The combination of strong expression of ZNF143 and high MIB-1 labelling index independently predicts shorter disease-specific survival in lung adenocarcinoma.

BACKGROUND: The transcription factor, zinc finger protein 143 (ZNF143), positively regulates many cell-cycle-related genes. The ZNF143 would show high expression of multiple solid tumours related closely to cancer cell growth, similar to the widely accepted Ki67 (MIB-1) protein, but the underlying mechanisms for ZNF143 remain unclear. We investigated the association of ZNF143 expression with clinicopathological features and prognoses of patients with lung adenocarcinoma. METHODS: Expressions of ZNF143 and MIB-1 were immunohistochemically analysed in 183 paraffin-embedded tumour samples of patients with lung adenocarcinoma. The ZNF143 expression was considered to be strong when >30% of the cancer cells demonstrated positive staining. RESULTS: Strong ZNF143+ expression showed a significantly close relationship to pathologically moderate to poor differentiation and highly invasive characteristics. The ZNF143 positivity potentially induced cell growth of lung adenocarcinoma, correlated significantly with high MIB-1 labelling index (⩾10%). Univariate and multivariate analyses demonstrated that both strong ZNF143+ and the high MIB-1 index group have only and significantly worse survival rates. CONCLUSIONS: The combination of strong ZNF143 expression and high MIB-1 index potentially predicts high proliferating activity and poor prognosis in patients with lung adenocarcinoma, and may offer a therapeutic target against ZNF143.

Prognostic significance of lymphovascular invasion for patients with stage I non-small cell lung cancer.

AIMS: This study retrospectively investigated the clinical significance of lymphovascular invasion (LVI) following a complete resection for stage I non-small cell lung cancer (NSCLC). METHODS: A total of 226 patients who underwent a complete resection for pathological stage I NSCLC were examined. RESULTS: Lymphatic invasion was pathologically diagnosed as ly0 in 156 patients, ly1 in 65, and ly2 in 5 patients. The pathological vascular invasion was diagnosed as v0 in 178 patients, v1 in 35, v2 in 10, and v3 in 3 patients. The 5-year survival rate after surgery of the patients with and without lymphatic invasion was 76.8 and 90.6%, respectively. There was a significantly more unfavorable prognosis in patients with lymphatic invasion (p = 0.042). The 5-year survival rate of the patients with vascular invasion was also significantly more unfavorable (67.8%) than that of patients without vascular invasion (90.4%; p = 0.004). LVI was found to significantly correlate with tumor size and the presence of pleural invasion. CONCLUSION: The LVI of NSCLC is a significant prognostic factor in patients with stage I tumors. In future clinical trials, it is necessary to evaluate the efficacy of adjuvant therapy for the selection of patients according to this criterion.

Is lung resection appropriate for late octogenarians? Surgical outcomes of patients aged ≥ 80 years with lung cancer.

PURPOSE: This study aimed to determine the outcomes and prognostic factors associated with octogenarians who underwent pulmonary resection for lung cancer. METHODS/PATIENTS: From 2009 to 2018, 76 octogenarians underwent pulmonary surgery for lung cancer at the Kanazawa Medical University, Japan. They were divided into two groups (early and late octogenarians), and their clinicopathological characteristics and outcomes were investigated. Overall survival rates and recurrence-free survival rates were determined using Kaplan-Meier curves. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Limited surgery was performed more often in the late octogenarian group; however, most perioperative factors were not significantly different between the two groups. The 3-year overall survival and recurrence-free survival rates were 61.2% and 52.8%, respectively. The median observation period was 37.5 (8.9-112.3) months postoperatively. Kaplan-Meier curves showed that age ≥ 85 years (late octogenarian), smoking history, and squamous cell carcinoma on histology were associated with worse survival rates. Multivariate analysis identified age ≥ 85 years (late octogenarian) (p = 0.011) and cigarette smoking (p = 0.025) as unfavorable prognostic factors for overall survival and recurrence-free survival, respectively. CONCLUSIONS: Most octogenarians with an indication for surgery can tolerate pulmonary surgery. However, owing to the limitations of this retrospective, single-center study, future studies involving multiple-institutions are required to confirm our findings.

[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.

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.

[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.

Y box-binding protein-1 binds preferentially to single-stranded nucleic acids and exhibits 3'-->5' exonuclease activity.

