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Simon S Cross

Publications and source records attributed to Simon S Cross.

At least 19 recordsLinked to original sources
PubMed2007

DNA methylation and immunohistochemical analysis of the S100A4 calcium binding protein in human prostate cancer.

BACKGROUND: The role of DNA methylation in the transcriptional regulation of S100A4 is unknown in human prostate cancer. METHODS: Critical CpG sites within intron 1 of S100A4 were sequenced in DNA obtained from prostatic adenocarcinoma, non-malignant epithelium, and prostate cancer cell lines. S100A4 protein expression was assessed by immunohistochemistry and Western blotting. RESULTS: Methylation was seen in all cases of cancer, non-malignant epithelium, and in prostate cancer cell lines, but was absent in all cases of blood DNA. S100A4 immunoexpression was absent in all cases of malignant and non-malignant epithelium, while strong-moderate expression was seen in the stroma and lymphocytes. Western blotting showed absent S100A4 expression in LNCaP and Du145 cells and low levels in PC-3 cells. CONCLUSIONS: S100A4 protein is not expressed in benign or malignant prostatic epithelium nor in LNCaP and Du145 cells. The mechanism underlying absent S100A4 expression in prostatic epithelium and cell lines may involve methylation.

Adenocarcinoma↗
PubMed2006

Endoscopic mucosal resection for flat neoplasia in chronic ulcerative colitis: can we change the endoscopic management paradigm?

BACKGROUND: The potential of endoscopic mucosal resection (EMR) for treating flat dysplastic lesions in chronic ulcerative colitis (CUC) has not been addressed so far. Historically, such lesions were referred for colectomy. Furthermore, there are only limited data to support endoscopic resection of exophytic adenoma-like mass (ALM) lesions in colitis. AIMS: To evaluate the safety and clinical outcomes of patients with colitis undergoing EMR for Paris class 0-II and class I ALM compared with sporadic controls. Secondary aims were to re-evaluate the prevalence, anatomical "mapping" and histopathological characteristics of both Paris class 0-II and class I lesions in the context of CUC. METHODS: Prospective clinical, pathological and outcome data of patients with colitis-associated Paris class 0-II and Paris class I ALM treated with EMR (primary end points being colorectal cancer development, resection efficacy, metachronous lesion rates and post-resection recurrence rates) were compared with those of sporadic controls. RESULTS: 204 lesions were diagnosed in 169 patients during the study period: 167 (82%) diagnosed at "entry" colonoscopy, and 36 (18%) diagnosed at follow-up. 170 ALMs, 18 dysplasia-associated lesion masses (DALMs) and 16 cancers were diagnosed. A total of 4316 colonoscopies were performed throughout the study period (median per patient: 6; range: 1-8). The median follow-up period for the complete cohort was 4.1 years (range: 3.6-5.21). 1675 controls were included from our prospective database of patients without CUC who had undergone EMR for sporadic Paris class 0-II and snare polypectomy of Paris type I lesions from 1998 onwards, and were considered to be at moderate to high lifetime risk of colorectal cancer. 3792 colonoscopies were performed throughout the study period in this group (median per patient: 4; range: 1-7). The median follow-up period was 4.8 years (range: 2.9-5.2). No statistically significant differences were observed between the CUC study group and controls with respect to age, sex, median number of colonoscopies per patient, median follow-up duration, post-resection complications, median lesional diameter or interval cancer rates. However, there was a significant between-group difference regarding the prevalence of Paris class 0-II lesions in the CUC group (82/155 (61%)) compared with controls (285/801 (35%); chi(2) = 31.13; p<0.001). Furthermore, recurrence rates of lateral spreading tumours were higher in the colitis cohort (1/7 (14%)) than among controls (0/10 (0%); p = 0.048 (95% CI 11.64% to 40.21%)). CONCLUSIONS: Flat DALM, similarly to Paris class I ALM, can be managed safely by EMR in CUC. A change in management paradigm to include EMR for the resection of flat dysplastic lesions in selected cases is proposed.

Adenoma↗
PubMed2006

Decreased alveolar macrophage apoptosis is associated with increased pulmonary inflammation in a murine model of pneumococcal pneumonia.

