic transplant recipients following transplantation. Our aims were to study the trend of EBV loads in renal (RTx), hepatic, and cardiothoracic transplant recipients and to compare their EBV loads with other healthy and patient controls. METHODS: A prospective study was performed using a real-time TaqMan polymerase chain reaction technique to measure EBV DNA loads from three types of organ transplant recipients and haemodialysis patients (HD). Their results were then compared with those from the healthy controls (HC); monospot test negative (MN-) and infectious mononucleosis positive (IM+) patients; patients who were previously treated for PTLD (pPTLD); those who were currently diagnosed to have PTLD (PTLD+); and patients who had a stable renal, hepatic, or cardiothoracic graft for more than a year. RESULTS: Post-transplant EBV loads were significantly higher than the pre-transplant levels. Asymptomatic transplant recipients were differentiated from the PTLD+group at 600 genome copies of EBV/mug DNA, and from IM+group at 100 genome copies. Both HC and MN- groups had significantly lower EBV loads than the three transplant groups. The dynamic change of EBV loads in RTx was greater in the first post-transplant month when compared with the HD group. All transplant recipients had transient rises of EBV loads whereas EBV load continued to rise in one suspected PTLD patient. CONCLUSIONS: Asymptomatic transplant recipients had higher baseline post-transplant EBV levels than the non-transplant and MN- groups. The rising post-transplant EBV load in these transplant recipients did not seem to be sustained for longer than 2 weeks. However, in a PTLD+patient the rising EBV load continued over a period of 4 weeks. Hence, the dynamic pattern of EBV loads is more important than absolute EBV DNA measurements alone in identifying those who might go on to develop PTLD.

Adolescent↗
PubMed2003

Mouse B7-H3 induces antitumor immunity.

Members of the B7 family costimulate the proliferation of lymphocytes during the initiation and maintenance of antigen-specific humoral and cell-mediated immune responses. While B7-1 and -2 are restricted to lymphoid tissues, and activate naïve T cells, recently identified members including B7-H2 and -H3 are widely expressed on nonlymphoid tissues, and regulate effector lymphocytes in the periphery. B7-H3 has properties that suggested it may display antitumor activity, including the ability to stimulate Th1 and cytotoxic T-cell responses. Here, we test this notion by determining whether intratumoral injection of an expression plasmid encoding a newly described mouse homologue of B7-H3 is able to eradicate EL-4 lymphomas. Intratumoral injection of a mouse B7-H3 pcDNA3 expression plasmid led to complete regression of 50% tumors, or otherwise significantly slowed tumor growth. Mice whose tumors completely regressed resisted a challenge with parental tumor cells, indicating systemic immunity had been generated. B7-H3-mediated antitumor immunity was mediated by CD8(+) T and NK cells, with no apparent contribution from CD4(+) T cells. In summary, the results indicate that B7-H3 interactions may play a role in regulating cell-mediated immune responses against cancer, and that B7-H3 is a potential therapeutic tool.

Amino Acid Sequence↗
PubMed2003

Regression of solid tumors by engineered overexpression of von Hippel-Lindau tumor suppressor protein and antisense hypoxia-inducible factor-1alpha.

The von Hippel-Lindau tumor suppressor protein (pVHL) suppresses tumor formation by binding the alpha subunits of hypoxia-inducible factors (HIFs) responsible for stimulating tumor angiogenesis and glycolysis, targeting them for ubiquitination and proteasomal destruction. Loss of pVHL leads to the development of sporadic renal cell carcinomas (RCCs). In the present study, we sought to determine whether engineered overexpression of pVHL in tumors other than RCC can inhibit tumor growth, either as a monotherapy, or in combination with antisense HIF-1alpha therapy. Intratumoral injection of subcutaneous EL-4 thymic lymphomas with an expression plasmid encoding pVHL resulted in the downregulation of HIF-1alpha and vascular endothelial growth factor (VEGF). There was a concomitant reduction in tumor angiogenesis and increased tumor cell apoptosis due in part to downregulation of Bcl-2 expression. VHL therapy resulted in the complete regression of small (0.1 cm diameter) tumors whereas, in contrast, large (0.4 cm diameter) EL-4 tumors were only slowed in their growth. Nevertheless, large tumors completely regressed in response to intratumoral injection of a combination of antisense HIF-1alpha and VHL plasmids. Combination therapy resulted in increased losses of HIF-1alpha, VEGF, and tumor blood vessels, and increased tumor cell apoptosis. These novel results suggest that synergistic therapies that simultaneously block the expression or function of HIF-1alpha, and enhance the expression or function of VHL may be beneficial in the treatment of cancer.

