Activated ras oncogenes in human thyroid cancers

Human thyroid epithelial (follicular) cells give rise to two malignant tumors--"follicular" carcinomas, which metastasize almost exclusively via the bloodstream, and "papillary" carcinomas, which metastasize predominantly via lymphatics (Williams, E. D. In: W. Duncan (ed.), Recent Results in Cancer Research: Thyroid Cancer, pp. 47-55. Berlin: Springer-Verlag, 1980). We have investigated whether this contrast in biological behavior might be associated with different patterns of oncogene activation. DNA transfection analysis of five follicular and ten papillary cancers indeed showed a statistically significant difference in the pattern of genes responsible, activated ras oncogenes being found in 80% of follicular tumors but only 20% of papillary tumors. In addition, in follicular cancers we have found activation of all three ras oncogenes (H-ras, K-ras, and N-ras), the first time that this has been demonstrated in a primary human tumor type (as opposed to cell lines). We suggest therefore that ras activation may be an important determinant of metastatic capability in these epithelial cancers.     

NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer

Instability in the composition of gut bacterial communities (dysbiosis) has been linked to common human intestinal disorders, such as Crohn’s disease and colorectal cancer. Here, we show that dysbiosis caused by Nod2 deficiency gives rise to a reversible, communicable risk of colitis and colitis-associated carcinogenesis in mice. Loss of either Nod2 or RIP2 resulted in a proinflammatory microenvironment that enhanced epithelial dysplasia following chemically induced injury. The condition could be improved by treatment with antibiotics or an anti–interleukin-6 receptor–neutralizing antibody. Genotype-dependent disease risk was communicable via maternally transmitted microbiota in both Nod2-deficient and WT hosts. Furthermore, reciprocal microbiota transplantation reduced disease risk in Nod2-deficient mice and led to long-term changes in intestinal microbial communities. Conversely, disease risk was enhanced in WT hosts that were recolonized with dysbiotic fecal microbiota from Nod2-deficient mice. Thus, we demonstrated that licensing of dysbiotic microbiota is a critical component of disease risk. Our results demonstrate that NOD2 has an unexpected role in shaping a protective assembly of gut bacterial communities and suggest that manipulation of dysbiosis is a potential therapeutic approach in the treatment of human intestinal disorders.     

HIV-1 Tat protein transduction domain peptide facilitates gene transfer in combination with cationic liposomes.

The protein transduction domain (PTD) of the HIV-1 Tat protein can facilitate the cellular and nuclear uptake of macromolecular particles. Here, we demonstrate that incorporation without covalent linkage of a 17-amino acid PTD peptide into gene delivery lipoplexes improves gene transfer. Tat/Liposome/DNA (TLD) transfection, as evaluated by Fluorescence Activated Cell Scan analysis of a Green Fluorescence Protein expression plasmid, enabled transfection of highly recalcitrant primary cells in the form of air/liquid interface cultures of sheep tracheal epithelium. Treatment with chloroquine increased, and incubation at low temperature decreased, TLD transfection, suggesting that the endocytosis uptake pathway is involved.     

Gene therapy developments for pancreatic cancer

Treatment options for pancreatic cancer have limited success and it is therefore an appropriate target for the development of new strategies, including gene therapy. Gene therapy approaches include inhibition of activated oncogenes (KRAS, LSM1) with antisense and RNA interference strategies, replacement of inactivated tumour suppressor genes (TP53, CDKN2A, CDKN1A), targeting of cell signalling pathways, gene-directed prodrug-activation therapies and the use of replication-competent oncolytic viruses. Angiogenesis and apoptosis have also been targeted for gene therapy. Clinical trials of gene therapy have shown only moderate anti-tumour effects. As there are many genetic abnormalities in pancreatic cancer, strategies combining different targets or indeed different modalities of treatment, may be more successful. Identification of new targets and improvements in delivery and targeting may further improve the efficacy of gene therapy in pancreatic cancer.     

