Asynchronous Rhythm of Steroidogenic Factor 1 and Period Homolog 2 mRNA Expression in Mouse Y1 Adrenocorticol Tumor Cells

The relationship between the expression of Steroidogenic factor 1 (Sf1) and the circadian-related gene, period homolog 2 (Per2), in the adrenal cortex is still unknown. We show here that in Y1 adrenocortical tumor cells, expression of steroidogenic-related genes such as P450scc mRNA and Sf1 mRNA were asynchronous with Per2 mRNA. SF1 promoter analyses showed that the E-box element functions in a rhythmic pattern. Rhythmic expression of Upstream factor 1 mRNA, correlated well with Sf1 mRNA expression. We propose that tumorigenesis of adrenocortical lesions cause disruption of synchronous expression of steroidogenic-related and circadian-related genes

BORTEZOMIB-ENHANCED RADIOSENSITIZATION IN HUMAN ORAL CANCER CELLS

Oral cancer cells have a significantly augmented nuclear factor-κB (NF-κB) activity and the inhibition of this activity suppresses tumor growth. Bortezomib is a proteasome inhibitor and a drug used for molecular-targeted therapy (targets NF-κB). In this study, we investigated whether bortezomib would be effective as an inhibitor of proliferation and a radiosensitizer for the treatment of oral cancer. We demonstrate that bortezomib inhibits NF-κB activity and cell proliferation. The combined treatment with bortezomib and radiation (RT) suppressed NF-κB activity and cell growth in vitro and in vivo compared with RT treatment alone. To investigate the mechanisms by which bortezomib suppresses tumor growth, the expression of signaling molecules downstream of NF-κB were examined by ELISA. The combined treatment significantly inhibited the radiation‑induced production of angiogenic factors and decreased the number of blood vessels in the tumor tissues. Although the expression of anti‑apoptotic proteins was upregulated by RT, bortezomib downregulated the RT-induced expression of these proteins. Moreover, the expression of cleaved poly(ADP‑ribose) polymerase in vitro and in vivo was enhanced by bortezomib, indicating that bortezomib inhibits tumor growth by inducing apoptosis. This study clearly demonstrates that bortezomib significantly inhibits tumor growth and that the combined treatment with bortezomib and RT results in a significant inhibition of tumor growth. The mechanisms underlying the inhibition of tumor growth by bortezomib include the suppression of angiogenesis and the induction of apoptosis. A novel molecular targeting therapy including bortezomib may be effective in the treatment of oral cancer by suppressing NF-κB activity

ANTI-TUMOR EFFICACY OF DOCETAXEL AND 5-FLUOROURACIL

Docetaxel (DOC) and 5-fluorouracil (5-FU) are important anticancer agents widely used in the treatment of a variety of cancers including oral squamous cell carcinoma (OSCC). The purpose of this study was to determine the antitumor efficacy of the sequential administration of DOC and 5-FU against OSCC cells (B88 and CAL27 cells) in vitro and in vivo. In in vitro growth inhibition assays, sequential treatment with DOC followed by 5-FU was more effective in inhibiting cancer cell growth than 5-FU followed by DOC, single treatment with DOC or 5-FU, or combined treatment with DOC and 5-FU. Furthermore, DOC followed by 5-FU significantly inhibited tumor growth in vivo compared to 5-FU followed by DOC. To understand the mechanisms underlying the enhanced growth inhibitory effect of the administration sequence, DOC followed by 5-FU, we examined the expression of 5-FU metabolic enzymes such as thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyl transferase (OPRT), which were known to regulate the antitumor effect of 5-FU, by real-time RT-PCR and western blot analysis. Downregulation of TS and DPD expression and upregulation of OPRT expression were induced by DOC treatment, suggesting that DOC enhanced the efficacy of 5-FU by altering the expression of its metabolic enzymes. These results indicate that sequential treatment with DOC followed by 5-FU could be a promising therapeutic strategy for oral cancer

Expression of monocyte chemoattractant protein-1 in idiopathic dilated cardiomyopathy

Immunological factors have been involved in the pathogenesis of dilated cardiomyopathy (DCM). The cytotoxic action of macrophages is one of the main factors causing cardiac myocyte damage. Monocyte chemoattractant protein-1 (MCP-1) is a major signal for the accumulation of monocytes/macrophages. We examined whether MCP-1 was expressed in the myocardium of DCM patients and whether the expression level was correlated with the degree of impairment of cardiac function. The expression of MCP-1 in the myocardium was determined by immunohistochemistry in endomyocardial biopsy samples from 13 patients. The expression of MCP-1 was found in all myocardial samples from DCM patients but not in those from control subjects. Positive staining for MCP-1 was distinct in cardiac myocytes, interstitium and infiltrating cells. Semi-quantitative analysis revealed that the expression of MCP-1 was inversely correlated with left ventricular ejection fraction. In conclusion, the expression level of MCP-1 in the myocardium was correlated with the degree of impairment of cardiac function in patients with DCM.</p

