Research

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Open AccessArticle Expression of Iron-Related Proteins Differentiate Non-Cancerous and Cancerous Breast Tumors

by Sara Pizzamiglio, Maida De Bortoli, Elena Taverna, Michele Signore, Silvia Veneroni, William Chi-shing Cho, Rosaria Orlandi, Paolo Verderio and Italia Bongarzone

Int. J. Mol. Sci. 2017, 18(2), 410; doi:10.3390/ijms18020410

Received: 19 December 2016 / Revised: 1 February 2017 / Accepted: 6 February 2017 / Published: 14 February 2017

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Abstract

We have previously reported hepcidin and ferritin increases in the plasma of breast cancer patients, but not in patients with benign breast disease. We hypothesized that these differences in systemic iron homeostasis may reflect alterations in different iron-related proteins also play a key

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We have previously reported hepcidin and ferritin increases in the plasma of breast cancer patients, but not in patients with benign breast disease. We hypothesized that these differences in systemic iron homeostasis may reflect alterations in different iron-related proteins also play a key biochemical and regulatory role in breast cancer. Thus, here we explored the expression of a bundle of molecules involved in both iron homeostasis and tumorigenesis in tissue samples. Enzyme-linked immunosorbent assay (ELISA) or reverse-phase protein array (RPPA), were used to measure the expression of 20 proteins linked to iron processes in 24 non-cancerous, and 56 cancerous, breast tumors. We found that cancerous tissues had higher level of hepcidin than benign lesions (p = 0.012). The univariate analysis of RPPA data highlighted the following seven proteins differentially expressed between non-cancerous and cancerous breast tissue: signal transducer and transcriptional activator 5 (STAT5), signal transducer and activator of transcription 3 (STAT3), bone morphogenetic protein 6 (BMP6), cluster of differentiation 74 (CD74), transferrin receptor (TFRC), inhibin alpha (INHA), and STAT5_pY694. These findings were confirmed for STAT5, STAT3, BMP6, CD74 and INHA when adjusting for age. The multivariate statistical analysis indicated an iron-related 10-protein panel effective in separating non-cancerous from cancerous lesions including STAT5, STAT5_pY694, myeloid differentiation factor 88 (MYD88), CD74, iron exporter ferroportin (FPN), high mobility group box 1 (HMGB1), STAT3_pS727, TFRC, ferritin heavy chain (FTH), and ferritin light chain (FTL). Our results showed an association between some iron-related proteins and the type of tumor tissue, which may provide insight in strategies for using iron chelators to treat breast cancer. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessArticle Prognostic Relevance of Methylenetetrahydrofolate Reductase Polymorphisms for Prostate Cancer

by Victor C. Lin, Te-Ling Lu, Hsin-Ling Yin, Sheau-Fang Yang, Yung-Chin Lee, Chia-Chu Liu, Chao-Yuan Huang, Chia-Cheng Yu, Ta-Yuan Chang, Shu-Pin Huang and Bo-Ying Bao

Int. J. Mol. Sci. 2016, 17(12), 1996; doi:10.3390/ijms17121996

Received: 19 October 2016 / Revised: 18 November 2016 / Accepted: 24 November 2016 / Published: 29 November 2016

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Abstract

Folate metabolism has been associated with cancers via alterations in nucleotide synthesis, DNA methylation, and DNA repair. We hypothesized that genetic variants in methylenetetrahydrofolate reductase (MTHFR), a key enzyme of folate metabolism, would affect the prognosis of prostate cancer. Three haplotype-tagging

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Folate metabolism has been associated with cancers via alterations in nucleotide synthesis, DNA methylation, and DNA repair. We hypothesized that genetic variants in methylenetetrahydrofolate reductase (MTHFR), a key enzyme of folate metabolism, would affect the prognosis of prostate cancer. Three haplotype-tagging single-nucleotide polymorphisms (SNPs) across the MTHFR gene region were genotyped in a cohort of 458 patients with clinically localized prostate cancer treated with radical prostatectomy. One SNP, rs9651118, was associated with disease recurrence, and the association persisted after multivariate analyses adjusting for known risk factors. Public dataset analyses suggested that rs9651118 affects MTHFR expression. Quantitative real-time polymerase chain reaction analysis revealed that MTHFR expression is significantly upregulated in prostate tumor tissues when compared with adjacent normal tissues. Furthermore, overexpression of MTHFR correlates with cancer recurrence and death in two independent publicly available prostate cancer datasets. In conclusion, our data provide rationale to further validate the clinical utility of MTHFR rs9651118 as a biomarker for prognosis in prostate cancer. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessArticle Detection of Natural Resistance-Associated Substitutions by Ion Semiconductor Technology in HCV1b Positive, Direct-Acting Antiviral Agents-Naïve Patients

by Nadia Marascio, Grazia Pavia, Alessio Strazzulla, Tim Dierckx, Lize Cuypers, Bram Vrancken, Giorgio Settimo Barreca, Teresa Mirante, Donatella Malanga, Duarte Mendes Oliveira, Anne-Mieke Vandamme, Carlo Torti, Maria Carla Liberto, Alfredo Focà and the SINERGIE-UMG Study Group