Parental psychopathology and migraine headaches among adolescent girls

Migraine headaches and depression often co-occur within individuals, and both syndromes run in families. However, knowledge about how these disorders relate across generations, as well as how migraine relates to other forms of psychopathology, is sparse. This study examined risk for migraine among female adolescent offspring of parents with different types of psychopathology. The sample was drawn from the Minnesota Twin Family Study, a community-based study of adolescents and their families ( n  = 674, 17-year-old female adolescents and their biological parents). Diagnoses of maternal, paternal and offspring major depression, antisocial behaviour, alcohol dependence and drug dependence were based on structured interviews. Migraine headaches in each family member were assessed via interviews with the mother. Parental depression, antisocial behaviour and drug dependence were associated with offspring migraine. These associations mostly remained significant even when parental migraine and the corresponding type of psychopathology in offspring were adjusted for. In contrast, there were no significant associations between parental psychopathology and offspring stomach problems, indicating that these associations did not extend to all offspring somatic symptoms. These results emphasize the need to look at antisocial behaviour and substance-related problems when examining associations between migraine and psychopathology, and indicate that more research on inter-generational links between migraine and psychopathology is needed.     

Management of Acute Postpartum Pain in Patients Maintained on Methadone or Buprenorphine During Pregnancy

Background: Empirical evidence is needed to guide adequate postpartum pain relief of methadone and buprenorphine stabilized patients. Objectives: To first determine the adequacy of pain control using non-opioid and opioid medication in participants stabilized on buprenorphine or methadone before a vaginal delivery. Second, to compare the amount of non-opioid and opioid medication needed for adequate pain control for buprenorphine-and methadone-maintained patients during the immediate postpartum period. Methods: Pain control adequacy and amount of non-opioid and opioid medication needed in buprenorphine- (n = 8) and methadone-maintained (n = 10) patients over the first five days postpartum were examined. Results: Pain ratings and number of opioid medication doses decreased over time in both medication groups. While the buprenorphine and methadone groups began with similar mean daily ibuprofen (IB) doses, the buprenorphine group decreased its IB use, while the methadone group increased its IB use. Conclusions and Scientific Significance: Patients treated daily with either buprenorphine or methadone can have adequate pain control postpartum with opioid medication and IB. Pain control is dependent on the opioid-agonist medication in use at delivery, and must be individualized.     

Ischaemic preconditioning of the graft in adult living related right lobe liver transplantation: impact on ischaemia�Creperfusion injury and clinical relevance

Background

Ischaemic preconditioning (IPC) of the right liver graft in the donor has not been studied in adult-to-adult living related liver transplantation (LRLT).

Objective

To assess the IPC effect of the graft on ischaemia reperfusion injury in the recipient and compare recipient and donor outcomes with and without preconditioned grafts.

Patients and methods

Alternate patients were transplanted with right lobe grafts that were (n =22; Group _Precond) or were not (n =22; Group _Control) subjected to IPC in the living donor. Liver ischaemia–reperfusion injury, liver/kidney function, morbidity/mortality rates and outcomes were compared. Univariate and multivariate analyses were performed to identify factors predictive of the aspartate aminotransferase (AST) peak and minimum prothrombin time.

Results

Both groups had similar length of hospital stay, morbidity/mortality, primary non-function and acute rejection rates. Post-operative AST (P =0.8) and alanine aminotransferase (ALT) peaks (P =0.6) were similar in both groups (307 ± 189 and 437 ± 302 vs. 290 ± 146 and 496 ± 343, respectively). In univariate analysis, only pre-operative AST and warm ischemia time (WIT) were significantly associated with post-operative AST peak (in recipients). In multivariate analysis, the graft/recipient weight ratio (P =0.003) and pre-operative bilirubin concentration (P =0.004) were significantly predictive of minimum prothrombin time post-transplantation.

Conclusions

Graft IPC in the living related donor is not associated with any benefit for the recipient or the donor and its clinical value remains uncertain.