Biomarkers in solid organ transplantation: establishing personalized transplantation medicine.

Technological advances in molecular and in silico research have enabled significant progress towards personalized transplantation medicine. It is now possible to conduct comprehensive biomarker development studies of transplant organ pathologies, correlating genomic, transcriptomic and proteomic information from donor and recipient with clinical and histological phenotypes. Translation of these advances to the clinical setting will allow assessment of an individual patient's risk of allograft damage or accommodation. Transplantation biomarkers are needed for active monitoring of immunosuppression, to reduce patient morbidity, and to improve long-term allograft function and life expectancy. Here, we highlight recent pre- and post-transplantation biomarkers of acute and chronic allograft damage or adaptation, focusing on peripheral blood-based methodologies for non-invasive application. We then critically discuss current findings with respect to their future application in routine clinical transplantation medicine. Complement-system-associated SNPs present potential biomarkers that may be used to indicate the baseline risk for allograft damage prior to transplantation. The detection of antibodies against novel, non-HLA, MICA antigens, and the expression of cytokine genes and proteins and cytotoxicity-related genes have been correlated with allograft damage and are potential post-transplantation biomarkers indicating allograft damage at the molecular level, although these do not have clinical relevance yet. Several multi-gene expression-based biomarker panels have been identified that accurately predicted graft accommodation in liver transplant recipients and may be developed into a predictive biomarker assay

Rank discriminants for predicting phenotypes from RNA expression

Statistical methods for analyzing large-scale biomolecular data are commonplace in computational biology. A notable example is phenotype prediction from gene expression data, for instance, detecting human cancers, differentiating subtypes and predicting clinical outcomes. Still, clinical applications remain scarce. One reason is that the complexity of the decision rules that emerge from standard statistical learning impedes biological understanding, in particular, any mechanistic interpretation. Here we explore decision rules for binary classification utilizing only the ordering of expression among several genes; the basic building blocks are then two-gene expression comparisons. The simplest example, just one comparison, is the TSP classifier, which has appeared in a variety of cancer-related discovery studies. Decision rules based on multiple comparisons can better accommodate class heterogeneity, and thereby increase accuracy, and might provide a link with biological mechanism. We consider a general framework ("rank-in-context") for designing discriminant functions, including a data-driven selection of the number and identity of the genes in the support ("context"). We then specialize to two examples: voting among several pairs and comparing the median expression in two groups of genes. Comprehensive experiments assess accuracy relative to other, more complex, methods, and reinforce earlier observations that simple classifiers are competitive.Comment: Published in at http://dx.doi.org/10.1214/14-AOAS738 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Mirna signature to identify lung asbestos-related malignancies

