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Biomedical subjects

G Kong

Publications and source records attributed to G Kong.

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

Resveratrol, an antioxidant present in red wine, induces apoptosis in human promyelocytic leukemia (HL-60) cells.

Resveratrol, a triphenolic stilbene present in grapes and other plants, has striking antioxidant and anti-inflammatory activities which have been considered to be responsible for the beneficial effects of red wine consumption on coronary heart disease. Recent studies reveal that resveratrol can inhibit each step of multistage carcinogenesis. However, the molecular mechanisms underlying anti-tumorigenic or chemopreventive activities of this phytochemical remain largely unknown. In the present work, we have found that resveratrol reduces viability and DNA synthesis capability of cultured human promyelocytic leukemia (HL-60) cells. The growth inhibitory and antiproliferative properties of resveratrol appear to be attributable to its induction of apoptotic cell death as determined by morphological and ultrastructural changes, internucleosomal DNA fragmentation, and increased proportion of the subdiploid cell population. Resveratrol treatment resulted in a gradual decrease in the expression of anti-apoptotic Bcl-2. These results, together with previous findings, suggest the cancer therapeutic as well as chemopreventive potential of resveratrol.

Anticarcinogenic Agents↗
PubMed1999

Cyclin D1 overexpression is an indicator of poor prognosis in resectable non-small cell lung cancer.

Cyclin D1 is one of the G1 cyclins that control cell cycle progression by allowing G1 to S transition. Overexpression of cyclin D1 has been postulated to play an important role in the development of human cancers. We have investigated the correlation between cyclin D1 overexpression and known clinicopathological factors and also its prognostic implication on resected non-small-cell lung cancer (NSCLC) patients. Formalin-fixed and paraffin-embedded tumour tissues resected from 69 NSCLC patients between stages I and IIIa were immunohistochemically examined to detect altered cyclin D1 expression. Twenty-four cases (34.8%) revealed positive immunoreactivity for cyclin D1. Cyclin D1 overexpression is significantly higher in patients with lymph node metastasis (50.0% vs 14.4%, P = 0.002) and with advanced pathological stages (I, 10%; II, 53.8%; IIIa, 41.7%, P = 0.048; stage I vs II, IIIa, P = 0.006). Twenty-four patients with cyclin D1-positive immunoreactivity revealed a significantly shorter overall survival than the patients with negativity (24.0 +/- 3.9 months vs 50.1 +/- 6.4 months, P = 0.0299). Among 33 patients between stages I and II, nine patients with cyclin D1-positive immunoreactivity had a much shorter overall survival (29.7 +/- 6.1 months vs 74.6 +/- 8.6 months, P = 0.0066). These results suggest that cyclin D1 overexpression is involved in tumorigenesis of NSCLCs from early stage and could be a predictive molecular marker for poor prognosis in resectable NSCLC patients, which may help us to choose proper therapeutic modalities after resection of the tumor.

Adult↗
PubMed1998

p53 mutations and human papillomavirus DNA in oral squamous cell carcinoma: correlation with apoptosis.

Forty-two oral squamous cell carcinomas (SCCs) were analysed for p53 mutations and human papillomavirus (HPV) infection to examine the prevalency of these factors and correlation with apoptotic index (AI; number of apoptotic cells per 100 tumour cells) of the tumour tissue. In polymerase chain reaction (PCR)-Southern blot analysis, HPV DNAs were detected from 22 out of 42 SCCs (52%) with predominance of HPV-16 (68%). p53 mutations in exons 5-8, screened by nested PCR-single-strand conformation polymorphism (PCR-SSCP) analysis, were observed in 16 of 42 tumours (38%). The state of the p53 gene did not show any correlation with HPV infection. The terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labelling (TUNEL) method was used for detection of apoptotic cells. The mean AI was 2.35, ranging from 0.31 to 6.63. SCCs associated with p53 mutation had significantly lower AI than those without p53 mutation (P < 0.01), whereas no difference in AI was found between SCCs with and without HPV infection. The results of this study confirmed that HPV infection and/or p53 mutations are implicated, but are not mutually exclusive events, in carcinogenesis of oral SCC and also showed that decrease in apoptosis is more closely related to p53 mutation than HPV infection.

