Revelation of p53-independent function of MTA1 in DNA damage response via modulation of the p21 WAF1-proliferating cell nuclear antigen pathway.

Although metastasis-associated protein 1 (MTA1), a component of the nucleosome remodeling and deacetylase (NuRD) complex, is a DNA-damage response protein and regulates p53-dependent DNA repair, it remains unknown whether MTA1 also participates in p53-independent DNA damage response. Here, we provide evidence that MTA1 is a p53-independent transcriptional corepressor of p21(WAF1), and the underlying mechanism involves recruitment of MTA1-histone deacetylase 2 (HDAC2) complexes onto two selective regions of the p21(WAF1) promoter. Accordingly, MTA1 depletion, despite its effect on p53 down-regulation, superinduces p21(WAF1), increases p21(WAF1) binding to proliferating cell nuclear antigen (PCNA), and decreases the nuclear accumulation of PCNA in response to ionizing radiation. In support of a p53-independent role of MTA1 in DNA damage response, we further demonstrate that induced expression of MTA1 in p53-null cells inhibits p21(WAF1) promoter activity and p21(WAF1) binding to PCNA. Consequently, MTA1 expression in p53-null cells results in increased induction of gamma H2AX foci and DNA double strand break repair, and decreased DNA damage sensitivity following ionizing radiation treatment. These findings uncover a new target of MTA1 and the existence of an additional p53-independent role of MTA1 in DNA damage response, at least in part, by modulating the p21(WAF1)-PCNA pathway, and thus, linking two previously unconnected NuRD complex and DNA-damage response pathways.

Clinicopathological and molecular characteristics of synchronous gastric adenocarcinoma and gastrointestinal stromal tumors.

Synchronous gastric tumors that consist of both gastrointestinal stromal tumor (GIST) and adenocarcinoma are rare. We studied the clinicopathological and molecular characteristics of six cases containing both gastric adenocarcinoma and GIST. By means of immunohistochemical analysis, all GIST cells expressed CD117, CD34 and Dog1 in all six synchronous gastric adenocarcinomas with GIST, and in GIST alone. Sequencing analysis demonstrated that exon 11 c-kit mutations were present in two of six synchronous tumors and four of five GISTs. One of the two exon 11 c-kit mutations in synchronous adenocarcinomas with GISTs was an uncommon mutation of CTT > CCA at amino acid 576, and the other was a GTT deletion at amino acid 560. The mutation was a homozygous A > G mutation in exon 12 (amino acid 567) of PDGFR-α. We concluded that the exon 11 mutations were the most important in both cases of synchronous gastric adenocarcinoma with GIST and GIST alone. The mutation rate was higher in GIST alone than in synchronous adenocarcinoma with GIST.

Significance and relationship between infiltrating inflammatory cell and tumor angiogenesis in hepatocellular carcinoma tissues.

AIM: To investigate the relationship between infiltrating inflammatory cell and tumor angiogenesis in hepatocellular carcinoma (HCC) tissues and their clinicopathological features. METHODS: The paraffin-embedded specimens from 70 cases with HCC were stained using EliVision immunohistochemistry with mAbs against CD68, tryptase, and CD34. The counts of tumor-associated macrophage (TAM), mast cell (MC) and tumor microvessel (MV) were performed in the tissue sections. RESULTS: The mean counts of TAM, MC, and MV in HCC tissues were significantly higher than those in pericarcinomatous liver tissues (TAM: 69.31+/-11.58 vs 40.23+/-10.36; MC:16.74+/-5.67 vs 7.59+/-4.18; MV: 70.11+/-12.45 vs 38.52+/-11.16, P<0.01). The MV count in the patients with metastasis was markedly higher than that with non-metastasis (P<0.01). In addition, the MC count in the patients with poorly differentiated HCC was obviously higher than that with well differentiated HCC (P<0.01). The correlation analysis showed that the TAM count was significantly correlated with the count of MV (r=0.712, P<0.01), and the MC count was obviously correlated with the MV count (r=0.336, P<0.05). CONCLUSION: TAM and MC might be closely related to the enhancement of tumor angiogenesis. The MV count might be associated with tumor invasion and metastasis. Moreover, the MC count might be associated with tumor differentiation and prognosis of HCC.

Prediction of short term re-exacerbation in patients with acute exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: The objective of the study is to develop a scoring system for predicting a 90-day re-exacerbation in hospitalized patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). METHODS: A total of 176 consecutive hospitalized patients with AECOPD were included. The sociodemographic characteristics, status before acute exacerbation (AE), presentations of and treatment for the current AE, and the re-exacerbation in 90 days after discharge from hospital were collected. RESULTS: The re-exacerbation rate in 90 days was 48.9% (86 out of 176). It was associated with the degree of lung function impairment (Global initiative for chronic Obstructive Lung Disease [GOLD] grades), frequency of AE in the previous year, and parameters of the current AE, including pleural effusion, use of accessory respiratory muscles, inhaled long-acting ß-2-agonists, inhaled corticosteroids, controlled oxygen therapy, noninvasive mechanical ventilation, and length of hospital stay, but was not associated with body mass index, modified Medical Research Council scale, or chronic obstructive pulmonary disease assessment test. A subgroup of ten variables was selected and developed into the re-exacerbation index scoring system (age grades, GOLD grades, AE times in the previous year, pleural effusion, use of accessory respiratory muscles, noninvasive mechanical ventilation, controlled oxygen therapy, inhaled long-acting ß-2-agonists and inhaled corticosteroids, and length of hospital stay). The re-exacerbation index showed good discrimination for re-exacerbation, with a C-statistic of 0.750 (P<0.001). CONCLUSION: A comprehensive assessment integrating parameters of stable chronic obstructive pulmonary disease, clinical presentations at exacerbation, and treatment showed a strong predictive capacity for short-term outcome in patients with AECOPD. Further studies are required to verify these findings.

