BRCA germline mutation test for all woman with ovarian cancer?

BACKGROUND: Delivering widespread BRCA testing to patients with ovarian cancer has been suggested by several scientists, recommended by professional societies and solicited by patients organizations. However, based on the lack of studies clearly demonstrating the cost-effectiveness of such approach compared to standard practice, we evaluated the possibility to better select subgroups of ovarian cancer (OC) patients with higher probability to be a BRCA mutation carrier'. METHODS: We analyzed the database of 2222 germline BRCA analyses from OC patients recently published by Song et al. (Song 2014) by applying multivariate and conditional inference regression tree-analyses. RESULTS: Overall, 178/2192 (8.1%) evaluable OC women showed pathogenic germline mutations in BRCA genes (84 BRCA1;94 BRCA2). BRCA mutations resulted significantly more frequent in Epithelial tumors (10.7%), less differentiated tumours (11.0%) and younger subjects (13.4%). Regression tree analysis permitted to individualize a subset of 66% OC patients with particularly low risk (3.5%) to carry a BRCA mutation vs a subgroup (24% of the series), with a probability higher than 17% to carry a pathogenic mutation. Younger age, OC and Breast Cancer family history were confirmed powerful factors in selecting subgroups of patients with significantly different BRCA mutation probability. CONCLUSIONS: Our regression tree-analysis can represent an innovative approach taking into consideration all main clinical pathological information to select OC patients to be candidated for BRCA test.

The Evaluation of a 5-miRNA Panel in Patients with Periodontitis Disease.

INTRODUCTION: Side by side with tooth decay, periodontitis remains one of the most common oral diseases and is increasingly recognized as a serious public health concern worldwide. OBJECTIVES: The present study aims at comparing the levels of 5 specific miRNAs (miR-29b-3p, miR-34a-5p, miR-155-5p, miR-181a-5p, and miR-192-5p) in patients with periodontal disease and healthy controls. METHODS: The pathogenic mechanism is related to the activation of immune response and significant alteration of coding and noncoding genes, including miRNA. The study includes 50 subjects (17 with periodontal disease and 33 healthy controls) with a mean age of 45.3 y. In both periodontitis patients and healthy controls, a panel of 5 miRNAs (miR-29b-3p, miR-34a-5p, miR-155-5p, miR-181a-5p, and miR-192-5p) is examined by determining their expression levels with quantitative reverse transcription polymerase chain reaction. RESULTS: The periodontitis patients express high levels of all the investigated miRNAs. Receiver operating characteristic curve analysis shows an area under the curve (AUC) of 0.69 to 0.74 for individual transcripts with the highest AUC value observed for miR-192, followed by miR-181a. CONCLUSIONS: The study indicates that the 5-miRNA panel can be used as biomarker for periodontitis. In this way, all implantology procedures and treatment options for patients diagnosed with periodontitis can be improved for better long-term results, predictability, and follow-up frequency. KNOWLEDGE TRANSFER STATEMENT: The discovery of a miRNA panel as a potential biomarker for periodontitis offers major opportunities for practical application. Our study can improve diagnostic accuracy; researchers can develop new theories on molecular mechanisms and biomarker discovery.

The significance of PDGF expression in serum of colorectal carcinoma patients--correlation with Duke's classification. Can PDGF become a potential biomarker?

BACKGROUND: The expression of serum angiogenic factors has been associated with tumor dissemination and poor prognosis in multiple cancer types. However, it is still unclear whether these angiogenic molecules can be used as an independent molecular marker or in correlation with other parameters for predicting the prognosis of colorectal carcinoma (CRC)patients. METHODS: Protein expression was evaluated in 28 CRC and 10 control cases using Angiogenesis Fast Quant technology. RESULTS: In this study, we found downregulation of PDGF-bb protein expression in the serum of patients with colorectal cancer compared with the control group. Thus, PDGF-bb might play an essential function in the progression of CRC. CONCLUSIONS: Our study indicated that the PDGF-bb protein expression might be an independent prognostic marker or in association with other parameters for CRC patients.

The clinical implications of platelet derived growth factor B, vascular endothelial growth factor and basic fibroblast growth factor in colorectal cancer.

