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Volume 9
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J. Pers. Med., Volume 9, Issue 1 (March 2019) – 17 articles

Cover Story (view full-size image): For patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer, immune checkpoint inhibitors have demonstrated impressive clinical efficacy. This hyper-mutated tumor subgroup is especially vulnerable to the effects of checkpoint blockade due to its high frequency of frameshift peptide neoantigens and characteristic immunogenic tumor microenvironment. This review explores current novel combination strategies that aim to incorporate these therapeutic antibodies into the treatment paradigm of patients with microsatellite stable colorectal cancer, with the goal of optimally sensitizing the relatively immuno-cold tumor microenvironment of these tumors to the immune-activating effects of checkpoint inhibition. View this paper.
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11 pages, 247 KiB  
Article
Metformin Pharmacogenetics: Effects of SLC22A1, SLC22A2, and SLC22A3 Polymorphisms on Glycemic Control and HbA1c Levels
by Laith N. AL-Eitan, Basima A. Almomani, Ahmad M. Nassar, Barakat Z. Elsaqa and Nesreen A. Saadeh
J. Pers. Med. 2019, 9(1), 17; https://doi.org/10.3390/jpm9010017 - 25 Mar 2019
Cited by 38 | Viewed by 8436
Abstract
Type 2 diabetes mellitus (T2DM) constitutes a major portion of Jordan’s disease burden, and incidence rates are rising at a rapid rate. Due to variability in the drug’s response between ethnic groups, it is imperative that the pharmacogenetics of metformin be investigated in [...] Read more.
Type 2 diabetes mellitus (T2DM) constitutes a major portion of Jordan’s disease burden, and incidence rates are rising at a rapid rate. Due to variability in the drug’s response between ethnic groups, it is imperative that the pharmacogenetics of metformin be investigated in the Jordanian population. The objective of this study was to investigate the relationship between twenty-one single nucleotide polymorphisms (SNPs) in the SLC22A1, SLC22A2, and SLC22A3 genes and their effects on metformin pharmacogenetics in Jordanian patients diagnosed with type 2 diabetes mellitus. Blood samples were collected from 212 Jordanian diabetics who fulfilled the inclusion criteria, which were then used in SNP genotyping and determination of HbA1c levels. The rs12194182 SNP in the SLC22A3 gene was found to have a significant association (p < 0.05) with lower mean HbA1c levels, and this association more pronounced in patients with the CC genotype (i.e., p-value was significant before correcting for multiple testing). Moreover, the multinomial logistic regression analysis showed that SNP genotypes within the SLC22A1, SLC22A2, and SLC22A3 genes, body mass index (BMI) and age of diagnosis were significantly associated with glycemic control (p < 0.05). The results of this study can be used to predict response to metformin and other classes of T2DM drugs, making treatment more individualized and resulting in better clinical outcomes. Full article
(This article belongs to the Special Issue Personalized Medicine Based on Drug Transporter Genetic Heterogeneity)
21 pages, 1155 KiB  
Review
Mutation-Based Therapeutic Strategies for Duchenne Muscular Dystrophy: From Genetic Diagnosis to Therapy
by Akinori Nakamura
J. Pers. Med. 2019, 9(1), 16; https://doi.org/10.3390/jpm9010016 - 4 Mar 2019
Cited by 29 | Viewed by 15227
Abstract
Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked muscle disorders caused by mutations of the DMD gene, which encodes the subsarcolemmal protein dystrophin. In DMD, dystrophin is not expressed due to a disruption in the reading frame of the DMD gene, resulting in [...] Read more.
Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked muscle disorders caused by mutations of the DMD gene, which encodes the subsarcolemmal protein dystrophin. In DMD, dystrophin is not expressed due to a disruption in the reading frame of the DMD gene, resulting in a severe phenotype. Becker muscular dystrophy exhibits a milder phenotype, having mutations that maintain the reading frame and allow for the production of truncated dystrophin. To date, various therapeutic approaches for DMD have been extensively developed. However, the pathomechanism is quite complex despite it being a single gene disorder, and dystrophin is expressed not only in a large amount of skeletal muscle but also in cardiac, vascular, intestinal smooth muscle, and nervous system tissue. Thus, the most appropriate therapy would be complementation or restoration of dystrophin expression, such as gene therapy using viral vectors, readthrough therapy, or exon skipping therapy. Among them, exon skipping therapy with antisense oligonucleotides can restore the reading frame and yield the conversion of a severe phenotype to one that is mild. In this paper, I present the significance of molecular diagnosis and the development of mutation-based therapeutic strategies to complement or restore dystrophin expression. Full article
(This article belongs to the Special Issue Molecular Diagnosis and Novel Therapies for Neuromuscular/Musculoskeletal Diseases)
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22 pages, 283 KiB  
Review
Genetic Testing to Guide Risk-Stratified Screens for Breast Cancer
by Ava Willoughby, Paul R. Andreassen and Amanda Ewart Toland
J. Pers. Med. 2019, 9(1), 15; https://doi.org/10.3390/jpm9010015 - 1 Mar 2019
Cited by 23 | Viewed by 9687
Abstract
Breast cancer screening modalities and guidelines continue to evolve and are increasingly based on risk factors, including genetic risk and a personal or family history of cancer. Here, we review genetic testing of high-penetrance hereditary breast and ovarian cancer genes, including BRCA1 and [...] Read more.
Breast cancer screening modalities and guidelines continue to evolve and are increasingly based on risk factors, including genetic risk and a personal or family history of cancer. Here, we review genetic testing of high-penetrance hereditary breast and ovarian cancer genes, including BRCA1 and BRCA2, for the purpose of identifying high-risk individuals who would benefit from earlier screening and more sensitive methods such as magnetic resonance imaging. We also consider risk-based screening in the general population, including whether every woman should be genetically tested for high-risk genes and the potential use of polygenic risk scores. In addition to enabling early detection, the results of genetic screens of breast cancer susceptibility genes can be utilized to guide decision-making about when to elect prophylactic surgeries that reduce cancer risk and the choice of therapeutic options. Variants of uncertain significance, especially missense variants, are being identified during panel testing for hereditary breast and ovarian cancer. A finding of a variant of uncertain significance does not provide a basis for increased cancer surveillance or prophylactic procedures. Given that variant classification is often challenging, we also consider the role of multifactorial statistical analyses by large consortia and functional tests for this purpose. Full article
(This article belongs to the Special Issue Risk-stratified Cancer Screening)
9 pages, 2045 KiB  
Review
Autonomy Challenges in Epigenetic Risk-Stratified Cancer Screening: How Can Patient Decision Aids Support Informed Consent?
by Maaike Alblas, Maartje Schermer, Yvonne Vergouwe and Ineke Bolt
J. Pers. Med. 2019, 9(1), 14; https://doi.org/10.3390/jpm9010014 - 18 Feb 2019
Cited by 7 | Viewed by 6522
Abstract
Information of an individual’s epigenome can be useful in cancer screening to enable personalised decision making on participation, treatment options and further screening strategies. However, adding this information might result in complex risk predictions on multiple diseases, unsolicited findings and information on (past) [...] Read more.
