Tooth enamel ESR doses and cytogenetic doses of Nagasaki atomic-bomb survivors in comparison with DS02R1 doses.

PURPOSE: Cancer risks for Nagasaki survivors once appeared to be lower than for Hiroshima survivors. The possibility that this was due to overestimation of the doses for the Nagasaki survivors was tested by measuring biological doses of Nagasaki survivors and comparing them with DS02R1 individual doses as previously done for Hiroshima survivors. MATERIALS AND METHODS: The electron spin resonance (ESR) method and cytogenetic method were used to estimate radiation doses for 24 Nagasaki survivors, and the results were compared to calculated DS02R1 doses. RESULTS: Six factory workers and 10 other survivors showed ESR or cytogenetically estimated doses that were in reasonably good agreement with their DS02R1 doses, while one factory worker was found to have an ESR dose estimate of nearly one half of the DS02R1 dose to the eye lens (a proxy organ for teeth). A few outliers were also observed. CONCLUSIONS: Although apparently lower cancer risks were observed in the past for Nagasaki survivors when compared to Hiroshima survivors, the present results do not indicate the existence of a trend that DS02R1 doses are overestimated when compared with biologically estimated tooth or cytogenetic doses. This observation is in line with the recent disappearance of the city difference in cancer risks.

Cancer mortality in residents of the terrain-shielded area exposed to fallout from the Nagasaki atomic bombing.

The health effects of radiation exposure from the atomic bomb fallout remain unclear. The objective of the present study is to elucidate the association between low-dose radiation exposure from the atomic bomb fallout and cancer mortality among Nagasaki atomic bomb survivors. Of 77 884 members in the Nagasaki University Atomic Bomb Survivors Cohort, 610 residents in the terrain-shielded area with fallout were selected for this analysis; 1443 residents in the terrain-shielded area without fallout were selected as a control group; and 3194 residents in the direct exposure area were also selected for study. Fifty-two deaths due to cancer in the terrain-shielded fallout area were observed during the follow-up period from 1 January 1970 to 31 December 2012. The hazard ratio for cancer mortality in the terrain-shielded fallout area was 0.90 (95% confidence interval: 0.65-1.24). No increase in the risk of cancer mortality was observed, probably because the dose of the radiation exposure was low for residents in the terrain-shielded fallout areas of the Nagasaki atomic bomb, and also because the number of study subjects was small.

Expression levels of SOX2, KLF4 and brachyury transcription factors are associated with metastasis and poor prognosis in oral squamous cell carcinoma.

The prognosis of oral squamous cell carcinoma (OSCC) patients is affected by tumor recurrence and metastasis, and cancer stem cells are hypothesized to be involved in these processes. Thus, the aim of the present study was to determine whether the expression levels of five stem cell-related transcription factors, sex determining region Y-box 2 (SOX2), octamer-binding transcription factor 4 (Oct4), avian myelocytomatosis viral oncogene homolog (c-Myc), Krüppel-like factor 4 (KLF4) and brachyury, are associated with metastasis and survival in OSCC. Immunohistochemistry was performed to analyze the expression of these proteins in biopsy specimens obtained from 108 OSCC patients. The results revealed that the expression of SOX2, Oct4, KLF4 and brachyury were significantly associated with lymph node metastasis (P=0.002, P=0.031, P=0.003 and P=0.007, respectively). In addition, the expression of KLF4 and brachyury were significantly associated with distant metastasis (P=0.014 and P=0.012, respectively). Furthermore, multivariate analysis revealed that SOX2 and KLF4 are predictive factors for lymph node metastasis [odds ratios (ORs), 4.526 and 4.851, respectively], and KLF4 is also a predictive factor for distant metastasis (OR, 9.607). In addition, OSCC patients with low co-expression of SOX2, KLF4 and brachyury exhibited a significantly lower disease-specific survival rate (78.6 vs. 100%; P=0.025; χ2=5.033) and disease-free survival rate (60.7 vs. 90.9%; P=0.015; χ2=5.897) when compared with OSCC patients with high co-expression of these factors. The results indicate that SOX2, KLF4 and brachyury serve important roles in tumor progression, and these transcription factors may thus represent clinically useful prognostic markers for OSCC.

miR-203 Inhibits Frizzled-2 Expression via CD82/KAI1 Expression in Human Lung Carcinoma Cells.