Int. J. Mol. Sci. 2016, 17(9), 1416; doi:10.3390/ijms17091416

Received: 7 July 2016 / Revised: 17 August 2016 / Accepted: 22 August 2016 / Published: 27 August 2016

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Abstract

Naturally occurring resistance-associated substitutions (RASs) can negatively impact the response to direct-acting antivirals (DAAs) agents-based therapies for hepatitis C virus (HCV) infection. Herein, we set out to characterize the RASs in the HCV1b genome from serum samples of DAA-naïve patients in the context

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Naturally occurring resistance-associated substitutions (RASs) can negatively impact the response to direct-acting antivirals (DAAs) agents-based therapies for hepatitis C virus (HCV) infection. Herein, we set out to characterize the RASs in the HCV1b genome from serum samples of DAA-naïve patients in the context of the SINERGIE (South Italian Network for Rational Guidelines and International Epidemiology, 2014) project. We deep-sequenced the NS3/4A protease region of the viral population using the Ion Torrent Personal Genome Machine, and patient-specific majority rule consensus sequence summaries were constructed with a combination of freely available next generation sequencing data analysis software. We detected NS3/4A protease major and minor variants associated with resistance to boceprevir (V36L), telaprevir (V36L, I132V), simeprevir (V36L), and grazoprevir (V36L, V170I). Furthermore, we sequenced part of HCV NS5B polymerase using Sanger-sequencing and detected a natural RAS for dasabuvir (C316N). This mutation could be important for treatment strategies in cases of previous therapy failure. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessArticle Challenges in Translating GWAS Results to Clinical Care

by Laura B. Scheinfeldt, Tara J. Schmidlen, Norman P. Gerry and Michael F. Christman

Int. J. Mol. Sci. 2016, 17(8), 1267; doi:10.3390/ijms17081267

Received: 10 June 2016 / Revised: 22 July 2016 / Accepted: 1 August 2016 / Published: 4 August 2016

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Abstract

Clinical genetic testing for Mendelian disorders is standard of care in many cases; however, it is less clear to what extent and in which situations clinical genetic testing may improve preventive efforts, diagnosis and/or prognosis of complex disease. One challenge is that much

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Clinical genetic testing for Mendelian disorders is standard of care in many cases; however, it is less clear to what extent and in which situations clinical genetic testing may improve preventive efforts, diagnosis and/or prognosis of complex disease. One challenge is that much of the reported research relies on tag single nucleotide polymorphisms (SNPs) to act as proxies for assumed underlying functional variants that are not yet known. Here we use coronary artery disease and melanoma as case studies to evaluate how well reported genetic risk variants tag surrounding variants across population samples in the 1000 Genomes Project Phase 3 data. We performed a simulation study where we randomly assigned a “functional” variant and evaluated how often this simulated functional variant was correctly tagged in diverse population samples. Our results indicate a relatively large error rate when generalizing increased genetic risk of complex disease across diverse population samples, even when generalizing within geographic regions. Our results further highlight the importance of including diverse populations in genome-wide association studies. Future work focused on identifying functional variants will eliminate the need for tag SNPs; however, until functional variants are known, caution should be used in the interpretation of genetic risk for complex disease using tag SNPs. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessArticle Common Genetic Variation in CYP17A1 and Response to Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer

by Moritz Binder, Ben Y. Zhang, David W. Hillman, Rhea Kohli, Tanvi Kohli, Adam Lee and Manish Kohli

Int. J. Mol. Sci. 2016, 17(7), 1097; doi:10.3390/ijms17071097

Received: 10 June 2016 / Revised: 24 June 2016 / Accepted: 5 July 2016 / Published: 9 July 2016

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Abstract

Treatment with abiraterone acetate and prednisone (AA/P) prolongs survival in metastatic castration-resistant prostate cancer (mCRPC) patients. We evaluated the genetic variation in CYP17A1 as predictive of response to AA/P. A prospective collection of germline DNA prior to AA/P initiation and follow-up of a

