bluuebunny/crossref_metadata_2025 huggingface dataset:
Utility of the Blood for Gene Expression Profiling and Biomarker Discovery in Chronic Fatigue Syndrome
Authors: Vernon Suzanne D. , Unger Elizabeth R. , Dimulescu Irina M. , Rajeevan Mangalathu , Reeves William C.
Published: June 2013

Chronic fatigue syndrome (CFS) is a debilitating illness lacking consistent anatomic lesions and eluding conventional laboratory diagnosis. Demonstration of the utility of the blood for gene expression profiling and biomarker discovery would have implications into the pathophysiology of CFS. The objective of this study was to determine if gene expression profiles of peripheral blood mononuclear cells (PMBCs) could distinguish between subjects with CFS and healthy controls. Total RNA from PBMCs of five CFS cases and seventeen controls was labeled and hybridized to 1764 genes on filter arrays. Gene intensity values were analyzed by various classification algorithms and nonparametric statistical methods. The classification algorithms grouped the majority of the CFS cases together, and distinguished them from the healthy controls. Eight genes were differentially expressed in both an age‐matched case‐control analysis and when comparing all CFS cases to all controls. Several of the diffrentially expressed genes are associated with immunologic functions (e.g., CMRF35 antigen, IL‐8, HD protein) and implicate immune dysfunction in the pathophysiology of CFS. These results successfully demonstrate the utility of the blood for gene expression profiling to distinguish subjects with CFS from healthy controls and for identifying genes that could serve as CFS biomarkers.
Quasimonomorphic Mononucleotide Repeats for High‐Level Microsatellite Instability Analysis
Authors: Umar Asad , Buhard Olivier , Suraweera Nirosha , Lectard Aude , Duval Alex , Hamelin Richard
Published: June 2013

Microsatellite instability (MSI) analysis is becoming more and more important to detect sporadic primary tumors of the MSI phenotype as well as in helping to determine Hereditary Non‐Polyposis Colorectal Cancer (HNPCC) cases. After some years of conflicting data due to the absence of consensus markers for the MSI phenotype, a meeting held in Bethesda to clarify the situation proposed a set of 5 microsatellites (2 mononucleotide repeats and 3 dinucleotide repeats) to determine MSI tumors. A second Bethesda consensus meeting was held at the end of 2002. It was discussed here that the 1998 microsatellite panel could underestimate high‐level MSI tumors and overestimate low‐level MSI tumors. Amongst the suggested changes was the exclusive use of mononucleotide repeats in place of dinucleotide repeats. We have already proposed a pentaplex MSI screening test comprising 5 quasimonomorphic mononucleotide repeats. This article compares the advantages of mono or dinucleotide repeats in determining microsatellite instability.
Prognostic and Predictive Markers in Cancer
Authors: Conley Barbara A. , Taube Sheila E.
Published: June 2013

The elucidation of the human genome and advances in knowledge about molecular abnormalities, signaling pathways, influence of the local tissue milieu and the relevance of genetic polymorphisms offer hope of designing more effective, individualized cancer treatment plans. Although the scientific and medical literature is replete with reports of putative prognostic or predictive markers for cancer, few new diagnostics have been incorporated into routine clinical practice. Criteria are needed to a) identify markers that have the promise to be clinically useful; b) assess the best methodology for clinical evaluation of the markers in question and c) confirm or validate that using the marker adds useful information compared to using standard prognostic factors alone. This review presents a methodology for the clinical evaluation of putative prognostic and predictive markers in cancer, with considerations of pitfalls in the early evaluation, rationale for development and optimization of assay methodology, and examples of possible clinical trials for assessing the clinical utility of putative markers.
Mutations Associated with HNPCC Predisposition — Update of ICG‐HNPCC/INSiGHT Mutation Database
Authors: Peltomäki Päivi , Vasen Hans
Published: June 2013

In 1994, the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (ICG‐HNPCC) established an international database of mutations identified in families with Lynch (HNPCC) syndrome. The data are publicly available at http://www.nfdht.nl. The information stored in the database was systematically analyzed in 1997, and at that time, 126 different predisposing mutations were reported affecting the DNA mismatch repair genes MSH2 and MLH1 and occurring in 202 families. In 2003, the ICG‐HNPCC and the Leeds Castle Polyposis Group (LCPG) merged into a new group, INSiGHT (International Society for Gastrointestinal Hereditary Tumors). The present update of the database of DNA mismatch repair gene mutations of INSiGHT includes 448 mutations that primarily involve MLH1 (50%), MSH2 (39%), and MSH6 (7%) and occur in 748 families from different parts of the world.
MSI‐Testing in Hereditary Non‐Polyposis Colorectal Carcinoma (HNPCC)
Authors: Müller Annegret , Edmonston Tina Bocker , Dietmaier Wolfgang , Büttner Reinhard , Fishel Richard , Rüschoff Josef
Published: June 2013