Angiogenesis Inhibitors↗
PubMed2002

Use of real-time PCR to measure Epstein-Barr virus genomes in whole blood.

The measurement of the Epstein-Barr viral load in peripheral blood has been recognised as an important way of monitoring the response to treatment in patients with Epstein-Barr virus (EBV)-related malignancies. In particular, EBV load in transplant recipients can be used as a predictive parameter for Post-transplant Lymphoproliferative Disorder (PTLD). The aim was to develop a rapid and reliable PCR protocol for the quantification of the cell-associated EBV genome. Real-time PCR using TaqMan methodology was established. This technique was applied to determine the EBV load in various study groups including healthy controls, transplant recipients, patients on haemodialysis, and patients with infectious mononucleosis. The baseline level of EBV genomes in the immunosuppressed renal transplant recipients was significantly different from that in the healthy controls.

DNA, Viral↗
PubMed2001

Pharmacological and biochemical characterization of A3 adenosine receptors in Jurkat T cells.

1. The present work was devoted to the study of A3 adenosine receptors in Jurkat cells, a human leukemia line. 2. The A3 subtype was found by means of RT-PCR experiments and characterized by using the new A3 adenosine receptor antagonist [3H]-MRE 3008F20, the only A3 selective radioligand currently available. Saturation experiments revealed a single high affinity binding site with K(D) of 1.9+/-0.2 nM and B(max) of 1.3+/-0.1 pmol mg(-1) of protein. 3. The pharmacological profile of [3H]-MRE 3008F20 binding on Jurkat cells was established using typical adenosine ligands which displayed a rank order of potency typical of the A3 subtype. 4. Thermodynamic data indicated that [3H]-MRE 3008F20 binding to A3 subtype in Jurkat cells was entropy- and enthalpy-driven, according with that found in cells expressing the recombinant human A3 subtype. 5. In functional assays the high affinity A3 agonists Cl-IB-MECA and IB-MECA were able to inhibit cyclic AMP accumulation and stimulate Ca(2+) release from intracellular Ca(2+) pools followed by Ca(2+) influx. 6. The presence of the other adenosine subtypes was investigated in Jurkat cells. A1 receptors were characterized using [3H]-DPCPX binding with a K(D) of 0.9+/-0.1 nM and B(max) of 42+/-3 fmol mg(-1) of protein. A2A receptors were studied with [3H]-SCH 58261 binding and revealed a K(D) of 2.5+/-0.3 nM and a B(max) of 1.4+/-0.2 pmol mg(-1) of protein. 7. In conclusion, by means of the first antagonist radioligand [3H]-MRE 3008F20 we could demonstrate the existence of functional A3 receptors on Jurkat cells.

Animals↗
PubMed2001

Pharmacological and biochemical characterization of adenosine receptors in the human malignant melanoma A375 cell line.

1. The present work characterizes, from a pharmacological and biochemical point of view, adenosine receptors in the human malignant melanoma A375 cell line. 2. Adenosine receptors were detected by RT - PCR experiments. A1 receptors were characterized using [3H]-DPCPX binding with a KD of 1.9+/-0.2 nM and Bmax of 23+/-7 fmol x mg(-1) of protein. A2A receptors were studied with [3H]-SCH 58261 binding and revealed a KD of 5.1+/-0.2 nM and a Bmax of 220+/-7 fmol x mg(-1) of protein. A3 receptors were studied with the new A3 adenosine receptor antagonist [3H]-MRE 3008F20, the only A3 selective radioligand currently available. Saturation experiments revealed a single high affinity binding site with KD of 3.3+/-0.7 nM and Bmax of 291+/-50 fmol x mg(-1) of protein. 3. The pharmacological profile of radioligand binding on A375 cells was established using typical adenosine ligands which displayed a rank order of potency typical of the different adenosine receptor subtype. 4. Thermodynamic data indicated that radioligand binding to adenosine receptor subtypes in A375 cells was entropy- and enthalpy-driven. 5. In functional assays the high affinity A2A agonists HE-NECA, CGS 21680 and A2A - A2B agonist NECA were able to increase cyclic AMP accumulation in A375 cells whereas A3 agonists Cl-IB-MECA, IB-MECA and NECA were able to stimulate Ca2+ mobilization. In conclusion, all these data indicate, for the first time, that adenosine receptors with a pharmacological and biochemical profile typical of the A1, A2A, A2B and A3 receptor subtype are present on A375 melanoma cell line.