We have previously shown that Y box-binding protein-1 (YB-1) binds preferentially to cisplatin-modified Y box sequences. Based on structural and biochemical data, we predicted that this protein binds single-stranded nucleic acids. In the present study we confirmed the prediction and also discovered some unexpected functional features of YB-1. We found that the cold shock domain of the protein is necessary but not sufficient for double-stranded DNA binding while the C-tail domain interacts with both single-stranded DNA and RNA independently of the cold shock domain. In an in vitro translation system the C-tail domain of the protein inhibited translation but the cold shock domain did not. Both in vitro pull-down and in vivo co-immunoprecipitation assays revealed that YB-1 can form a homodimer. Deletion analysis mapped the C-tail domain of the protein as the region of homodimerization. We also characterized an intrinsic 3'-->5' DNA exonuclease activity of the protein. The region between residues 51 and 205 of its 324-amino acid extent is required for full exonuclease activity. Our findings suggest that YB-1 functions in regulating DNA/RNA transactions and that these actions involve different domains.

Y-box binding protein 1 expression in gastric cancer subtypes and association with cancer neovasculature.

PURPOSE: Y-box binding protein 1 (YB-1) expression in cancer cells is closely associated with malignant progression and poor prognosis in various cancers. Recently, we demonstrated that YB-1 expression in cancer cells is an immunomarker for patient prognosis and liver metastasis of gastric cancer (GC), and identified YB-1 as an excellent biomarker of angiogenic and proliferating endothelial cells in cancers. We further explored the expression patterns of YB-1 in gastric vasculature and the relationship with the clinical pathologic characteristics, as well as YB-1 phenotype in cancer cells. METHODS/PATIENTS: Immunohistochemical analysis of YB-1 was performed using 163 surgically resected primary GC specimens. RESULTS: YB-1 expression in cancer cells significantly differed with respect to Lauren type, JGCA classification, vascular invasion (VI), and microvessel density (MVD) of cancers (P = 0.018, P = 0.002, P < 0.001, and P < 0.001, respectively). No correlation was found between cancer-cell YB-1 expression and TNM stage or lymphatic invasion. However, YB-1 expression in vascular endothelial cells significantly correlated with N stage, M stage, TNM stage, and MVD of cancers (P < 0.001, P = 0.013, P < 0.001, and P < 0.001, respectively). Notably, cases with YB-1 expression in cancer vasculature also demonstrated YB-1 expression in cancer cells (P = 0.040). CONCLUSIONS: YB-1 may promote GC development through its function in both cancer cells and cancer vascular cells, and thus represent a potential biomarker in this disease.

Fas expression in non-small cell lung cancer: its prognostic effect in completely resected stage III patients.

The aim of this study was to examine Fas expression in non-small cell lung cancer (NSCLC) and examine its correlation with clinicopathological features and prognosis. Fas expression was determined by an immunohistochemical analysis using the labelled streptavidin-biotin method from 220 paraffin specimens of completely resected primary stage I-III NSCLC. 80 (36%) of 220 cases were positive for Fas immunostaining. These 80 cases included 44 adenocarcinomas (33%) and 30 squamous cell carcinomas (40%). 33 stage I (33%) 13 (43%) stage II and 34 (37%) stage III tumours were Fas positive. No statistically significant differences were observed regarding the Fas status with respect to age, sex, histological type, or stage of disease. There was no significant difference in survival between early stage (stages I-II) disease patients with positive Fas expression and those with a negative expression (P = 0.719). However, for patients with completely resected stage III tumours, the patients with positive Fas staining were found to survive for a longer period than those with negative staining (P = 0.026).

Caffeine mimics dopamine receptor agonists without stimulation of dopamine receptors.

The purpose of this study was to examine whether caffeine stimulates dopamine (DA) receptors. The effects of caffeine on the binding of [3H]spiperone to membranes from the striatum, accumulation of L-DOPA in the striatum in mice receiving gamma-butyrolactone, and regional levels of 3,4-dihydroxyphenylacetic acid in the brain of the rat were investigated and compared with those elicited by DA receptor agonists. Caffeine did not inhibit the binding of [3H]spiperone to membranes or the accumulation of L-DOPA in the striatum, produced by gamma-butyrolactone. Caffeine decreased the levels of 3,4-dihydroxyphenylacetic acid significantly in the striatum, olfactory tubercle and nucleus accumbens and slightly in the frontal cortex of rats, whereas it delayed utilization of DA in all those regions except the frontal cortex. Taken together these results suggest that caffeine fails to stimulate pre- or postsynaptic DA receptors. The possible mechanism by which caffeine mimics DA receptor in DA metabolism and behavior are discussed.

