bluuebunny/crossref_metadata_2025 huggingface dataset:
C242T Polymorphism in CYBA Gene (p22phox) and Risk of Coronary Artery Disease in a Population of Caucasian Italians
Authors: Nasti Sabina , Spallarossa Paolo , Altieri Paola , Garibaldi Silvano , Fabbi Patrizia , Polito Luisa , Bacino Luca , Brunelli Michele , Brunelli Claudio , Barsotti Antonio , Ghigliotti Giorgio
Published: June 2013

Background: specific polymorphisms of genes regulating intracellular redox balance and oxidative stress are related to atherogenesis. Some studies have identified a relationship between progression of atherosclerosis and C242T mutation in CYBA gene coding for p22phox, a subunit of the NADH/NADPH oxidase system.

Design: we investigated whether the C242T nucleotide transition is associated with the presence of coronary artery disease (CAD) in a population of 494 Caucasian Italians undergoing coronary angiography to diagnose the cause of chest pain.

Results: the frequency of the T mutant allele that we found in 276 patients with angiographically documented CAD was significantly higher compared to what we observed in 218 subjects with normal coronary arteries (Controls) (respectively: 0.400 and 0.332, p < 0.01). The prevalence of the T allele was even stronger when we compared: 1) early onset (age ≤55) vs late onset (age ≥65) single‐vessel CAD patients (respectively: 0.75 and 0.48, p < 0.05), and 2) the subgroup of CAD patients with at least one ≥98% stenosis in a coronary vessel vs those with no ≥98% stenosis in a coronary vessel (respectively: 0.425 and 0.365, p < 0.05).

Conclusions: these results support the increased risk of developing early CAD and of having rapid progression of coronary stenosis in subjects carrying the C242T nucleotide transition among the Italian population.
Biomarkers Indicative of Blood‐Brain Barrier Disruption in Multiple Sclerosis
Authors: Waubant Emmanuelle
Published: June 2013

Blood‐brain barrier (BBB) disruption is one of the hallmarks of multiple sclerosis (MS). It is incompletely understood whether BBB disruption is the initial MS event leading to MS lesion formation or whether it is merely a consequence of cellular infiltration in the central nervous system (CNS). The presence of gadolinium enhancing (Gd+) lesions on serial brain MRI scans is frequently used to evaluate BBB disruption. The presence of Gd enhancement has therefore been used as a reference for most works evaluating promising biomarkers of BBB disruption that are reviewed here. These promising biomarkers include cytokines and chemokines, and their receptors, cell surface markers, and matrix metalloproteinases and their natural inhibitors. At this time, none of these markers have been shown as sensitive as the presence of Gd enhancement to reflect BBB disruption. However, MRI scanning is not only unpractical and expensive; it may also under represent the overall extent of BBB disruption. Developing new MS biomarkers that are sensitive and specific for BBB disruption could 1) improve the monitoring of disease activity; 2) improve the monitoring of response to MS therapies which target BBB disruption; and 3) advance our understanding of dynamic MS processes participating in BBB disruption.
Expression of Telomerase Reverse Transcriptase in Psoriatic Lesional Skin
Authors: Mahmoud Moushira A. , Mohamed Roshdy W. , Attia Fadia M. , Atwa Mona A. , Abdel-moneim Samir M.
Published: June 2013

Background: Little information is known about telomerase expression in the chronic benign hyperproliferative skin disease, psoriasis. Further studies are still required to investigate its usefulness as a biomarker of this skin disorder. Aim: To investigate the expression of human telomerase reverse transcriptase (hTERT) in psoriatic lesional skin and its relation to disease severity. Methods: The levels of hTERT‐mRNA were quantified using real time RT‐PCR in lesional versus nonlesional skin specimens from 24 psoriatic patients. Results: The expression of hTERT was detected in 16 psoriatic lesional specimens (66.7%), but in none of the normal skin. There was no relation between hTERT expression level and age of the patient or the duration of the disease. Among hTERT‐positive patients, a significant positive correlation was observed between hTERT‐mRNA levels and both the Psoriasis Area‐and‐Severity Index (PASI) and scaling scores (p = 0.012 & p = 0.006, respectively). Conclusion: Telomerase mRNA is detectable in lesional skin of most psoriatic patients and correlates with the severity of the disease and the rate of epidermal proliferation.
MGMT Methylation Status: The Advent of Stratified Therapy in Glioblastoma?
Authors: Hau Peter , Stupp Roger , Hegi Monika E.
Published: June 2013

Glioblastomas are the most malignant gliomas with median survival times of only 15 months despite modern therapies. All standard treatments are palliative. Pathogenetic factors are diverse, hence, stratified treatment plans are warranted considering the molecular heterogeneity among these tumors. However, most patients are treated with "one fits all" standard therapies, many of them with minor response and major toxicities. The integration of clinical and molecular information, now becoming available using new tools such as gene arrays, proteomics, and molecular imaging, will take us to an era where more targeted and effective treatments may be implemented.

