Vertical variation of mixing within porous sediment beds below turbulent flows.

River ecosystems are influenced by contaminants in the water column, in the pore water and adsorbed to sediment particles. When exchange across the sediment-water interface (hyporheic exchange) is included in modeling, the mixing coefficient is often assumed to be constant with depth below the interface. Novel fiber-optic fluorometers have been developed and combined with a modified EROSIMESS system to quantify the vertical variation in mixing coefficient with depth below the sediment-water interface. The study considered a range of particle diameters and bed shear velocities, with the permeability Péclet number, PeK between 1000 and 77,000 and the shear Reynolds number, Re*, between 5 and 600. Different parameterization of both an interface exchange coefficient and a spatially variable in-sediment mixing coefficient are explored. The variation of in-sediment mixing is described by an exponential function applicable over the full range of parameter combinations tested. The empirical relationship enables estimates of the depth to which concentrations of pollutants will penetrate into the bed sediment, allowing the region where exchange will occur faster than molecular diffusion to be determined.

Short-term outcomes of the prone perineal approach for extra-levator abdomino-perineal excision (elAPE).

BACKGROUND: Many studies report that low rectal cancer treated with abdomino-perineal excision (APE) have higher rates of CRM involvement with associated local recurrence and worse survival when compared to low anterior resection. We present a single surgeon's short-term outcomes using the prone perineal extra-levator (elAPE) approach. METHODS: Thirty-one patients between 2006 and 2010 underwent elAPE with curative intent. Data was collected prospectively recording patient tumour characteristics and histological outcome. Outcome measures included circumferential resection margins, recurrence rates, 30-day morbidity and mortality. RESULTS: Mean distance of tumour from anal verge was 3.63 ± SD 1.52 cm. 14 patients had pre-operative chemo-radiotherapy. The involved circumferential resection margin rate was 3.2%. Median follow-up was 20 (0-45) months, with overall mortality of 13.3% and 30 day mortality of 6.6%. CONCLUSIONS: The prone position elAPE has a low circumferential resection margin involved rate and, through improved vision, reduces the risk of inadvertent tumour or specimen perforation.

Genomic gain and over expression of CCL2 correlate with vascular invasion in stage I non-seminomatous testicular germ-cell tumours.

Testicular germ-cell tumours (TGCT) are the most frequent solid tumour to affect young Caucasian adult males and have increased in incidence over recent decades. In clinical stage I non-seminomas, (NSGCT) histological vascular invasion (VI) is a prognostic factor for metastatic relapse. Using array comparative genomic hybridization, we have previously shown that the presence of VI is associated with gain of a region at 17q12, containing a cluster of genes encoding inflammatory cytokines. We here confirm this finding using fluorescence in situ hybridization (FISH) demonstrating gain in 12 out of 42 (29%) assessable samples. Interrogation of previously published expression microarray data suggests that of the genes contained within this region, CCL2 [monocyte chemoattractant protein 1 (MCP1)] is frequently overexpressed in TGCT. Immunohistochemistry confirms this finding in a collection of 67 clinical stage I NSGCT, demonstrating an association with the presence of VI (p=0.049) that was not seen with VEGF-A, MMP2 or MMP9, although all were frequently expressed. This work gives further insight into the mechanisms involved in invasion in this tumour type, which may ultimately have implications for the management of patients with stage I disease.

Clinical and biological significance of CXCL12 and CXCR4 expression in adult testes and germ cell tumours of adults and adolescents.

Interaction between the chemokine CXCL12 (SDF1) and the G-protein coupled receptor CXCR4 is responsible for the maintenance of adult stem cell niches and is known to play an important role in utero in the migration of primordial germ cells. We demonstrate expression of CXCL12 by Sertoli cells and confirm CXCR4 expression by the germ cell population of the adult human testes. CXCR4 is also known to mediate organ-specific patterns of metastases in a range of common cancers. We identify consistent expression of CXCR4 mRNA and protein in testicular germ cell tumours (TGCT) that accounts for their patterns of relapse in sites of known CXCL12 expression. Extragonadal primary germ cell tumours express CXCR4 and their sites of occurrence are coincident with areas of known CXCL12 expression in utero. We show that CXCL12 stimulates the invasive migration of a TGCT cell line in vitro in a CXCR4-dependent fashion and activates ERK. Furthermore, we demonstrate that expression of CXCL12 in stage I non-seminomas is significantly associated with organ-confined disease post-orchidectomy and reduced risk of relapse (p = 0.003). This may be through the loss of CXCL12 gradients that might otherwise attract cells away from the primary tumour. We propose CXCL12 expression as a potential predictor of subsequent relapse that could lead to avoiding unnecessary treatment and associated late toxicities. Our observations support a role for CXCL12/CXCR4 in the adult germ cell population and demonstrate pathological function in germ cell tumour development and metastasis that may have clinical utility.