Regulation of the inflammatory infiltrate is critical to the successful outcome of pneumonia. Alveolar macrophage apoptosis is a feature of pneumococcal infection and aids disease resolution. The host benefits of macrophage apoptosis during the innate response to bacterial infection are incompletely defined. Because NO is required for optimal macrophage apoptosis during pneumococcal infection, we have explored the role of macrophage apoptosis in regulating inflammatory responses during pneumococcal pneumonia, using inducible NO synthase (iNOS)-deficient mice. iNOS(-/-) mice demonstrated decreased numbers of apoptotic macrophages as compared with wild-type C57BL/6 mice following pneumococcal challenge, greater recruitment of neutrophils to the lung and enhanced expression of TNF-alpha. Pharmacologic inhibition of iNOS produced similar results. Greater pulmonary inflammation was associated with greater levels of early bacteremia, IL-6 production, lung inflammation, and mortality within the first 48 h in iNOS(-/-) mice. Labeled apoptotic alveolar macrophages were phagocytosed by resident macrophages in the lung and intratracheal instillation of exogenous apoptotic macrophages decreased neutrophil recruitment in iNOS(-/-) mice and decreased TNF-alpha mRNA in lungs and protein in bronchial alveolar lavage, as well as chemokines and cytokines including IL-6. These changes were associated with a lower probability of mice becoming bacteremic. This demonstrates the potential of apoptotic macrophages to down-regulate the inflammatory response and for the first time in vivo demonstrates that clearance of apoptotic macrophages decreases neutrophil recruitment and invasive bacterial disease during pneumonia.

Animals↗
PubMed2006

Osteoprotegerin (OPG)--a potential new role in the regulation of endothelial cell phenotype and tumour angiogenesis?

The progression of cancer depends on the establishment of a tumour blood supply, and therefore tumour angiogenesis has been identified as a major target for new anticancer agents. Recent reports have suggested that osteoprotegerin (OPG) is involved in the control of endothelial cell survival through the inhibition of the activity of tumour necrosis factor- (TNF) related apoptosis-inducing ligand (TRAIL). The role of OPG in human tumour development and angiogenesis is currently unknown. In the present study we demonstrate the ability of OPG to support endothelial cell survival, as well as the formation of cord-like structures in vitro using a matrigel tubule formation assay. Investigation of various human cancers demonstrated endothelial OPG expression in 59% of malignant tumours (n=512), but in contrast, OPG was absent in endothelial cells associated with benign tumours and normal tissues (n=178). In a series of 400 breast tumours, endothelial OPG expression was associated with high tumour grade and certain histological types. Our data show a clear separation in endothelial OPG expression between malignant tumours and nonmalignant tissues, supporting a potential biological role for this molecule in the development and/or maintenance of the tumour vasculature. This is the first study to report the proangiogenic effects of OPG in vitro, as well as correlating expression of OPG by tumour endothelial cells with clinicopathological data in human tumours.

Breast Neoplasms↗
PubMed2006

WFDC2 (HE4): a potential role in the innate immunity of the oral cavity and respiratory tract and the development of adenocarcinomas of the lung.

BACKGROUND: The Whey Acidic Protein domain is an evolutionarily conserved motif found in a number of proteins, the best studied of which are antiproteinases involved in the innate immune defence of multiple epithelia. We recently characterised the WFDC2 gene which encodes a two WAP domain-containing protein, initially suggested as a marker for epididymis, and showed that it is highly expressed in the lung and salivary gland. The precise location of WFDC2 protein in these sites has not been described. METHODS: We used immunohistochemistry to localise WFDC2 in normal tissues of the respiratory tract, naso- and oropharynx, as well as in chronically inflamed lung from Cystic Fibrosis and a range of pulmonary carcinomas. We have complemented these studies with molecular analysis of WFDC2 gene expression in primary human lung cell cultures. RESULTS: WFDC2 is expressed in some epithelial cells of the upper airways as well as in mucous cells and ducts of submucosal glands. No staining was seen in peripheral lung. Intense staining is found in major salivary glands and in minor glands of the nose, sinuses, posterior tongue and tonsil. Studies with the related protein Secretory Leukocyte Protease Inhibitor (SLPI) show that although both proteins are expressed in similar tissues, the precise cellular localisation differs. Significant increases in expression and localisation of WFDC2 are seen in patients with Cystic Fibrosis. SLPI expression was greatly reduced in the same samples. In cultures of tracheobronchial epithelial cells, expression of WFDC2 and SLPI are differentially regulated during differentiation yet WFDC2 is not induced by pro-inflammatory mediators. The majority of adenocarcinomas stain with WFDC2 whilst a significant minority of squamous, small cell and large cell carcinomas exhibit focal staining. There is no clear association with tumour grade. CONCLUSION: We believe that these studies support the hypothesis that WFDC2 may be a component of the innate immune defences of the lung, nasal and oral cavities and suggest that WFDC2 functions in concert with related WAP domain containing proteins in epithelial host defence. We also suggest that WFDC2 re-expression in lung carcinomas may prove to be associated with tumour type and should be studied in further detail.