A first step towards the design of such therapies is the identification of relevant molecular mechanisms driving the aggressive biological behavior of glioblastoma. The accumulation of diverse aberrations in regulatory processes enables tumor cells to bypass the effects of most classical therapies available. Molecular alterations underlying such mechanisms comprise aberrations on the genetic level, such as point mutations of distinct genes, or amplifications and deletions, while others result from epigenetic modifications such as aberrant methylation of CpG islands in the regulatory sequence of genes. Epigenetic silencing of the MGMT gene encoding a DNA repair enzyme was recently found to be of predictive value in a randomized clinical trial for newly diagnosed glioblastoma testing the addition of the alkylating agent temozolomide to standard radiotherapy. Determination of the methylation status of the MGMT promoter may become the first molecular diagnostic tool to identify patients most likely to respond that will allow individually tailored therapy in glioblastoma.

To date, the test for the MGMT‐methylation status is the only tool available that may direct the choice for alkylating agents in glioblastoma patients, but many others may hopefully become part of an arsenal to stratify patients to respective targeted therapies within the next years.
Etiology and Pathogenesis of Epithelial Ovarian Cancer
Authors: Mok Samuel C. , Kwong Joseph , Welch William R. , Samimi Goli , Ozbun Laurent , Bonome Tomas , Birrer Michael J. , Berkowitz Ross S. , Wong Kwong-Kwok
Published: June 2013

Ovarian cancer is complex disease composed of different histological grades and types. However, the underlying molecular mechanisms involved in the development of different phenotypes remain largely unknown. Epidemiological studies identified multiple exogenous and endogenous risk factors for ovarian cancer development. Among them, an inflammatory stromal microenvironment seems to play a critical role in the initiation of the disease. The interaction between such a microenvironment, genetic polymorphisms, and different epithelial components such as endosalpingiosis, endometriosis, and ovarian inclusion cyst in the ovarian cortex may induce different genetic changes identified in the epithelial component of different histological types of ovarian tumors. Genetic studies on different histological grades and types provide insight into the pathogenetic pathways for the development of different disease phenotypes. However, the link between all these genetic changes and the etiological factors remains to be established.
Two Insulin Gene Single Nucleotide Polymorphisms Associated with Type 1 Diabetes Risk in the Finnish and Swedish Populations
Authors: Laine Antti-Pekka , Holmberg Hanna , Nilsson Anita , Örtqvist Eva , Kiviniemi Minna , Vaarala Outi , Åkerblom Hans K. , Simell Olli , Knip Mikael , Ludvigsson Johnny , Ivarsson Sten-A. , Larsson Karin , Lernmark Åke , Ilonen Jorma
Published: June 2013

We have developed high‐throughput tests for the detection of the insulin gene region SNPs −23HphI and −2221MspI. The potential of these markers to enhance the efficiency of type 1 diabetes risk screening was then evaluated by analyzing them in Finnish and Swedish populations. Blood spots on filter paper were analyzed using PCR followed by sequence‐specific hybridization and time‐resolved fluorometry reading. Distribution of the genotypes at both positions differed significantly among the affected children compared to the controls. The risk genotypes (CC, AA) were significantly more common in Finland than in Sweden, both among patients and controls. The VNTR genotype homozygous for the protective class III alleles showed a significantly stronger protective effect than the heterozygote (p = 0.02). Analyzing both SNPs enabled the detection of VNTR class III subclasses IIIA and IIIB. The observed significance between effects of the protective genotypes was due to the strong protective effect of the IIIA/IIIA genotype. IIIA/IIIA was the only genotype with significant discrepancy between protective effects compared to the other class III genotypes. These observations suggest that heterogeneity between the protective IDDM2 lineages could exist, and analyzing both −23HphI and −2221MspI would thus potentially enhance the sensitivity and specificity of type 1 diabetes risk estimation.
Epigenetic Markers and Response to Chemotherapy in Cancer
Authors: Strathdee Gordon
Published: June 2013

The last ten years has seen an explosion in interest in epigenetic mechanisms of control of gene expression. This is particularly true in the field of cancer research where epigenetic alterations are now regarded as equally important as genetic alterations in the development and progression of cancer. Of particular interest is altered DNA methylation, which is a key feature of essentially all tumour types. Aberrant methylation of CpG islands represents an ideal candidate for both diagnostic and prognostic markers in cancer. It is highly prevalent, very largely tumour specific and potentially far more readily detectible than most genetic alterations. This review will discuss the genes already identified as potential epigenetic markers of drug response, as well as the rapidly improving technology for detection of methylation which has greatly expanded the potential sources of tumour specific DNA that can be used for epigenetic marker analysis.
Lipoprotein Lipase Gene PvuII Polymorphism Serum Lipids and Risk for Coronary Artery Disease: Meta‐Analysis
Authors: Cagatay Penbe , Susleyici-Duman Belgin , Ciftci Cavlan
Published: June 2013

Our aim was to determine whether lipoprotein lipase gene PvuII polymorphism can be considered as an independent risk factor for coronary artery disease (CAD) by conducting a meta‐analysis of all available published trials, including our own study. In 7 seperate studies, 3289 subjects were screened for this substitution; meta‐analysis included only some of these individuals. Among the 7 studies, 6 were performed on white subjects, whereas 1 was on patients with Saudi Arabic descent.Subgroup analysis indicated that individuals with PvuII substitution does not have an increased risk for CAD. The LPL‐PvuII genotype and allele frequency distributions did not differ significantly between CAD patients and healthy controls. There was no difference in the distribution of LPL‐PvuII genotypes between the healthy subjects and the patients with CAD. However, no significant differences in lipid variables (triglyceride and HDL‐cholesterol) were determined for the PvuII polymorphisms in the patients with CAD. No significant differences were found in serum triglyceride and HDL‐cholesterol levels for LPL‐PvuII genotypes when the control and CAD groups were pooled. In conclusion, LPL‐Pvu II polymorphism cannot be used as independent genetic risk factor for CAD.
DNA Methylation in Colorectal cancer—Impact on Screening and Therapy Monitoring Modalities?
Authors: Zitt Marion , Zitt Matthias , Müller Hannes M.
Published: June 2013