Genomic instability at simple repeated sequences, termed microsatellite instability (MSI), plays an important role in the analysis of sporadic and hereditary colon cancers. In hereditary non‐polyposis colorectal cancer syndrome (HNPCC) more than 90% of cases show MSI, whereas only 10–15% of sporadic colorectal cancers do so. Thus, microsatellite analysis is commonly used as the first diagnostic screening test for HNPCC. In 1997, an international collaborative workshop sponsored by the National Cancer Institute (NCI) proposed a set of guidelines for MSI‐testing to improve reliability and reproducibility of the analysis as well to allow comparisons between different studies and different laboratories. In this review we assess the value of current protocols forMSI‐testing and discuss some diagnostic pitfalls. Our findings support continued use of the MSI marker panel recommended in 1997. Additionally, MSI‐testing should be improved by use of microdissection, which helps to identify additional patients with MSI due to enrichment of tumor cells and therefore increased sensitivity. In our view, immunohistochemical staining for mismatch repair protein expression is not a substitute for MSI‐analysis but complements MSI screening and helps direct further testing. In summary, MSI‐analysis is a highly sensitive and reliable screening method for HNPCC, that requires a well‐equipped laboratory as well as an experienced pathologist. Integration of family history and histo‐pathological features is also critical.
Neuroendocrine Differentiation in Sporadic CRC and Hereditary Nonpolyosis Colorectal Cancer
Authors: Sun M. H.
Published: June 2013

Extent neuroendocrine differentiation can be encountered in many human neoplasm derived from different organs and systems using immunohistochemistry and ultrastructural techniques. The tumor cells′ behaviors resemble those of neurons and neuroendocrine cells. The presence of neuroendocrine differentiation reputedly appears to be associated with a poorer prognosis than the adenocarcinoma counterparts in sporadic human neoplasm. In this review the neuroendocrine carcinoma and the adenocarcinoma with neuroendocrine differentiation of colon and rectum both in sporadic colorectal carcinoma and the hereditary nonpolyposis colorectal cancer, the relationship of neuroendocrine differentiation and some possible molecular pathways in tumorogenesis of colorectal cancer will be discussed. Possible treatment strategy will also be addressed.
Manganese Superoxide Dismutase Gene Polymorphisms in Psoriatic Arthritis
Authors: Yen Jeng-Hsien , Tsai Wen-Chun , Lin Chia-Hui , Ou Tsan-Teng , Hu Chaur-Jong , Liu Hong-Wen
Published: June 2013

The purpose of the present study is to investigate the role of manganese superoxide dismutase (MnSOD) gene polymorphisms in the susceptibility to psoriatic arthritis. MnSOD gene polymorphisms were determined by polymerase chain reaction/restriction fragment length polymorphisms method in fifty‐two patients with psoriatic arthritis and 90 healthy controls. The genotype frequency of MnSOD 1183C/T was significantly higher in patients with psoriatic arthritis than in controls. In contrast, the frequency of MnSOD 1183T/T was significantly decreased in patients with psoriatic arthritis. The phenotype frequency of MnSOD 1183C was significantly increased in patients with psoriatics arthritis in comparison to healthy controls. Therefore, MnSOD 1183C polymorphisms may be a precipitating factor for the development of psoriatic arthritis.
GSTT1 Gene Deletion Is Associated with Lung Cancer in Mexican Patients
Authors: Gallegos-Arreola M. P. , Gómez-Meda B. C. , Morgan-Villela G. , Arechavaleta-Granell M. R. , Arnaud-López L. , Beltrán-Jaramillo T. J. , Gaxiola R. , Zúñiga-González G.
Published: June 2013

Glutathione S‐transferase (GST) is a dimeric detoxifying isoenzyme, involved in the deactivation of carcinogens, several tobacco‐derived carcinogens, and xenobiotics. It catalyzes the reduction of glutathione to its thioester; thus, deficiency in GST activity due to homozygous deletion of the GSTT1 gene (null genotype) may play a role in the induction of lung cancer by smoking.

We studied the distribution of GSTT1 gene deletion in peripheral blood DNA samples from 178 healthy controls (41 nonsmokers, 63 passive smokers and 74 smokers) and 52 lung cancer patients. Comparisons between groups showed that there was an increased lung cancer risk for individuals with the GSTT1 null genotype. Cancer patients showed significant differences when compared with controls: nonsmokers, passive smokers, and smokers. Twenty‐one percent of lung cancer patients carried the deletion versus 2% among nonsmokers not exposed to passive smoking, 6% among passive smokers, and 5% among smokers. Thus, there is a significant association between this genotype and the possibility to risk of developing lung cancer.
Tissue Factor in the Myocardium: Evidence of Roles in Haemostasis and Inflammation
Authors: Mumford Andrew D. , McVey John H.
Published: June 2013

The interaction between cell‐surface tissue factor (TF) and the plasma coagulation factor VII (FVII) initiates the coagulation network that leads to the generation of thrombin and the formation of a fibrin clot. Thrombin also activates cellular protease activated receptors (PARs) through which it activates components of the inflammatory pathway. TF is expressed constitutively by cardiomyocytes and evidence from mice transgenic for a human TF mini‐gene that express very low levels of human TF suggests that the TF‐FVII interaction is critical for haemostasis within the heart. Pathological contact between TF and FVII may occur in the heart during ischaemia‐reperfusion (I‐R) injury and this may lead to activation of coagulation and thrombin generation. Evidence from animal models now suggests that thrombin is an important mediator of inflammation in I‐R injury. The coagulation pathway therefore represents a novel therapeutic target for intervention in the prevention of I‐R injury.
TH01, a Tetrameric Short Tandem Repeat Locus in the Tyrosine Hydroxylase Gene: Association with Myocardial Hypertrophy and Death from Myocardial Infarction?
Authors: Klintschar Michael , Immel Uta-Dorothee , Stiller Dankwart , Kleiber Manfred
Published: June 2013

