Journal of Personalized Medicine — Open Access Journal

Ex vivo cell/tissue-based models are an essential step in the workflow of pathophysiology studies, assay development, disease modeling, drug discovery, and development of personalized therapeutic strategies. For these purposes, both scientific and pharmaceutical research have adopted ex vivo stem cell models because of their better predictive power. As matter of a fact, the advancing in isolation and in vitro expansion protocols for culturing autologous human stem cells, and the standardization of methods for generating patient-derived induced pluripotent stem cells has made feasible to generate and investigate human cellular disease models with even greater speed and efficiency. Furthermore, the potential of stem cells on generating more complex systems, such as scaffold-cell models, organoids, or organ-on-a-chip, allowed to overcome the limitations of the two-dimensional culture systems as well as to better mimic tissues structures and functions. Finally, the advent of genome-editing/gene therapy technologies had a great impact on the generation of more proficient stem cell-disease models and on establishing an effective therapeutic treatment. In this review, we discuss important breakthroughs of stem cell-based models highlighting current directions, advantages, and limitations and point out the need to combine experimental biology with computational tools able to describe complex biological systems and deliver results or predictions in the context of personalized medicine. Full article

Population genomic screening has been demonstrated to detect at-risk individuals who would not be clinically identified otherwise. However, there are concerns about the increased utilization of unnecessary services and the associated increase in costs. The objectives of this study are twofold: (1) determine whether there is a difference in healthcare utilization and costs following disclosure of a pathogenic/likely pathogenic (P/LP) BRCA1/2 variant via a genomic screening program, and (2) measure the post-disclosure uptake of National Comprehensive Cancer Network (NCCN) guideline-recommended risk management. We retrospectively reviewed electronic health record (EHR) and billing data from a female population of BRCA1/2 P/LP variant carriers without a personal history of breast or ovarian cancer enrolled in Geisinger’s MyCode genomic screening program with at least a one-year post-disclosure observation period. We identified 59 women for the study cohort out of 50,726 MyCode participants. We found no statistically significant differences in inpatient and outpatient utilization and average total costs between one-year pre- and one-year post-disclosure periods ($18,821 vs. $19,359, p = 0.76). During the first year post-disclosure, 49.2% of women had a genetic counseling visit, 45.8% had a mammography and 32.2% had an MRI. The uptake of mastectomy and oophorectomy was 3.5% and 11.8%, respectively, and 5% of patients received chemoprevention. Full article

Background: Mandibular reconstruction, after extensive resection of the mandible for the treatment of oral cancer, is a well-known procedure, however, relatively little is known about bone integration into the titanium implant after reconstruction with a temporary plastic implant. The main goal of this experimental study was to study the process of osseous integration into the titanium implant in an in vivo experiment following prior mandibular reconstruction with a temporary plastic implant. Materials and Methods: Four ewes initially underwent a partial one-sided resection of the mandible, with the formation of an approximately 3 × 1 cm defect. All of the subjects received reconstruction with an implantation of a plastic plate (3 cm). The plastic plate was removed and replaced by a titanium implant at 1, 3, 6, and 12 months, accordingly. Both plastic and titanium implants were made via 3D-printing technology and personalized modeling. A total of 6 months after titanium implantation, a histological evaluation of biointegration was performed. Results: All surgeries were uncomplicated. The integration of osseous tissue into the titanium implant was seen in all cases. Histologically, each case showed variable integration of dense fibrotic tissue with fibroblasts and non-mature bone tissue with a definitive layer of bone matrix with many osteoblasts on the periphery. The prior implantation of the plastic plate did not interfere with bone integration into the titanium implant. Conclusion: Preliminary results demonstrated that a temporary plastic implant for mandibular reconstruction does not interfere with the consequent osseous biointegration of a permanent titanium implant. This shows that temporary reconstruction is a safe solution when delayed mandibular reconstruction is required due to disease severity. Full article

