Involvement of inhibitory PAS domain protein in neuronal cell death in Parkinson's disease.

Inhibitory PAS domain protein (IPAS), a repressor of hypoxia-inducible factor-dependent transcription under hypoxia, was found to exert pro-apoptotic activity in oxidative stress-induced cell death. However, physiological and pathological processes associated with this activity are not known. Here we show that IPAS is a key molecule involved in neuronal cell death in Parkinson's disease (PD). IPAS was ubiquitinated by Parkin for proteasomal degradation following carbonyl cyanide m-chlorophenyl hydrazone treatment. Phosphorylation of IPAS at Thr12 by PTEN-induced putative kinase 1 (PINK1) was required for ubiquitination to occur. Activation of the PINK1-Parkin pathway attenuated IPAS-dependent apoptosis. IPAS was markedly induced in the midbrain following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, and IPAS-deficient mice showed resistance to MPTP-induced degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). A significant increase in IPAS expression was found in SNpc neurons in patients with sporadic PD. These results indicate a mechanism of neurodegeneration in PD.

Involvement of brain oxidation in the cognitive impairment in a triple transgenic mouse model of Alzheimer's disease: noninvasive measurement of the brain redox state by magnetic resonance imaging.

Oxidative stress is considered to be related to the onset and/or progression of Alzheimer's disease (AD), but there is insufficient evidence of its role(s). In this study, we evaluated the relationships between the brain redox state and cognitive function using a triple transgenic mouse model of AD (3 × Tg-AD mouse). One group of 3 × Tg-AD mice started to receive an α-tocopherol-supplemented diet at 2 months of age and another group of 3 × Tg-AD mice was fed a normal diet. The levels of α-tocopherol, reduced glutathione, oxidized glutathione, and lipid peroxidation were decreased in the cerebral cortex and hippocampus at 4 months of age in the 3 × Tg-AD mice fed a normal diet. These reductions were abrogated by the supplementation of α-tocopherol in the diet. During Morris water maze testing, the 3 × Tg-AD mice did not exhibit cognitive impairment at 4 months of age, but started to show cognitive dysfunction at 6 months of age, and α-tocopherol supplementation suppressed this dysfunction. Magnetic resonance imaging (MRI) using 3-hydroxymethyl-proxyl as a probe showed decreases in the signal intensity in the brains of 3 × Tg-AD mice at 4 months of age, and this reduction was clearly attenuated by α-tocopherol supplementation. Taken together, these findings suggest that oxidative stress can be associated with the cognitive impairment in 3 × Tg-AD mice. Furthermore, MRI might be a powerful tool to noninvasively evaluate the increases in reactive radicals, especially those occurring during the early stages of AD.

Variations in the structure and transcription of the mitochondrial atp and cox genes in wild Solanum species that induce male sterility in eggplant (S. melongena).

In order to determine the molecular basis of cytoplasmic male sterility (CMS) in alloplasmic lines of eggplant, the genomic structures and transcription patterns of mitochondrial ATP synthase subunit (atp) and cytochrome oxidase subunit (cox) genes were studied for wild and cultivated eggplants. Alloplasmic eggplant lines with cytoplasms of wild Solanum species showing either anther indehiscent type of CMS or non-pollen production type of CMS were studied with the cultivated eggplant Solanum melongena, used as a control. Southern hybridization of the mitochondrial genes indicated the difference between the two types of CMS and showed complete identity within each type. The cytoplasmic patterns of all wild species differed from that of the cultivated eggplant. Thus, the cytoplasm of the six wild eggplants and the one cultivated eggplant was classified into three groups. Male sterile plants of both types of CMS showed novel transcription patterns of atp1, whereas a different transcription pattern of cox2 was observed only in the anther indehiscent type. Based on these differences, we determined the DNA sequences of about a 4 kbp segment in the atp1 region. Although the coding and 3' flanking regions were almost identical among the cytoplasms, the 5' flanking region was completely different and novel open reading frames (orfs) were found for each of the CMS types and the cultivated eggplant. The cytoplasm of Solanum kurzii inducing the anther indehiscent type CMS had orf312, and those of Solanum aethiopicum and Solanum grandifolium of non-pollen production type CMS had orf218. The correspondence between the transcription patterns of these orfs and phenotypic expression of male sterility strongly suggests that these orfs are causal genes for each type of CMS.

