Dexamethasone versus Prednisone in Childhood Acute Lymphoblastic Leukemia Treatment: Results of the Indonesian Randomized Trial

Background: Randomized trials report that, compared to prednisone, dexamethasone has reduced CNS relapse and improved event-free survival (EFS), despite a trend toward a higher risk for induction death. Because toxic death is a specific problem in the Indonesian setting, this study compares the outcome of dexamethasone versus prednisone. Methods: In the period 2006 - 2011, 196 patients with childhood acute lymphoblastic leukemia (ALL) treated on the Indonesia-ALL-2006 protocol [first standard risk (SR) and later high risk (HR) patients] were randomized to receive dexamethasone or prednisone as steroid. Patients in the dexamethasone arm (n = 102: 68 SR, 34 HR) received dexamethasone 4 mg/m2/day (SR) or 6 mg/m2/day (HR), while the prednisone arm (n = 94: 66 SR, 28 HR) received prednisone 40 mg/m2/day (SR and HR). Results: Patients in the dexamethasone arm showed no significant difference compared to the prednisone arm in abandonment rate (24.5% vs. 25.5%, P = 0.91), death rate (17.7% vs. 14.9%, P = 0.54), or leukemic events (13.7 vs. 11.7%, P = 0.59). After stratification for risk group, a trend towards a higher death rate was found in the dexamethasone arm of SR patients (16.2 vs. 6.1%, P = 0.06). The 3-year survival for EFS in SR and HR patients for dexamethasone versus prednisone was 31.5% ± 6.6% vs. 41.5% ± 5.9% (P = 0.51), for leukemia-free survival (LFS) it was 63.7% ± 9.3% vs. 74.5% ± 7.6% (P = 0.47), and for overall survival (OS) it was 49.5% ± 7.7% vs. 69.3% ± 6.1% (P = 0.09). Conclusions: In our setting, a trend toward higher induction deaths was observed in the dexamethasone arm of SR patients and the 3-year EFS;LFS and OS rates were lower in the dexamethasone group;however, these differences were not significant.

Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia

CDC42 controls intestinal epithelial(IEC)stem cell(IESC)division.How aberrant CDC42 initiates intestinal inflammation or neoplasia is unclear.We utilized models of inflam-matory bowel diseases(IBD),colorectal cancer,aging,and IESC injury to determine the loss of intestinal Cdc42 upon inflammation and neoplasia.Intestinal specimens were collected to determine the levels of CDC42 in IBD or colorectal cancer.Cdc42 floxed mice were crossed with Villin-Cre,Villin-CreERT2 and/or Lgr5-eGFP-IRES-CreERT2,or Bmi1-CreERT2 mice to generate Cdc42 deficient mice.Irradiation,colitis,aging,and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation,IESC/progenitor regenerative capacity,and IEC repair.Our studies revealed that increased CDC42 in colorectal cancer correlated with lower survival;in contrast,lower levels of CDC42 were found in the inflamed IBD colon.Colonic Cdc42 depletion significantly reduced Lgr5+IEsCs,increased progenitors'hyperplasia,and induced mucosal inflammation,which led to crypt dysplasia.Colonic Cdc42 depletion markedly enhanced irra-diation-or chemical-induced colitis.Depletion or inhibition of Cdc42 reduced colonic Lgr5+IESC regeneration.In conclusion,depletion of Cdc42 reduces the IESC regeneration and IEC repair,leading to prolonged mucosal inflammation.Constitutive monogenic loss of Cdc42 in-duces mucosal inflammation,which could result in intestinal neoplasia in the context of aging.

Force-dependent calcium signaling and its pathway of human neutrophils on P-selectin in flow

P-selectin engagement of P-selectin glycoprotein Iigand-1 （PSGL-1） causes circulating leukocytes to roll on and adhere to the vascular surface, and mediates intracellular calcium flux, a key but unclear event for subsequent arresting firmly at and migrating into the infection or injured tissue. Using a parallel plate flow chamber technique and intracellular calcium ion detector （Fluo-4 AM）, the intracellular calcium flux of firmly adhered neutrophils on immobilized P-selectin in the absence of chemokines at various wall shear stresses was investigated here in real time by fluorescence microscopy. The results demon- strated that P-selectin engagement of PSGL-1 induced the intracellular calcium flux of firmly adhered neutrophils in flow, increasing P-selectin concentration enhanced cellu- lar calcium signaling, and, force triggered, enhanced and quickened the cytoplasmic calcium bursting of neu- trophils on immobilized P-selectin. This P-selectin-induced calcium signaling should come from intracellular calcium release rather than extracellular calcium influx, and be along the mechano-chemical signal pathway involving the cytoskeleton, moesin and Spleen tyrosine kinase （Syk）. These results provide a novel insight into the mechano-chemical regulation mechanism for P-selectininduced calcium signaling of neutrophils in flow.