Objectives: The hierarchical structure of enamel gives insight on the properties of enamel and can influence its strength and ultimately caries experience. Currently, past caries experience is quantified using the decayed, missing, filled teeth/decayed, missing, filled surface (DMFT/DMFS for permanent teeth; dmft/dmfs for primary teeth), or international caries detection and assessment system (ICDAS) scores. By analyzing the structure of enamel, a new measurement can be utilized clinically to predict susceptibility to future caries experience based on a patient’s individual’s biomarkers. The purpose of this study was to test the hypothesis that number of prisms by square millimeter in enamel and average gap distance between prisms and interprismatic areas, influence caries experience through genetic variation of the genes involved in enamel formation. Materials and Methods: Scanning electron microscopy (SEM) images of enamel from primary teeth were used to measure (i) number of prisms by square millimeter and interprismatic spaces, (ii) prism density, and (iii) gap distances between prisms in the enamel samples. The measurements were tested to explore a genetic association with variants of selected genes and correlations with caries experience based on the individual’s DMFT+ dmft score and enamel microhardness at baseline, after an artificial lesion was created and after the artificial lesion was treated with fluoride. Results: Associations were found between variants of genes including ameloblastin, amelogenin, enamelin, tuftelin, tuftelin interactive protein 11, beta defensin 1, matrix metallopeptidase 20 and enamel structure variables measured (number of prisms by square millimeter in enamel and average gap distance between prisms and interprismatic areas). Significant correlations were found between caries experience and microhardness and enamel structure. Negative correlations were found between number of prisms by square millimeter and high caries experience (r value= −0.71), gap distance between prisms and the enamel microhardness after an artificial lesion was created (r value= −0.70), and gap distance between prisms and the enamel microhardness after an artificial lesion was created and then treated with fluoride (r value= −0.81). There was a positive correlation between number of prisms by square millimeter and prism density of the enamel (r value = 0.82). Conclusions: Our data support that genetic variation may impact enamel formation, and therefore influence susceptibility to dental caries and future caries experience. Clinical Relevance: The evaluation of enamel structure that may impact caries experience allows for hypothesizing that the identification of individuals at higher risk for dental caries and implementation of personalized preventative treatments may one day become a reality. Full article

Biotinidase deficiency is an autosomal recessive metabolic disorder whose diagnosis currently depends on clinical symptoms and a biotinidase enzyme assay. This study aimed to investigate the mutational status and enzymatic activity of biotinidase deficiency in seven unrelated Jordanian families including 10 patients and 17 healthy family members. Amplified DNA was analyzed by the automated Sanger sequencing method, and the enzymatic assay was performed using a colorimetric assessment. Biotinidase level was significantly lower (p < 0.001) in BTD children compare to their non-affected family members. Genetic sequencing revealed six different mutations in Jordanian patients. One mutation was novel and located in exon 4, which could be a prevalent mutation for biotinidase deficiency in the Jordanian population. Identification of these common mutations and combing the enzymatic activity with genotypic data will help clinicians with regard to better genetic counseling and management through implementing prevention programs in the future. Full article

Background: The cytochrome P450 drug metabolizing enzymes CYP2D6 and CYP2C19 are the major targets for pharmacogenomics (PGx) testing and determining for drug response. Clinical dosing guidelines for specific drug-gene interactions (DGI) are publicly available through PharmGKB. The aim of this register study was to map the use of drugs in Denmark for drugs having actionable dosing guidelines (AG) i.e., dosing recommendations different from standard dosing for CYP2D6 or CYP2C19 DGI in terms of consumption. Methods: The Danish Register of Medicinal Product Statistics was the source to retrieve consumption in Defined Daily Dose (DDD) i.e., the assumed average maintenance dose per day for a drug used for its main indication in adults and number of users (2017 data). Clinical dosing guidelines were available from the PharmGKB website. Results: Forty-nine drugs have guidelines corresponding to 14.5% of total sales in DDD. Twenty-eight drugs have AG corresponding to 375.2 million DDD. Pantoprazole, lansoprazole, omeprazole, clopidogrel, and metoprolol constituted fifty-eight percent of the consumption in DDD of drugs having AG. The consumption of antidepressant drugs, opioids, and antipsychotic drugs were 157.0 million DDD; with 441,850 users, 48.9 million DDD; with 427,765 users, and 23.7 million DDD; with 128,935 users, respectively. Age distributions of consumption of drugs and drug combinations, e.g., for sertraline redeemed either alone or in combination with metoprolol and tramadol, are presented. Conclusion: This exploratory register study clearly showed that a large fraction of the Danish population, especially the elderly, are exposed to drugs or drug combinations for which there exist AG related to PGx of CYP2D6 or CYP2C19. Full article