Apoptosis↗
PubMed1998

Bcl-2 and p53 expressions in invasive bladder cancers.

We investigated the Bcl-2 and P53 protein expressions in 89 patients with bladder cancers using immunohistochemical analysis. In superficial tumors, the times of tumor recurrence and progression were significantly shorter in the P53-positive group than in the negative group (p < 0.005, p < 0.05, respectively). In invasive tumors, the disease-specific actuarial survivals were significantly lower in the P53 and Bcl-2-positive groups (p <0.05, p < 0.025, respectively). In multivariate analysis, overexpression of p53 and Bcl-2 had independent prognostic value for survivals in invasive tumor, while disease-free survival was related independently to overexpression of p53 in superficial tumor. The results of our assessment for chemoeffectiveness revealed that the patients with Bcl-2-positive tumors had significantly lower response rates than those with Bcl-2-negative tumors (p < 0.05). We conclude that p53 expression is an independent, poor prognostic marker in invasive tumors as well as in superficial tumors and that overexpression of Bcl-2 is independently associated with a reduced-survival in patients with invasive tumors. These prognostic differences related to P53 and Bcl-2 expression in invasive bladder cancers may be partly due to chemo- or radio-sensitivity in relation to apoptotic process.

Adult↗
PubMed1998

Expression of cyclin dependent kinase inhibitor p21WAF1 alone and in combination with p27KIP1 shows prognostic value in gastric carcinoma.

Evidence suggests that multiple molecular events, including alteration of cell cycle regulators are involved in the development and progression of gastric carcinoma. Recently, it has been reported that the expression of p21 and p27, integrating the effects of one or more cell cycle regulators, consequently, acting as a single indicator of several possible cell cycle gene alterations is associated with tumor suppression. In the present study, we studied the immunohistochemical expression of p21 and p27 in gastrectomy specimens from 84 patients with gastric adenocarcinoma, and analysed its correlation to clinicopathologic data, including patients survival. Loss of p21 and p27 expression was noted in 45 (53.6%) and 44 (52.4%) of the 84 gastric carcinoma tissues, respectively. The expression of p21 was significantly correlated with histological type (p= 0.005), recurrence (p=0.002) and death (p=0.002) after surgery, and p27 expression (p=0.001). Kaplan-Meier survival plots showed p21 negative group (p= 0.0014) or both p21 and p27 negative group (p=0.0048) was significantly poorer in overall survival than both p21 and p27 positive or one of both positive group. Our results suggest that the status of p21 and p27 expression in immunohistochemical stain may be a useful prognostic marker of gastric carcinoma.

Adenocarcinoma↗
PubMed1997

Beta-adrenergic receptor kinase-1 acutely regulates PTH/PTHrP receptor signalling in human osteoblastlike cells.

To investigate whether G protein-coupled receptor kinases (GRKs) are involved in the regulation of the PTH/PTHrPR, we have established mutant SaOS-2 cells which stably overexpress (> 10-20-fold) a dominant negative form of the beta-adrenergic receptor kinase-1 (beta ARK-1). Acute (< or = 2 h) incubation with hPTH (1-34) induced significantly less (by up to 50%) downregulation of the PTH/PTHrPR in beta ARK-1 mutant SaOS-2 cells than observed in wild-type cells. Pretreatment of wild-type cells with PTH for 2 h induced homologous cAMP desensitisation to a second challenge with PTH, while the effect was blunted by up to 60% in beta ARK-1 mutant cells. We conclude that activation of beta ARK-1 (or a closely related GRK) is a critical component of the acute phase (< or = 2 h) of PTH-induced receptor downregulation and homologous cAMP desensitisation of the PTH/PTHrPR.

Cell Line↗
PubMed1997

Overexpression of cyclin D1 correlates with early recurrence in superficial bladder cancers.

