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1.  Statins inhibit tumor progression via an enhancer of zeste homolog 2-mediated epigenetic alteration in colorectal cancer 
While statin intake has been proven to reduce the risk of colorectal cancer (CRC), the mechanism of antitumor effects and clinical significance in survival benefits remain unclear. Statin-induced antiproliferative effects and its underlying mechanism were examined using six CRC cell lines. Statins except pravastatin showed antiproliferative effects (simvastatin ≥ fluvastatin > atorvastatin) even though both of simvastatin and pravastatin could activate mevalonate pathways, suggesting the statin-mediated antiproliferative effects depended on non-mevalonate pathway. Indeed, statin induced p27KIP1 expression by downregulation of histone methyltransferase enhancer of zeste homolog 2 (EZH2), which acts as an epigenetic gene silencer. Additionally, the use of simvastatin plus classII histone deacetylase (HDAC) inhibitor (MC1568) induced further overexpression of p27KIP1 by inhibiting HDAC5 induction originated from downregulated EZH2 in CRC cells and synergistically led to considerable antiproliferative effects. In the clinical setting, Statin intake (except pravastatin) displayed the downregulated EZH2 expression and inversely upregulated p27KIP1 expression in the resected CRC by immunohistochemical staining and resulted in the significantly better prognoses both in overall survival (p = 0.02) and disease free survival (p < 0.01) compared to patients without statin intake. Statins may inhibit tumor progression via an EZH2-mediated epigenetic alteration, which results in survival benefits after resected CRC. Furthermore, statin plus classII HDAC inhibitor could be a novel anticancer therapy by their synergistic effects in CRC.
doi:10.1002/ijc.28672
PMCID: PMC4233976  PMID: 24346863
colorectal cancer; statins; EZH2; HDAC; p27
2.  RPN2 expression predicts response to docetaxel in oesophageal squamous cell carcinoma 
British Journal of Cancer  2012;107(8):1233-1238.
Background:
Neoadjuvant chemotherapy – often using docetaxel in various combinatorial regimens – is a standard treatment choice for advanced oesophageal squamous cell carcinoma (ESCC) in Japan. However, no useful markers exist that predict docetaxel's effects on ESCC. Ribophorin II (RPN2) silencing, which reduces glycosylation of P-glycoproteins and decreases membrane localisation, promotes docetaxel-dependent apoptosis. We investigated whether RPN2 expression in ESCC biopsy specimens could be a predictive biomarker in docetaxel-based neoadjuvant chemotherapy.
Methods:
We evaluated RPN2 expression immunohistochemically in biopsy specimens from 79 patients with node-positive ESCC, who received docetaxel-based adjuvant chemotherapy, and compared clinical and pathological responses between the RPN2-positive and RPN2-negative groups. We also studied susceptibility of RPN2-suppressed ESCC cells to docetaxel.
Results:
The RPN2-negative group had better clinical and pathological responses to docetaxel than the RPN2-positive group. We also found RPN2 suppression to alter docetaxel susceptibility in vitro.
Conclusion:
Expression of RPN2 in biopsy specimens could be a useful predictive marker for response to docetaxel-based neoadjuvant chemotherapy in ESCC.
doi:10.1038/bjc.2012.396
PMCID: PMC3494434  PMID: 22955852
docetaxel; neoadjuvant chemotherapy; ESCC; RPN2; predictive marker
3.  Overexpression of microRNA-223 regulates the ubiquitin ligase FBXW7 in oesophageal squamous cell carcinoma 
British Journal of Cancer  2011;106(1):182-188.
Background:
F-box and WD repeat domain-containing 7 (FBXW7) is a cell cycle regulatory gene whose protein product ubiquitinates positive cell cycle regulators such as c-Myc, cyclin E, and c-Jun, thereby acting as a tumour-suppressor gene. This study focused on microRNA-223 (miR-223), which is a candidate regulator of FBXW7 mRNA. The aim of this study was to clarify the clinical significance of miR-223 and FBXW7 in oesophageal squamous cell carcinoma (ESCC) patients, and to elucidate the mechanism by which FBXW7 is regulated by miR-223.
Methods:
The expression levels of miR-223 and the expression of FBXW7 protein was examined using 109 resected specimens to determine the clinicopathological significance. We also investigated the role of miR-223 in the regulation of FBXW7 expression in ESCC cell lines in an in vitro analysis.