Adenocarcinoma↗
PubMed2005

Promoter hyper-methylation of calcium binding proteins S100A6 and S100A2 in human prostate cancer.

BACKGROUND: S100A6 and S100A2 are members of the S100 family of calcium binding proteins, which are down regulated in prostate cancer, however the molecular mechanism(s) underlying their loss of expression is unknown. METHODS: The promoter and exon 1 region of the S100A6 and S100A2 genes was sequenced in bisulfite modified DNA from non-malignant, benign prostatic hyperplasia (BPH), malignant and metastatic prostate tissues and in cell lines. Immunohistochemistry was performed to correlate S100A2 expression with methylation status. RESULTS: S100A6 methylation was absent or occurred at isolated sites in 14/14 cases of non-malignant epithelium and 5/5 cases of BPH tissues, whereas methylation was seen in 14/27 (52%) cases of prostatic cancer (P<0.0001), 2/2 cases of metastatic cancer and in the CWR22 prostatic cancer xenograft. Critical CpG sites within the S100A2 promoter were methylated in LNCaP, LNCaP-LN3, and CWR22 cells but not in Du145, PC3 or BPH45 cells. In tissues, S100A2 methylation was seen in 32/34 (94%) cases of adenocarcinoma and 5/5 cases of metastatic cancer. However, S100A2 methylation was also seen in 9/12 (75%) cases of non-malignant tissues and in 5/5 cases of BPH. Immunostaining, showed absent S100A2 expression all 41 cases of prostatic cancer, whereas staining was seen in the basal cells of non-malignant epithelium. CONCLUSIONS: Loss of S100A6 and S100A2 proteins is frequent in human prostatic cancer. A major mechanism underlying the loss of S100A6 expression appears to involve promoter hyper-methylation. However, mechanisms other than methylation of the known promoter are involved in silencing S100A2 in the prostate.

Adenocarcinoma↗
PubMed2005

Promoter hypermethylation is associated with tumor location, stage, and subsequent progression in transitional cell carcinoma.

PURPOSE: Transitional cell carcinoma (TCC) is a pan-urothelial disease characterized by multiplicity. Although little is known about the molecular events in upper-tract TCC, similar carcinogenic mechanisms are thought to occur throughout the urinary tract. However, we have previously shown that distinct patterns of microsatellite instability occur in upper and lower urinary tract TCC, suggesting biologic differences between these tumors. Here we investigate the extent of promoter hypermethylation in TCC throughout the urinary tract. PATIENTS AND METHODS: Tissue was obtained from 280 patients (median follow-up, 56 months) whose tumors comprised 116 bladder and 164 upper-tract tumors (UTT). Analysis for hypermethylation at 11 CpG islands, using methylation-sensitive polymerase chain reaction and bisulfite sequencing, was performed for each sample and compared with the tumor's clinicopathologic details, microsatellite instability status, and subsequent behavior. RESULTS: Promoter methylation was present in 86% of TCC and occurred both more frequently and more extensively in UTT (94%) than in bladder tumors (76%; P < .0001). Methylation was associated with advanced tumor stage (P = .0001) and higher tumor progression (P = .03) and mortality rates (P = .04), when compared with tumors without methylation. Multivariate analysis revealed that methylation at the RASSF1A and DAPK loci, in addition to tumor stage and grade, were associated with disease progression (P < .04). CONCLUSION: Despite morphologic similarities, there are genetic and epigenetic differences between TCC in the upper and lower urinary tracts. Methylation occurs commonly in urinary tract tumors, may affect carcinogenic mechanisms, and is a prognostic marker and a potential therapeutic target.

