Citations

Abstract A common method of treating PASTA (partial articular surface tendon avulsion) lesions involves completing the tear followed by arthroscopic repair. Frequently, the boundaries of the tear are difficult to determine from the bursal side with the use of a single marking stitch. Therefore, we describe a simple technique that allows the surgeon to reproducibly define the boundaries of the partial tear. Following a standard arthroscopic examination of the articular portion of the shoulder joint, the PASTA lesion is identified. A spinal needle is introduced and the most anterior and posterior aspects of the tear are marked by passing 2 sutures. Following a bursectomy, the 2 sutures that clearly define the boundaries of the tear are identified. The tear is then completed by “connecting the dots” outlined by the sutures and an arthroscopic repair is performed in the standard manner.

AbstractThis article reviews progress in chemopreventive drug development, especially data and concepts that are new since the 2002 AACR report on treatment and prevention of intraepithelial neoplasia. Molecular biomarker expressions involved in mechanisms of carcinogenesis and genetic progression models of intraepithelial neoplasia are discussed and analyzed for how they can inform mechanism-based, molecularly targeted drug development as well as risk stratification, cohort selection, and end-point selection for clinical trials. We outline the concept of augmenting the risk, mechanistic, and disease data from histopathologic intraepithelial neoplasia assessments with molecular biomarker data. Updates of work in 10 clinical target organ sites include new data on molecular progression, significant completed trials, new agents of interest, and promising directions for future clinical studies. This overview concludes with strategies for accelerating chemopreventive drug development, such as integrating the best science into chemopreventive strategies and regulatory policy, providing incentives for industry to accelerate preventive drugs, fostering multisector cooperation in sharing clinical samples and data, and creating public-private partnerships to foster new regulatory policies and public education.

The centrosome is an integral component of the eukaryotic cell cycle machinery, yet very few centrosomal proteins have been fully characterized to date. We have undertaken a series of biochemical and RNA interference (RNAi) studies to elucidate a role for CP110 in the centrosome cycle. Using a combination of yeast two-hybrid screens and biochemical analyses, we report that CP110 interacts with two different Ca 2+ -binding proteins, calmodulin (CaM) and centrin, in vivo. In vitro binding experiments reveal a direct, robust interaction between CP110 and CaM and the existence of multiple high-affinity CaM-binding domains in CP110. Native CP110 exists in large (∼300 kDa to 3 MDa) complexes that contain both centrin and CaM. We investigated a role for CP110 in CaM-mediated events using RNAi and show that its depletion leads to a failure at a late stage of cytokinesis and the formation of binucleate cells, mirroring the defects resulting from ablation of either CaM or centrin function. Importantly, expression of a CP110 mutant unable to bind CaM also promotes cytokinesis failure and binucleate cell formation. Taken together, our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis.

ABSTRACTPneumocystiscontinues to represent an important opportunistic fungal pathogen of those with compromised immunity. Thus, it is crucial to identify factors that affect its viability and pathogenicity. We previously reported the first identification of melanins inPneumocystis. In the present study, we sought to further characterize these components and define the function for these melanins. Melanins extracted fromPneumocystisand melanizedPneumocystiscells were analyzed by electron spin resonance spectroscopy, revealing spectra consistent with melanins from other fungi. Immunofluorescence assays using anti-melanin monoclonal antibodies showed that melanins are widely present acrossPneumocystishost species, including mouse-, ferret-, and human-derivedPneumocystisorganisms, as well asPneumocystis cariniiderived from rat. Using immunoelectron microscopy, melanins were found to localize to the cell wall and cytoplasm ofP. cariniicysts, as well as to intracystic bodies within mature cysts. Next, the role of melanins on the maintenance ofPneumocystisviability was determined by using quantitative reverse transcription-PCR measurement of the heat shock protein mRNA under adverse environmental conditions. Using a new method to promote the melanization ofPneumocystis, we observed that strongly melanizedPneumocystisretained viability to a greater degree when exposed to UV irradiation or desiccation compared to less-pigmented organisms. These studies support our previous identification ofPneumocystismelanins across the genus, further characterize thesePneumocystiscomponents, and demonstrate that melanins protectPneumocystisfrom environmental stressors.

Purpose To address early and late treatment failures in older patients with diffuse large B-cell lymphoma (DLBCL), we designed a two-stage randomized trial of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus rituximab plus CHOP (R-CHOP), with a second random assignment to maintenance rituximab (MR) or observation in responding patients. Patients and Methods Untreated DLBCL patients who were 60 years or older were randomly assigned to R-CHOP (n = 318) or CHOP (n = 314); 415 responders were randomly assigned to MR (n = 207) or observation (n = 208). The primary end point was failure-free survival (FFS). All P values were two sided. Results Three-year FFS rate was 53% for R-CHOP patients and 46% for CHOP patients (P = .04) at a median follow-up time of 3.5 years. Two-year FFS rate from second random assignment was 76% for MR compared with 61% for observation (P = .009). No significant differences in survival were seen according to induction or maintenance therapy. FFS was prolonged with MR after CHOP (P = .0004) but not after R-CHOP (P = .81) with 2-year FFS rates from second random assignment of 77%, 79%, 74%, and 45% for R-CHOP, R-CHOP + MR, CHOP + MR, and CHOP, respectively. In a secondary analysis excluding MR patients, R-CHOP alone reduced the risks of treatment failure (P = .003) and death (P = .05) compared with CHOP alone. Conclusion Rituximab administered as induction or maintenance with CHOP chemotherapy significantly prolonged FFS in older DLBCL patients. After R-CHOP, no benefit was provided by MR. These results, which are consistent with an additive effect of rituximab, suggest that future studies could focus on maintenance strategies with novel agents as well as new induction therapies.

ABSTRACT Initially, it was thought that there was no intracellular signaling mediated by NRP‐1 alone in response to its ligands. However, the emerging data from our group as well as others suggest that the signaling through NRP‐1 actually promotes angiogenesis and is mediated through its C‐terminal domain and downstream molecules such as phosphoinositide 3‐kinase. Hence, understanding the signal transduction pathways mediated by NRP‐1 and identification of its downstream molecules are of importance. By using both in vivo zebrafish model and in vitro tissue culture system, we have shown that the C‐terminal three amino acids of NRP‐1 (SEA‐COOH) are required for NRP‐1‐mediated angiogenesis. Furthermore, knocking down of RGS‐GAIP‐interacting protein C terminus (GIPC) in zebrafish, which is associated with C‐terminal domain of NRP‐1, exhibits similar vasculature phenotypes to those from NRP‐1 null. Specific and effective silencing of GIPC in vascular endothelium results in inhibition of NRP‐1‐mediated migration. In both cases as described, PDZ domain of GIPC is responsible for its function. Taken together, our data suggest a novel role of GIPC in angiogenesis and vessel formation and also support our hypothesis that NRP‐1 can facilitate downstream signaling to promote angiogenesis through GIPC.—Wang, L., Mukhopadhyay, D., Xu, X. C terminus of RGS‐GAIP‐interacting protein conveys neuropilin‐1‐mediated signaling during angiogenesis. FASEB J. 20, E732–E741 (2006)