ABSTRACT
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.
Subject(s)
Crohn Disease , Inflammatory Bowel Diseases , Age of Onset , Child , Crohn Disease/diagnosis , Humans , Inflammatory Bowel Diseases/therapy , Nitriles , Phenotype , Pyrazoles , PyrimidinesABSTRACT
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.
Subject(s)
Gastrostomy/adverse effects , Hernias, Diaphragmatic, Congenital/surgery , Postoperative Complications/epidemiology , Weight Gain , Case-Control Studies , Child Development , Female , Gastrostomy/instrumentation , Gastrostomy/methods , Humans , Infant, Newborn , MaleABSTRACT
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.
Subject(s)
B-Lymphocytes/metabolism , Graft vs Host Disease/immunology , Graft vs Host Disease/metabolism , Receptors, Antigen, B-Cell/physiology , Adult , Aged , B-Cell Activating Factor/metabolism , B-Lymphocytes/pathology , Cell Proliferation , Cells, Cultured , Chronic Disease , Female , Humans , Lymphocyte Activation/physiology , Male , Middle Aged , Primary Cell Culture , Receptors, Antigen, B-Cell/agonists , Young AdultABSTRACT
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.
