Search

Supplementary Figure 1 from Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance

Supplementary Legends 1-2 from Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance

Supplementary Figure 2 from Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance

Camptothecin (CPT) derivatives are effective anticancer drugs, especially against solid tumors. As CPTs are chemically unstable and have clinical limitations, we have synthesized indenoisoquinolines as novel topoisomerase I (Top1) inhibitors. We presently report two indenoisoquinoline derivatives, NSC 725776 and NSC 724998, which have been selected for therapeutic development. Both are potent Top1 inhibitors and induce Top1 cleavage at unique genomic positions compared with CPT. Consistent with Top1 poisoning, protein-linked DNA breaks were detected in cells treated with NSC 725776 and NSC 724998 at nanomolar concentrations. Those drug-induced protein-linked DNA breaks persisted longer after drug removal than those produced by CPT. Studies in human cells in culture show that NSC 725776 and NSC 724998 exert antiproliferative activity at submicromolar concentrations. Furthermore, NSC 725776 and NSC 724998 show cross-resistance in cells deficient or silenced for Top1, which is consistent with their selective Top1 targeting. Similar to other known Top1 inhibitors, NSC 725776–treated and NSC 724998–treated cells show an arrest of cell cycle progression in both S and G2-M and a dependence on functional p53 for their cytotoxicity. Dose-dependent γ-H2AX foci formation was readily observed in cells treated with NSC 725776 and NSC 724998. These γ-H2AX foci were detectable at pharmacologically relevant doses for up to 24 h and thus could be used as biomarkers for clinical trials (phase 0). [Cancer Res 2007;67(21):10397–405]

Applying a $0.25 \ \mu\text{m GaN}$ HEMT MMIC technology and a class-F harmonic tune technique, a design of a small-sized high-efficiency 2 W X-band MMIC power amplifier is presented. The fabricated MMIC power amplifier exhibits the output power of 32.7-33.3 dBm and the PAE of 41–45 % at $\text{Vds}= 30\ \mathbf{V}$ · under pulse operation of duty of 10% in the frequency range of 8.8-9.8 GHz, which are in good agreement with simulated results.

We have developed a miniaturized high efficiency X-band power amplifier MMIC with $\pmb{0.25} \ \pmb{\mu}\ \mathbf{m} \ \mathbf{AlGaN}\mathbf{/GaN}$ HEMT on SiC technology. Class-F two-stage MMICs are designed and fabricated, and the chip size is $\pmb{3.0} \ \mathbf{mm} \ \mathbf{x}\ \pmb{3.3}\ \mathbf{mm.}$ The MMICs had an output power of 45.1 dBm (32.4W), a power added efficiency of 53.4% and an associated gain of 15.1 dB with a drain voltage of 36 V at 9.3GHz.

In APMC2014, many excellent papers were submitted from Japanese microwave industries. Among them, 7 papers are invited from Japanese major microwave related companies, namely Mitsubishi Electric Corp., NTT Docomo, Murata Manufacturing Co., Hitachi Ltd, Toshiba Corp., Fujitsu limited and NEC Corp. They are all cutting-edge researches or most recent deployments of microwave technologies in Japan. In this paper, points of the 7 papers are introduced.

We report the first patient to develop ALL with a fusion gene of the erythropoietin receptor (EPOR) with immunoglobulin heavy chain (IgH) 22 years after a diagnosis of secondary erythrocytosis with unknown etiology. The IgH-EPOR rearrangement is known to induce increased expression of EPOR, and activates EPO-associated signal pathways by exogenous EPO stimulation, resulting in the increased proliferation and survival of IgH-EPOR-positive leukemic cells. Interestingly, this case may provide supporting the possibility that IgH-EPOR-positive ALL has a growth advantage under sustained high concentrations of EPO.

