Phase I trial of gemtuzumab ozogamicin in intensive combination chemotherapy for relapsed or refractory adult acute myeloid leukemia (AML): Japan Adult Leukemia Study Group (JALSG)-AML206 study

In order to investigate better molecular-target therapy for acute myeloid leukemia (AML), we conducted a phase I trial of a combination of gemtuzumab ozogamicin (GO) with conventional chemotherapy. Between January 2007 and December 2009, a total of 19 adult Japanese patients with relapsed or refractory CD33-positive AML (excluding acute promyelocytic leukemia) were enrolled. All registered patients received a standard dose of cytarabine (Ara-C) (100 mg/m(2) × 7 days), combined with either idarubicin (IDR) (10-12 mg/m(2) × 3 days) or daunorubicin (DNR) (50 mg/m(2) × 3-5 days), and then GO (3-5 mg/m(2) ), which was administered 1 day after the last infusion of IDR (IAG regimen) or DNR (DAG regimen). While doses of both GO and IDR and the administration period of only DNR were increased, the dose-limiting toxicity (DLT) was assessed. Among 19 patients (nine in the IAG regimen, 10 in the DAG regimen), the median age was 59 years (range 33-64), and the relapsed/refractory ratio was 13/6. In the therapy using 3 mg/m(2) GO in the IAG or DAG regimen, grade 3/4 leukopenia and neutropenia were observed in all patients, but none had grade 3/4 non-hematological toxicities, except febrile neutropenia. Three patients in the IAG regimen who were administered 5 mg/m(2) GO showed DLT. No patients had veno-occlusive disease or sinusoidal obstructive syndrome. In conclusion, 3 mg/m(2) GO combined with Ara-C and IDR or DNR can be safely administered, and phase II trials should be conducted to investigate the clinical efficacy of the combination therapy.     

Three-dimensional culture promotes reconstitution of the tumor-specific hypoxic microenvironment under TGFβ stimulation

In vitro tumor growth in a three-dimensional (3D) architecture has been demonstrated to play an important role in biology not only for developmental organogenesis and carcinogenesis, but also for analyses on reconstitution and maintenance in a variety of biological environments surrounding the cells. In addition to providing architectural similarity to living organisms, 3D culture with a radial flow bioreactor (RFB) can also closely mimic the living hypoxic microenvironment under which specific organogenesis or carcinogenesis occurs. The findings of the present study under the RFB culture conditions show that cancer cells underwent a shift from aerobic to hypoxic energy metabolism, in addition to protein expression to maintain the 3D structure. In RFB-cultured cells, protein stability of hypoxia-inducible factor 1 (HIF1) α, a subunit of HIF1, was increased without upregulation of its mRNA. Under these conditions, PHD2, HIF-prolyl-4-hydroxy-lase 2 and a HIF1 downstream enzyme, were stabilized without affecting the mRNA levels via downregulation of FK506-binding protein 8. PHD2 accumulation, which occurred concomitant with HIF1 stabilization, may have compensated for the lack of oxygen under hypoxic conditions to regulate the HIF levels. 3D-culture-induced overexpression of carbonic anhydrase (another representative HIF downstream enzyme) was found to occur independently of cell density in RFB--cultured cells, suggesting that the RFB provided an adequately hypoxic microenvironment for the cultured cells. From these results, it was hypothesized that the key factors are regulatory molecules, which stabilize and degrade HIF molecules, thereby activating the HIF1 pathway under a hypoxic milieu.     