Colorectal cancer (CRC) remains a major health problem worldwide. Angiogenesis is a key process for tumor growth and metastasis. The conversion of tumor cells to an angiogenic phenotype involves the change in the balance of angiogenic growth factors and angiogenesis inhibitors. In our study we evaluated by qRT-PCR the level of expression of 3 growth factors involved in angiogenesis: platelet derived growth factor-B (PDGFb), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) in patients with different stages of colon cancer. Our results showed the level of VEGF increased on all tumor without difference, statistically significant according with tumor stage whereas the others the levels of bFGF and PDGF were higher, statistically significant, on tumor classified stage B compared with stage C. The early implication of these molecules in colon carcinogenesis justifies the development of new biologic individualized therapies.

Oxaliplatin in patients with metastatic colorectal cancer: efficacy and pharmacokinetics parameters.

PURPOSE: The aim of this study was to investigate the efficiency of the FOLFOX-4 regimen and to evaluate the pharmacokinetics of oxaliplatin in untreated patients with metastatic colorectal cancer. METHODS: 43 patients were enrolled in the study. Patients received oxaliplatin 85 mg/m(2) as 2-h i.v. infusion, on day 1, and bolus 5-fluorouracil (5FU) 400 mg/m(2) plus leucovorin (LV) 200 mg/m(2) followed by 5FU 600 mg/m(2) as 22-h infusion on day 1 and 2, every 2 weeks. The pharmacokinetics of oxaliplatin evaluated in 4 patients was performed in blood, plasma and ultrafiltered plasma (UFT) by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). RESULTS: The overall response rate and the median time to progression (TTP) were 53.49% and 7.1 months, respectively. Grade 3-4 toxic effects were observed in 11 (25.5%) patients. Grade 3 neuropathy was observed in 13.95% of the cases. In univariate analysis only Eastern Cooperative Oncology Group (ECOG) performance status (PS) was correlated with response. No correlation was found between grade 3-4 adverse events and the patient characteristics. The area under the time-concentration curve (AUC) in UFT was 4.8 + or - 0.72 standard deviation (SD) microg h/ml and the total clearance 30.17 + or - 7.75 l/min. The values for volume of distribution and the maximum concentration were 567 + or - 20 liters and 0.38 + or - 0.17 ug/ml, respectively. CONCLUSION: FOLFOX-4 was an effective regimen with good tolerability in previously untreated metastatic colorectal cancer patients. The pharmacokinetics of oxaliplatin was triphasic with a short initial distribution phase and a long terminal elimination phase.

Celiac disease: a multi-faceted medical condition.

Celiac disease (CD) is a systemic condition of autoimmune origin, affecting genetically predisposed individuals who at some point lose tolerance towards dietary gluten. Prevalence in the general population is 0.5 - 1%, with a higher frequency in women. The most important environmental factor for CD is ingestion of specific gluten peptides. It triggers a sequence of molecular events, involving the intestinal permeability and the immune system, which ends in damage of the intestinal mucosa. A number of studies have demonstrated the correlation between the intestinal microbiota and celiac disease. MicroRNAs through their regulatory role on gene expression have been implicated in the pathogenesis of CD and suggested as potential biomarkers. In the pediatric and adult population, CD displays different clusters of clinical symptoms. Persistent diarrhea, abdominal pain and involuntary weight loss are the classic symptoms of CD. In the majority of cases diagnosis relies on the combination of serum autoantibodies (anti-transglutaminase and anti-endomisium IgA) and duodenal biopsy showing villous atrophy, crypt hyperplasia and intraepithelial lymphocytes. Observance of a lifelong gluten-free diet, which interrupts the immune response to gluten peptides, is the only effective treatment of CD.

p53 gene therapy using RNA interference.

p53 gene, discovered almost 35 years ago, keeps the main role in cell cycle control, apoptosis pathways and transcription. p53 gene is found mutated in more than 50% of all human cancers in different locations. Many structures from viral to non viral were designed to incorporate and deliver in appropriate conditions forms of p53 gene or its transcripts, systemically to target tumor cells and to eliminate them through apoptosis or to restore the normal tumor suppressor gene role. Each delivery system presents advantages and low performance in relation to immune system recognition and acceptance. One of the major discoveries in the last years, silencing of RNA, represents a powerful tool for inhibiting post transcriptional control of gene expression. According to several studies, the RNA silencing technology for p53 transcripts together with other carriers or transporters at nano level can be used for creating new therapeutic models. RNA interference for p53 uses different double-stranded (ds) molecules like short interfering (si) RNA and, despite the difficulty of introducing them into mammalian cells due to immune system response, it can be exploited in cancer therapy.

