Reversing hepatocellular carcinoma progression by using networked biological therapies.

The liver is distinguished from other tissues by (a) its detoxifying function, (b) its resistance to apoptosis, and (c) its regenerative response to damage. Hepatocellular carcinoma arises when chronic insults, such as hepatitis or iron overload, constitutively activate this regenerative program. Here, we propose that the proliferative response of the liver to damage underlies the resistance of hepatocellular carcinoma to cytotoxic therapy, and that hepatocellular carcinoma growth should therefore be more readily controlled by using a networked combination of noncytotoxic interventions to interrupt the damage-inducible regenerative pathway. To this end, hepatocellular carcinoma boasts a wealth of potential drug targets, including viral replication, the antiapoptotic immunosuppressant alpha-fetoprotein, hepatic iron overload, inflammatory signaling, extracellular proteases, and growth factors. By blocking these positive feedback loops in parallel, and so returning the host environment to a more normal state, epigenetic repression of tumor-suppressor gene function may be reversed and tumor dormancy restored. Noncytotoxic maneuvers that short circuit damage resistance loops may thus represent an indirect form of gene therapy meriting incorporation into hepatocellular carcinoma clinical trials.     

Reduction in acute rejections decreases chronic rejection graft failure in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).

Chronic rejection accounted for 32% of all graft losses in 7123 pediatric transplants. In a previous study acute, multiple acute and late acute rejections were risk factors for the development of chronic rejection. We postulated that the recent decrease in acute rejections would translate into a lower risk for chronic rejection among patients with recent transplants. We reviewed our data on patients transplanted from 1995 to 2000, and using multivariate analysis and a proportional hazards model developed risk factors for patients whose grafts had failed due to chronic rejection. A late initial rejection increased the risk of chronic rejection graft failure 3.6-fold (p < 0.001), while a second rejection resulted in further increase of 4.2-fold (p < 0.001). Recipients who received less than 5 mg/kg of cyclosporine at 30 days post-transplant had a relative risk (RR) of 1.9 (p = 0.02). Patients transplanted from 1995 to 2000 had a significantly lower risk (RR = 0.54, p < 0.001) of graft failure from chronic rejection than those who received their transplants earlier (1987-94). Since we were able to demonstrate that there is a decreased risk of chronic rejection graft failure in our study cohort, we would conclude that the goal of future transplants should be to minimize acute rejections.     

An effective treatment of comminuted fractures of the distal radius

One hundred cases of comminuted fracture of the distal radius were treated by a simple uniform method consisting of distraction by an external fixator for 3 weeks followed by functional bracing. During the application of the external fixator, autogenous cancellous bone chips were taken from the iliac crest and packed into the fracture site to realign the juxtaarticular fragments and to fill up the bone gap. Complications have been minimal. The results, after an average follow-up period of 20 months, taking into consideration subjective assessment of pain, objective measurement of wrist motion, and radiologic angles, have been excellent.     

Phase II study of high-dose ifosfamide in hepatocellular carcinoma

Summary A phase II study of high-dose ifosfamide in hepatocellular carcinoma was conducted among 17 Chinese patients. The dose of ifosfamide used was 2.5 g/m² daily given as a continuous infusion for 5 days. In all, 15 patients were evaluable for tumour response. There was no complete or partial responder. The treatment was well tolerated. The most frequent toxicity was alopecia, which occurred in 11 patients, and 5 patients developed mild haematological toxicity. There was no evidence of liver or bladder toxicity. Overall, 14 patients were evaluable for survival. The median survival was 92 days (range, 30–568 days). We conclude that high-dose ifosfamide is well tolerated but ineffective in hepatocellular carcinoma in Chinese patients.     