Colorectal cancer (CRC) is a common malignancy. It arises from benign neoplasms and evolves into adenocarcinomas through a stepwise histological progression sequence, proceeding from either adenomas or hyperplastic polyps/serrated adenomas. Genetic alterations have been associated with specific steps in this adenoma‐carcinoma sequence and are believed to drive the histological progression of CRC. Recently, epigenetic alterations (especially DNA methylation) have been shown to occur in colon polyps and CRC. The aberrant methylation of genes appears to act together with genetic alterations to drive the initiation and progression of colon polyps to CRC.

DNA methylation changes have been recognized as one of the most common molecular alterations in human tumors, including CRC. Because of the ubiquity of DNA methylation changes and the ability to detect methylated DNA in several body fluids (blood, stool), this specifically altered DNA may serve, on the one hand, as a possible new screening marker for CRC and, on the other hand, as a tool for therapy monitoring in patients having had neoplastic disease of the colorectum.

As many CRC patients present with advanced disease, early detection seems to be one of the most important approaches to reduce mortality. Therefore, an effective screening test would have substantial clinical benefits. Furthermore, early detection of progression of disease in patients having had CRC permits immediate commencement of specific treatment regimens (e.g. curative resection of liver and lung metastases) and probably longer survival and better quality of life.
Dickkopf‐3 As a New Potential Marker for Neoangiogenesis in Colorectal Cancer: Expression in Cancer Tissue and Adjacent Non‐Cancerous Tissue
Authors: Zitt Matthias , Untergasser Gerold , Amberger Albert , Moser Patrizia , Stadlmann Sylvia , Zitt Marion , Müller Hannes M. , Mühlmann Gilbert , Perathoner Alexander , Margreiter Raimund , Gunsilius Eberhard , Öfner Dietmar
Published: June 2013

Gene expression of Dickkopf‐3 (Dkk‐3) has been shown to be upregulated in tumor endothelium of colorectal cancer (CRC). For the first time, we analyzed Dkk‐3 protein expression in CRC and its potential as a marker for neoangiogenesis. We used tissue microarrays (TMAs) to investigate Dkk‐3 in microvessels of 403 CRC samples, 318 appropriate adjacent non‐cancerous samples and 127 normal colorectal samples. Of cancer samples with CD31‐positive microvessels, 67.7% were positive for Dkk‐3. Dkk‐3 staining was demonstrated in endothelial cells of all microvessels in nearly all cases. Dkk‐3‐positive samples showed a higher mean microvessel count than did Dkk‐3‐negative samples (P=0.001). Dkk‐3 expression increased with rising numbers of microvessels per sample (P<0.0001). In adjacent samples with CD31‐positive microvessels, 56% were Dkk‐3‐positive in all microvessels. Similar to cancer samples, Dkk‐3‐positive adjacent samples had a higher mean microvessel count than did Dkk‐3‐negative samples (P<0.0001), and Dkk‐3 expression also increased with rising numbers of microvessels (P<0.0001). All microvessels in normal mucosa samples were negative for Dkk‐3.

Dkk‐3 can be considered a putative pro‐angiogenic protein in neovascularization and may possibly be a marker for neoangiogenesis in CRC. Further investigations will elucidate whether Dkk‐3 is a target structure for novel therapies.
Fucosylated Glycoproteins as Markers of Liver Disease
Authors: Mehta Anand , Block Timothy M.
Published: June 2013

Changes in N‐linked glycosylation are known to occur during the development of various diseases. For example, increased branching of oligosaccharides has been associated with cancer metastasis and has been correlated to tumor progression in human cancers of the breast, colon and melanomas. Increases in core fucosylation have also been associated with the development of hepatocellular carcinoma (HCC). Recently, changes in both the total serum glycome and the glycosylation of specific IgG molecules have been observed in people with liver fibrosis and cirrhosis. The mechanisms by which changes in glycosylation are observed and their use as biomarkers of disease will be discussed.
Association of Cortactin, Fascin‐1 and Epidermal Growth Factor Receptor (EGFR) Expression in Ovarian Carcinomas: Correlation with Clinicopathological Parameters
Authors: Lin Chih-kung , Su Her-Young , Tsai Wen-Chiuan , Sheu Lai-Fa , Jin Jong-Shiaw
Published: June 2013