CD82/KAI1, a member of the tetraspanin superfamily, is a suppressor of metastasis and CD82 inhibits canonical Wnt signaling via downregulation of several Frizzled (FZD) isoforms, resulting in accumulation of ß-catenin at the cell membrane. In this study, we investigated the mechanism through which CD82 inhibited FZD expression by examining the effects of microRNAs (miRNAs). The miRanda algorithm predicted 11 miRNAs from FZD sequences. Among these miRNAs, CD82 caused upregulation of miR-203 (by 2.095-fold) and downregulation of miR-338-3p (by 0.354-fold) as compared with control cells. Transfection with miR-203 and miR338-3p mimics or inhibitors revealed that miR-203 downregulated FZD2 mRNA (by 0.268-fold) and protein expression (by 0.701-fold). Moreover, transfection with the miR-203 mimic also inhibited cell migration. Therefore, these findings suggested that CD82 enhanced the expression of miR-203 and directly downregulate FZD2 expression, suppressing cancer metastasis by inhibition of the Wnt signaling pathway.

A Novel Function of CD82/KAI1 in Sialyl Lewis Antigen-Mediated Adhesion of Cancer Cells: Evidence for an Anti-Metastasis Effect by Down-Regulation of Sialyl Lewis Antigens.

We have recently elucidated a novel function for CD82 in E-cadherin-mediated homocellular adhesion; due to this function, it can inhibit cancer cell dissociation from the primary cancer nest and limit metastasis. However, the effect of CD82 on selectin ligand-mediated heterocellular adhesion has not yet been elucidated. In this study, we focused on the effects of the metastasis suppressor CD82/KAI1 on heterocellular adhesion of cancer cells to the endothelium of blood vessels in order to further elucidate the function of tetraspanins. The over-expression of CD82 in cancer cells led to the inhibition of experimentally induced lung metastases in mice and significantly inhibited the adhesion of these cells to human umbilical vein epithelial cells (HUVECs) in vitro. Pre-treatment of the cells with function-perturbing antibodies against sLea/x significantly inhibited the adhesion of CD82-negative cells to HUVECs. In addition, cells over-expressing CD82 exhibited reduced expression of sLea/x compared to CD82-negative wild-type cells. Significant down-regulation of ST3 ß-galactoside α-2, 3-sialyltransferase 4 (ST3GAL4) was detected by cDNA microarray, real-time PCR, and western blotting analyses. Knockdown of ST3GAL4 on CD82-negative wild-type cells inhibited expression of sLex and reduced cell adhesion to HUVECs. We concluded that CD82 decreases sLea/x expression via the down-regulation of ST3GAL4 expression and thereby reduces the adhesion of cancer cells to blood vessels, which results in inhibition of metastasis.

Clinical features of pulmonary cryptococcosis in non-HIV patients in Japan.

OBJECTIVE: To clarify the clinical features of pulmonary cryptococcosis in Japanese non-HIV population. METHODS: Retrospective investigation of 151 pulmonary cryptococcosis cases between 1977 and 2012 was executed. The underlying disease (UDs), aggravating factors, radiological characteristics, and treatment were examined. RESULTS: Sixty-seven patients (44.4%) had no UDs. The common UDs were diabetes (32.1%) followed by hematologic disease (22.6%), and collagen disease (22.6%). Peripherally distributed pulmonary nodules/masses were most commonly seen. Lesions in the right middle lobe (p = 0.01) and air bronchogram (P = 0.05) were significantly more frequent, respectively, in patients with UDs than patients without them. Azoles were mainly selected for the patients without meningoencephalitis. Mean treatment duration for patients with and without UDs was 6.64 and 2.87 months, respectively. Patients whose pulmonary nodules improved after treatment continued to experience gradual reduction of cryptococcosis antigen titers, even if antigen titers were positive at the time of treatment cessation. The average time for antigen titers to become negative after treatment cessation was 13.1 and 10.7 months for patients with and without UDs, respectively. When groups were compared according to the presence of meningoencephalitis complications, deaths, and survivals, factors contributing to cryptococcosis prognosis included higher age, hypoproteinemia, hypoalbuminemia, steroid use, high C-reactive protein levels, and meningoencephalitis complications. CONCLUSIONS: It is crucial to consider the presence of UDs and meningoencephalitis for the choice of antifungals and treatment duration for cryptococcosis in non-HIV patients. Three- and six months-administration of azoles for pulmonary cryptococcosis with or without UDs, respectively is reasonable.

