Paclitaxel (PTX) is one of the most effective anticancer agents. In clinical practice, however, high incidences of adverse reactions of the drug, for example, neurotoxicity, myelosuppression, and allergic reactions, have been reported. NK105, a micellar nanoparticle formulation, was developed to overcome these problems and to enhance the antitumour activity of PTX. Via the self-association process, PTX was incorporated into the inner core of the micelle system by physical entrapment through hydrophobic interactions between the drug and the well-designed block copolymers for PTX. NK105 was compared with free PTX with respect to their in vitro cytotoxicity, in vivo antitumour activity, pharmacokinetics, pharmacodynamics, and neurotoxicity. Consequently, the plasma area under the curve (AUC) values were approximately 90-fold higher for NK105 than for free PTX because the leakage of PTX from normal blood vessels was minimal and its capture by the reticuloendothelial system minimised. Thus, the tumour AUC value was 25-fold higher for NK105 than for free PTX. NK105 showed significantly potent antitumour activity on a human colorectal cancer cell line HT-29 xenograft as compared with PTX (Po0.001) because the enhanced accumulation of the drug in the tumour has occurred, probably followed by its effective and sustained release from micellar nanoparticles. Neurotoxicity was significantly weaker with NK105 than with free PTX. The neurotoxicity of PTX was attenuated by NK105, which was demonstrated by both histopathological (Po0.001) and physiological (Po0.05) methods for the first time. The present study suggests that NK105 warrants a clinical trial for patients with metastatic solid tumours.

No abstract

The low-mass X-ray binary 4U 0614+091 is a source of sporadic thermonuclear (type I) X-ray bursts. We find bursts with a wide variety of characteristics in serendipitous wide-field X-ray observations by the WATCH on EURECA, the ASM on RXTE, the WFCs on BeppoSAX, the FREGATE on HETE-2, the IBIS/ISGRI on INTEGRAL, and the BAT on Swift, as well as pointed observations with the PCA and HEXTE on RXTE. Most of the bursts are bright, i.e., they reach a peak flux of about 15 Crab, but a few are weak and only reach a peak flux below a Crab. One of the bursts shows a very strong photospheric radius-expansion phase. This allows us to evaluate the distance to the source, which we estimate to be 3.2 kpc. The burst durations vary generally from about 10 s to 5 min. However, after one of the intermediate-duration bursts, a faint tail is seen to at least about 2.4 h after the start of the burst. One very long burst was observed, which lasted for several hours. This superburst candidate was followed by a normal type-I burst only 19 days later. This is, to our knowledge, the shortest burst-quench time among the superbursters. The observation of a superburst in this system is difficult to reconcile if the system is accreting at about 1% of the Eddington limit. We describe the burst properties in relation to the persistent emission. No strong correlations are apparent, except that the intermediate-duration bursts occurred when 4U 0614+091's persistent emission was lowest and calm, and when bursts were infrequent (on average roughly one every month to 3 months). The average burst rate increased significantly after this period. The maximum average burst recurrence rate is about once every week to 2 weeks. The burst behaviour may be partly understood if there is at least an appreciable amount of helium present in the accreted material from the donor star. If the system is an ultra-compact X-ray binary with a CO white-dwarf donor, as has been suggested, this is unexpected. If the bursts are powered by helium, we find that the energy production per accumulated mass is about 2.5 times less than expected for pure helium matter.

The in-orbit performance and calibration of the Hard X-ray Detector (HXD) on board the X-ray astronomy satellite Suzaku are described. Its basic performances, including a wide energy bandpass of 10–600 keV, energy resolutions of $\sim 4 \,\mathrm{keV}$ (FWHM) at 40 keV and $\sim 11\%$ at 511 keV, and a high background rejection efficiency, have been confirmed by extensive in-orbit calibrations. The long-term gains of PIN-Si diodes have been stable within 1% for half a year, and those of scintillators have decreased by 5–20%. The residual non-X-ray background of the HXD is the lowest among past non-imaging hard X-ray instruments in energy ranges of 15–70 and 150–500 keV. We provide accurate calibrations of energy responses, angular responses, timing accuracy of the HXD, and relative normalizations to the X-ray CCD cameras using multiple observations of the Crab Nebula.