The primary objective of the present study was to correlate blood cell counts (lymphocyte, monocyte and platelet counts) with early disease relapse following the attainment of complete remission (CR) by the rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP)-like regimen in patients with advanced diffuse large B-cell lymphoma (DLBCL). In total, 30 patients were evaluated, with a median follow-up period of 43 months. All the participating patients attained CR. In total, eight patients experienced relapse within two years of the diagnosis, and the three-year overall survival rate was recorded as 77%. The peripheral counts for lymphocytes, monocytes and platelets, and the lymphocyte-monocyte ratio, all of which have been reported to be prognostic in DLBCL, were assessed. None of these parameters were correlated with the incidence of early relapse or with the prognosis. The lymphocyte count was higher in the patients with durable remission than in those who relapsed, however, no significant differences were identified. Thus, the present study concluded that early disease relapse was not predicted by peripheral blood cell counts in advanced DLBCL that reached CR using the R-CHOP-like regimen.

Background: Hyperuricemia cases (HU) can be classified into four subgroups by combining the two main causes of hyperuricemia, i.e. urate underexcretion and overproduction. These subgroups are as follows: underexcretion-type cases (UE); overproduction-type cases (OP); combined-type cases, and normal-type cases. Since urinary urate excretion (Uua) and urate clearance differ significantly between UE and OP, urate transport in the nephrons and the intratubular urate contents might also differ. Such differences might help clarify the pathophysiology of urate underexcretion in subgroups of hyperuricemia, and thus reveal its underlying mechanisms. Methods: Urate transport coefficients in each subtype of HU were determined employing the previously reported benzbromarone-loading urate clearance tests. The subtype cases of HU were plotted on a graph of urate transport coefficients versus Uua as coordinates. The characteristic features in the distribution of subtype cases on graphs were analyzed in relation to Uua. Results: The mean (±standard error) tubular secretion rate (TSR) in the UE (48.7 ± 1.7 ml/min) was significantly lower and the postsecretory urate reabsorption rate (R2) in the UE (0.904 ± 0.004) was significantly higher than those in the normal controls (78.0 ± 2.1 ml/min and 0.877 ± 0.003) or the OP (61.1 ± 3.2 ml/min and 0.861 ± 0.009). Decrements of TSR and increments of R2 in the UE were largest in the subtypes of the HU, in terms of case numbers and the deviation rate of the group. Conversely, decrements of TSR and increments of R2 were smallest in the OP. A significant correlation was identified between TSR and Uua (r = 0.345, p < 0.0001), and a significant negative correlation was also found between R2 and Uua (r = -0.393, p < 0.0001). Conclusion: In the UE, hyperuricemia is induced mainly by urate underexcretion, which results from the combination of two main causes in urate transporters of the nephron: significantly lower TSR and significantly higher R2. Neither of these was observed in OP. Differences in urate transporters in subtypes of the HU might be important not only for understanding the pathophysiology and mechanisms of urate underexcretion and hyperuricemia, but also for providing a strategic therapy for hyperuricemia.

Summary Objectives The rapid diagnosis of bacteremia is crucial for patient management including the choice of antimicrobial therapy, especially in cases of hematological disease, because neutropenia occurs frequently during antineoplastic chemotherapy or disease progression. We describe a rapid detection and identification system that uses universal PCR primers to amplify a variable region of bacterial 16S ribosomal DNA (rDNA), followed by DNA microarray hybridization. Methods Probes for 72 microorganisms including most causal clinical pathogens were spotted onto a microarray plate. The DNA microarray and conventional methods of identification were applied to 335 cultures from patients with hematological diseases. Results Forty-one samples (12.2%) tested positive by conventional blood culture test in a few days, while 40 cases (11.9%) were identified by the new method within 24h. The sensitivity and specificity of this new method were 93% and 99%, respectively, compared with conventional blood culture testing. Conclusions PCR combined with a DNA microarray is useful for the management of febrile patients with hematological diseases.

Although glucocorticoids are effective for patients with IgG4-related disease, the treatment has not yet been standardized. Therefore, the treatment strategy should be established.Patients who fulfilled the comprehensive diagnostic criteria for definite IgG4-related disease were started on prednisolone (0.6 mg/kg body weight) with the dose reduced every two weeks. The subsequent maintenance dose and need for prednisolone were determined for individual patients. The primary endpoint was the complete remission (CR) rate at one year. Secondary endpoints included overall response rate (ORR), the maintenance dose, the relapse rate, and adverse events.This study enrolled 61 patients. After clinicopathological review, three patients were excluded, and one, 13, and 44 patients were diagnosed with probable, possible, and definite IgG4-related disease, respectively. Of the 44 patients with definite IgG4-RD, 29 (65.9%) achieved CR, and the ORR was 93.2%. No patient was refractory to primary treatment. The most frequent adverse events were glucose intolerance. Six patients relapsed.Glucocorticoid treatment is usually effective for patients with IgG4-RD, and we should examine the possibility of other disorders when a patient is glucocorticoid refractory. Some patients are misdiagnosed, making central clinicopathological review of diagnosis very important in conducting clinical studies.