Cortactin, fascin‐1 and EGFR are recognized as important factors in tumor progression. We tested the hypothesis that cortactin, fascin‐1 and EGFR expression correlates with clinicopathological parameters of the four most common ovarian surface epithelial carcinomas – serous cystadenocarcinoma, mucinous cystadenocarcinoma, endometrioid adenocarcinoma, and clear cell carcinoma. Immunohistochemical analysis of cortactin, fascin‐1 and EGFR was performed using tissue microarrays of 172 specimens comprising 69 serous cystadenocarcinomas, 44 mucinous cystadenocarcinomas, 45 endometrioid adenocarcinomas and 14 clear cell carcinomas. All ovarian carcinomas showed significant expression of cortactin, fascin‐1 and EGFR in staining intensity, tumor percentages and immunostaining scores. In addition, higher immunostaining scores of fascin‐1 correlated with more advanced cancer stages (TNM), poorer histological differentiation and poorer survival rate of mucinous cystadenocarcinoma. Similarly, higher immunostaining scores of cortactin correlated with T stages and histological differentiation of serous cystadenocarcinoma. The immunostaining scores of EGFR did not correlate with TNM stages, tumor differentiation or prognosis in the four ovarian surface epithelial carcinomas. Our findings suggest that cortactin and fascin‐1 may serve as good biomarkers in evaluating aggressiveness of ovarian serous and mucinous cystadenocarcinoma. And the pharmacological inhibitors of fascin‐1 activity may slow down tumor progression and prolong survival time in patients with mucinous cystadenocarcinoma.
Biological Signatures of Brain Damage Associated with High Serum Ferritin Levels in Patients with Acute Ischemic Stroke and Thrombolytic Treatment
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
Published: June 2013

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.
Extracellular Matrix Markers for Disease Progression and Follow‐Up of Therapies in Familial Amyloid Polyneuropathy V30M TTR‐Related
Authors: Cardoso I. , Brito M. , Saraiva M.J.
Published: June 2013

Familial Amyloidotic Polyneuropathy (FAP) is a disorder characterized by the extracellular deposition of fibrillar Transthyretin (TTR) amyloid, with a special involvement of the peripheral nerve. Several extracellular matrix proteins have been found elevated in tissues from FAP patients, namely metalloproteinase‐9 (MMP‐9), neutrophil gelatinase associated lipocalin (NGAL) and biglycan. In this work we assessed the levels of MMP‐9, tissue inhibitor of metalloproteinase 1 (TIMP‐1), NGAL, biglycan and chondroitin sulphate (CSPG) in an FAP V30M TTR‐related transgenic mouse model at different stages of TTR deposition and after two different treatment approaches to remove fibrillar deposits. Immunohistochemistry or RT‐PCR analysis showed that biglycan was already increased in animals presenting TTR deposited in a non‐fibrillar state, whereas MMP‐9, TIMP‐1, NGAL and CSPG were elevated only in mice with TTR amyloid deposits. Mice treated with doxycycline, a TTR fibril disrupter, presented lower levels of MMP‐9, TIMP‐1 and NGAL, suggestive of matrix recovery. Mice immunized with TTR Y78F to remove TTR deposition showed significantly lower levels of all the five tested markers, suggesting removal of fibrillar and non‐fibrillar deposits. Cellular studies using oligomeric TTR showed induction of MMP‐9 when compared to soluble TTR, large aggregates or fibrils. Furthermore, this induction was neutralized by an anti‐receptor for advanced glycation end products (RAGE) antibody, indicating RAGE engagement in this process. Further studies in a larger number of tissue samples will indicate the application of these ECM markers in parallel with Congo Red staining in tissue characterization of pre‐clinical and clinical stages in FAP and other amyloidoses.
Mitochondrial Transcription Factors TFA, TFB1 and TFB2: A Search for DNA Variants/Haplotypes and the Risk of Cardiac Hypertrophy
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
Published: June 2013

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.
Intrinsic Near‐Infrared Spectroscopic Markers of Breast Tumors
Authors: Kukreti Shwayta , Cerussi Albert , Tromberg Bruce , Gratton Enrico
Published: June 2013

We have discovered quantitative optical biomarkers unique to cancer by developing a double‐differential spectroscopic analysis method for near‐infrared (NIR, 650–1000 nm) spectra acquired non‐invasively from breast tumors. These biomarkers are characterized by specific NIR absorption bands. The double‐differential method removes patient specific variations in molecular composition which are not related to cancer, and reveals these specific cancer biomarkers. Based on the spectral regions of absorption, we identify these biomarkers with lipids that are present in tumors either in different abundance than in the normal breast or new lipid components that are generated by tumor metabolism. Furthermore, the O‐H overtone regions (980–1000 nm) show distinct variations in the tumor as compared to the normal breast. To quantify spectral variation in the absorption bands, we constructed the Specific Tumor Component (STC) index. In a pilot study of 12 cancer patients we found 100% sensitivity and 100% specificity for lesion identification. The STC index, combined with other previously described tissue optical indices, further improves the diagnostic power of NIR for breast cancer detection.
Transcriptionally Less Active Prodynorphin Promoter Alleles are Associated with Temporal Lobe Epilepsy: A Case‐Control Study and Meta‐Analysis
Authors: Kauffman Marcelo A. , Consalvo Damián , Gonzalez Moron Dolores , Kochen Silvia
Published: June 2013

