Lee et al. demonstrate that mannose receptor–mediated infection of M2-like dermal macrophages plays a critical role in nonhealing cutaneous infection by L. major. The dermal macrophages are radio resistant and self-renewed and efficiently maintain their M2 phenotype during Th1 immunity.

A collaborative multidisciplinary research project is described in which new natural product anticancer drug leads are obtained from a diverse group of organisms, constituted by tropical plants, aquatic cyanobacteria, and filamentous fungi. Information is provided on how these organisms are collected and processed. The types of bioassays are indicated in which crude extracts of these acquisitions are tested. Progress made in the isolation of lead bioactive secondary metabolites from three tropical plants is discussed.

Apoptosis in embryonic C3H/10T/2 (done 8) cells is marked by specific changes in morphology and DNA fragmentation that differ from those found in apoptotic thymocytes. These results demonstrate that ultrastructural changes within the nucleus associated with endonucleolytic degradation are linked with structural degradation at higher levels of chromatin organization. Strand modifications within the internucdeosomal linker region are shown to involve alkaline-sensitive sites that appear to be sensitive to Si endonudease. Our results suggest that apoptosis is not dependent upon internucleosomal cleavage and may reveal the penultimate step and the nature of the metabolic cascade that leads to cell death.Apoptosis is a term originally proposed by Kerr, Wyllie, and Currie (1) to describe a process of controlled cell deletion in tissues following either physiological or pathological stimuli. The concept of apoptosis implies that a common metabolic pathway leading to cell death may be initiated by a wide variety of signals, including hormones, serum growth factor deprivation, chemotherapeutic agents, and ionizing radiation (2)(3)(4)(5)(6). Understanding this process of apoptosis is critical to understanding the mechanisms of cell death common to embryonic development, cellular immunology, and protection against the expression of heritable genotypic changes in cells linked with mutagenesis and carcinogenesis (see ref. 7).Much of the basic research on apoptosis has focused upon the phenomenon as it occurs in thymocytes and lymphocytederived cell lines. Perhaps the most widely accepted markers of apoptotic cell death are morphological changes observed by electron microscopy (EM) and the nonrandom nature of the fragmentation of nuclear DNA. We have focused our research on the study of regulation of cell proliferation and death as it is expressed in the pluripotent, untransformed mouse embryonic cell, C3H/1OTY2 clone 8 (10T1/2). Previ-ously published evidence has shown that this cell exhibits the ability to modulate proliferation, differentiation, and death. Its phenotype is subject to transformation by various physical and chemical agents and it has been used to study the process of multistage carcinogenesis in vitro (see ref. 8).There has been considerable debate over the precise role of DNA fragmentation in apoptosis and the mechanism by which the integrity of the genome is irreversibly damaged.This report demonstrates that apoptosis does not require double-strand DNA cleavage in the internucleosomal linker region and that apoptosis in the 1OTY2 cell is marked by specific changes in morphology and DNA fragmentation unlike that in thymocytes. Our results suggest that ultrastructural changes previously associated with apoptosis are actually linked with DNA structural degradation at levels ofDNA organization above that of the nucleosome. Furthermore, although it is generally assumed that DNA degradation in apoptotic cells progresses through a series of steps or metabolic cascade, the evidence presented here demonstr...

γ-tilmanocept (Technetium-99m–labeled- or 99mTc-tilmanocept) is the first mannose-containing, receptor-directed, radiolabeled tracer for the highly sensitive imaging of sentinel lymph nodes (SLNs) in solid tumor staging. To elucidate the mannose-binding receptor that retains tilmanocept in this microenvironment, human macrophages were used which have high expression of the C-type lectin mannose receptor (MR, CD206). Cy3-labeled tilmanocept exhibited high specificity binding to macrophages that was nearly abolished in competitive inhibition experiments. Furthermore, Cy3-tilmanocept binding was markedly reduced on macrophages deficient in the MR by siRNA treatment, and increased on MR-transfected HEK 293 cells. Finally, confocal microscopy revealed co-localization of Cy3-tilmanocept with the macrophage membrane MR and binding of labeled tilmanocept to MR-positive cells [macrophages and/or dendritic cells (DCs)] in human SLN tissues. Together these data provide strong evidence that CD206 is a major binding receptor for γ-tilmanocept. Identification of CD206 as the γ-tilmanocept-binding receptor enables opportunities for designing receptor-targeted advanced imaging agents and therapeutics for cancer and other diseases.

Background-Several 99m Tc-labeled agents that are not approved by the U.S. Food and Drug Administration are used for lymphatic mapping. A new low-molecular-weight mannose receptorbased, reticuloendothelial cell-directed, 99m Tc-labeled lymphatic imaging agent, 99m Tc-tilmanocept, was used for lymphatic mapping of sentinel lymph nodes (SLNs) from patients with primary breast cancer or melanoma malignancies. This novel molecular species provides the basis for potentially enhanced SLN mapping reliability.

Sentinel lymph node (SLN) mapping is common, however question remains as to what the ideal imaging agent is and how such an agent might provide reliable and stable localization of SLNs. (99m)Tc-labeled nanocolloid human serum albumin (Nanocoll) is the most commonly used radio-labeled colloid in Europe and remains the standard of care (SOC). It is used in conjunction with vital blue dyes (VBDs) which relies on simple lymphatic drainage for localization. Although the exact mechanism of Nanocoll SLN localization is unknown, there is general agreement that Nanocoll exhibits the optimal size distribution and radiolabeling properties of the commercially available radiolabel colloids. [(99m)Tc]Tilmanocept is a novel radiopharmaceutical designed to address these deficiencies. Our aim was to compare [(99m)Tc]Tilmanocept to Nanocoll for SLN mapping in breast cancer. Data from the Phase III clinical trials of [(99m)Tc]Tilmanocept's concordance with VBD was compared to a meta-analysis of a review of the literature to identify a (99m)Tc albumin colloid SOC. The primary endpoints were SLN localization rate and degree of localization. Six studies were used for a meta-analysis to identify the colloid-based SOC. Five studies (6,134 patients) were used to calculate the SOC localization rate of 95.91 % (CI 0.9428-0.9754) and three studies (1,380 patients) were used for the SOC SLN degree of localization of 1.6683 (CI 1.5136-1.8230). The lower bound of the confidence interval was used for comparison to Tilmanocept. Tilmanocept data included 148 patients, and pooled analysis revealed a 99.99 % (CI 0.9977-1.0000) localization rate and degree of localization of 2.16 (CI 1.964-2.3600). Tilmanocept was superior to the Nanocoll SOC for both endpoints (P < 0.0001).

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