Seroprevalence of Bartonella species, Coxiella burnetii and Toxoplasma gondii among patients with hematological malignancies: A pilot study in Romania.

Patients receiving immunosuppressive cancer treatments in settings where there is a high degree of human-animal interaction may be at increased risk for opportunistic zoonotic infections or reactivation of latent infections. We sought to determine the seroprevalence of selected zoonotic pathogens among patients diagnosed with haematologic malignancies and undergoing chemotherapeutic treatments in Romania, where much of the general population lives and/or works in contact with livestock. A convenience sample of 51 patients with haematologic cancer undergoing chemotherapy at a referral clinic in Cluj-Napoca, Romania, was surveyed regarding animal exposures. Blood samples were obtained and tested for evidence of infection with Bartonella species, Coxiella burnetii and Toxoplasma gondii, which are important opportunistic zoonotic agents in immunocompromised individuals. 58.8% of participants reported living or working on a farm, and living or working on a farm was associated with contact with livestock and other animals. 37.5% of participants were IgG seroreactive against one or more of five Bartonella antigens, and seroreactivity was statistically associated with living on farms. Farm dwellers were 3.6 times more likely to test IgG seroreactive to Bartonella antibodies than non-farm dwellers. 47.1% of the participants tested T. gondii IgG positive and 13.7% tested C. burnetii IgG positive, indicating past or latent infection. C. burnetii IgM antibodies were detected in four participants (7.8%), indicating possible recent infection. These results indicate that a large proportion of patients with haematologic cancer in Romania may be at risk for zoonotic infections or for reactivation of latent zoonotic infections, particularly with respect to Bartonella species. Special attention should be paid to cancer patients' exposure to livestock and companion animals in areas where much of the population lives in rural settings.

Exosomes as divine messengers: are they the Hermes of modern molecular oncology?

Exosomes are cell-derived vesicles that convey key elements with the potential to modulate intercellular communication. They are known to be secreted from all types of cells, and are crucial messengers that can regulate cellular processes by 'trafficking' molecules from cells of one tissue to another. The exosomal content has been shown to be broad, composed of different types of cytokines, growth factors, proteins, or nucleic acids. Besides messenger RNA (mRNA) they can also contain noncoding transcripts such as microRNAs (miRNAs), which are small endogenous cellular regulators of protein expression. In diseases such as cancer, exosomes can facilitate tumor progression by altering their vesicular content and supplying the tumor niche with molecules that favor the progression of oncogenic processes such as proliferation, invasion and metastasis, or even drug resistance. The packaging of their molecular content is known to be tissue specific, a fact that makes them interesting tools in clinical diagnostics and ideal candidates for biomarkers. In the current report, we describe the main properties of exosomes and explain their involvement in processes such as cell differentiation and cell death. Furthermore, we emphasize the need of developing patient-targeted treatments by applying the conceptualization of exosomal-derived miRNA-based therapeutics.

Junk DNA and the long non-coding RNA twist in cancer genetics.

The central dogma of molecular biology states that the flow of genetic information moves from DNA to RNA to protein. However, in the last decade this dogma has been challenged by new findings on non-coding RNAs (ncRNAs) such as microRNAs (miRNAs). More recently, long non-coding RNAs (lncRNAs) have attracted much attention due to their large number and biological significance. Many lncRNAs have been identified as mapping to regulatory elements including gene promoters and enhancers, ultraconserved regions and intergenic regions of protein-coding genes. Yet, the biological function and molecular mechanisms of lncRNA in human diseases in general and cancer in particular remain largely unknown. Data from the literature suggest that lncRNA, often via interaction with proteins, functions in specific genomic loci or use their own transcription loci for regulatory activity. In this review, we summarize recent findings supporting the importance of DNA loci in lncRNA function and the underlying molecular mechanisms via cis or trans regulation, and discuss their implications in cancer. In addition, we use the 8q24 genomic locus, a region containing interactive SNPs, DNA regulatory elements and lncRNAs, as an example to illustrate how single-nucleotide polymorphism (SNP) located within lncRNAs may be functionally associated with the individual's susceptibility to cancer.