Journal of Molecular Biomarkers & Diagnosis

Trastuzumab is a humanized monoclonal antibody directed against extracellular domain IV of Human Epidermal Growth Factor Receptor 2 (HER2) and is approved for the treatment of HER2-positive breast cancers either alone or in combination with chemotherapeutic agents [1,2]. HER2 is a member of HER/ErbB family of receptor tyrosine kinases, which play important role in breast cancer development and progression [1]. HER2 is overexpressed in approximately 20-30% of invasive breast cancer and is associated with poor disease-free survival and poor response to chemotherapy [3-5]. Over the past two decades, the development of monoclonal antibodies targeting HER2 has been intensely pursued as important cancer therapeutic strategy. While treatment with trastuzumab very successfully improves outcomes for women with HER2-positive breast cancer, therapeutic resistance to trastuzumab, including primary and acquired resistance, pose a significant hurdle in the treatment of HER2-positive breast cancers [2,6,7], Better understanding of molecular mechanisms underlying primary or acquired resistance to trastuzumab is critical to improving the survival of patients with HER2-positive breast cancer.

Over the past several years, there has been increasing research and clinical interest in using nanotechnology for cancer therapy. Nanoparticle provides tremendous potential for future medical therapy. Besides targeting cancer cells, delivering and releasing drugs in a regulated manner, the specificity of nanoparticles is what makes thermal therapy as attractive as a cancer therapy. In this mini review, we discuss some of the recent advances of nanotechnology for thermal therapy of prostate cancer.

Nowadays, proteomic-related studies have developed rapidly and improvement has been made in the scientific and technological fields. Besides the proteome, the peptidome with low molecular weight has apparently attracted increasing attention in recent years too. The peptidome performs a large array of vital biological functions to contribute to homeostasis in the certain tissues. However, due to the interference by high-abundance proteins in complex biological body fluids such as saliva and serum, selective enrichment of peptides with low molecular weight is the first and most important step before analyzing the peptidome. This review mainly illustrates the general concept of the peptidome, specific methods of saliva collection, advanced peptidomic technologies and the recently developed peptidomic-related reports, as well as some limitations of the application in salivary peptidome. The future prospects of the peptidome are also involved.

Objective: To evaluate the usefulness of STREM-1 level in synovial fluid (SF) to differentiate septic from aseptic arthritis. Methods: A cross sectional study performed in the Pediatrics ward of Rasoul Hospital, Tehran, IRAN (2008- 2009). Out of 66 children, 53 synovial fluid (SF) samples studied. Direct gram stain, conventional and Bactec culture, quantification of STREM-1 level (EIA Quantikine, R&D systems, USA) had done.STREM-1 levels compared between septic (n=26) and aseptic (n=27) arthritis. Chi square values (CI 95%, p<0.05) were considered statistically significant. Results: Septic arthritis diagnosed in 26 cases; S. Aureus (7/18, 38%). SF-STREM-1 Cut off level 825 pg./ml yielded 50% sensitivity, 70% specificity, 64% PPV, 64% NPV. The AUC was 0.603 (95% CI; 0.448-0.757, P = 0.2). SF-STREM-1 Levels were higher in patients with bacterial arthritis in compare with aseptic arthritis (95% Confidence Interval Odds Ratio 9.852-1.039; fisher exact test; P value: 0.056). Conclusion: SF-STREM-1 level even in very low amount (825 pg/ml) had intermediate (50%) sensitivity for diagnosis of septic arthritis. 70% specificity is excellent and sufficient for definite diagnosis, but it could misdiagnosed just in 30% of septic arthritis cases ( from other inflammatory arthritis), 64% NPV or the test is a limited factor. In our opinion the presence of STREM-1 in SFA can potentially assist clinicians in the diagnosis of half but not all cases with bacterial arthritis. The Positive SF culture as gold-standard test for diagnosis would obtain up to 80%. Combination of new biologic markers (PCT and sTREM-1) in SFA could be more helpful in high suspicious cases with negative culture (already on antibiotic treatment; or normally under growth of SF culture).

