Disease Markers - Volume 25, issue 3

Authors: Alonso-Montes, Cristina | Castro, Mónica G. | Reguero, Julián R. | Perrot, Andreas | Özcelik, Cemil | Geier, Christian | Posch, Maximilian G. | Morís, César | Alvarez, Victoria | Ruiz-Ortega, Marta | Coto, Eliecer

Article Type: Research Article

Abstract: Mitochondrial transcription factors mtTFA, mtTFB1 and mtTFB2 are required for the replication of mitochondrial DNA (mtDNA), regulating the number of mtDNA copies. Mice with a mtTFA deletion showed a reduced number of mtDNA copies, a reduction in respiratory chain activity, and a characteristic dilated cardiomyopathy. DNA variants in these genes could be involved in the risk for cardiac hypertrophy (HCM). We determined the variation in the TFAM, TFB1M, and TFB2M genes (using SSCA, DHPLC, and …direct sequencing) in a total of 200 HCM-patients from Spain and Germany, and in 250 healthy controls. We found several common polymorphisms that defined haplotype blocks in these genes, with frequencies that did not differ between patients and controls. We also found four novel variants in patients which were absent in the controls: -91 C > A (5'-UTR) and Ala105 > Thr in TFAM, and Thr211 > Ala and Arg256 > Lys in TFB1M. The three missense changes were in highly conserved amino acids, and could be involved in HCM-risk. In conclusion, common variants in the mitochondrial transcription factors were not associated with the risk for HCM. However, rare DNA variants (putative mutations) could be involved in the pathogenesis of HCM in a reduced number of cases. Show more

Keywords: Cardiac hypertrophy, mitochondria DNA, transcription factors, mutations

Citation: Disease Markers, vol. 25, no. 3, pp. 131-139, 2008

Authors: Tzao, Ching | Lee, Shih-Chun | Tung, Ho-Jui | Hsu, Han-Shui | Hsu, Wen-Hu | Sun, Guang-Huan | Yu, Cheng-Ping | Jin, Jong-Shiaw | Cheng, Yeung-Leung

Article Type: Research Article

Abstract: Hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) are important angiogenic factors in human cancers. Relative to VEGF-C, prognostic significance of VEGF-D expression and its association with HIF-1α expression remain elusive in esophageal squamous cell cancer (ESCC). We studied expression of HIF-1α and VEGF-D using immunohistochemistry in 85 resected ESCC specimens and correlated results with patients' clinicopathologic parameters and survival. Association between expression of HIF-1α and VEGF-D was …investigated using a concordance analysis. High expression of HIF-1α and VEGF-D was observed in 52 (61.2%) and 56 (65.9%) patients, respectively. HIF-1α expression correlated well with tumor stage (P = 0.041), whereas VEGF-D expression correlated with tumor stage (P = 0.027) and N status (P = 0.019). Groups of high HIF-1α and VEGF-D showed worse survivals than those of low expression (P = 0.002 and 0.001, respectively). Multivariate analysis supported expression of HIF-1α and VEGF-D as significant survival predictors (P = 0.044 and 0.035, respectively). A concordance rate of 69.5% was observed between expression of HIF-1α and VEGF-D. In conclusion, protein expression of HIF-1α and VEGF-D are independent prognostic predictors. An association between expression of HIF-1α and VEGF-D suggests that these two angiogenic factors are essential in progression of ESCC. Show more

Keywords: , vascular endothelial growth factor (VEGF)-D, esophageal squamous cell carcinoma, prognosis, survival

Citation: Disease Markers, vol. 25, no. 3, pp. 141-148, 2008

Authors: Santos-Rebouças, C.B. | Corrêa, J.C. | Bonomo, A. | Fintelman-Rodrigues, N. | Moura, K.C.V. | Rodrigues, C.S.C. | Santos, J.M. | Pimentel, M.M.G.

