Up-regulation of macrophage wnt gene expression in adenoma-carcinoma progression of human colorectal cancer

Defects in the APC-β-catenin pathway are common in colon cancer. We investigated whether aberrant regulation of upstream ligands stimulating this pathway occur in colon cancer. Using RNAase protection analysis, six out of eight wnt genes were expressed in 14 matched cases of normal, adenomatous and malignant colorectal tissues. Wnt 2 and wnt 5a were significantly up-regulated in the progression from normal through adenoma to carcinoma. Transcripts for wnts 4, 7b, 10b and 13, but not wnt 2 and wnt 5a were detected in several colorectal cell lines. In situ hybridization demonstrated that wnt 2 and wnt 5a transcripts were mainly in the lamina propria/stroma region with labelling predominantly in macrophages. Immunostaining with CD68 confirmed the wnt-expressing cells as macrophages. These results show a major difference in wnt expression in colon cancer compared to colon adenomas and suggest stromal wnt expression may play a role in tumour progression. © 1999 Cancer Research Campaig

The genome-wide dynamics of purging during selfing in maize

Self-fertilization (also known as selfing) is an important reproductive strategy in plants and a widely applied tool for plant genetics and plant breeding. Selfing can lead to inbreeding depression by uncovering recessive deleterious variants, unless these variants are purged by selection. Here we investigated the dynamics of purging in a set of eleven maize lines that were selfed for six generations. We show that heterozygous, putatively deleterious single nucleotide polymorphisms are preferentially lost from the genome during selfing. Deleterious single nucleotide polymorphisms were lost more rapidly in regions of high recombination, presumably because recombination increases the efficacy of selection by uncoupling linked variants. Overall, heterozygosity decreased more slowly than expected, by an estimated 35% to 40% per generation instead of the expected 50%, perhaps reflecting pervasive associative overdominance. Finally, three lines exhibited marked decreases in genome size due to the purging of transposable elements. Genome loss was more likely to occur for lineages that began with larger genomes with more transposable elements and chromosomal knobs. These three lines purged an average of 398 Mb from their genomes, an amount equivalent to three Arabidopsis thaliana genomes per lineage, in only a few generations

Role of biological markers in the clinical outcome of colon cancer

We investigated a number of biological markers, evaluated under strict intralaboratory quality control conditions, in terms of their role in predicting clinical outcome of patients with colon cancer treated with 5-FU-containing regimens. Colon cancer tissue from 263 patients enrolled onto two randomised clinical trials were studied for their cytofluorimetrically determined DNA content and their immunohistochemically evaluated microvessel density, vascular endothelial growth factor expression, thymidylate synthase expression and tumour lymphocyte infiltration. Disease-free survival and overall survival of patients were analysed as a function of the different variables. At a median follow up of 57 months, age, gender and Dukes' stage showed an impact on disease-free survival, whereas no biological marker emerged as an indicator of better or worse disease-free survival. Only histological grade and Dukes' stage were found to influence overall survival. The different biological variables, studied with particular attention for determination reliability, proved to have no impact on the clinical outcome of patients with colon cancer. Therefore, other markers must be identified to complement clinico-pathological variables in the management of this disease

Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature

We performed a meta-analysis of all published studies relating intratumoural microvessel density (MVD) (45 studies) or vascular endothelial growth factor (VEGF) expression (27 studies), both reflecting angiogenesis, to relapse free (RFS) and overall survival (OS) in colorectal cancer (CRC). For each study, MVD impact was measured by risk ratio between the two survival distributions with median MVD as cutoff. Eleven studies did not mention survival data or fit inclusion criteria, six were multiple publications of same series, leaving 32 independent studies for MVD (3496 patients) and 18 for VEGF (2050 patients). Microvessel density was assessed by immunohistochemistry, using antibodies against factor VIII (16 studies), CD31 (10 studies) or CD34 (seven studies). Vascular endothelial growth factor expression was mostly assessed by immunohistochemistry. Statistics were performed for MVD in 22 studies (the others lacking survival statistics) including nine studies (n=957) for RFS and 18 for OS (n=2383) and for VEGF in 17 studies, including nine studies for RFS (n=1064) and 10 for OS (n=1301). High MVD significantly predicted poor RFS (RR=2.32 95% CI: 1.39–3.90; P<0.001) and OS (RR=1.44; 95% CI: 1.08–1.92; P=0.01). Using CD31 or CD34, MVD was inversely related to survival, whereas it was not using factor VIII. Vascular endothelial growth factor expression significantly predicted poor RFS (RR=2.84; 95% CI: 1.95–4.16) and OS (RR=1.65; 95% CI: 1.27–2.14). To strengthen our findings, future prospective studies should explore the relation between MVD or VEGF expression and survival or response to therapy (e.g. antiangiogenic therapy). Assessment of these angiogenic markers should be better standardised in future studies

Conversion to hypertrophic vertebral pseudarthrosis following percutaneous vertebroplasty

To determine the role of percutaneous vertebroplasty (PVP) in bone formation and the union of vertebral pseudarthrosis, we analyzed 14 patients with an average follow-up duration of 21 months. Evaluation methods included back pain (visual analog scale: VAS), wedge angle, dynamic mobility, radiographic remodeling including callus and spur formation, and union status. The Student's t test was used for statistical analysis and a probability of less than 0.05 was determined as a significant difference. Back pain improved in all 14 patients with a VAS score of 57.8 ± 23.5 mm (average ± standard deviation) preoperatively and 14.7 ± 16.4 mm at the final follow-up (P < 0.001). The wedge angle decreased from 21.6° ± 8.3° (average ± standard deviation) preoperatively to 13.2° ± 6.9° at the final follow-up (P < 0.001). Callus formation was seen in four patients. Bony spurs were seen in the affected vertebra in preoperative radiographs in all patients, and were further developed to a solidified form during follow up after PVP. Dynamic mobility of the affected vertebrae was 6.9 ± 2.9 mm preoperatively, which decreased to 1.1° ± 0.7° at the final follow-up (P < 0.001). Notably, all patients showed the dynamic vertebral mobility of 2 mm or less. Nevertheless, only two patients exhibited the dynamic vertebral mobility of 0 mm at the final follow-up, which is referred to as bone union. These findings indicate that PVP serves as a mechanical stabilizer for vertebral pseudarthrosis, which leads to immediate pain relief and segmental bony responses