Several genetic variants have been identified that cause variation among different populations and even within individuals of a similar descent. This leads to interindividual variations in the optimal dose of the drug that is required to sustain the treatment efficiency. In this study, 56 single nucleotide polymorphisms (SNPs) within several pharmacogenes were analyzed in 128 unrelated subjects from a genetically isolated group of Circassian people living in Jordan. We also compared these variant distributions to other ethnic groups that are available at two databases (Genome 1000 and eXAC). Our results revealed that the distribution of allele frequencies within genes among Circassians in Jordan showed similarities and disparities when compared to other populations. This study provides a powerful base for clinically relevant SNPs to enhance medical research and future pharmacogenomic studies. Rare variants detected in isolated populations can significantly guide to novel loci involved in the development of clinically relevant traits. Full article

Introduction: Though disease-related differences between the sexes have increasingly attracted attention, the renal impact of pulse pressure (PP) in patients with chronic kidney disease (CKD) has never been investigated comprehensively in relation to differences associated with sex. We aimed to examine sex differences in PP as a related factor of CKD progression from the perspective of atherosclerosis. Methods: A total of 156 patients with CKD matched according to age and estimated glomerular filtration rate (eGFR) were separated into sex-based cohorts. Multivariate Cox proportional hazards analyses were performed to identify factors associated with renal outcomes. Kaplan–Meier analyses were performed to assess disease progression, which was defined as a ≥50% estimated glomerular filtration rate (eGFR) decline or end-stage renal disease. Results: The mean age of the study participants was 58.9 ± 13.1 years, and the median follow-up period was 114.0 months. A multivariate Cox regression analysis showed that PP was significantly associated with disease progression among the entire cohort (p = 0.007). In the sex-based sub-cohort analyses, PP was significantly associated with disease progression in men (p = 0.0004) but not in women. Among the entire cohort, PP was correlated positively with age (p = 0.03) and negatively with high-density lipoprotein-cholesterol (HDL-C) level (p = 0.003). PP was significantly correlated with visceral fat area (VFA) (p = 0.04) and hemoglobin level (p = 0.04) in men and with HDL-C level (p = 0.003) in women. Conclusion: A high PP is a significant related factor of CKD progression, especially in men, in whom it is significantly associated with greater VFA and lower hemoglobin level. Full article

MicroRNAs (miRNAs) are endogenous, small (18–23 nucleotides), non-coding RNA molecules. They regulate the posttranscriptional expression of their target genes. MiRNAs control vital physiological processes such as metabolism, development, differentiation, cell cycle and apoptosis. The control of the gene expression by miRNAs requires efficient binding between the miRNA and their target mRNAs. Genome-wide association studies (GWASs) have suggested the association of single-nucleotide polymorphisms (SNPs) with certain diseases in various populations. Gene polymorphisms of miRNA target sites have been implicated in diseases such as cancers, diabetes, cardiovascular and Parkinson’s disease. Likewise, gene polymorphisms of miRNAs have been reported to be associated with diseases. In this review, we discuss the SNPs in miRNA genes that have been associated with diabetes and atherosclerotic cardiovascular disease in different populations. We also discuss briefly the potential underlining mechanisms through which these SNPs increase the risk of developing these diseases. Full article

