Theragnostic Biomarkers Research Articles

In Severe Alcoholic Hepatitis, Serum Keratin-18 Fragments Are Diagnostic, Prognostic, and Theragnostic Biomarkers.

Up to 40% of patients with severe alcoholic hepatitis (AH) die within 6 months of presentation, making prompt diagnosis and appropriate treatment essential. We determined the associations between serum keratin-18 (K18) and histological features, prognosis, and differential response to prednisolone in patients with severe AH. Total (K18-M65) and caspase-cleaved K18 (K18-M30) were quantified in pretreatment sera from 824 patients enrolled in the Steroids or Pentoxifylline for Alcoholic Hepatitis trial (87 with suitable histological samples) and disease controls. K18 fragments were markedly elevated in severe AH and strongly predicted steatohepatitis (alcoholic steatohepatitis) on biopsy (area under receiver operating characteristics: 0.787 and 0.807). Application of published thresholds to predict alcoholic steatohepatitis would have rendered biopsy unnecessary in 84% of all AH cases. K18-M30 and M65 were associated with 90-day mortality, independent of age and Model for End-stage Liver Disease score in untreated patients. The association for K18-M65 was independent of both age and Model for End-stage Liver Disease in prednisolone-treated patients. Modelling of the effect of prednisolone on 90-day mortality as a function of pretreatment serum K18 levels indicated benefit in those with high serum levels of K18-M30. At low pretreatment serum K18 levels, prednisolone was potentially harmful. A threshold of K18-M30 5 kIU/L predicted therapeutic benefit from prednisolone above this level (odds ratio: 0.433, 95% confidence interval: 0.19-0.95, P = 0.0398), but not below (odds ratio: 1.271, 95% confidence interval: 0.88-1.84, P = 0.199). Restricting prednisolone usage to the former group would have reduced exposure by 87%. In a large cohort of patients with severe AH, serum K18 strongly correlated with histological severity, independently associated with 90-day mortality, and predicted response to prednisolone therapy. Quantification of serum K18 levels could assist in clinical decision-making.

The stability of blood eosinophils in stable chronic obstructive pulmonary disease: a retrospective study in Belgian primary care

BackgroundBlood eosinophil counts (BEC) were recently included in the 2019 Global Initiative for Obstructive Lung Disease (GOLD) guideline as an easily accessible theragnostic biomarker for Chronic Obstructive Pulmonary Disease (COPD). However, the stability of BEC remains insufficiently studied.MethodsWe conducted a retrospective study in six primary care practices in Belgium on data from Electronic Health Records of stable COPD patients, to characterise the stability of blood eosinophils over time. We report the percentage of patients with BEC persistently below or above the 2019 GOLD guideline thresholds (100 and 300 cells/μL). For each patient the mean, standard deviation (SD) and relative standard deviation (RSD) of the BEC were calculated to determine the intra-patient variability.ResultsNinety-eight patients were included, yielding 1082 eosinophil measurements (median 8 measurements/patient), with BEC ranging between 0 and 1504 cells/μL. Four (4.1%) patients had BEC persistently below 100 cells/μL, 34 (34.7%) had measurements persistently above this threshold. Approximately half of the patients (51.0%) had BEC persistently below 300 cells/μL and 3 (3.1%) patients had counts persistently above this threshold. 28.6% of patients crossed both threshold values throughout the registration period. The mean BEC per patient ranged between 15 and 846 cells/μL with an intra-patient SD between 5 and 658 cells/μL. The mean intra-patient RSD was 0.46. There was a significant strong positive correlation (Pearson analyses) between the mean BEC and SD (r = 0.765; n = 98). Simple linear regression was used to further describe the influence of the mean eosinophil count on the SD (B = 0.500; 95%CI 0.415–0.586; n = 98; p < 0.001).ConclusionBEC can be variable in individual COPD patients. Therefore, the use of a single measurement to guide therapeutic decisions remains debatable. Further prospective research remains necessary to validate the reproducibility of this biomarker.

