TGFß promotes mesenchymal phenotype of pancreatic cancer cells, in part, through epigenetic activation of VAV1.

The highly homeostasis-resistant nature of cancer cells leads to their escape from treatment and to liver metastasis, which in turn makes pancreatic ductal adenocarcinoma (PDAC) difficult to treat, especially the squamous/epithelial-to-mesenchymal transition (EMT)-like subtype. As the molecular mechanisms underlying tumour heterogeneity remain elusive, we investigated whether epigenetic regulation might explain inter-individual differences in the progression of specific subtypes. DNA methylation profiling performed on cancer tissues prior to chemo/radiotherapy identified one hypermethylated CpG site (CpG6882469) in the VAV1 gene body that was correlated with demethylation of two promoter CpGs (CpG6772370/CpG6772811) in both PDAC and peripheral blood. Transforming growth factor ß treatment induced gene-body hypermethylation, dissociation of DNMT1 from the promoter, and VAV1 expression via SMAD4 and mutant KrasG12D. Pharmacological inhibition of TGFß-VAV1 signalling decreased the squamous/EMT-like cancer cells, promoted nuclear VAV1 localization, and enhanced the efficacy of gemcitabine in prolonging the survival of KPfl/flC mice. Together, the three VAV1 CpGs serve as biomarkers for prognosis and early detection, and the TGFß-VAV1 axis represents a therapeutic target.

The risk of colorectal cancer is related to frequent hospitalization of IBD in an Asian population: results from a nationwide study.

BACKGROUND: The occurrence of inflammatory bowel disease (IBD) is higher in Western countries and is increasing worldwide. The incidence of IBDs is about nearly 20-fold in Western countries than Asia and has risen in Taiwan over the past few decades. Epidemiological studies have demonstrated an increased risk of colorectal cancer (CRC) in patients with IBD. The prevalence of IBD as well as IBD-associated CRC is changing and the risk of CRC in patients with IBD appears to be greater in Western countries, but CRC risk in IBD patients is less well understood in low endemic areas, such as Asia. METHODS: This population-based cohort study collected data from the Taiwan Health Insurance Research Database (from January 1998 to December 2011). In total, 10 650 patients with confirmed diagnosis of IBD served as the IBD cohort and 42 600 non-IBD subjects were enrolled. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) were used to assess the risk of CRC. RESULTS: The incidence of CRC was slightly lower in the IBD cohort compared with that in the non-IBD cohort (0.94 vs. 1.13 per 1000 person-years), with an adjusted HR of 0.99 (95% CI: 0.71-1.37). More than four hospitalizations were associated with a significantly higher risk of CRC in IBD patients in the Cox model (adjusted HR = 3.48, 95% CI: 1.59-7.63). CONCLUSIONS: The risk for CRC was not increased among IBD patients overall, but appeared to be increased with cumulative frequency of hospitalizations for IBD.

Rhabdomyolysis and brain ischemic stroke in a heroin-dependent male under methadone maintenance therapy.

OBJECTIVE: There are several complications associated with heroin abuse, some of which are life-threatening. Methadone may aggravate this problem. METHOD: A clinical case description. RESULTS: A 33-year-old man presented with rhabdomyolysis and cerebral ischemic stroke after intravenous heroin. He had used heroin since age 20, and had used 150 mg methadone daily for 6 months. He was found unconsciousness at home and was sent to our hospital. In the ER, his opiate level was 4497 ng/ml. In the ICU, we found rhabdomyolysis, acute renal failure and acute respiratory failure. After transfer to an internal ward, we noted aphasia and weakness of his left limbs. After MRI, we found cerebral ischemic infarction. CONCLUSION: Those using methadone and heroin simultaneously may increase risk of rhabdomyolysis and ischemic stroke. Patients under methadone maintenance therapy should be warned regarding these serious adverse events. Hypotheses of heroin-related rhabdomyolysis and stroke in heroin abusers are discussed.

Microfluidic assisted synthesis of multi-functional polycaprolactone microcapsules: incorporation of CdTe quantum dots, Fe3O4 superparamagnetic nanoparticles and tamoxifen anticancer drugs.

This paper demonstrates a proof-of-concept approach for encapsulating the anticancer drug tamoxifen, Fe3O4 nanoparticles (NPs) and CdTe quantum dots (QDs) into size-controlled polycaprolactone (PCL) microcapsules utilizing microfluidic emulsification, which combined magnetic targeting, fluorescence imaging and drug controlled release properties into one drug delivery system. Cross-linking the composite PCL microcapsules with poly(vinyl alcohol) (PVA) tailored their size, morphology, optical and magnetic properties and drug release behaviors. The flow conditions of the two immiscible solutions were adjusted in order to successfully generate various sizes of polymer droplets. The result showed superparamagnetic and fluorescent properties, and was used as a controlled drug release vehicle. The composite magnetic and fluorescent PCL microcapsules are potential candidates for a smart drug delivery system.