Gut-lung crosstalk in pulmonary involvement with inflammatory bowel diseases.

Pulmonary abnormalities, dysfunction or hyper-reactivity occurs in association with inflammatory bowel disease (IBD) more frequently than previously recognized. Emerging evidence suggests that subtle inflammation exists in the airways among IBD patients even in the absence of any bronchopulmonary symptoms, and with normal pulmonary functions. The pulmonary impairment is more pronounced in IBD patients with active disease than in those in remission. A growing number of case reports show that the IBD patients develop rapidly progressive respiratory symptoms after colectomy, with failure to isolate bacterial pathogens on repeated sputum culture, and often request oral corticosteroid therapy. All the above evidence indicates that the inflammatory changes in both the intestine and lung during IBD. Clinical or subclinical pulmonary inflammation accompanies the main inflammation of the bowel. Although there are clinical and epidemiological reports of chronic inflammation of the pulmonary and intestinal mucosa in IBD, the detailed mechanisms of pulmonary-intestinal crosstalk remain unknown. The lung has no anatomical connection with the main inflammatory site of the bowel. Why does the inflammatory process shift from the gastrointestinal tract to the airways? The clinical and subclinical pulmonary abnormalities, dysfunction, or hyper-reactivity among IBD patients need further evaluation. Here, we give an overview of the concordance between chronic inflammatory reactions in the airways and the gastrointestinal tract. A better understanding of the possible mechanism of the crosstalk among the distant organs will be beneficial in identifying therapeutic strategies for mucosal inflammatory diseases such as IBD and allergy.

[A case-control study on the risk factors of nosocomial infection caused by imipenem-resistant Pseudomonas aeruginosa].

OBJECTIVE: To explore the risk factors for nosocomial infection caused by imipenem-resistant Pseudomonas aeruginosa (IRPA). METHODS: A case-control study was carried out for the comparison of 2 groups of 'case' patients with 'controlled' patients. The first group of 'case' patients had nosocomial isolation of IRPA, and the second group had imipenem-susceptible Pseudomonas aeruginosa (ISPA). 'Control' patients were selected from the same medical or surgical services from which 'case' patients were receiving care when isolation of IRPA or ISPA occurred. Risk factors analyzed included the use of antimicrobials, comorbid conditions, and demographic variables. IRPA was recovered from 67 patients, and ISPA from 150 patients while the control case were 200 and 159 respectively. All patients were from Renmin Hospital of Wuhan University during Jan 2002 to Dec 2003. Data were analyzed with unconditional logistic regression and principal component analysis. RESULTS: Data from multivariate unconditional logistic regression analysis showed that the independent risk factors for IRPA nosocomial infection were: time at risk (OR = 1.03, 95% CI: 1.01-1.04), imipenem (OR = 4.65, 95% CI: 1.35-11.52), PIP/TAZ (OR = 3.37, 95% CI 1.85-9.43) and quinolones (OR = 1.85, 95% CI: 1.25-5.34) while the third cephalosporins (OR = 2.54, 95% CI: 1.26-5.23) and aminoglycoside antibiotics (OR = 1.86, 95% CI 1.42-3.26) time at risk (OR = 1.05, 95% CI: 1.03-1.05) were associated with isolated ISPA. CONCLUSION: Nosocomial infection of IRPA could be caused by the use of imipenem and other antibiotics, suggesting that to limit the use of imipenem was not sufficient to contain the increasing incidence of IRPA.

[Expression of cyclins in hepatocellular carcinoma and its correlation to tumor cell apoptosis].

BACKGROUND & OBJECTIVE: Cyclins overexpress in various tumors, but its expression in hepatocellular carcinoma (HCC) and its correlation to cell proliferation and apoptosis are unclear. This study was to determine the expression of Cyclins, proliferating cell nuclear antigen (PCNA), and cell apoptosis in HCC, and to analyze their interrelations. METHODS: Tissue microarray technology and SP immunohistochemistry were used to detect expressions of Cyclins A, B1, D1, E, and PCNA in 122 specimens of HCC. In situ terminal deoxyribonucleotide transferase labeling was used to detect cell apoptosis. RESULTS: In the 122 HCC specimens, positive rate of Cyclin A was 50.0%, of Cyclin B1 was 47.5%, of Cyclin D1 was 42.6%, of Cyclin E was 35.2%. Cyclins levels were significantly higher in HCC tissues of grade II, III, and IV than in HCC tissues of grade I(P 0.05). Densities of apoptotic cells were significantly lower in HCC tissues of grade II, III, and IV than in HCC tissues of grade I(P 0.05); PCNA scores were significantly higher in HCC tissues of grade II, III, and IV than in HCC tissues of grade I(P 0.01). The poorer differentiation, the lower density of apoptotic cells in HCC, the higher PCNA score in HCC. Cyclins levels were negatively related to density of apoptotic cells (r=-0.686, P < 0.01), and positively related to PCNA score (r=0.599, P < 0.01); density of apoptotic cells was negatively related to PCNA score (r=-0.701, P < 0.01). CONCLUSION: Cyclins overexpress in HCC, which may shorten tumor cell cycle phase, accelerate cell proliferation and decrease apoptosis, and result in increased malignant phenotypes.