TH01 is a tetrameric short tandem repeat locus located in intron 01 of the tyrosine hydroxylase gene. The tyrosine hydroxylase catalyzes the hydroxylation of L‐tyrosine to L‐DOPA and is the rate limiting enzyme in the synthesis of catecholamines like noradrenaline or adrenaline, which are pivotal in the regulation of blood pressure. In a clinical study a strong correlation between alleles *9.3 and *10 and essential hypertension was observed ([2] Hypertension 32: 676–682). To further investigate this association, we typed TH01 in 296 autopsy cases and correlated the genotypes to the heart weight as parameter for myocardial hypertrophy. No significant correlation was observed. Moreover, dividing the studied cases into 2 groups, one including 172 casualties from hypertension‐associated diseases (myocardial infarction, left heart failure, aortic aneurysm, spontaneous intracerebral bleeding and cerebral infarction) and one consisting of 124 cases of death unrelated to hypertension, revealed similar allelic frequencies for both groups. Our data thus suggest that TH01 long alleles appear not to lead to a significant increase in the incidence of myocardial hypertrophy or other hypertension associated diseases. This could be explained by a relatively small impact of the TH01 genotype on the blood pressure or by counteraction of another mechanism related to catecholamines and their effect on the human body.
CYP1A1 Genetic Polymorphisms in Ecuador, South America
Authors: Paz-y-Miño César , Arévalo Melissa , Muñoz G. María José , Leone Paola. E.
Published: June 2013

A total of 108 individuals from the Ecuadorian population from rural and urban places were analyzed for two CYP1A1 gene polymorphisms. The frequency of the val allele at codon 462 was 0.50, while the frequency of the Msp I restriction site, m2 allele at the T6235C position was 0.70. These polymorphisms in Ecuador have higher frequencies if we compare with others around the world, with the exception of some South American population in Brazil and Chile.

Erratum to “CYP1A1 Genetic Polymorphisms in Ecuador, South America” dx.doi.org/10.1155/2005/231396
α‐SM Actin Expression as Prognostic Indicator in IgA Nephropathy (Berger’s Disease)
Authors: Pastorello M. T. , Costa R. S. , Ravinal R. C. , Coimbra M. , dos Reis M.A , Dantas M.
Published: June 2013

Recent studies have demonstrated that α‐Smooth Muscle actin expression in glomerular and tubulointerstitial compartments of renal tissue could represent a prognostic marker in several renal diseases. Our objective was to identify the prognostic value of α‐SM actin actin expression on the evolution of renal damage in Primary IgA nephropathy (Berger’s Disease). 43 patients followed up from 1988 to 1999 at the University Hospital, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil, was studied. Clinical‐laboratory data were obtained from the medical records of the patients using a protocol containing name, race, gender, origin, profession, age at clinical presentation of the disease and personal and family history. The parameters assessed in the approach to IgA nephropathy were serum creatinine, creatinine clearance, serum albumin, total serum protein, 24 hours proteinuria, glycaemia, serum sodium, potassium, calcium and phosphorus ions, analysis of urinary sediment, serum complement profile, blood count, and renal biopsy. Morphological evaluation was performed by renal biopsy using common light and immunofluorescence microscopy. Immunohistochemical studies were performed using a murine monoclonal antibody to α‐SM actin. Our data showed that α‐SM actin expression in the glomerular and tubulointerstitial compartments are not correlated with unfavorable clinical course of primary IgA nephropathy.
Age‐Dependent Decrease in Serum Transforming Growth Factor (TGF)‐Beta 1 in Healthy Japanese Individuals; Population Study of Serum TGF‐Beta 1 Level in Japanese
Authors: Okamoto Yoshihiro , Gotoh Yoshimitsu , Uemura Osamu , Tanaka Soichi , Ando Tsunesaburo , Nishida Mikio
Published: June 2013

Transforming growth factor‐beta1 (TGF‐β1), a multi‐functional cytokine, is involved in regulating a variety of cellular activities and the serum/plasma TGF‐β1 level is altered with various diseases. However, most published reports have described adult patients, and so we investigated the clinical significance of serum TGF‐β1 level in pediatric patients. The diagnostic application of the measurement of serum TGF‐β1 level depends critically on the control value, however, there is no information on the control value of serum TGF‐β1 for children.