Correlation between variable-number tandem-repeat-based genotypes and drug susceptibility in Mycobacterium avium isolates.

Little is known about the correlation between genotype and drug susceptibility in Mycobacterium avium (Mav) strains isolated from patients with Mav infections. To examine whether drug susceptibility profile of Mav is associated with genotype, we carried out variable-number tandem-repeat (VNTR) typing and drug susceptibility testing for Mav isolates from Japanese with nodular-bronchiectasis (NB)-type and cavitary disease (CA)-type diseases. We performed M. avium tandem repeat (MATR)-VNTR typing and drug susceptibility testing by the broth dilution method, using macrolides, rifamycins, ethambutol, isoniazid, aminoglycosides, and quinolones, for Mav isolates from patients with NB and CA-type diseases (NB-Mav and CA-Mav). Based on the VNTR genotyping, the Mav strains were grouped into three clusters. There was no difference with respect to the distribution of NB-Mav and CA-Mav among the clusters. We observed a strong association between VNTR genotype and susceptibility to quinolones (levofloxacin, moxifloxacin, gatifloxacin, sitafloxacin, and garenoxacin) and ethambutol. There was essentially no significant difference in drug susceptibility between NB- and CA-Mav strains, although NB-Mav was somewhat more resistant to fluoroquinolones, especially gatifloxacin, than CA-Mav. There was a significant association between VNTR genotype and susceptibility to quinolones and ethambutol in Mav isolates from Japanese patients.

Results of a surgical resection for patients with thymic carcinoma.

OBJECTIVES: This study investigated the clinical features of patients with complete resection of thymic carcinoma. PATIENTS AND METHODS: The clinical records from 11 patients who underwent a complete re-section of thymic carcinoma were retrospectively reviewed. RESULTS: Twelve of 22 patients underwent a resection (a complete resection in 11 and an in-complete in 1). Six of the 11 patients with complete had confirmed recurrent tumors. The 5-year survival rate was 45.4%, and the median survival time was 50.6 months. The patients who underwent complete resection showed significantly better prognosis than cases with incomplete resection and inoperable cases (p = 0.048). Three of the 6 patients had a recurrence within 1 year. Frequent sites of recurrence were the pleura, pericardium, and lung. CONCLUSIONS: A complete resection improved the prognosis of thymic carcinoma. Further prospective studies regarding postoperative adjuvant therapy are necessary to prevent local recurrence after a surgical resection for thymic carcinoma.

Pro-apoptotic activity of inhibitory PAS domain protein (IPAS), a negative regulator of HIF-1, through binding to pro-survival Bcl-2 family proteins.

Inhibitory PAS (Per/Arnt/Sim) domain protein (IPAS) is a dominant negative transcription factor that represses hypoxia-inducible factor 1 (HIF-1) activity. In this study, we show that IPAS also functions as a pro-apoptotic protein through binding to pro-survival Bcl-2 family members. In a previous paper, we reported that NF-κB-dependent IPAS induction by cobalt chloride repressed the hypoxic response in PC12 cells. We found that prolonged incubation under the same conditions caused apoptosis in PC12 cells. Repression of IPAS induction protected cells from apoptosis. Furthermore, knockdown of IPAS recovered cell viability. EGFP-IPAS protein was localized in both the nucleus and the cytoplasm, with a large fraction associated with mitochondria. Mitochondrial IPAS induced mitochondria depolarization and caspase-3 activation. Immunoprecipitation assays revealed that IPAS is associated with Bcl-x(L), Bcl-w and Mcl-1. The association of IPAS with Bcl-x(L) was also observed in living cells by the FLIM-based FRET analysis, indicating direct binding between the two proteins. IPAS contributed to dysfunction of Bcl-x(L) by inhibiting the interaction of Bcl-x(L) with Bax. These results demonstrate that IPAS functions as a dual function protein involved in transcription repression and apoptosis.