Rationale and design of the Medical Research Council's Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial

BackgroundMicrovascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ETA receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina.MethodsWe will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan.The PRIZE trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo.ConclusionPRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial.

Clinical Theragnostic Potential of Diverse miRNA Expressions in Prostate Cancer: A Systematic Review and Meta-Analysis.

Background: Prostate cancer (PrC) is the second-most frequent cancer in men, its incidence is emerging globally and is the fifth leading cause of death worldwide. While diagnosis and prognosis of PrC have been studied well, the associated therapeutic biomarkers have not yet been investigated comprehensively. This systematic review and meta-analysis aim to evaluate the theragnostic effects of microRNA expressions on chemoresistance in prostate cancer and to analyse the utility of miRNAs as clinical theragnostic biomarkers. Methods: A systematic literature search for studies reporting miRNA expressions and their role in chemoresistance in PrC published until 2018 was collected from bibliographic databases. The evaluation of data was performed as per PRISMA guidelines for systematic review and meta-analysis. Meta-analysis was performed using a random-effects model using Comprehensive Meta-Analysis (CMA) software. Heterogeneity between studies was analysed using Cochran’s Q test, I2 and the Tau statistic. Quality assessment of the studies was performed using the Newcastle–Ottawa Scale (NOS) for the methodological assessment of cohort studies. Publication bias was assessed using Egger’s bias indicator test, Orwin and classic fail-safe N test, Begg and Mazumdar rank collection test, and Duval and Tweedie’s trim and fill methods. Findings: Out of 2909 studies retrieved, 79 studies were shortlisted and reviewed. A total of 17 studies met our eligibility criteria, from which 779 PrC patients and 17 chemotherapy drugs were examined, including docetaxel and paclitaxel. The majority of the drug regulatory genes reported were involved in cell survival, angiogenesis and cell proliferation pathways. We studied 42 miRNAs across all studies, out of which two miRNAs were found to be influencing chemosensitivity, while 21 were involved in chemoresistance. However, the remaining 19 miRNAs did not appear to have any theragnostic effects. Besides, the prognostic impact of the miRNAs was evaluated and had a pooled HR value of 1.960 with 95% CI (1.377–2.791). Interpretation: The observation of the current study depicts the significance of miRNA expression as a theragnostic biomarker in medical oncology. This review suggests the involvement of specific miRNAs as predictors of chemoresistance and sensitivity in PrC. Hence, the current systematic review and meta-analysis provide insight on the use of miRNA as PrC biomarkers, which can be harnessed as molecular candidates for therapeutic targeting.

Myeloid-related proteins 8/14 failed to act as theragnostic biomarker in axial spondyloarthritis patients on combination disease-modifying anti-rheumatic drugs therapy

Background: Reports signifying the utility of myeloid-related proteins (MRP) 8/14 in axial spondyloarthritis (AxSpA) as a theragnostic biomarker are scarce. Objectives: Evaluating the utility of serum MRP 8/14 (baseline levels and change from baseline to 3 months) in AxSpA as a predictor of Assessment of SpondyloArthritis International Society (ASAS) 20 response at 6 months post combination disease-modifying anti-rheumatic drugs (DMARD) therapy. Methods: Serum MRP 8/14 was assayed using enzyme-linked immunosorbent assay platforms (RD treated with a combination of methotrexate, sulfasalazine at optimum tolerated doses with on-demand nonsteroidal anti-inflammatory agents and 30 healthy age-matched controls. Repeat measurement was done at 3 months in 60 patients. Results: Median MRP 8/14 levels in AxSpA patients was 3.00 (3.96) μg/ml compared to 2.3 (3.29) μg/ml in controls (P = 0.2). Median baseline MRP 8/14 levels in ASAS 20 responders at 6 months (n = 36) was 3.6 (4.1) μg/ml compared to 2.4 (4.8) μg/ml in nonresponders (n = 35) (P = 0.4). Median △ (baseline to 3 months) MRP 8/14 levels in ASAS 20 responders at 6 months (n = 33) was – 1 (−2.7) μg/ml compared to − 0.2 (−3.8) μg/ml for nonresponders (n = 27) (P = 0.5). Among the 83 patients with 138 disease activity assessments at baseline and 3 months post therapy, median MRP 8/14 in active disease (bath ankylosing spondylitis disease activity index [BASDAI] ≥4) (n = 112) was 2.2 (3.8) μg/ml, compared to 2 (2.3) μg/ml (P = 0.5) in inactive disease (BASDAI Conclusion: Serum MRP 8/14 did not serve as a theragnostic biomarker in our cohort of AxSpA patients treated with combination DMARDs and on-demand NSAIDs.