Information of an individual’s epigenome can be useful in cancer screening to enable personalised decision making on participation, treatment options and further screening strategies. However, adding this information might result in complex risk predictions on multiple diseases, unsolicited findings and information on (past) environmental exposure and behaviour. This complicates informed consent procedures and may impede autonomous decision-making. In this article we investigate and identify the specific features of epigenetic risk-stratified cancer screening that challenge the current informed consent doctrine. Subsequently we describe current and new informed consent models and the principle of respect for autonomy and argue for a specific informed consent model for epigenetic risk-stratified screening programmes. Next, we propose a framework that guides the development of Patient Decision Aids (PDAs) to support informed consent and promote autonomous choices in the specific context of epigenetic cancer screening programmes. Full article
(This article belongs to the Special Issue Risk-stratified Cancer Screening)
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13 pages, 755 KiB  
Article
The Association between Plasma Omega-6/Omega-3 Ratio and Anthropometric Traits Differs by Racial/Ethnic Groups and NFKB1 Genotypes in Healthy Young Adults
by Jeremy Bauman-Fortin, David W.L. Ma, David M. Mutch, Salma A. Abdelmagid, Alaa Badawi, Ahmed El-Sohemy and Bénédicte Fontaine-Bisson
J. Pers. Med. 2019, 9(1), 13; https://doi.org/10.3390/jpm9010013 - 16 Feb 2019
Cited by 9 | Viewed by 6989
Abstract
Evidence for a relationship between omega-6/omega-3 (n-6/n-3) polyunsaturated fatty acid (PUFA) ratio and obesity in humans is inconsistent, perhaps due to differences in dietary intake or metabolism of PUFAs between different subsets of the population. Since chronic inflammation is central to obesity and [...] Read more.
Evidence for a relationship between omega-6/omega-3 (n-6/n-3) polyunsaturated fatty acid (PUFA) ratio and obesity in humans is inconsistent, perhaps due to differences in dietary intake or metabolism of PUFAs between different subsets of the population. Since chronic inflammation is central to obesity and inflammatory pathways are regulated by PUFAs, the objective of this study was to examine whether variants in the NFKB1 gene, an upstream regulator of the inflammatory response, modify the association between the n-6/n-3 ratio (from diet and plasma) and anthropometric traits in a multiethnic/multiracial population of young adults. Participants’ (n = 898) dietary PUFA intake was assessed using a food frequency questionnaire and plasma PUFA concentrations by gas chromatography. Nine tag single nucleotide polymorphisms (SNP) in NFKB1 were genotyped. Significant interactions were found between racial/ethnic groups and plasma n-6/n-3 ratio for body mass index (BMI) (p = 0.02) and waist circumference (WC) (p = 0.007). Significant interactions were also observed between racial/ethnic groups and three NFKB1 genotypes (rs11722146, rs1609798, and rs230511) for BMI and WC (all p ≤ 0.04). Significant interactions were found between two NFKB1 genotypes and plasma n-6/n-3 ratio for BMI and WC (rs4648090 p = 0.02 and 0.03; rs4648022 p = 0.06 and 0.04, respectively). Our findings suggest that anthropometric traits may be influenced by a unique combination of n-6/n-3 ratio, racial/ethnic background, and NFKB1 genotypes. Full article
(This article belongs to the Special Issue Nutrigenomics)
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23 pages, 416 KiB  
Review
The Developing Story of Predictive Biomarkers in Colorectal Cancer
by Stergios Boussios, Mehmet Akif Ozturk, Michele Moschetta, Afroditi Karathanasi, Nikolaos Zakynthinakis-Kyriakou, Konstantinos H. Katsanos, Dimitrios K. Christodoulou and Nicholas Pavlidis
J. Pers. Med. 2019, 9(1), 12; https://doi.org/10.3390/jpm9010012 - 7 Feb 2019
Cited by 131 | Viewed by 13808
Abstract
Colorectal cancer (CRC) is the third most common malignancy worldwide. Surgery remains the most important treatment for non-metastatic CRC, and the administration of adjuvant chemotherapy depends mainly on the disease stage, which is still the strongest prognostic factor. A refined understanding of the [...] Read more.