In the present study, we determined the serum TGF‐β1 level of healthy Japanese children as a control value with enzyme‐linked immunosorbent assay (ELISA). The serum TGF‐β1 level of children (0–14 years old) was significantly higher than that of adults (over 15 years old) (p < 0.01). Thus, it is recommended that when the serum TGF‐β1 levels of patients are evaluated, they should be compared with those of age‐matched controls.
Polymorphisms in the Promoter Region of Catalase Gene and Essential Hypertension
Authors: Zhou Xiao Feng , Cui Jing , DeStefano Anita L. , Chazaro Irmarie , Farrer Lindsay A. , Manolis Athanasios J. , Gavras Haralambos , Baldwin Clinton T.
Published: June 2013

Genetic variations that predispose individuals to complex disorders, such as essential hypertension, may be found in gene coding regions, intronic regions or in gene promoter regions. Most studies have focused on gene variations that result in amino acid substitutions because they result in different isoforms of the protein, presumably resulting in differences in protein properties. Less attention has been placed on the role of intronic or promoter mutations. In this report, we examined two single nucleotide polymorphisms (SNPs) in the catalase (CAT) gene prompter region in a cohort of hypertensive Caucasians and African Americans with a Mass Spec based Homogenous MassEXTEND assay. We found an association when a specific combination of the two promoter SNPs was examined in Caucasians. No association was observed in African Americans. Our data suggest that genetic variations in the promoter region of catalase gene influence the susceptibility to essential hypertension. In addition, the genetic factors that contribute to hypertension maybe different between ethnic groups.
Complete Mutation Screening and Haplotype Characterization of the BRCA1 Gene in 61 Familial Breast Cancer Patients from Norway
Authors: Frost Petter , Jugessur Astanand , Apold Jaran , Heimdal Ketil , Aloysius Thomas , Eliassen Aud K. , Fauske Lars , Matre Guri , Eiken Hans Geir
Published: June 2013

Mutations in the Breast-Cancer-1 (BRCA1) gene are the major cause of familial breast/ovarian cancer. Among familial breast cancer only, 15–20% have been suggested to have a deleterious mutation in BRCA1. A highly sensitive method (REF‐SSCP) was applied to screen the open reading frame and the 5’UTRs of BRCA1 for mutations. The patient cohort comprised 61 unrelated moderate to high risk breast cancer patients from Western‐Norway.

Only one known deleterious BRCA1 mutation (c.816‐817delGT) was found in two of the 61 patients (3.3%). Four haplotypes were established based on nine known single nucleotide polymorphisms. Two patients had a novel deletion (c.‐33_‐29delAAAAA) in the 5’UTR, and a novel amino acid substitution (L523W) was found in one patient. Size variations analysis in the 5’UTR was repeated in a cohort of 159 unrelated familial breast/ovarian cancer patients and 94 healthy blood donors. Two patients were identified with 5’UTR (c.‐30 to ‐60) variations (CAAAA)5 and (CAAAA)7, instead of the (CAAAA)6‐repeat. All of the identified 5’UTR size variations were localized between the start codon and the most stable secondary structures previously proposed for the exon 1b transcript. No such alterations were found among the healthy blood donors but association studies of the 5′UTR variations within the respective families were not conclusive.
Estimation of Diabetes Risk in Brazilian Population by Typing for Polymorphisms in HLA‐DR‐DQ, INS and CTLA‐4 Genes
Authors: Hauache Omar M. , Reis André F. , Oliveira Carolina S.V. , Vieira José Gilberto H. , Sjüroos Minna , Ilonen Jorma
Published: June 2013

The study aimed to further characterise HLA encoded risk factors of type 1 diabetes (T1D) in Brazilian population and test the capability of a low resolution full‐house DR‐DQ typing method to find subjects at diabetes risk. Insulin and CTLA‐4 gene polymorphisms were also analysed. The method is based on an initial DQB1 typing supplemented by DQA1 and DR4 subtyping when informative. Increased frequencies of both (DR3)‐DQA1*05‐DQB1*02 and DRB1*04‐DQA1*03‐DQB1*0302 haplotypes were detected among patients. DRB1*0401, *0402, *0404 and *0405 alleles were all common in DQB1*0302 haplotypes and associated with T1D. (DRB1*11/12/1303)‐DQA1*05‐DQB1*0301, (DRB1*01/10)‐DQB1*0501, (DRB1*15)‐DQB1*0602 and (DRB1*1301)‐*0603 haplotypes were significantly decreased among patients. Genotypes with two risk haplotypes or a combination of a susceptibility associated and a neutral haplotype were found in 78 of 126 (61.9%) T1D patients compared to 8 of 75 (10.7%) control subjects (P < 0.0001). Insulin gene −2221 C/T polymorphism was also associated with diabetes risk: CC genotype was found among 83.1% of patients compared to 69.3% of healthy controls (P = 0.0369, OR 1.98) but CTLA‐4 gene +49 A/G polymorphism did not significantly differ between patients and controls. Despite the diversity of the Brazilian population the screening sensitivity and specificity of the used method for T1D risk was similar to that obtained in Europe.
The Process Chain for Peptidomic Biomarker Discovery
Authors: Schrader Michael , Selle Hartmut
Published: June 2013