Adenosine Deaminase↗
PubMed2001

Angiostatin enhances B7.1-mediated cancer immunotherapy independently of effects on vascular endothelial growth factor expression.

Tumors must develop an adequate vascular network to meet their increasing demands for nutrition and oxygen. Angiostatin, a multiple kringle (1-4)-containing fragment of plasminogen, is an effective natural inhibitor of tumor angiogenesis. Here we show that gene transfer of angiostatin into small (0.1 cm in diameter) solid EL-4 lymphomas established in syngeneic C57BL/6 mice led to reduced tumor angiogenesis and weak inhibition of tumor growth. In contrast, when angiostatin gene therapy was preceded by in situ gene transfer of the T-cell costimulator B7.1, large (0.4 cm in diameter) tumors were rapidly and completely eradicated, whereas B7.1 and angiostatin monotherapies were ineffective. Combined gene transfer of B7.1 and angiostatin generated potent systemic antitumor immunity that was effective in eradicating a systemic challenge of 10(7) EL-4 cells. Gene transfer of angiostatin expression plasmids led to overexpression of angiostatin in tumors, increased apoptosis of tumor cells, and decreased density of tumor blood vessels, which may allow the immune system to overcome tumor immune resistance. The latter effects were not the result of a decrease in vascular endothelial growth factor expression, as tumoral vascular endothelial growth factor expression increased slightly after angiostatin gene transfer, presumably in response to increasing hypoxia. These results suggest that combining immunogene therapy with a vascular attack by angiostatin is a particularly effective approach for eliciting antitumor immunity.

Angiostatins↗
PubMed2001

Gene transfer of antisense hypoxia inducible factor-1 alpha enhances the therapeutic efficacy of cancer immunotherapy.

Solid tumors meet their demands for nascent blood vessels and increased glycolysis, to combat hypoxia, by activating multiple genes involved in angiogenesis and glucose metabolism. Hypoxia inducible factor-1 (HIF-1) is a constitutively expressed basic helix-loop-helix transcription factor, formed by the assembly of HIF-1alpha and HIF-1beta (Arnt), that is stablized in response to hypoxia, and rapidly degraded under normoxic conditions. It activates the transcription of genes important for maintaining oxygen homeostasis. Here, we demonstrate that engineered down-regulation of HIF-1alpha by intratumoral gene transfer of an antisense HIF-1alpha plasmid leads to the down-regulation of VEGF, and decreased tumor microvessel density. Antisense HIF-1alpha monotherapy resulted in the complete and permanent rejection of small (0.1 cm in diameter) EL-4 tumors, which is unusual for an anti-angiogenic agent where transient suppression of tumor growth is the norm. It induced NK cell-dependent rejection of tumors, but failed to stimulate systemic T cell-mediated anti-tumor immunity, and synergized with B7-1-mediated immunotherapy to cause the NK cell and CD8 T cell-dependent rejection of larger EL-4 tumors (0.4 cm in diameter) that were refractory to monotherapies. Mice cured of their tumors by combination therapy resisted a rechallenge with parental tumor cells, indicating systemic antitumor immunity had been achieved. In summary, whilst intensive investigations are in progress to target the many HIF-1 effectors, the results herein indicate that blocking hypoxia-inducible pathways and enhancing NK-mediated antitumor immunity by targeting HIF-1 itself may be advantageous, especially when combined with cancer immunotherapy.

Animals↗
PubMed2001

Allosteric adenosine modulation to reduce allodynia.