Adult↗
PubMed2005

SPLUNC1 (PLUNC) is expressed in glandular tissues of the respiratory tract and in lung tumours with a glandular phenotype.

Short PLUNC1 (SPLUNC1) is the founding member of a novel family of proteins (PLUNC) expressed in the upper respiratory tract that may function in host defence. It is one of the most highly expressed genes in the upper airways and the protein has been detected in sputum and nasal secretions. This study describes, for the first time, the precise cellular localization of SPLUNC1 in human tissues from the respiratory tract. Although SPLUNC1 is found in some epithelial cells of the upper airways and coats the surface epithelial cell lining of the major airways, the most significant site of protein localization is in mucous cells and ducts of submucosal glands. Intense staining is also seen in minor glands of the nose, sinuses, posterior tongue and tonsil, suggesting that the protein is secreted into mucoid secretions of these tissues, where it probably functions in host defence. No staining was seen in peripheral lung tissue. As SPLUNC1 has been suggested to be a novel lung cancer marker, a limited panel of lung cancers was also studied. The findings suggest that SPLUNC1 is commonly expressed in adenocarcinomas, muco-epidermoid carcinoma, and bronchio-alveloar carcinoma, and is absent from small-cell carcinoma and squamous cell carcinoma. This expression pattern is consistent with the presumed phenotypic origin of these tumours and suggests that SPLUNC1 may be a useful marker for lung cancer.

Antibody Specificity↗
PubMed2005

Osteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo--a role in tumour cell survival?

In addition to its role in bone turnover, osteoprotegerin (OPG) has been reported to bind to and inhibit Tumour necrosis factor-related apoptosis inducing ligand (TRAIL). TRAIL is produced in tumours by invading monocytes, inducing apoptosis in neoplastic cells sensitive to this cytokine. OPG production by tumour cells would therefore be a novel mechanism whereby cancer cells evade host defences and gain a growth advantage. In this study we show that OPG produced by breast cancer cells enhances tumour cell survival by inhibiting TRAIL-induced apoptosis. OPG expression by breast cancer cells (MDA-MB 436/231) grown in vitro was examined using PCR and ELISA, and the sensitivity of these cells to TRAIL was determined. The effects of OPG on TRAIL induced apoptosis was investigated by exposing MDA-MB 436 cells to TRAIL, in the presence or absence of OPG, followed by assessment of nuclear morphology. We found that the levels of OPG produced were sufficient to inhibit TRAIL-induced apoptosis, suggesting that OPG may play a role in tumour cell survival. We also examined the expression pattern of OPG in a selection of breast tumours (n=400) by immunohistochemistry, and related OPG expression to the clinico-pathological data for each tumour. OPG expression was found to be negatively correlated with increasing tumour grade. To our knowledge these results are the first to demonstrate that OPG can act as an endocrine survival factor for breast cancer cells, as well as reporting the expression patterns of OPG in a large cohort of human breast tumours.

Apoptosis↗
PubMed2005

Prospective evaluation of high-frequency mini-probe ultrasound colonoscopic imaging in ulcerative colitis: a valid tool for predicting clinical severity.