Over the last few years the interest in diagnostic markers for specific diseases has increased continuously. It is expected that they not only improve a patient′s medical treatment but also contribute to accelerating the process of drug development. This demand for new biomarkers is caused by a lack of specific and sensitive diagnosis in many diseases. Moreover, diseases usually occur in different types or stages which may need different diagnostic and therapeutic measures. Their differentiation has to be considered in clinical studies as well. Therefore, it is important to translate a macroscopic pathological or physiological finding into a microscopic view of molecular processes and vice versa, though it is a difficult and tedious task. Peptides play a central role in many physiological processes and are of importance in several areas of drug research. Exploration of endogenous peptides in biologically relevant sources may directly lead to new drug substances, serve as key information on a new target and can as well result in relevant biomarker candidates. A comprehensive analysis of peptides and small proteins of a biological system corresponding to the respective genomic information (peptidomics®methods) was a missing link in proteomics. A new peptidomic technology platform addressing peptides was recently presented, developed by adaptation of the striving proteomic technologies. Here, concepts of using peptidomics technologies for biomarker discovery are presented and illustrated with examples. It is discussed how the biological hypothesis and sample quality determine the result of the study. A detailed study design, appropriate choice and application of technology as well as thorough data interpretation can lead to significant results which have to be interpreted in the context of the underlying disease. The identified biomarker candidates will be characterised in validation studies before use. This approach for discovery of peptide biomarkes has potential for improving clinical studies.
Prostaglandin D Synthase Isoforms from Cerebrospinal Fluid Vary with Brain Pathology
Authors: Harrington Michael G. , Fonteh Alfred N. , Biringer Roger G. , Hühmer Andreas F. R. , Cowan Robert P.
Published: June 2013

Glutathione independent prostaglandin D synthase (Swissprot P41222, PTGDS) has been identified in human cerebrospinal fluid and some changes in PTGDS in relation to disease have been reported. However, little is known of the extent that PTGDS isoforms fluctuate across a large range of congenital and acquired diseases. The purpose of this study was to examine changes in PTGDS isoforms in such a population. Spinal fluid from 22 healthy study participants (normal controls) with no classifiable neurological or psychiatric diagnosis was obtained and PTGDS isoforms were identified by specific immunostaining and mass spectrometry after denaturing 2D gel electrophoresis. The PTGDS isoforms in controls consisted of five charge isoforms that were always present and a small number of occasional, low abundance isoforms. A qualitative survey of 98 different people with a wide range of congenital and acquired diseases revealed striking changes. Loss of the control isoforms occurred in congenital malformations of the nervous system. Gain of additional isoforms occurred in some degenerative, most demyelinating and vasculitic diseases, as well as in Creutzfeldt‐Jakob disease. A retrospective analysis of published data that quantified relative amounts of PTGDS in multiple sclerosis, schizophrenia and Parkinson’s disease compared to controls revealed significant dysregulation. It is concluded that qualitative and quantitative fluctuations of cerebrospinal fluid PTGDS isoforms reflect both major and subtle brain pathophysiology.
Serum Levels of Platelet Released CD40 Ligand Are Increased in Early Onset Occlusive Carotid Artery Disease
Authors: Balla József , Magyar Mária Tünde , Bereczki Dániel , Valikovics Attila , Nagy Emöke , Barna Erika , Pál András , Balla György , Csiba László , Blaskó György
Published: June 2013

Objective: Soluble CD40 ligand (sCD40L) has been suggested as a key mediator between inflammation and atherosclerosis, and the CD40‐CD40L interaction has a role in atherosclerotic lesion progression. We evaluated if platelet released serum sCD40L and sCD40 levels differ between patients with early onset occlusive carotid artery disease and age‐matched controls.

Methods: sCD40L and sCD40 levels were measured in serum samples of 60 patients with occlusive carotid artery disease and 30 age‐matched controls using ELISA. Degree of stenosis of the internal carotid artery (ICA), and intima‐media thickness (IMT) in the common carotid artery were measured by high resolution ultrasound. Values are given as mean ± SD.

Results: Mean age was 50.9 ± 3.5 and 50.1 ± 3.5 years in the patient and control groups. IMT was significantly thicker in patients than in controls (0.89 ± 0.14 vs. 0.78 ±0.12 mm, p = 0.0003). Serum levels of sCD40L were significantly higher (6.9 ± 5 vs. 4.5 ± 3.0 ng/mL, p = 0.038) in patients, whereas sCD40 did not differ significantly between patients and controls (85 ± 56.9 vs. 79.3 ± 18.7 pg/mL, p = 0.34). IMT did not correlate with sCD40L or sCD40 levels (R = −0.03, p = 0.77; and R = 0.109, p = 0.308, respectively).