Article Type: Research Article

Abstract: Polymorphisms in genes encoding folate metabolizing enzymes have been linked to an increased risk of maternal chromosomal nondisjunction in several populations. With the purpose of evaluating this relationship, we compared the frequencies of 677C>T and 1298A>C polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and 66A>G in the methionine synthase reductase gene (MTRR) between 103 young mothers of Down syndrome (DS) individuals and 108 control mothers, whose offspring was karyotypically …normal, correlating it with an estimative of folate and – related micronutrients levels intake. Maternal and paternal transmission frequencies of MTHFR 677T allele were also examined to access potential parent-of-origin effects. PCR-RFLP for genomic DNA was accomplished and allele/genotype frequencies differences were determined using the x^{2} test, whereas pattern of transmission of the MTHFR 677 allele was analyzed by transmission disequilibrium test. None of the polymorphisms seemed to be more frequent in case mothers than in controls, either individually or combined. The estimative of nutritional intake revealed that folate consumption median was inadequate in both groups, whereas methionine and zinc consumption medians were significantly greater in control mothers. It suggests that such interaction between genetic profile and environment could predispose this sub group of women to have a DS child. Additional studies focusing the interaction between nutritional intakes, biochemical data and folate pathway polymorphisms are needed to confirm the present results. The possibility of neutralize the biochemical negative effects of folate-related polymorphisms through oral supplementation could provide new targets for DS prevention. Show more

Keywords: Down syndrome, trisomy 21, folate, homocysteine, MTHFR

Citation: Disease Markers, vol. 25, no. 3, pp. 149-157, 2008

Authors: Zitt, Matthias | Müller, Hannes M. | Rochel, Marina | Schwendinger, Verena | Zitt, Marion | Goebel, Georg | DeVries, Alexander | Margreiter, Raimund | Oberwalder, Michael | Zeillinger, Robert | Öfner, Dietmar

Article Type: Research Article

Abstract: Circulating cell-free DNA opens up an interesting field for therapy monitoring, in particular during multimodal therapy protocols. The objective of this proof of principle study was to evaluate whether the amount of circulating plasma DNA has the potential to serve as a marker for therapy monitoring during the treatment course of locally advanced rectal cancer patients. We especially focused on kinetics of circulating DNA to assess whether variances in kinetics have the potential to discriminate between …therapy responders and nonresponders. The amount of circulating DNA in plasma of rectal cancer patients undergoing preoperative chemoradiation was determined using real-time PCR before chemoradiation, after the end of chemoradiation and at the end of treatment. The study population was divided into responders (ypT0-T2 stage) and nonresponders (ypT3-T4 stage). Both groups showed comparable median plasma DNA values before and after the end of chemoradiation. At the end of treatment responders showed a further decrease in circulating DNA, whereas in nonresponders the circulating DNA manifestly increased (P = 0.006). This study demonstrates that circulating DNA in plasma of rectal cancer patients undergoing preoperative chemoradiation might serve as a surrogate marker to discriminate between responders and nonresponders. Therefore, we hypothesize that quantification of plasma DNA could be of use as an easily accessible tool for therapy monitoring in these patients. Show more

Keywords: Circulating DNA, plasma, rectal cancer, preoperative chemoradiation, therapy monitoring

Citation: Disease Markers, vol. 25, no. 3, pp. 159-165, 2008

Authors: Nanetti, L. | Vignini, A. | Raffaelli, F. | Taffi, R. | Silvestrini, M. | Provinciali, L. | Mazzanti, L.

Article Type: Research Article

Abstract: Stroke is a heterogeneous syndrome caused by multiple disease mechanisms, resulting in a disruption of cerebral blood flow with subsequent tissue damage. It is well known that erythrocytes have a large amount of sialic acid and could represent a model to investigate changes occurring in a pathology like stroke. The aim of this study was to investigate a possible relationship among erythrocyte membrane, plasma and sialic acid content. The possible impact of the sialic acid content …and the activity of sialidase on stroke severity was also evaluated. The study population consisted of 54 patients with a first stroke and of 53 age-and sex matched healthy volunteers. The total bound sialic acid was substantially decreased in patients. There was a significant correlation between the sialidase activity values and the severity of the neurological deficit defined by the National Institute of Health Stroke Scale. This study shows that low sialic acid erythrocyte concentrations with contemporary high sialic acid plasma levels and elevated sialidase activity can be considered as markers of ischemic stroke. Further investigations are needed to clarify the possible role of these biochemical changes in producing and sustaining cerebral ischemic damage. Show more

