Ruxolitinib: Targeted Approach for Treatment of Autoinflammatory Very Early Onset Inflammatory Bowel Disease.

Very early onset inflammatory bowel disease (VEO-IBD), diagnosed <6 years old, can be genetically and phenotypically distinct and more refractory than older-onset IBD. Identified causal monogenic defects have been targeted therapeutically in a small subset of VEO-IBD1; however, for most of these children, treatment strategies, such as phenotypic profiles, are critically needed to improve outcomes.

Gastrostomy tube placement in infants with congenital diaphragmatic hernia: Frequency, predictors, and growth outcomes.

BACKGROUND: Gastrostomy tube (G-tube) placement is a common intervention for newborns with severe feeding difficulties. Infants with congenital diaphragmatic hernia (CDH) are at high risk for feeding problems. Prevalence of G-tube placement and consequent nutritional outcomes of infants with CDH and G-tubes has not been described. AIMS: Determine factors associated with G-tube placement and growth in infants with congenital diaphragmatic hernia. STUDY DESIGN: Retrospective cohort study of infants with CDH to evaluate the association of G-tube placement with risk factors using logistic regression. We also assessed the association between growth velocity and G-tube placement and other risk factors using linear regression. SUBJECTS: The subjects of the study were infants with CDH treated at Duke University Medical Center from 1997 to 2013. OUTCOME MEASURES: Weight gain in infants with CDH that had G-tube placement compared to those infants with CDH that did not. RESULT: Of the 123 infants with CDH, 85 (69%) survived and G-tubes were placed in 25/85 (29%) survivors. On adjusted analysis, extracorporeal membrane oxygenation (OR=11.26 [95% CI: 1.92-65.89]; P=0.01) and proton pump inhibitor use (OR=17.29 [3.98-75.14], P≤0.001) were associated with G-tube placement. Infants without G-tubes had a growth velocity of 6.5g/day (95% CI: 2.5-10.4) more than infants with G-tubes. CONCLUSION: Survivors with more complex inpatient courses were more likely to receive G-tubes. Further investigation is needed to identify optimal feeding practices for infants with CDH.

Increased BCR responsiveness in B cells from patients with chronic GVHD.

Although B cells have emerged as important contributors to chronic graft-versus-host-disease (cGVHD) pathogenesis, the mechanisms responsible for their sustained activation remain unknown. We previously showed that patients with cGVHD have significantly increased B cell-activating factor (BAFF) levels and that their B cells are activated and resistant to apoptosis. Exogenous BAFF confers a state of immediate responsiveness to antigen stimulation in normal murine B cells. To address this in cGVHD, we studied B-cell receptor (BCR) responsiveness in 48 patients who were >1 year out from allogeneic hematopoietic stem cell transplantation (HSCT). We found that B cells from cGVHD patients had significantly increased proliferative responses to BCR stimulation along with elevated basal levels of the proximal BCR signaling components B cell linker protein (BLNK) and Syk. After initiation of BCR signaling, cGVHD B cells exhibited increased BLNK and Syk phosphorylation compared with B cells from patients without cGVHD. Blocking Syk kinase activity prevented relative post-HSCT BCR hyper-responsiveness of cGVHD B cells. These data suggest that a lowered BCR signaling threshold in cGVHD associates with increased B-cell proliferation and activation in response to antigen. We reveal a mechanism underpinning aberrant B-cell activation in cGVHD and suggest that therapeutic inhibition of the involved kinases may benefit these patients.

Caspase-8 dependent histone acetylation by a novel proteasome inhibitor, NPI-0052: a mechanism for synergy in leukemia cells.

Combination studies of histone deacetylase inhibitors (HDACi) and proteasome inhibitors are providing preclinical framework to build better strategies against hematologic malignancies. Our previous work found that a novel proteasome inhibitor, NPI-0052, and HDACi synergistically induce apoptosis in leukemia cells in a caspase-8- and oxidant-dependent manner. Here we extend those observations to primary leukemia cells and identify novel mechanisms of synergy. Because the proximal targets of NPI-0052 and HDACi are inhibition of proteasome activity and histone acetylation, we initially examined those biochemical events. Increased acetylation of histone-H3 was detected in Jurkat and CLL primary cells treated with NPI-0052, alone or in combination with various HDACi (MS/SNDX-275 or vorinostat). Hyperacetylation by NPI-0052 occurred to a lesser extent in caspase-8-deficient cells and in cells treated with an antioxidant. These results indicate that NPI-0052 is eliciting caspase-8 and oxidative stress-dependent epigenetic alterations. In addition, real-time PCR revealed that MS/SNDX-275 repressed expression of the proteasomal beta5, beta2, and beta1 subunits, consequently inhibiting respective enzymatic activities. Overall, our results suggest that crosstalk by NPI-0052 and HDACi are contributing, along with caspase-8 activation and oxidative stress, to their synergistic cytotoxic effects in leukemia cells, reinforcing the potential clinical utility of combining these 2 agents.