Biologically active polymer - targeting polymeric antitumor agents-

To synthesize targeting polymeric antitumor agents, poly[(2-acetoxy-3,4-dihydro-2H-pyran)-alt-(maleic anhydride)] as polymer backbone, chlorophyll derivatives(CpD) extracted from silkworm excreta as targeting moiety and 5-fluorouracil and 6-mercaptopurine as pharmacons were selected. The polymer exhibited an antitumor activity comparable to that of cyclophosphamide in vivo. CpD as well as CpD-polymer conjugate were localized on tumor cells in vitro and delivered to tumor tissues in vivo specifically. The targeting polymeric antitumor agents were synthesized by coupling pharmacons and CpD on the polymer chain with the aid of reactions between functionalities of the reactants and anhydride groups on the polymer backbone. Various tests of their biological activities in vivo are in progress.     

An aptamer agonist of the insulin receptor acts as a positive or negative allosteric modulator,depending on its concentration

Aptamers are widely used as binders that interact with targets with high affinity or as inhibitors of the function of target molecules. However, they have also been used to modulate target protein function, which they achieve by activating the target or stabilizing its conformation. Here, we report a unique aptamer modulator of the insulin receptor (IR), IR-A62. Alone, IR-A62 acts as a biased agonist that preferentially induces Y1150 monophosphorylation of IR. However, when administered alongside insulin, IR-A62 shows variable binding cooperativity depending on the ligand concentration. At low concentrations, IR-A62 acts as a positive allosteric modulator (PAM) agonist that enhances insulin binding, but at high concentrations, it acts as a negative allosteric modulator (NAM) agonist that competes with insulin for IR. Moreover, the concentration of insulin affects the binding of IR-A62 to IR. Finally, the subcutaneous administration of IR-A62 to diabetic mice reduces blood glucose levels with a longer-lasting effect than insulin administration. These findings imply that aptamers can elicit various responses from receptors beyond those of a simple agonist or inhibitor. We expect further studies of IR-A62 to help reveal the mechanism of IR activation and greatly expand the range of therapeutic applications of aptamers.Subject terms: Cell signalling, DNA and RNA     

Clinical implications of proliferation activity in T1 or T2 male gastric cancer patients

Proliferation activity has already been established as a prognostic marker or as a marker for anticancer drug sensitivity. In gastric cancer, however, the prognostic significance of proliferation activity is still being debated. Several studies evaluating proliferation activity using Ki-67 have shown controversial results in terms of the relationship between proliferation activity and overall survival (OS) or drug sensitivity in gastric cancer patients. Because cytoskeleton-associated protein 2 (CKAP2) staining has recently been introduced as a marker of proliferation activity, we analyzed 437 gastric cancer tissues through CKAP2 immunohistochemistry, and we evaluated the chromatin CKAP2-positive cell count (CPCC) for proliferation activity. Although the CPCC did not show any significant correlation with OS in the male, female or total number of cases, it did show a significant correlation in the T1 or T2 male patient subgroup, according to log-rank tests (P=0.001) and univariate analysis (P=0.045). Additionally, multivariate analysis with the Cox proportional hazard regression model showed a significant correlation between the CPCC and OS (P=0.039) for the co-variables of age, gender, T stage, N stage, histology, tumor location, tumor size and adjuvant chemotherapy. In male gastric cancer cell lines, faster-growing cancer cells showed higher sensitivity to cisplatin than slow-growing cells. Thus our study indicates that CPCC-measured proliferation activity demonstrates a significantly worse prognosis in T1 or T2 male gastric cancer patients. The CPCC will help to more precisely classify gastric cancer patients and to select excellent candidates for adjuvant chemotherapy, which in turn will facilitate further clinical chemotherapeutic trials.     

Synthesis and characterization of multiblock sulfonated poly(arylene ether sulfone) membranes with different hydrophilic moieties for application in polymer electrolyte membrane fuel cell

Multiblock sulfonated poly(arylene ether sulfone)s were synthesized to investigate the structural effects on their membrane properties. Three different types of sulfonated hydrophilic blocks were used; their structures possessed different acidity and local concentration of sulfonic acid groups. For the comparison between the block copolymers, a hydrophobic block with the same chemical structure and block length was used. The different acidities and local concentration were achieved using different sulfonation methods, such as postsulfonation and direct condensation with sulfonated monomers, and different monomers for preparing the hydrophilic block. The higher acidity and concentration of sulfonic acid groups resulted in higher proton conductivity under certain relative humidity conditions and phase separation as shown in the transmission electron microscopy analysis. The synthesized oligomers and polymers were well characterized, and the other physical properties were also investigated. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 2947–2957     

Distinct genomic profiles of gestational choriocarcinoma,a unique cancer of pregnant tissues

Little is known about genomic alterations of gestational choriocarcinoma (GC), unique cancer that originates in pregnant tissues, and the progression mechanisms from the nonmalignant complete hydatidiform mole (CHM) to GC. Whole-exome sequencing (20 GCs) and/or single-nucleotide polymorphism microarray (29 GCs) were performed. We analyzed copy-neutral loss-of-heterozygosity (CN-LOH) in 29 GCs that exhibited androgenetic CN-LOHs (20 monospermic, 8 dispermic) and no CN-LOH (one with NLRP7 mutation). Most GCs (25/29) harboring recurrent copy number alterations (CNAs) and gains on 1q21.1-q44 were significantly associated with poor prognosis. We detected five driver mutations in the GCs, most of which were chromatin remodeling gene (ARID1A, SMARCD1, and EP300) mutations but not in common cancer genes such as TP53 and KRAS. One patient’s serial CHM/invasive mole/GC showed consistent CN-LOHs, but only the GC harbored CNAs, indicating that CN-LOH is an early pivotal event in HM-IM-GC development, and CNAs may be a late event that promotes CHM progression to GC. Our data indicate that GCs have unique profiles of CN-LOHs, mutations and CNAs that together differentiate GCs from non-GCs. Practically, CN-LOH and CNA profiles are useful for the molecular diagnosis of GC and the selection of GC patients with poor prognosis for more intensive treatments, respectively.Subject terms: Cancer genomics, Endometrial cancer     

Politics,strong institution and competitive advantage: an examination of organizational aspiration for competition

This study seeks to elucidate the interplay of interfirm rivalry and aspiration formation. Organizational aspiration serves as a categorical judgment over a desirable level of organizational performance. While aspiration as a driver of collective decision-making inside the firm is well recognized, our understanding is still limited as to the competitive consequence of aspiration-induced actions. From a computational model of aspiration-induced R&D, where competition is biased towards the status quo, this study suggests that although radical innovation calls for flexibility and diversity inside the firm, aspiration-induced action favors consensus such as a firm with machine bureaucracy either (1) in a market where a majority of consumers are unable to discern a small quality improvement, i.e., demand difficult to satisfy or (2) in a market where competitive advantage dissipates quickly, i.e., an unstable environment. In particular, this study shows that: (1) the level of organizational aspiration has little to do with the sustainability of competitive advantage; (2) aspiration strength—i.e., the extent of consensus among decision makers of the firm as to a legitimate level of organizational aspiration—interacts with the change in competitive advantage. The leading firm is likely to lose its competitive advantage when a follower has a stronger aspiration than the leader in a market whose demand is difficult to satisfy; and (3) the effect of aspiration strength on the sustainability of competitive advantage increases whenever organizational assets depreciate over time.