The intracellular signal transduction pathways that mediate the stimulatory effects of platelet-derived growth factor (PDGF)-BB and transforming growth factor (TGF)-beta on hyaluronan biosynthesis in human fibroblasts were investigated. The stimulatory effects of both PDGF-BB and TGF-beta 1 were dependent on protein kinase C (PKC), since the PKC inhibitor calphostin C inhibited the stimulation by the growth factors. Direct activation of PKC by phorbol 12-myristate 13-acetate (PMA) also stimulated hyaluronan production, and the combination of either PDGF-BB or TGF-beta 1 and PMA gave an increased effect. One possible mechanism for activation of PKC is via induction of phospholipase C (PLC) activity; U-17322, an inhibitor of PLC-gamma, was found to inhibit partially PDGF-BB-stimulated hyaluronan synthesis. PDGF-BB is known to activate PLC-gamma through tyrosine phosphorylation; however, a PDGF beta-receptor mutant unable to interact with and activate PLC-gamma was still able to mediate induction of hyaluronan biosynthesis, indicating that PDGF-mediated stimulation is not entirely dependent on PLC-gamma. The stimulations by PDGF-BB and TGF-beta 1 were partly dependent on protein synthesis, since parts of the effects were inhibited by cycloheximide; in contrast, the effects mediated by PMA were not. Our results indicate that PKC is involved in the transduction of the effects of growth factors on hyaluronan biosynthesis, and that the effects involve direct or indirect activation of existing hyaluronan synthetase molecules, as well as induction of new enzyme molecules.

We report the analysis of the first superburst from a transiently accreting neutron star system with the All-Sky Monitor (ASM) on the Rossi X-ray Timing Explorer. The superburst occurred 55 days after the onset of an accretion outburst in 4U 1608-522. During that time interval, the accretion rate was at least 7% of the Eddington limit. The peak flux of the superburst is 22 to 45% of the Eddington limit, and its radiation energy output is between 4 × 10 41 and 9 × 10 41 erg for a distance of 3.2 kpc. Fits of cooling models to the superburst light curve indicate an ignition column depth between 1.5 × 10 12 and 4.1 × 10 12 g cm −2 . Extrapolating the accretion history observed by the ASM, we derive that this column was accreted over a period of 26 to 72. The superburst characteristics are consistent with those seen in other superbursting low-mass X-ray binaries. However, the transient nature of the hosting binary presents significant challenges for superburst theory, requiring additional ingredients for the models. The carbon that fuels the superburst is thought to be produced mostly during the accretion outbursts and destroyed in the frequent type-I X-ray bursts. Mixing and sedimentation of the elements in the neutron star envelope may significantly influence the balance between the creation and destruction of carbon. Furthermore, predictions for the temperature of the neutron star crust fail to reach the values required for the ignition of carbon at the inferred column depth.

A total synthesis of NK109 (7-hydroxy-8-methoxy-5-methyl-2,3-methylenedioxybenzo[c]phenanthridinium hydrogensulfate dihydrate), an anticancer benzo[c]phenanthridine alkaloid, is reported. The primary structure of this compound was erroneously communicated in 1973 as fagaridine (from Fagara xanthoxyloides) which is the 8-hydroxy regioisomer. NK109 has not yet been isolated from a natural source and therefore can only be obtained by synthesis. To study a wide variety of analogues, we decided to use a synthetic route via substituted benzylamine 5, which was obtained from the appropriate benzaldehyde and naphthylamine units. The benzo[c]phenanthridine ring was constructed by radical cyclization with tri-n-octyltin hydride and 2,2‘-azobis(2-methylbutyronitrile), followed by oxidative aromatization with MnO2. The resulting benzo[c]phenanthridine 6 was successfully methylated with methyl 2-nitrobenzenesulfonate. After deprotection of the benzyl group and subsequent hydration, NK109 was obtained. All reactions were performed under normal conditions. Purification was achieved only by recrystallization to give an overall yield of 40%.

Purpose of the Study: We aimed to compare the short-term outcome of patients with acute low-tone sensorineural hearing loss (ALHL) treated with steroid alone, diuretics alone or combination treatment. Procedures: Between April 2000 and March 2009, we retrospectively reviewed the medical records of 156 patients with a diagnosis of ALHL. All patients were followed up until improvement or for 8 weeks from the initial examination. Patients were treated with steroid alone (n = 49), diuretics alone (n = 40), combination treatment (n = 46) or they received neither steroid nor diuretics (n = 21). Results: The steroid-diuretic combination therapy for ALHL showed significantly better results than the steroid or diuretic treatments alone (p < 0.05). There were no clinically significant differences in the outcome between the steroid- and diuretic-alone treatments. Conclusion and Message: The etiology of ALHL is described as both an endolymphatic hydrops and an autoimmunological mechanism so that, as expected, the steroid-diuretic combination therapy was more effective than the steroid or diuretic treatments alone.