Bone mineral density in treated at a young age for differentiated thyroid cancer after Chernobyl female patients on TSH-suppressive therapy receiving or not Calcium-D3 supplementation.

Long-term management of patients with differentiated thyroid cancer (DTC) commonly includes TSH-suppressive therapy with L-T4 and, in case of postsurgical hypoparathyroidism, Calcium-D3 supplementation, both of which may affect skeletal health. Experience with female patients treated for DTC at a young age and who were then receiving long-term therapy with L-T4 and Calcium-D3 medication is very limited to date. This cross-sectional study set out to investigate effects of Calcium-D3 supplementation and TSH-suppressive therapy on bone mineral density (BMD) in 124 young female patients treated for DTC at a mean age of 14 years and followed-up for an average of 10 years. BMD was found to be significantly higher in patients receiving Calcium-D3 medication than in patients not taking supplements. The level of ionized calcium was the strongest factor determining lumbar spine BMD in patients not receiving Calcium-D3 supplementation. Pregnancy ending in childbirth and HDL-cholesterol were associated with a weak adverse effect on spine and femoral BMD. No evidence of adverse effects of L-T4 and of radioiodine therapies on BMD was found. We conclude that Calcium-D3 medication has a beneficial effect on BMD, and that TSH-suppressive therapy does not affect BMD in women treated for DTC at young age, at least after 10 years of follow-up.

Serum heat shock protein 47 levels are elevated in acute interstitial pneumonia.

BACKGROUND: Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagen. We hypothesized that HSP47 could be a useful marker for fibrotic lung disease. The aim of this study was to evaluate serum levels of HSP47 in patients with various idiopathic interstitial pneumonias (IIPs). METHODS: Subjects comprised 9 patients with acute interstitial pneumonia (AIP), 12 with cryptogenic organizing pneumonia (COP), 16 with nonspecific interstitial pneumonia (NSIP), 19 with idiopathic pulmonary fibrosis (IPF), and 19 healthy adult volunteers. RESULTS: Patients with AIP had serum HSP47 levels that were significantly higher than those of COP, NSIP or IPF patients and those of healthy volunteers. In contrast, serum levels of HSP47 among patients with COP, NSIP, IPF, and healthy volunteers did not differ significantly. Receiver operating characteristic curves revealed that the cut-off level for HSP47 that resulted in the highest diagnostic accuracy for discriminating between AIP and COP, NSIP, IPF, and healthy controls was 859.3 pg/mL. The sensitivity, specificity, and diagnostic accuracy were 100.0%, 98.5%, and 98.7%, respectively. CONCLUSION: The present results demonstrate that, among patients with various IIPs, serum levels of HSP47 were elevated specifically in patients with AIP.

Chest tube insertion is one important factor leading to intercostal nerve impairment in thoracic surgery.