Recruitment of CCR6-expressing Th17 cells by CCL 20 secreted from IL-1 beta-, TNF-alpha-, and IL-17A-stimulated endometriotic stromal cells

In a novel paradigm of T cell differentiation, type 17 T helper (Th17) cells may play a significant role in endometriosis, a chronic inflammatory disease. However, the mechanism regulating the accumulation of Th17 cells in endometriotic tissues remains unknown. We hypothesized that Th17 cells migrate to endometriotic tissues through an interaction of the chemokine CC chemokine ligand (CCL)20 and its receptor CCR6. Using endometriotic tissues from women with endometriosis, we demonstrated, by flow cytometry, that Th17 cells in endometriotic tissues express CC chemokine receptor (CCR)6. Immunohistochemistry also revealed that CCL20 was expressed in the epithelial cells and stromal cells beneath the epithelium of endometriotic tissues. CCR6+ cells were small and round and scattered in the stroma in which abundant CCL20+ cells were detected. CCL20 caused selective migration of Th17 cells in the peripheral blood in a migration assay. IL-1β, TNF-α, and IL-17A increased the secretion of CCL20 in cultured endometriotic stromal cells. Inhibitors of p38- and p42/44-MAPKs, and stress-activated protein kinase/c-Jun kinase suppressed the secretion of CCL20 increased by IL-1β, TNF-α, and IL-17A. This suggests that the CCL20/CCR6 system is involved in the migration of Th17 cells to endometriotic tissues and that proinflammatory cytokines contribute to the development of endometriosis via up-regulation of CCL20 secretion from endometriotic stromal cells.     

Estimation of Benchmark Rice Cadmium Doses as Threshold Values for Abnormal Urinary Findings with Adjustment for Consumption of Jinzu River Water

We performed this study to determine whether both eating cadmium (Cd)-polluted rice and drinking and/or cooking with Jinzu River water are associated with renal tubular dysfunction. A multiple logistic regression analysis of retrospective data indicated that both factors may contribute to this condition. Estimated threshold values of rice Cd concentration in men were 0.13–0.27 ppm and 0.09–0.18 ppm in women, without adjustment for use of Jinzu River water. The additional influence of drinking and/or cooking with Jinzu River water was estimated to be about 0.008 ppm.     

Space-time database for standardization of adult magnetocardiogram-making standard MCG parameters

Background: The magnetocardiogram (MCG) is a promising medical tool for detecting and visualizing abnormal cardiac electrical activation in heart-disease patients. However, there is no large-scale MCG database of healthy subjects, and there is little knowledge of gender- and age-related influences on MCG data.
Methods and Results: We obtained MCG data from 869 subjects (554 men, 315 women) using a conventional 64-channel MCG system, which covers the whole heart. Electrocardiogram (ECG) data were also obtained; 464 people (268 men, 196 women) were identified as a normal group using ECG data. Time intervals (PQ, QRS, QT, and QTc), current distributions (maximum current vector (MCV), and the total current vector (TCV)) of MCG data of the 464 normal subjects were analyzed to obtain basic MCG parameters.
Although mean values of PQ and QRS intervals of the male subjects were slightly longer than those of the female subjects, no intervals were correlated with gender or age. The correlation between PQ intervals of ECG and those of MCG was better than the correlation between QRS and QT intervals of ECG and those of MCG. Both MCV and TCV angles were much smaller than the electrical-axis angle in ECG. Although TCVs of the QRS and T waves were stable, the women's mean T-wave-TCV angles significantly increased with age. The maximum amplitude of the P wave was about 1.7 pT, and the value of the QRS complex was about 20–25 pT. Moreover, the T-wave amplitude decreases with age.
Conclusion: The MCG standard space-time parameters determined here provide a normal range for MCG parameters.     

Association of objective measures of trauma exposure from motor vehicle accidents and posttraumatic stress symptoms

Associations of objective measures of trauma exposure with psychological sequelae following motor vehicle accidents (MVA) were examined in a Japanese population. Impact and injury severity of 93 MVA victims was assessed using on-the-scene in-depth investigations measured by the Injury Severity Score (ISS), barrier equivalent speed (BES), and change in velocity during the impact (Delta-v). Results showed that ISS, BES, and Delta-v were not related to posttraumatic stress symptoms (PTSS) or psychiatric symptoms at 5 and 14 months after the MVA. Subjective measures (e.g., perceived life risk, persistent medical problems) were significantly related to psychological sequelae. These findings suggest that the objective measures of trauma exposure are not associated directly with PTSS or psychiatric symptoms after an MVA.