Morphine: double-faced roles in the regulation of tumor development

Morphine, a highly potent analgesic, is one of the most effective drugs for the treatment of severe pain associated with cancer. It directly acts on the central nervous system to relieve pain, but also cause secondary complications, such as addiction, respiratory depression and constipation due to its activities on peripheral tissues. Besides pain relief, morphine is of great importance on cancer management with its effect on tumor development being the subject of debate for many years with some contradictory findings. Morphine has shown both tumor growth-promoting and growth-inhibiting effects in many published research studies. And various signaling pathways have been suggested to be involved in these effects of morphine. Based on a thorough literature review, we summarized the double-faced effects of morphine in tumor development, including tumor cell growth and apoptosis, metastasis, angiogenesis, immunomodulation and inflammation. And we attempted to optimize morphine administration in cancer patients to attenuate its tumor growth-promoting effects

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Post-conditioning anti-PUMA treatment protects mice against mice heart I/R injury.

OBJECTIVE: PUMA is a pro-apoptotic gene, which has been found to be critical to the pathogenesis during heart ischemia-reperfusion injury (IRI). We investigate whether anti-PUMA protect mice from acute heart failure. MATERIALS AND METHODS: Mice were subjected to 30 min ischemia and 24 hrs reperfusion in the presence or absence of anti-PUMA. Treated mice were evaluated for heart PUMA protein and mRNA expression, and apoptosis by terminal deoxy nucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining. RESULTS: In mice, anti-PUMA post conditioning markedly reduced PUMA mRNA and protein expression in the heart 4-fold. Hearts from mice that received anti-PUMA had substantially fewer heart muscles apoptosis by TUNEL staining. Anti-PUMA post-conditioning greatly reduced infarct size to 14.4±3.7%, from 38.2±3.9% in the untreated I/R group. Furthermore, survival experiments revealed that more than 90% of control mice died from lethal I/R, whereas 20% of the anti-PUMA post-treated mice survived until the end of the 10-day observation period. CONCLUSIONS: This study confirms the importance of PUMA-mediated apoptosis in heart ischemia-reperfusion injury. Silencing PUMA by recombinant PUMA has therapeutic promise to limit ischemia-reperfusion injury.

A novel KLF6-Rho GTPase axis regulates hepatocellular carcinoma cell migration and dissemination.

The presence of invasion into the extra-hepatic portion of the portal vein or the development of distant metastases renders hepatocellular carcinoma (HCC) patients ineligible for the only potential curative options for this malignancy-tumor resection or organ transplantation. Gene expression profiling of murine HCC cell lines identified KLF6 as a potential regulator of HCC cell migration. KLF6 knockdown increases cell migration, consistent with the correlation between decreased KLF6 mRNA levels and the presence of vascular invasion in human HCC. Concordantly, single-copy deletion of Klf6 in a HCC mouse model results in increased tumor formation, increased metastasis to the lungs and decreased survival, indicating that KLF6 suppresses both HCC development and metastasis. By combining gene expression profiling and chromatin immunoprecipitation coupled to deep sequencing, we identified novel transcriptional targets of KLF6 in HCC cells including VAV3, a known activator of the RAC1 small GTPase. Indeed, RAC1 activity is increased in KLF6-knockdown cells in a VAV3-dependent manner, and knockdown of either RAC1 or VAV3 impairs HCC cell migration. Together, our data demonstrate a novel function for KLF6 in constraining HCC dissemination through the regulation of a VAV3-RAC1 signaling axis.

Rapid molecular diagnosis of the Gilbert's syndrome-associated exon 1 mutation within the UGT1A1 gene.

Gilbert's syndrome is suspected in patients with unconjugated hyperbilirubinemia caused by decreased activity of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene in the absence of abnormal liver function and hemolysis. The major genetic variants underlying Gilbert's syndrome are TATA-box repeats of the promoter region and exon 1 G211A of the coding region, particularly in Asians. The efficacy of DNA melting curve analysis, however, has not been established for the G211A mutation. For rapid and accurate molecular diagnosis of Gilbert's syndrome, DNA melting curve analysis was evaluated for its genotyping capability not only for TATA-box repeats of the UGT1A1 promoter, but also for G211A of UGT1A1 exon 1. TA repeats within the TATA-box sequence and the exon 1 G211A mutation of the UGT1A1 gene were analyzed by DNA melting curve analysis. To evaluate the assay reliability, direct sequencing or polyacrylamide gel electrophoresis was used as a comparative method. All homozygous and heterozygous polymorphisms of A(TA)7TAA within the TATA-box allele and of exon 1 G211A mutants of the UGT1A1 gene were successfully identified with DNA melting curve analysis. DNA melting curve analysis is, therefore, an effective molecular method for the rapid diagnosis of Gilbert's syndrome, as it detects not only TATA-box polymorphisms but also the exon 1 G211A mutation located within the UGT1A1 gene.