OBJECTIVES: Chest tube insertion seems to be one important factor leading to intercostal nerve impairment. The purpose of this prospective study was to objectively evaluate intercostal nerve damage using current perception threshold testing in association with chest tube insertion. METHODS: Sixteen patients were enrolled in this study. Intercostal nerve function was assessed with a series of 2000-Hz (Aß fiber), 250-Hz (Aδ fiber), and 5-Hz (C fiber) stimuli using current perception threshold testing (Neurometer CPT/C(®)). Current perception threshold values at chest tube insertion were measured before surgery, during chest tube insertion and after removal of the chest tube. Intensities of ongoing pain were also assessed using a numeric rating scale (0-10). RESULTS: Current perception thresholds at each frequency after surgery were significantly higher than before surgery. Numeric rating scale scores for pain were significantly reduced from 3.3 to 1.9 after removal of the chest tube (p = 0.004). The correlation between current perception threshold value at 2000 Hz and intensity of ongoing pain was marginally significant (p = 0.058). CONCLUSIONS: This is the first study to objectively evaluate intercostal nerve damage at chest tube insertion. The results confirmed that chest tube insertion has clearly deleterious effects on intercostal nerve function.

Serum heat shock protein 47 levels in patients with drug-induced lung disease.

BACKGROUND: Heat shock protein (HSP) 47 is a collagen-specific molecular chaperone that is required for molecular maturation of various types of collagens. We recently reported that HSP47 serum levels were markedly higher in patients with acute exacerbations of idiopathic pulmonary fibrosis (IPF) when compared with patients with stable IPF, suggesting that serum HSP47 levels correlate with interstitial pneumonia activity. The aim of this study was to evaluate serum HSP47 levels in patients with drug-induced lung disease (DILD). METHODS: Findings from high-resolution computed tomographic chest scans of 47 patients with DILD were classified into one of four predominant patterns: organizing pneumonia (OP) (n = 4), nonspecific interstitial pneumonia (NSIP) (n = 24), hypersensitivity pneumonitis (HP) (n = 11), and diffuse alveolar damage (DAD) (n = 8). Serum levels of HSP47, Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-A, and SP-D were measured in these patients. RESULTS: The PaO2/fraction of inspired oxygen (FiO2) (P/F) ratios were significantly lower and the alveolar-arterial difference of oxygen (A-a DO2) was significantly higher in the DAD group than in the other groups. Patients with DAD had the worst outcomes among the different subgroups. Patients in the DAD group had significantly higher serum HSP47 levels than those in other groups. Receiver operating characteristic curves revealed that HSP47 was superior to KL-6, SP-A, and SP-D for discriminating between the DAD group and the other groups. The cut-off level for HSP47 that resulted in the highest diagnostic accuracy was 1711.5 pg/mL. The sensitivity, specificity, and diagnostic accuracy were 87.5%, 97.4%, and 95.7%, respectively. Serum levels of HSP47 in the group of patients requiring glucocorticoids were significantly higher than those in patients who experienced clinical improvement without glucocorticoid administration. Serum HSP47 levels also significantly correlated with various respiratory parameters. CONCLUSION: This study demonstrated that serum HSP47 levels were elevated in patients with DILD with a DAD pattern who had the worst outcomes among the different subgroups, and that this was correlated with P/F ratio and A-a DO2.

Future population of atomic bomb survivors in Nagasaki.

The Nagasaki University Atomic Bomb Survivor Database, which was established in 1978 for elucidating the long-term health effects of the atomic bombing, has registered since 1970 about 120,000 atomic bomb survivors with a history of residence in Nagasaki city. Since the number of atomic bomb survivors has steadily been decreasing, prediction of future population is important for planning future epidemiologic studies, and we tried to predict the population of atomic bomb survivors in Nagasaki city from 2008 to 2030. In addition, we evaluated our estimated population comparing with the actual number from 2008 to 2011.

Effects of radiation on the incidence of prostate cancer among Nagasaki atomic bomb survivors.