[Surgical treatment for patients with descending necrotizing mediastinitis].

Descending necrotizing mediastinitis (DNM) originating from deep cervical infection is a rare and serious clinical condition with a high mortality rate. Clinical feature of 5 patients undergone surgical drainage for DNM, between 2006 and 2009 were assessed. There were 3 male and 2 female patients whose age ranged from 57 to 83 years old (mean 69.8). All 5 patients had no underlying disease except for 1 patient with severe dental caries. The primary infections of these patients were tonsillitis and pharyngitis. The mean duration from onset of symptom to the referral to our hospital was 14 days (ranged 2 to approximately 41). Two patients underwent cervical drainage for upper mediastinum, and 3 patients were required mediastinal drainage by thoracotomy. There was no post-operative death. Early and aggressive surgical drainage of the neck and mediastinum by a multidisciplinary team of surgeons is very important in the treatment of DNM.

Comparative study for the virulence of Mycobacterium avium isolates from patients with nodular-bronchiectasis- and cavitary-type diseases.

Mycobacterium avium (Mav) lung infections, called nodular-bronchiectasis (NB)-type M. avium complex (MAC) disease, are globally increasing. To elucidate whether there are unusual populations of Mav, causing NB-type disease rather than cavitary (CA)-type disease, we compared the virulence of Mav isolates from patients with NB-type (NB-Mav) and those from CA-type (CA-Mav) diseases, based on intracellular growth in various types of human cells. Five strains each of NB-Mav and CA-Mav were compared with each other for their invasiveness and ability to intracellularly replicate in various types of cultured cells of human origin. The two types of Mav isolates showed a similar ability, on average, to replicate in macrophages and lung epithelial cells. Moreover, they showed a similar ability to induce the production of reactive nitrogen intermediates and reactive oxygen intermediates by macrophages and susceptibility to antimicrobial molecules. Therefore, it appears that there is no essential difference in virulence in terms of infectivity to human macrophages and lung cells between Mav strains isolated from NB-MAC disease and those from CA-MAC disease. These findings indicate the importance of further studies to elucidate the mechanism for the establishment of NB-type MAC diseases based on host immunological conditions rather than the pathogenic nature of MAC organisms themselves.

[Postoperative recurrence of spontaneous pneumothorax].

Few reports on recurrence after thoracoscopic bullectomy for spontaneous pneumothorax specify the follow-up period and follow-up ratio. Because of the variation in follow-up periods, many reported recurrence rates were not comparable. Some reports compared simple recurrence rate (number of recurrent cases/number of operated cases) of different groups with different follow-up periods. In this study, we employ the Kaplan-Meier method along with a set of optimal follow-up periods and ratios in order to determine a more reliable recurrence rate. Consecutive 68 patients (74 surgical procedures) underwent thoracoscopic bullectomy for spontaneous pneumothorax at our institution between November 2000 and December 2005. A follow-up survey was conducted by phone to determine the rate of recurrent pneumothorax. The follow-up ratio and the mean follow-up period were 92.6% and 1,316 +/- 481 days, respectively. Postoperative recurrence was confirmed for 4 patients. The interval up to recurrence was 144, 345, 476 and 616 days after the bullectomy, respectively. All cases of recurrent pneumothorax occurred within 2 years following the bullectomy. The 1-year, 2-year and 3-year cumulative recurrence rate was 3.0%, 6.3% and 6.3%, respectively. In light of these findings, we feel that comparison analysis of pneumothorax recurrence rates should be evaluated using the Kaplan-Meier method, furthermore, our data suggests that a follow-up period of 2 or more years is advisable.

