The Novel Deacetylase Inhibitor AR-42 Demonstrates Pre-Clinical Activity in B-Cell Malignancies In Vitro and In Vivo

While deacetylase (DAC) inhibitors show promise for the treatment of B-cell malignancies, those introduced to date are weak inhibitors of class I and II DACs or potent inhibitors of class I DAC only, and have shown suboptimal activity or unacceptable toxicities. We therefore investigated the novel DAC inhibitor AR-42 to determine its efficacy in B-cell malignancies.In mantle cell lymphoma (JeKo-1), Burkitt's lymphoma (Raji), and acute lymphoblastic leukemia (697) cell lines, the 48-hr IC(50) (50% growth inhibitory concentration) of AR-42 is 0.61 microM or less. In chronic lymphocytic leukemia (CLL) patient cells, the 48-hr LC(50) (concentration lethal to 50%) of AR-42 is 0.76 microM. AR-42 produces dose- and time-dependent acetylation both of histones and tubulin, and induces caspase-dependent apoptosis that is not reduced in the presence of stromal cells. AR-42 also sensitizes CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL), potentially through reduction of c-FLIP. AR-42 significantly reduced leukocyte counts and/or prolonged survival in three separate mouse models of B-cell malignancy without evidence of toxicity.Together, these data demonstrate that AR-42 has in vitro and in vivo efficacy at tolerable doses. These results strongly support upcoming phase I testing of AR-42 in B-cell malignancies

Long-Term Persistance of the Pathophysiologic Response to Severe Burn Injury

Main contributors to adverse outcomes in severely burned pediatric patients are profound and complex metabolic changes in response to the initial injury. It is currently unknown how long these conditions persist beyond the acute phase post-injury. The aim of the present study was to examine the persistence of abnormalities of various clinical parameters commonly utilized to assess the degree hypermetabolic and inflammatory alterations in severely burned children for up to three years post-burn to identify patient specific therapeutic needs and interventions. Nine-hundred seventy-seven severely burned pediatric patients with burns over 30% of the total body surface admitted to our institution between 1998 and 2008 were enrolled in this study and compared to a cohort non-burned, non-injured children. Demographics and clinical outcomes, hypermetabolism, body composition, organ function, inflammatory and acute phase responses were determined at admission and subsequent regular intervals for up to 36 months post-burn. Statistical analysis was performed using One-way ANOVA, Student's t-test with Bonferroni correction where appropriate with significance accepted at p<0.05. Resting energy expenditure, body composition, metabolic markers, cardiac and organ function clearly demonstrated that burn caused profound alterations for up to three years post-burn demonstrating marked and prolonged hypermetabolism, p<0.05. Along with increased hypermetabolism, significant elevation of cortisol, catecholamines, cytokines, and acute phase proteins indicate that burn patients are in a hyperinflammatory state for up to three years post-burn p<0.05. Severe burn injury leads to a much more profound and prolonged hypermetabolic and hyperinflammatory response than previously shown. Given the tremendous adverse events associated with the hypermetabolic and hyperinflamamtory responses, we now identified treatment needs for severely burned patients for a much more prolonged time

Validity of the +1.50 plus lens screening test as a predictor of uncorrected moderate hyperopia

Purpose: Screening for uncorrected hyperopia in school children is important given its association with poorer visual function and academic performance. However, standard distance visual acuity screening may not detect low to moderate hyperopia. The plus lens test is used to screen for hyperopia in many school screening protocols, but has not been well validated. The current study investigated the effectiveness of the plus lens test to identify hyperopia in school children. Methods: Participants included Grade 2 school children. Monocular distance visual acuity (logMAR letter chart) was measured unaided, and then through a +1.50D lens, known as the plus lens test. Cycloplegic refraction was undertaken to classify moderate hyperopia (≥+2.00D). Sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) were calculated for commonly used cut-offs for the plus lens test: 6/6, 6/9 and less than two lines difference between unaided acuity and acuity through the plus lens test. Results: The sample included 59 children (mean age 7.2 ± 0.4 years). Fourteen (24%) children were classified as having uncorrected hyperopia. The sensitivity and specificity of the +1.50 plus lens test for identifying hyperopia were 0% and 98% respectively for a 6/6 cut-off, 29% and 91% for 6/9 cut-off, and 50% and 76% for a <2 line reduction between unaided acuity and acuity through the plus lens test. Receiver Operating Curve (ROC) analysis revealed area under curves of 0.69 based on acuity through the plus lens test, and 0.65 for a reduction in acuity through the plus lens test. Conclusions: The plus lens test has low sensitivity for detecting uncorrected hyperopia using traditional cut-offs of 6/9 or better. This raises questions about the role of the plus lens test in school screening batteries.</p