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Background: The clinico-pathological and molecular heterogeneity of epithelial ovarian cancer (EOC) complicates its early diagnosis and successful treatment. Highly aneuploid tumours and the presence of ascitic fluids are hallmarks of EOC. Two microcephaly-associated proteins, abnormal spindle-like microcephaly-associated protein (ASPM) and microcephalin, are involved in mitosis and DNA damage repair. Their expression is deregulated at the RNA level in EOC. Here, ASPM and microcephalin protein expression in primary cultures established from the ascites of patients with EOC was determined and correlated with clinical data to assess their suitability as biomarkers. Methods: Five established ovarian cancer cell lines, cells derived from two benign ovarian ascites samples and 40 primary cultures of EOC derived from ovarian ascites samples were analysed by protein slot blotting and/or immunofluorescence to determine ASPM and microcephalin protein levels and their cellular localisation. Results were correlated with clinico-pathological data. Results: A statistically significant correlation was identified for ASPM localisation and tumour grade, with high levels of cytoplasmic ASPM correlating with grade 1 tumours. Conversely, cytoplasmic microcephalin was only identified in high-grade tumours. Furthermore, low levels of nuclear microcephalin correlated with reduced patient survival. Conclusion: Our results suggest that ASPM and microcephalin have the potential to be biomarkers in ovarian cancer.

In this report we describe the developmental expression and function of Sp8, a member of the Sp family of zinc finger transcription factors, and provide evidence that the legless transgene insertional mutant is a hypomorphic allele of the Sp8 gene. Sp8 is expressed during embryogenesis in the forming apical ectodermal ridge (AER), restricted regions of the central nervous system, and tail bud. Targeted deletion of the Sp8 gene gives a striking phenotype, with severe truncation of both forelimbs and hindlimbs, absent tail, as well as defects in anterior and posterior neuropore closure leading to exencephaly and spina bifida. Out-growth of the limb depends on formation of the AER, a signaling center that forms at the limb bud apex. In Sp8 mutants, the AER precursor cells are induced and initially express multiple appropriate marker genes, but expression of these genes is not maintained and progression to a mature AER is blocked. These observations indicate that Sp8 functions downstream of Wnt3, Fgf10, and Bmpr1a in the signaling cascade that mediates AER formation.

Cultured skin substitutes have been used as adjunctive therapies in the treatment of burns and chronic wounds, but they are limited by lack of a vascular plexus. This deficiency leads to greater time for vascularization compared with native skin autografts and contributes to graft failure. Genetic modification of cultured skin substitutes to enhance vascularization could hypothetically lead to improved wound healing. To address this hypothesis, human keratinocytes were genetically modified by transduction with a replication incompetent retrovirus to overexpress vascular endothelial growth factor, a specific and potent mitogen for endothelial cells. Cultured skin substitutes consisting of collagen-glycosaminoglycan substrates inoculated with human fibroblasts and either vascular endothelial growth factor-modified or control keratinocytes were prepared, and were cultured in vitro for 21 d. Northern blot analysis demonstrated enhanced expression of vascular endothelial growth factor mRNA in genetically modified keratinocytes and in cultured skin substitutes prepared with modified cells. Furthermore, the vascular endothelial growth factor-modified cultured skin substitutes secreted greatly elevated levels of vascular endothelial growth factor protein throughout the entire culture period. The bioactivity of vascular endothelial growth factor protein secreted by the genetically modified cultured skin substitutes was demonstrated using a microvascular endothelial cell growth assay. Vascular endothelial growth factor-modified and control cultured skin substitutes were grafted to full-thickness wounds on athymic mice, and elevated vascular endothelial growth factor mRNA expression was detected in the modified grafts for at least 2 wk after surgery. Vascular endothelial growth factor-modified grafts exhibited increased numbers of dermal blood vessels and decreased time to vascularization compared with controls. These results indicate that genetic modification of keratinocytes in cultured skin substitutes can lead to increased vascular endothelial growth factor expression, which could prospectively improve vascularization of cultured skin substitutes for wound healing applications.

