Neonatal Lethality in Knockout Mice Expressing the Kinase-Dead Form of the Gefitinib Target GAK Is Caused by Pulmonary Dysfunction

Gefitinib (Iressa) is an inhibitor of the epidermal growth factor receptor (EGFR) that has shown promising activity in the treatment of patients with non-small cell lung cancer (NSCLC). However, adverse side effects of gefitinib treatment, such as respiratory dysfunction, have limited the therapeutic benefit of this targeting strategy. The present results show that this adverse effect can be attributed to the inhibition of the novel gefitinib target GAK (Cyclin G-associated kinase), which is as potently inhibited by the drug as the tyrosine kinase activity of EGFR. Knockout mice expressing the kinase-dead form of GAK (GAK-kd) died within 30 min after birth primarily due to respiratory dysfunction. Immunohistochemical analysis revealed that surfactant protein A (SP-A) was abundant within alveolar spaces in GAK-kd+/+ mice but not in GAK-kd-/- pups. E-cadherin and phosphorylated EGFR signals were also abnormal, suggesting the presence of flat alveolar cells with thin junctions. These results suggest that inhibition of GAK by gefitinib may cause pulmonary alveolar dysfunction, and the present study may help prevent side effects associated with gefitinib therapy in NSCLC patients

Conservation with moving meshes over orography

Adaptive meshes have the potential to improve the accuracy and efficiency of atmospheric modelling by increasing resolution where it is most needed. Mesh re-distribution, or r-adaptivity, adapts by moving the mesh without changing the connectivity. This avoids some of the challenges with h-adaptivity (adding and removing points): the solution does not need to be mapped between meshes, which can be expensive and introduces errors, and there are no load balancing problems on parallel computers. A long standing problem with both forms of adaptivity has been changes in volume of the domain as resolution changes at an uneven boundary. We propose a solution which achieves exact local conservation and maintains a uniform scalar field while the mesh changes volume as it moves over orography. This is achieved by introducing a volume correction parameter which tracks the cell volumes without using expensive conservative mapping. A finite volume solution of the advection equation over orography on moving meshes is described and results are presented demonstrating improved accuracy for cost using moving meshes. Exact local conservation and maintenance of uniform scalar fields is demonstrated and the correct mesh volume is preserved. We use optimal transport to generate meshes which are guaranteed not to tangle and are equidistributed with respect to a monitor function. This leads to a Monge-Ampère equation which is solved with a Newton solver. The superiority of the Newton solver over other techniques is demonstrated in the appendix. However the Newton solver is only efficient if it is applied to the left hand side of the Monge-Ampère equation with fixed point iterations for the right hand side

Antioxidant and antitumor promoting activities of the flavonoids from Hedychium thyrsiforme

Five flavonoids, including 3,7,4′-trimethoxy-5-hydroxyflavone (1), 3,4′-dimethoxy-5,7-dihydroxyflavone (2), 5,7,4′-trimethoxy-3-hydroxyflavone (3), 3,5,7,4′-tetramethoxyflavone (4), and 7,4′-dimethoxy-3,5-dihydroxyflavone (5), were isolated from the rhizome of Hedychium thyrsiforme and assayed for antioxidant and antitumor promoting activities. The antioxidant assays showed that 5,7,4′-trimethoxy-3-hydroxyflavone, 7,4′-dimethoxy-3,5-dihydroxyflavone and 3,4′-dimethoxy-5,7-dihydroxyflavone had strong activities. Only two compounds, 5,7,4′-trimethoxy-3-hychoxyflavone and 7,4′-dimethoxy-3,5-dihydroxyflavone, were found to be strong 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavengers with fifty percent inhibition concentration (IC50) values of 92 and 119 μM, respectively. Antitumor promoting assays indicated that all the flavonoids showed strong inhibition activity towards Epstein-Barr virus (EBV) activation in Raji cells

Screening of Zingiberaceae extracts for antimicrobial and antioxidant activities

Dichloromethane and methanol extracts of 13 Zingiberaceae species from the Alpinia, Costus and Zingiber genera were screened for antimicrobial and antioxidant activities. The antimicrobial activity of most of the extracts was antibacterial with only the methanol extract of Costus discolor showing very potent antifungal activity against only Aspergillus ochraceous (MID, 15.6 μg per disc). All the extracts showed strong antioxidant activity comparable with or higher that of α-tocopherol

Discrepancy between magnetic resonance imaging and cranial nerve neuropathies associated with the involvement of diffuse large B-cell lymphoma（DLBL）.

An 83-year-old female developed diffuse large B-cell lymphoma（DLBL） of the left nasal cavity. Complete remission was achieved after two courses of Rituximab and CHOP（R-CHOP） . During the fourth course of R-CHOP, sensory disturbance and palsy of the left face developed. Left trigeminal nerve swelling was observed in magnetic resonance imaging（MRI） followed by double vision in the left eye, and MRI revealed swelling of both trigeminal nerves but not of the abducens nerve. Although the swelling of the trigeminal nerves and the double vision subside after administration of prednisolone, the palsy of the left face persisted. Two months after the fourth course of R-CHOP, symptoms of the palsy of the left face progressed and palsy of the right face, double vision, and palsy of the left facialis nerve developed. Then,blepharoptosis of the right eye developed and palsy of the right oculomotorius nerve was observed. MRI showed the presence of trigeminal nerve and oculomotorius nerve swelling but no swelling of the other cranial nerves. Furthermore, skin eruption developed around the left eye.Cytology of this lesion revealed the invasion of lymphoma cells

Discovery of nucleotide polymorphisms in the Musa gene pool by Ecotilling

Musa (banana and plantain) is an important genus for the global export market and in local markets where it provides staple food for approximately 400 million people. Hybridization and polyploidization of several (sub)species, combined with vegetative propagation and human selection have produced a complex genetic history. We describe the application of the Ecotilling method for the discovery and characterization of nucleotide polymorphisms in diploid and polyploid accessions of Musa. We discovered over 800 novel alleles in 80 accessions. Sequencing and band evaluation shows Ecotilling to be a robust and accurate platform for the discovery of polymorphisms in homologous and homeologous gene targets. In the process of validating the method, we identified two single nucleotide polymorphisms that may be deleterious for the function of a gene putatively important for phototropism. Evaluation of heterozygous polymorphism and haplotype blocks revealed a high level of nucleotide diversity in Musa accessions. We further applied a strategy for the simultaneous discovery of heterozygous and homozygous polymorphisms in diploid accessions to rapidly evaluate nucleotide diversity in accessions of the same genome type. This strategy can be used to develop hypotheses for inheritance patterns of nucleotide polymorphisms within and between genome types. We conclude that Ecotilling is suitable for diversity studies in Musa, that it can be considered for functional genomics studies and as tool in selecting germplasm for traditional and mutation breeding approaches