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Treatment with abiraterone acetate and prednisone (AA/P) prolongs survival in metastatic castration-resistant prostate cancer (mCRPC) patients. We evaluated the genetic variation in CYP17A1 as predictive of response to AA/P. A prospective collection of germline DNA prior to AA/P initiation and follow-up of a mCRPC cohort was performed. Five common single-nucleotide polymorphisms (SNPs) in CYP17A1 identified using a haplotype-based tagging algorithm were genotyped. Clinical outcomes included biochemical response and time to biochemical progression on AA/P. Logistic regression was used to assess the association between tag SNPs and biochemical response. Proportional hazards regression was used to assess the association between tag SNPs and time to biochemical progression. Odds or hazard ratio per minor allele were estimated and p-values below 0.05 were considered statistically significant. Germline DNA was successfully genotyped for four tag SNPs in 87 patients. The median age was 73 years (54–90); the median prostate-specific antigen was 66 ng/dL (0.1–99.9). A single SNP, rs2486758, was associated with lower odds of experiencing a biochemical response (Odds ratio 0.22, 95% confidence interval 0.07–0.63, p = 0.005) and a shorter time to biochemical progression (Hazard ratio 2.23, 95% confidence interval 1.39–3.56, p < 0.001). This tag SNP located in the promoter region of CYP17A1 will need further validation as a predictive biomarker for AA/P therapy. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

Open AccessArticle A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma

by Jun Lai, Zhan Zhou, Xiao-Jing Tang, Zhi-Bin Gao, Jie Zhou and Shu-Qing Chen

Int. J. Mol. Sci. 2016, 17(5), 739; doi:10.3390/ijms17050739

Received: 22 March 2016 / Revised: 28 April 2016 / Accepted: 4 May 2016 / Published: 14 May 2016

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Abstract

Malignant peritoneal mesothelioma (MPM) is an aggressive rare malignancy associated with asbestos exposure. A better understanding of the molecular pathogenesis of MPM will help develop a targeted therapy strategy. Oncogene targeted depth sequencing was performed on a tumor sample and paired peripheral blood

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Malignant peritoneal mesothelioma (MPM) is an aggressive rare malignancy associated with asbestos exposure. A better understanding of the molecular pathogenesis of MPM will help develop a targeted therapy strategy. Oncogene targeted depth sequencing was performed on a tumor sample and paired peripheral blood DNA from a patient with malignant mesothelioma of the peritoneum. Four somatic base-substitutions in NOTCH2, NSD1, PDE4DIP, and ATP10B and 1 insert frameshift mutation in BAP1 were validated by the Sanger method at the transcriptional level. A 13-amino acids neo-peptide of the truncated Bap1 protein, which was produced as a result of this novel frameshift mutation, was predicted to be presented by this patient’s HLA-B protein. The polyclonal antibody of the synthesized 13-mer neo-peptide was produced in rabbits. Western blotting results showed a good antibody-neoantigen specificity, and Immunohistochemistry (IHC) staining with the antibody of the neo-peptide clearly differentiated neoplastic cells from normal cells. A search of the Catalogue of Somatic Mutations in Cancer (COSMIC) database also revealed that 53.2% of mutations in BAP1 were frameshift indels with neo-peptide formation. An identified tumor-specific neo-antigen could be the potential molecular biomarker for personalized diagnosis to precisely subtype rare malignancies such as MPM. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Review

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Open AccessReview Big Data Analytics for Genomic Medicine

by Karen Y. He, Dongliang Ge and Max M. He

Int. J. Mol. Sci. 2017, 18(2), 412; doi:10.3390/ijms18020412

Received: 24 October 2016 / Revised: 8 February 2017 / Accepted: 9 February 2017 / Published: 15 February 2017

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Abstract

Genomic medicine attempts to build individualized strategies for diagnostic or therapeutic decision-making by utilizing patients’ genomic information. Big Data analytics uncovers hidden patterns, unknown correlations, and other insights through examining large-scale various data sets. While integration and manipulation of diverse genomic data and

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Genomic medicine attempts to build individualized strategies for diagnostic or therapeutic decision-making by utilizing patients’ genomic information. Big Data analytics uncovers hidden patterns, unknown correlations, and other insights through examining large-scale various data sets. While integration and manipulation of diverse genomic data and comprehensive electronic health records (EHRs) on a Big Data infrastructure exhibit challenges, they also provide a feasible opportunity to develop an efficient and effective approach to identify clinically actionable genetic variants for individualized diagnosis and therapy. In this paper, we review the challenges of manipulating large-scale next-generation sequencing (NGS) data and diverse clinical data derived from the EHRs for genomic medicine. We introduce possible solutions for different challenges in manipulating, managing, and analyzing genomic and clinical data to implement genomic medicine. Additionally, we also present a practical Big Data toolset for identifying clinically actionable genetic variants using high-throughput NGS data and EHRs. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessReview Detecting Blood-Based Biomarkers in Metastatic Breast Cancer: A Systematic Review of Their Current Status and Clinical Utility

by A. M. Sofie Berghuis, Hendrik Koffijberg, Jai Prakash, Leon W. M. M. Terstappen and Maarten J. IJzerman