Comprehensive analysis of common mitochondrial DNA variants and colorectal cancer risk.

Several lines of evidence implicate mitochondrial dysfunction in the development of cancer. To test the hypothesis that common mtDNA variation influences the risk of colorectal cancer (CRC), we genotyped 132 tagging mtDNA variants in a sample of 2854 CRC cases and 2822 controls. The variants examined capture approximately 80% of mtDNA common variation (excluding the hypervariable D-loop). We first tested for single marker associations; the strongest association detected was with A5657G (P=0.06). Overall the distribution of association P-values was consistent with a null distribution. Next, we classified individuals into the nine common European haplogroups and compared their distribution in cases and controls. This analysis also provided no evidence of an association between mitochondrial variation and CRC risk. In conclusion, our results provide little evidence that mitochondrial genetic background plays a role in modifying an individual's risk of developing CRC.

Sites of surgical wasting in the abdominoperineal specimen.

BACKGROUND: In the abdominoperineal excision (APE) specimen 'surgical wasting' has been described, where the least amount of tissue covers the rectum. This is associated with high positive margin rates. The aim of this study was to locate the site of surgical wasting, namely the least amount of tissue excised at APE. METHODS: Distances from the anal verge to the distal and proximal edges of the sphincter, puborectalis and levator muscles were measured in 12 patients using morphological features on magnetic resonance images. Distances from the mucularis propria to the outer surface of the pelvic muscles and the outer edge of the specimen were measured on axial images. The height from the anal verge at which axial measurements of tissue were minimal was determined. RESULTS: The presence of a surgical waist between 35 and 42 mm above the anal verge, corresponding to the puborectalis, was confirmed. A smaller amount of perirectal tissue was resected at this level than at other heights (P < 0.001). CONCLUSION: Because less tissue is excised at the puborectalis, careful dissection along the levator plane is necessary, especially if tumour is present. More radical excision of the levators and puborectalis may be of benefit in such patients.

Interobserver agreement in grading of colorectal cancers-findings from a nationwide web-based survey of histopathologists.

AIMS: Tumour grade represents a gestalt of all molecular changes in malignancy, reflecting aggressiveness and has been shown to add prognostic information independent of stage for many malignancies, including colorectal cancer. Despite the grade of colorectal cancer being reported routinely in the UK, there is paucity of data on the level of agreement between histopathologists and hence the value of this metric in clinical practice. The aim was to estimate the degree of inter-observer variation in grading by conducting a nationwide web-based survey of histopathologists. METHODS AND RESULTS: Individuals were asked to grade a series of 20 tumours. Data from 104 pathologists surveyed indicates that agreement using both two and three grade systems is at best fair. CONCLUSION: Given that for the foreseeable future the histopathological criteria of stage and grade will still provide the mainstay of prognostication and therefore clinical decision-making, efforts should be made to improve grading criteria and standardize use of the low- and high-grade categories.

Can the fatty acid selectivity of plant lipases be predicted from the composition of the seed triglyceride?

To address the question can the fatty acid selectivity of plant lipases be predicted from the composition of the seed triglyceride, we have characterised the selectivity of lipases from a wide range of oilseeds with diverse fatty acid compositions. For this study, a novel hydrolysis assay using a fully randomised oil, was developed. From some seed sources (e.g. Cinnamomum camphora), lipases show high preference for particular fatty acids, whilst from others (e.g. Brassica napus, Theobroma cacao80% saturated or 'unusual' fatty acids may contain lipases which exhibit selectivity. It therefore follows that since the majority of seeds are composed of unsaturated fatty acids, that highly selective lipases will be unusual in nature. However lipases from some species of the Cuphea genera show exceptionally high preference for particular fatty acids. For example, lipase from seeds of Cuphea procumbans has over 20-fold selectivity for C10:0.

