This study shows an association of elevated Lp-PLA(2) activity with CAD risk in relation to oxidant stress and thus supports a proatherogenic role of Lp-PLA(2).

BackgroundCaldesmon (CaD), a major actin-associated protein, is found in smooth muscle and non-muscle cells. Smooth muscle caldesmon, h-CaD, is a multifunctional protein, and non-muscle cell caldesmon, l-CaD, plays a role in cytoskeletal architecture and dynamics. h-CaD is thought to be an useful marker for smooth muscle tumors, but the role(s) of l-CaD has not been examined in tumors.MethodsPrimary colon cancer and liver metastasis tissues were obtained from colon cancer patients. Prior to chemoradiotherapy (CRT), normal and cancerous tissues were obtained from rectal cancer patients. Whole-tissue protein extracts were analyzed by 2-DE-based proteomics. Expression and phosphorylation level of main cellular signaling proteins were determined by western blot analysis. Cell proliferation after CaD siRNA transfection was monitored by MTT assay.ResultsThe expression level of l-CaD was significantly increased in primary colon cancer and liver metastasis tissues compared to the level in the corresponding normal tissues. In cancerous tissues obtained from the patients showing poor response to CRT (Dworak grade 4), the expression of l-CaD was increased compared to that of good response group (Dworak grade 1). In line with, l-CaD positive human colon cancer cell lines were more resistant to 5-fluorouracil (5-FU) and radiation treatment compared to l-CaD negative cell lines. Artificial suppression of l-CaD increased susceptibility of colon cancer cells to 5-FU, and caused an increase of p21 and c-PARP, and a decrease of NF-kB and p-mTOR expression.ConclusionUp-regulated expression of l-CaD may have a role for increasing metastatic property and decreasing CRT susceptibility in colorectal cancer cells.

simple anthropometric measurement, such as waist circumference (WC) or waist to hip ratio (WHR), is widely used in clinical practice as a surrogate for central obesity in order to assess health status. 1,2 However, for a given WC, body fat distribution differs significantly according to gender, menopausal status, age, and so forth. 3,4 Particularly in premenopausal women, subcutaneous fat is relatively predominant over abdominal visceral fats, 5 and so using WC to evaluate visceral obesity could underestimate metabolic disorders.Metabolic syndrome (MetS) is a major public health challenge because of its implications in the increased risk of type 2 diabetes and cardiovascular disease (CVD). 6,7 During the past decade, various sets of diagnostic criteria for MetS have been proposed [8][9][10][11] and all share the major metabolic risk factors (RF) such as abdominal obesity, insulin resistance/glucose intolerance, dyslipidemia and hypertension. However, there are 2 major differences in the organization of the criteria and the emphasis on excessive adiposity. [8][9][10][11] Thus, discrepant cases are often reported in studies of the prevalence of MetS, or in the subjects' characteristics classified to MetS, depending on the definition used. 12-14 Currently, the International Diabetes Federation (IDF) criteria, 11 which define WC as an obligatory factor for diagnosing MetS, are under discussion for thier inability to detect metabolically abnormal but non-obese individuals. 12,15 In addition, a WHO expert consultation addressed the fact that Asians generally have a higher percentage of body fat and show greater abdominal obesity at a lower body mass index (BMI) than Caucasians. 16 The consultation also identified an additional trigger point for public health action or clinical intervention as being 23 kg/m 2 BMI because the relative risk for type 2 diabetes or CVD in Asian populations is substantial, even below 25 kg/m 2 BMI.Therefore, in order to evaluate the risk of MetS in premenopausal Asian women, the present study aimed to (a) elucidate the best marker of central obesity among the obesity-related anthropometric indices including computed tomography (CT) results, (b) define the optimal cut-off point of visceral fat area (VFA) in premenopausal women and (c) examine whether or not the WC derived from the cut-off point of the VFA can also reflect the features of MetS, particularly in subjects with BMI ≥23 kg/m 2 . J 2008; 72: 1308 -1315 (Received November 9, 2007 revised manuscript received March 12, 2008; accepted April 4, 2008 Background In clinical practice, using the patient's waist circumference (WC) to evaluate visceral obesity may underestimate disorders with a metabolic origin. This study examined whether or not the WC derived from the cut-off point of the visceral fat area (VFA) can reflect the features of metabolic syndrome (MetS) in premenopausal women. Circ Methods and ResultsComputed tomography-scanned VFA, MetS components and the concentrations of highsensitivity C-reactive protein (CRP) and adipone...