[Molecular targeted therapy and tailor-made therapy for lung cancer].

Somatically acquired mutations in the epidermal growth factor receptor (EGFR) gene in lung cancer are associated with significant clinical responses to gefitinib, a tyrosine kinase inhibitor (TKI) that targets EGFR. In our previous report, 42.2% of adenocarcinoma patients has EGFR mutations, and these mutations were more frequently found in women than in men, in well differentiated tumors than poorly differentiated tumors, and in patients who were never smokers than in patients who were current/former smokers. Retrospectively, we screened the EGFR gene of tumors in 37 NSCLC patients who had been treated with gefitinib. EGFR mutations were found in 22 patients. Gefitinib was effective (CR/PR) in 15 of 22 (68.2%) patients with mutations compared with none of 15 patients without mutations. Patients with EGFR mutations survived for a longer period than without the mutations after initiation of gefitinib treatment (p = 0.0005). Gefitinib was not effective in 3 patients with K-ras mutations. Three of 4 tumors obtained from patients with acquired resistant to gefitinib, had a secondary T790M mutation. No T790M mutation was detected in pretreatment tumors. Molecular targeted therapy using TKI indicates an effective therapy specifically in lung cancer patients with EGFR mutations, and analyses of mechanisms of resistance to TKI are necessary for establishment of tailor-made therapy.

Acute lung injury following an esophagectomy for esophageal cancer, with special reference to the clinical factors and cytokine levels of peripheral blood and pleural drainage fluid.

Acute lung injury (ALI) is one of most serious complications to occur after an esophagectomy for esophageal cancer. However, the pathogenesis of ALI is still unclear. The cytokine levels of pleural drainage fluid as well as peripheral blood were measured in 27 patients who had undergone an extended radical esophagectomy. Both the clinical factors and cytokine levels were compared between 11 patients with (group I) and 16 without ALI (group II). ALI occurred more frequently in patients who underwent colon interposition than in those who received a gastric tube reconstruction (86%vs 25%, P = 0.009). The operation time of group I was significantly longer than that of group II. A logistic regression analysis revealed colon interposition to be an independent factor associated with the ALI (P < 0.05). Postoperative anastomotic leakage and systemic inflammatory response syndrome (SIRS) occurred more frequently in group I than in group II (P < 0.01). Both the serum interleukin-6 (IL-6) and IL-8 levels of group I were significantly higher than those of group II. IL-1beta and tumor necrosis factor-alpha were undetectable in the peripheral blood, whereas they were detectable in the pleural effusion. The IL-1beta of pleural effusion was higher in group I than group II. In conclusion, greater surgical stress, such as a longer operative time, is thus considered to be associated with the first attack of ALI. The adverse events developing in the extra-thoracic site, such as necrosis and local infection around anastomosis may therefore be the second attack. Furthermore, ALI may cause not only SIRS but also other complications such as anastomotic leakage.

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines.

The mechanisms underlying cellular drug resistance have been extensively studied, but little is known about its regulation. We have previously reported that activating transcription factor 4 (ATF4) is upregulated in cisplatin-resistant cells and plays a role in cisplatin resistance. Here, we find out a novel relationship between the circadian transcription factor Clock and drug resistance. Clock drives the periodical expression of many genes that regulate hormone release, cell division, sleep-awake cycle and tumor growth. We demonstrate that ATF4 is a direct target of Clock, and that Clock is overexpressed in cisplatin-resistant cells. Furthermore, Clock expression significantly correlates with cisplatin sensitivity, and that the downregulation of either Clock or ATF4 confers sensitivity of A549 cells to cisplatin and etoposide. Notably, ATF4-overexpressing cells show multidrug resistance and marked elevation of intracellular glutathione. The microarray study reveals that genes for glutathione metabolism are generally downregulated by the knockdown of ATF4 expression. These results suggest that the Clock and ATF4 transcription system might play an important role in multidrug resistance through glutathione-dependent redox system, and also indicate that physiological potentials of Clock-controlled redox system might be important to better understand the oxidative stress-associated disorders including cancer and systemic chronotherapy.

