Chondrosarcoma of the Thorax

Although a rare entity, chondrosarcoma is the most common malignant tumor of the chest wall. Most patients present with an enlarging, painful anterior chest wall mass arising from the costochondrosternal junction. CT scan with intravenous contrast is the gold standard radiographic study for diagnosis and operative planning. Contrary to previous dictum, resection may be performed in an appropriate surgical candidate based on imaging characteristics or image-guided percutaneous biopsy results; incisional biopsy is rarely required. The keys to successful treatment are early recognition and radical excision with adequate margins, as chondrosarcoma is relatively resistant to radiotherapy and conventional cytotoxic chemotherapy. Overall survival is excellent in most surgical series from experienced centers. Complete excision with widely negative microscopic margins at the initial operation is of the utmost importance, as local recurrence portends systemic metastasis and eventual tumor-related mortality. This paper summarizes data from relevant surgical series and thereupon draws conclusions regarding preoperative, intraoperative, and postoperative management of thoracic chondrosarcoma

Characterization of bortezomib-adapted I-45 mesothelioma cells

<p>Abstract</p> <p>Background</p> <p>Bortezomib, a proteasome-specific inhibitor, has emerged as a promising cancer therapeutic agent. However, development of resistance to bortezomib may pose a challenge to effective anticancer therapy. Therefore, characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib-mediated cancer therapy.</p> <p>Results</p> <p>The present study reports the development of I-45-BTZ-R, a bortezomib-resistant cell line, from the bortezomib-sensitive mesothelioma cell line I-45. I-45-BTZ-R cells showed no cross-resistance to the chemotherapeutic drugs cisplatin, 5-fluorouracil, and doxorubicin. Moreover, the bortezomib-adapted I-45-BTZ-R cells had decreased growth kinemics and did not over express proteasome subunit β5 (PSMB5) as compared to parental I-45 cells. I-45-BTZ-R cells and parental I-45 cells showed similar inhibition of proteasome activity, but I-45-BTZ-R cells exhibited much less accumulation of ubiquitinated proteins following exposure to 40 nm bortezomib. Further studies revealed that relatively low doses of bortezomib did not induce an unfolded protein response (UPR) in the bortezomib-adapted cells, while higher doses induced UPR with concomitant cell death, as evidenced by higher expression of the mitochondrial chaperone protein Bip and the endoplasmic reticulum (ER) stress-related pro-apoptotic protein CHOP. In addition, bortezomib exposure did not induce the accumulation of the pro-apoptotic proteins p53, Mcl-1S, and noxa in the bortezomib-adapted cells.</p> <p>Conclusion</p> <p>These results suggest that UPR evasion, together with reduced pro-apoptotic gene induction, accounts for bortezomib resistance in the bortezomib-adapted mesothelioma cell line I-45-BTZ-R.</p

Complete roughness and conductivity corrections for the recent Casimir force measurement

We consider detailed roughness and conductivity corrections to the Casimir force in the recent Casimir force measurement employing an Atomic Force Microscope. The roughness of the test bodies-a metal plate and a sphere- was investigated with the Atomic Force Microscope and the Scanning Electron Microscope respectively. It consists of separate crystals of different heights and a stochastic background. The amplitude of roughness relative to the zero roughness level was determined and the corrections to the Casimir force were calculated up to the fourth order in a small parameter (which is this amplitude divided by the distance between the two test bodies). Also the corrections due to finite conductivity were found up to the fourth order in relative penetration depth of electromagnetic zero point oscillations into the metal. The theoretical result for the configuration of a sphere above a plate taking into account both corrections is in excellent agreement with the measured Casimir force

The downregulation of Mcl-1 via USP9X inhibition sensitizes solid tumors to Bcl-xl inhibition

BACKGROUND: It has been shown in many solid tumors that the overexpression of the pro-survival Bcl-2 family members Bcl-xL and Mcl-1 confers resistance to a variety of chemotherapeutic agents. Mcl-1 is a critical survival protein in a variety of cell lineages and is critically regulated via ubiquitination. METHODS: The Mcl-1, Bcl-xL and USP9X expression patterns in human lung and colon adenocarcinomas were evaluated via immunohistochemistry. Interaction between USP9X and Mcl-1 was demonstrated by immunoprecipitation-western blotting. The protein expression profiles of Mcl-1, Bcl-xL and USP9X in multiple cancer cell lines were determined by western blotting. Annexin-V staining and cleaved PARP western blotting were used to assay for apoptosis. The cellular toxicities after various treatments were measured via the XTT assay. RESULTS: In our current analysis of colon and lung cancer samples, we demonstrate that Mcl-1 and Bcl-xL are overexpressed and also co-exist in many tumors and that the expression levels of both genes correlate with the clinical staging. The downregulation of Mcl-1 or Bcl-xL via RNAi was found to increase the sensitivity of the tumor cells to chemotherapy. Furthermore, our analyses revealed that USP9X expression correlates with that of Mcl-1 in human cancer tissue samples. We additionally found that the USP9X inhibitor WP1130 promotes Mcl-1 degradation and increases tumor cell sensitivity to chemotherapies. Moreover, the combination of WP1130 and ABT-737, a well-documented Bcl-xL inhibitor, demonstrated a chemotherapeutic synergy and promoted apoptosis in different tumor cells. CONCLUSION: Mcl-1, Bcl-xL and USP9X overexpression are tumor survival mechanisms protective against chemotherapy. USP9X inhibition increases tumor cell sensitivity to various chemotherapeutic agents including Bcl-2/Bcl-xL inhibitors