The monoclonal antibody D2-40 recognizes the membrane protein podoplanin, which is an established marker for germ cell tumors, mesotheliomas, and other tumor types and is also expressed in a variety of normal cells including follicular dendritic cells (FDCs). To determine whether podoplanin represents an effective FDC marker for pathologic lymph nodes, we compared immunohistochemical studies (sensitivity, staining patterns, and intensity of staining) for podoplanin (D2-40) with those of the traditional FDC markers CD21, CD35, and clusterin. Paraffin sections of 26 lymph nodes were analyzed, including 4 cases of nodular lymphocyte-predominant Hodgkin lymphoma, 4 angioimmunoblastic T-cell lymphoma, 8 follicular lymphoma (including 3 cases with a component of diffuse large B-cell lymphoma), 5 hyaline-vascular Castleman disease, and 5 reactive lymph nodes with follicular hyperplasia. In all cases, qualitatively and quantitatively podoplanin represented a highly effective marker for detection of FDCs, with staining intensity equal to or greater than that observed for other FDC markers. This study demonstrates that podoplanin is an excellent marker for FDCs and adds to its growing list of diagnostic applications.

RET/PTC1 is a rearranged form of the RET tyrosine kinase commonly seen in papillary thyroid carcinomas. It has been shown that RET/PTC1 decreases expression of the sodium/iodide symporter (NIS), the molecule that mediates radioiodide therapy for thyroid cancer. Using proteomic analysis, we identify hsp90 and its co-chaperone p50 cdc37 as novel proteins associated with RET/ PTC1. Inhibition of hsp90 function with 17-allylamino-17-demothoxygeldanamycin (17-AAG) reduces RET/ PTC1 protein levels. Furthermore, 17-AAG increases radioiodide accumulation in thyroid cells, mediated in part through a protein kinase A-independent mechanism. We show that 17-AAG does not increase the total amount of NIS protein or cell surface NIS localization. Instead, 17-AAG increases radioiodide accumulation by decreasing iodide efflux. Finally, the ability of 17-AAG to increase radioiodide accumulation is not restricted to thyroid cells expressing RET/PTC1. These findings suggest that 17-AAG may be useful as a chemotherapeutic agent, not only to inhibit proliferation but also to increase the efficacy of radioiodide therapy in patients with thyroid cancer.Members of the heat shock protein family function as molecular chaperones, ensuring the proper folding of newly translated proteins (1). Heat shock protein 90 (hsp90) 1 is an abundant cytosolic protein, which is highly conserved across a number of species. hsp90 mediates the folding of a limited number of client proteins, including steroid hormone receptors and signaling kinases. The ability of hsp90 to facilitate client protein folding requires the presence of co-chaperone proteins, which vary depending on the client protein (2). In the case of client kinases, the interaction with hsp90 is mediated by the co-chaperone p50 cdc37 .A number of signaling kinases, such as phosphatidylinositol 3-kinase (3), Raf (4), AKT (5), IKK (6), c-Src (7), and ErbB2 (8), have been demonstrated to interact with hsp90. Structural studies of hsp90 have demonstrated the presence of a molecular clamp, whose open or closed state is regulated by the presence of ATP (9). The co-chaperone p50 cdc37 has been shown to interact with the molecular clamp, maintaining hsp90 in the open state and facilitating client protein loading (10). In contrast, hsp90 function can be inhibited by several members of the ansamycin family of antibiotics, including herbimycin A, geldanamycin, and 17-allylamino-17-demethoxygeldanamycin (17-AAG).Ansamycin antibiotics were thought to function as tyrosine kinase inhibitors (11), however, it was subsequently demonstrated that their molecular target is hsp90 (12, 13). Geldanamycin and 17-AAG have been shown to reduce cellular proliferation and induce apoptosis, and interest has risen in their use as anti-neoplastic agents (14). The utility of geldanamycin, however, is limited by significant hepatotoxicity (15). In contrast, 17-AAG is well tolerated in animal studies and has recently entered phase I clinical trials (14).Geldanamycin and 17-AAG represent novel chemotherapeutic agents for thyro...

The Na þ /I À symporter (NIS) is a membrane glycoprotein that facilitates the uptake of iodine into thyroid follicular cells. Recently, we and others have demonstrated the feasibility of imaging subcutaneous xenografts expressing exogenous NIS, suggesting that NIS may serve as an imaging reporter gene to monitor vector delivery and therapeutic gene expression. In this study, we established NIS-expressing pulmonary tumors in nude mice to investigate the minimal tumor size required for in vivo detection of pulmonary tumors by single photon emission computed tomography (SPECT) with pinhole collimation. In order to define the anatomic location of NIS-expressing tumor nodules detectable by SPECT, we performed simultaneous, dual-isotope imaging. We injected 1 mCi 99m Tc-MAA via tail vein to image pulmonary perfusion and injected 1 mCi Na 125 I intraperitoneally to image NIS-expressing tumors. Fused images showed that 99m Tc-MAA perfusion defects correlated with NIS-mediated 125 I uptake. Post-mortem analysis revealed that tumors 3 mm in diameter could be detected by SPECT with pinhole collimation. These studies demonstrate the feasibility of SPECT to detect pulmonary tumors expressing exogenous NIS in mice.

We report the case of a young woman who developed a subcutaneous granulomatous response after administration of the quadrivalent human papillomavirus vaccine. The inciting agent was most likely an aluminum adjuvant, which previously has been reported to be associated with a granulomatous response after administration of other vaccines. Histologically, the lesion consisted of a necrotic/necrobiotic center surrounded by palisading epithelioid histiocytes closely resembling deep granuloma annulare or rheumatoid nodule. The histiocytes contained abundant intracytoplasmic violaceous/gray granular material. An ammonium aurintricarboxylate (Aluminon) stain demonstrated the presence of aluminum in the granular material. Aluminum granulomas should be included in the differential diagnosis of deep granulomatous reaction in young women, due to the high frequency of vaccination in this population.