L'associazione tra esposizione all'amianto e neoplasie polmonari è ben consolidata. Tuttavia, precisi dati istopatologici sono scarsamente considerati quando si studia il legame tra cancro e amianto in un approccio compensatorio. L'espressione dei miRNA è precocemente alterata dall'esposizione ad agenti cancerogeni professionali /ambientali, quindi utile per identificare un nuovo profilo correlato all'amianto in grado di distinguere una neoplasia indotta da asbesto rispetto a quella con diversa eziologia. Abbiamo condotto uno studio multifasico per identificare i miRNA associati alle neoplasie indotte dall'amianto. Sono stati inclusi quattro gruppi: pazienti con carcinoma polmonare non a piccole cellule asbesto-correlato e non (NSCLC-Asb e NSCLC), mesotelioma maligno (MM) e soggetti di controllo (CTRL). Successivamente, i miRNA selezionati sono stati valutati in una popolazione esposta all'amianto ed è stato realizzato un modello "in vitro" per identificare il meccanismo di regolazione dei miRNA indotto da asbesto. Quattro miRNA sierici costituiti dal miR-126, miR-205, miR-222 e miR-520g sono risultati coinvolti nelle neoplasie asbesto-correlate. In particolare, l'aumento dell'espressione del miR-126 e del miR-222 è stato trovato in soggetti attualmente esposti all’asbesto ed entrambi i miRNA sono coinvolti nelle principali pathway collegate allo sviluppo tumorale. Un'aumentata espressione dell’EGFR è stata trovata nelle cellule pre-cancerose indotte da asbesto, causando l'attivazione di effettori a valle (AKT e MAPK p38). L'attivazione asbesto-mediata della via EGFR-AKT ha portato alla sovra-espressione del miR-222 e alla sotto-espressione del miR-520g, che sono stati invertiti inibendo l'EGFR, suggerendo il suo coinvolgimento nella regolazione dei miRNA indotta da asbesto. Questo studio evidenzia miRNA che sono potenzialmente coinvolti in neoplasie legate all'amianto e i meccanismi di espressione in cui possono essere coinvolti nella patogenesi indotta da asbesto.The association between asbestos exposure and lung malignancies is well established. Nevertheless, precise histopathological data are poorly considered when investigating the asbestos-cancer link in compensatory approach. MiRNA expression is early altered by exposure to occupational/environmental carcinogens, thus, useful to identify a novel asbestos-related profile able to distinguish asbestos-induced cancer from cancer with different etiology. We performed consequential study phases to identify miRNAs associated with the asbestos-induced malignancies. Four groups have been included: patients with asbestos-related and non-asbestos-related non-small cell lung cancer (NSCLC-Asb and NSCLC), malignant mesothelioma (MM), and disease-free subjects (CTRL). Next, the selected miRNAs were evaluated in an asbestos-exposed population and an ‘in vitro’ model was performed to identify the mechanism of asbestos-induced miRNA regulation. Four serum miRNAs consisting of miR-126, miR-205, miR-222 and miR-520g were found to be involved in asbestos-related malignant diseases. Notably, increased expression of miR-126 and miR-222 were found in currently exposed subjects, and both miRNAs were involved in major pathways linked to cancer development. Increased expression of EGFR was found in the asbestos-induced pre-cancerous cells, causing activation of the down-stream effector AKT and p38 MAPK signalling. Asbestos-mediated activation of EGFR-AKT pathway resulted in miR-222 upregulation and miR-520g downregulation, which were reversed by inhibiting EGFR, suggesting its involvement in asbestos-induced miRNA regulation. This study uncovers miRNAs that are potentially involved in asbestos-related malignancies and their expression outline mechanisms whereby miRNAs may be involved in asbestos-induced pathogenesis

MicroRNAs as noninvasive biomarkers for the diagnosis and prognosis of liver fibrosis in HCV genotype 4 patients

Hepatitis C virus (HCV) is a major world health problem affecting millions of people worldwide. HCV causes fibrosis of the liver; untreated, it leads to complications such as hepatic cirrhosis, decompensation, and hepatocellular carcinoma (HCC). Current methodologies used to determine the progression of hepatic fibrosis rely heavily on liver biopsy, a dangerous and invasive procedure, with subjective analysis of the results of the biopsy. Liver biopsies are also difficult to perform in the developing world, where the strain of HCV infection is great. A new methodology, that is both convenient and inexpensive, is needed for monitoring the progression of liver fibrosis in HCV patients. Small noncoding RNAs known as microRNAs are up-regulated or down-regulated when damage occurs in the liver. miRNAs are stable and present in almost all body fluids, therefore the measurement of circulating miRNAs in serum of liver fibrosis as a noninvasive method to evaluate disease severity and progression is promising. Currently, miRNAs have been found to play essential roles in hepatic stellate cell (HSC) differentiation, proliferation, apoptosis and migration linking them to aberrant expression variations in the development of liver fibrosis. Several microRNAs have shown promise as noninvasive biomarkers of hepatic fibrosis, and some even in the treatment of HCV. To study regulation of genes at the miRNA level is a huge advantage as gene expression is regulated at an epigenetic level before even the formation of proteins. Hepatitis C-genotype 4 infected patients were selected to detect and study the progression of liver fibrosis. The study consisted of three patient groups: 42 cases of chronic hepatitis C (CHC) with early stage fibrosis, 45 cases of CHC with late stage fibrosis, and 40 healthy patients with no CHC or fibrosis as controls. Blood samples were taken from each patient and RNA was extracted using the miRNeasy extraction kit. Expression patterns of 5 miRNAs (miR-16, miR-146a, miR-214-5p, miR-221, miR-222) were measured in each group using TaqMan real-time reverse transcription-polymerase chain reaction. MiRNA analysis was performed to determine the most specific and sensitive miRNA to be used as a diagnostic biomarker. Serum levels of miRNA-16, miRNA-146a, miRNA-221, and miRNA-222 were all significantly upregulated in early and late stage fibrosis compared to the control (p\u3c0.001). MiRNA-222 had the highest sensitivity and specificity values in both early and late stage fibrosis with values of (69.23 %, 83.83%) and (100%, 96.77%) respectively. MiRNA-221 had the second highest sensitivity and specificity values with the late stage fibrosis group having values of 100% and 88.24% respectively. MiRNA-222 and miRNA-221 suggest promising potential as biomarkers for HCV-induced liver fibrosis as they had the highest sensitivity and specificity values. MiRNA-221 showed significant positive correlations with both miRNA-16 and miRNA-146a in the early and late stage fibrosis groups, with the early stage having a stronger correlation (at the 0.01 level). These correlations have great substantial values for future uses in formulating liver fibrosis diagnostic assays. â€

