Tryptophan Metabolism as Source of New Prognostic Biomarkers for FAP Patients

Familial adenomatous polyposis (FAP), a common inherited form of colorectal cancer (CRC), causes the development of hundreds to thousands of colonic adenomas in the colorectum beginning in early adolescence. In absence of a prophylactic surgery, FAP patients almost inevitably develop CRC by the age of 40 to 50. The lack of valuable prognostic biomarkers for FAP patients makes it difficult to predict when the progression from adenoma to malignant carcinoma occurs. Decreased tryptophan (TRP) plasma levels and increased indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan hydroxylase 1 (TPH1) enzymatic activities have been associated to tumour progression in CRC. In the present study, we aimed at investigating whether an altered TRP metabolism might also exist in FAP patients. Our results highlighted that plasma levels of TRP and its main catabolites are comparable between FAP patients and healthy subject. On the contrary, FAP patients presented significantly higher TRP levels with respect to high-grade adenoma (ADE) subjects and CRC patients. Obtained data lead us to evaluate IDO1 and TPH1 enzymes activity in the study groups. For both enzymes, it was possible to discriminate correctly between FAP subject and ADE/CRC patients with high sensitivities and specificities. By receiver operating characteristic (ROC) curve analysis, the cut-off values of IDO1 and TPH1 enzymatic activities associated to the presence of an active malignant transformation have been calculated as >38 and >5.5, respectively. When these cut-off values are employed, the area under the curve (AUC) is > 0.8 for both, indicating that TRP metabolism in patients with FAP may be used to monitor and predict the tumorigenic evolution

A functional biological network centered on XRCC3: a new possible marker of chemoradiotherapy resistance in rectal cancer patients

Preoperative chemoradiotherapy is widely used to improve local control of disease, sphincter preservation and to improve survival in patients with locally advanced rectal cancer. Patients enrolled in the present study underwent preoperative chemoradiotherapy, followed by surgical excision. Response to chemoradiotherapy was evaluated according to Mandard's Tumor Regression Grade (TRG). TRG 3, 4 and 5 were considered as partial or no response while TRG 1 and 2 as complete response. From pretherapeutic biopsies of 84 locally advanced rectal carcinomas available for the analysis, only 42 of them showed 70% cancer cellularity at least. By determining gene expression profiles, responders and non-responders showed significantly different expression levels for 19 genes (P < 0.001). We fitted a logistic model selected with a stepwise procedure optimizing the Akaike Information Criterion (AIC) and then validated by means of leave one out cross validation (LOOCV, accuracy = 95%). Four genes were retained in the achieved model: ZNF160, XRCC3, HFM1 and ASXL2. Real time PCR confirmed that XRCC3 is overexpressed in responders group and HFM1 and ASXL2 showed a positive trend. In vitro test on colon cancer resistant/susceptible to chemoradioterapy cells, finally prove that XRCC3 deregulation is extensively involved in the chemoresistance mechanisms. Protein-protein interactions (PPI) analysis involving the predictive classifier revealed a network of 45 interacting nodes (proteins) with TRAF6 gene playing a keystone role in the network. The present study confirmed the possibility that gene expression profiling combined with integrative computational biology is useful to predict complete responses to preoperative chemoradiotherapy in patients with advanced rectal cance

Fat body of the frog Rana esculenta: An ultrastructural study

In the frog, the fat body is the largest body lipid deposit and is associated with the gonad. The aim of the present work was to investigate the fine structure of the fat body at different periods of the annual cycle and during prolonged starvation. Results indicate that fat body cells of Rana esculenta caught in autumn and after winter hibernation resemble mammalian adipocytes of white adipose tissue and contain markers of adipose tissue, such as S-100 protein and lipoproteinlipase. However, unlike mammalian adipocytes, fat body adipocytes consistently show small lipid droplets associated with their single, large lipid deposits, a lack of a definite external lamina, and the presence of cellular prolongations and spicula at their surfaces. Transmission and scanning electron microscopy in association with lanthanum tracer experiments suggest that in fat body adipocytes a vesicular-tubular system connects the cytoplasm and the interstitial space. In June (i.e., during the reproductive period), fat body adipocytes appear to have lost much of their lipid deposit and adjacent adipocytes show interdigitation of their plasma membranes and prominent Golgi complexes. In starved frogs, fat body cells can be almost devoid of lipid and in regression to a near-mesenchymal state. Nevertheless, these fat bodies still contain lipoproteinlipase activity ( apprx 45% of that found in lipid-filled ones), indicating persistent adipose differentiation of the cells therein. Results presented here show that the R. esculenta fat body is an adipose organ undergoing reversible extreme changes in adipocyte fat content, which are associated with definite ultrastructural features. The fat body represents a suitable model for studying adipose tissue under different and extreme physiological conditions

Omental and epigastric adipose tissue lipolytic activity in human obesity: effect of abdominal fat distribution and relationship with hyperinsulinemia.