BACKGROUND: High-frequency mini-probe ultrasound imaging permits trans-mural cross-sectional imaging of the colorectal wall. In ulcerative colitis, prognosis is dependent on the severity of mucosal inflammatory change where accurate assessment of disease activity is required to optimize medical therapy. Furthermore, predicting relapse of disease using conventional endoscopic, histopathological and clinical criteria has not proven reliable. AIM: To evaluate the correlation of high-frequency mini-probe imaging with standardized measures of clinical, endoscopic and histopathological severity. METHODS: High-frequency ultrasound images were obtained from the caecum to rectum in 200 patients. Tsuga colorectal ultrasound criteria were then compared to the endoscopic Baron score, Seo activity score and Matts histopathological grade. RESULTS: For rectal disease, the kappa coefficient between Tsuga criteria I/II and Matts grade 1/2 was 0.78 (95% CI, 0.67-0.89), 0.57 (95% CI, 0.46-0.68) and 0.48 (95% CI, 0.34-0.62) for Tsuga class IIIa/b, IVa/b and Matts grade 3a/b and 4, respectively. Colonic imaging showed a kappa coefficient between Tsuga class I/II and Matts grade1/2 of 0.76 (95% CI, 0.72-0.8). Tsuga class IIIa-IIIb/IVa-IVb as compared to Matts grade 3a-3b/4 yielded kappa coefficients of 0.49 (95% CI, 0.43-0.55) and 0.62 (95% CI, 0.56-0.69), respectively. In the rectum both the total wall thickness, mucosa and submucosa were significantly thicker in Matts grade 3b and 4 disease as compared to Matts grade 1/2 (P < 0.02) for all parameters. A significant increase in colonic total wall thickness was observed between Matts score 4 and Tsuga grade 1-3a disease (P < 0.001). CONCLUSIONS: High-frequency ultrasound is a valid adjunctive 'tool' for the trans-mural assessment of the colorectal wall in ulcerative colitis. This technique may aid in the initial diagnosis, and ongoing chronic management of disease.

Adult↗
PubMed2005

20-MHz high-frequency endoscopic ultrasound-assisted endoscopic mucosal resection for colorectal submucosal lesions: a prospective analysis.

GOALS: To prospectively assess the safety and efficacy of high-frequency ultrasound assisted mini-probe endoscopic mucosal resection for the treatment of colorectal submucosal tumors. Primary endpoints were tumor free vertical/horizontal resection margins and positive histopathologic diagnosis. Outcome data over a 24-month period were assessed. BACKGROUND: A 20-MHz high-frequency mini-probe ultrasound is an accurate modality for the diagnosis of stage T1m and T1 colorectal lesions. Few studies have addressed the safety and efficacy of this technology as applicable to submucosal lesions of the colorectum. METHODS: Thirty patients underwent high-frequency mini-probe ultrasound-guided endoscopic mucosal resection of 30 lesions (<20 mm diameter) using the inject and cut technique. Repeat endoscopy and ultrasound was performed at 3, 6, and 12 months post-"index" resection. RESULTS: A total of 27 lesions (90%) underwent complete resection with negative histologic margin status (median diameter, 8 mm; range, 3-20 mm). No statistical difference (P > 0.1) was observed between submucosal lesion position and histologic resection margin negativity. Three rectal lesions (10%) within the submucosal layer 3 failed to separate from the muscularis and underwent transanal excision of tumor. Bleeding occurred in 1 patient (3%). No recurrence was evident at the resection site in 27 cases (median follow-up, 9 months; range, 4-18 months). CONCLUSIONS: High-frequency mini-probe ultrasound-guided endoscopic mucosal resection is a safe and effective therapeutic modality for submucosal lesions of the colorectum. The technique offers a single-stage diagnostic and therapeutic technique for selected submucosal lesions and may offer an alternative to surgical resection.

Adult↗
PubMed2005

Role of aberrant crypt foci detected using high-magnification-chromoscopic colonoscopy in human colorectal carcinogenesis.

Abstract Liaison between gastrointestinal endoscopists and histopathologists is essential to provide the highest standards of diagnostic accuracy and patient management. The histopathologist needs to be aware of the endoscopic findings when interpreting endoscopic biopsies. High-magnification-chromoscopic-colonoscopy (HMCC) is a new technology that provides the endoscopists with much greater resolution and functional staining of the gastrointestinal tract. Using HMCC, the endoscopist is now able to identify subtle changes in the colorectal luminal openings or crypts. Changes in crypt appearances now allow detection of aberrant crypt foci (ACF) in the colon, which might themselves be precancerous lesions but additionally might serve as a valid biomarker of subsequent adenoma and colorectal cancer formation. This article describes the role of the aberrant crypt focus in colorectal carcinogenesis and discusses the clinical impact of HMCC techniques as applicable to ACF.

Cell Transformation, Neoplastic↗
PubMed2005

Rectal aberrant crypt foci identified using high-magnification-chromoscopic colonoscopy: biomarkers for flat and depressed neoplasia.