Conclusions: sCD40L but not sCD40 levels are significantly higher in patients with occlusive carotid artery disease. Platelet derived sCD40L may be a key mediator among inflammation, thrombosis and atherosclerosis.
Prognostic Value of RT‐PCR Tyrosinase Detection in Peripheral Blood of Melanoma Patients
Authors: Carrillo Esmeralda , Prados José , Marchal Juan Antonio , Boulaiz Houria , Martínez Antonio , Rodríguez-Serrano Fernando , Caba Octavio , Serrano Salvio , Aránega Antonia
Published: June 2013

Malignant melanoma (MM) prognosis has been related to tumour thickness and clinical stage and metastasis risk has been associated with presence of tumour cells in peripheral blood. The aim of this study was to determine the relationship between presence of tyrosinase in peripheral blood of MM patients and their clinical prognosis. Blood samples from 58 MM patients (stage I–IV) were analysed, using RT‐PCR assay to detect tyrosinase mRNA. The results showed that positive RT‐PCR assay for tyrosinase were significantly associated with clinical status and tumour thickness. After a median follow‐up of 24 months, RT‐PCR results were found to be significant correlated with recurrence (p < 0.05) and clinical stage III (p < 0.05). Separate analysis of stage III tumours to determine the prognostic value of tyrosinase presence in peripheral blood showed an overall 24‐month survival rate of 70% in the RT‐PCR negative group versus 10% in the positive group (p < 0.02). These results suggest that detection of circulating melanoma cells may be especially relevant in stage III patients, in whom RT‐PCR positivity defines a subpopulation at high risk of recurrence.
NMO‐IgG: A Specific Biomarker for Neuromyelitis Optica
Authors: Weinshenker Brian G. , Wingerchuk Dean M. , Pittock Sean J. , Lucchinetti Claudia F. , Lennon Vanda A.
Published: June 2013

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that principally targets the optic nerves and spinal cord and often leads to severe disability and occasionally life threatening respiratory failure. Although its clinical manifestations overlap with those of multiple sclerosis (MS), in established cases these two conditions can be distinguished on the basis of clinical, radiological, and routine spinal fluid studies. The diagnosis in early cases or limited forms of NMO is difficult. We recently discovered a unique IgG autoantibody (NMO‐IgG) that is highly specific to patients with NMO and thus a valuable diagnostic aid. Its antigen, aquaporin‐4 (AQP4), is the central nervous system’s predominant water channel protein. This antibody has not yet been proven to be pathogenic, but several facts suggest that it might be, including the similarity of the immunohistochemical pattern of NMO‐(AQP4) IgG binding to mouse CNS tissues to the pattern of immune complex deposition in autopsied patients’ spinal cord tissue. The spectrum of diseases identified by NMO‐IgG is broader than has previously been recognized clinically and includes incomplete forms of NMO, such as recurrent transverse myelitis without optic neuritis and recurrent optic neuritis without myelitis.
Markers of Angiogenesis in Ovarian Cancer
Authors: Merritt William M. , Sood Anil K.
Published: June 2013

Tumor development and progression are inherently dependent on the process of angiogenesis. Recently, anti‐angiogenic therapy has started to show promise as an effective treatment strategy in many solid tumors including ovarian carcinoma. Unfortunately, lack of effective biomarkers presents a challenge for oncologists in treatment planning as well as monitoring response of new anti‐vascular agents. Previously, quantification of angiogenesis by microvessel density analysis provided useful prognostic information, however, its utility following anti‐angiogenic therapy remains to be determined. Moreover, since secreted cytokines play an active part in angiogenesis by mediating neovascularization in tumors, investigations have focused on their potential role to serve as candidate biomarkers of disease detection, prognosis, and treatment response. In this article, we review the role of key angiogenesis markers as potential biomarkers in ovarian carcinoma.
The Role of RASSF1A Methylation in Cancer
Authors: Hesson Luke B. , Cooper Wendy N. , Latif Farida
Published: June 2013

Tumour suppressor gene inactivation is critical to the pathogenesis of cancers; such loss of function may be mediated by irreversible processes such as gene deletion or mutation. Alternatively tumour suppressor genes may be inactivated via epigenetic processes a reversible mechanism that promises to be more amenable to treatment by therapeutic agents. The CpG dinucleotide is under‐represented in the genome, but it is found in clusters within the promoters of some genes, and methylation of these CpG islands play a critical role in the control of gene expression. Inhibitors of the DNA methyltransferases DNMT1 and DNMT3b have been used in a clinical setting, these nucleotide analogues lack specificity but the side effects of low dose treatments were minimal and in 2004 Vidaza (5‐azacitidine) was licensed for use in myelodysplastic syndrome. Methylation inhibitors are also entering trials in conjunction with another class of epigenetic modifiers, the histone deacetylase inhibitors and this epigenetic double bullet offers hope of improved treatment regimes. Recently there has been a plethora of reports demonstrating epigenetic inactivation of genes that play important roles in development of cancer, including Ras‐association domain family of genes. Epigenetic inactivation of RASSF1A (Ras‐association domain family 1, isoform A) is one of the most common molecular changes in cancer. Hypermethylation of the RASSF1A promoter CpG island silences expression of the gene in many cancers including lung, breast, prostate, glioma, neuroblastoma and kidney cancer. Several recent studies have illustrated the diagnostic and prognostic potential of RASSF1A methylation. This presents RASSF1A methylation as an attractive biomarker for early cancer detection which, for most cancers, results in improved clinical outcome. DNA methylation analysis is applicable to a range of body fluids including serum, urine, bronchioalveolar lavage and sputum. The ease with which these body fluids can be acquired negates the need for invasive procedures to obtain biopsy material. This review will discuss the feasibility of using RASSF1A methylation as a diagnostic and prognostic marker in cancer management.
Early Detection of Ovarian Cancer
Authors: Badgwell Donna , Bast Robert C.
Published: June 2013