Mutations within the tyrosine kinase domain of EGFR gene specifically occur in lung adenocarcinoma patients with a low exposure of tobacco smoking.

Somatically acquired mutations in the epidermal growth factor receptor (EGFR) gene in lung cancer are associated with significant clinical responses to gefitinib, a tyrosine kinase inhibitor that targets EGFR. We screened the EGFR in 469 resected tumours of patients with lung cancer, which included 322 adenocarcinomas, 102 squamous cell carcinomas, 27 large cell carcinomas, 13 small cell carcinomas, and five other cell types. PCR with a specific condition was performed to identify any deletion in exon 19, while mutant-allele-specific amplification was performed to identify a mutation in codon 858 of exon 21. EGFR mutations were found in 136 cases (42.2%) with adenocarcinoma, in one case with large cell carcinoma, and in one case with pleomorphic carcinoma. An in-frame deletion in exon 19 was found in 62 cases while an L858R mutation was found in 77 cases. In the 322 cases with adenocarcinoma, these mutations were more frequently found in women than in men (P=0.0004), in well differentiated tumours than in poorly differentiated tumours (P=0.0014), and in patients who were never smokers than in patients who were current/former smokers (P<0.0001). The mutation was more frequently observed in patients who smoked

Low expression of polypeptide GalNAc N-acetylgalactosaminyl transferase-3 in lung adenocarcinoma: impact on poor prognosis and early recurrence.

Initial glycosylation of mucin-type O-linked protein is catalysed by one of the UDP-GalNAc: polypeptide N-acetyl-galactosaminyl transferase-3 (GalNAc-T3). O-glycosylation is important in the binding of cell adhesion molecules, cell differentiation, invasion, and metastasis in tumours. This study was designed to detect GalNAc-T3 expression in lung adenocarcinoma by using immunohistochemical staining, and to evaluate the relationship between the GalNAc-T3 expression level and prognosis and recurrence in completely resected lung adenocarcinoma patients. A low expression of GalNAc-T3 was detected in the cytoplasm of tumour cells in 79 of 148 patients (53.4%) with lung adenocarcinoma. The low expression of GalNAc-T3 was associated with poorly differentiated tumour (P<0.0001), poor pathologic stage (P<0.0001), lymph node metastasis (P<0.0001), and tumour recurrence (P=0.016). The lung carcinoma patients with low GalNAc-T3 expression had a poorer prognosis than those with high GalNAc-T3 expression, using both univariate and multivariate analyses (overall survival: P<0.0001 and P=0.011, respectively). In addition, multivariate analysis of the clinicopathological characteristics of stage I lung adenocarcinoma indicated that the low expression of GalNAc-T3 was a significant independent factor for predicting poor prognosis and early recurrence (P=0.006, rr=2.87 and P=0.019, rr=3.05, respectively). The low expression of GalNAc-T3 may be a useful marker for predicting poor prognosis and early recurrence in completely resected lung carcinoma patients, particularly patients with stage I diseases.

CD44: functional relevance to inflammation and malignancy.

CD44 is a principal cell surface receptor for hyaluronan, a major component of extracellular matrices. Cells are surrounded by and encounter matrix in vivo, which in turn serves a variety of cell functions through the direct adhesion via their receptors. CD44 communicates cell-matrix interactions into the cell via "outside-in signaling" and has an important role in biological activities. The interaction of CD44 with fragmented hyaluronan on rheumatoid synovial cells induces expression of VCAM-1 and Fas on the cells, which leads to Fas-mediated apoptosis of synovial cells by the interaction of T cells bearing FasL. On the other hand, engagement of CD44 on tumor cells derived from lung cancer reduces Fas expression and Fas-mediated apoptosis, resulting in less susceptibility of the cells to CTL-mediated cytotoxicity through Fas-FasL pathway. Thus, although the CD44-mediated signaling differs among cells and circumstances, we here propose the functional role of CD44 in inflammatory processes and tumor susceptibility and the rational design of future therapeutic strategies including the exploitation of CD44-mediated pathway in vivo.

