Mapping of electromagnetic waves generated by free-running self-oscillating devices.

Near-field mapping has proven to be a powerful technique for characterizing and diagnosing antennas in the microwave frequency range. However, conventional measurement methods based on a network analyzer cannot be applied to on-chip antenna devices extensively studied for future wireless communication in the millimeter wave (mm-wave) (30-300 GHz) and terahertz (THz) wave (0.1-10 THz) frequency regions. Here, we present a new asynchronous mapping technique to investigate the spatial distribution of not only the amplitude but also the phase of the electric field generated by free-running, self-oscillating generators including CMOS oscillators, Gunn oscillators, resonant tunneling diodes, and quantum cascaded lasers. Using a photonic-electronic hybrid measurement system, a wide frequency coverage, minimal invasiveness of the field to be measured, and phase distribution measurements with a theoretically-limited sensitivity are simultaneously achieved. As a proof-of-concept experiment, we demonstrate the mapping of a mm-wave (77 GHz) generated by a free-running Gunn oscillator and antenna characterization based on near-to-far field transformation.

Atropisomeric Chiral Diiododienes (Z,Z)-2,3-Di(1-iodoalkylidene)tetralins: Synthesis, Enantiomeric Resolution, and Application in Asymmetric Catalysis.

The C2-symmetric tetralin-fused 1,4-diiodo-1,3-butadiene derivatives, (Z,Z)-2,3-di(1-iodoalkylidene)tetralin 1a-c, are atropisomeric and can be resolved into the two persistent axially chiral enantiomers by HPLC on a chiral stationary phase. The enantiomerically pure compounds can serve as chiral organocatalysts for dearomatizing spirolactonization to show good performance in up to 73% ee.

Atropisomeric chiral dienes in asymmetric catalysis: C(2) -symmetric (Z,Z)-2,3-bis[1-(diphenylphosphinyl)ethylidene]tetralin as a highly active Lewis base organocatalyst.

Diene catalysts with a twist: The title C2 -symmetric tetralin-fused 1,3-butadiene derivative is atropisomeric and can be resolved into the two helical enantiomers. The optically pure compound showed excellent enantioselectivity as well as unusually high catalytic activity as a chiral Lewis basic organocatalyst in the asymmetric allylation of various aldehydes with ß-substituted allyltrichlorosilanes.

Effect of axitinib (AG-013736) on fatigue, thyroid-stimulating hormone, and biomarkers: a phase I study in Japanese patients.

Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, antitumor activity, and recommended starting dose of axitinib in patients with advanced solid tumors. Twelve patients received single-dose axitinib 5 mg and were monitored for > or =48 h. Continuous 5 mg twice-daily dosing was then initiated. One patient had dose-limiting toxicity (grade 3 proteinuria and fatigue). Common treatment-related adverse events were anorexia, fatigue, and diarrhea. Grade 3 treatment-related adverse events were fatigue and hypertension. Maximum axitinib plasma concentration occurred 1-4 h after steady-state dosing. Eleven patients experienced thyroid-stimulating hormone elevation; time-course change and fatigue onset appeared to be related in some patients. Significant correlation was observed between thyroid-stimulating hormone change and area under the plasma concentration-time curve (AUC; r = 0.80, P = 0.005). Axitinib decreased plasma soluble vascular endothelial growth factor receptor 2 (s-VEGFR2), with significant correlation between change in s-VEGFR2 and AUC (r = -0.92, P < 0.0001). Fluorodeoxyglucose positron emission tomography revealed a substantial decrease in tumor metabolic activity associated with axitinib. Tumor size decreased in nine patients. The time-course of thyroid-stimulating hormone change appeared correlated with fatigue. There were significant correlations between thyroid-stimulating hormone or s-VEGFR2 and axitinib exposure. Axitinib 5 mg twice-daily is the recommended starting dose for Japanese patients. This trial is registered with ClinicalTrials.gov, identifier NCT00447005.

Synthesis of hybrid analogues of caffeine and eudistomin D and its affinity for adenosine receptors.

Four bis-N-n-propyl analogues (3-6) in the uracil ring of two hybrid molecules (1 and 2) of caffeine and eudistomin D, a beta-carboline alkaloid from a marine tunicate, were synthesized, and their affinity and selectivity for adenosine receptors A(1), A(2A), and A(3) were examined. All the compounds (3-6) showed better potency as adenosine receptor ligands than caffeine. Bis-N-n-propylation (3 and 4, respectively) of the uracil ring in 1 and 2 resulted in higher affinity for A(1) and A(2A) adenosine receptors. Furthermore, it was found that a compound (5) possessing a n-propyloxy group at C-7 in compound 3 with a nitrogen at the beta-position of the pyridine ring (beta-N type) enhanced remarkably affinity for adenosine receptor A(3) subtype, while n-propyloxy substitution (compound 6) at C-5 in compound 4 with a nitrogen at the delta-position of the pyridine ring (delta-N type) reduced affinity for all the adenosine receptor, A(1), A(2A), and A(3). Among all the compounds (1-6) examined, compound 5 showed the most potent affinity for adenosine receptor A(3) subtype (K(i) value, 0.00382 microM).

Phase I and pharmacokinetic study of sorafenib, an oral multikinase inhibitor, in Japanese patients with advanced refractory solid tumors.