Colorectal cancer (CRC) is the third most common malignancy worldwide. Surgery remains the most important treatment for non-metastatic CRC, and the administration of adjuvant chemotherapy depends mainly on the disease stage, which is still the strongest prognostic factor. A refined understanding of the genomics of CRC has recently been achieved thanks to the widespread use of next generation sequencing with potential future therapeutic implications. Microsatellite instability (MSI) has been suggested as a predictive marker for response to anti-programmed-cell-death protein 1 (PD-1) therapy in solid tumors, including CRC. It should be noted that not all cancers with MSI phenotype respond to anti-PD-1 immunotherapy, highlighting the urgent need for even better predictive biomarkers. Mitogen-Activated Protein Kinase (MAPK) pathway genes KRAS, NRAS, and BRAF represent important molecular targets and could serve as independent prognostic biomarkers in CRC, and identify those who potentially benefit from anti-epidermal growth factor receptor (EGFR) treatment. Emerging evidence has attributed a significant role to inflammatory markers including blood cell ratios in the prognosis and survival of CRC patients; these biomarkers can be easily assessed in routine blood exams and be used to identify high-risk patients or those more likely to benefit from chemotherapy, targeted therapies and potentially immunotherapy. Analysis of cell-free DNA (cfDNA), circulating tumor cells (CTC) and/or micro RNAs (miRNAs) could provide useful information for the early diagnosis of CRC, the identification of minimal residual disease and, the evaluation of the risk of recurrence in early CRC patients. Even the selection of patients suitable for the new targeted therapy is becoming possible with the use of predictive miRNA biomarkers. Finally, the development of treatment resistance with the emergence of chemo-resistance clones after treatment remains the most important challenge in the clinical practice. In this context it is crucial to identify potential biomarkers and therapeutic targets which could lead to development of new and more effective treatments. Full article
(This article belongs to the Special Issue Biomarkers in Colorectal Cancer)
16 pages, 506 KiB  
Article
The Interaction between Genetic Polymorphisms in FTO and TCF7L2 Genes and Dietary Intake with Regard to Body Mass and Composition: An Exploratory Study
by Lara Nasreddine, Reem Akika, Aurelie Mailhac, Hani Tamim and Nathalie Khoueiry Zgheib
J. Pers. Med. 2019, 9(1), 11; https://doi.org/10.3390/jpm9010011 - 5 Feb 2019
Cited by 9 | Viewed by 7857
Abstract
In contrast to the large number of genetic studies on obesity, there has been significantly less nutrigenetics investigation of the interaction between diet and single nucleotide polymorphisms (SNPs) in obesity, especially within Eastern Mediterranean populations. The aim of this study was to evaluate [...] Read more.
In contrast to the large number of genetic studies on obesity, there has been significantly less nutrigenetics investigation of the interaction between diet and single nucleotide polymorphisms (SNPs) in obesity, especially within Eastern Mediterranean populations. The aim of this study was to evaluate the potential interactions between three candidate SNPs, namely, rs1558902 and rs9939609 in the fat mass and obesity (FTO) gene and the rs7903146 variant of the Transcription factor 7 like 2 (TCF7L2) gene, and macronutrient intake with regard to obesity, body fat, and muscle composition. Three hundred and eight healthy Lebanese adults were included in this study. Data collection included a questionnaire for demographics and lifestyle in addition to a detailed dietary assessment using a culture-specific 80-item semi-quantitative food frequency questionnaire. This was coupled with anthropometric measurements and peripheral blood withdrawal for DNA and genotyping using Taqman allele discrimination assays. The two FTO candidate SNPs were not associated with risk of obesity in this population sample, yet there was a trend, though not a significant one, towards lower muscle mass among carriers of the risk allele of either FTO SNPs. To our knowledge, these results have not been previously reported. As for the TCF7L2 rs7903146 variant, results were congruent with the literature, given that individuals who were homozygous for the risk allele had significantly higher body mass index (BMI) and body fat despite lower intakes of saturated fat. Similar interactions, though not significant, were shown with muscle mass, whereby individuals who were homozygous for the risk allele had lower muscle mass with higher intakes of saturated fat, a result that, to our knowledge, has not been previously reported. Full article
(This article belongs to the Special Issue Nutrigenomics)
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7 pages, 201 KiB  
Commentary
Understanding Implementation Challenges to Genetic Testing for Familial Hypercholesterolemia in the United States
by Rachele M. Hendricks-Sturrup and Christine Y. Lu
J. Pers. Med. 2019, 9(1), 9; https://doi.org/10.3390/jpm9010009 - 1 Feb 2019
Cited by 14 | Viewed by 7664
Abstract
Cardiovascular disease (CVD) is the leading cause of death in the United States (US), with familial hypercholesterolemia (FH) being a major inherited and genetic risk factor for premature CVD and atherosclerosis. Genetic testing has helped patients and providers confirm the presence of known [...] Read more.