Keywords: Sialic acid, sialidase, erythrocytes, plasma, acute stroke

Citation: Disease Markers, vol. 25, no. 3, pp. 167-173, 2008

Authors: Kitahara, Kei | Kawa, Shigeyuki | Katsuyama, Yoshihiko | Umemura, Takeji | Ozaki, Yayoi | Takayama, Mari | Arakura, Norikazu | Ota, Masao

Article Type: Research Article

Abstract: Alcohol abuse is one of the most common risk factor for chronic pancreatitis, but the underlying pathophysiological mechanisms remain unclear. The aim of this study was to identify genes that contribute to susceptibility or resistance for alcoholic chronic pancreatitis by screening the whole genome. Sixty-five patients with alcoholic chronic pancreatitis (63 men and 2 women, mean age 55.2 years) and 99 healthy Japanese controls were enrolled in this study. This was an association study using 400 …polymorphic microsatellite markers with an average spacing of 10.8 cM distributed throughout the whole genome. This search revealed 10 candidate susceptibility regions and 5 candidate resistant regions throughout the genome. No specific microsatellite markers were detected in association with previously reported susceptibility genes for chronic pancreatitis, such as PRSS1, PRSS2, CTRC, SPINK1, CFTR, ALDH2, and CYP2E1. Among the statistically significant markers, D15S1007 on chromosome 15q14 showed strong evidence for disease susceptibility (70.8% vs. 35.1%, Pc = 0.0001). Within 500 kb of D15S1007, several genes were candidate genes for susceptibility, including FMN1, DKFZP686C2281, LOC440268, RYR3, and AVEN, This study identified 10 candidate susceptibility and 5 candidate resistant regions that may contain genes involved in ACP pathogenesis. Show more

Keywords: Chronic pancreatitis, microsatellite, D15S1007, RYR3

Citation: Disease Markers, vol. 25, no. 3, pp. 175-180, 2008

Authors: Millán, Mónica | Sobrino, Tomás | Arenillas, Juan Francisco | Rodríguez-Yáñez, Manuel | García, María | Nombela, Florentino | Castellanos, Mar | de la Ossa, Natalia Pérez | Cuadras, Patricia | Serena, Joaquín | Castillo, José | Dávalos, Antoni

Article Type: Research Article

Abstract: Background and purpose: Increased body iron stores have been related to greater oxidative stress and brain injury in clinical and experimental cerebral ischemia and reperfusion. We aimed to investigate the biological signatures of excitotoxicity, inflammation and blood brain barrier disruption potentially associated with high serum ferritin levels-related damage in acute stroke patients treated with i.v. t-PA. Methods: Serum levels of ferritin (as index of increased cellular iron stores), glutamate, interleukin-6, matrix metalloproteinase-9 and …cellular fibronectin were determined in 134 patients treated with i.v. t-PA within 3 hours from stroke onset in blood samples obtained before t-PA treatment, at 24 and 72 hours. Results: Serum ferritin levels before t-PA infusion correlated to glutamate (r = 0.59, p < 0.001) and interleukin-6 (r = 0.55, p < 0.001) levels at baseline, and with glutamate (r = 0.57, p < 0.001), interleukin-6 (r = 0.49, p < 0.001), metalloproteinase-9 (r = 0.23, p = 0.007) and cellular fibronectin (r = 0.27, p = 0.002) levels measured at 24 hours and glutamate (r = 0.415, p < 0.001), interleukin-6 (r = 0.359, p < 0.001) and metalloproteinase-9 (r = 0.261, p = 0.004) at 72 hours. The association between ferritin and glutamate levels remained after adjustment for confounding factors in generalized linear models. Conclusions: Brain damage associated with increased iron stores in acute ischemic stroke patients treated with iv. tPA may be mediated by mechanisms linked to excitotoxic damage. The role of inflammation, blood brain barrier disruption and oxidative stress in this condition needs further research. Show more

Keywords: Iron stores, thrombolysis, ferritin, biomarkers, excitotoxicity, blood-brain-barrier disruption, inflammation

Citation: Disease Markers, vol. 25, no. 3, pp. 181-188, 2008