Gemtuzumab ozogamicin (GO) consists of the CD33 antibody linked to calicheamicin. The binding of GO to the CD33 antigen on leukemic cells results in internalization followed by the release of calicheamicin, thereby inducing DNA strand breaks. We hypothesized that the induction of DNA strand breaks would be a surrogate marker of GO cytotoxcity. Here, two GO‐resistant variants (HL/GO‐CSA [225‐fold], HL/GO [200‐fold]) were established by serially incubating human leukemia HL‐60 cells with GO with or without a P‐glycoprotein (P‐gp) inhibitor, cyclosporine A, respectively. The CD33 positivity was reduced in both variants. The HL/GO‐CSA cells showed an increased multidrug resistance protein‐1 (MRP1) transcript, and an MRP1 inhibitor partially reversed GO resistance. The HL/GO cells had neither P‐gp nor MRP1 overexpression. Microarray analysis and Western blotting indicated elevated levels of DNA repair‐associated proteins in both variants. Two other leukemic subclones, showing either P‐gp or MRP1 overexpression, were also GO‐resistant. Using single cell gel electrophoresis analysis, it was determined that GO‐induced DNA strand breaks increased dose‐dependently in HL‐60 cells, whereas the number of breaks was reduced in the GO‐resistant cell lines. The induction of DNA strand breaks was correlated with GO sensitivity among these cell lines. The CD33 positivity and the expression levels of transporters were not proportional to drug sensitivity. Using primary leukemic cells, the induction of DNA strand breaks appeared to be associated with GO sensitivity. Thus, GO‐induced DNA strand breaks as the final output of the mechanism of action would be critical to predict GO cytotoxicity.

Slight etching of an AlGaN layer at ohmic contact was investigated to reduce contact resistance in AlGaN/GaN HEMTs in Ka-band operation. In the etching process, etched depth was precisely controlled by ICP-RIE system with a mixture of BCl3 and Cl2 gases. The relation between ohmic contact resistance and etched depth was examined to determine the optimum depth. It was found that a resistance at an etched depth of 5 nm was reduced to 44% of that in the case of the conventional process. This process was applied to fabrication of GaN HEMTs with a gate length of 0.2 μm, and Ka-band power characteristics were measured. The linear gain of the device was 11.4 dB, the maximum power-added efficiency was 45%, and the output power density was 5.1 W/mm, under the conditions of a frequency of 31 GHz, a drain bias of 24 V, and a class-AB operation. The values are higher than those in the case of the conventional process by 0.5 dB for the linear gain, 2 points for the power-added efficiency, and 11% for the output power. (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Overcoming drug resistance remains a major obstacle to curing relapsed or refractory lymphoma and obtaining a beneficial long-term prognosis for patients, despite the introduction of several salvage regimens to date. Our ultimate purpose is to establish a standard second-line salvage chemotherapy regimen for curing relapsed/refractory lymphoma. In this basic pre-clinical study, we evaluated a combination regimen consisting of 9-β-D: -arabinofuranosyl-2-fluoroadenine (F-araA) and carboplatin that targeted nucleotide excision repair (NER) of DNA in five representative leukemia lineages in vitro. Isobologram analysis demonstrated that simultaneous exposure to these two drugs produced synergistic interactions in U937 and K562 cells, in which lines showed enhanced NER activity by the measurement of UV or drug-induced DNA strand break (comet assay), or quantitation of ERCC1 mRNA (RT-PCR), a key enzyme for NER. Histone γH2AX formation was synergistically induced, but no such formation was observed after exposure to either agent alone in K562 cells. In summary, we synergistically inhibited the NER activity of leukemia cells by treating them with a combination of F-araA and carboplatin, suggesting that this combinatory regimen could be used as a novel salvage therapy for refractory or drug-resistant lymphoma.