Cardiovascular disease (CVD) is the leading cause of death in the United States (US), with familial hypercholesterolemia (FH) being a major inherited and genetic risk factor for premature CVD and atherosclerosis. Genetic testing has helped patients and providers confirm the presence of known pathogenic and likely pathogenic variations in FH-associated genes. Key organizations, such as the Centers for Disease Control and Prevention (CDC), American Heart Association (AHA), FH Foundation, and National Lipid Association (NLA), have recognized the clinical utility of FH genetic testing. However, FH genetic testing is underutilized in clinical practice in the US for reasons that are underexplored through the lens of implementation science. In this commentary, we discuss seven key implementation challenges that must be overcome to strengthen the clinical adoption of FH genetic testing in the US. These implementation challenges center on evidence of cost-effectiveness, navigating patient and provider preferences and concerns, gender and ethnic diversity and representation in genetic testing, and establishing clinical consensus around FH genetic testing based on the latest and most relevant research findings. Overcoming these implementation challenges is imperative to the mission of reducing CVD risk in the US. Full article
(This article belongs to the Collection Genomic Medicine and Policy)
12 pages, 434 KiB  
Article
VARIFI—Web-Based Automatic Variant Identification, Filtering and Annotation of Amplicon Sequencing Data
by Milica Krunic, Peter Venhuizen, Leonhard Müllauer, Bettina Kaserer and Arndt von Haeseler
J. Pers. Med. 2019, 9(1), 10; https://doi.org/10.3390/jpm9010010 - 1 Feb 2019
Cited by 1 | Viewed by 7556
Abstract
Fast and affordable benchtop sequencers are becoming more important in improving personalized medical treatment. Still, distinguishing genetic variants between healthy and diseased individuals from sequencing errors remains a challenge. Here we present VARIFI, a pipeline for finding reliable genetic variants (single nucleotide polymorphisms [...] Read more.
Fast and affordable benchtop sequencers are becoming more important in improving personalized medical treatment. Still, distinguishing genetic variants between healthy and diseased individuals from sequencing errors remains a challenge. Here we present VARIFI, a pipeline for finding reliable genetic variants (single nucleotide polymorphisms (SNPs) and insertions and deletions (indels)). We optimized parameters in VARIFI by analyzing more than 170 amplicon-sequenced cancer samples produced on the Personal Genome Machine (PGM). In contrast to existing pipelines, VARIFI combines different analysis methods and, based on their concordance, assigns a confidence score to each identified variant. Furthermore, VARIFI applies variant filters for biases associated with the sequencing technologies (e.g., incorrectly identified homopolymer-associated indels with Ion Torrent). VARIFI automatically extracts variant information from publicly available databases and incorporates methods for variant effect prediction. VARIFI requires little computational experience and no in-house compute power since the analyses are conducted on our server. VARIFI is a web-based tool available at varifi.cibiv.univie.ac.at. Full article
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14 pages, 956 KiB  
Review
Personalized Assessment of the Coronary Atherosclerotic Arteries by Intravascular Ultrasound Imaging: Hunting the Vulnerable Plaque
by Theodore G. Papaioannou, Charalampos Kalantzis, Efstratios Katsianos, Despina Sanoudou, Manolis Vavuranakis and Dimitrios Tousoulis
J. Pers. Med. 2019, 9(1), 8; https://doi.org/10.3390/jpm9010008 - 24 Jan 2019
Cited by 14 | Viewed by 10158
Abstract
The term “vulnerable plaque” is commonly used to refer to an atherosclerotic plaque that is prone to rupture and the formation of thrombosis, which can lead to several cardiovascular and cerebrovascular events. Coronary artery atherosclerosis has a wide variety of different phenotypes among [...] Read more.