We performed an association study in a population of patients with Mesial Temporal Lobe Epilepsy (TLE) with Hippocampal Sclerosis (MTEHS) together with a systematic revision of the literature to investigate the role of transcriptionally less active polymorphic alleles of Prodynorphin (PDYN) gene in this pathology. We included 102 patients with a diagnosis of MTEHS and 86 healthy controls. The positive antecedent of family history for epileptic events defined a TLE subgroup with familial predisposition for epileptic disorders. The PDYN promoter polymorphism was genotyped by means of a PCR assay. For meta‐analysis, we identified case‐control association studies between TLE and PDYN by searching PUBMED. The pooled OR was estimated using a fixed effects model under dominant and co‐dominant heredity models. No differences in genotypic and allelic frequencies were found between cases and controls (p = 0.61) in our population, neither in the whole cohort nor in the analysis limited to TLE with familial predisposition (p = 0.71). The Meta‐Analysis included 591 TLE patients and 1117 healthy controls. We found an association between L allele (p = 0.003; OR = 1.40; IC 95 = 1.12–1.74) and a modestly higher risk to develop TLE in the group of patients with familial predisposition. Therefore, functional allelic variants in the PDYN promoter might modify the risk to develop TLE in subjects with familial predisposition.
The Different Roles of hRAD50 in Microsatellite Stable and Unstable Colorectal Cancers
Authors: Gao Jingfang , Zhang Hong , Arbman Gunnar , Sun Xiao-Feng
Published: June 2013

RAD50 protein is essential for DNA double‐strand break repair and maintaining genomic integrity. In this study, we investigated the clinicopathological significance of hRAD50 expression and mutation in microsatellite stable (MSS) and unstable (MSI) colorectal cancers (CRCs). hRAD50 expression was examined in primary CRC (n=268), the corresponding distant (n=69) and adjacent normal mucosa (n=138), and lymph node metastasis (n=44) by immunohistochemistry. hRAD50 mutation was analyzed in 87 primary CRCs by PCR‐SSCP‐DNA sequencing. hRAD50 expression was increased in MSS primary CRCs, but not MSI ones, compared with distant/adjacent normal mucosa (p<0.05). There was no difference in the hRAD50 expression between primary and metastatic CRCs. The increased hRAD50 expression in MSS primary CRCs was related (p<0.05) or tended to be related (p=0.05) to early tumor stage, better differentiation, high inflammatory infiltration, p53 overexpression. Frameshift mutations of (A)9 at coding region of hRAD50 were only found in MSI CRCs. Our results suggest that hRAD50 may play different roles in the development of MSS and MSI CRCs: increased hRAD50 expression in MSS CRCs may be a cellular response against tumor from further progression, while hRAD50 mutation may be involved in the development of MSI CRCs.
Polymorphisms of the Fibrinogen‐Beta Gene are Related to 2‐Hour Glucose Level after Oral Glucose Tolerance Test in Hong Kong Chinese
Authors: Wong Louisa Y. F. , Ong Kwok Leung , Cheung Bernard M. Y. , Leung Raymond Y. H. , Man Yu Bun , Lam Tai Hing
Published: June 2013

Fibrinogen, an acute phase protein, is an important inflammatory marker that is associated with cardiovascular diseases. We studied the association of three common human fibrinogen‐β gene (FGB) variants, −455G>A, −249C>T, and −148C>T with glycemic parameters in 265 non‐diabetic Hong Kong Chinese subjects. Both FGB variants, −455G>A and −148C>T were in complete linkage disequilibrium and were associated with higher levels of plasma fibrinogen and 2‐h glucose after a 75‐g oral glucose load (p <0.01). Carriers of FGB AC‐haplotype, comprising the two nucleotide variants at positions −455 and −249, had higher fibrinogen level (2.64 ± 0.65 vs 2.42 ± 0.52 g/L, p = 0.002) and 2‐h glucose after a 75‐g oral glucose load (5.87 ± 1.14 vs 5.47 ± 1.22 g/L, p = 0.006). The associations were significant in men, but not women. In stepwise multiple regression analysis, AC‐haplotype was independently associated with plasma fibrinogen level and 2‐h glucose (p = 0.002 and 0.010 respectively). This suggests that fibrinogen may play a role in the development of impaired glucose tolerance.
Investigating Population Risk Factors of Pancreatic Cancer by Evaluation of Optical Markers in the Duodenal Mucosa
Authors: Turzhitsky Vladimir , Liu Yang , Hasabou Nahla , Goldberg Michael , Roy Hemant K. , Backman Vadim , Brand Randall
Published: June 2013

Pancreatic cancer screening has been hampered by the high rate of complications associated with interrogating the pancreas. The closest non‐invasively accessible mucosa available for pancreatic cancer screening is the periampullary duodenal tissue. Our earlier report has shown the potential of using optical markers to interrogate this tissue for the presence of pancreatic cancer. In this study, we report a larger data set of low‐coherence enhanced backscattering (LEBS) and elastic light scattering fingerprinting (ELF) optical markers from the periampullary duodenal mucosa. Optical measurements from biopsy samples were acquired from a total of 203 patients with varying clinical classification including healthy controls, a family history of pancreatic cancer, pancreatitis, mucinous cystic precursor lesions, pancreatic cancer, and other pancreatic malignancies. Evaluation of the performance of an independent testing set for discriminating healthy control patients from pancreatic cancer patients showed a 95% sensitivity, 71% specificity, and 85% area under the receiver operator characteristic (AUROC) curve. Importantly, this performance was uncompromised for detecting potentially curable stages of the disease. Additionally, optical markers in higher risk populations such as family history and pancreatitis had values between those of healthy control and pancreatic cancer patients, thus allowing for future investigations of screening from these high risk groups.