Background: Autosomal dominant Charcot Marie Tooth disease (CMT) diseases is an inherited peripheral neuropathies disease, the prevalence is 17-40 per 100,000 individuals 17-40 per 100,000 individuals. The complex genetic mode and large number of CMT causing genes and loci made it is very hard for clinicians and researchers when trying to determine the underlying genetic diagnosis. In this work, we want to identify the cause for a Chinese family with Charcot-Marie-Tooth disease.

Methods: Family history data were recorded. Clinical and Electromyography examinations were performed on the ten affected and ten unaffected family members. All the members were genotyped with microsatellite markers at loci considered to be associated with CMT. Two-point LOD scores were calculated using the Linkage software after genotyping. Some highly suspect genes were excluded by direct sequencing.

Results and Conclusions: The clinical and pathological features were relatively gently, but which became gradually worse, with the increased genetic generation, and the onset age of the affected members. Linkage analysis was obtained at markers D19S433 (LOD score [Z]=2.03, recombination fraction [θ]=0.0) and D19S916 (Z=1.6, θ=0.0). Sequencing the dynamin 2 gene (DNM2) didn’t found any variation in the translated region. There may be some other gene or loci associated with this disease.

Background: Although cholangiocarcinoma (CC) is an uncommon and highly lethal malignancy, early detection enables the application of potentially curative therapies and improves survival. Consequently, tools to improve the early diagnosis of CC are urgently needed. During a screen for genes epigenetically suppressed by methylation in CC that might serve as methylation markers for CC, we found that the BMP3 gene is methylated in CC cell lines, but the potential diagnostic value and the function of BMP3 in CC are unknown.

Methods: We aimed to quantitatively assess BMP3 methylation in resected CC tumor specimens using methylation specific PCR and evaluate the tumor suppressor role of BMP3 in biliary cancer cell lines in comparison to an immortalized normal cholangiocyte cell line. Expression of BMP3 was quantified by mRNA levels before and after treatment with 5-Aza-2’-deoxycytidine and trichostatin A. After transfection with a BMP3-containing plasmid, cell viability was measured using the bromodeoxyuridine incorporation assay and apoptosis quantified by caspase assay.

Results: In primary CC tumor tissue specimens significantly more methylated BMP3 copies were found when compared to matched benign bile duct epithelium from the same patient, with high specificity. BMP3 expression was absent in cell lines with BMP3 methylation; this suppression of BMP3 expression was reversed by treatment with a DNA demethylating agent and histone de-acetylase inhibitor. Transfection of a BMP3-expressing construct into a BMP3-negative biliary cancer cell line restored BMP3 mRNA expression and reduced cell proliferation and cell viability while increasing the rate of apoptosis.

Conclusion: These findings strongly support a tumor suppressor role for BMP3 in CC and suggest that BMP3 methylation may be a new biomarker for early detection of CCs.of the peptidome are also involved.

Inflammatory mediators may play key roles in both atherosclerosis and cardiovascular disorders and in cancer development. Pentraxins are a family of proteins characterized by the structural motif pentraxin domain. Long pentraxin 3 (PTX3), a protein that in humans is encoded by the PTX3 gene, is rapidly produced and released by several cell types in response to inflammatory stimuli. This review discusses the evidence supporting the role of PTX3 in predicting primary cardiovascular events and diagnosis and prognosis of cancer.