The term “vulnerable plaque” is commonly used to refer to an atherosclerotic plaque that is prone to rupture and the formation of thrombosis, which can lead to several cardiovascular and cerebrovascular events. Coronary artery atherosclerosis has a wide variety of different phenotypes among patients who may have a substantially variable risk for plaque rupture and cardiovascular events. Mounting evidence has proposed three distinctive histopathological mechanisms: plaque rupture, plaque erosion and calcified nodules. Studies have demonstrated the characteristics of plaques with high vulnerability such as the presence of a thin fibrous cap, a necrotic lipid-rich core, abundant infiltrating macrophages and neovascularization. However, traditional coronary angiographic imaging fails to determine plaque vulnerability features, and its ability to individualize treatment strategies is limited. In recent decades, catheter-based intravascular ultrasound imaging (IVUS) modalities have been developed to identify vulnerable plaques and ultimately vulnerable patients. The aim is to individualize prediction, prevention and treatment of acute coronary events based on the identification of specific features of high-risk atherosclerotic plaques, and to identify the most appropriate interventional procedures for their treatment. In this context, the aim of this review is to discuss how personalized assessment of coronary atherosclerotic arteries can be achieved by intravascular ultrasound imaging focusing on vulnerable plaque detection. Full article
(This article belongs to the Special Issue Personalized and Targeted Atherosclerosis Treatments)
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18 pages, 1117 KiB  
Review
Pharmacogenomics of Novel Direct Oral Anticoagulants: Newly Identified Genes and Genetic Variants
by Sri H. Kanuri and Rolf P. Kreutz
J. Pers. Med. 2019, 9(1), 7; https://doi.org/10.3390/jpm9010007 - 17 Jan 2019
Cited by 91 | Viewed by 12717
Abstract
Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a [...] Read more.
Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs. Full article
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2 pages, 113 KiB  
Editorial
Acknowledgement to Reviewers of JPM in 2018
by JPM Editorial Office
J. Pers. Med. 2019, 9(1), 6; https://doi.org/10.3390/jpm9010006 - 17 Jan 2019
Viewed by 4780
Abstract
Rigorous peer-review is the corner-stone of high-quality academic publishing [...] Full article
13 pages, 810 KiB  
Review
The Emerging Role of Checkpoint Inhibition in Microsatellite Stable Colorectal Cancer
by David J. Hermel and Darren Sigal
J. Pers. Med. 2019, 9(1), 5; https://doi.org/10.3390/jpm9010005 - 16 Jan 2019
Cited by 28 | Viewed by 8313
Abstract
Checkpoint inhibitor therapy has introduced a revolution in contemporary anticancer therapy. It has led to dramatic improvements in patient outcomes and has spawned tremendous research into novel immunomodulatory agents and combination therapy that has changed the trajectory of cancer care. However, clinical benefit [...] Read more.