Erratum to “Investigating Population Risk Factors of Pancreatic Cancer by Evaluation of Optical Markers in the Duodenal Mucosa”dx.doi.org/10.3233/DMA-2009-0686
Genetic Association of DLG5 R30Q with Familial and Sporadic Inflammatory Bowel Disease in Men
Authors: Lin Z. , Poritz L. , Franke A. , Li T.Y. , Ruether A. , Byrnes K.A. , Wang Y. , Gebhard A.W. , MacNeill C. , Thomas N.J. , Wu R. , Schreiber S. , Koltun W.A.
Published: June 2013

Background: The association of DLG5 R30Q with IBD has been replicated in several populations, but is not statistically significant in others. We studied the incidence of DLG5 alleles in a population of IBD patients from Pennsylvania.

Methods: DLG5 R30Q (rs1248696) and G1066G (rs1248634) were analyzed with PCR-based RFLP methods in a total of 521 subjects, that included 105 individuals with IBD and 139 without IBD from a familial IBD registry, 107 with sporadic IBD, and 170 unrelated healthy controls. R30Q was further analyzed with SNPlex™ Genotyping System in 473 samples.

Results: RFLP genotyping data showed that, DLG5 R30Q was significantly associated with IBD overall (p=0.006), and separately with CD (p=0.009) and UC (p=0.024). The association of R30Q with IBD was entirely due to a male-associated effect (male vs femalep=0.015 vs 0.241 (IBD),p=0.024 vs 0.190 (CD), andp=0.019 vs 0.575 (UC)). The frequency of the A allele carriage was elevated in both affected and unaffected members in the familial IBD cohort compared to healthy controls (p=0.037). In the family pedigrees, we observed differences in the expression of IBD in individuals carrying the A allele between families.

Conclusions: In the studied population, DLG5 R30Q was associated with all forms of IBD. An elevated presence of the R30Q variant was observed in all members of a familial IBD registry. This association of the R30Q variant with IBD was male-specific.
HLA-DR in Brazilian Patients with Polyarteritis Nodosa (PAN) and Microscopic Polyangiitis (MPA)
Authors: de Lira Freire Alzírton , Conde Roseneide Aparecida , Bertolo Manoel Barros , Costallat Lílian Teresa Lavras , Levy-Neto Maurício , Fernandes Sandra Regina Muchinechi
Published: June 2013

The aim of this study was to evaluate the frequency and clinical associations of HLA-DR alleles in Brazilian Caucasian patients with polyarteritis nodosa (PAN) or microscopic polyangiitis (MPA). We evaluated 29 Caucasian patients with vasculitis classified as PAN or MPA according to the American College of Rheumatology (ACR) 1990 Criteria, Chapel Hill Consensus Conference (CHCC) nomenclature for vasculitis and EULAR recommendations for conducting clinical studies in systemic vasculitis. HLA-DR alleles were typed using polymerase chain reaction-amplified DNA, hybridized with sequence-specific low resolution primers. DNA obtained from 59 Caucasian healthy blood donors were used as control. In order to evaluate if a specific HLA may have influence on the clinical profile of those diseases, we also divided the patients according to Birmingham vasculitis score (BVAS) and Five-Factors Score (FFS) at the time of diagnosis. Increased frequency of HLA-DRB1*16 (p= 0.023) and DRB4*01 (p= 0.048) was found in patients with higher disease activity at the time of diagnosis (BVAS ≥ 22). Patients with less severe disease (FFS = 0) had a higher frequency of HLA-DRB1*03 (p= 0.011). Patients with gastrointestinal tract involvement had significantly increased frequency of HLA-DRB1*11 or B1*12 (p= 0.046), B1*13 (p= 0.021) and B3 (p= 0.008). In contrast, patients with renal disease, had higher frequency of DRB1*15 or DRB1*16 (p= 0.035) and B5 (p= 0.035). In the subgroup of patients with MPA, increased frequency of HLA-DRB1*15 was found in patients with BVAS ≥ 22 (p= 0.038) and FFS ≥ 1 (p= 0.039) suggesting that this allele is associated with more aggressive disease. Antineutrophil cytoplasmic antibodies (ANCA) negative MPA patients had significantly increased frequency of HLA-DRB1*11 or DRB1*12 when compared to ANCA positive patients (p= 0.023). Our results suggest that HLA-DR alleles may influence PAN and MPA clinical expression and outcome and that in MPA they participate in the mechanisms involved in the development to ANCA.
Molecular Profiling of Glatiramer Acetate Early Treatment Effects in Multiple Sclerosis
Authors: Achiron Anat , Feldman Anna , Gurevich Michael
Published: June 2013

Background: Glatiramer acetate (GA, Copaxone®) has beneficial effects on the clinical course of relapsing-remitting multiple sclerosis (RRMS). However, the exact molecular mechanisms of GA effects are only partially understood.

Objective: To characterized GA molecular effects in RRMS patients within 3 months of treatment by microarray profiling of peripheral blood mononuclear cells (PBMC).

Methods: Gene-expression profiles were determined in RRMS patients before and at 3 months after initiation of GA treatment using Affimetrix (U133A-2) microarrays containing 14,500 well-characterized human genes. Most informative genes (MIGs) of GA-induced biological convergent pathways operating in RRMS were constructed using gene functional annotation, enrichment analysis and pathway reconstruction bioinformatic softwares. Verification at the mRNA and protein level was performed by qRT-PCR and FACS.

Results: GA induced a specific gene expression molecular signature that included altered expression of 480 genes within 3 months of treatment; 262 genes were up-regulated, and 218 genes were down-regulated. The main convergent mechanisms of GA effects were related to antigen-activated apoptosis, inflammation, adhesion, and MHC class-I antigen presentation.

