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  • Author or Editor: Isao Kitajima x
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Yoshifumi Tsuboi, Masanori Kurimoto, Shoichi Nagai, Yumiko Hayakawa, Hironaga Kamiyama, Nakamasa Hayashi, Isao Kitajima and Shunro Endo

Object

The intrinsic radioresistance of certain cancer cells may be closely associated with the constitutive activation of nuclear factor–kappa B (NF-κB) activity, which may lead to protection from apoptosis. Recently, nonapoptotic cell death, or autophagy, has been revealed as a novel response of cancer cells to ionizing radiation. In the present study, the authors analyzed the effect of pitavastatin as a potential inhibitor of NF-κB activation on the radiosensitivity of A172, U87, and U251 human glioma cell lines.

Methods

The pharmacological inhibition of NF-κB activation was achieved using pitavastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Growth and radiosensitivity assays were performed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Hoechst 33258 staining, supravital acridine orange staining, and electron microscopy were performed utilizing 3 glioma cell lines with or without pitavastatin pretreatment to identify apoptosis or autophagy after irradiation.

Results

The growth of these 3 glioma cell lines was not significantly inhibited by pitavastatin at a concentration of up to 1 μM. Treatment with 0.1 μM of pitavastatin enhanced radiation-induced cell death in all glioma cell lines, with different sensitivity. Apoptosis did not occur in any pretreated or untreated (no pitavastatin) cell line following irradiation. Instead, autophagic cell changes were observed regardless of the radiosensitivity of the cell line. An inhibitor of autophagy, 3-methyladenine suppressed the cytotoxic effect of irradiation with pitavastatin, indicating that autophagy is a result of an antitumor mechanism. Using the most radiosensitive A172 cell line, the intracellular localization of p50, a representative subunit of NF-κB, was evaluated through immunoblotting and immunofluorescence studies. The NF-κB of A172 cells was immediately activated and translocated from the cytosol to the nucleus in response to irradiation. Pitavastatin inhibited this activation and translocation of NF-κB.

Conclusions

Autophagic cell death rather than apoptosis is a possible mechanism of radiation-induced and pitavastatin-enhanced cell damage, and radiosensitization by the pharmacological inhibition of NF-κB activation may be a novel therapeutic strategy for malignant gliomas.

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Katsuhito Yoshioka, Isao Kitajima, Tamon Kabata, Mineko Tani, Norio Kawahara, Hideki Murakami, Satoru Demura, Tsunehisa Tsubokawa and Katsuro Tomita

Object

The goal of this study was to determine the incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE) after spine surgery. Another purpose was to clarify the rapid changes of the fibrin monomer complex (FMC) and D-dimer levels during the perioperative period of spine surgery for early diagnosis of venous thromboembolism (VTE).

Methods

The participants were 72 patients who underwent spine surgery between September 2007 and March 2008. The FMC and D-dimer levels were measured 6 times: 1) at induction of general anesthesia; 2) just after implantation or during surgery; 3) immediately following surgery; 4) 1 day after surgery; 5) 3 days postsurgery; and 6) 7 days after surgery. All patients received mechanical prophylaxis, including compression stockings and intermittent pneumatic compression devices, and all were examined with duplex ultrasonography assessments of both lower extremities and with lung perfusion scintigraphy 7–10 days after surgery. If DVT or PE was suspected, the patient underwent multidetector CT venography.

Results

There were no patients with clinical signs of DVT and PE, but 6 (8.3%) showed VTE, among whom 5 had DVT and 3 had PE. Patients with VTE had significantly higher FMC levels 1 day after surgery, compared with those without VTE (55.9 ± 17.2 μg/ml vs 11.1 ± 2.89 μg/ml; p < 0.01). Patients with VTE had significantly higher D-dimer levels 7 days postsurgery, compared with those without VTE (12.5 ± 2.95 μg/ml vs 4.3 ± 0.39 μg/ml; p < 0.01). Receiver operating characteristic analysis showed that the FMC result was more useful than the D-dimer assay for diagnosis of VTE. When the cutoff value was set to 20.8 μg/ml for FMC, sensitivity was 100% and specificity was 86.3%.

Conclusions

In this study the prevalence of VTE after spine surgery was 8.3%. The FMC measured 1 day after spine surgery is considered to be useful as an indicator of VTE.