Checkpoint inhibitor therapy has introduced a revolution in contemporary anticancer therapy. It has led to dramatic improvements in patient outcomes and has spawned tremendous research into novel immunomodulatory agents and combination therapy that has changed the trajectory of cancer care. However, clinical benefit in patients with colorectal cancer has been generally limited to tumors with loss of mismatch repair function and those with specific germline mutations in the DNA polymerase gene. Unfortunately, tumors with these specific mutator phenotypes are in the minority. Recent pre-clinical and clinical studies have begun to reveal encouraging results suggesting that checkpoint inhibitor therapy can be expanded to an increasing number of colorectal tumors with microsatellite stability and the absence of traditional predictive biomarkers of checkpoint inhibitor response. These studies generally rely on combinations of checkpoint inhibitors with chemotherapy, molecular targeted therapy, radiation therapy, or other novel immunomodulatory agents. This article will review the most current data in microsatellite stable colorectal cancer. Full article
(This article belongs to the Special Issue Biomarkers in Colorectal Cancer)
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14 pages, 250 KiB  
Review
Re-Examining Genetic Screening and Oral Contraceptives: A Patient-Centered Review
by Bridget Hiedemann, Erin Vernon and Bonnie H. Bowie
J. Pers. Med. 2019, 9(1), 4; https://doi.org/10.3390/jpm9010004 - 15 Jan 2019
Cited by 8 | Viewed by 8374
Abstract
The World Health Organization classifies combined hormonal contraception as an unacceptable health risk in the presence of a known thrombogenic mutation but advises against routine thrombophilia screening before initiating combined oral contraceptives (COCs) on the grounds of high screening costs and low prevalence. [...] Read more.
The World Health Organization classifies combined hormonal contraception as an unacceptable health risk in the presence of a known thrombogenic mutation but advises against routine thrombophilia screening before initiating combined oral contraceptives (COCs) on the grounds of high screening costs and low prevalence. From the perspective of patient-centered care, we examine cost, prevalence, and other published arguments for and against thrombophilia screening before initiating COCs. Our patient-centered review draws on relevant empirical evidence concerning the advantages and disadvantages of thrombophilia screening, while placing the discussion in the broader context of evolving attitudes toward genetic testing and a shifting policy landscape that provides many women direct access to COCs and/or thrombophilia screening. Given variation in prior probabilities of thrombophilia, expected exposure to other risk factors for venous thromboembolism, attitudes towards risk, expected reactions to a positive test result, ability to pay, and concerns about genetic discrimination, we conclude that the current one-size-fits-most approach is not consistent with patient-centered care. Instead, we advocate for greater patient and provider education concerning the implications of thrombophilia screening. Moreover, we recommend offering patients optional thrombophilia screening before initiating COCs. Full article
20 pages, 261 KiB  
Review
Colorectal Cancer Biomarkers in the Era of Personalized Medicine
by Jai N. Patel, Mei Ka Fong and Megan Jagosky
J. Pers. Med. 2019, 9(1), 3; https://doi.org/10.3390/jpm9010003 - 14 Jan 2019
Cited by 32 | Viewed by 10125
Abstract
The 5-year survival probability for patients with metastatic colorectal cancer has not drastically changed over the last several years, nor has the backbone chemotherapy in first-line disease. Nevertheless, newer targeted therapies and immunotherapies have been approved primarily in the refractory setting, which appears [...] Read more.
The 5-year survival probability for patients with metastatic colorectal cancer has not drastically changed over the last several years, nor has the backbone chemotherapy in first-line disease. Nevertheless, newer targeted therapies and immunotherapies have been approved primarily in the refractory setting, which appears to benefit a small proportion of patients. Until recently, rat sarcoma (RAS) mutations remained the only genomic biomarker to assist with therapy selection in metastatic colorectal cancer. Next generation sequencing has unveiled many more potentially powerful predictive genomic markers of therapy response. Importantly, there are also clinical and physiologic predictive or prognostic biomarkers, such as tumor sidedness. Variations in germline pharmacogenomic biomarkers have demonstrated usefulness in determining response or risk of toxicity, which can be critical in defining dose intensity. This review outlines such biomarkers and summarizes their clinical implications on the treatment of colorectal cancer. It is critical that clinicians understand which biomarkers are clinically validated for use in practice and how to act on such test results. Full article
9 pages, 433 KiB  
Article
Association of TLR4 Polymorphisms, Expression, and Vitamin D with Helicobacter pylori Infection
by Shafika Assaad, Christy Costanian, Lama Jaffal, Fida Tannous, Maria G. Stathopoulou and Said El Shamieh
J. Pers. Med. 2019, 9(1), 2; https://doi.org/10.3390/jpm9010002 - 11 Jan 2019
Cited by 17 | Viewed by 6404
Abstract
Helicobacter pylori (H. pylori) infection is the strongest recognized risk factor for gastric adenocarcinoma. Since previous observations have shown that polymorphisms in innate immune system genes, as well as vitamin D (VitD) levels, could modify the risk of infection with Helicobacter [...] Read more.