Ovarian clear cell carcinoma (OCCC) accounts for a small but significant proportion of all ovarian cancers and is a distinct clinical and pathological entity. It tends to be associated with poorer response rates to chemotherapy and with a worse prognosis. Little is known about possible underlying genetic changes. DNA extracted from paraffin-embedded samples of 18 pure OCCC cases was analysed for genetic imbalances using comparative genomic hybridisation (CGH). All of the 18 cases showed genomic alterations. The mean number of alterations detected by CGH was 6 (range 1–15) indicating a moderate level of genetic instability. Chromosome deletions were more common than amplifications. The most prominent change involved chromosome 9 deletions in 10 cases (55%). This correlates with changes seen in other epithelial ovarian cancers. This deletion was confirmed using microsatellite markers to assess loss of heterozygosity (LOH) at four separate loci on chromosome 9. The most distinct region of loss detected was around the IFNA marker at 9p21 with 41% (11 out of 27cases) LOH. Other frequent deletions involved 1p (five out of 18; 28%); 11q (four out of 18; 22%) and 16 (five out of 18; 28%). Amplification was most common at chromosome 3 (six out of 18; 33%); 13q (four out of 18; 22%) and 15 (three out of 18; 17%). No high-level amplifications were identified. These features may serve as useful prognostic indicators in the management of OCCC.

Background and aims: Germline mutations in mismatch repair (MMR) genes cause a greatly increased risk of cancer of the gastrointestinal and female reproductive tracts (hereditary non-polyposis colorectal cancer (HNPCC)). Loss of MMR expression is common in colorectal cancer (CRC) overall. Such loss is assumed to be acquired predominantly, although a population of CRC cases will include individuals with unrecognised MMR mutations. This study examines the association between MMR gene expression and family history of cancer among the CRC population. Methods: Individuals with CRC were identified from two well characterised populations: (1) consecutive hospital patients (n = 644) and (2) a population based cases series (n = 249). CRC was examined for expression of hMLH1 and hMSH2 using immunohistochemistry, and expression was related to family history using logistic regression. Results: hMLH1 and hMSH2 expression was assessed in 732 CRCs with 8% showing loss of expression. No association was seen overall for hMLH1 or hMSH2 expression and family history of CRC. Loss of hMSH2 was predicted by family history of extracolonic cancer (odds ratio (OR) 5.78 (95% confidence interval (CI) 0.95–35.18)) and family history suggestive of HNPCC (OR 27.84 (95% CI 4.37–177.56)). Loss of hMLH1 was not predicted by family history of extracolonic cancer or a family history suggestive of HNPCC but was for a family history of at least two affected relatives (OR 4.88 (95% CI 1.25–19.03)). Conclusions: Individuals with hMSH2 deficient CRC in the general population exhibit a family history and other characteristics suggestive of HNPCC, and may carry germline MMR mutations. Loss of hMLH1 is only associated with a strong family history of extracolonic cancer at older ages, suggesting a novel mechanism of susceptibility.

Zeolites and related crystalline microporous oxides—tetrahedrally coordinated atoms covalently linked into a porous framework—are of interest for applications ranging from catalysis to adsorption and ion-exchange 1 . In some of these materials (such as zeolite rho) adsorbates 2 , ion-exchange, and dehydration and cation relocation 3 , 4 can induce strong framework deformations. Similar framework flexibility has to date not been seen in mixed octahedral/tetrahedral microporous framework materials, a newer and rapidly expanding class of molecular sieves 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . Here we show that the framework of the titanium silicate ETS-4, the first member of this class of materials 8 , can be systematically contracted through dehydration at elevated temperatures to ‘tune’ the effective size of the pores giving access to the interior of the crystal. We show that this so-called ‘molecular gate’ effect can be used to tailor the adsorption properties of the materials to give size-selective adsorbents 17 suitable for commercially important separations of gas mixtures of molecules with similar size in the 4.0 to 3.0 Å range, such as that of N 2 /CH 4 , Ar/O 2 and N 2 /O 2 .