Atomic bomb survivors have been reported to have an increased risk of some cancers, especially leukemia. However, the risk of prostate cancer in atomic bomb survivors is not known to have been examined previously. This study examined the association between atomic bomb radiation and the incidence of prostate cancer among male Nagasaki atomic bomb survivors. The subjects were classified by distance from the hypocenter into a proximal group (<2 km), a distal group (≥2 km), and an early entrance group (those who entered the region <2 km from the hypocenter within 2 weeks after the explosion). Between 1996 and 2009, 631 new cases of prostate cancer were identified among approximately 18 400 male Nagasaki atomic bomb survivors who were alive in 1996. The Cox proportional hazard model was used to estimate the risk of prostate cancer development, with adjustment for age at atomic bomb explosion, attained age, smoking status, and alcohol consumption. Compared with the distal group, the proximal group had significant increased risks of total, localized, and high-grade prostate cancer (relative risk and 95% confidence interval: 1.51 [1.21-1.89]; 1.80 [1.26-2.57]; and 1.88 [1.20-2.94], respectively). This report is the first known to reveal a significant relationship between atomic bomb radiation and prostate cancer.

Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis.

Little is known about the pathophysiology of acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF). Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is essential for biosynthesis and secretion of collagen molecules. Previous studies in experimental animal fibrosis models have shown that downregulation of HSP47 expression reduces collagen production and diminishes fibrosis progression. In this study, serum HSP47 levels were evaluated to elucidate pathogenic differences involving HSP47 between AE-IPF and stable (S)-IPF. Subjects comprised 20 AE-IPF and 33 S-IPF patients. Serum levels of HSP47, Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-A, SP-D, and lactate dehydrogenase (LDH) were measured. Immunohistochemical analysis of lung HSP47 expression was determined in biopsy and autopsy tissues diagnosed as diffuse alveolar damage (DAD) and usual interstitial pneumonia (UIP). Serum levels of HSP47 were significantly higher in AE-IPF than in S-IPF patients, whereas serum levels of KL-6, SP-A, and SP-D did not differ significantly. Receiver operating characteristic curves revealed that HSP47 was superior for discriminating AE-IPF and S-IPF. The cutoff for HSP47 resulting in the highest diagnostic accuracy was 559.4 pg/mL; sensitivity, specificity, and diagnostic accuracy were 100.0%, 93.9%, and 96.2%, respectively. Immunohistochemical analysis revealed that pulmonary HSP47 expression was greater in DAD than UIP tissues. Serum HSP47 was significantly higher in AE-IPF than in S-IPF patients, suggesting that underlying fibrogenic mechanisms involving HSP47 differ in the two conditions.

Bronchoalveolar lavage galactomannan for the diagnosis of chronic pulmonary aspergillosis.

Diagnosing chronic pulmonary aspergillosis (CPA) is complicated, and there are limited data available regarding the identification of galactomannan (GM) in clinical specimens to assist the detection of this infection. The purpose of this study was to evaluate the detection of GM in bronchoalveolar lavage fluid (BALF) and serum and to assess its utility for diagnosing CPA. We retrospectively reviewed the diagnostic and clinical characteristics of 144 patients, with and without CPA, in Nagasaki University Hospital, Japan, whose BAL and serum specimens were examined for the presence of GM. The Platelia Aspergillus enzyme immunoassay (PA EIA) was performed according to the manufacturer's instructions. The mean values of BALF GM antigen were 4.535 (range, 0.062-14.120) and 0.430 (range, 0.062-9.285) in CPA (18) and non-CPA (126) patients, respectively. The mean values of serum GM antigen were 1.557 (range, 0.232-5.397) and 0.864 (range, 0.028-8.956) in CPA and non-CPA patients, respectively. PA EIA of BALF is superior to the test with serum, with the optimal cut-off values for BALF and serum of 0.4 and 0.7, respectively. The sensitivity and specificity of PA EIA in BALF at a cut-off of 0.4 were 77.2% and 77.0%, respectively, whereas with serum at a cut-off of 0.7, they were 66.7% and 63.5%, respectively. GM testing using BALF showed reasonable sensitivity and specificity as compared to that using serum. Thus, assessing GM levels in BALF may enhance the accuracy of diagnosing CPA.

Mutational and clinico-pathological analysis of papillary thyroid carcinoma in Serbia.