[Assessment of prognosis and p 53 mutations in patients with multiple tumors of the lung; intrapulmonary metastasis or double primary cancers?].

To assess whether a satellite lesion in the primary-tumor lobe is intrapulmonary metastasis from primary cancer (pm 1) or they are double primary lung cancers, we examined the postoperative prognosis of patients with pm 1 and the p 53 genetic differentiation between a satellite lesion and a primary lesion. Of 772 consecutive patients with N0-2M0 non-small cell lung cancer who underwent surgical resections between 1979 and 2000, 31 patients had a satellite lesion in the primary-tumor lobe. The 5-year survival rate was 26.3% in the pm 1 (+) T 4 group (n = 37), 14.7% in the pm 1 (-) T 4 group (n = 43), and 32.5% in the T 3 group (n = 132), suggesting that pm 1 cases should be classified as T 3. We examined 16 of 37 patients with pm 1 for mutations of the p 53 gene occurring exons 5 through 8 by the fluorescence-based polymerase chain reaction single-strand conformation polymorphism. Seven of the 16 patients analyzed had at least one p 53 mutations in their tumors. The mutational status of the p 53 gene was discordant in 5 patients, suggesting they were double primary lung cancers. The mutational status including DNA sequencing of the p 53 gene was concordant in 2 patients, suggesting they were intrapulmonary metastases. It remains arguable in the TNM staging system whether a satellite lesion in the primary-tumor lobe is intrapulmonary metastasis from primary cancer or they are double primary lung cancers.

Association of plasma free-3-methoxy-4-hydroxyphenyl (ethylene)glycol, natural killer cell activity and delirium in postoperative patients.

We measured and compared levels of plasma free 3-methoxy-4-hydroxyphenyl (ethylene)glycol (pMHPG), a major metabolite of noradrenaline, and natural killer (NK) cell activity in 26 patients prior to their undergoing an operation for cardiovascular diseases; 11 of whom expressed delirium and 15 who did not. In conclusion, we found that pMHPG levels before an operation were higher in patients with postoperative delirium than in the patients without, while NK cell activity showed no difference between the two groups. It is possible that hyperactivity of noradrenargic neurons is connected with the development of postoperative delirium. Furthermore, we considered that measurement of pMHPG level before operation might be a useful tool to predict the occurrence of postoperative delirium.

Analysis of MAGE-3 derived synthetic peptide as a human lung cancer antigen recognized by cytotoxic T lymphocytes.

BACKGROUND: The human MAGE-3 gene was originally discovered in melanoma cells that encode tumor antigens, and has been reported to be expressed in various types of tumors, including lung cancer, but not in normal tissues other than testis or placenta. Our aim in this study was to clarify whether HLA-A2 restricted MAGE-3 peptide (FLWGPRALV) could be a lung cancer antigen recognized by cytotoxic T lymphocytes (CTL). METHODS: MAGE-3-derived peptide-specific CTL were induced from the peripheral blood mononuclear cells (PBMC) of HLA-A0201-positive healthy donors and the regional lymph node lymphocytes (RLNL) of HLA-A2-positive patients with lung cancer by multiple stimulations with peptide-pulsed HLA-A0201-positive antigen-presenting cells. RESULTS: Lymphocytes stimulated with MAGE-3 peptide exhibited specific lysis of Epstein-Barr virus-transformed B cells (EBV-B) pulsed with MAGE-3 peptide, but not with control peptide derived from influenza matrix protein, erbB-2, or wild type p53. Specific activity for MAGE-3-presenting targets was found after the second stimulation, and increased depending on the number of stimulations. The peptide-specific activity was inhibited by the addition of monoclonal antibodies against MHC class I and HLA-A2. Such CTL also recognized tumor cell lines expressing both HLA-A2 and MAGE-3 in an MHC class I-restricted manner, but did not recognize tumor cell lines that did not express HLA-A2 or MAGE-3. CONCLUSION: These results suggested the MAGE-3 peptide could be a potential target of specific immunotherapy for HLA-A2 patients with lung cancer.