It has been shown that visceral obesity is associated with an increased incidence of hyperinsulinemia. In such a condition, hyperinsulinemia could be due to an increased lipolytic activity of omental adipose tissue (AT), through an enhanced portal flux of FFA. The purpose of our study was to evaluate the lipolytic activity of omental and epigastric AT obtained from morbid obese patients either with prevalently visceral or subcutaneous abdominal fat accumulation, evaluated by computerized tomography. The relationship between plasma insulin values and in vitro lipolytic activity in both tissues was studied. Thirteen visceral (VO) and 13 subcutaneous (SO) obese patients, matched for sex and body mass index, undergoing vertical banded gastroplasty, were studied. Before surgery, in each patient an OGTT was performed. During surgery, samples of epigastric subcutaneous and omental AT were obtained for evaluation of fat cell weight (FCW) and basal, noradrenaline 10(-5)M and isoprenaline 10(-5) M induced lipolytic activities. No significant differences in basal lipolysis were found between the two types of obesity, both in omental and in epigastric AT. In omental AT, a higher noradrenaline and isoprenaline induced lipolysis was observed in VO than in SO. Isoprenaline induced lipolysis of omental AT (expressed per cell surface area) correlated directly with FCW. VO patients showed plasma insulin values after OGTT significantly higher than SO patients. In the whole group of patients, independently from fat distribution, significant correlations were found between the incremental areas of the plasma insulin curve during OGTT and the noradrenaline an isoprenaline induced lipolytic activities both in omental and epigastric adipose tissue

Shoulder-girdle lipomatosis.

IF JCR 2009: 16.22

Mediastino-abdominal lipomatosis: deep accumulation of fat mimicking a respiratory disease and ascites. Clinical aspects and metabolic studies in vitro

We report on clinical and metabolic studies of a newly delineated lipomatosis, characterised by an abnormal mediastinal and abdominal accumulation of fat, without obesity. The clinical features, which occurred in all the patients studied, are: Exertional dyspnoea due to a space-occupying mediastinal accumulation of fat, without evidence of cardiac or pulmonary disease. A pseudo-ascitic abdominal enlargement, due to intra- and retroperitoneal accumulation of fatty tissue. Insulin-independent diabetes mellitus. Type IV hyperlipidaemia and elevated levels of plasma uric acid were observed in four patients. Intra-abdominal lipomatous tissue, obtained during laparoscopy from four patients, demonstrated a reduced lipolytic response to beta-adrenergic stimulation. Thus, fat deposition in the abdominal and mediastinal areas could be causally related to defective lipid mobilization in lipomatocytes. Lipoprotein lipase activity in abdominal adipose tissue were normal in two patients (10.0 and 10.6 nmol/g/min) and markedly elevated in another two patients (37.3 and 49.9 nmol/g/min), as compared with controls (12.7 +/- 2.1 nmol/g/min). When expressed on per cell basis, LPL activity in lipomatous tissue was significantly higher than in control tissue (3.21 +/- 1.1 nmol/10(5) cell/min vs 0.92 +/- 0.16 nmol/10(5) cell/min). Lipoprotein fractionation did not demonstrate consistent modification of the serum lipoprotein pattern. HDL and HDL2 cholesterol values were reduced, even in patients with elevated LPL activity in adipose tissu

Attivi\ue0\ua0 lipolitica e lipoproteinlipasica nel tessuto adiposo sottocutaneo e viscerale nella sindrome di Cushing.

Cushing's syndrome has been recently compared to visceral-type obesity, since it is characterised by the accumulation of adipose tissue at a deep abdominal site, to the detriment of the subcutaneous adipose panniculus, and is associated with insulin-resistance and hyperlipemia. The aim of the present study was to evaluate the influence of glucocorticoid hormones on lipolytic activity (index of FFA mobilisation) and on lipoproteinlipase (LPL) activity (an index of the accumulation of triglycerides) in subcutaneous and perirenal adipose tissue in order to clarify the mechanisms involved in this type of accumulation in Cushing's syndrome. Five patients (4 F and 1 M) were included in the study, mean age 27.8 +/- 3.7 years and BMI 21.3 +/- 1.2 kg/m2; patients were hospitalised in the 2nd Surgical Clinic at the University of Padua and underwent surgery for secondary corticosurrenal hyperplasia with ACTH secreting hypophysial adenoma. Lipolytic activity in subcutaneous adipose tissue in these patients was significantly lower (p less than 0.05) than in control subjects, in particular after noradrenalin stimulation (p less than 0.01). No significant difference was observed when lipolytic activity in subcutaneous adipose tissue was compared to that one in perirenal tissue. LPL activity in subcutaneous adipose tissue did not reveal statistically significant differences compared to control subjects, although values were lower. A further decrease in LPL activity, which was not however significant, was observed in perirenal tissue in comparison to subcutaneous tissues in the same patients. The mean weight of adipocytes (ug) was slightly lower in subcutaneous adipose tissue compared to control subjects and even lower in perineal tissue in comparison to the subcutis in the same patients