Cyclin D1 is a cell cycle regulator essential for G1 phase progression and is frequently overexpressed in several human tumour types as a consequence of gene amplification or chromosomal rearrangements. We analysed the expression of cyclin D1 in 75 patients with transitional cell carcinoma (TCC) to investigate the possible relationship between its expression and clinical outcome as well as histopathological findings using the immunohistochemical method. We observed strong staining (++, > 50% positive cells) for cyclin D1 in 19 cases (25.3%) and weak staining (+, 5-50% positive cells) in 19 cases (25.3%). Overexpression of cyclin D1 was not associated with tumour invasion. No significant association was found between overexpression of cyclin D1 and tumour grade (P > 0.05). We assessed the differences of disease-free interval in superficial tumours and actuarial survival probability in invasive tumours according to the status of cyclin D1 expression. Tumours with (++) staining for cyclin D1 recurred much more rapidly than (-) and/or (+) staining tumours (P < 0.01 for - vs ++; P < 0.05 for + vs ++). However, overexpression of cyclin D1 was not associated with a shortened overall survival of patients with invasive tumours (P < 0.1). These results suggest that genetic alteration of cyclin D1 appears to be an early event in the tumorigenesis of bladder TCC and is associated with early recurrence in superficial tumours.

Adult↗
PubMed1996

Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function.

Two families of tyrosine kinases, the Src and Syk families, are required for T-cell receptor activation. While the Src kinases are responsible for phosphorylation of receptor-encoded signaling motifs and for up-regulation of ZAP-70 activity, the downstream substrates of ZAP-70 are unknown. Evidence is presented herein that the Src homology 2 (SH2) domain-containing leukocyte protein of 76 kDa (SLP-76) is a substrate of ZAP-70. Phosphorylation of SLP-76 is diminished in T cells that express a catalytically inactive ZAP-70. Moreover, SLP-76 is preferentially phosphorylated by ZAP-70 in vitro and in heterologous cellular systems. In T cells, overexpression of wild-type SLP-76 results in a hyperactive receptor, while expression of a SLP-76 molecule that is unable to be tyrosine-phosphorylated attenuates receptor function. In addition, the SH2 domain of SLP-76 is required for T-cell receptor function, although its role is independent of the ability of SLP-76 to undergo tyrosine phosphorylation. As SLP-76 interacts with both Grb2 and phospholipase C-gamma1, these data indicate that phosphorylation of SLP-76 by ZAP-70 provides an important functional link between the T-cell receptor and activation of ras and calcium pathways.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Distinct tyrosine phosphorylation sites in ZAP-70 mediate activation and negative regulation of antigen receptor function.

Biochemical and genetic evidence has implicated two families of protein tyrosine kinases (PTKs), the Src- and Syk-PTKs, in T- and B-cell antigen receptor signaling. ZAP-70 is a member of the Syk-PTKs that associates with the T-cell antigen receptor and undergoes tyrosine phosphorylation following receptor activation. Three tyrosine residues, Tyr-292, -492, and -493, have been identified as sites of phosphorylation following T-cell antigen receptor engagement. Utilizing ZAP-70- and Syk-deficient lymphocytes (Syk-DT40 cells), we provide biochemical and functional evidence that heterologous trans-phosphorylation of Tyr-493 by a Src-PTK is required for antigen receptor-mediated activation of both the calcium and ras pathways. In contrast, cells expressing mutations at Tyr-292 or -492 demonstrate hyperactive T- and B-cell antigen receptor phenotypes. Thus, phosphorylation of ZAP-70 mediates both activation and inactivation of antigen receptor signaling.

Amino Acid Sequence↗
PubMed1994

A beta-adrenergic receptor kinase dominant negative mutant attenuates desensitization of the beta 2-adrenergic receptor.

The beta-adrenergic receptor kinase (beta ARK) specifically phosphorylates the activated form of the beta 2-adrenergic receptor (beta 2AR) and related G protein-coupled receptors. To further elucidate the role of beta ARK in receptor desensitization, we generated a beta ARK dominant negative mutant by converting an invariant lysine residue in the protein kinase catalytic domain to an arginine. Expressed and purified beta ARK-K220R was able to inhibit wild type beta ARK phosphorylation of the beta 2AR in vitro. When stably transfected into human bronchial epithelial BEAS-2B cells, beta ARK-K220R promoted a > 2-fold increase in beta-agonist-stimulated cAMP production without affecting beta 2AR sequestration. In contrast, beta ARK-K220R had no effect on the desensitization of the prostaglandin E2 receptor response in BEAS-2B cells. These findings directly demonstrate a role for beta ARK in desensitization of the beta 2AR in intact cells and establish the potential utility of using dominant negative mutants to elucidate the substrate specificity of G protein-coupled receptor kinases.