Int. J. Mol. Sci. 2017, 18(2), 363; doi:10.3390/ijms18020363

Received: 20 December 2016 / Revised: 27 January 2017 / Accepted: 3 February 2017 / Published: 9 February 2017

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Abstract

Reviews on circulating biomarkers in breast cancer usually focus on one single biomarker or a selective group of biomarkers. An overview summarizing the discovery and evaluation of all blood-based biomarkers in metastatic breast cancer is lacking. This systematic review aims to identify the

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Reviews on circulating biomarkers in breast cancer usually focus on one single biomarker or a selective group of biomarkers. An overview summarizing the discovery and evaluation of all blood-based biomarkers in metastatic breast cancer is lacking. This systematic review aims to identify the available evidence of known blood-based biomarkers in metastatic breast cancer, regarding their clinical utility and state-of-the-art position in the validation process. The initial search yielded 1078 original studies, of which 420 were assessed for eligibility. A total of 320 studies were included in the final synthesis. A Development, Evaluation and Application Chart (DEAC) of all biomarkers was developed. Most studies focus on identifying new biomarkers and search for relations between these biomarkers and traditional molecular characteristics. Biomarkers are usually investigated in only one study (68.8%). Only 9.8% of all biomarkers was investigated in more than five studies. Circulating tumor cells, gene expression within tumor cells and the concentration of secreted proteins are the most frequently investigated biomarkers in liquid biopsies. However, there is a lack of studies focusing on identifying the clinical utility of these biomarkers, by which the additional value still seems to be limited according to the investigated evidence. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessReview Severe Cutaneous Adverse Reactions: The Pharmacogenomics from Research to Clinical Implementation

by Shih-Chi Su, Shuen-Iu Hung, Wen-Lang Fan, Ro-Lan Dao and Wen-Hung Chung

Int. J. Mol. Sci. 2016, 17(11), 1890; doi:10.3390/ijms17111890

Received: 28 September 2016 / Revised: 7 November 2016 / Accepted: 7 November 2016 / Published: 15 November 2016

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Abstract

Severe cutaneous adverse reactions (SCARs), previously thought to be idiosyncratic or unpredictable, are a deadly form of adverse drug reactions with skin manifestations. Current pharmacogenomic studies of SCARs have made important strides, as the prevention of SCARs, to some extent, appears attainable with

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Severe cutaneous adverse reactions (SCARs), previously thought to be idiosyncratic or unpredictable, are a deadly form of adverse drug reactions with skin manifestations. Current pharmacogenomic studies of SCARs have made important strides, as the prevention of SCARs, to some extent, appears attainable with the identification of genetic variants for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). Despite the improvement of incidence, a treatment guideline for this devastating condition is still unavailable, highlighting the inadequacy of contemporary accepted therapeutic interventions. As such, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we discuss recent cutting-edge findings concerning the discovery of biomarkers for SCARs and their clinical utilities in the better prediction and early diagnosis of this disease. The knowledge compiled herein provides clues for future investigations on deciphering additional genetic markers for SCARs and the design of clinical trials for the prospective identification of subjects at genetic risk for this condition, ultimately personalizing the medicine. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessReview Towards Stratified Medicine in Plasma Cell Myeloma

by Philip Egan, Stephen Drain, Caroline Conway, Anthony J. Bjourson and H. Denis Alexander

Int. J. Mol. Sci. 2016, 17(10), 1760; doi:10.3390/ijms17101760

Received: 24 July 2016 / Revised: 26 September 2016 / Accepted: 5 October 2016 / Published: 21 October 2016

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Abstract

Plasma cell myeloma is a clinically heterogeneous malignancy accounting for approximately one to 2% of newly diagnosed cases of cancer worldwide. Treatment options, in addition to long-established cytotoxic drugs, include autologous stem cell transplant, immune modulators, proteasome inhibitors and monoclonal antibodies, plus further

