Dana Elena Giza

MicroRNAs and ceRNAs: therapeutic implications of RNA networks

Introduction: A new concept of gene regulation, in which competitive endogenous RNAs (ceRNAs) compete for common microRNAs (miRNAs), suggests that mRNA targets have an active role as key elements in the regulation of miRNA availability within cells. ceRNAs are considered to be natural decoys of miRNA activity and can influence the expression of multiple miRNAs. Areas covered: A new complex network of indirect interaction among the RNA transcripts competing for the same pool of miRNAs has been described; in this network, the nodes are the targets, and the links between the nodes are the miRNAs the targets have in common, which form smaller subnetworks. The incidence, state and severity of cancer can be evaluated on the basis of this network signature. The study of these new genome-scale regulatory networks involving miRNAs and ceRNAs may provide information that researchers can use to fine-tune these networks to improve responses to cancer therapy and/or develop new therapeutic interventions. Expert opinion: Combinational approaches based on complex regulatory ceRNA networks (ceRNETs) may be one of the most promising strategies for silencing important mediators of cancer-promoting pathways. Targeting a single miRNA may in fact represent a combined intervention that acts on the feedback and compensatory pathways that can impair treatment response or cause treatment resistance.

Cellular and Kaposi's sarcoma-associated herpes virus microRNAs in sepsis and surgical trauma.

Once a patient is in septic shock, survival rates drop by 7.6% for every hour of delay in antibiotic therapy. Biomarkers based on the molecular mechanism of sepsis are important for timely diagnosis and triage. Here, we study the potential roles of a panel of cellular and viral miRNAs as sepsis biomarkers. We performed genome-wide microRNA (miRNA) expression profiling in leukocytes from septic patients and nonseptic controls, combined with quantitative RT-PCR in plasmas from two cohorts of septic patients, two cohorts of nonseptic surgical patients and healthy volunteers. Enzyme-linked immunosorbent assay, miRNA transfection and chromatin immunoprecipitation were used to study the effects of Kaposi sarcoma herpes virus (KSHV) miRNAs on interleukins secretion. Differences related to sepsis etiology were noted for plasma levels of 10 cellular and 2 KSHV miRNAs (miR-K-10b and miR-K-12-12*) between septic and nonseptic patients. All the sepsis groups had high KSHV miRNAs levels compared with controls; Afro-American patients had higher levels of KSHV-miR-K12-12* than non-Afro-American patients. Both KSHV miRNAs were increased on postoperative day 1, but returned to baseline on day 7; they acted as direct agonists of Toll-like receptor 8 (TLR8), which might explain the increased secretion of the IL-6 and IL-10. Cellular and KSHV miRNAs are differentially expressed in sepsis and early postsurgical patients and may be exploited for diagnostic and therapeutic purposes. Increased miR-K-10b and miR-K12-12* are functionally involved in sepsis as agonists of TLR8, forming a positive feedback that may lead to cytokine dysregulation.

Key principles of miRNA involvement in human diseases

Although rapid progress in our understanding of the functions of miRNA has been made by experimentation and computational approach, a considerable effort still has to be done in determining the general principles that govern the miRNA’s mode of action in human diseases. We will further discuss how these principles are being progressively approached by molecular studies, as well as the importance of miRNA in regulating different target genes and functions in specific biological contexts. There is a great demand to understand the principles of context-specific miRNA target recognition in order to design future experiments and models of normal developmental and disease states.

Morphometrical differences between resectable and non-resectable pancreatic cancer: a fractal analysis.

BACKGROUND/AIMS Pancreatic cancer is a highly aggressive cancer with a rising incidence and poor prognosis despite active surgical treatment. Candidates for surgical resection should be carefully selected. In order to avoid unnecessary laparotomy it is useful to identify reliable factors that may predict resectability. Nuclear morphometry and fractal dimension of pancreatic nuclear features could provide important preoperative information in assessing pancreas resectability. METHODOLOGY Sixty-one patients diagnosed with pancreatic cancer were enrolled in this retrospective study between 2003 and 2005. Patients were divided into two groups: one resectable cancer group and one with non-resectable pancreatic cancer. Morphometric parameters measured were: nuclear area, length of minor axis and length of major axis. Nuclear shape and chromatin distribution of the pancreatic tumor cells were both estimated using fractal dimension. RESULTS Morphometric measurements have shown significant differences between the nuclear area of the resectable group and the non-resectable group (61.9 ± 19.8µm vs. 42.2 ± 15.6µm). Fractal dimension of the nuclear outlines and chromatin distribution was found to have a higher value in the non-resectable group (p<0.05). CONCLUSIONS Objective measurements should be performed to improve risk assessment and therapeutic decisions in pancreatic cancer. Nuclear morphometry of the pancreatic nuclear features can provide important pre-operative information in resectability assessment. The fractal dimension of the nuclear shape and chromatin distribution may be considered a new promising adjunctive tool for conventional pathological analysis.

