An extended phase Ib study of epertinib, an orally active reversible dual EGFR/HER2 tyrosine kinase inhibitor, in patients with solid tumours.

BACKGROUND: Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity. PATIENTS AND METHODS: Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8. RESULTS: We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months. CONCLUSION: Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases. EUDRACT NUMBER: 2009-017817-31

Discovery of the rpl10 Gene in Diverse Plant Mitochondrial Genomes and Its Probable Replacement by the Nuclear Gene for Chloroplast RPL10 in Two Lineages of Angiosperms

Mitochondrial genomes of plants are much larger than those of mammals and often contain conserved open reading frames (ORFs) of unknown function. Here, we show that one of these conserved ORFs is actually the gene for ribosomal protein L10 (rpl10) in plant. No rpl10 gene has heretofore been reported in any mitochondrial genome other than the exceptionally gene-rich genome of the protist Reclinomonas americana. Conserved ORFs corresponding to rpl10 are present in a wide diversity of land plant and green algal mitochondrial genomes. The mitochondrial rpl10 genes are transcribed in all nine land plants examined, with five seed plant genes subject to RNA editing. In addition, mitochondrial-rpl10-like cDNAs were identified in EST libraries from numerous land plants. In three lineages of angiosperms, rpl10 is either lost from the mitochondrial genome or a pseudogene. In two of them (Brassicaceae and monocots), no nuclear copy of mitochondrial rpl10 is identifiably present, and instead a second copy of nuclear-encoded chloroplast rpl10 is present. Transient assays using green fluorescent protein indicate that this duplicate gene is dual targeted to mitochondria and chloroplasts. We infer that mitochondrial rpl10 has been functionally replaced by duplicated chloroplast counterparts in Brassicaceae and monocots

Transcriptional Analysis of Arabidopsis thaliana Response to Lima Bean Volatiles

Exposure of plants to herbivore-induced plant volatiles (HIPVs) alters their resistance to herbivores. However, the whole-genome transcriptional responses of treated plants remain unknown, and the signal pathways that produce HIPVs are also unclear.Time course patterns of the gene expression of Arabidopsis thaliana exposed to Lima bean volatiles were examined using Affymetrix ATH1 genome arrays. Results showed that A. thaliana received and responded to leafminer-induced volatiles from Lima beans through up-regulation of genes related to the ethylene (ET) and jasmonic acid pathways. Time course analysis revealed strong and partly qualitative differences in the responses between exposure at 24 and that at 48 h. Further experiments using either A. thaliana ET mutant ein2-1 or A. thaliana jasmonic acid mutant coi1-2 indicated that both pathways are involved in the volatile response process but that the ET pathway is indispensable for detecting volatiles. Moreover, transcriptional comparisons showed that plant responses to larval feeding do not merely magnify the volatile response process. Finally, (Z)-3-hexen-ol, ocimene, (3E)-4,8-dimethyl-1,3,7-nonatriene, and (3E,7E)-4,8,12-trimethyl-1,3,7,11-tridecatetraene triggered responses in A. thaliana similar to those induced by the entire suite of Lima bean volatiles after 24 and 48 h.This study shows that the transcriptional responses of plants to HIPVs become stronger as treatment time increases and that ET signals are critical during this process

Functional Synchronization of Biological Rhythms in a Tritrophic System

In a tritrophic system formed by a plant, an herbivore and a natural enemy, each component has its own biological rhythm. However, the rhythm correlations among the three levels and the underlying mechanisms in any tritrophic system are largely unknown. Here, we report that the rhythms exhibited bidirectional correlations in a model tritrophic system involving a lima bean, a pea leafminer and a parasitoid. From the bottom-up perspective, the rhythm was initiated from herbivore feeding, which triggered the rhythms of volatile emissions; then the rhythmic pattern of parasitoid activities was affected, and these rhythms were synchronized by a light switch signal. Increased volatile concentration can enhance the intensity of parasitoid locomotion and oviposition only under light. From the top-down perspective, naive and oviposition-experienced parasitoids were able to utilize the different volatile rhythm information from the damaged plant to locate host leafminers respectively. Our results indicated that the three interacting organisms in this system can achieve rhythmic functional synchronization under a natural light-dark photoperiod, but not under constant light or darkness. These findings provide new insight into the rhythm synchronization of three key players that contribute to the utilization of light and chemical signals, and our results may be used as potential approaches for manipulating natural enemies