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Plasma cell myeloma is a clinically heterogeneous malignancy accounting for approximately one to 2% of newly diagnosed cases of cancer worldwide. Treatment options, in addition to long-established cytotoxic drugs, include autologous stem cell transplant, immune modulators, proteasome inhibitors and monoclonal antibodies, plus further targeted therapies currently in clinical trials. Whilst treatment decisions are mostly based on a patient’s age, fitness, including the presence of co-morbidities, and tumour burden, significant scope exists for better risk stratification, sub-classification of disease, and predictors of response to specific therapies. Clinical staging, recurring acquired cytogenetic aberrations, and serum biomarkers such as β-2 microglobulin, and free light chains are in widespread use but often fail to predict the disease progression or inform treatment decision making. Recent scientific advances have provided considerable insight into the biology of myeloma. For example, gene expression profiling is already making a contribution to enhanced understanding of the biology of the disease whilst Next Generation Sequencing has revealed great genomic complexity and heterogeneity. Pathways involved in the oncogenesis, proliferation of the tumour and its resistance to apoptosis are being unravelled. Furthermore, knowledge of the tumour cell surface and its interactions with bystander cells and the bone marrow stroma enhance this understanding and provide novel targets for cell and antibody-based therapies. This review will discuss the development in understanding of the biology of the tumour cell and its environment in the bone marrow, the implementation of new therapeutic options contributing to significantly improved outcomes, and the progression towards more personalised medicine in this disorder. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessReview A Personalized Approach in Progressive Multiple Sclerosis: The Current Status of Disease Modifying Therapies (DMTs) and Future Perspectives

by Emanuele D’Amico, Francesco Patti, Aurora Zanghì and Mario Zappia

Int. J. Mol. Sci. 2016, 17(10), 1725; doi:10.3390/ijms17101725

Received: 21 July 2016 / Revised: 29 September 2016 / Accepted: 2 October 2016 / Published: 17 October 2016

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Abstract

Using the term of progressive multiple sclerosis (PMS), we considered a combined population of persons with secondary progressive MS (SPMS) and primary progressive MS (PPMS). These forms of MS cannot be challenged with efficacy by the licensed therapy. In the last years, several

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Using the term of progressive multiple sclerosis (PMS), we considered a combined population of persons with secondary progressive MS (SPMS) and primary progressive MS (PPMS). These forms of MS cannot be challenged with efficacy by the licensed therapy. In the last years, several measures of risk estimation were developed for predicting clinical course in MS, but none is specific for the PMS forms. Personalized medicine is a therapeutic approach, based on identifying what might be the best therapy for an individual patient, taking into account the risk profile. We need to achieve more accurate estimates of useful predictors in PMS, including unconventional and qualitative markers which are not yet currently available or practicable routine diagnostics. The evaluation of an individual patient is based on the profile of disease activity.Within the neurology field, PMS is one of the fastest-moving going into the future. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessReview The Importance of Patient-Specific Factors for Hepatic Drug Response and Toxicity

by Volker M. Lauschke and Magnus Ingelman-Sundberg

Int. J. Mol. Sci. 2016, 17(10), 1714; doi:10.3390/ijms17101714

Received: 12 September 2016 / Revised: 23 September 2016 / Accepted: 27 September 2016 / Published: 12 October 2016

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Abstract

Responses to drugs and pharmacological treatments differ considerably between individuals. Importantly, only 50%–75% of patients have been shown to react adequately to pharmacological interventions, whereas the others experience either a lack of efficacy or suffer from adverse events. The liver is of central

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Responses to drugs and pharmacological treatments differ considerably between individuals. Importantly, only 50%–75% of patients have been shown to react adequately to pharmacological interventions, whereas the others experience either a lack of efficacy or suffer from adverse events. The liver is of central importance in the metabolism of most drugs. Because of this exposed status, hepatotoxicity is amongst the most common adverse drug reactions and hepatic liabilities are the most prevalent reason for the termination of development programs of novel drug candidates. In recent years, more and more factors were unveiled that shape hepatic drug responses and thus underlie the observed inter-individual variability. In this review, we provide a comprehensive overview of different principle mechanisms of drug hepatotoxicity and illustrate how patient-specific factors, such as genetic, physiological and environmental factors, can shape drug responses. Furthermore, we highlight other parameters, such as concomitantly prescribed medications or liver diseases and how they modulate drug toxicity, pharmacokinetics and dynamics. Finally, we discuss recent progress in the field of in vitro toxicity models and evaluate their utility in reflecting patient-specific factors to study inter-individual differences in drug response and toxicity, as this understanding is necessary to pave the way for a patient-adjusted medicine. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessReview Omics-Based Strategies in Precision Medicine: Toward a Paradigm Shift in Inborn Errors of Metabolism Investigations

by Abdellah Tebani, Carlos Afonso, Stéphane Marret and Soumeya Bekri

Int. J. Mol. Sci. 2016, 17(9), 1555; doi:10.3390/ijms17091555

Received: 27 July 2016 / Revised: 6 September 2016 / Accepted: 7 September 2016 / Published: 14 September 2016

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Abstract

The rise of technologies that simultaneously measure thousands of data points represents the heart of systems biology. These technologies have had a huge impact on the discovery of next-generation diagnostics, biomarkers, and drugs in the precision medicine era. Systems biology aims to achieve