Cancer as a Risk Factor for Cardiovascular Disease

Improvements in early diagnosis and cancer treatments have contributed to high survival rates for many cancer patients. However, these patients often die of cardiovascular disease rather than recurrence of their cancer. Heart disease manifesting after cancer may be due to several mechanisms: shared cardiovascular risks between cancer and cardiovascular disease, inflammatory states associated with malignancies, and/or cardiotoxic effects of cancer therapy. Cancer treatment increases the risk of cardiovascular diseases directly by damaging critical structures of the heart or indirectly by promoting accelerated atherosclerosis. Estimating cardiovascular risk by using advanced imaging and monitoring of the cardiac biomarkers can be used for early detection and treatment of subclinical cardiac injury. Better knowledge of these early and late cardiac effects in cancer patients will enable adoption of both primary and secondary prevention measures of long-term treatment complications in cancer survivors.

Plasma Viral miRNAs Indicate a High Prevalence of Occult Viral Infections

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Cellular and viral microRNAs in sepsis: Mechanisms of action and clinical applications

Regardless of its etiology, once septic shock is established, survival rates drop by 7.6% for every hour antibiotic therapy is delayed. The early identification of the cause of infection and prognostic stratification of patients with sepsis are therefore important clinical priorities. Biomarkers are potentially valuable clinical tools in this context, but to date, no single biomarker has been shown to perform adequately. Hence, in an effort to discover novel diagnostic and prognostic markers in sepsis, new genomic approaches have been employed. As a result, a number of small regulatory molecules called microRNAs (miRNAs) have been identified as key regulators of the inflammatory response. Although deregulated miRNA expression is increasingly well described, the pathophysiological roles of these molecules in sepsis have yet to be fully defined. Moreover, non-human miRNAs, including two Kaposi Sarcoma herpesvirus-encoded miRNAs, are implicated in sepsis and may drive enhanced secretion of pro-inflammatory and anti-inflammatory cytokines exacerbating sepsis. A better understanding of the mechanism of action of both cellular and viral miRNAs, and their interactions with immune and inflammatory cascades, may therefore identify novel therapeutic targets in sepsis and make biomarker-guided therapy a realistic prospect.

Circulating miRNAs in sepsis—A network under attack: An in-silico prediction of the potential existence of miRNA sponges in sepsis

Biomarkers based on the molecular mechanism of sepsis are important for timely diagnosis and treatment. A large panel of small non-coding microRNAs was reported to modulate the immune response in sepsis but have not been tested in clinical practice. Large-scale identification of microRNA networks in sepsis might reveal a new biological mechanism that can be also targeted by gene therapy. Therefore, the main objective of this study is to perform a comparison of the miRNA network between septic patients and healthy controls. We used the previously measured levels of expression of 16 different circulating human and viral microRNAs in plasma from 99 septic patients and 53 healthy controls. We used three different computational methods to find correlations between the expressions of microRNAs and to build microRNA networks for the two categories, septic patients and healthy controls. We found that the microRNA network of the septic patients is significantly less connected when compared to miRNA network of the healthy controls (21 edges vs 52 edges, P < 0.0001). We hypothesize that several microRNAs (miR-16, miR-29a, miR-146, miR-155, and miR-182) are being sponged in sepsis explaining the loss of connection in the septic patient miRNA network. This was specific for sepsis, as it did not occur in other conditions characterized by an increased inflammatory response such as in post-surgery patients. Using several target prediction instruments, we predicted potential common sponges for the miRNA network in sepsis from several signaling pathways. Understanding the dynamics of miRNA network in sepsis is useful to explain the molecular pathophysiology of sepsis and for designing therapeutic strategies that target essential components of the immune response pathways.

microRNA and Chronic Lymphocytic Leukemia

Expression profiling of microRNAs identified important differences in microRNA expression between CLL samples and normal CD5+ B-cells. Researchers have first discussed the dual role of miRNAs working as tumor suppressors (inhibiting malignant potential) or as oncogenes (activating malignant potential) in CLL pathogenesis. Understanding the roles of miRNAs in leukemic cells brings information on a new layer of gene regulation and also provides new markers for improved diagnosis and prognosis, as well as novel therapeutic options for CLL patients. Herein we will focus on the roles of miRNAs in CLL, highlighting what is already known about their function, proposing a novel model of CLL predisposition and progression, and describing the challenges for the near future.

Ischemic Heart Disease: Special Considerations in Cardio-Oncology

Opinion statementThe interplay and balance between the competing morbidity and mortality of cardiovascular diseases and cancer have a significant impact on both short- and long-term health outcomes of patients who survived cancer or are being treated for cancer. Ischemic heart disease in patients with cancer or caused by cancer therapy is a clinical problem of emerging importance. Prompt recognition and optimum management of ischemic heart disease mean that patients with cancer can successfully receive therapies to treat their malignancy and reduce morbidity and mortality due to cardiovascular disease. In this sense, the presence of cancer and cancer-related comorbidities (e.g., thrombocytopenia, propensity to bleed, thrombotic status) substantially complicates the management of cardiovascular diseases in cancer patients. In this review, we will summarize the current state of knowledge on the management strategies for ischemic disease in patients with cancer, focusing on the challenges encountered when addressing these complexities.