Cytarabine (ara-C) is the key agent for treating acute myeloid leukemia (AML). After being transported into leukemic cells by human equilibrative nucleoside transporter 1 (hENT1), ara-C is phosphorylated to ara-C triphosphate (ara-CTP), an active metabolite, and then incorporated into DNA, thereby inhibiting DNA synthesis. Deoxycytidine kinase (dCK) and cytosolic 5'-nucleotidase II (cN-II) are associated with the production of ara-CTP. Because ara-C's cytotoxicity depends on ara-CTP production, parameters that are most related to ara-CTP formation would predict ara-C sensitivity and the clinical outcome of ara-C therapy. The present study focused on finding any correlation between the capacity to produce ara-CTP and ara-C-metabolizing factors. In vitro ara-CTP production, mRNA levels of hENT1, dCK, and cN-II, and ara-C sensitivity were evaluated in 34 blast samples from 33 leukemic patients including 26 with AML. A large degree of heterogeneity was seen in the capacity to produce ara-CTP and in mRNA levels of hENT1, dCK, and cN-II. Despite the lack of any association between each of the transcript levels and ara-CTP production, the ratio of dCK/cN-II transcript levels correlated significantly with the amount of ara-CTP among AML samples. The HL-60 cultured leukemia cell line and its three ara-C-resistant variants (HL-60/R1, HL-60/R2, HL-60/R3), which were 8-, 10-, and 500-fold more resistant than HL-60, respectively, were evaluated similarly. The dCK/cN-II ratio was again proportional to ara-CTP production and to ara-C sensitivity. The dCK/cN-II ratio may thus predict the capacity for ara-CTP production and ultimately, ara-C sensitivity in AML.

Purpose: Ecteinascidin 743 (Et743; trabectedin, Yondelis) has recently been approved in Europe for the treatment of soft tissue sarcomas and is undergoing clinical trials for other solid tumors. Et743 selectively targets cells proficient for TC-NER, which sets it apart from other DNA alkylating agents. In the present study, we examined the effects of Et743 on RNA Pol II. Experimental Design and Results: We report that Et743 induces the rapid and massive degradation of transcribing Pol II in various cancer cell lines and normal fibroblasts. Pol II degradation was abrogated by the proteasome inhibitor MG132 and was dependent on TC-NER. Cockayne syndrome (CS) cells and xeroderma pigmentosum (XP) cells (XPD, XPA, XPG, and XPF) were defective in Pol II degradation, whereas XPC cells whose defect is limited to global genome NER in nontranscribing regions were proficient for Pol II degradation. Complementation of the CSB and XPD cells restored Pol II degradation. We also show that cells defective for the VHL complex were defective in Pol II degradation and that complementation of those cells restores Pol II degradation. Moreover, VHL deficiency rendered cells resistant to Et743-induced cell death, a similar effect to that of TC-NER deficiency. Conclusion: These results suggest that both TC-NER–induced and VHL-mediated Pol II degradation play a role in cell killing by Et743.

Thymic epithelial cells can produce many kinds of cytokines, and interleukin (IL)-6-producing thymic carcinoma cases have been reported. However, a cytokine-producing human thymic tumor cell line has not previously been established. In this paper, we report a novel, multiple inflammatory cytokine-productive cell line that was established from a patient with thymic carcinoma. This cell line, designated ThyL-6, positively expressed epithelial membrane antigen, cytokeratins, vimentin intermediate filament and CD5, although hematological markers were not present in the cells. Cytokine antibody array analysis showed that the cells secreted several cytokines including IL-1alpha, IL-6, IL-8, RANTES, soluble TNFalpha-receptor 1, VEGF and CTLA into the culture medium. The addition of ThyL-6-cultured supernatant supported the growth of human myeloma ILKM-3 cells, which require the presence of IL-6 in the culture medium for the maintenance of cell growth, suggesting that the secreted IL-6 from ThyL-6 cells was biologically active. Chromosome analysis demonstrated that ThyL-6 cells had complex karyotype anomalies, including der(16)t(1;16); the latter has been recognized in thymic squamous cell carcinoma and thymic sarcomatoid carcinoma cases, as well as in several other kinds of malignancies. Heterotransplantation of the cells into nude mice showed tumorigenesis with neutrophil infiltration and liquefactive necrosis. These findings suggest that ThyL-6 cells will provide us with a new experimental tool for investigating not only the pathogenesis, biological behavior, chromo-somal analysis and therapeutic reagents of human thymic carcinoma, but also for studying cytokine-chemokine network systems.