Clinical Theragnostic Relationship between Drug-Resistance Specific miRNA Expressions, Chemotherapeutic Resistance, and Sensitivity in Breast Cancer: A Systematic Review and Meta-Analysis.

Awareness of breast cancer has been increasing due to early detection, but the advanced disease has limited treatment options. There has been growing evidence on the role of miRNAs involved in regulating the resistance in several cancers. We performed a comprehensive systematic review and meta-analysis on the role of miRNAs in influencing the chemoresistance and sensitivity of breast cancer. A bibliographic search was performed in PubMed and Science Direct based on the search strategy, and studies published until December 2018 were retrieved. The eligible studies were included based on the selection criteria, and a detailed systematic review and meta-analysis were performed based on PRISMA guidelines. A random-effects model was utilised to evaluate the combined effect size of the obtained hazard ratio and 95% confidence intervals from the eligible studies. Publication bias was assessed with Cochran’s Q test, I2 statistic, Orwin and Classic fail-safe N test, Begg and Mazumdar rank correlation test, Duval and Tweedie trim and fill calculation and the Egger’s bias indicator. A total of 4584 potential studies were screened. Of these, 85 articles were eligible for our systematic review and meta-analysis. In the 85 studies, 188 different miRNAs were studied, of which 96 were upregulated, 87 were downregulated and 5 were not involved in regulation. Overall, 24 drugs were used for treatment, with doxorubicin being prominently reported in 15 studies followed by Paclitaxel in 11 studies, and 5 drugs were used in combinations. We found only two significant HR values from the studies (miR-125b and miR-4443) and our meta-analysis results yielded a combined HR value of 0.748 with a 95% confidence interval of 0.508–1.100; p-value of 0.140. In conclusion, our results suggest there are different miRNAs involved in the regulation of chemoresistance through diverse drug genetic targets. These biomarkers play a crucial role in guiding the effective diagnostic and prognostic efficiency of breast cancer. The screening of miRNAs as a theragnostic biomarker must be brought into regular practice for all diseases. We anticipate that our study serves as a reference in framing future studies and clinical trials for utilising miRNAs and their respective drug targets.

Gut Microbiota as a Therapeutic Target to Ameliorate the Biochemical, Neuroanatomical, and Behavioral Effects of Traumatic Brain Injuries.

Current efficacious treatments for traumatic brain injury (TBI) are lacking. Establishment of a protective gut microbiota population offers a compelling therapeutic avenue, as brain injury induces disruptions in the composition of the gut microbiota, i.e., gut dysbiosis, which has been shown to contribute to TBI-related neuropathology and impaired behavioral outcomes. The gut microbiome is involved in the modulation of a multitude of cellular and molecular processes fundamental to the progression of TBI-induced pathologies including neuroinflammation, blood brain barrier permeability, immune system response, microglial activation, and mitochondrial dysfunction, as well as intestinal motility and permeability. Additionally, gut dysbiosis further aggravates behavioral impairments in animal models of TBI and spinal cord injury, as well as negatively affects health outcomes in murine stroke models. Recent studies indicate that microbiota transplants and probiotics ameliorate neuroanatomical damage and functional impairments in animal models of stroke and spinal cord injury. In addition, probiotics have been shown to reduce the rate of infection and time spent in intensive care of hospitalized patients suffering from brain trauma. Perturbations in the composition of the gut microbiota and its metabolite profile may also serve as potential diagnostic and theragnostic biomarkers for injury severity and progression. This review aims to address the etiological role of the gut microbiome in the biochemical, neuroanatomical, and behavioral/cognitive consequences of TBI, as well as explore the potential of gut microbiome manipulation in the form of probiotics as an effective therapeutic to ameliorate TBI-induced pathology and symptoms.