BACKGROUND: Aberrant crypt foci may represent preneoplastic lesions in the human colon. The prevalence of aberrant crypt foci detected using magnification chromoscopic colonoscopy is known to follow a stepwise progression from normal subjects to those with exophytic adenomas and colon cancer. No studies have addressed the prevalence of rectal aberrant crypt foci in patients with flat and depressed colonic lesions that cluster within the right hemi-colon and may undergo de novo neoplastic transformation. METHODS: All patients underwent total colonoscopy by a single endoscopist using the Olympus CF240Z magnifying colonoscope. Flat and depressed lesions were diagnosed using targeted indigo carmine chromoscopy. Prior to extubation, pan high-magnification-chromoscopy using indigo carmine was applied to the rectum and the distal 10 cm of mucosa examined using forward and retroflexed views. Aberrant crypt foci were defined as two or more crypts with dilated or slit-like openings that were raised above the adjacent mucosa. Using high-magnification chromoscopic colonoscopy we assessed the prevalence and dysplastic features of aberrant crypt foci in three groups: endoscopically "normal" subjects, patients with flat/depressed adenoma, and flat/depressed cancer. RESULTS: Two thousand five hundred and fifty-nine patients underwent colonoscopy of which 1,000 were eligible for inclusion. The median number of aberrant crypt foci per patient in the endoscopically normal, adenoma, and cancer group was 1 (range: 0-5), 9 (range: 0-22), and 38 (range: 14-64), respectively. The estimated relative risk of dysplastic aberrant crypt foci when comparing the flat adenoma group with the endoscopically "normal" group was 4.68 (95% CI: 2.23-9.91) with the relative risk for flat cancer versus endoscopically normal group being 21.8 (95% CI: 10.9-23.8). Patients with >5 flat adenomas had higher crypt foci densities than those with <5 adenomas (r=0.53; p<0.001). CONCLUSIONS: The number of aberrant crypt foci in normal patients, patients with flat adenoma, and flat cancer follow a stepwise incremental change as previously observed for exophytic adenomas and cancer. Detection of aberrant crypt foci in the rectum may be a useful biomarker for proximal colonic flat neoplasia and could be used at index flexible sigmoidoscopic screening to stratify risk of proximal colonic neoplasia. Patients with dysplastic aberrant crypt foci of high density should receive total colonoscopy.

Adenoma↗
PubMed2005

The role of high-magnification-chromoscopic colonoscopy in hereditary nonpolyposis colorectal cancer screening: a prospective "back-to-back" endoscopic study.

BACKGROUND: In hereditary nonpolyposis colorectal cancer flat and diminutive adenomas occur, particularly in the right colon. Such lesions may assume a high risk of malignant transformation. Interval cancers are known to occur in this group. Chromoscopic colonoscopy enhances detection in patients assuming a moderate to high lifetime risk of colorectal cancer. AIM: To prospectively assess the efficacy of high-magnification-chromoscopic colonoscopy for the detection of neoplastic lesions in patients undergoing hereditary nonpolyposis colorectal cancer screening. METHODS: Twenty-five asymptomatic patients fulfilling modified Amsterdam criteria underwent "back-to-back" colonoscopy. Conventional colonoscopy with targeted chromoscopy was performed initially followed by pan-colonic chromoscopic colonoscopy. Diagnostic extubation times and volumes of normal saline and indigo carmine (IC) were controlled. RESULTS: Using conventional colonoscopy and targeted chromoscopy 24 lesions were detected in 13 patients (20 exophytic/4 flat). Pan-colonic chromoscopy identified a further 52 lesions in 16 patients (17 exophytic/35 flat). Pan-chromoscopy identified significantly more adenomas than conventional colonoscopy (p= 0.001) and a significantly high number of flat adenomas (p= 0.004). CONCLUSIONS: Pan-colonic chromoscopic colonoscopy improves detection of significant neoplastic lesions in hereditary nonpolyposis colorectal cancer screening. Pan-chromoscopy may help better stratify colorectal cancer "risk" in this cohort and aid planning of surveillance colonoscopic follow-up.

Adult↗