Indole is an essential herbivore-induced volatile priming signal in maize

Herbivore-induced volatile organic compounds prime non-attacked plant tissues to respond more strongly to subsequent attacks. However, the key volatiles that trigger this primed state remain largely unidentified. In maize, the release of the aromatic compound indole is herbivore-specific and occurs earlier than other induced responses. We therefore hypothesized that indole may be involved in airborne priming. Using indole-deficient mutants and synthetic indole dispensers, we show that herbivore-induced indole enhances the induction of defensive volatiles in neighbouring maize plants in a species-specific manner. Furthermore, the release of indole is essential for priming of mono- and homoterpenes in systemic leaves of attacked plants. Indole exposure markedly increases the herbivore-induced production of the stress hormones jasmonate-isoleucine conjugate and abscisic acid, which represents a likely mechanism for indole-dependent priming. These results demonstrate that indole functions as a rapid and potent aerial priming agent that prepares systemic tissues and neighbouring plants for incoming attacks

Observation of variations in cosmic ray single count rates during thunderstorms and implications for large-scale electric field changes

We present the first observation by the Telescope Array Surface Detector (TASD) of the effect of thunderstorms on the development of cosmic ray single count rate intensity over a 700 km2 area. Observations of variations in the secondary low-energy cosmic ray counting rate, using the TASD, allow us to study the electric field inside thunderstorms, on a large scale, as it progresses on top of the 700 km2 detector, without dealing with the limitation of narrow exposure in time and space using balloons and aircraft detectors. In this work, variations in the cosmic ray intensity (single count rate) using the TASD, were studied and found to be on average at the ~(0.5-1)% and up to 2% level. These observations were found to be both in excess and in deficit. They were also found to be correlated with lightning in addition to thunderstorms. These variations lasted for tens of minutes; their footprint on the ground ranged from 6 km to 24 km in diameter and moved in the same direction as the thunderstorm. With the use of simple electric field models inside the cloud and between cloud to ground, the observed variations in the cosmic ray single count rate were recreated using CORSIKA simulations. Depending on the electric field model used and the direction of the electric field in that model, the electric field magnitude that reproduces the observed low-energy cosmic ray single count rate variations was found to be approximately between 0.2 GV-0.4 GV. This in turn allows us to get a reasonable insight on the electric field and its effect on cosmic ray air showers inside thunderstorms

A new phenotype of mitochondrial disease characterized by familial late-onset predominant axial myopathy and encephalopathy

Axial myopathy is a rare neuromuscular disease that is characterized by paraspinal muscle atrophy and abnormal posture, most notably camptocormia (also known as bent spine). The genetic cause of familial axial myopathy is unknown. Described here are the clinical features and cause of late-onset predominant axial myopathy and encephalopathy. A 73-year-old woman presented with a 10-year history of severe paraspinal muscle atrophy and cerebellar ataxia. Her 84-year-old sister also developed late-onset paraspinal muscle atrophy and generalized seizures with encephalopathy. Computed tomography showed severe atrophy and fatty degeneration of their paraspinal muscles. Their mother and maternal aunt also developed bent spines. The existence of many ragged-red fibers and cytochrome c oxidase-negative fibers in the biceps brachii muscle of the proband indicated a mitochondrial abnormality. No significant abnormalities were observed in the respiratory chain enzyme activities; however, the activities of complexes I and IV were relatively low compared with the activities of other complexes. Sequence analysis of the mitochondrial DNA from the muscle revealed a novel heteroplasmic mutation (m.602C>T) in the mitochondrial tRNAPhe gene. This familial case of late-onset predominant axial myopathy and encephalopathy may represent a new clinical phenotype of a mitochondrial disease

First High-Speed Video Camera Observations of a Lightning Flash Associated With a Downward Terrestrial Gamma-Ray Flash

In this paper, we present the first high-speed video observation of a cloud-to-ground lightning flash and its associated downward-directed Terrestrial Gamma-ray Flash (TGF). The optical emission of the event was observed by a high-speed video camera running at 40,000 frames per second in conjunction with the Telescope Array Surface Detector, Lightning Mapping Array, interferometer, electric-field fast antenna, and the National Lightning Detection Network. The cloud-to-ground flash associated with the observed TGF was formed by a fast downward leader followed by a very intense return stroke peak current of −154 kA. The TGF occurred while the downward leader was below cloud base, and even when it was halfway in its propagation to ground. The suite of gamma-ray and lightning instruments, timing resolution, and source proximity offer us detailed information and therefore a unique look at the TGF phenomena