Correlation between SF-36 and six-minute walk distance in liver donors.

OBJECTIVE: We employed the 36-item short-form health survey (SF-36) and 6-minute walk distance (6MWD) to assess the quality of life (QoL) of donors after living-donor liver transplantation (LDLT). METHODS: This longitudinal prospective study had data collection via an interview and test or a mailed survey. Fifty-one liver LDLT donors underwent testing before and after donation using the SF-36 questionnaire and 6MWD. RESULTS: The physical component summary (PCS) of the SF-36 declined (P < .0001) and the mental component summary (MCS) increased significantly (P = .04) at 1 month after donation. The 6MWD declined significantly at 2 weeks after donation (P < .0001). After standardization, there was a high correlation between PCS and 6MWD (r(2) = 0.766). CONCLUSIONS: Liver donation had a moderate impact on donor physical status, but enhanced mental status. Similar decreasing trends were observed in 6MWD and PCS. After donation, real physical performance predicted PCS but not MCS.

Preliminary experience with gemcitabine and cisplatin adjuvant chemotherapy after liver transplantation for hepatocellular carcinoma.

AIM: Liver transplantation (LT) criteria for treatment of hepatocellular carcinoma (HCC) were refined to improved survival and disease-free rates. Adjuvant chemotherapy might eliminate disseminated tumor cells after removal of the primary liver cancer and thereby benefit LT recipients. Our purpose was to evaluate the effect of an adjuvant chemotherapy (gemcitabine and cisplatin) on outcome of patients treated with LT for HCC. METHODS: Of the 99 patients who underwent liver transplantation from October 2001 through February 2006, there were 58 with HCC. Nine patients with extra-hepatic metastasis and four who died for noncancer-related reasons were excluded. Three groups (total n=45) were compared: Group A (n=15) met the Milan criteria and did not receive study chemotherapy, Group B (n=13) did not fit the Milan criteria and did not receive chemotherapy, and Group C (n=17) did not fit the Milan criteria and received gemcitabine and cisplatin. RESULTS: The chemotherapy regimen was well tolerated. Leukopenia, the need for granulocyte colony-stimulating factor treatment, or both occurred in four patients. The disease-specific survival rates were better for groups A and C than for group B (p=0.02) and the disease-free survival rates were also better for groups A and C than for group B (p=0.01). CONCLUSIONS: Systemic gemcitabine and cisplatin may improve disease-specific and disease-free survival in HCC patients who do not meet the Milan criteria after LT.

Effects of music on gastric myoelectrical activity in healthy humans.

The aim was to study the effects of listening to music on gastric myoelectrical activity in healthy humans. Gastric myoelectrical activity was recorded using surface electrogastrography from 17 healthy volunteers before and for 30 min after they listened to music. All subjects listened to the same music. Ten perceived the music as enjoyable and seven did not. The percentages of normal slow wave, dominant frequency and dominant power did not differ significantly between baseline and during music intervention. An analysis of covariance model that included the subjects' feelings about the music and dominant power showed significantly higher dominant power during music intervention in subjects who enjoyed the music (p < 0.01). In the individuals who enjoyed the music, dominant power (55.0 +/- 9.2 dB) was significantly higher during music intervention than at baseline (49.5 +/- 6.8 dB, p = 0.03). In the subjects who did not enjoy the music, dominant power was significantly lower during music intervention than at baseline (48.8 +/- 6.8 and 55.7 +/- 6.2 dB, respectively; p < 0.01). Listening to enjoyable music increases the amplitude of gastric myoelectrical activity in healthy humans. Music therapy may improve gastric motility and may be used to stimulate gastric emptying.