We report a case of toxic shock-like syndrome due to a rare infection of group G Streptococcus bacteremia in a patient with idiopathic thrombocytopenic purpura and its successful treatment with continuous venovenous hemofiltration (CVVH). As the result of sepsis treatment with CVVH, in addition to administration of vasopressors and antibiotics, serum levels of interleukin-1β, interleukin-10 and tumor necrosis factor-α fell and shock was controlled.

A Ka-band high power amplifier MMIC developed from 0.18μm gate-length AlGaN/GaN HEMT on SiC is presented. The MMIC chip was measured on-wafer across 29GHz to 31GHz under pulsed bias condition. At VDD=28V, the MMIC achieved an output power of 19W to 21W. To the authors’ best knowledge, this is the highest output power ever reported for GaN high power amplifier MMIC at Ka-band. The 2-stage amplifier GaN MMIC has 10dB linear gain and a die-size of 4.0mm x 5.5mm. The MMIC can realize high power Solid-State Power Amplifier (SSPA) for Ka-band. Keywords—Gallium Nitride, MMIC, power amplifiers, millimeter wave

Background. Urate underexcretion has been reported as the major cause of hyperuricemia in gouty patients. The four-component theory of urate transport in nephrons has been a valuable hypothesis for studying the mechanism of the urate underexcretion, but accurate quantitative analysis of urate transport in nephrons at different sites has not yet been carried out. To determine the amount of urate transport in nephrons more accurately, we applied mathematical calculations to urate transport in nephrons based on the four-component theory. Methods. In 20 gouty patients and 14 normal controls, 60-min urine fractions and blood samples taken at the midpoint of the urine collection period were collected before and after pyradinamide or benzbromarone administration, and urate clearance (Cua) was determined. Urate excretion (Uua) was defined as {Ccr(1-R1) + Cs} Sua(1-R2), where Ccr is creatinine clearance, R1 is the presecretory reabsorption rate, Cs (ml/min) is the secretion rate, Sua is serum urate level, and R2 is the postsecretory reabsorption rate. Results. In the gouty patients, urate glomerular filtration was significantly higher than in the normal controls, but approximately 96% of the filtered urate was reabsorbed. The urate secretion rate of gouty patients was markedly lower than that of the controls, but the amount of urate secretion was slightly and not significantly lower than that of the controls. Postsecretory reabsorption was proportional to intratubular urate concentration. Subsequent urinary excretion in gouty patients was significantly lower than that in the normal controls. Presecretory reabsorption, secretion, postsecretory reabsorption, and urinary excretion comprised 95.9%, 38.9% 38.6%, and 4.4% of urate glomerular filtration in gouty patients, and 96.2%, 52.2%, 49.6%, and 6.5% in normal controls, respectively. Conclusions. Urate secretion in the nephrons of gouty patients was significantly decreased compared with that in normal controls in terms of its rate and its proportion to urate glomerular filtration, which resulted in significant reduction of urinary urate excretion.

A numerical device model is proposed for the design of reliable AlGaN/GaN HEMT structures. In the model, shear stress due to the inverse piezoelectric effect is used to predict high-temperature DC stress test results. The calculated shear stress is compared with test results for various AlGaN/GaN HEMT structures. The comparison shows that structures passing the test have shear stress lower than 0.19 GPa under the test conditions. An AlGaN/GaN HEMT structure for the Ka band was designed so that stress would be lower than this value. The designed structure was fabricated and passed the test. These results indicate that the model can be used to design reliable AlGaN/GaN HEMT structures.