Results:
We found that miR-223 expression was significantly higher in cancerous tissues than in the corresponding normal tissues. There was a significant inverse relationship between the expression levels of miR-223 and FBXW7 protein. Moreover, patients with high miR-223 expression demonstrated a significantly poorer prognosis than those with low expression. On the basis of a series of gain-of-function and loss-of-function studies in vitro, we identified FBXW7 as a functional downstream target of miR-223.
Conclusion:
Our present study indicates that high expression of miR-223 had a significant adverse impact on the survival of ESCC patients through repression of the function of FBXW7.
doi:10.1038/bjc.2011.509
PMCID: PMC3251856  PMID: 22108521
microRNA; FBXW7; ubiquitin ligase
4.  Radon-Domain Detection of the Nipple and the Pectoral Muscle in Mammograms 
Journal of Digital Imaging  2007;21(1):37-49.
In this paper, methods are presented for automatic detection of the nipple and the pectoral muscle edge in mammograms via image processing in the Radon domain. Radon-domain information was used for the detection of straight-line candidates with high gradient. The longest straight-line candidate was used to identify the pectoral muscle edge. The nipple was detected as the convergence point of breast tissue components, indicated by the largest response in the Radon domain. Percentages of false-positive (FP) and false-negative (FN) areas were determined by comparing the areas of the pectoral muscle regions delimited manually by a radiologist and by the proposed method applied to 540 mediolateral-oblique (MLO) mammographic images. The average FP and FN were 8.99% and 9.13%, respectively. In the detection of the nipple, an average error of 7.4 mm was obtained with reference to the nipple as identified by a radiologist on 1,080 mammographic images (540 MLO and 540 craniocaudal views).
doi:10.1007/s10278-007-9035-6
PMCID: PMC3043822  PMID: 17436047
Digital mammography; nipple detection; pectoral muscle detection; radon transform; image processing
5.  Polyclonal nature of diffuse proliferation of interstitial cells of Cajal in patients with familial and multiple gastrointestinal stromal tumours 
Gut  2002;51(6):793-796.
Background: Diffuse proliferation of interstitial cells of Cajal (ICCs) in the myenteric plexus layer of the intestine has been described in patients with familial and multiple gastrointestinal stromal tumours (GISTs). However, it is not fully understood whether proliferation is polyclonal or monoclonal.
Aims: To evaluate the clonal nature of diffuse ICC proliferation in familial and multiple GIST cases, we carried out clonal analysis using inactivation at the human androgen receptor (HUMARA) locus.
Materials and methods: Diffuse ICC proliferation tissues from three female patients were microdissected using a laser capture microdissection (LCM) system. Normal intestinal mucosal tissues were also microdissected for polyclonal controls and GIST tissues for monoclonal controls from the same patients, and genomic DNA was extracted. After digestion by restriction enzyme HhaI, the HUMARA locus was amplified by a fluorescent polymerase chain reaction (PCR) procedure and the PCR products were analysed.
Results: One case was uninformative because it was homozygous at the HUMARA locus. In the two other cases, PCR products from the diffuse ICC proliferation showed two alleles as well as those from normal intestinal mucosal tissues, indicating that ICC proliferation was polyclonal. In contrast, PCR products from associated GIST tissues showed only one allele, indicating that GISTs were monoclonal.
Conclusion: The results suggested that diffuse ICC proliferation in familial and multiple GIST cases was non-neoplastic hyperplasia.
PMCID: PMC1773468  PMID: 12427778
clonality; gastrointestinal stromal tumour; human androgen receptor gene; interstitial cells of Cajal; X chromosome inactivation; mosaicism
8.  Chemoprevention of DMBA-induced mammary carcinogenesis in rats by low-dose EPA and DHA. 
British Journal of Cancer  1997;75(3):348-353.
We investigated the effects of low-dose eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the incidence and growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in rats fed a high-fat (HF) diet. We also examined the effects of these treatments on the fatty acid composition of tumour and serum. Tumour incidence was significantly decreased by the administration of low-dose EPA and DHA, whereas their inhibitory effects on tumour growth did not reach significance. Serum arachidonic acid (AA) level was decreased by the administration of low-dose EPA and tended to be decreased by the administration of low-dose DHA, whereas tumour AA levels were not changed. The administration of low-dose EPA and DHA may be useful for inhibiting the incidence of breast cancer.
PMCID: PMC2063366  PMID: 9020478
9.  Poor prognostic value of proliferating cell nuclear antigen labelling index in breast carcinoma. 
Journal of Clinical Pathology  1993;46(6):525-528.