Search for Theragnostic Biomarkers in Colorectal Liver Metastases: Focus on the Host Immune Cells

Search for Theragnostic Biomarkers in Colorectal Liver Metastases: Focus on the Host Immune Cells

Neutrophil gelatinase associated lipocalin (NGAL) as a theragnostic biomarker for perihilar cholangiocarcinoma

Neutrophil gelatinase associated lipocalin (NGAL) as a theragnostic biomarker for perihilar cholangiocarcinoma

What the alcohol doctor ordered from the neuroscientist: Theragnostic biomarkers for personalized treatments.

Major advances in the neuroscientific understanding of alcohol actions have so far not translated into measurably improved clinical outcomes in alcoholism. Future treatment development should be guided by accumulating insights into a diverse range of biological mechanisms that maintain the pathophysiology of alcoholism in different individuals, but also at different points in time within any given patient. This biological diversity calls for the development and use of biological markers predictive of treatment response in the individual case, at the specific stage of the disease, here called "theragnostics." As novel therapeutic mechanisms and molecules targeting these mechanisms are discovered, the use of theragnostics will be critical for their successful clinical development, as well as their optimal subsequent clinical use. During clinical development, lest theragnostics are utilized, efficacy signals will risk remaining undetected when diluted in study populations that are not appropriately selected. Similarly, for treatments that reach approval, clinical acceptance, and optimal use will require the proper identification of responsive patients. Here, we discuss desirable properties of theragnostic biomarkers in alcohol addiction using two examples: alcohol-induced activation of brain reward circuitry as assessed using positron emission tomography of functional magnetic resonance imaging; and central glutamate tone, as assessed using MR spectroscopy.

Metabolomics and its integration with systems biology: PSI 2014 conference panel discussion report

Metabolomics, being a relatively new field, is facing multiple challenges related to data acquisition and interpretation, reproducibility across analytical platforms, integration with other omics approaches and translation into theragnostic biomarkers. There is an immediate need to overcome these challenges in order to make metabolomics more useful and reliable in terms of improving our current understanding of disease biology and help in developing predictive biomarkers. Researchers interested in metabolomics gathered for a panel discussion on ‘Metabolomics and its integration with systems biology’ during the 6th Annual Meeting of Proteomics Society-India and International Conference on “Proteomics from Discovery to Function” held at the Indian Institute of Technology, Bombay from December 7–9, 2014. The panel discussed various challenges related to metabolomics and also proposed several effective solutions for optimum implementation of metabolomics in clinical practice. The key areas of panel discussion were improvement in metabolite databases with comprehensive spectral libraries, need for extensive bioinformatics tools for integrative approaches and serious considerations for clinical validation of the biomarkers for the successful implementation of metabolomics in clinics. Biological significanceInformation drafted in this report is significant for researchers working in metabolomics field to overcome the challenges and successful implementation of metabolomics in clinical practice.This article is part of a special issue titled: Proteomics in India.

Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study

Idiopathic pulmonary fibrosis, a progressive and inevitably fatal disorder, has a highly variable clinical course. Biomarkers that reflect disease activity are urgently needed to inform patient management and for use as biomarkers of therapeutic response (theragnostic biomarkers) in clinical trials. We aimed to determine whether dynamic change in markers of extracellular matrix (ECM) turnover predicts progression of idiopathic pulmonary fibrosis as determined by change in forced vital capacity and death. In this ongoing prospective, multicentre, observational cohort study (PROFILE), participants with idiopathic pulmonary fibrosis or idiopathic non-specific interstitial pneumonia diagnosed within the preceding 6 months were recruited from two coordinating centres (Nottingham, UK, and, Royal Brompton Hospital, London, UK). Serum samples were prospectively collected at baseline, 1 month, 3 months, and 6 months and were analysed for a panel of novel matrix metalloprotease (MMP)-degraded ECM proteins, by ELISA-based, neoepitope assay. 11 neoepitopes were tested in a discovery cohort of 55 patients to identify biomarkers of sufficient rigour for more detailed analyses. Eight were then further assessed in a validation cohort of 134 patients with 50 age-matched and sex-matched controls. Changes in biomarker concentrations were related to subsequent progression of idiopathic pulmonary fibrosis (defined as death or decline in forced vital capacity >10% at 12 months after study enrolment) using a repeated measures model. The PROFILE study is registered on ClinicalTrials.gov, numbers NCT01134822 and NCT01110694. Of 214 eligible participants recruited between Sept 1, 2010, and March 31, 2012, 189 had a confirmed diagnosis of idiopathic pulmonary fibrosis and were included in subsequent analyses. In the discovery cohort, mean concentrations of seven neoepitopes (BGM, p=0·009; C1M, p=0·009; C3M, p=0·046; C6M, p=0·032; CRPM, p=0·008; ELM2, p=0·02; and VICM, p=0·0007) differed significantly between healthy controls and participants with idiopathic pulmonary fibrosis. Baseline concentrations of six neoepitopes (C1M, p=0·012; C3A, p=0·012; C3M, p=0·0005; C6M, p=0·0003; CRPM, p=0·021; and VICM, p=0·046) were significantly higher in patients with progressive idiopathic pulmonary fibrosis (n=32) than in those with stable disease (n=23). In the validation cohort, mean concentrations of C1M (p=0·001), C3M (p=0·044), C6M (p=0·003), and CRPM (p=0·024) at baseline were higher in patients with idiopathic pulmonary fibrosis than in healthy controls. When assessed longitudinally, concentrations of six neoepitopes (BGM, C1M, C3A, C3M, C6M, and CRPM) were significantly higher in patients with progressive idiopathic pulmonary fibrosis (n=71) than in patients with stable idiopathic pulmonary fibrosis (n=60) by 6 months. Baseline concentrations of two neoepitopes were associated with increased mortality (C1M: HR 1·62 [95% CI 1·14-2·31], p=0·0069; C3A: 1·91 [1·06-3·46], p=0·032). The rate of change between baseline and 3 months of six neoepitopes (BGM: HR 1·084 [95% CI 1·03-1·14], p=0·0019; C1M: 1·01 [1·003-1·017], p=0·0039; C3M: 1·106 [1·045-1·170], p=0·0005; C5M: 1·003 [1·001-1·005], p=0·0011; C6M: 1·042 [1·007-1·078], p=0·017; and CRPM: 1·38 [1·16-1·63], p=0·0002) was strongly predictive of overall survival, and the increased risk was proportional to the magnitude of change in neoepitope concentrations. The strongest association with 3-month rate of biomarker change was recorded for CRPM; greater than 0 ng/mL per month conferred a HR of 2·16 (95% CI 1·15-4·07), whereas a rate greater than 1 ng/mL per month resulted in an HR 4·08 (2·14-7·8), and a rate greater than 1·7 ng/mL per month was associated with an HR 6·61 (2·74-15·94). Concentrations of protein fragments generated by MMP activity are increased in the serum of individuals with idiopathic pulmonary fibrosis compared with healthy controls. Increased neoepitope concentrations were associated with disease progression, and the rate of this increase predicted survival. Serial measurements of neoepitopes have potential to be used as theragnostic biomarkers in clinical trials and to guide management of idiopathic pulmonary fibrosis. GlaxoSmithKline R&D and the Medical Research Council.