The first phase of a project to determine the distribution of pre-colonial farming settlement through space and time in the former Transkei, Eastern Cape, was carried out during 1983—87. This archaeological reconnaissance, using a stratified random sampling method, located 15 Early Iron Age settlement sites within and two next to five of the 12 study areas searched. These findings have largely escaped subsequent attention. An additional site was found adjacent to the Great Kei River after the project finished. The distribution and altitude of these sites indicate that they are confined to localities in deeply incised river valleys (as predicted from the pattern in KwaZulu-Natal), but at decreasing distances from the sea and declining altitudes in a south-westerly direction across the Eastern Cape. This might reflect the operation of a human rather than a physical geographical factor. One possibility is the early presence of Khoekhoen herders, perhaps with seasonal camps along rivers, westward of about 29°E. The distribution of a) rivers with names derived from Khoekhoen, b) isiXhosa dialects with a strong Khoekhoen component, and c) herder pottery along the coastline, all strongly support this proposal. The geographic limit of Early Iron Age settlement southwestward of East London remains to be determined. Woodland disturbance by early farmers in the larger, incised river valleys would have initiated processes of plant succession in a geographical patch-work in the later first millennium AD, that continue in places today, albeit with far greater intensity. This can be relevant to the management of such vegetation in protected areas.

Food-deprivation increases the reinforcing efficacy of cocaine and other drugs within self-administration experiments. In this study, the effects of food-deprivation on cocaine-induced conditioned place preference were investigated. Male Sprague-Dawley rats were assigned to one of two feeding conditions: satiated (with ad libitum food) or deprived (maintained at 80% of free-feeding body weights). During conditioning trials, on alternate days, rats received IP injections of cocaine (0.0, 2.5, 5.0, or 10.0 mg/kg; n = 12 per dose group) and were confined for 30 min in one of two distinct environments. On intervening days, the same rats were injected with saline and confined for 30 min in the opposite environment. After four cocaine and four saline trails, a 15-min choice test (with no injections) was given. During this time, the rats were able to move freely through a passageway between both environments. Relative to the food-satiated rats, the food-deprived rats showed a greater conditioned preference for the cocaine-paired environment during the choice test, greater cocaine-induced locomotor activity during conditioning trials, and a greater degree of sensitization to the activating effects of cocaine across conditioning trials. This study extends the general findings of food deprivation-induced increases in the reinforcing efficacy of cocaine to include the conditioned place preference paradigm.

BackgroundAutologous haemopoietic stem cell transplantation (AHSCT) is an evolving therapy for multiple sclerosis (MS). Here we present the Sheffield experience since 2006.MethodsRetrospective review of MS cases referred for and treated with AHSCT. Toxicity, clinical and radiological outcome were assessed.Results14 patients (8 Rapidly evolving severe [REMS], 3 Relapsing Remitting [RRMS], 3 Secondary Progressive [SPMS]) were selected for AHSCT. One patient underwent AHSCT on a clinical trial (data excluded from analysis). Mean age 34.6 years (SD 8.69), median pretreatment EDSS 6.5 (IQR0.5). All had clinically and radiologically aggressive disease, non-responsive to standard treatment. Follow up range was 3 to 96 months.All patients were successfully mobilized, 2 patients progressed only to harvest (1 compliance issues, 1 leg ulcer). All patients were treated according to international guidelines. No excess toxicity or treatment related mortality was observed.Post-transplant MRI's showed no active disease. No patients with RRMS suffered relapse post-transplant, median reduction in EDSS scores was 2 at both 100 days (IQR 2) and at last follow up (IQR 2.5). EDSS scores stabilised in patients with SPMS.ConclusionAHSCT is an effective treatment with acceptable toxicity in patients with aggressive, inflammatory MS.

One hundred five participants from a random sample of elementary and middle school children completed measures of reading achievement and cognitive abilities presumed, based on a synthesis of current dyslexia research, to underlie reading. Factor analyses of these cognitive variables (including auditory processing, phonological awareness, short-term auditory memory, visual memory, rapid automatized naming, and visual processing speed) produced three empirically and theoretically derived factors (auditory processing, visual processing/speed, and memory), each of which contributed to the prediction of reading and spelling skills. Factor scores from the three factors combined predicted 85% of the variance associated with letter/sight word naming, 70% of the variance associated with reading comprehension, 73% for spelling, and 61% for phonetic decoding. The auditory processing factor was the strongest predictor, accounting for 27% to 43% of the variance across the different achievement areas. The results provide practitioner and researcher with theoretical and empirical support for the inclusion of measures of the three factors, in addition to specific measures of reading achievement, in a standardized assessment of dyslexia. Guidelines for a thorough, research-based assessment are provided.