Clinical features and therapeutic outcomes of 65 patients with acromegaly at Tokyo Women's Medical University.

OBJECTIVE: The purpose of this study was to survey the clinical characteristics, complications, and therapeutic outcome in patients with acromegaly. PATIENTS AND METHODS: The clinical features of 65 patients with acromegaly (31 males, 34 females; mean age: 50+/-2 yr.) who were admitted to Tokyo Women's Medical University between 1990 and 1999 were analyzed retrospectively from medical records. RESULTS: The retrospective analysis revealed that the diagnosis of acromegaly was preceded by approximately 8.1+/-1.1 years of signs and symptoms of the disease. Forty-six of the 65 patients (71%) had macroadenomas, 16 (25%) had microadenomas, and the remaining three had empty sella. The rate of biochemical cure or remission was 81% for microadenoma (13/16), 64% for macroadenoma without extrasellar extension (9/14), and 13% for macroadenoma with cavernous sinus extension (2/15). Eighteen (28%) patients had impaired glucose tolerance (IGT) and 32 (49%) had diabetes mellitus (DM). After treatment for acromegaly, glucose metabolism was analyzed again in 38 patients, and it improved in 26 patients with IGT or DM. Twenty-five of 65 patients (38%) had hypertension. Of 26 patients who underwent barium enema or colonoscopy, 10 had colonic polyps and 4 had colon cancer. CONCLUSION: This study suggests that long-term excessive growth hormone (GH) secretion causes many complications. Therefore, awareness of the early symptoms and signs of acromegaly and long-term careful management of complications, along with therapy to reduce serum GH/insulin-like growth factor (IGF)-I levels, are important for patients with acromegaly.

Expression of Y box-binding protein-1 correlates with DNA topoisomerase IIalpha and proliferating cell nuclear antigen expression in lung cancer.

Y box-binding protein-1 (YB-1), a member of the DNA binding protein family, interacts with inverted CCAAT boxes (Y-boxes). Y-boxes are located on the promoter of numerous genes, such as DNA topoisomerase IIalpha (Topo IIalpha), proliferating cell nuclear antigen (PCNA) and multidrug resistance 1 (MDR1). In this study, we used immunohistochemical (IHC) staining to detect YB-1 expression in 59 lung cancer tissues and to evaluate whether YB-1 expression was associated with the expression of YB-1 target genes such as Topo IIalpha, PCNA and MDR1 in human lung carcinoma. Twenty-eight out of 59 cases (47.5%) were stained positive for YB-1 in the cytoplasm, while 30 out of 59 cases (50.8%) were positive for PCNA in the nuclei. Topo IIalpha-positive cells were detected in 16 out of 59 cases (27.1%). Eight out of 59 cases (13.6%) had greater than 5% P-gp positive cells expression. There was a significant correlation between the YB-1 and Topo IIalpha expression in small cell lung cancer (SCLC) (p=0.0242). YB-1 expression also correlated with PCNA expression in non-small cell lung cancer (NSCLC) (p=0.0001). Higher levels of YB-1 expression were associated with T3-4 and Stage III-IV tumors in adenocarcinomas (p=0.0072; p=0.0168). In contrast, no relationship was found between YB-1 expression and P-gp expression. Our study suggests that YB-1 expression correlates with Topo IIalpha and PCNA expression in lung cancer.