Helicobacter pylori (H. pylori) infection is the strongest recognized risk factor for gastric adenocarcinoma. Since previous observations have shown that polymorphisms in innate immune system genes, as well as vitamin D (VitD) levels, could modify the risk of infection with Helicobacter pylori (H. pylori), we analyzed the relation between single nucleotide polymorphisms (SNPs) in TLRs (TLR1, TLR2, TLR4) CD14, RUNX3 and VitD levels with H. pylori infection. A case-control study on four hundred sixty Lebanese individuals was conducted. Eleven SNPs in total were genotyped and gene expression analysis using real-time PCR was performed in white blood cells of a subsample of eight individuals. A total of 49% of the participants were affected. Although no direct association was found between the SNPs and H. pylori infection, rs4986790G>A and rs4986791T>C in TLR4 were negatively associated with VitD levels (β = −0.371, p = 5 × 10−3 and β = −0.4, p = 2 × 10−3, respectively), which was negatively associated with H. pylori infection (OR = 0.01, p < 1 × 10−3). TLR4 expression was 3× lower in individuals with H. pylori compared with non-infected (p = 0.01). TLR4 polymorphisms, expression, and VitD could be implicated in H. pylori infection and further development of gastric adenocarcinoma. Full article
(This article belongs to the Special Issue Systems Medicine and Personalised Health and Therapy – Special Focus on Cardio-Metabolic Diseases and Cancer)
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14 pages, 247 KiB  
Review
Restoring Dystrophin Expression in Duchenne Muscular Dystrophy: Current Status of Therapeutic Approaches
by Yuko Shimizu-Motohashi, Hirofumi Komaki, Norio Motohashi, Shin’ichi Takeda, Toshifumi Yokota and Yoshitsugu Aoki
J. Pers. Med. 2019, 9(1), 1; https://doi.org/10.3390/jpm9010001 - 7 Jan 2019
Cited by 70 | Viewed by 16156
Abstract
Duchenne muscular dystrophy (DMD), a rare genetic disorder characterized by progressive muscle weakness, is caused by the absence or a decreased amount of the muscle cytoskeletal protein dystrophin. Currently, several therapeutic approaches to cure DMD are being investigated, which can be categorized into [...] Read more.
Duchenne muscular dystrophy (DMD), a rare genetic disorder characterized by progressive muscle weakness, is caused by the absence or a decreased amount of the muscle cytoskeletal protein dystrophin. Currently, several therapeutic approaches to cure DMD are being investigated, which can be categorized into two groups: therapies that aim to restore dystrophin expression, and those that aim to compensate for the lack of dystrophin. Therapies that restore dystrophin expression include read-through therapy, exon skipping, vector-mediated gene therapy, and cell therapy. Of these approaches, the most advanced are the read-through and exon skipping therapies. In 2014, ataluren, a drug that can promote ribosomal read-through of mRNA containing a premature stop codon, was conditionally approved in Europe. In 2016, eteplirsen, a morpholino-based chemical capable of skipping exon 51 in premature mRNA, received conditional approval in the USA. Clinical trials on vector-mediated gene therapy carrying micro- and mini- dystrophin are underway. More innovative therapeutic approaches include CRISPR/Cas9-based genome editing and stem cell-based cell therapies. Here we review the current status of therapeutic approaches for DMD, focusing on therapeutic approaches that can restore dystrophin. Full article
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