Conclusions: Our findings demonstrate that GA treatment induces alternations of immunomodulatory gene expression patterns that are important for suppression of disease activity already at three months of treatment and can be used as molecular markers of GA activity.
Could High Levels of Tissue Polypeptide Specific Antigen, a Marker of Apoptosis Detected in Nonalcoholic Steatohepatitis, Improve after Weight Loss?
Authors: Tarantino Giovanni , Mazzarella Claudia , Tarantino Marianna , Di Minno Matteo Nicola Dario , Conca Paolo
Published: June 2013

Background: Tissue Polypeptide Specific antigen has recently been proposed as diagnostic marker of apoptosis in NonAlcoholic SteatoHepatitis.

The aim of this study was to validate in patients suffering from NonAlcoholic SteatoHepatitis the clinical utility of this marker after different programs of weight reduction.

Methods: Overweight/obese patients with visceral adiposity and liver histology compatible were assigned to a Calorically-Restricted diet (n= 22), a Calorically-Restricted diet plus EXercise (n= 19) or No Healthy Life Style (control group,n= 21) for six months. The presence of Body-Weight loss was assessed by a Body Mass Index decrease of at least three points. Serum ALanine aminoTransferase, HOmeostasis Model Assessment method value and Tissue Polypeptide Specific antigen concentrations were determined at time 0, after 3 and 6 months in both the Intervention groups and in the controls’ one.

Results: In NonAlcoholic SteatoHepatitis patients who obtained Body-Weight reduction, a significant decrease of the serum Tissue Polypeptide Specific antigen values was showed with a clear linear trend across time,P= 0.0001.

Decrement of Tissue Polypeptide Specific antigen concentrations best differentiated the Body-Weight loss from the body-weight maintenance in respect to Tissue Polypeptide Specific antigen and HOmeostasis Model Assessment method values.

Conclusion: This study support the clinical utility of serum Tissue Polypeptide Specific antigen antigen levels in the follow-up of overweight/obese patients with NonAlcoholic SteatoHepatitis on weight reduction programs.
Oxidative Stress is Increased in Serum from Mexican Patients with Relapsing-Remitting Multiple Sclerosis
Authors: Ortiz Genaro Gabriel , Macías-Islas Miguel Ángel , Pacheco-Moisés Fermín P. , Cruz-Ramos José A. , Sustersik Silvia , Barba Elías Alejandro , Aguayo Adriana
Published: June 2013

Objective: To determine the oxidative stress markers in serum from patients with relapsing-remitting multiple sclerosis.Methods: Blood samples from healthy controls and 22 patients 15 women (7 aged from 20 to 30 and 8 were > 40 years old) and 7 men (5 aged from 20 to 30 and 2 were > 40 years old) fulfilling the McDonald Criteria and classified as having Relapsing-Remitting Multiple Sclerosis accordingly with Lublin were collected for oxidative stress markers quantification.Results: Nitric oxide metabolites (nitrates/nitrites), lipid peroxidation products (malondialdehyde plus 4-hidroxialkenals), and glutathione peroxidase activity were significantly increased in serum of subjects with relapsing-remitting multiple sclerosis in comparison with that of healthy controls. These data support the hypothesis that multiple sclerosis is a component closely linked to oxidative stress.
High Serum Levels of Pro-Brain Natriuretic Peptide (pro BNP) Identify Cardioembolic Origin in Undetermined Stroke
Authors: Rodríguez-Yáñez Manuel , Sobrino Tomás , Blanco Miguel , de la Ossa Natalia Pérez , Brea David , Rodríguez-González Raquel , Leira Rogelio , Dávalos Antonio , Castillo José
Published: June 2013

Background: Stroke subtype diagnosis leads to specific therapies to reduce recurrences. Because nearly one third of patients remain with unknown etiology after a complete screening workup, we aim to investigate whether molecular markers of myocardial damage were associated with cardioembolic stroke and if they were useful to reclassify strokes of undetermined etiology.

Methods: We included 262 patients with first ischemic stroke within the first 12 hours. Stroke subtype was evaluated by TOAST criteria. Stroke of undetermined origin were reclassified into likely atherothrombotic or likely cardioembolic according to a predefined non-validated algorithm. Blood samples were obtained on admission to determine serum levels of molecular markers (pro-BNP, pro-ANP and CK-MB) of myocardial damage.

Results: Patients with cardioembolic infarct showed higher levels of pro-BNP, pro-ANP and CK-MB. Pro-BNP > 360 pg/mL was independently associated with cardioembolic stroke (OR: 28.51, CI95%: 5.90–136.75,p< 0.0001). Stroke etiology was undetermined in 82 patients (31%); 34 were reclassified as likely cardioembolic, 22 as likely atherothrombotic, and 26 remained as undetermined. Pro-BNP > 360 pg/mL was the only factor independently associated with likely cardioembolic stroke.