Altered expression of amyloid precursors proteins after traumatic brain injury in rats: in situ hybridization and immunohistochemical study.

The expression of alternatively spliced mRNAs for amyloid precursor protein (APP) isoforms and their translation products were examined in the rat cerebral cortex 1, 3, 6, and 12 h and 1, 3, and 7 days (n = 4-5 in each group) after fluid-percussion brain injury. In situ hybridization studies demonstrated that the expression of APP695 mRNA decreased in and around the damaged area of the cerebral cortex exposed to fluid-percussion injury 1 h after the insult. On the other hand, APP751/770 mRNAs were increased in the regions surrounding the damaged cortical areas 1 day after the injury. An increase of immunoreactive APP was detected in the regions around the damaged cortical areas 3 h after traumatic injury and maintained for the following 3 days. The APP immunoreactivity in the damaged cortices declined to the level of sham-operated animals by post-experimental day 7. Using an anti-amyloid beta (Abeta) protein (17-24) antibody, no deposits of immunoreactive Abeta (17-24) were observed in any of the samples examined in these experiments. These results suggest that the induction of Kunitz-type protease inhibitor (KPI) domain-containing APP mRNAs and the increased accumulation of APP are involved in the physiological and neuropathological responses of brains under various neurodegenerative conditions, including head trauma.

Evaluations of p53 immunoreactivity, nucleolar organizer regions, and proliferating cell nuclear antigen in non-small cell lung carcinoma.

We examined p53 protein expression, proliferating cell nuclear antigen (PCNA), and argyrophilic nuclear organizer regions (AgNOR), in 102 patients with surgically-treated non-small cell lung cancer (NSCLC). p53 positive cases with DO-1 were defined when more than 10% of the tumor cell nuclei were stained. Mean AgNOR count and PCNA LI were 2.80 and 40.7 and there were no significant differences of AgNOR count and PCNA LI between p53 positive and negative cases. We assessed the relationship between the p53 immunoreactivity and various clinical or pathological parameters. p53 positive rate of stage III disease (46.3%) was significantly higher than that of stage II disease (28.6%). The p53 positive rate of squamous cell carcinoma (42.1%) tended to be higher than that of adenocarcinoma (33.9%). In the survival curves of patients with NSCLC according to the p53 immunoreactivity, there was no significant difference between p53 positive and negative cases. Eight potential prognostic parameters (p53 immunoreactivity, AgNOR count, PCNA LI, sex, age, year of operation, histology, and stage) were also estimated, using univariate and multivariate analysis. In univariate analysis, PCNA LI and AgNOR count, and stage were significantly related to shortened survival. In multivariate analysis, PCNA LI, Age, and stage were independently associated with shortened survival of NSCLC patients. PCNA staining may be more useful than p53 and AgNOR staining in assessing the aggressiveness of surgically-treated NSCLC, although the most useful clinical prognostic parameter should be achieved by the combined analysis of several prognostic indicators.

Chronic expanding hematoma in the chest.

We report the successful surgical treatment of chronic expanding hematoma in the chest. Four patients who had previously undergone artificial pneumothorax, thoracoplasty or tumor extirpation more than 30 years earlier recently became aware of a slowly growing mass. Chronic expanding hematoma which developed into very large masses over a long period of time were thus successfully resected. These patients are now all in good health with no recurrence after the operation. It is important to monitor such patients' laboratory data for hemostasis including the platelet cell counts, the % prothrombin time and the D-dimer, both before and immediately after operation, and the intraoperative bleeding volume.

Inferior vena cava injury after catheterization: report of a case.

We present a patient with retroperitoneal hematoma suspicious of inferior vena cava injury after catheterization for hemodialysis. Emergency computed tomography revealed extensive retroperitoneal hematoma and inferior vena cava angiography revealed extravasation. Emergent laparotomy was performed and repaired the perforation of inferior vena cava. His postoperative courses were uneventful and he remains well after the operation.

Differences in the influence of AIN-purified and non-purified diets on the development of hypertension in SHR and DOCA-salt hypertensive rats.