Background Immunomodulatory cytokines and systemic inflammatory markers are important during cancer development and progression. This study investigated the association and prognostic impact of systemic cytokine profiles and inflammatory markers in colorectal cancer (CRC). Methods Interleukin (IL)-1β, IL-6, IL-8, IL-9, IL-10, tumour necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) serum levels were measured using multiplex bead assays in CRC patients. Data on systemic inflammatory markers, such as the modified Glasgow prognostic score (mGPS), the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), prognostic nutritional index (PNI) and fibrinogen, were collected. Survival analysis was performed to identify factors associated with progression-free survival (PFS) and overall survival (OS). Results There were moderate-to-strong correlations within serum cytokines, as well as within systemic inflammatory markers, whereas the associations between serum cytokines and systemic inflammatory markers were generally weak. IL-8 and the LMR were independent significant prognostic factors for PFS and OS. The low IL-8 and high LMR group had the best survival (both PFS and OS) of all groups. Conclusions Systemic cytokine profiles and inflammatory markers have relatively weak intergroup correlations. A composite classification of systemic cytokine profiles and inflammatory markers has an enhanced prognostic value in CRC.

Serpin B5 is a candidate tumour suppressor, but its oncogenic activity has also been reported. Its function may be affected by protein interactions. The aim of this study was to assess the relationship between serpin B5 and carcinoembryonic antigen (CEA) expression in colorectal cancer (CRC). We also analysed the clinicopathological significance of serpin B5 expression in patients with CRC. Downregulation of serpin B5 was identified in a CEA-suppressed LoVo cell line using two-dimensional gel electrophoresis (2-DE) and matrix-associated laser desorption ionisation-mass spectrometry (MALDI-MS). The specific interaction and co-localisation of serpin B5 with CEA were confirmed by co-immunoprecipitation and confocal microscopy. Western blot analysis and ELISAs revealed significant positive correlations between levels of serpin B5 and CEA in human colon cancer cell lines and in the blood of patients with CRC. Tissue expression of serpin B5 in 377 patients with CRC was significantly associated with serum CEA, histological grade, stage, lymph node metastasis, lymphatic and perineural invasion, and infiltrative border. Strong expression of serpin B5 was also associated with a reduced DFS (p 5 0.001) and OS (p 5 0.017). Together, these findings describe a relationship between serpin B5 and CEA expression in CRC. Strong expression of serpin B5 was associated with a worse prognosis in patients with CRC and its expression may correlate with CEA levels in CRC.

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BackgroundResistance to 5-fluorouracil (5-FU) in patients with colorectal cancer prevents effective treatment and leads to unnecessary and burdensome chemotherapy. Therefore, prediction of 5-FU resistance is imperative.MethodsTo identify the proteins linked to 5-FU resistance, two-dimensional gel electrophoresis-based proteomics was performed using the human colon cancer cell line SNU-C4R with induced 5-FU resistance. Proteins showing altered expression in SNU-C4R were identified by matrix-associated laser desorption/ionization–time-of-flight analysis, and their roles in susceptibility to 5-FU or radiation were evaluated in various cell lines by transfection of specific siRNA or creation of overexpression constructs. Changes in cellular signaling and expression of mitochondrial apoptotic factors were investigated by Western Blot analysis. A mitochondrial membrane potential probe (JC-1 dye) and a flow cytometry system were employed to determine the mitochondrial membrane potential. Finally, protein levels were determined by Western Blot analysis in tissues from 122 patients with rectal cancer to clarify whether each identified protein is a useful predictor of a chemoradiation response.ResultsWe identified mitochondrial phosphoenolpyruvate carboxykinase (mPEPCK) as a candidate predictor of 5-FU resistance. PEPCK was downregulated in SNU-C4R compared with its parent cell line SNU-C4. Overexpression of mPEPCK did not significantly alter the susceptibility to either 5-FU or radiation. Suppression of mPEPCK led to a decrease in both the cellular level of phosphoenolpyruvate and the susceptibility to 5-FU and radiation. Furthermore, the cellular levels of phosphoenolpyruvate (an end product of PEPCK and a substrate of pyruvate kinase), phosphorylated AKT, and phosphorylated 4EBP1 were decreased significantly secondary to the mPEPCK suppression in SNU-C4. However, mPEPCK siRNA transfection induced changes in neither the mitochondrial membrane potential nor the expression levels of mitochondrial apoptotic factors such as Bax, Bcl-2, and Bad. Downregulation of total PEPCK was observed in tissues from patients with rectal cancer who displayed poor responses to preoperative 5-FU-based radiation therapy.ConclusionOur overall results demonstrate that mPEPCK is a useful predictor of a response to chemoradiotherapy in patients with rectal cancer.

Tissue CEA expression is a prognostic factor in patients with colorectal cancer. Analysis of tissue CEA expression may be helpful in determining the clinical utility of serial measurements of serum CEA as surveillance in patients with curatively resected colorectal cancer.