Effect of oral immunotherapy in children with milk allergy: The ORIMA study

BackgroundThis study was aimed at evaluating the efficacy and safety of oral immunotherapy (OIT) in children with severe cow's milk allergy.MethodsThe subjects comprised 28 children (aged 3–12 years) with allergic symptoms that were induced by ≤ 10 mL of cow's milk in an oral food challenge test (OFC). The subjects were randomly allocated to the treatment group (n = 14) and control group (n = 14); the former received rush immunotherapy for 2 weeks, followed by a gradual increase of cow's milk volume to 100 mL for 1 year, and the latter completely eliminated cow's milk for 1 year. Both groups underwent an OFC with 100 mL of cow's milk after 1 year.ResultsThe treatment group had significantly higher rates of a negative OFC [7/14 (50%) vs. 0/14 (0%), p < 0.01] compared with the control group. The cow's milk-specific IgE level significantly decreased in the treatment group (p < 0.01) but not in the control group (p = 0.63). During the study period, adrenaline was required in 6/14 patients (43%) of the treatment group and in 0/14 patients (0%) of the control group. Long follow-up data were available at the 2-year point after the study for 8 in the treatment group and 7 (87.5%) of these continued to ingest milk (>100 mL).ConclusionsThe effect of immunotherapy was 50%, but the incidence of adverse events was not low. Further studies focusing on safety is necessary to standardize OIT for cow's milk allergy.     

Vascular endothelial growth factor promotes proliferation and function of hepatocyte-like cells in embryoid bodies formed from mouse embryonic stem cells

BACKGROUND/AIMS: Embryoid bodies (EBs) formed from embryonic stem cells (ESCs) differentiate into hepatocyte-like cells (HLCs), and are thus thought to be a useful cell source for drug testing and bioartificial liver. The aim of this study was to induce proliferation and function of ESC-derived HLCs in EBs using HLC-endothelial cell interaction. METHODS: EBs were cultured in the presence of vascular endothelial growth factor (VEGF) and/or VEGF receptor (VEGFR) inhibitors. To reproduce HLC-endothelial cell interaction, we overexpressed VEGF in ESC-derived HLCs under the control of Cyp7a1 gene in EBs. RESULTS: VEGF added to the cultured EBs increased the proliferation of ESC-derived endothelial cells, resulting in the promotion of proliferation and function of ESC-derived HLCs. In EBs, the VEGFR2 inhibitor suppressed expression of albumin and endothelial cell marker genes, whereas the inhibitor for both VEGFR1 and VEGFR2 suppressed expression of Cyp7a1 and hepatocyte growth factor (Hgf) genes. Upon exposure to VEGF, the endothelial cells in EBs increased Hgf mRNA expression. Forced VEGF expression in ESC-derived HLCs in EBs induced angiogenesis around the HLCs and resulted in an increase in the amount of HLCs. CONCLUSIONS: VEGF indirectly induces the proliferation and function of ESC-derived HLCs through VEGFR1 and VEGFR2 signaling in endothelial cells.     

Results of internal mammary artery-coronary artery bypass surgery and the characteristics of internal mammary artery grafts

Coronary artery bypass grafting utilizing the internal mammary artery (IMA) was performed in 108 patients with an operative mortality (less than 1 month) of 0% and a hospital mortality of 1.9%. The IMA was used most often in the left anterior descending artery system in combination with saphenous vein grafts (SVG) to the right and left circumflex artery systems. Although the IMA flow was smaller than the SVG flow when measured intraoperatively by an electromagnetic flow meter, postoperative clinical, electrocardiographic, isotopic, angiographic and coronary sinus flow-metric studies all demonstrated that the IMA can respond well to myocardial blood flow demand both at rest and during exercise, resulting in excellent clinical improvements with no detectable signs of flow deficiency. In addition, no signs of ischemia were detected in any of the 15 patients with stenosis in the left main trunk treated with an IMA graft. The IMA graft appears to have a great adaptive capacity to meet increased myocardial demand. Postoperative angiography performed at an average of 3 months after surgery in 60 unselected patients demonstrated an IMA patency rate of 98% in comparison with 88% patency in SVGs to the left anterior descending artery (p less than 0.05). Not only the patency rate, but also the graft wall characteristics were much better in IMA grafts than in SVGs. Some SVGs showed marked wall irregularity as early as 3 months after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thrombopoietin Induces Association of Crkl With STAT5 But Not STAT3 in Human Platelets