Uric acid in serum (S-UA) is produced by the breakdown of the cellular nucleic acids of leukemia cells, and may be a marker of disease aggressiveness. S-UA levels were examined for association with clinical outcomes in patients with acute myeloid leukemia (AML). Fifty-six patients with AML admitted to our Institution were evaluated retrospectively. The median S-UA level at diagnosis was 5.0 mg/dl (range 2-13.8 mg/dl). The S-UA levels did not correlate with peripheral lactate dehydrogenase, peripheral white blood cell counts, or peripheral blast counts, and were not proportional to bone marrow blast counts or marrow cellularity. The S-UA levels in the patients who achieved complete remission were slightly lower than those in those who did not. S-UA levels less than, or equal to the median (5.0 mg/dl) were significantly associated with better prognoses, compared with S-UA levels greater than 5.0 mg/dl. Thus, the S-UA level may predict the prognosis of AML, and is a versatile and cost-effective test for such a purpose.

The present retrospective study was conducted to measure Wilms' tumor-1 (WT1) mRNA levels in the peripheral blood of patients with acute myeloid leukemia (AML) in order to examine any association with the clinical outcomes.A total of 58 AML patients were evaluated retrospectively in our institution. WT1 transcripts were determined by real-time reverse transcriptase-polymerase chain reaction in peripheral blood samples.WT1 levels at diagnosis did not vary according to response of induction treatments, and the levels were comparable between the patients with durable remission and the patients with relapse of disease. WT1 levels at the completion of the treatment were higher in the group with relapse of disease than in the group with sustained remission. Detectable WT1 transcripts after the completion of chemotherapy courses were associated with poor prognoses.WT1 mRNA levels at treatment completion may predict for prognosis of AML.

Pancytopenia is caused by acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia (AA), or by non-hematological diseases. Because Wilms' tumor-1 (WT1) is overexpressed in patients with AML and MDS, its expression level may be helpful for diagnosing these hematological malignancies.We retrospectively investigated the WT1 transcripts in peripheral blood (PB) from 47 patients with decreased blood cell counts.The final diagnoses included AML, MDS, AA, drug poisoning, and non-hematological diseases. PB WT1 mRNA was overexpressed in AML and MDS, whereas the patients with other diseases mostly tested negatively for the transcript. The patients with MDS with higher marrow blast counts had higher PB WT1 mRNA levels. The sensitivity of the PB WT1 transcript in detecting AML and MDS was 78%, and the specificity was 90%.The WT1 mRNA level in PB may help diagnose AML and MDS in patients with pancytopenia.

Patients with acute myelogenous leukemia complicate with disseminated intravascular coagulation (DIC), not only at the time of the initially leukemia diagnosis, but also during induction chemotherapy. In Japan, recently, a recombinant human soluble thrombomodulin alpha (Recomodulin) has been introduced as a new type of anti-DIC agent for clinical use in patients with hematological cancer or infectious disease. We describe a 67-year-old female case in which 25,600 units of Recomodulin for 6 days were successfully administered for both initially complicating and therapy-induced DIC without any troubles of bleeding in an acute monoblastic leukemia (AML-M5a) patient with theMLL genetranslocation. Furthermore, the levels of DIC biomarkers recovered rapidly after the Recomodulin treatment. Our case suggests that DIC control using Recomodulin is one of the crucial support-therapies during remission induction chemotherapy in patients with acute leukemia of which type tends to complicate extramedullary or extranodal infiltration having potential to onset DIC.

Summary form only given, as follows. AlGaN/GaN High Electron Mobility Transistors (HEMTs) with pre-match circuit were developed for Ka-band. The developed device showed 138 GHz of fmax, which depended on the thickness of the AlGaN barrier layer and the gate length. The chip had a pre-match circuit to achieve an impedance matching at 31GHz. It had a 6.4 mm gate periphery on a metal carrier plate. The output power achieved 18.5 W with impedance matching circuits.

An efficiency of AlGaN/GaN High Electron Mobility Transistors(HEMTs) were improved for Ku band. The AlGaN/GaN HEMTs were developed with an achievable fmax of 138GHz, which depended on the thickness of the AlGaN barrier layer and the gate length. A 6.4mm gate periphery device was thereafter designed with matching circuits on an alumina substrate on a metal carrier plate. The output power achieved 20 W at 26GHz.

AlGaN/GaN High Electron Mobility Transistors(HEMTs) were developed for Ka-band. The developed device showed 138 GHz of fmax, which depended on the thickness of the AlGaN barrier layer and the gate length. It had a 6.4 mm gate periphery on a metal carrier plate. The output power achieved 20 W with impedance matching circuits.

