[Coordination of Community-Based Integrated Care and Cancer Treatment-In Order to Live Safe Local Life Naturally].

Cancer has been the leading cause of death among Japanese people continuously since 1981. With recent advances in cancer drug therapy and the increasing number of treatment options, it is not uncommon for patients in a state of physical decline who have been transferred to home care to request continuation of treatment. Under such circumstances, it is an important issue for local major hospitals and medical institutions, such as clinics, providing community medical care to be able to cooperate and support patients together. The Japanese government has proposed the Community-based Integrated Care System as a way to support the home care provided by the health care team so that patients can live safe local life naturally in their neighborhoods as long as they could. For example, in order to smoothly build a relationship of trust between patients/families and visiting physicians, the treating physicians and visiting physicians should collaborate with each other from the later stages of chemotherapy treatment. In this collaboration, it is necessary to have someone who can pick up the needs of patients and their families, bridge the gap between the team medical members involved in community medical care (doctors, visiting nurses, visiting pharmacists, care managers, etc)and the local major hospital, and play a coordinating role. As such, it is useful to utilize specialists who are skilled in assessment, care, and coordination of cancer patients, such as professional nurses and certified nurses.

Structure of macrophage migration inhibitory factor in complex with methotrexate.

Methotrexate (MTX) is an anticancer and anti-rheumatoid arthritis drug that is considered to block nucleotide synthesis and the cell cycle mainly by inhibiting the activity of dihydrofolate reductase (DHFR). Using affinity-matrix technology and X-ray analysis, the present study shows that MTX also interacts with macrophage migration inhibitory factor (MIF). Fragment molecular-orbital calculations quantified the interaction between MTX and MIF based on the structure of the complex and revealed the amino acids that are effective in the interaction of MTX and MIF. It should be possible to design new small-molecule compounds that have strong inhibitory activity towards both MIF and DHFR by structure-based drug discovery.

TEI-A00114: a new vitamin D3 analogue that inhibits neutrophil recruitment in an acute lung injury hamster model while showing reduced hypercalcemic activity.

While searching for vitamin D(3) analogues which inhibit neutrophil recruitment in the lung without elevating plasma calcium level, we found that (5Z,7E)-(1S,3R)-20(R)-[(5E)-(2S)-2-hydroxy-2-methyl-cyclopentanone-5-ylidene]methyl-9,10-secopregna-5,7,10(19)-triene-1,3-diol (TEI-A00114) had the best efficacy and calcemic action. TEI-A00114 has a vitamin D receptor affinity 2.5-fold weaker and a vitamin D binding protein affinity 330.9-fold weaker than those of 1α,25(OH)(2)D(3). The estimated effective doses for 40% inhibition (ED(40)) via peroral and intratracheal administration are 7.6 and 0.4 µg/kg, respectively. TEI-A00114 was also tested by inhaled administration, and its ED(40) was calculated as 0.2 µg/kg. The estimated 40% inhibitory concentration (IC(40)) of TEI-A00114 on interleukin (IL)-8 production induced by lipopolysaccharide and on IL-1ß in human whole blood cells in vitro were 9.8 × 10(-8) or 1.8 × 10(-9)M, respectively. These levels of TEI-A00114's activities are equal to those of 1α,25(OH)(2)D(3). On the other hand, the calcemic action of TEI-A00114, which was evaluated at day 14 after sequential peroral quaque die administration, was 89-fold weaker (molar ratio) than that of 1α,25(OH)(2)D(3). These results indicate that TEI-A00114 has a dissociated profile between inhibition of neutrophil recruitment in the lung and calcemic action, suggesting its suitability over 1α,25(OH)(2)D(3) as a candidate for the treatment of acute lung injury.

Development of affinity chromatography using a bioactive peptide as a ligand.

By repeatedly introducing hydrophilic polyethylene glycol (PEG) spacer (2) onto affinity resin bearing a bioactive peptide (1/2 secretory leukocyte protease inhibitor, 1/2SLPI) as a ligand, the adsorption of nonspecific binding proteins was effectively reduced and the purification efficacy of elastase, which is one of the target molecules for 1/2SLPI, from a protein mixture was improved. Moreover, using this resin, we also successfully detected L-plastin, as an endogenous target molecule for SLPI, from HL-60 cell lysate.

Reduction of nonspecific binding proteins to self-assembled monolayer on gold surface.

We developed a gold coated glass chip bearing a poly(ethyleneglycol) (PEG) type compound as hydrophilic spacer for surface plasmon resonance studies, which enabled adequate estimation of K(d) value between FK506 and FKBP12 not only using purified FKBP12 (K(d)=22 nM) but also using Escherichia coli lysate expressing FKBP12 (K(d)=15 nM). These results indicated effectiveness of the PEG spacer for reduction of nonspecific interactions. Chemical stability and simple surface-structure of the novel chip are also attractive.

Design and synthesis of novel hydrophilic spacers for the reduction of nonspecific binding proteins on affinity resins.

Tubulin and actin often bind nonspecifically to affinity chromatography resins, complicating research toward identifying the cellular targets. Reduction of nonspecific binding proteins is important for success in finding such targets. We herein disclose the design, synthesis, and effectiveness in reduction of nonspecific binding proteins, of novel hydrophilic spacers (2-5), which were introduced between matrices and a ligand. Among them, tartaric acid derivative (5) exhibited the most effective reduction of nonspecific binding proteins, whilst maintaining binding of the target protein. Introduction of 5 on TOYOPEARL reduced tubulin and actin by almost 65% and 90% compared to that without the hydrophilic spacer, respectively, with effective binding to the target protein, FKBP12.