Despite advances in therapy, ovarian cancer remains the most deadly of the gynecological cancers. Less than 30% of women with advanced stage disease survive long‐term. When diagnosed in stage I, up to 90% of patients can be cured with conventional surgery and chemotherapy. At present, only 25% of ovarian cancers are detected in stage I due, in part, to the absence of specific symptoms and to lack of an effective screening strategy. Early detection of ovarian cancer might significantly improve the overall survival rate of women with ovarian cancer if 1) most cancers are clonal and unifocal, arising in the ovary rather than in the peritoneum, 2) metastatic disease results from progression of clinically detectable stage I lesions, and 3) cancers remain localized for a sufficient interval to permit cost‐effective screening. Given the prevalence of ovarian cancer, strategies for early detection must have high sensitivity for early stage disease (> 75%), but must have extremely high specificity (99.6%) to attain a positive predictive value of at least 10%. Transvaginal sonography (TVS), serum markers and a combination of the two modalities have been evaluated for early detection of ovarian cancer. Among the serum markers, CA125 has received the most attention, but lacks the sensitivity or specificity to function alone as a screening test. Greater specificity can be achieved by combining CA125 and TVS and/or by monitoring CA125 over time. Two stage screening strategies promise to be cost effective, where abnormal serum assays prompt TVS to detect lesions that require laparotomy. Accrual has been completed for a 200,000 woman trial in the United Kingdom that will test the ability of a rising CA125 to trigger TVS and subsequent exploratory surgery. Given the heterogeneity of ovarian cancer, it is unlikely that any single marker will be sufficiently sensitive to provide an effective initial screen. Sensitivity of serum assays might be enhanced by utilizing a panel of biomarkers. Candidate biomarkers have been discovered through empirical development of monoclonal antibodies, studies of gene expression, cloning of gene families and proteomic techniques. The development of technologies that measure multiple serum markers simultaneously, linked to the creation of statistical methods that enhance sensitivity without sacrificing specificity hold great promise.
Epigenetic Markers for Molecular Detection of Prostate Cancer
Authors: Costa Vera L. , Henrique Rui , Jerónimo Carmen
Published: June 2013

Prostate cancer is a highly prevalent malignancy, which is clinically silent but curable while organ‐confined. Because available screening methods show poor sensitivity and specificity, the development of new molecular markers is warranted. Epigenetic alterations, mainly promoter hypermethylation of cancer‐related genes, are common events in prostate cancer and might be used as cancer biomarkers. Moreover, the development of quantitative, high‐throughput techniques to assess promoter methylation enabled the simultaneous screening of multiple clinical samples. From the numerous cancer‐related genes hypermethylated in prostate cancer only a few proved to be strong candidates to become routine biomarkers. This small set of genes includes GSTP1, APC, RARβ2, Cyclin D2, MDR1, and PTGS2. Single and/or multigene analyses demonstrated the feasibility of detecting early prostate cancer, with high sensitivity and specificity, in body fluids (serum, plasma, urine, and ejaculates) and tissue samples. In addition, quantitative hypermethylation of several genes has been associated with clinicopathologic features of tumor aggressiveness, and also reported as independent prognostic factor for relapse. The identification of age‐related methylation at specific loci and the differential frequency of methylation among ethnical groups, also provided interesting data linking methylation and prostate cancer risk. Although large trials are needed to validate these findings, the clinical use of these markers might be envisaged for the near future.
Claudin Proteins in Ovarian Cancer
Authors: Morin Patrice J.
Published: June 2013

Members of the claudin family of tight junction proteins have been found altered in several malignancies, including ovarian cancer. Because claudin‐3 and ‐4 are elevated in the vast majority of ovarian tumors, they may represent useful biomarkers for detection and prognosis, as well as ideal targets for therapy using the Clostridium perfringens enterotoxin.
Biomarkers in Cervical Cancer Screening
Authors: Wentzensen Nicolas , von Knebel Doeberitz Magnus
Published: June 2013

In industrialized countries, population wide cytological screening programs using the Pap test have led to a substantial reduction of the incidence of cervical cancer. Despite this evident success, screening programs that rely on Pap‐stained cytological samples have several limitations. First, a number of equivocal or mildly abnormal test results require costly work up by either repeated retesting or direct colposcopy and biopsy, since a certain percentage of high grade lesions that require immediate treatment hide among these unclear test results. This work up of mildly abnormal or equivocal cytological tests consumes a large amount of the overall costs spent for cervical cancer screening. Improved triage of these samples might substantially reduce the costs. Cervical cancer is induced by persistent infections with oncogenic human papilloma viruses (HPV). While HPV infection is an indispensable factor, it is not sufficient to cause cancer. The majority of acute HPV infections induce low grade precursor lesions that are cleared spontaneously after several months in more than 90% of cases, and less than 10% eventually progress to high grade lesions or invasive cancer. Progression is characterized by the deregulated expression of the viral oncogenes E6 and E7 in infected basal and parabasal cells. Novel biomarkers that allow monitoring these essential molecular events in histological or cytological specimens are likely to improve the detection of lesions that have a high risk of progression in both primary screening and triage settings. In this review, we will discuss potential biomarkers for cervical cancer screening with a focus on the level of clinical evidence that supports their application as novel markers in refined cervical cancer screening programs.
Possible Application of Raman Microspectroscopy to Verify the Interstitial Cystitis Diagnosis after Potassium Sensitivity Test: Phenylalanine or Tryptophan as a Biomarker
Authors: Hsieh Tzu-Feng , Yu Ken-Jen , Lin Shan-Yang
Published: June 2013