BACKGROUND: Adenosine and adenosine agonists reduce hypersensitivity following inflammation and peripheral nerve injury models of chronic pain. Because inhibitors of adenosine reuptake or metabolism are also effective at reducing hypersensitivity, it is likely that there is a tonic release of spinal adenosine in these models. One approach to avoid adverse effects from direct agonists is to enhance the effect of the endogenous ligand by administering a positive allosteric modulator of its receptor. METHODS: Rats with mechanical hypersensitivity after spinal nerve ligation received intrathecal injections of adenosine, the allosteric adenosine receptor modulator T62, or their combination, or received systemic T62 alone or with intrathecal injection of a specific A1 adenosine antagonist. RESULTS: Both adenosine and T62 reduced hypersensitivity alone, with 50% maximal doses (ED50) of 14+/-5.9 and 3.7+/-0.8 microg, respectively. They interacted in an additive manner as determined by isobolography. T62 also reduced mechanical hypersensitivity after systemic administration (15 mg/kg), and this effect was blocked by intrathecal injection of 9 microg of the A1-specific adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. CONCLUSIONS: These results add to previous studies that suggest ongoing spinal release of adenosine, which is antiallodynic, in this animal model of neuropathic pain. Positive allosteric modulation of the adenosine receptor reduces hypersensitivity by a spinal mechanism involving A1 adenosine receptor stimulation. Although obvious adverse effects were not observed in this investigation, further study is required to determine the feasibility of the use of such modulators in the treatment of chronic pain associated with hyperalgesia and allodynia.

Adenosine↗
PubMed2001

The CD40-CD40 ligand system: a potential therapeutic target in atherosclerosis.

Atherosclerosis is a leading cause of cardiovascular disease in the westernized world. This review highlights emerging evidence linking atherosclerosis to the CD40-CD40 ligand (CD154) pathway. Recently, atherosclerosis has been associated with chronic inflammation, linking it to the immune system. This novel viewpoint may serve as an additional target for therapeutic intervention. CD40 and CD154 are highly expressed in atherosclerotic human plaques. Recent data from preclinical animal models of atherosclerosis show that disruption of the CD40-CD154 pathway can prevent atherosclerotic progression and may reverse established lesions. Blockade of the CD40-CD154 pathway by biologicals or small molecules may prove valuable in the treatment of atherosclerosis.

Animals↗
PubMed2000

Pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives as highly potent and selective human A(3) adenosine receptor antagonists: influence of the chain at the N(8) pyrazole nitrogen.

An enlarged series of pyrazolotriazolopyrimidines previously reported, in preliminary form (Baraldi et al. J. Med. Chem. 1999, 42, 4473-4478), as highly potent and selective human A(3) adenosine receptor antagonists is described. The synthesized compounds showed A(3) adenosine receptor affinity in the sub-nanomolar range and high levels of selectivity evaluated in radioligand binding assays at human A(1), A(2A), A(2B), and A(3) adenosine receptors. In particular, the effect of the chain at the N(8) pyrazole nitrogen was analyzed. This study allowed us to identify the derivative with the methyl group at the N(8) pyrazole combined with the 4-methoxyphenylcarbamoyl moiety at the N(5) position as the compound with the best binding profile in terms of both affinity and selectivity (hA(3) = 0.2 nM, hA(1)/hA(3) = 5485, hA(2A)/hA(3) = 6950, hA(2B)/hA(3) = 1305). All the compounds proved to be full antagonists in a specific functional model where the inhibition of cAMP generation by IB-MECA was measured in membranes of CHO cells stably transfected with the human A(3) receptor. The new compounds are among the most potent and selective A(3) antagonists so far described. The derivatives with higher affinity at human A(3) adenosine receptors proved to be antagonists, in the cAMP assay, capable of inhibiting the effect of IB-MECA with IC(50) values in the nanomolar range, with a trend strictly similar to that observed in the binding assay. Also a molecular modeling study was carried out, with the aim to identify possible pharmacophore maps. In fact, a sterically controlled structure-activity relationship was found for the N(8) pyrazole substituted derivatives, showing a correlation between the calculated molecular volume of pyrazolo[4,3-e]1,2, 4-triazolo[1,5-c]pyrimidine derivatives and their experimental K(i) values.

Animals↗