Animals↗
PubMed1994

Molecular mechanisms of agonist-induced desensitization of the cloned mouse kappa opioid receptor.

Prolonged exposure of opioid receptors to agonists can cause desensitization, a cellular event linked to tolerance. Although evidence exists for mu and delta opioid receptor desensitization, much less information is available concerning the in vitro regulation of kappa opioid receptors because no cell lines exist that specifically express this class of opioid receptor. Recently we have cloned the mouse kappa opioid receptor. After expression in COS-7 cells, this protein exhibits the pharmacological specificity of a kappa 1 receptor and mediates agonist inhibition of cAMP formation. Continuous exposure of COS-7 cells expressing the kappa receptor to the agonist trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide methanesulfonate salt (U50,488) reduces the specific binding of the kappa-selective agonist [3H]U69,593. Furthermore, the potency of U50,488 to inhibit the binding of the opiate antagonist [3H]naloxone to the kappa receptor is reduced. However, total specific binding of [3H]naloxone is not altered, indicating that short-term (2-4 hr) agonist treatment of the kappa receptor reduces the affinity of the receptor for agonists but does not reduce the density of kappa receptors. The reduction in affinity of the kappa receptor for agonists is dependent on the time of agonist exposure and is reversible. The reduced affinity of the receptor for agonists is associated with kappa receptor desensitization, because kappa receptor-mediated inhibition of cAMP formation is lost in cells pretreated with U50,488. The desensitization of the kappa receptor is dependent on the time and concentration of agonist treatment, is blocked by the kappa-selective antagonist nor-binaltorphimine and is reversible.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1991

Response of recurrent giant cell myocarditis in a transplanted heart to intensive immunosuppression.

A 35-year-old man developed giant cell myocarditis resulting in severe congestive cardiac failure. He needed urgent orthotopic cardiac transplantation despite maximal doses of inotropes and augmentation with an intra-aortic balloon pump. The patient presented with rhythm disturbances and echocardiographically diminished ventricular function at subsequent follow-up. Biopsies then taken revealed recurrence of myocarditis in the transplanted heart. Investigations revealed no obvious cause for the myocardial granulomas nor any evidence of systemic granulomatous disease. The patient received, in addition to maintenance cyclosporin A and azathioprine, high doses of corticosteroids which resulted in complete resolution of the inflammatory process and no recurrence has been detected to date. This case shows that giant cell myocarditis can recur in the transplanted heart despite routine immunosuppression with azathioprine and cyclosporin A and that additional treatment with high dose corticosteroids is effective in causing regression of the inflammatory process.

Adult↗
PubMed1990

[A study on pharmacokinetics of 3H-mitoxantrone in experimental animals].

Mitoxantrone (DHAQ) we studied is a new semisynthetic antitumor drug prepared in China. This paper reports the pharmacokinetic studies of 3H-mitoxantrone in mice by liquid scintillation. The results showed that the decline of radioactivity in the plasma was a biphasic curve after intramuscular and intravenous injection in rats. The adsorption of 3H-DHAQ was ready and complete after intramuscular injection, it was widely distributed in body tissues. The concentration order of various organs was liver greater than intestine greater than kidney greater than lung greater than heart greater than muscles greater than brain. The elimination of the drug was slow, T1/2 was 42.56 h. In 72 h after administration the cumulative excretion of radioactivity in urine was 7% of the total dose, while that in feces was 43%. The main forms of the drug in urine were its metabolites.

Animals↗
PubMed1965

Middle-ear disease in Indians of the Mount Currie Reservation, British Columbia.