There is lack of a worldwide standard technique for clinical diagnosis of interstitial cystitis (IC). Raman spectroscopy with higher specificity and sensitivity has been extensively used to act as a non‐destructive analytical technique without special sample preparation. In this preliminary study, possible use of Raman microspectroscopy as an IC diagnostic tool was attempted. Twenty‐two participants were screened by clinical features, history, urodynamic evaluations and potassium sensitivity test (PST). The freeze‐dried water samples voided from all the participants after PST were directly determined by using a confocal Raman microspectroscopy to search the biomarker. Participants with or without IC symptom were separated into control and clinical groups, according to the above screening. The participants in the clinical group were further divided into mild and severe subgroups by PST. The symptom of urinary pain and urgency was significant difference between the mild and severe subgroups (p < 0.05). A significant increase in urinary frequency but a marked reduction in bladder capacity, maximum cystometric capacity and maximum voiding flow rate were obtained for clinical group of IC participants, as compared with the result of control group (p < 0.05). By using Raman microspectroscopic determination, the band near 1003 or 1005 cm−1 assigned to phenylalanine was respectively detected from the freeze‐dried water sample of control group or mild subgroup, but the band at 1010 cm−1 due to tryptophan was found in the freeze‐dried water sample of severe subgroup. The result of this preliminary study first suggests a possible application of Raman microspectroscopy to strongly certify the results of PST for IC diagnosis. Phenylalanine or tryptophan might be acted as a biomarker to assist the diagnosis of IC after PST. Particularly, the appearance of tryptophan might be used to discriminate the severity of IC symptom.
Characterization of Malignant Brain Tumor Using Elastic Light Scattering Spectroscopy
Authors: Gong Jianmin , Yi Ji , Turzhitsky Vladimir M. , Muro Kenji , Li Xu
Published: June 2013

We report a pilot study designed to test elastic light‐scattering (ELS) spectroscopy for characterizing normal, tumor, and tumor‐infiltrated brain tissues. ELS spectra were measured from 393 sites on 36 ex vivo tissue specimen obtained from 29 patients. We employed and compared the performances of three methods of spectral classification for tissue characterization, including spectral slope analysis, principle component analysis (PCA), and artificial neural network (ANN) classification. The ANN classifier yielded the best correlation between spectral pattern and histopathological diagnosis, with a typical sensitivity of 80% and specificity of 93% for differentiating tumor from normal brain tissues. We also demonstrate that all three classification methods discriminate between tumor and normal tissue and have the potential to identify and quantitatively characterize tumor‐infiltrated brain tissues.
Microsatellite Scan Identifies New Candidate Genes for Susceptibility to Alcoholic Chronic Pancreatitis in Japanese Patients
Authors: Kitahara Kei , Kawa Shigeyuki , Katsuyama Yoshihiko , Umemura Takeji , Ozaki Yayoi , Takayama Mari , Arakura Norikazu , Ota Masao
Published: June 2013

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.
Expression of Hypoxia‐Inducible Factor (HIF)‐1α and Vascular Endothelial Growth Factor (VEGF)‐D As Outcome Predictors in Resected Esophageal Squamous Cell Carcinoma
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
Published: June 2013

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.
PINCH Expression and Its Significance in Esophageal Squamous Cell Carcinoma
Authors: Zhu Zhenlong , Yang Yanhong , Zhang Yu , Wang Zhengmin , Cui Dongsheng , Zhang Jinting , Wang Mingwei , Sun Xiao-Feng
Published: June 2013

Particularly interesting new cysteine‐histidine rich protein (PINCH), as a newly discovered protein of LIM family members, may play a role in signal transduction of integrin and growth factor, and involved in the incidence and development of tumors. PINCH protein is overexpressed in tumor‐associated stroma of several types of tumors. However, there is no study of the PINCH in esophageal cancer, therefore we investigated PINCH expression in esophageal squamous cell carcinomas and its clinicopathological significance in the patients. PINCH expression was immunohistochemically examined in 20 normal esophageal samples and 64 esophageal squamous cell carcinomas. The results showed that PINCH expression in the stroma of cancers was heterogeneous, and its positive rate (56%) was higher than that of normal esophageal mucosa (5%, p < 0.0001).
The stronger staining was observed at the invasive edge of tumor when compared to the inner area of tumor. The rate of positive
PINCH (90%) in the cases with lymph node metastasis was higher than that (41%) in the cases without metastasis (p < 0.0001).
PINCH expression was not correlated with patients’ gender, age, tumor location, size and differentiation (p > 0.05). The results
suggest that PINCH protein may be a marker of tumor associated‐stroma involving tumor development, and predicting the ability
of invasion and metastasis of esophageal squamous cell carcinoma.