Reduction of peritoneal carcinomatosis by intraperitoneal administration of phospholipids in rats

<p>Abstract</p> <p>Background</p> <p>Intraperitoneal tumor cell attachment after resection of gastrointestinal cancer may lead to a developing of peritoneal carcinosis. Intraabdominal application of phospholipids shows a significant decrease of adhesion formation even in case of rising tumor cell concentration.</p> <p>Methods</p> <p>In experiment A 2*10⁶colonic tumor cells (DHD/K12/Trb) were injected intraperitonely in female BD-IX-rats. A total of 30 rats were divided into three groups with treatments of phospholipids at 6% or 9% and the control group. In experiment B a total of 100 rats were divided into ten groups with treatments of phospholipids at 9% and the control group. A rising concentration of tumor cells (10,000, 50,000, 100,000, 250,000 and 500,000) were injected intraperitonely in female BD-IX-rats of the different groups. After 30 days, the extent of peritoneal carcinosis was determined by measuring the tumor volume, the area of attachment and the Peritoneal Cancer Index (PCI).</p> <p>Results</p> <p>In experiment A, we found a significant reduction (control group: tumor volume: 12.0 ± 4.9 ml; area of tumor adhesion: 2434.4 ± 766 mm²; PCI 28.5 ± 10.0) of peritoneal dissemination according to all evaluation methods after treatment with phospholipids 6% (tumor volume: 5.2 ± 2.2 ml; area of tumor adhesion: 1106.8 ± 689 mm²; PCI 19.0 ± 5.0) and phospholipids 9% (tumor volume: 4.0 ± 3.5 ml; area of tumor adhesion: 362.7 ± 339 mm²; PCI 13.8 ± 5.1). In experiment B we found a significant reduction of tumor volume in all different groups of rising tumor cell concentration compared to the control. As detected by the area of attachment we found a significant reduction in the subgroups 1*10⁴, 25*10⁴and 50*10⁴. The reduction in the other subgroups shows no significance. The PCI could be reduced significantly in all subgroups apart from 5*10⁴.</p> <p>Conclusion</p> <p>In this animal study intraperitoneal application of phospholipids resulted in reduction of the extent of peritoneal carcinomatosis after intraperitoneal administration of free tumor cells. This effect was exceptionally noticed when the amount of intraperitoneal tumor cells was limited. Consequently, intraperitoneal administration of phospholipids might be effective in reducing peritoneal carcinomatosis after surgery of gastrointestinal tumors in humans.</p

A Novel BMPR2 Mutation Associated with Pulmonary Arterial Hypertension in an Octogenarian

We describe the case of an 83-year-old man with a family history of pulmonary hypertension (PH) who presented with severe pulmonary arterial hypertension (PAH) and later tested positive for a novel bone morphogenetic protein receptor 2 (BMPR2) gene mutation. To our knowledge, this may be the oldest reported patient with PAH in whom a BMPR2 mutation was initially identified

Effect of manipulation of primary tumour vascularity on metastasis in an adenocarcinoma model

One explanation for the clinical association between tumour vascularity and probability of metastasis is that increased primary tumour vascularity enhances haematogenous dissemination by offering greater opportunity for tumour cell invasion into the circulation (intravasation). We devised an experimental tumour metastasis model that allowed manipulation of primary tumour vascularity with differential exposure of the primary and metastatic tumour site to angiogenic agents. We used this model to assess the effects of local and systemic increases in the level of the angiogenic agent basic fibroblast growth factor on metastasis. BDIX rats with implanted hind limb K12/TR adenocarcinoma tumours received either intratumoural or systemic, basic fibroblast growth factor or saline infusion. Both intratumoural and systemic basic fibroblast growth factor infusion resulted in significant increases in tumour vascularity, blood flow and growth, but not lung metastasis, compared with saline-infused controls. Raised basic fibroblast growth factor levels and increase in primary tumour vascularity did not increase metastasis. The clinical association between tumour vascularity and metastasis is most likely to arise from a metastatic tumour genotype that links increased tumour vascularity with greater metastatic potential

Genome-Wide Effects of Long-Term Divergent Selection

To understand the genetic mechanisms leading to phenotypic differentiation, it is important to identify genomic regions under selection. We scanned the genome of two chicken lines from a single trait selection experiment, where 50 generations of selection have resulted in a 9-fold difference in body weight. Analyses of nearly 60,000 SNP markers showed that the effects of selection on the genome are dramatic. The lines were fixed for alternative alleles in more than 50 regions as a result of selection. Another 10 regions displayed strong evidence for ongoing differentiation during the last 10 generations. Many more regions across the genome showed large differences in allele frequency between the lines, indicating that the phenotypic evolution in the lines in 50 generations is the result of an exploitation of standing genetic variation at 100s of loci across the genome