Complete otological examinations, including audiograms, were carried out on 504 British Columbia Indians of the Mount Currie Reservation. Of these, 79 were found to have evidence of current middle ear pathology, while 226 were known to have had previous disease. Among 364 subjects who could be formally tested, 112 had a 15-decibel or greater hearing loss in the speech frequencies. Among these Indians, middle-ear disease began early in life and recurrences were frequent. The prevalence of aural disease was related to poor social conditions, family history and presence of nasal discharge. No other relationships could be demonstrated, and there was no evident benefit from adenotonsillectomy. No secretory otitis or otosclerosis and almost no sensorineural high-tone hearing loss were discovered.

Canada↗
PubMedDate not supplied

Hyperthermia and liposomes.

Hyperthermia and liposomal drug delivery are treatment modalities that have been used to treat cancer over the last two decades. More recently, the two therapies have been used together in an attempt to exploit their mutual interactions against cancer. The goal of this review is to explore the literature related to combined hyperthermia and liposomal drug delivery for cancer therapy. The motivation behind combining hyperthermia and liposomal drug delivery is discussed from a physical chemical and physiological standpoint. Two types of therapeutic ratios were calculated for in vivo studies from across the literature. These ratios compared the results obtained from hyperthermia and liposomes to hyperthermia and free drug as well as to liposomes without hyperthermia. These two therapeutic ratios were applied to both tumour drug uptake and tumour growth delay studies. In all studies reviewed, hyperthermia in combination with liposomal drug showed an enhanced therapeutic effect compared to either treatment modality alone or hyperthermia and free drug. Future work needs to be focused on optimizing thermosensitive liposomes and understanding the effect of thermal dose on liposomal drug delivery. Though not currently used in the clinic, this combination therapy seems to hold great promise towards improving current cancer therapeutic regimens.

Antineoplastic Agents↗
PubMedDate not supplied

Expression of Wilms tumor gene (WT1) in children with acute leukemia.

Wilms tumor gene (WT1) expression occurs in various malignancies including adult leukemia. WT1 expression was studied in children with acute leukemia according to morphological types and immunophenotypes. RT-PCR was used to examine relative level of WT1 transcripts from the peripheral blood of 15 children diagnosed with acute leukemia: 12 acute lymphoblastic leukemias (ALLs) and 3 acute myelogenous leukemias (AMLs); 8 ALLs newly diagnosed, 2 ALLs in first marrow relapse, 2 ALLs in remission over 2 years, 2 AMLs newly diagnosed, and 1 AML in second marrow relapse. Six healthy adult volunteers were studied for controls. WT1 was detectable in 7 out of 10 ALLs and all 3 AMLs, but not in 2 ALLs in remission and the controls. The expression levels were higher for AMLs than for ALLs. According to the types of ALL, WT1 was detectable in 2 out of 2 non-T group II, 4 out of 6 non-T group III, but not in one CD20+ non-T group IV, while one T-ALL showed a relatively high level. WT1 expression was detectable more frequently in ALL-L2 than in ALL-L1 and with higher levels for ALL-L2. WT1 expression was frequently noted in children with acute leukemia. The results suggest that WT1 transcripts may prove to be a significant tumor marker, possibly as an MRD monitor in evaluating remission status and early relapse, and may also prove to be useful in predicting outcomes in acute leukemia in children.

Acute Disease↗
PubMedDate not supplied

Profiling of differentially expressed genes in human uterine leiomyomas.

Uterine leiomyomas are very common benign tumors resulting in clinically serious gynecological problems in women of reproductive age. Approximately, 1% of leiomyosarcoma was reported to arise in a preexisting leiomyoma. However, the molecular basis of these tumors is poorly understood. To understand the molecular changes during leiomyoma development, we profiled differentially expressed genes in ten paired leiomyoma and normal myometrial tissues using cDNA microarray chip analysis. We identified 67 genes (27 overexpressed and 40 underexpressed) which were scored as differentially expressed at least twofold in at least eight of ten patients. Eighteen of 67 genes have been already reported to be differentially expressed without their established functions in uterine leiomyoma and others have never been reported. Subsequently, the relative expression levels of representative genes from identified 67 genes were confirmed by reverse-transcriptase polymerase chain reaction and immunohistochemistry and were found to be consistent with the microarray data. This study could provide a new insight into the understanding of leiomyoma and leiomyosarcoma.

Adult↗