This mini-review analyzes advantages and limitations of current methods of assessment of cerebral concussions
considering functional, structural and metabolic factors in decision making for return to play. Novel neurotoxicity
biomarkers, AMPA and NMDA receptor peptide/antibodies are proposed for evaluation of subtle brain injury
following concussions. Neurotoxicity biomarkers can now be detected in the blood and are associated with severity
of concussion and transient or persistent changes in the brain including diffuse axonal injury and microvascular
dysfunction (edema formation).
We surveyed 84 students (20.5 ± 2.5 years) participating in contact-sports and enrolled at Kennesaw State
University. Based on neurotoxicity biomarkers values and diminished ImPACT scores, 18 athletes with concussions
were selected for longitudinal assessment (1.5 year). Within the study, values of four neurotoxicity biomarkers
decreased to normal in 11 (61%) concussed athletes while seven subjects maintained at least one acute and chronic
biomarkers elevated reflecting structural changes in the brain defined by 3T DTI.
It was demonstrated that neurotoxicity biomarkers in conjunction with neurocognitive testing might improve
diagnostic certainty of suspected concussions. Additionally the use of biomarkers may provide valuable information
on severity of concussions and help select subjects (about 2%) for advanced neuroimaging. Athletes with abnormal
levels of neurotoxicity biomarkers and structural changes on DTI should be withheld from contact sports and be
considered for therapeutic intervention and treatment to protect the brain from further neurological complications.

Data are paramount to modern targeted drug design. Precious revelations obtained by applying data mining and
computational chemistry on large molecular databases, innovative at one time, are now everyday procedures for
therapy identification. However, there is an even larger source of valuable information available that can potentially
be tapped for discoveries: repositories constituted by research documents.
While numerical methods for the analysis of structured data like those in genomics and proteomics databases
are well developed and standard toolboxes are easily available, knowledge discovery from unstructured data in text
documents is still considered the “Holy Grail” of text mining and no stable methodology has yet emerged from the
scant few known attempts.
Here we review a recent pilot experiment to discover novel biomarkers and phenotypes for diabetes and obesity
by self-organized text mining of about 120,000 PubMed abstracts, public clinical trial summaries, and internal Merck
research documents by the InfoCodex semantic engine. Retrieval of known entities missed by other traditional
approaches could be demonstrated and the InfoCodex semantic engine was shown to discover new diabetes and
obesity biomarkers and phenotypes, although noticeable noise (uninteresting or obvious terms) was generated.
The reported text mining approach to biomarker discovery shows much promise and has the potential to be
developed into a new avenue for pharmaceutical research, especially to shorten time-to-market of novel drugs, or
speed up early recognition of dead ends and adverse reactions.

Background: We studied the usefulness of ROMA for preoperative stratification of patients in relation to the
menopausal status, etiopathogenesis of epithelial ovarian tumors and FIGO stage.
Material and methods: The study group (n=214) consisted of 116 premenopausal and 98 postmenopausal
patients, including 83 with ovarian cancer and 131 with benign lesions. CA125 and HE4 were determined in each pre- and postmenopausal patient. ROC analysis was done to calculate the sensitivity, specificity, PPV, and NPV and a contingency table was applied to assess the usefulness of ROMA.
Results: ROC analysis identified AUC (area under curve) as the most valuable component of ROMA (0.921)
in the study group with respect to CA125 (0.919) and HE4 (0.855). Sensitivity was highest for CA125 (90.4% for the whole group, 85.7% for premenopausal and 91.7% for postmenopausal patients). Specificity was highest for ROMA with cutoff points determined by us (95.4% for the whole group, 96.8% for premenopausal and 91.7% for postmenopausal patients). AUC, sensitivity, specificity, PPV, and NPV calculated from a contingency table demonstrated the superiority of ROMA with our cutoff points in type II cancers (0.979, 93.3%, 95.4%, 87.5%, 97.7%) and advanced cancers (0.980, 95.1%, 95.4%, 90.7%, 97.7%), compared with type I (0.851, 76.3%, 95.4%, 82.9%, 93.3%) not advanced (0.754, 59.1%, 95.4%, 68.4%, 93.3%) cancers.
Conclusions: ROMA is actually a useful diagnostic method for preoperative stratification of patients with a
pelvic mass. It performs better in type II and more advanced ovarian cancers. However, its sensitivity, specificity, PPV, and NPV values in type I ovarian cancer make ROMA useful in this group of cancer patients as well.