AIM--To investigate the association between proliferating cell nuclear antigen immunostaining and various clinicopathological variables, and its prognostic value in breast carcinoma. METHODS--A monoclonal antibody PC10 was applied to formalin fixed, paraffin wax embedded tissue in 144 cases of primary breast cancer. PCNA immunostaining was scored by counting 1000 cells; the percentage of positive stained cells was recorded as the PCNA labelling index (PCNA-LI). RESULTS--The PCNA-LI varied from 0-77% with a mean of 18%. When tumours were separated on the basis of the mean value, 93 had a low PCNA-LI of less or equal than 18% and 47 a high PCNA-LI of more than 18%. There was no significant correlation between PCNA-LI and all prognostic factors included in this study. Moreover, PCNA-LI failed to show any prognostic value for overall and disease free survival. CONCLUSION--PCNA immunostaining is not correlated with clinicopathological variables and patient survival in breast cancer.
Images
PMCID: PMC501287  PMID: 8101192
10.  Prognostic significance of Helix pomatia lectin and c-erbB-2 oncoprotein in human breast cancer. 
British Journal of Cancer  1993;68(3):621-626.
We investigated the prognostic significance of Helix pomatia lectin (HPA) staining on disease-free and overall survival in 120 primary breast carcinomas. HPA staining was present in 58 (48%) of these carcinomas. It was significantly associated with axillary lymph node metastases (P < 0.001) and c-erbB-2 expression (P < 0.01). A univariate study revealed that disease-free and overall survival were significantly correlated with clinical stage, tumour size, axillary lymph node metastases. HPA staining and c-erbB-2 expression. In a multivariate study, all previous prognostic indicators except HPA staining and c-erbB-2 expression were independent factors. However, stratifying the patients on the basis of HPA and c-erbB-2 status suggested that HPA +/c-erbB-2+ status was predictive of a higher incidence of axillary lymph node metastases (P = 0.000001) and a poorer overall (P < 0.0002) and a shorter disease-free (P < 0.000006) survival when compared with the other subgroups, although this combination did not provide any additional prognostic information for overall (P = 0.3544) or disease-free (P = 0.7152) survival by a multivariate analysis. For patients in whom axillary lymph node dissection has not been performed, therefore, HPA and c-erbB-2 status seems to be a powerful tool to discriminate subpopulations with a high recurrence risk and shorter survival who should undergo more aggressive therapy.
PMCID: PMC1968392  PMID: 8102537
11.  Further analysis of predictive value of Helix pomatia lectin binding to primary breast cancer for axillary and internal mammary lymph node metastases. 
British Journal of Cancer  1993;67(6):1368-1371.
We investigated the relation between Helix pomatia (HPA) staining of primary breast cancer and the presence of axillary (AX) or internal mammary (IM) metastases, and evaluated its predictive value for AX or IM metastases in comparison with the use of clinical variables. There was a significant association between the HPA staining and AX or IM metastases. When HPA staining was regarded as an indicator of AX metastases, a diagnostic accuracy of 72%, a sensitivity of 69% and a specificity of 75% were achieved. As an indicator of IM metastases, these values were 64%, 76% and 62%, respectively. In predicting the presence of AX metastases using a discriminant function with clinical AX status, location of tumour and tumour size, diagnostic accuracy, sensitivity and specificity were 79%, 69% and 87%, respectively. In predicting the presence of IM metastases using the discriminant function with clinical AX status and tumour size, these values were 74%, 71% and 75%, respectively. Therefore, it was concluded that the HPA staining may be useful, but it was equivalent with the discriminant function with clinical variables in prediction of AX or IM metastases.
PMCID: PMC1968528  PMID: 7685619
12.  Waveform and spectral analysis of crackles. 
Thorax  1980;35(11):843-850.
Crackles were recorded from six patients, four with tuberculosis and two with chronic bronchitis. It was observed by waveform and spectral analysis that most of the frequency components of a crackle were limited within a range of 0.1 to 1 kHz. Characteristically, waveforms of crackles were separable into two segments, initial "starting segments" and subsequent "decay segments." It is suggested that the former represents a shock wave caused by an abrupt opening of the airway and that the latter is a damped sinusoid caused by this shock wave exciting a resonator in the lung. It is speculated that the starting segment is determined by the pressure ratio at the site of the airway opening, and the decay segment by the resonant frequency and the quality factor of the resonator. Because transmission of a crackle is highly directional the waveforms recorded on the chest wall are modified by the positional relationship between the sound source and the microphone.
Images
PMCID: PMC471395  PMID: 7221981

Results 1-12 (12)