Soluble HER2 (sHER2) as a prognostic serum biomarker of non-small cell lung cancer.

e21000 Background: The human epidermal growth factor receptor (EGFR/HER) gene family encodes four homologous tyrosine kinases that regulate cell growth and proliferation, survival, motility, and adhesion. HER2 gene amplification and receptor overexpression have been observed in &lt; 20% of non-small cell lung cancers (NSCLC). Serum concentrations of soluble HER2 (sHER2), a proteolytic fragment of the receptor’s extracellular domain, have been associated with tumor HER2 overexpression, advanced stage, and high grade. This study evaluated serum sHER2 as a prognostic biomarker of NSCLC. Methods: Patients with primary NSCLC (n=149) were recruited at the University of Kentucky prospectively between 2002 and 2008 by the Markey Cancer Center Biospecimen Core Program and linked to the Kentucky Cancer Registry - a population-based cancer registry of the NCI Surveillance, Epidemiology and End Results (SEER) Program - to obtain clinicopathological data. Serum samples were collected prior to surgery and quantified to determine sHER2 concentrations by sp185HER-2 ELISA (Bender MedSystems Diagnostics GmbH). Non-parametric tests were performed to assess whether sHER2 concentrations differed between NSCLC patients stratified by gender, stage, histology, and grade. Cox regression analyses were performed to assess whether sHER2 concentrations, age, gender, stage, histology, and grade are associated with progression free and overall survival. Results: Mean patient age in this case series is 62 years (SD = 10.84 years) and median overall survival is 30 months. Over 97% of patients are smokers. Although serum concentrations do not differ between males and females (p = 0.12), high sHER2 concentrations portend a 72% lower relative risk of death (H.R. = 0.283, p = 0.009) and longer overall survival among men, but not among women (H.R. = 1.012, p = 0.965) adjusted for stage. Conclusions: The results show that low serum sHER2 concentration is an adverse prognosticator of overall survival in males, but not females, and suggest that low serum sHER2 could be useful for stratifying male NSCLC patients for HER2-targeted therapy. Further investigation is warranted to assess sHER2 as a gender dependent prognostic (and potential theragnostic) biomarker of NSCLC.

Identification of Immunoreactive Regions of Homology between Soluble Epidermal Growth Factor Receptor and α5-Integrin

Proteins encoded by the epidermal growth factor receptor (EGFR/HER1/ERBB1) gene are being studied as diagnostic, prognostic, and theragnostic biomarkers for numerous human cancers. The clinical application of these tissue/tumor biomarkers has been limited, in part, by discordant results observed for epidermal growth factor receptor (EGFR) expression using different immunological reagents. Previous studies have used EGFR-directed antibodies that cannot distinguish between full-length and soluble EGFR (sEGFR) expression. We have generated and characterized an anti-sEGFR polyclonal antiserum directed against a 31-mer peptide (residues 604-634) located within the unique 78-amino acid carboxy-terminal sequence of sEGFR. Here, we use this antibody to demonstrate that sEGFR is coexpressed with EGFR in a number of carcinoma-derived cell lines. In addition, we show that a second protein of ~140 kDa (p140) also is detected by this antibody. Rigorous biochemical characterization identifies this second protein to be α5-integrin. We show that a 26-amino acid peptide in the calf domain of α5-integrin (residues 710-735) is 35% identical in sequence with a 31-mer carboxy-terminal sEGFR peptide and exhibits an approximately 5-fold lower affinity for anti-sEGFR than the homologous 31-mer sEGFR peptide does. We conclude that the carboxy terminus of sEGFR and the calf-1 domain of α5-integrin share a region of sequence identity, which results in their mutual immunological reactivity with anti-sEGFR. We also demonstrate that anti-sEGFR promotes three-dimensional tissue cohesion and compaction in vitro, further suggesting a functional link between sEGFR and α5-integrin and a role of the calf-1 domain in cell adhesion. These results have implications for the study of both EGFR and sEGFR as cancer biomarkers and also provide new insight into the mechanisms of interaction between cell surface EGFR isoforms and integrins in complex processes such as cell adhesion and survival signaling.