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The rise of technologies that simultaneously measure thousands of data points represents the heart of systems biology. These technologies have had a huge impact on the discovery of next-generation diagnostics, biomarkers, and drugs in the precision medicine era. Systems biology aims to achieve systemic exploration of complex interactions in biological systems. Driven by high-throughput omics technologies and the computational surge, it enables multi-scale and insightful overviews of cells, organisms, and populations. Precision medicine capitalizes on these conceptual and technological advancements and stands on two main pillars: data generation and data modeling. High-throughput omics technologies allow the retrieval of comprehensive and holistic biological information, whereas computational capabilities enable high-dimensional data modeling and, therefore, accessible and user-friendly visualization. Furthermore, bioinformatics has enabled comprehensive multi-omics and clinical data integration for insightful interpretation. Despite their promise, the translation of these technologies into clinically actionable tools has been slow. In this review, we present state-of-the-art multi-omics data analysis strategies in a clinical context. The challenges of omics-based biomarker translation are discussed. Perspectives regarding the use of multi-omics approaches for inborn errors of metabolism (IEM) are presented by introducing a new paradigm shift in addressing IEM investigations in the post-genomic era. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessReview Pharmacogenomics in Pediatric Oncology: Review of Gene—Drug Associations for Clinical Use

by Vid Mlakar, Patricia Huezo-Diaz Curtis, Chakradhara Rao Satyanarayana Uppugunduri, Maja Krajinovic and Marc Ansari

Int. J. Mol. Sci. 2016, 17(9), 1502; doi:10.3390/ijms17091502

Received: 21 July 2016 / Revised: 2 August 2016 / Accepted: 15 August 2016 / Published: 8 September 2016

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Abstract

During the 3rd congress of the European Society of Pharmacogenomics and Personalised Therapy (ESPT) in Budapest in 2015, a preliminary meeting was held aimed at establishing a pediatric individualized treatment in oncology and hematology committees. The main purpose was to facilitate the transfer

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During the 3rd congress of the European Society of Pharmacogenomics and Personalised Therapy (ESPT) in Budapest in 2015, a preliminary meeting was held aimed at establishing a pediatric individualized treatment in oncology and hematology committees. The main purpose was to facilitate the transfer and harmonization of pharmacogenetic testing from research into clinics, to bring together basic and translational research and to educate health professionals throughout Europe. The objective of this review was to provide the attendees of the meeting as well as the larger scientific community an insight into the compiled evidence regarding current pharmacogenomics knowledge in pediatric oncology. This preliminary evaluation will help steer the committee’s work and should give the reader an idea at which stage researchers and clinicians are, in terms of personalizing medicine for children with cancer. From the evidence presented here, future recommendations to achieve this goal will also be suggested. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessReview Epigenetic Mechanisms in Bone Biology and Osteoporosis: Can They Drive Therapeutic Choices?

by Francesca Marini, Luisella Cianferotti and Maria Luisa Brandi

Int. J. Mol. Sci. 2016, 17(8), 1329; doi:10.3390/ijms17081329

Received: 1 July 2016 / Revised: 27 July 2016 / Accepted: 5 August 2016 / Published: 12 August 2016

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Abstract

Osteoporosis is a complex multifactorial disorder of the skeleton. Genetic factors are important in determining peak bone mass and structure, as well as the predisposition to bone deterioration and fragility fractures. Nonetheless, genetic factors alone are not sufficient to explain osteoporosis development and

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Osteoporosis is a complex multifactorial disorder of the skeleton. Genetic factors are important in determining peak bone mass and structure, as well as the predisposition to bone deterioration and fragility fractures. Nonetheless, genetic factors alone are not sufficient to explain osteoporosis development and fragility fracture occurrence. Indeed, epigenetic factors, representing a link between individual genetic aspects and environmental influences, are also strongly suspected to be involved in bone biology and osteoporosis. Recently, alterations in epigenetic mechanisms and their activity have been associated with aging. Also, bone metabolism has been demonstrated to be under the control of epigenetic mechanisms. Runt-related transcription factor 2 (RUNX2), the master transcription factor of osteoblast differentiation, has been shown to be regulated by histone deacetylases and microRNAs (miRNAs). Some miRNAs were also proven to have key roles in the regulation of Wnt signalling in osteoblastogenesis, and to be important for the positive or negative regulation of both osteoblast and osteoclast differentiation. Exogenous and environmental stimuli, influencing the functionality of epigenetic mechanisms involved in the regulation of bone metabolism, may contribute to the development of osteoporosis and other bone disorders, in synergy with genetic determinants. The progressive understanding of roles of epigenetic mechanisms in normal bone metabolism and in multifactorial bone disorders will be very helpful for a better comprehension of disease pathogenesis and translation of this information into clinical practice. A deep understanding of these mechanisms could help in the future tailoring of proper individual treatments, according to precision medicine’s principles. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessReview MicroRNAs: Potential Biomarkers and Therapeutic Targets for Alveolar Bone Loss in Periodontal Disease

by Tadayoshi Kagiya

Int. J. Mol. Sci. 2016, 17(8), 1317; doi:10.3390/ijms17081317

Received: 28 June 2016 / Revised: 24 July 2016 / Accepted: 3 August 2016 / Published: 11 August 2016