Fine mapping and replication of QTL in outbred chicken advanced intercross lines

Background: Linkage mapping is used to identify genomic regions affecting the expression of complex traits. However, when experimental crosses such as F2 populations or backcrosses are used to map regions containing a Quantitative Trait Locus (QTL), the size of the regions identified remains quite large, i.e. 10 or more Mb. Thus, other experimental strategies are needed to refine the QTL locations. Advanced Intercross Lines (AIL) are produced by repeated intercrossing of F2 animals and successive generations, which decrease linkage disequilibrium in a controlled manner. Although this approach is seen as promising, both to replicate QTL analyses and fine-map QTL, only a few AIL datasets, all originating from inbred founders, have been reported in the literature. Methods: We have produced a nine-generation AIL pedigree (n = 1529) from two outbred chicken lines divergently selected for body weight at eight weeks of age. All animals were weighed at eight weeks of age and genotyped for SNP located in nine genomic regions where significant or suggestive QTL had previously been detected in the F2 population. In parallel, we have developed a novel strategy to analyse the data that uses both genotype and pedigree information of all AIL individuals to replicate the detection of and fine-map QTL affecting juvenile body weight. Results: Five of the nine QTL detected with the original F2 population were confirmed and fine-mapped with the AIL, while for the remaining four, only suggestive evidence of their existence was obtained. All original QTL were confirmed as a single locus, except for one, which split into two linked QTL. Conclusions: Our results indicate that many of the QTL, which are genome-wide significant or suggestive in the analyses of large intercross populations, are true effects that can be replicated and fine-mapped using AIL. Key factors for success are the use of large populations and powerful statistical tools. Moreover, we believe that the statistical methods we have developed to efficiently study outbred AIL populations will increase the number of organisms for which in-depth complex traits can be analyzed

Learning physical examination skills outside timetabled training sessions: what happens and why?

Lack of published studies on students’ practice behaviour of physical examination skills outside timetabled training sessions inspired this study into what activities medical students undertake to improve their skills and factors influencing this. Six focus groups of a total of 52 students from Years 1–3 using a pre-established interview guide. Interviews were recorded, transcribed and analyzed using qualitative methods. The interview guide was based on questionnaire results; overall response rate for Years 1–3 was 90% (n = 875). Students report a variety of activities to improve their physical examination skills. On average, students devote 20% of self-study time to skill training with Year 1 students practising significantly more than Year 3 students. Practice patterns shift from just-in-time learning to a longitudinal selfdirected approach. Factors influencing this change are assessment methods and simulated/real patients. Learning resources used include textbooks, examination guidelines, scientific articles, the Internet, videos/DVDs and scoring forms from previous OSCEs. Practising skills on fellow students happens at university rooms or at home. Also family and friends were mentioned to help. Simulated/real patients stimulated students to practise of physical examination skills, initially causing confusion and anxiety about skill performance but leading to increased feelings of competence. Difficult or enjoyable skills stimulate students to practise. The strategies students adopt to master physical examination skills outside timetabled training sessions are self-directed. OSCE assessment does have influence, but learning takes place also when there is no upcoming assessment. Simulated and real patients provide strong incentives to work on skills. Early patient contacts make students feel more prepared for clinical practice

Activation of tissue plasminogen activator by metastasis-inducing S100P protein

S100P protein in human breast cancer cells is associated with reduced patient survival and, in a model system of metastasis, it confers a metastatic phenotype upon benign mammary tumour cells. S100P protein possesses a C-terminal lysine residue. Using a multiwell in vitro assay, S100P is now shown for the first time to exhibit a strong, C-terminal lysine-dependent activation of tissue plasminogen activator (tPA), but not of urokinase-catalysed plasminogen activation. The presence of 10 μM calcium ions stimulates tPA activation of plasminogen 2-fold in an S100P-dependent manner. S100P physically interacts with both plasminogen and tPA in vitro, but not with urokinase. Cells constitutively expressing S100P exhibit detectable S100P protein on the cell surface, and S100P-containing cells show enhanced activation of plasminogen compared with S100P-negative control cells. S100P shows C-terminal lysine-dependent enhancement of cell invasion. An S100P antibody, when added to the culture medium, reduced the rate of invasion of wild-type S100P-expressing cells, but not of cells expressing mutant S100P proteins lacking the C-terminal lysine, suggesting that S100P functions outside the cell. The protease inhibitors, aprotinin or α-2-antiplasmin, reduced the invasion of S100P-expressing cells, but not of S100P-negative control cells, nor cells expressing S100P protein lacking the C-terminal lysine. It is proposed that activation of tPA via the C-terminal lysine of S100P contributes to the enhancement of cell invasion by S100P and thus potentially to its metastasis-promoting activity