Human neuroepithelial cells express NMDA receptors.

L-glutamate, an excitatory neurotransmitter, binds to both ionotropic and metabotropic glutamate receptors. In certain parts of the brain the BBB contains two normally impermeable barriers: 1) cerebral endothelial barrier and 2) cerebral epithelial barrier. Human cerebral endothelial cells express NMDA receptors; however, to date, human cerebral epithelial cells (neuroepithelial cells) have not been shown to express NMDA receptor message or protein. In this study, human hypothalamic sections were examined for NMDA receptors (NMDAR) expression via immunohistochemistry and murine neuroepithelial cell line (V1) were examined for NMDAR via RT-PCR and Western analysis. We found that human cerebral epithelium express protein and cultured mouse neuroepithelial cells express both mRNA and protein for the NMDA receptor. These findings may have important consequences for neuroepithelial responses during excitotoxicity and in disease.

One cancer destroys another: short report of a myeloid sarcoma causing ischaemic necrosis of an adenocarcinoma.

We present a highly unusual case and histological images of a patient who underwent complete resection of a perforated caecal adenocarcinoma caused by angiodestruction of the proximal vasculature by a distinct acute myeloid infiltrate. Both tumours were removed in their entirety at one visit to theatre and the patient remains well and in remission 18 months later.

National study of colorectal cancer genetics.

Approximately, a third of all colorectal cancer (CRC) is due to inherited susceptibility. However, high-risk mutations in APC, the mismatch repair (MMR) genes, MUTYH/MYH, SMAD4, ALK3 and STK11/LKB1 are rare and account for <5% of cases. Much of the remaining variation in genetic risk is likely to be explained by combinations of more common gene variants that modestly increase risk. Reliable identification of such 'low penetrance' alleles would provide insight into the aetiology of CRC and might highlight potential therapeutic and preventative interventions. In 2003, the National Study of Colorectal Cancer Genetics (NSCCG) was established with the aim of collecting DNA and clinicopathological data from 20,000 CRC cases and a series of spouse/partner controls, thereby creating a unique resource for identifying low-penetrance CRC susceptibility alleles. The National Cancer Research Network (NCRN) adopted NSCCG onto its portfolio of trials and 148 centres in the United Kingdom (UK) are now actively participating. Over 8,700 cases and 2,185 controls have so far been entered into NSCCG. Our experience in developing NSCCG serves to illustrate how world-class DNA databases for genetic analyses can be rapidly developed in the United Kingdom.

A prospective, blinded analysis of thymidylate synthase and p53 expression as prognostic markers in the adjuvant treatment of colorectal cancer.

BACKGROUND: Despite previous studies, uncertainty has persisted about the role of thymidylate synthase (TS) and p53 status as markers of prognosis in colorectal cancer (CRC). PATIENTS AND METHODS: A total of 967 patients accrued to a large adjuvant trial in CRC were included in a prospectively planned molecular substudy, and of them, 59% had rectal cancer and about 90% received adjuvant chemotherapy (either systemically or randomly allocated to intraportal 5-fluorouracil infusion or both). TS and p53 status were determined, blinded to any clinical data, by immunohistochemistry using a validated polyclonal antibody or the DO-7 clone, respectively, and their relationships with overall survival were examined. RESULTS: High TS expression was observed in 58% and overexpression of p53 in 60% of tumours. TS expression correlated with tumour stage, and p53 overexpression, with rectal cancers. There was no evidence that either marker was significantly associated with survival by either univariate (TS hazard ratio (HR) = 0.94, 95% CI 0.76-1.18 and P = 0.6 and p53 HR = 0.98, 95% CI 0.78-1.23 and P = 0.9) or multivariate analyses (TS HR = 0.99, 95% CI 0.79-1.25 and P = 0.9 and p53 HR = 0.98, 95% CI 0.78-1.23 and P = 0.8). CONCLUSIONS: Neither TS nor p53 expression has significant prognostic value in the adjuvant setting of CRC.