The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia.

Growing evidence links abnormal epigenetic control to the development of hematological malignancies. Accordingly, inhibition of epigenetic regulators is emerging as a promising therapeutic strategy. The acetylation status of lysine residues in histone tails is one of a number of epigenetic post-translational modifications that alter DNA-templated processes, such as transcription, to facilitate malignant transformation. Although histone deacetylases are already being clinically targeted, the role of histone lysine acetyltransferases (KAT) in malignancy is less well characterized. We chose to study this question in the context of acute myeloid leukemia (AML), where, using in vitro and in vivo genetic ablation and knockdown experiments in murine models, we demonstrate a role for the epigenetic regulators CBP and p300 in the induction and maintenance of AML. Furthermore, using selective small molecule inhibitors of their lysine acetyltransferase activity, we validate CBP/p300 as therapeutic targets in vitro across a wide range of human AML subtypes. We proceed to show that growth retardation occurs through the induction of transcriptional changes that induce apoptosis and cell-cycle arrest in leukemia cells and finally demonstrate the efficacy of the KAT inhibitors in decreasing clonogenic growth of primary AML patient samples. Taken together, these data suggest that CBP/p300 are promising therapeutic targets across multiple subtypes in AML.

HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias.

The Lim Domain Only 2 (LMO2) leukaemia oncogene encodes an LIM domain transcriptional cofactor required for early haematopoiesis. During embryogenesis, LMO2 is also expressed in developing tail and limb buds, an expression pattern we now show to be recapitulated in transgenic mice by an enhancer in LMO2 intron 4. Limb bud expression depended on a cluster of HOX binding sites, while posterior tail expression required the HOX sites and two E-boxes. Given the importance of both LMO2 and HOX genes in acute leukaemias, we further demonstrated that the regulatory hierarchy of HOX control of LMO2 is activated in leukaemia mouse models as well as in patient samples. Moreover, Lmo2 knock-down impaired the growth of leukaemic cells, and high LMO2 expression at diagnosis correlated with poor survival in cytogenetically normal AML patients. Taken together, these results establish a regulatory hierarchy of HOX control of LMO2 in normal development, which can be resurrected during leukaemia development. Redeployment of embryonic regulatory hierarchies in an aberrant context is likely to be relevant in human pathologies beyond the specific example of ectopic activation of LMO2.

Effects of irradiation intensity and pH on nutrients release and solids destruction of waste activated sludge using the microwave-enhanced advanced oxidation process.

Using the microwave-enhanced advanced oxidation process (MW/H2O2-AOP), the pH and irradiation intensity on waste activated sludge samples were investigated to provide insight to the athermal effects on nutrients release, solids destruction, particle size distribution and dewaterability, and to demonstrate their interrelationships. Carbonaceous matters and nutrients released into solution depended on the irradiation intensity and time. Higher irradiation levels tended to be more effective in the solubilization of nutrients and had more pronounced effects in the dewaterability of sludge. In terms of particle size distribution, detectable particles increased in size for treatments in acidic conditions, while the dewaterability of treated sludge was improved. In treatments under neutral and alkaline conditions, the particle size range increased, with more small particles formed, thereby significantly deteriorating the dewaterability of sludge treated in alkaline conditions. The best results for the solubilization of nutrients were in alkaline conditions with high irradiation power, but dewaterability of the sludge was compromised. Sludge treatment with the MW/H2O2-AOP in acidic conditions with high irradiation power yielded the best dewaterable sludge and significant nutrient solubilization; therefore, it is the recommended treatment condition for activated sludge.

Extraction of nutrients from foam in a membrane activated sludge system.

This study investigated the feasibility of treating the foams generated in enhanced biological phosphorus removal processes with the microwave-enhanced advanced oxidation process to reduce solids and solubilize nutrients for recovery purposes. It was found that more than half of the total chemical oxygen demand was solubilized during the treatment with just a small dose of hydrogen peroxide, signifying effective destruction of foam solids. Significant solubilization of phosphates, volatile fatty acids and ammonia was also observed, along with the release of metals contained in the foam, including calcium, potassium, and magnesium, which thereby represents additional potential benefits for nutrient recovery via subsequent crystallization processes. Since the solids content of foam is typically high, pretreatment for thickening sludge solids is not necessary prior to the use of microwave-enhanced advanced oxidation processes. As a result, this also offers further potential for reduction of energy costs. The process could be an efficient method for the removal and control of foam and the recovery of all available phosphorus at the same time.

Disinfection and solubilization of sewage sludge using the microwave enhanced advanced oxidation process.

The microwave enhanced advanced oxidation process (MW/H(2)O(2)-AOP) was used to treat municipal sewage sludge for solids disintegration, nutrient solubilization, with an emphasis on pathogen destruction and regrowth. Pathogen reduction, in terms of fecal coliform concentrations were found below detection limit (1000 CFU/L) immediately after treatment when sludge was treated at 70 degrees C with more than 0.04% of H(2)O(2) (w/w). Significant regrowth of fecal coliforms was observed for the treated samples after 72 h. However, no regrowth was observed for samples treated at 70 degrees C with 0.08% H(2)O(2) or higher, suggesting a complete elimination of fecal coliforms. The range of hydrogen peroxide used did not have a significant effect on orthophosphate release regardless of temperature. Ammonia release at these low temperatures was found to be insignificant. The soluble chemical oxygen demand increased with an increase of hydrogen peroxide dosage at 70 degrees C. However, there was no clear trend of soluble chemical oxygen demand over varying hydrogen peroxide dosage at 55 degrees C. The MW/H(2)O(2)-AOP is a novel process for the pasteurization and stabilization of sewage sludge to meet and maintain Class A biosolids criteria.

Fitz-Hugh-Curtis syndrome: three cases confirmed by laparoscopy.

There were 3 cases of Fitz-Hugh-Curtis syndrome,--pelvic inflammatory disease (PID) complications and perihepatitis,--caused by Chlamydia trachomatis infection. All 3 patients complained of sudden right upper quadrant pain in addition to PID symptoms. Enzyme immunoassay of uterine cervical specimens revealed that the positive chlamydial antigen and serum antibody titer against anti-Chlamydia trachomatis were also high. In all cases the laparoscopy revealed findings of perihepatitis on the anterior surface of the right hepatic lobe. In 2 cases, typical violin-string adhesions were also observed between the liver capsule and parietal peritoneum. In both cases, adhesiolysis was conducted during the laparoscopy.