Conclusions: Pro-BNP levels higher than 360 pg/mL are associated with cardioembolic stroke and may be useful to reclassify undetermined strokes as of cardioembolic origin.
Endothelin-Converting Enzyme-1 Promoter Polymorphisms and Susceptibility to Sporadic Late-Onset Alzheimer's Disease in a Chinese Population
Authors: Jin Zhao , Luxiang Chi , Huadong Zhou , Yanjiang Wang , Zhiqiang Xu , Hongyuan Cao , Lihua Huang , Xu Yi
Published: June 2013

Endothelin converting enzyme (ECE-1) is a candidate Alzheimer disease susceptibility gene. It was previously reported that western individuals homozygous for the C-338A polymorphism (AA) within theECE1gene promoter region are at reduced risk of developing late onset Alzheimer disease (LOAD). A further polymorphism, T-839G, is present within theECE1promoter region but a potential association with LOAD has not been studied. We therefore studied possible associations between theseECE1polymorphisms and LOAD in a Chinese population. Subjects comprised 376 Chinese LOAD patients and 376 age- and sex-matched controls; all subjects were typed for theECE1C-338A and the T-839G polymorphisms. We report that the frequency of the 338A allele was decreased in LOAD patients compared to controls (adjusted OR =0.73; 95% CI=0.54–0.98;P=0.03). There was no significant association between T-839G genotype and LOAD, however the combined 839T/338A haplotype was significantly associated with decreased risk of LOAD (OR=0.73; 95% CI=0.57–0.93;P=0.01). This study argues that theECE1338A allele is protective against LOAD in a Chinese population.
Methylene Tetrahydrofolate Reductase and Angiotensin Converting Enzyme Gene Polymorphisms Related to Overweight/Obesity among Saudi Subjects from Qassim Region
Authors: Settin Ahmad A. , Algasham Abdullah , Dowaidar Moataz , Ismail Hisham
Published: June 2013

Background: This work was planned to check for the association of polymorphisms related to methylenetetrahydrofolate reductase (MTHFR) and angiotensin converting enzyme (ACE) genes with overweight/obesity among Saudi subjects from Qassim region.

Methods: This work included 130 subjects having overweight or obesity and 111 normal controls. Their age mean ± SD was 27 ± 9.8 and 24 ± 8.8 years respectively. Their DNA was analyzed for polymorphisms of MTHFR; 677C/T and 1298 A/C and ACE; I/D genes using real-time PCR.

Results: Genotype and allele frequencies of studied polymorphisms in cases of overweight/obesity showed no significant statistical difference compared to that of controls. However, on analysis of body mass index (BMI), cases showed slightly higher but statistically nonsignificant mean ± SD values among those carrying the mutant MTHFR 677 T allele (CT + TT vs. CC, 30.7 ± 4.5 vs. 29.9 ± 4.9), 1298 C allele (AC + CC vs. AA, 29.9 ± 4.1 vs. 29.7 ± 5.5) and ACE D allele (ID + DD vs. II, 30.0 ± 5.1 vs. 29.1 ± 2.8). In addition controls having the DD and ID genotypes showed higher statistically significant values of BMI than those of the II genotype (22.0 ± 1.9, 21.7 ± 2.6 and 19.5 ± 2.3 respectively,p< 0.05).

Conclusion: There is no solid association of polymorphisms related to MTHFR and ACE genes with non-complicated overweight or obesity among Saudi subjects from Qassim Region.
Temporal Patterns of Soluble Adhesion Molecules in Cerebrospinal Fluid and Plasma in Patients with the Acute Brain Infraction
Authors: Selakovic Vesna , Raicevic Ranko , Radenovic Lidija
Published: June 2013

The aim of this study was to define concentration changes of soluble adhesion molecules (sICAM-1, sVCAM-1 and sE-Selectin) in cerebrospinal fluid and plasma, as well as, number of peripheral blood leukocytes and the albumin coefficient in the patients with the acute brain infarction. We also, analyzed the correlation between the measured levels, the infarct volume and the degree of neurological and the functional deficit. The study included 50 patients with the acute cerebral infarction and the control group consisted of 16 patients, age and sex matched. Obtained results showed significant increase in number of leukocytes, the albumin coefficient and the level of soluble adhesion molecules within the first seven days in patients. The highest values of measured parameters were noted within the third and the fourth day after the insult, which is the suggested period of maximal intensity of inflammatory reactions. Significant correlation was found between measured parameters and the infarct volume, the degree of neurological and the functional deficit. The results suggest that investigated parameters in CSF and blood represent a dynamic index of inflammatory events as one of the fundametal mechanisms responsible for neuron damage during acute phase of brain infarction.
Homocysteine Disulphides and Vascular Disease
Authors: Iuliano Mauro , De Tommaso Gaetano , Ragone Raffaele
Published: June 2013

The total plasma concentration of homocysteine is a marker of this amino acid's atherogenic potential. However, the homocysteine pool exists almost entirely as oxidized homocysteine equivalents (OHcyE), composed of homocystine and cysteine-homocysteine disulphides (20–30%), and protein-bound disulphide (70–80%). We have noticed that the total concentration of OHcyE in injured coronary artery tissue is higher than the aqueous solubility of homocystine (∼1.4–1.5 × 10-3mol kg-1versus ∼0.6 mol kg-1). Based on the measurement of the solubility of homocystine in a plasma-mimetic condition (0.17 mol kg-1NaCl at 37°C), we have estimated that OHcyE may really reach their saturation limit in the vascular tissue (0.93–1.02 × 10-3mol kg-1), above which their deposition as solid phase may occur. This means that significant leakage of intracellular fluid can promote OHcyE crystallization in tissue fluids, which may serve to initiate inflammation. We speculate that deposition of OHcyE crystals could damage blood vessels and act as a primer of homocysteine-triggered inflammation, thus being along the causal pathway that leads to vascular dysfunction.