Iridium complex, a phosphorescent light-emitting diode material, serves as a novel chemical probe for imaging hypoxic tumor tissues

Iridium complex, a promising organic light-emitting diode for next generation television displays, emits phosphorescence. Phosphorescence is quenched by oxygen. We used this oxygen-quenching feature for imaging tumor hypoxia. Red light-emitting iridium complex Ir(btp)~2~(acac) (BTP) presented hypoxia-dependent light emission in culture cell lines, whose intensity was in parallel with HIF-1[alpha] expression. BTP was further applied to imaging five tumors (four from human origin and one from mouse origin) transplanted in athymic mice. All tumors presented a bright BTP-emitting image even 5 min after the injection. The BTP-dependent tumor image peaked at 1 to 2 h after the injection, and was then cleared from tumors within 24 h. The minimal BTP image recognition size was 3 to 4 mm in diameter. Compared with ^18^F-FDG/PET images, BTP delineated a clearer image for a tumor profile. We suggest that iridium complex has a vast potential for imaging hypoxic lesions such as tumor tissues

Assessment of benthic disturbance associated with stingray foraging for ghost shrimp by aerial survey over an intertidal sandflat

One notable type of bioturbation in marine soft sediments involves the excavation of large pits and displacement of sediment associated with predator foraging for infaunal benthos. Batoids are among the most powerful excavators, yet their impact on sediment has been poorly studied. For expansive tidal flats, only relatively small proportions of the habitat can be sampled due to physical and logistical constraints. The knowledge of the dynamics of these habitats, including the spatial and temporal distribution of ray bioturbation, thus remains limited. We combined the use of aerial photogrammetry and in situ benthic sampling to quantify stingray feeding pits in Tomioka Bay, Amakusa, Japan. Specifically, we mapped newly-formed pits over an 11-ha section of an intertidal sandflat over two consecutive daytime low tides. Pit size and distribution patterns were assumed to scale with fish size and reflect size-specific feeding behaviors, respectively. In situ benthic surveys were conducted for sandflat-surface elevation and prey density (callianassid shrimp). The volume versus area relationship was established as a logistic function for pits of varying sizes by photographing and refilling them with sediment. This relationship was applied to the area of every pit detected by air to estimate volume, in which special attention was paid to ray ontogenetic change in space utilization patterns. In total, 18,103 new pits were formed per day, with a mean individual area of 1060cm2. The pits were divided into six groups (G1 to G6 in increasing areas), with abundances of G1, G2+G3, and G4-G6 being medium, high, and low, respectively. Statistical analyses using generalized linear models revealed a marked preference for the higher prey-density areas in G1 and the restriction of feeding grounds of G4-G6 to the lower shore, with G2+G3 being generalists for prey density and sandflat elevation. The lower degrees of overall bioturbation by G1 and G4-G6 were spatially structured for the eight sub-areas demarcated by prey density and sandflat elevation, while G2+G3 homogenized the state over the sandflat. The newly-formed pits[U+05F3] sub-areal mean numerical, excavated-areal, and displaced-sediment-volume densities per day were confined to small ranges: 0.14-0.17m-2, 132-223cm2m-2, and 551-879cm3m-2 (latter two including 119 shallow non-pit excavations). These bioturbation rates are positioned at relatively high levels compared with those by rays from other geographic regions. The present procedure is applicable to the assessment of disturbance by any surface-sediment excavators on tidal flats if their pit dimensions are discernible from the air

Ligand-triggered resistance to molecular targeted drugs in lung cancer: Roles of hepatocyte growth factor and epidermal growth factor receptor ligands

がん進展制御研究所Recent advances in molecular biology have led to the identification of new molecular targets, such as epidermal growth factor receptor (EGFR) mutations and echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene, in lung cancer. Dramatic response has been achieved with EGFR inhibitors (gefitinib and erlotinib) and an ALK inhibitor (crizotinib) in lung cancer expressing corresponding targets. However, cancer cells acquire resistance to these drugs and cause recurrence. Known major mechanisms for resistance to molecular targeted drugs include gatekeeper mutations in the target gene and activation of bypass survival signal via receptors other than the target receptors. The latter mechanism can involve receptor gene amplification and ligand-triggered receptor activation as well. For example, hepatocyte growth factor (HGF), the ligand of a tyrosine kinase receptor Met, activates Met and the downstream PI3K/Akt pathway and triggers resistance to EGFR inhibitors in EGFR mutant lung cancer cells. Moreover, EGFR ligands activate EGFR and downstream pathways and trigger resistance to crizotinib in EML4-ALK lung cancer cells. These observations indicate that signals from oncogenic drivers (EGFR signaling in EGFR -mutant lung cancer and ALK signaling in EML4-ALK lung cancer) and ligand-triggered bypass signals (HGF-Met and EGFR ligands-EGFR, respectively) must be simultaneously blocked to avoid the resistance. This review focuses specifically on receptor activation by ligand stimulation and discusses novel therapeutic strategies that are under development for overcoming resistance to molecular targeted drugs in lung cancer. © 2012 Japanese Cancer Association