Crkl, a 39-kD SH2, SH3 domain-containing adapter protein, isconstitutively tyrosine phosphorylated in hematopoietic cells fromchronic myelogenous leukemia (CML) patients. We recently reported thatthrombopoietin induces tyrosine phosphorylation of Crkl in normalplatelets. In this study, we demonstrate that thrombopoietin inducesassociation of Crkl with a tyrosine phosphorylated 95- to 100-kDprotein in platelets and in UT7/TPO cells, a thrombopoietin-dependent megakaryocytic cell line. With specific antibodies against STAT5, wedemonstrate that the 95- to 100-kD protein in Crkl immunoprecipitates is STAT5. This coimmunoprecipitation was specific in that Crkl immunoprecipitates do not contain STAT3, although STAT3 becomes tyrosine phosphorylated in thrombopoietin-stimulated platelets. Thecoimmunoprecipitaion of Crkl with STAT5 was inhibited by the immunizingpeptide for Crkl antisera or phenyl phosphate (20 mmol/L). Afterdenaturing of Crkl immunoprecipitates, Crkl was stillimmunoprecipitated by Crkl antisera. However, coimmunoprecipitation ofSTAT5 was not observed. Coincident with STAT5 tyrosine phosphorylation, thrombopoietin induces activation of STAT5 DNA-binding activity asdemonstrated by electrophoretic mobility shift assays (EMSA). Using a-casein promoter STAT5 binding site as a probe, we have alsodemonstrated that Crkl antisera supershift the STAT5-DNA complex,suggesting that Crkl is a component of the complex in the nucleus.Furthermore, interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoietin also induce Crkl-STAT5 complex formation in responding cells in astimulation-dependent manner. In vitro, glutathione S-transferase(GST)-Crkl bound to STAT5 inducibly through its SH2 domain. Theseresults indicate that thrombopoietin, IL-3, GM-CSF, and erythropoietincommonly induce association of STAT5 and Crkl and that the complextranslocates to the nucleus and binds to DNA. Interestingly, suchassociation between STAT5 and Crkl was not observed incytokine-stimulated murine cells, suggesting an intriguing possibilitythat components of the human STAT5-DNA complex may be different fromthose of the murine counterpart.     

An internally and externally validated nomogram for predicting the risk of irinotecan-induced severe neutropenia in advanced colorectal cancer patients

Background:

In Asians, the risk of irinotecan-induced severe toxicities is related in part to UGT1A1*6 (UGT, UDP glucuronosyltransferase) and UGT1A1*28, variant alleles that reduce the elimination of SN-38, the active metabolite of irinotecan. We prospectively studied the relation between the UGT1A1 genotype and the safety of irinotecan-based regimens in Japanese patients with advanced colorectal cancer, and then constructed a nomogram for predicting the risk of severe neutropenia in the first treatment cycle.

Methods:

Safety data were obtained from 1312 patients monitored during the first 3 cycles of irinotecan-based regimen in a prospective observational study. In development of the nomogram, multivariable logistic regression analysis was used to test the associations of candidate factors to severe neutropenia in the first cycle. The final nomogram based on the results of multivariable analysis was constructed and validated internally using a bootstrapping technique and externally in an independent data set (n=350).

Results:

The UGT1A1 genotype was confirmed to be associated with increased risks of irinotecan-induced grade 3 or 4 neutropenia and diarrhoea. The final nomogram included type of regimen, administered dose of irinotecan, gender, age, UGT1A1 genotype, Eastern Cooperative Oncology Group performance status, pre-treatment absolute neutrophil count, and total bilirubin level. The model was validated both internally (bootstrap-adjusted concordance index, 0.69) and externally (concordance index, 0.70).

Conclusions:

Our nomogram can be used before treatment to accurately predict the probability of irinotecan-induced severe neutropenia in the first cycle of therapy. Additional studies should evaluate the effect of nomogram-guided dosing on efficacy in patients receiving irinotecan.