The Metastasectomy and Timing of Pulmonary Metastases on the Outcome of Osteosarcoma Patients

Background The author intended to clarify the therapeutic effect and prognostic factors of metastasectomy and timing of pulmonary metastases in osteosarcoma patents. Methods Data was obtained retrospectively on all consecutive osteosarcoma patients from 1985 to 2005 in author's institute. Fifty-two patients with pulmonary nodules were identified, including 24 patients undergoing pulmonary metastasectomy treatment. These patients were categorized into four groups: group 1, patients with lung metastases at the initial presentation; group 2, lung metastases identified during the period of pre-operative chemotherapy; group 3, lung metastases identified during period of the post-operative chemotherapy; group 4, lung metastases identified after therapy for the primary osteosarcoma completed. Results In our study, the 2-, 3-, and 5-year overall survival rates for 52 patients were 49%, 39% and 20%. The 2-year overall survival rates were 18% for group 1, 32% for group 3, and 70% for group 4 (p < 0.001). The 5-year overall survival rate was 34% for group 4. Patients who underwent metastesectomy showed a better survival outcome as compared with the patients not undergoing metastasectomy (p = 0.003). The 2-year and 5-year overall survival rates of only one lung metastatic nodule were 62% and 50%, and for initially multiple lung metastatic nodules, 45% and 5%, respectively. In addition, the patients presented with lung metastases had a worse prognosis as compared with those without initial lung metastases (p = 0.0001). Conclusions The patients having single metastatic nodule showed a better prognosis than those with multiple lung nodules. Furthermore, those patients who underwent metastasectomy survived longer than those not undergoing metastasectomy. Patients who had late metastases after complete chemotherapy had a better prognosis; whereas those who had metastases identified at the initial presentation predicted a poor prognosis

Infectomic Analysis of Gene Expression Profiles of Human Brain Microvascular Endothelial Cells Infected with Cryptococcus neoformans

In order to dissect the pathogenesis of Cryptococcus neoformans meningoencephalitis, a genomic survey of the changes in gene expression of human brain microvascular endothelial cells infected by C. neoformans was carried out in a time-course study. Principal component analysis (PCA) revealed significant fluctuations in the expression levels of different groups of genes during the pathogen-host interaction. Self-organizing map (SOM) analysis revealed that most genes were up- or downregulated 2 folds or more at least at one time point during the pathogen-host engagement. The microarray data were validated by Western blot analysis of a group of genes, including β-actin, Bcl-x, CD47, Bax, Bad, and Bcl-2. Hierarchical cluster profile showed that 61 out of 66 listed interferon genes were changed at least at one time point. Similarly, the active responses in expression of MHC genes were detected at all stages of the interaction. Taken together, our infectomic approaches suggest that the host cells significantly change the gene profiles and also actively participate in immunoregulations of the central nervous system (CNS) during C. neoformans infection

Lipid raft/caveolae signaling is required for Cryptococcus neoformans invasion into human brain microvascular endothelial cells

<p>Abstract</p> <p>Background</p> <p><it>Cryptococcus neoformans </it>has a predilection for central nervous system infection. <it>C. neoformans </it>traversal of the blood brain barrier, composed of human brain microvascular endothelial cells (HBMEC), is the crucial step in brain infection. However, the molecular mechanism of the interaction between <it>Cryptococcus neoformans </it>and HBMEC, relevant to its brain invasion, is still largely unknown.</p> <p>Methods</p> <p>In this report, we explored several cellular and molecular events involving the membrane lipid rafts and caveolin-1 (Cav1) of HBMEC during <it>C. neoformans </it>infection. Immunofluorescence microscopy was used to examine the roles of Cav1. The knockdown of Cav1 by the siRNA treatment was performed. Phosphorylation of Cav1 relevant to its invasion functions was investigated.</p> <p>Results</p> <p>We found that the host receptor CD44 colocalized with Cav1 on the plasma membrane, and knockdown of Cav1 significantly reduced the fungal ability to invade HBMEC. Although the CD44 molecules were still present, HBMEC membrane organization was distorted by Cav1 knockdown. Concomitantly, knockdown of Cav1 significantly reduced the fungal crossing of the HBMEC monolayer <it>in vitro</it>. Upon <it>C. neoformans </it>engagement, host Cav1 was phosphorylated in a CD44-dependent manner. This phosphorylation was diminished by filipin, a disrupter of lipid raft structure. Furthermore, the phosphorylated Cav1 at the lipid raft migrated inward to the perinuclear localization. Interestingly, the phospho-Cav1 formed a thread-like structure and colocalized with actin filaments but not with the microtubule network.</p> <p>Conclusion</p> <p>These data support that <it>C. neoformans </it>internalization into HBMEC is a lipid raft/caveolae-dependent endocytic process where the actin cytoskeleton is involved, and the Cav1 plays an essential role in <it>C. neoformans </it>traversal of the blood-brain barrier.</p

Structural analysis of metalloform-selective inhibition of methionine aminopeptidase

One of the challenges in the development of methionine aminopeptidase (MetAP) inhibitors as antibacterial and anticancer agents is to define the metal ion actually used by MetAP in vivo and to discover MetAP inhibitors that can inhibit the metalloform that is relevant in vivo. Two distinct classes of novel nonpeptidic MetAP inhibitors that are not only potent but also highly selective for either the MnII or CoII form have been identified. Three crystal structures of Escherichia coli MetAP complexed with the metalloform-selective inhibitors 5-(2,5-dichlorophenyl)furan-2-carboxylic acid (2), 5-[2-(trifluoromethyl)phenyl]furan-2-carboxylic acid (3) and N-cyclopentyl-N-(thiazol-2-yl)oxalamide (4) have been solved and analysis of these structures has revealed the structural basis for their metalloform-selective inhibition. The MnII-form selective inhibitors (2) and (3) both use their carboxylate group to coordinate with the two MnII ions at the dinuclear metal site and both adopt a non-coplanar conformation for the two aromatic rings. The unique coordination geometry of these inhibitors may determine their MnII-form selectivity. In contrast, the CoII-form selective inhibitor (4) recruits an unexpected third metal ion, forming a trimetallic enzyme–metal–inhibitor complex. Thus, an important factor in the selectivity of (4) for the CoII form may be a consequence of a greater preference for a softer N,O-donor ligand for the softer CoII