Molecular pathogenesis of papillary thyroid carcinoma (PTC) is largely associated with mutational changes in the BRAF, RAS family and RET genes. Our aim was to assess clinico-pathological and prognostic correlations of these PTC-specific gene alterations, with a particular emphasis on the BRAF mutation, in a group of 266 Serbian PTC patients, for the first time. The reference center-based retrospective cohort included 201 (75.6%) females and 65 (24.4%) males aged 48.0±16.1 years (8-83 years old, range) diagnosed and treated for PTC during 1993-2008. Follow-up period was 53.1±41.6 months (7-187 months, range). BRAF and RAS mutations were determined by direct sequencing of genomic DNA. RET/PTC rearrangements were analyzed by RT-PCR/Southern blotting. Genetic alterations were detected in 150/266 tumors (56.4%). One tumor displayed two genetic alterations. The BRAF(V600E) was found in 84/266 (31.6%) cases, RAS mutations in 11/266 (4.1%) and RET/PTC in 55/266 (20.7%; 42/266 (15.8%) RET/PTC1 and 13/266 (4.9%) RET/PTC3). On multivariate analysis BRAF(V600E) was associated with the classical papillary morphology (P = 0.05), the higher pT category (P = 0.05) and advanced clinical stage (P = 0.03). In a proportional hazard model, BRAF(V600E) did not appear to be an independent risk factor for the faster recurrence (P = 0.784). We conclude that under the extensive thyroid surgery and limited application of radioiodine ablation BRAF(V600E) may not be an indicator of poorer disease-free survival during the short to middle follow-up period. However, it has a potential to contribute to patients stratification into high- and low-risk groups.

Direct hemoperfusion using immobilized polymyxin B in patients with rapidly progressive interstitial pneumonias: a retrospective study.

BACKGROUND: Rapidly progressive interstitial pneumonia (IP), including acute exacerbation of IP, has a high mortality rate. Direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) was recently identified as an effective treatment for sepsis-associated acute respiratory distress syndrome. However, little is known about the effectiveness of PMX-DHP for rapidly progressive IP. OBJECTIVES: The present study investigates whether PMX-DHP is safe and effective against rapidly progressive IP. METHODS: We retrospectively examined the effects of PMX-DHP in 33 consecutive patients with rapidly progressive IP who were resistant to steroid pulse therapy. Patients were hospitalized at Nagasaki University Hospital between 2006 and 2009. RESULTS: Seventy-two hours after PMX-DHP, the arterial oxygen tension/inspiratory oxygen fraction ratio (median 127-153 mm Hg) had significantly improved. One week after PMX-DHP, the arterial oxygen tension/inspiratory oxygen fraction ratio (median 127-227 mm Hg), the alveolar-arterial difference of oxygen (median 371-177 mm Hg) and the number of positive criteria for systemic inflammatory response syndrome had significantly improved, despite the ineffectiveness of corticosteroid pulse therapy. The serum level of monocyte chemotactic protein 1 was significantly decreased immediately after PMX-DHP. CONCLUSIONS: PMX-DHP was safe and effective in improving oxygenation and systemic inflammatory response syndrome in patients with rapidly progressive IP. The beneficial effects of PMX-DHP may be at least partially due to the inhibition of monocyte activation.

Assessment and follow-up of intercostal nerve damage after video-assisted thoracic surgery.

OBJECTIVE: Chronic pain is a common complication after thoracic surgery. The most important factor appears to be intercostal nerve damage. The purpose of this prospective study was to objectively evaluate intercostal nerve damage associated with post-thoracotomy pain after three surgical procedures using current perception threshold testing. METHODS: The 32 patients were classified into three groups: the video-assisted thoracic surgery group (n=7), the video-assisted minithoracotomy with metal retractors group (n=15), and the conventional thoracotomy group (n=10). Intercostal nerve function was assessed by a series of 2000-Hz (Aß fiber), 250-Hz (Aδ fiber), and 5-Hz (C fiber) stimuli using current perception threshold testing (Neurometer CPT/C). The current perception threshold values were measured before and 1, 2, 4, 12, and 24 weeks after surgery. The intensities of ongoing pain were also assessed using a numeric rating scale (0-10). RESULTS: The video-assisted thoracic surgery group showed no changes in any current perception threshold values and no residual pain more than 12 weeks after surgery. The video-assisted minithoracotomy with metal retractors group and the conventional thoracotomy group showed significantly higher current perception threshold values at 2000 Hz 1 week after surgery (p=0.0013, p=0.0012, respectively), with pain in approximately 70% of patients 12 weeks after surgery. The correlation between current perception threshold values at 2000 Hz and the intensities of ongoing pain 4 and 12 weeks after surgery was significant (p=0.03, p=0.04, respectively). CONCLUSIONS: This is the first study that objectively evaluated pain after video-assisted thoracic surgery. The results suggest that the Aß and Aδ fibers play a significant role in the development of intercostal nerve damage. The current perception threshold values clearly demonstrated that video-assisted thoracic surgery is a less-invasive procedure resulting in less post-thoracotomy pain and, they have some possibilities to objectively evaluate the ongoing pain after surgery.