Resminostat in EGFR-mutated lung cancer

Drug-tolerant cells are mediators of acquired resistance. BIM-intron2 deletion polymorphism (BIM-del) is one of the mechanisms underlying the resistance to epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI)-mediated apoptosis that induces drug tolerance. Here, we investigated whether resminostat, a histone deacetylase inhibitor, circumvents BIM-del-associated apoptosis resistance. The human EGFR-mutated non-small cell lung cancer (NSCLC) cell line PC-9 and its homozygous BIM-del-positive variant (PC-9 BIMi2-/-), established by editing with zinc finger nuclease, were used. In comparison with PC-9 cells, PC-9 BIMi2-/- cells were less sensitive to apoptosis mediated by EGFR-TKIs such as gefitinib and osimertinib. The combined use of resminostat and an EGFR-TKI preferentially induced the expression of the pro-apoptotic BIM transcript containing exon 4 rather than that containing exon 3, increased the level of pro-apoptotic BIM protein (BIMEL), and stimulated apoptosis in vitro. In a subcutaneous tumor model derived from PC-9 BIMi2-/- cells, gefitinib monotherapy decreased tumor size but retained residual lesions, indicative of the presence of tolerant cells in tumors. The combined use of resminostat and gefitinib increased BIMEL protein level and induced apoptosis, subsequently leading to the remarkable shrinkage of tumor. These findings suggest the potential of resminostat to circumvent tolerance to EGFR-TKIs associated with BIM deletion polymorphism

Leaf litter, a critical habitat for juvenile Japanese giant salamander, Andrias japonicus (Amphibia: Caudata)

東広島市椋梨川水系にはオオサンショウウオが生息している。2011 年から，生息状況や産卵，幼生の離散などの生態学的な調査が行われている。この過程で幼生が巣穴から離散した直後の隠れ家や餌となる水生昆虫の生息場所として流水中の落ち葉・落枝が重要な役割を担う可能性が示唆されている。本研究では流水中の落ち葉・落枝の詳細を明らかにするため，河畔林のフロラを調査するとともに，幼生が発見された場所の落ち葉との比較を行った。その結果，流水中の落ち葉・落枝として29種の維管束植物が同定できた。流水中の落ち葉・落枝の大半がコナラやスギなどの木本で，離散後の幼生や餌となる水生昆虫の生息場所として周辺の植生が強い影響を与える可能性が示唆された。Japanese giant salamanders Andrias japonicus inhabit the Mukunashi River around Higashi-Hiroshima City in Hiroshima Prefecture, southwestern Japan; researchers and local people have collaborated to investigate the species’ behavior, particularly its oviposition and the movement of larvae after leaving the nest. In this research we focused on leaf litter in the stream as habitat in which salamander larvae and the aquatic insects which are its critical food cohabit. We studied the flora of the riparian forest to identify the species of leaf litter in the stream among which salamander larvae were found. Leaf litter and branches belonging to 29 species of vascular plants were identified, and most leaves were from the deciduous oak Quercus serrata and the conifer Cryptomeria japonica. It is suggested that the surrounding flora has an important influence on the survival of Japanese giant salamander larvae that have left the nest

Identification of baseline gene expression signatures predicting therapeutic responses to three biologic agents in rheumatoid arthritis: a retrospective observational study

Ranked gene list by GSEA (TCZ analysis). (XLSX 984 kb

Frequent p53 Accumulation in the Chronically Sun-Exposed Epidermis and Clonal Expansion of p53 Mutant Cells in the Epidermis Adjacent to Basal Cell Carcinoma

p53 expression was studied immunohistochemically to identify a precursor lesion of basal cell carcinoma (BCC) in the epidermis adjacent to BCC. With two different anti-p53 antibodies of CM1 and DO7, p53 expression was frequently detected in the epidermis adjacent to BCCs arising on the face and in the normal epidermis with usual sun exposure. In the epidermis adjacent to BCC, stained cells were occasionally clustered in a small area, but no cluster was found in the normal epidermis with usual sun exposure. The expression was less frequent in the normal epidermis with rare sun exposure. Ten cases of normal skin with usual sun exposure, showing CM1 staining in the epidermis, were screened for p53 gene mutations with polymerase chain reaction-single- strand conformation polymorphism analysis using DNAs obtained from the epidermis. No mutation was detected in exons 2 to 10 of the p53 gene in these 10 cases. The epidermis flanking three BCCs that was stained with CM1, on the other hand, carried a missense mutation of C to G transversIon at a dipyrimidine site of codon 249. This alteration replaced arginine with threonine. The mutation of codon 249 was not detected in the three BCCs. Our results first suggest that ultraviolet light irradiating the skin in a daily life induces p53 accumulation in the epidermis and secondly that the frequent clonal expansion of p53 mutant cells occurs in the epidermis adjacent to BCCs. This clonal expansion of mutant p53 may provide a molecular basis for high risk of developing subsequent new skin cancers in patients with BCC