Sorafenib is a novel oral multikinase inhibitor that targets Raf serine/threonine and receptor tyrosine kinases, and inhibits tumor cell proliferation and angiogenesis. We have conducted a phase I study of sorafenib to determine the safety, tolerability, pharmacokinetics, and potential efficacy of this agent in 31 Japanese patients with advanced refractory solid tumors. Sorafenib (100-600 mg) was given as a single dose followed by a 7-day wash-out period, and then administrated twice daily (bid). The most frequent drug-related adverse events were rash/desquamation (61%), hand-foot skin reactions (39%), diarrhea (36%), and elevations of serum lipase (36%) and amylase (26%) levels. Dose-limiting toxicities (DLTs) were grade 3 diarrhea at 200 mg bid and grade 3 fatigue at 600 mg bid. Grade 3 and 4 pancreatic enzyme elevations were observed at 200-600 mg bid, but they were not deemed dose-limiting because they were asymptomatic and were not associated with pancreatitis or chronic damage to the pancreas. The AUC and C(max) of sorafenib increased linearly with dose up to 400 mg bid. Partial responses were observed in one of 10 patients with non-small cell lung cancer and one of three patients with renal cell carcinoma. In conclusion, sorafenib 400 mg bid was well tolerated in Japanese patients with advanced refractory solid tumors. The recommended dose for future clinical trials is 400 mg bid.

[Cord blood transplantation supported with ex vivo expanded fraction for a patient with myelodysplastic syndrome and metastatic breast cancer].

Despite the promising outcomes of unrelated cord blood transplantations (UCBT) in pediatric recipients, the major limitation in the widespread use of cord blood (CB) as a source of hematopoietic stem cells (HSC), particularly in adults, is the physiological small number of cells. To overcome this limitation, we developed an ex vivo expansion system for HSC, in which CB CD34+ cells are cultured on feeder cells (HESS-5 cells) in the presence of cytokines (TPO, SCF and Flt3 ligand). A phase I/II clinical trial, approved by our institutional review board, has been started to assess the safety and effectiveness of this system. A 52-year-old woman with metastatic breast cancer and myelodysplastic syndrome (MDS) received a non-myeloablative preparative regimen followed by UCBT. On day 0, 75% of the whole CB and a fraction of CD34 negative cells were transplanted. The remaining 25% of the CB was CD34-selected and expanded on HESS-5 in a non-serum media in the presence of TPO, SCF, and Flt3-L. On day 5, the ex vivo-expanded, CD34+ cells were transplanted. The patient received 1.83 x 10(7)/kg of total nucleated cells and 7.7 X 10(4)/kg of CD34+ cells (expanded and unexpanded). No acute adverse effects were observed after the infusion of the cultured cells. She suffered from pneumonia on day 37, a cerebral hemorrhage on day 48, and died on day 50. Further studies are required to assess the effectiveness of this protocol.

The Fifth Nagoya International Blood And Marrow Transplantation Symposium: unlimited possibilities of hematopoietic cell transplantation: lessons from the past and prospects for the future.

In this symposium, a new concept, alloreactive NK cells regulated by KIR, was discussed extensively. There is no doubt that KIR epitope compatibility has a critical impact on the transplantation outcome; however, it is too early to determine the significance of KIR genotyping over KIR epitope assumption based on HLA type. We need to wait for a large-scale analysis to be done before we know the answer. What became clear in this meeting is that big collaborations or multicenter studies are becoming more important as sources of ethnic background data, and many other factors are found to affect clinical outcomes, making center-to-center comparisons more difficult.

The BCR/ABL transgene causes abnormal NK cell differentiation and can be found in circulating NK cells of advanced phase chronic myelogenous leukemia patients.

NK cells from the blood of chronic myelogenous leukemia (CML) patients are progressively decreased in number as the disease progresses from chronic phase to blast crisis. We hypothesize that BCR/ABL may be directly responsible by interfering with NK cell differentiation. CD34(+)HLA-DR(+) cells from CML patients were studied for their capacity to differentiate into NK cells. The NK cell cloning frequency was significantly decreased from CML CD34(+)HLA-DR(+) cells compared with cells from normal donors, yet CD34(+)HLA-DR(+) cells gave rise to BCR/ABL(+) NK cells in some patients. This finding prompted us to further investigate circulating NK cells from the blood of CML patients. CD56(+)CD3(-) NK cells were sorted from CML patients and examined by fluorescence in situ hybridization (FISH). In contrast to chronic phase CML, significant numbers of NK cells from advanced phase CML patients were BCR/ABL(+), whereas T cells were always BCR/ABL(-) regardless of the disease stage. To test the effects of BCR/ABL as the sole genetic abnormality, BCR/ABL was transduced into umbilical cord blood CD34(+) cells, and NK development was studied. p210-enhanced green fluorescence protein-transduced cells gave rise to significantly decreased numbers of NK cells compared with enhanced green fluorescence protein transduction alone. In addition, the extrinsic addition of BCR/ABL-transduced autologous CD34(+) cells suppressed the NK cell differentiation of normal umbilical cord blood CD34(+)CD38(-) cells. This study provides the first evidence that BCR/ABL is responsible for the altered differentiation of NK cells and that the NK cell lineage can be involved with the malignant clone in advanced stage CML.