A series of sodium selenocarboxylates 2 were isolated from the reaction of diacyl selenides with sodium ethanolate and characterized. A convenient preparation of the sodium salts 2 by the direct reaction of acyl chlorides with sodium selenide was also established. The salts are colourless to slightly pale yellow crystals and labile towards moisture. They readily react with alkyl iodides at room temperature to give the corresponding Se-alkyl esters 3.

AlGaN/GaN High Electron Mobility Transistors (HEMTs) were improved for X-band and Ku-band applications. The power added efficiency (PAE) was achieved over 40% for X-band and over 30% for Ku-band. The developed devices combined two AlGaN/GaN HEMTs of 12 mm gate periphery and exhibited the output power of over 50W. An AlGaN/GaN HEMT with four dies of 12 mm gate periphery was developed and exhibited the output power of over 120W.

Gout is a type of inflammatory arthritis that is triggered by the crystallization of monosodium urate (MSU) within the joints and is often associated with hyperuricemia. Further understanding the physiology and dynamics of uric acid in human is required to make sure the disease mechanism of both gout and hyperuricemia in clinic. The amount of urate in the body consists urate pool, and which depends on the balance between dietary intake, synthesis, and excretion. Uric acid is a weak acid that exists largely as MSU, the ionized form, in urate pool at physiologic pH. But the solubility of MSU is influenced of pH, temperature and protein of blood and tissue.

More than 250 W of peak output power (pulse width 64 mus, duty cycle 7%) is achieved with newly developed X-band solid-state power amplifier. The final stage of the SSPA consists of four 80 W class GaN power HEMTs and a low loss 4-way combiner. Compared with the conventional klystron tubes, our newly developed SSPAs are smaller, more reliable and require less amounts of occupied frequency bandwidth.

A series of sodium selenocarboxylates 2 were isolated from the reaction of diacyl selenides with sodium ethanolate and characterized. A convenient preparation of the sodium salts 2 by the direct reaction of acyl chlorides with sodium selenide was also established. The salts are colourless to slightly pale yellow crystals and labile towards moisture. They readily react with alkyl iodides at room temperature to give the corresponding Se-alkyl esters 3.

Camptothecin (CPT) analogues are powerful anticancer agents but are chemically unstable due to their α-hydroxylactone six-membered E-ring structure, which is essential for trapping topoisomerase I (Top1)-DNA cleavage complexes. To stabilize the E-ring, CPT keto analogues with a five-membered E-ring lacking the oxygen of the lactone ring (S38809 and S39625) have been synthesized. S39625 has been selected for advanced preclinical development based on its promising activity in tumor models. Here, we show that both keto analogues are active against purified Top1 and selective against Top1 in yeast and human cancer cells. The keto analogues show improved cytotoxicity toward colon, breast, and prostate cancer cells and leukemia cells compared with CPT. The drug-induced Top1-DNA cleavage complexes induced by the keto analogues show remarkable persistence both with purified Top1 and in cells following 1-h drug treatments. Moreover, we find that S39625 is not a substrate for either the ABCB1 (multidrug resistance-1/P-glycoprotein) or ABCG2 (mitoxantrone resistance/breast cancer resistance protein) drug efflux transporters, which sets S39625 apart from the clinically used CPT analogues topotecan or SN-38 (active metabolite of irinotecan). Finally, we show that nanomolar concentrations of S38809 or S39625 induce intense and persistent histone γ-H2AX. The chemical stability of the keto analogues and the ability of S39625 to produce high levels of persistent Top1-DNA cleavage complex and its potent antiproliferative activity against human cancer cell lines make S39625 a promising new anticancer drug candidate. Histone γ-H2AX could be used as a biomarker for the upcoming clinical trials of S39625. [Mol Cancer Ther 2007;6(12):3229–38]