West Virginia is a rural state with an aging population that may experience barriers to accessing nutritional and lifestyle counseling. This study examined feasibility of an online personalized nutrition tracking application, Good Measures (GM), with patients at seven health care clinics throughout the state. Fourteen healthcare providers and 64 patients 18 years or older with a Body Mass Index (BMI) greater than or equal to 30 and access to the Internet were recruited for this 12-week feasibility study. Patient participants logged meals and exercise into the GM application via smart phone, tablet, or computer and virtually engaged with a Registered Dietitian Nutritionist (RDN) in one-on-one sessions. The primary endpoint was to examine feasibility of the program by usage of the application and feedback questions regarding the benefits and challenges of the application. Participants were predominately white (92%) and female (76%). Minimal improvements in weight and systolic blood pressure were found. Participant attitude survey data declined from 4-weeks to 12-weeks of the intervention. Interestingly though, patients in a rural clinic had lesser declines in attitudes than peri-urban participants. Qualitative feedback data identified participants predominately had a positive overall feeling toward the approach. Participants expressed favorability of RDN access, the variety of foods, but did give suggestions for in-person meetings and more updating of the application. Implementing a technology approach to nutrition in rural areas of West Virginia using a mobile application with RDN access may be one strategy to address public health issues such as obesity. Full article

Microneedles (MNs) have been extensively explored in the literature as a means to deliver drugs in the skin, surpassing the stratum corneum permeability barrier. MNs are potentially easy to produce and may allow the self-administration of drugs without causing pain or bleeding. More recently, MNs have been investigated to collect/assess the interstitial fluid in order to monitor or detect specific biomarkers. The integration of these two concepts in closed-loop devices holds the promise of automated and minimally invasive disease detection/monitoring and therapy. These assure low invasiveness and, importantly, open a window of opportunity for the application of population-specific and personalised therapies. Full article

Background: Acromegaly is almost always caused by a pituitary adenoma and is associated with high morbidity and mortality when uncontrolled. Trans-sphenoidal removal of the adenoma is the mainstay of therapy, but fails to control the disease in a significant number of patients who require further treatment. Somatostatin analogues (SSAs) as monotherapy or in combination with growth hormone (GH)-receptor antagonists and/or dopamine agonists are used either alone or in combination following surgical failure to achieve disease control. The use of specific biomarkers may help to individualize the therapeutic plan after surgical failure and direct towards a more personalized approach. Methods: We report a 41-year-old man with acromegaly and residual disease after repeated surgery that was resistant to first-generation SSAs. Results: Biochemical and tumor control were achieved following the administration of a second-generation SSA, pasireotide, combined with pegvisomant, both at maximal doses and along with cabergoline. Histology specimens showed a sparsely-granulated GH-immunostaining pituitary adenoma with intense positivity for somatostatin receptors 2 and 5 and low levels of E-cadherin. Conclusion: Personalized medical therapy guided by currently available biomarkers, such as immunohistochemically-characterized receptor profiling or adhesion molecules, resulted in controlled insulin-like growth factor-1 (IGF-1) and GH levels and symptom alleviation following the combination of three drug-classes. Full article

Health systems and physicians nationwide aspire to consistently and reliably apply genetic and genomic information to guide disease prevention, management, and treatment. However, clinical information, including genetics/genomics data from within and outside of the care delivery system, is expanding rapidly. Between November 2017 and April 2018, we surveyed 1502 Permanente Medical Group primary care and specialist physicians to assess the degree to which direct-to-consumer genetic test results were being presented to physicians and identify genetics educational needs among physicians (response rate 15%). Adjusted logistic regression (according to respondent characteristics) was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing responses within groups. Results showed 35% and 12% of respondents reported receiving at least one direct-to-consumer health risk genetic result (DTC-health risk) or direct-to-consumer pharmacogenomic test result (DTC-PGx), respectively, from a patient in the past year. Of those receiving at least one test result, 40% (DTC-health risk) and 39% (DTC-PGx) of physicians reported 1+ referral(s); 78% (DTC-health risk) and 42% (DTC-PGx) of referrals were to clinical genetics. In total, 85% of physicians would spend ≥2 h/year on genetics/genomics education. Full article