Polymorphisms in manganese superoxide dismutase and catalase genes: functional study in Hong Kong Chinese asthma patients

BACKGROUND: Reactive oxygen species may contribute to the pathogenesis of asthma. Functional genetic polymorphisms of antioxidant enzymes, superoxide dismutase (SOD) and catalase are good candidates for asthma susceptibility. OBJECTIVE: To investigate the association of the manganese-containing form of SOD (MnSOD) gene at amino acid position 16 (Val16Ala) and catalase gene in the promoter at A-21T and C-262T polymorphisms and asthma in a Hong Kong Chinese population. METHODS: The association study was conducted in a case-control design in asthma patients (n=251) and healthy controls (n=316) by genotyping. The functional significance was assessed by determining erythrocyte SOD and catalase activity. RESULTS: The Val allele of MnSOD at Val16Ala and the A allele of catalase gene at A-21T were not different between patients and controls, while the C allele of catalase gene at C-262T was found to be significantly different between patients and controls (P=0.033). The less frequent variant of catalase gene (-262T) was found to be protective from the development of asthma in a Hong Kong Chinese non-smoking population (adjusted odds ratio=0.35, 0.15-0.85; P=0.017). Asthma patients had elevated erythrocyte SOD and catalase activities in comparison with healthy controls (P<0.01). However, their activities were not associated with different genotypes within healthy controls or asthma patients. CONCLUSION: This is the first report showing that SOD and catalase functional activities are not associated with their respective genetic polymorphisms but related to the presence of asthma in a Hong Kong Chinese population.     

Expression of beta-2-microglobulin by nasopharyngeal carcinoma.

Serum beta-2-microglobulin (beta 2M) levels of 274 Chinese patients with different stages of nasopharyngeal carcinoma at presentation and that of 35 patients who developed distant metastases post-treatment were assayed. beta 2M level was found to increase with advancing stage of disease, with statistically significant differences among early-stage, advanced-stage, and metastatic disease. Elevated pre-treatment beta 2M levels were expressed more frequently by tumours with lower degree of histological differentiation. The sensitivity of serum beta 2M for diagnosis of nasopharyngeal carcinoma, however, is low.     

RS 39604: a potent, selective and orally active 5-HT4 receptor antagonist.

1. Selective antagonism of 5-HT4 receptors may provide therapeutic benefit in certain disorders of the myocardium, alimentary and lower urinary tract. We now report on RS 39604, a novel and selective 5-HT4 receptor antagonist and compare its pharmacological properties with those of SB 204070. 2. In guinea-pig striatal membranes, both RS 39604 and SB 204070 inhibited specific binding of [3H]-GR 113808 in a concentration-dependent manner yielding pKi estimates of 9.1 and 10.9, respectively. RS 39604 displayed a low affinity (pKi < 6.5) for 5-HT1A, 5-HT2C, 5-HT3, alpha 1c, D1, D2, M1, M2, AT1, B1 and opioid mu receptors and moderate affinity for sigma 1, (pKi = 6.8) and sigma 2 (pKi = 7.8) sites. 3. In the rat isolated oesophagus, precontracted with carbachol, RS 39604 (30-300 nM) behaved as a competitive antagonist towards 5-HT-induced relaxation (pA2 = 9.3; Schild slope = 1.0). We and others have shown previously that SB 204070 behaves as an unsurmountable antagonist in this preparation (pA2 approximately 10.5). In the guinea-pig isolated ileal mucosa, RS 39604 (30 nM) antagonized 5-MeOT-induced increase in short-circuit current (pA2 = 9.1). 4. In anaesthetized vagotomized micropigs, RS 39604, administered by the i.v. or intraduodenal (i.duod.) route, produced dose-dependent inhibition of 5-HT-induced tachycardia (ID50 = 4.7 micrograms kg-1, i.v. and 254.5 micrograms kg-1, i.duod). At maximal doses of 30 micrograms kg-1, i.v. and 6 mg kg-1, i.duod., the inhibitory effects of RS 39604 lasted for more than 6 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment with triiodothyronine decreases the abundance of the alpha-subunits of Gi1 and Gi2 in the cerebral cortex.

Treatment of rats for 3 days with T3 halved the abundance of the alpha-subunits of Gi1 and Gi2 in synaptosomal membranes isolated from the cerebral cortex. It is suggested that these changes could contribute to behavioural abnormalities in hyperthyroidism. Similar T3 treatment did not alter abundance of Gi1 alpha or Gi2 alpha in the medulla oblongata nor did it alter abundance of G(o) alpha-subunits in three tested brain regions.