Camptothecin (CPT) derivatives are effective anticancer drugs, especially against solid tumors. As CPTs are chemically unstable and have clinical limitations, we have synthesized indenoisoquinolines as novel topoisomerase I (Top1) inhibitors. We presently report two indenoisoquinoline derivatives, NSC 725776 and NSC 724998, which have been selected for therapeutic development. Both are potent Top1 inhibitors and induce Top1 cleavage at unique genomic positions compared with CPT. Consistent with Top1 poisoning, protein-linked DNA breaks were detected in cells treated with NSC 725776 and NSC 724998 at nanomolar concentrations. Those drug-induced protein-linked DNA breaks persisted longer after drug removal than those produced by CPT. Studies in human cells in culture show that NSC 725776 and NSC 724998 exert antiproliferative activity at submicromolar concentrations. Furthermore, NSC 725776 and NSC 724998 show cross-resistance in cells deficient or silenced for Top1, which is consistent with their selective Top1 targeting. Similar to other known Top1 inhibitors, NSC 725776–treated and NSC 724998–treated cells show an arrest of cell cycle progression in both S and G2-M and a dependence on functional p53 for their cytotoxicity. Dose-dependent γ-H2AX foci formation was readily observed in cells treated with NSC 725776 and NSC 724998. These γ-H2AX foci were detectable at pharmacologically relevant doses for up to 24 h and thus could be used as biomarkers for clinical trials (phase 0). [Cancer Res 2007;67(21):10397–405]

Low-dose cytarabine (ara-C) has been used to treat older patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), but has resulted in complete remission for20% of cases. A pilot study of the efficacy of a combination chemotherapy using low-dose ara-C, melphalan (Mel), and mitoxantrone (Mit) was conducted.The treatment comprised ara-C (10 mg/m2) twice daily, melphalan (2 mg/body) every other day, and mitoxantrone (3 mg/m2) every 3 days. The treatment was discontinued if the nuclear cell count was15,000/microl with20% blast count in the bone marrow. The primary end-points were initial response and tolerability.The study comprised 9 patients with AML or high-risk MDS (median age, 75 years). Complete remission was achieved in 3 patients. All the patients displayed grade 4 neutropenia and thrombocytopenia. One patient died from sepsis.The present regimen was more effective and displayed similar safety, compared with low-dose ara-C alone.

AlGaN/GaN high electron mobility transistors (HEMTs) were developed for Ku-band applications. The operating voltage characteristics in CW operating conditions were investigated. The developed AlGaN/GaN HEMT with combined two dies of 12 mm gate periphery exhibits output power of over 30 W with a power added efficiency (PAE) of 12% under VDS = 30 V, CW operating condition at 14.25 GHz, and a gain compression level of 3 dB.

AlGaN/GaN High Electron Mobility Transistors (HEMTs) were developed for X-band applications. The operating voltage and temperature dependence of output power characteristics in CW operating conditions were investigated. The developed AlGaN/GaN HEMT with combined two dies of 11.52 mm gate periphery exhibits output power of over 81.3W with a power added efficiency (PAE) of 34% under VDS=30V, CW operating condition at 9.5GHz, and a gain compression level of 3dB.

Previous studies including ours have demonstrated that DNA repair is one of the important targets of fludarabine. The aim of this study is to clarify a mechanistic interaction of carboplatin and F-ara-A, from the perspective of F-ara-A-mediated inhibition of DNA repair initiated by carboplatin. Using human quiescent lymphocytes, we focused on DNA repair, since these cells provide a model of dormant cells. To evaluate the carboplatin-induced DNA incision and its repair, we used the alkaline comet assay. When lymphocytes were incubated with carboplatin, a dose-dependent increase in the tail-moment was observed. Then, tail-moment decreased in proportion to the incubation period in fresh media and recovered to the control level at 4 h. DNA rejoining was completely inhibited by F-ara-A at 10 microM through 0 to 6 h after washing out of these drugs and this F-ara-A-induced inhibition was concentration-dependent. Cellular damage after drug exposure was evaluated with the induction of apoptosis as well as cytotoxic effect. Exposure to carboplatin alone did not induce any apparent cellular damage in quiescent lymphocytes. In contrast, a more than additive induction of apoptosis as well as an enhancement of cytotoxic action was observed in cells treated with a combination of carboplatin and F-ara-A. In the CEM cell line, there was no enhancement of the cytotoxic action of these drugs, despite the clear demonstration of an inhibitory effect on DNA repair. These results indicate that chemotherapy with carboplatin opened a new target for F-ara-A by initiating DNA repair in quiescent cells.