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Kosuke Narise, Kensuke Okuda, Yukihiro Enomoto, Tasuku Hirayama, Hideko Nagasawa Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, Daigaku-nishi, Gifu, Japan Abstract: Adaptive cellular responses resulting from multiple microenvironmental stresses, such as hypoxia and nutrient deprivation, are potential novel drug targets for cancer treatment. Accordingly, we focused on developing anticancer agents targeting the tumor microenvironment (TME). In this study, to search for selective antitumor agents blocking adaptive responses in the TME, thirteen new compounds, designed and synthesized on the basis of the arylmethylbiguanide scaffold of phenformin, were used in structure activity relationship studies of inhibition of hypoxia inducible factor (HIF)-1 and unfolded protein response (UPR) activation and of selective cytotoxicity under glucose-deprived stress conditions, using HT29 cells. We conducted luciferase reporter assays using stable cell lines expressing either an HIF-1-responsive reporter gene or a glucose-regulated protein 78 promoter-reporter gene, which were induced by hypoxia and glucose deprivation stress, respectively, to screen for TME-targeting antitumor drugs. The guanidine analog (compound 2), obtained by bioisosteric replacement of the biguanide group, had activities comparable with those of phenformin (compound 1). Introduction of various substituents on the phenyl ring significantly affected the activities. In particular, the o-methylphenyl analog compound 7 and the o-chlorophenyl analog compound 12 showed considerably more potent inhibitory effects on HIF-1 and UPR activation than did phenformin, and excellent selective cytotoxicity under glucose deprivation. These compounds, therefore, represent an improvement over phenformin. They also suppressed HIF-1- and UPR-related protein expression and secretion of vascular endothelial growth factor-A. Moreover, these compounds exhibited significant antiangiogenic effects in the chick chorioallantoic membrane assay. Our structural development studies of biguanide derivatives provided promising candidates for a novel anticancer agent targeting the TME for selective cancer therapy, to be subjected to further in vivo study. Keywords: HIF-1, UPR, antiangiogenesis, hypoxia, glucose deprivation

This paper documents the first report of Sarcocysli s cruzi infection in domesticated cattle (Bos taurus) in the Philippines. Fusiformshaped microscopic sarcocysts (183-578 μm long and 20-98 μm wide) with distinct septae were found in the skeletal, striated and heart muscle. The sarcocyst wall or parasitophorous vacuolar membrane, 1.37-2.75 μm thick consisted of closely-packed villar protrusions 80-400 nm in dm. Middle and distal segments of VP were bent approximately 90 degrees parallel to the cyst wall surface. The villar core lacked microtubules, and at some points, the distal ends of the VP collectively formed conical tufts. Primary cyst wall had numerous 70-100 nm bubble-like undulations, and the ground substance was 0.25-0.5 μm in thickness. The ultrastructure of S. cruzi cyst wall typifies the Type 7 sarcocyst wall, and bears close similarities with the Philippine and the Vietnam strain of bubaline Sarcocystis levinei.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ejor.2004.05.024 Byline: K.H. Widodo (a), H. Nagasawa (a), K. Morizawa (a), M. Ota (b) Keywords: Agriculture; Supply chain; Decision analysis Abstract: Total loss of agricultural fresh products amounts to 20% through 60% of the total amount of harvested products in any country, requiring an effective supply chain management model in agro-industry. This paper constructs a basic model of agricultural fresh products by formulating the plant growing process and the loss process of fresh products in mathematical forms. The model deals with periodical harvests through periodical flowering to satisfy demand. It is assumed that any on-hand inventory is not carried through more than one period and that any requirement for harvesting fresh products should be satisfied through the earliest plant maturing as possible. An optimal harvesting pattern is derived analytically to maximize the demand level satisfied. Author Affiliation: (a) Department of Industrial Engineering, Graduate School of Engineering, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan (b) Graduate School of Business, Osaka City University, Osaka, Osaka 588-8585, Japan Article History: Received 8 December 2003; Accepted 7 May 2004

A supply-chain management model for reducing produce loss in agricultural industry is presented.