The influence of non-purified and AIN purified diets on the development of hypertension was examined in deoxycorticosterone acetate (DOCA)-salt hypertensive rats and SHRs. For DOCA-salt hypertensive rats, the development of hypertension was slower in rats fed the AIN 76-purified diet than in those fed the non-purified diet throughout the experimental period of about five weeks. In an experiment using spontaneously hypertensive rats (SHRs), 4-week-old rats were fed either a non-purified diet, a AIN76-purified diet or a AIN93G-purified diet for about nine weeks. In the first 1-2 weeks, the blood pressure was lower in the SHRs fed the AIN93G-purified diet than in those fed the non-purified diet. However, no significant difference in blood pressure was observed within the SHR group thereafter.

Lack of influence of a long-term high or low vitamin E diet on the oxidative DNA damage in the bone marrow of mice.

To investigate the influence of dietary vitamin E (VE) on DNA damage in bone marrow, we fed mice either a low VE diet (-VE), a basal VE diet (+30 mg VE/kg) or a high VE diet (+1000 mg VE/kg) for 50 weeks. DNA damage was evaluated by two cytogenetic methods: micronucleus (MN) assay using peripheral blood, and examination of sister chromatid exchanges (SCE) in bone marrow cells. The MN assay was performed periodically from 6 to 50 weeks, and showed that the incidence of reticulocytes containing MNs did not increase in the low VE diet group, and did not decrease in the high VE diet group. SCE assay done at 50 weeks also showed no difference among the VE diet groups. VE in bone marrow was markedly lower in the low VE diet group and higher in the high VE diet group compared to that in the basal VE diet group at 6 weeks. The VE at 50 weeks was not markedly different from that at 6 weeks. Corresponding to the changes in the VE, lipid peroxide in bone marrow was higher in the low VE diet group, but was not lower in the high VE diet group. Glutathione and vitamin C in the bone marrow, which were about 100-1000 times higher than that of VE, were not different among the groups.

Benign mesenchymoma of the mediastinum.

We report our recent experience of a rare case of a benign mesenchymoma in the mediastinum. A 24-year-old man was admitted to our hospital with an abnormal shadow on chest X-ray. A chest computerized tomography scan and magnetic resonance imaging showed an anterior mediastinal mass along the right border of the pericardium. The tumor was surgically resected. It was yellow on the surface, 12.5 x 10.0 x 3.8 cm in size, and 230 g in weight. The histopathological diagnosis was a benign mesenchymoma. The postoperative course was uneventful. A search of the literature revealed that a benign mesenchymoma in the mediastinum is extremely rare. It seems to be difficult to reach a definitive diagnosis preoperatively. Surgical resection can confirm the diagnosis, and is curative.

[Treatment and results of interstitial lung diseases in video assisted thoracoscopic lung biopsy].

In order to establish treatment of interstitial lung diseases in video assisted thoracoscopic lung biopsy, we retrospectively reviewed our experiences. The present study included 7 patients with a mean age of 46.4, range from 24 to 61, who were treated at our department from 1996 through 1999. They were 5 men and 2 women. The pathologic diagnosis was nonspecific interstitial pneumonia in 3 patients who responded to steroid therapy. Three other patients had usual interstitial pneumonia. One patient had lymphocytic interstitial pneumonia. No complications occurred. The results indicate that video assisted thoracoscopic lung biopsy is an effective and safe way to diagnose interstitial lung diseases.

Influence of aging on stress ulcer formation in rats.

The effects of aging on stress ulcer formation were examined in male Fischer 344 rats at 2, 8-9, 11-12, 17-18 and 21-24 months old. The animals were restrained and immersed in a water bath (22 degrees C) for 1, 2, 4 and 8 h. The incidence and severity of gastric corpus ulceration increased linearly with age. Basal acid secretion, determined 4 h after pylorus ligation, decreased with age, but there were no age-related differences in the effect on acid secretion of histamine and vagal nerve stimulation in the lumen-perfused stomachs of anesthetized rats. On morphological examination, surface epithelial cells in aged rats (21-24 months) were found to be intact, but the gastric foveolae were shallow and the chief cell layer was thick in aged rats. Deficiencies of vascular networks were observed in aged rat stomachs. These results indicate that an insufficiency of gastric mucosal microvascular networks and the preserved gastric acid response in the vulnerable mucosa may be involved in the mechanisms underlying aggravation of stress ulcer formation in aged rats.