Ginkgo biloba Responds to Herbivory by Activating Early Signaling and Direct Defenses

Background: Ginkgo biloba (Ginkgoaceae) is one of the most ancient living seed plants and is regarded as a living fossil. G. biloba has a broad spectrum of resistance or tolerance to many pathogens and herbivores because of the presence of toxic leaf compounds. Little is known about early and late events occurring in G. biloba upon herbivory. The aim of this study was to assess whether herbivory by the generalist Spodoptera littoralis was able to induce early signaling and direct defense in G. biloba by evaluating early and late responses. Methodology/Principal Findings: Early and late responses in mechanically wounded leaves and in leaves damaged by S. littoralis included plasma transmembrane potential (Vm) variations, time-course changes in both cytosolic calcium concentration ([Ca 2+]cyt) and H2O2 production, the regulation of genes correlated to terpenoid and flavonoid biosynthesis, the induction of direct defense compounds, and the release of volatile organic compounds (VOCs). The results show that G. biloba responded to hebivory with a significant Vm depolarization which was associated to significant increases in both [Ca 2+] cyt and H 2O 2. Several defense genes were regulated by herbivory, including those coding for ROS scavenging enzymes and the synthesis of terpenoids and flavonoids. Metabolomic analyses revealed the herbivore-induced production of several flavonoids and VOCs. Surprisingly, no significant induction by herbivory was found for two of the most characteristic G. biloba classes of bioactive compounds; ginkgolides and bilobalides

Pharmacokinetic characteristics and anticancer effects of 5-Fluorouracil loaded nanoparticles

<p>Abstract</p> <p>Background</p> <p>It is expected that prolonged circulation of anticancer drugs will increase their anticancer activity while decreasing their toxic side effects. The purpose of this study was to prepare 5-fluorouracil (5-FU) loaded block copolymers, with poly(γ-benzyl-L-glutamate) (PBLG) as the hydrophobic block and poly(ethylene glycol) (PEG) as the hydrophilic block, and then examine the 5-FU release characteristics, pharmacokinetics, and anticancer effects of this novel compound.</p> <p>Methods</p> <p>5-FU loaded PEG-PBLG (5-FU/PEG-PBLG) nanoparticles were prepared by dialysis and then scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to observe the shape and size of the nanoparticles, and ultraviolet spectrophotometry was used to evaluate the 5-FU in vitro release characteristics. The pharmacokinetic parameters of 5-FU/PEG-PBLG nanoparticles in rabbit plasma were determined by measuring the 5-FUby high-performance liquid chromatography (HPLC). To study in vivo effects, LoVo cells (human colon cancer cell line) or Tca8113 cells (human oral squamous cell carcinoma cell line) were implanted in BALB/c nude mice that were subsequently treated with 5-FU or 5-FU/PEG-PBLG nanospheres.</p> <p>Results</p> <p>5-FU/PEG-PBLG nanoparticles had a core-shell spherical structure with a diameter of 200 nm and a shell thickness of 30 nm. The drug loading capacity was 27.1% and the drug encapsulation was 61.5%. Compared with 5-FU, 5-FU/PEG-PBLG nanoparticles had a longer elimination half-life (t_1/2, 33.3 h vs. 5 min), lower peak concentration (C, 4563.5 μg/L vs. 17047.3 μg/L), and greater distribution volume (V_D, 0.114 L vs. 0.069 L). Compared with a blank control, LoVo cell xenografts and Tca8113 cell xenografts treated with 5-FU or 5-FU/PEG-PBLG nanoparticles grew slower and had prolonged tumor doubling times. 5-FU/PEG-PBLG nanoparticles showed greater inhibition of tumor growth than 5-FU (p < 0.01). In the PEG-PBLG nanoparticle control group, there was no tumor inhibition (p > 0.05).</p> <p>Conclusion</p> <p>In our model system, 5-FU/PEG-PBLG nanoparticles changed the pharmacokinetic behavior of 5-FU, thus increasing its anticancer activity. 5-Fluorouracil loaded nanoparticles have potential as a novel anticancer drug that may have useful clinical applications.</p