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Abstract

Periodontal disease is an inflammatory disease caused by bacterial infection of tooth-supporting structures, which results in the destruction of alveolar bone. Osteoclasts play a central role in bone destruction. Osteoclasts are tartrate-resistant acid phosphatase (TRAP)-positive multinucleated giant cells derived from hematopoietic stem cells.

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Periodontal disease is an inflammatory disease caused by bacterial infection of tooth-supporting structures, which results in the destruction of alveolar bone. Osteoclasts play a central role in bone destruction. Osteoclasts are tartrate-resistant acid phosphatase (TRAP)-positive multinucleated giant cells derived from hematopoietic stem cells. Recently, we and other researchers revealed that microRNAs are involved in osteoclast differentiation. MicroRNAs are novel, single-stranded, non-coding, small (20–22 nucleotides) RNAs that act in a sequence-specific manner to regulate gene expression at the post-transcriptional level through cleavage or translational repression of their target mRNAs. They regulate various biological activities such as cellular differentiation, apoptosis, cancer development, and inflammatory responses. In this review, the roles of microRNAs in osteoclast differentiation and function during alveolar bone destruction in periodontal disease are described. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessReview Rheumatoid Arthritis: The Stride from Research to Clinical Practice

by Ill-Min Chung, Sarada Ketharnathan, Muthu Thiruvengadam and Govindasamy Rajakumar

Int. J. Mol. Sci. 2016, 17(6), 900; doi:10.3390/ijms17060900

Received: 9 May 2016 / Revised: 29 May 2016 / Accepted: 1 June 2016 / Published: 8 June 2016

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Abstract

Over 70 different genetic variants with a significant association with rheumatoid arthritis (RA) have been discovered. Anti-citrullination protein antibodies (ACPA)-positive RA variants are more well-defined than their ACPA-negative counterparts. The human leukocyte antigen, HLA-DRB1 locus remains the prime suspect in anti-citrullination protein antibodies

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Over 70 different genetic variants with a significant association with rheumatoid arthritis (RA) have been discovered. Anti-citrullination protein antibodies (ACPA)-positive RA variants are more well-defined than their ACPA-negative counterparts. The human leukocyte antigen, HLA-DRB1 locus remains the prime suspect in anti-citrullination protein antibodies (ACPA)—positive RA. Different HLA-DRB1 alleles are linked to RA susceptibility across different ethnicities. With evolving techniques, like genome-wide association studies (GWAS) and single nucleotide polymorphism (SNP) arrays, more non-HLA susceptibility loci have been identified for both types of RA. However, the functional significance of only a handful of these variants is known. Their roles include increasing susceptibility to RA or in determining the speed at which the disease progresses. Additionally, a couple of variations are associated with protection from RA. Defining such clear-cut biological functions can aid in the clinical diagnosis and treatment of RA. Recent research has focused on the implication of microRNAs, with miR-146a widely studied. In addition to disease susceptibility, genetic variations that influence the efficacy and toxicity of anti-RA agents have also been identified. Polymorphisms in the MTHFR gene influence the effectiveness of methotrexate, the first line of therapy in RA. Larger studies are, however, needed to identify potential biomarkers for early disease identification and monitoring disease progression. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

Open AccessReview Sirolimus and Everolimus Pathway: Reviewing Candidate Genes Influencing Their Intracellular Effects

by Simona Granata, Alessandra Dalla Gassa, Amedeo Carraro, Matteo Brunelli, Giovanni Stallone, Antonio Lupo and Gianluigi Zaza

Int. J. Mol. Sci. 2016, 17(5), 735; doi:10.3390/ijms17050735

Received: 10 March 2016 / Revised: 21 April 2016 / Accepted: 6 May 2016 / Published: 14 May 2016

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Abstract

Sirolimus (SRL) and everolimus (EVR) are mammalian targets of rapamycin inhibitors (mTOR-I) largely employed in renal transplantation and oncology as immunosuppressive/antiproliferative agents. SRL was the first mTOR-I produced by the bacterium Streptomyces hygroscopicus and approved for several medical purposes. EVR, derived from SRL,