Epigenomic Regulation of Androgen Receptor Signaling: Potential Role in Prostate Cancer Therapy.

Androgen receptor (AR) signaling remains the major oncogenic pathway in prostate cancer (PCa). Androgen-deprivation therapy (ADT) is the principle treatment for locally advanced and metastatic disease. However, a significant number of patients acquire treatment resistance leading to castration resistant prostate cancer (CRPC). Epigenetics, the study of heritable and reversible changes in gene expression without alterations in DNA sequences, is a crucial regulatory step in AR signaling. We and others, recently described the technological advance Chem-seq, a method to identify the interaction between a drug and the genome. This has permitted better understanding of the underlying regulatory mechanisms of AR during carcinogenesis and revealed the importance of epigenetic modifiers. In screening for new epigenomic modifiying drugs, we identified SD-70, and found that this demethylase inhibitor is effective in CRPC cells in combination with current therapies. The aim of this review is to explore the role of epigenetic modifications as biomarkers for detection, prognosis, and risk evaluation of PCa. Furthermore, we also provide an update of the recent findings on the epigenetic key processes (DNA methylation, chromatin modifications and alterations in noncoding RNA profiles) involved in AR expression and their possible role as therapeutic targets

Predictive Biomarkers to Chemoradiation in Locally Advanced Rectal Cancer

There has been a high local recurrence rate in rectal cancer. Besides improvements in surgical techniques, both neoadjuvant short-course radiotherapy and long-course chemoradiation improve oncological results. Approximately 40–60% of rectal cancer patients treated with neoadjuvant chemoradiation achieve some degree of pathologic response. However, there is no effective method of predicting which patients will respond to neoadjuvant treatment. Recent studies have evaluated the potential of genetic biomarkers to predict outcome in locally advanced rectal adenocarcinoma treated with neoadjuvant chemoradiation. The articles produced by the PubMed search were reviewed for those specifically addressing a genetic profile’s ability to predict response to neoadjuvant treatment in rectal cancer. Although tissue gene microarray profiling has led to promising data in cancer, to date, none of the identified signatures or molecular markers in locally advanced rectal cancer has been successfully validated as a diagnostic or prognostic tool applicable to routine clinical practice

MicroRNAs as Biomarkers for Predicting Complications Following Aneurysmal Subarachnoid Hemorrhage

Aneurysmal subarachnoid hemorrhage (aSAH) is a high mortality hemorrhagic stroke that affects nearly 30,000 patients annually in the United States. Approximately 30% of aSAH patients die during initial hospitalization and those who survive often carry poor prognosis with one in five having permanent physical and/or cognitive disabilities. The poor outcome of aSAH can be the result of the initial catastrophic event or due to the many acute or delayed neurological complications, such as cerebral ischemia, hydrocephalus, and re-bleeding. Unfortunately, no effective biomarker exists to predict or diagnose these complications at a clinically relevant time point when neurologic injury can be effectively treated and managed. Recently, a number of studies have demonstrated that microRNAs (miRNAs) in extracellular biofluids are highly associated with aSAH and complications. Here we provide an overview of the current research on relevant human studies examining the correlation between miRNAs and aSAH complications and discuss the potential application of using miRNAs as biomarkers in aSAH management