Establishment of ponasterone A-inducible the wild-type p53 protein-expressing clones from HSC-1 cells, cell growth suppression by p53 expression and the suppression mechanism.

Gene therapy for a variety of human cancers containing the mutant p53 (mt-p53) gene has been performed by direct injection of a retroviral or adenoviral vector containing the wild-type p53 (wt-p53) gene. Because many individuals with skin squamous cell carcinoma (SCC) have been shown to carry the p53 gene mutation, these patients are candidates for p53 gene therapy. For this reason, we established ponasterone A-inducible the wild-type p53 (wt-p53) protein-expressing clones by transfecting a ponasterone-inducible vector containing the wt-p53 gene into HSC-1 cells, which harbor the mutated p53 (m/w) at codon 173 (GTG --> TTG in one allele). Upon the induction of the wt-p53 protein, severe growth suppression was observed. Based on the results of the expression patterns of the p21, p16, RB, BAX and Bcl-2 proteins, as well as on the results of senescence-associated beta-galactosidase staining, the suppression was caused by senescence-like growth arrest of the cells. Although it is generally accepted that the suppression of tumor cell growth is caused by p53-induced apoptosis, permanent G1 arrest induced by p53 is also an important part of the growth-suppression mechanism in p53 gene therapy. The present results should expand the possibilities for p53 gene therapy for human skin SCCs containing the mutant p53 gene.

A novel role of serum cytochrome c as a tumor marker in patients with operable cancer.

PURPOSE: This study aimed to evaluate serum cytochrome c (cyto-c) levels as a novel role of tumor marker in patients with operable malignant tumors. METHODS: Serum cyto-c levels and lactate dehydrogenase (LD) activity were measured in a total of 257 cases (232 malignant and 25 benign). To identify the relationship between serum cyto-c and current tumor markers, six variables, such as gender, age, invasion, lymph node metastasis, distant metastasis, and LD, were analyzed by uni- and multivariate regression analysis methods. The test performance of serum cyto-c for the prediction of malignant behavior was evaluated by receiver operating characteristic (ROC) curves. RESULTS: The serum cyto-c level was significantly higher in patients with malignant tumors than patients with benign tumors (20.6 vs. 15.5 ng/mL; P = 0.017, Mann-Whitney U test). No difference in the levels among subtypes of cancer was found, indicating that the change in serum cyto-c levels reflect cancer individually and not specific subtypes of cancer. The survival in patients with serum cyto-c levels over 40 ng/mL was poor (Kaplan-Meier test, P < 0.0001, Hazard ratio 16.76, 95% confidential interval 4.45-63.04). Multiple linear regression analyses disclosed the close association of serum cyto-c levels with invasion (P = 0.0004), metastasis (P = 0.0262) except for regional lymph node metastasis, and activity of serum LD (P < 0.0001), all of which are well known to represent malignant behavior. Conversely, the measurement of serum cyto-c was verified to have excellent diagnostic accuracy of 0.802 and 0.781 for the detection of invasion and metastasis (the area under curves of the constructed ROCs). CONCLUSION: Serum cyto-c is a potent tumor marker as a predictor for malignant potential in cancers.