Nuclear Receptor Expression Defines a Set of Prognostic Biomarkers for Lung Cancer

The identification of prognostic tumor biomarkers that also would have potential as therapeutic targets, particularly in patients with early stage disease, has been a long sought-after goal in the management and treatment of lung cancer. The nuclear receptor (NR) superfamily, which is composed of 48 transcription factors that govern complex physiologic and pathophysiologic processes, could represent a unique subset of these biomarkers. In fact, many members of this family are the targets of already identified selective receptor modulators, providing a direct link between individual tumor NR quantitation and selection of therapy. The goal of this study, which begins this overall strategy, was to investigate the association between mRNA expression of the NR superfamily and the clinical outcome for patients with lung cancer, and to test whether a tumor NR gene signature provided useful information (over available clinical data) for patients with lung cancer. Using quantitative real-time PCR to study NR expression in 30 microdissected non-small-cell lung cancers (NSCLCs) and their pair-matched normal lung epithelium, we found great variability in NR expression among patients' tumor and non-involved lung epithelium, found a strong association between NR expression and clinical outcome, and identified an NR gene signature from both normal and tumor tissues that predicted patient survival time and disease recurrence. The NR signature derived from the initial 30 NSCLC samples was validated in two independent microarray datasets derived from 442 and 117 resected lung adenocarcinomas. The NR gene signature was also validated in 130 squamous cell carcinomas. The prognostic signature in tumors could be distilled to expression of two NRs, short heterodimer partner and progesterone receptor, as single gene predictors of NSCLC patient survival time, including for patients with stage I disease. Of equal interest, the studies of microdissected histologically normal epithelium and matched tumors identified expression in normal (but not tumor) epithelium of NGFIB3 and mineralocorticoid receptor as single gene predictors of good prognosis. NR expression is strongly associated with clinical outcomes for patients with lung cancer, and this expression profile provides a unique prognostic signature for lung cancer patient survival time, particularly for those with early stage disease. This study highlights the potential use of NRs as a rational set of therapeutically tractable genes as theragnostic biomarkers, and specifically identifies short heterodimer partner and progesterone receptor in tumors, and NGFIB3 and MR in non-neoplastic lung epithelium, for future detailed translational study in lung cancer. Please see later in the article for the Editors' Summary.

Protéomique et cancer du sein : à la recherche de nouveaux biomarqueurs diagnostiques et théragnostiques

A major challenge of breast cancer research is the identification of accurate biomarkers that improve screening, early diagnosis, prediction of aggressiveness and prediction of therapeutic response or toxicity as well as the identification of novel molecular therapeutic targets. Following the sequencing of the human genome and pioneer developments of transcriptomics, analysis of the proteome (the repertoire of proteins expressed in a biological samples) was recently introduced as a promising tool in the study of biology of human cancers. In spite of their current limitations, proteomics, either array-based (such as tissue microarrays, antibody arrays or reverse phase protein microarrays) or mass spectrometry-based, make possible to envision major improvements in the molecular knowledge of breast cancer and for the identification of tissue-based or circulating diagnostic and theragnostic biomarkers relevant to this disease. The current techniques applied to clinical samples of breast cancer and the most important results obtained are summarized in this review.

Apport des modèles transgéniques dans la recherche de nouvelles cibles pharmacologiques dans l’insuffisance cardiaque : l’exemple du récepteur de l’aldostérone

Heart failure is a complex illness with multiple etiologies. Therapeutic targets are numerous such as neurohormonal blockade (adrenergic and renin-angiotensin-aldosterone systems). Progress in therapeutic strategy and efficacy could be expected from individual treatment taking into account biomarkers so called "theragnostic". Animal models, classical or genetically modified, have conducted to a better identification and validation of signal pathways in heart failure. Furthermore these models allow testing of new hypothesis and therapeutic approaches, although cardiovascular physiology and physiopathological patterns are far different in animals than in humans (haemodynamic conditions, kinetic development of the illness, old age, ...). Last, identification of putative theragnostic biomarkers is easier (i.e. free access, homogeneity of experimental cohorts). Genetically modified models by classical additive transgenesis techniques or gene targeting have an important role in discovery of new pharmacological targets in heart failure. Study of the role of aldosterone and of its receptor (mineralocorticosteroid receptor) in the physiopathology of heart failure and as a new therapeutic target will be used as an Ariane's clew to demonstrate that translational bidirectional research (from integrated experimental model to bedside and from clinical results to bench) has allowed from these 15 last years: i) to propose changes in therapeutic strategies and ii) to stimulate research of new targets and new mineralocorticosteroid receptor antagonists.