Proteomic Biomarkers for Acute Interstitial Lung Disease in Gefitinib-Treated Japanese Lung Cancer Patients

Interstitial lung disease (ILD) events have been reported in Japanese non-small-cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. We investigated proteomic biomarkers for mechanistic insights and improved prediction of ILD. Blood plasma was collected from 43 gefitinib-treated NSCLC patients developing acute ILD (confirmed by blinded diagnostic review) and 123 randomly selected controls in a nested case-control study within a pharmacoepidemiological cohort study in Japan. We generated ∼7 million tandem mass spectrometry (MS/MS) measurements with extensive quality control and validation, producing one of the largest proteomic lung cancer datasets to date, incorporating rigorous study design, phenotype definition, and evaluation of sample processing. After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD. Multivariate peptide, protein, and pathway modeling achieved ILD prediction comparable to previously identified clinical variables; combining the two provided some improvement. The acute phase response pathway was strongly represented (17 of 29 proteins, p = 1.0×10−25), suggesting a key role with potential utility as a marker for increased risk of acute ILD events. Validation by Western blotting showed correlation for identified proteins, confirming that robust results can be generated from an MS/MS platform implementing strict quality control

シンケイ センイショウ 1ガタ ノ セキチュウ ヘンケイ ニ トモナウ ロッコツ ズ ノ セキチュウカン ナイ ダッキュウ

2006 年4 月～2010 年3 月の神経線維腫症1 型に伴う脊柱変形手術例10 例中3 例に肋骨頭の脊柱管内脱臼がみられた.症例1 は6 歳の男児でT4-8:74°,T8-11:72° の側弯があり,左第4 と第5 肋骨頭の脊柱管内への陥入を認めた.症例2 は11 歳の男児でT3-7:100° の側弯とT3-T9:90° の後弯があり,左第6 肋骨頭が脊柱管内へ脱臼し,脊髄を圧排していた.症例3 は27 歳の女性でT6～9:73°,T9～12:68° の側弯とT6-10:91°の後弯を認め,右第7 肋骨頭の脊柱管内脱臼がみられた.本病態の報告例は少ないが,決して希な病態ではなくdystrophic change を伴う脊柱変形においては,肋骨頭の脊柱管内脱臼による潜在的リスクに注意する必要があると考える.Spinal deformities are common features in neurofibromatosistype-1( NF-1). Several types of deformities have been reported, however, intraspinal rib head dislocation (IRD)due to dystrophic change is very rare and not well understood. Between April 2006 and March 2010, we experienced3 patients with IRD out of 10 consecutive patients who underwent surgical treatment for dystrophic spinal deformities in NF-1. Case 1:A 6-year-old boy who had 74 ° short angular scoliosis at T4-8 and 72 ° at T8-11 underwent surgery in our institute. CT myelography demonstrated dystrophic changes with for aminal enlargement, vertebral body scalloping, rib penciling and mild IRD. He underwent the Growing Rod techniques and finally underwent posterior spinal fusion (PSF) from T1 to L2 combined with prophylactic rib head resection followed by anterior spinal fusion(ASF) with autologous fibular strut graft. No neurological complications were observed postoperatively and complete bony fusions were achieved. Case 2:Neurologically intact11-year-old boy presented with spinal deformity and caf&eacute;au-lait spots. Radiography showed 100 ° scoliosis at T3-7and 72 ° at T3-9. CT myelography demonstrated dystrophic changes and IRD and impingement of spinal cord. He underwent PSF with removal of the T6 rib head followed by ASF. Case 3:A 27-year-old woman presented with back pain and spinal deformities. Radiography showed 73 °scoliosis at T6-9 and 91 ° at T9-12. CT myelography demonstrated dystrophic changes and IRD. She also underwentPSF with removal of T7 rib head followed by ASF. AllIRDs were observed at the apex of the convex side of scoliosis.It has a potential risk of spinal cord compression and may cause paraplegia or paraparesis. Therefore, high degree of suspicion is warranted for the treatments of scoliosis with intraspinal rib displacement in NF-1