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Sirolimus (SRL) and everolimus (EVR) are mammalian targets of rapamycin inhibitors (mTOR-I) largely employed in renal transplantation and oncology as immunosuppressive/antiproliferative agents. SRL was the first mTOR-I produced by the bacterium Streptomyces hygroscopicus and approved for several medical purposes. EVR, derived from SRL, contains a 2-hydroxy-ethyl chain in the 40th position that makes the drug more hydrophilic than SRL and increases oral bioavailability. Their main mechanism of action is the inhibition of the mTOR complex 1 and the regulation of factors involved in a several crucial cellular functions including: protein synthesis, regulation of angiogenesis, lipid biosynthesis, mitochondrial biogenesis and function, cell cycle, and autophagy. Most of the proteins/enzymes belonging to the aforementioned biological processes are encoded by numerous and tightly regulated genes. However, at the moment, the polygenic influence on SRL/EVR cellular effects is still not completely defined, and its comprehension represents a key challenge for researchers. Therefore, to obtain a complete picture of the cellular network connected to SRL/EVR, we decided to review major evidences available in the literature regarding the genetic influence on mTOR-I biology/pharmacology and to build, for the first time, a useful and specific “SRL/EVR genes-focused pathway”, possibly employable as a starting point for future in-depth research projects. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessReview Association between Genetic Polymorphisms and Response to Anti-TNFs in Patients with Inflammatory Bowel Disease

by Rocío Prieto-Pérez, Berta Almoguera, Teresa Cabaleiro, Hakon Hakonarson and Francisco Abad-Santos

Int. J. Mol. Sci. 2016, 17(2), 225; doi:10.3390/ijms17020225

Received: 11 January 2016 / Revised: 1 February 2016 / Accepted: 3 February 2016 / Published: 6 February 2016

Cited by 2 | PDF Full-text (438 KB) | HTML Full-text | XML Full-text

Abstract

Tumor necrosis factor (TNF) alpha is a major proinflammatory cytokine involved in the immune response in inflammatory bowel disease (IBD). Anti-TNF drugs such as infliximab and adalimumab are used to treat IBD; however, approximately 30% of patients do not respond to treatment. Individual

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Tumor necrosis factor (TNF) alpha is a major proinflammatory cytokine involved in the immune response in inflammatory bowel disease (IBD). Anti-TNF drugs such as infliximab and adalimumab are used to treat IBD; however, approximately 30% of patients do not respond to treatment. Individual genetic differences could contribute to lack of efficacy. Genetic studies have tried to uncover the factors underlying differences in response, however, knowledge remains limited, and the results obtained should be validated, so that pharmacogenetic information can be applied in clinical practice. In this review, we gather current knowledge in the pharmacogenetics of anti-TNF drugs in patients with IBD. We observed a connection between the major genes described as possible predictors of response to anti-TNF drugs in IBD and the cytokines and molecules involved in the T helper (Th) 17 pathway. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessReview Biobanking of Exosomes in the Era of Precision Medicine: Are We There Yet?

by Edna M. Mora, Silvia Álvarez-Cubela and Elisa Oltra

Int. J. Mol. Sci. 2016, 17(1), 13; doi:10.3390/ijms17010013

Received: 26 November 2015 / Revised: 14 December 2015 / Accepted: 17 December 2015 / Published: 24 December 2015

Cited by 6 | PDF Full-text (773 KB) | HTML Full-text | XML Full-text

Abstract

The emerge of personalized medicine demands high-quality human biospecimens with appropriate clinical annotation, especially in complex diseases such as cancer, neurodegenerative, cardiovascular, and metabolic alterations in which specimen heterogeneity and individual responses often complicate the development of precision therapeutic programs. In the growing

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The emerge of personalized medicine demands high-quality human biospecimens with appropriate clinical annotation, especially in complex diseases such as cancer, neurodegenerative, cardiovascular, and metabolic alterations in which specimen heterogeneity and individual responses often complicate the development of precision therapeutic programs. In the growing field of extracellular vesicles (EVs) research, exosomes (EXOs)—a particular type of EVs—have been proposed as an advantageous diagnostic tool, as effective delivery vehicles and as therapeutic targets. However, the lack of consensus on isolation methods and rigorous criteria to characterize them puts the term EXO into question at the time that might explain some of the controversial results found in the literature. A lack of response in the biobank network to warrant standard optimized procedures for the isolation, characterization, and storage of EXOs will undoubtedly lead to a waste of resources and failure. This review is aimed at highlighting the increasing importance of EXOs for the clinic, especially in the cancer field, and at summarizing the initiatives taken to improve current isolation procedures, classification criteria, and storage conditions of EXOs as an effort to identify technological demands that biobank platforms face for the incorporation of EXOs and other extracellular vesicle fractions as valuable biospecimens for research. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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