Tumour necrosis factor (TNF)-α is a key mediator of inflammation in rheumatoid arthritis, and its discovery led to the development of highly successful anti-TNF therapy. Subsequently, other biologic drugs targeting immune pathways, namely interleukin-6 blockade, B cell depletion, and T cell co-stimulation blockade, have been developed. Not all patients respond to a biologic drug, leading to a knowledge gap between biologic therapies available and the confident prediction of response. So far, genetic studies have failed to uncover clinically informative biomarkers to predict response. Given that the targets of biologics are immune pathways, immunological study has become all the more pertinent. Furthermore, advances in single-cell technology have enabled the characterization of many leucocyte subsets. Studying the blood immunophenotype may therefore, define biomarker profiles relevant to each individual patient’s disease and treatment outcome. This review summarises our current understanding of how immune biomarkers might be able to predict treatment response to biologic drugs. Full article

Drug metabolic enzymes and transporters are responsible for an important variability in drug disposition. The cocktail approach is a sound strategy for the simultaneous evaluation of several enzyme and transporter activities for a personalized dosage of medications. Recently, we have demonstrated the reliability of the Geneva cocktail, combining the use of dried blood spots (DBS) and reduced dose of phenotyping drugs for the evaluation of the activity of six cytochromes and P-glycoprotein (P-gp). As part of a study evaluating potential drug–drug interactions between probe drugs of the Geneva cocktail, the present paper focuses on the impact of cytochromes (CYP) probe drugs on the disposition of fexofenadine, a P-gp test drug. In a randomized four-way Latin-square crossover study, 30 healthy volunteers (15 men and 15 women) received caffeine 50 mg, bupropion 20 mg, flurbiprofen 10 mg, omeprazole 10 mg, dextromethorphan 10 mg, midazolam 1 mg, and fexofenadine 25 mg alone (or as part of a previously validated combination) and all together (Geneva cocktail). The determination of drug concentrations was performed in DBS samples and pharmacokinetic parameters were calculated. Fexofenadine AUC_{0–8 h} and C_max decreased by 43% (geometric mean ratio: 0.57; CI 90: 0.50–0.65; p < 0.001) and 49% (geometric mean ratio: 0.51; CI 90: 0.44–0.59; p < 0.001), respectively, when fexofenadine was administered as part of the Geneva cocktail in comparison to fexofenadine alone. Consequently, the apparent oral clearance (Cl/F) increased 1.7-fold (CI 90: 1.49–1.93; p < 0.001). There was no interaction between the remaining probes. In conclusion, an unexpected interaction occurred between fexofenadine and one or several of the following substances: caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, and midazolam. Further studies are necessary to elucidate the mechanism of this interaction. Full article

Cancer is a leading cause of death worldwide and therefore one of the most important public health concerns. In this contribution, we discuss recent key enabling technological innovations (and their challenges), including biomarker-based technologies, that potentially allow for decentralization (e.g., self-monitoring) with the increasing availability of point-of-care technologies in the near future. These technological innovations are moving the field one step closer toward personalized oncology. Full article

The molecular characterization of patient tumors provides a rational and highly promising approach for guiding oncologists in treatment decision-making. Notwithstanding, genomic medicine still remains in its infancy, with innovators and early adopters continuing to carry a significant portion of the clinical and financial risk. Numerous innovative precision oncology trials have emerged globally to address the associated need for evidence of clinical utility. These studies seek to capitalize on the power of predictive biomarkers and/or treatment decision support analytics, to expeditiously and cost-effectively demonstrate the positive impact of these technologies on drug resistance/response, patient survival, and/or quality of life. Here, we discuss the molecular foundations of these approaches and highlight the diversity of innovative trial strategies that are capitalizing on this emergent knowledge. We conclude that, as increasing volumes of clinico-molecular outcomes data become available, in future, we will begin to transition away from expert systems for treatment decision support (TDS), towards the power of AI-assisted TDS—an evolution that may truly revolutionize the nature and success of cancer patient care. Full article

Pharmacogenetics and biomarkers are becoming normalised as important technologies to improve drug efficacy rates, reduce the incidence of adverse drug reactions, and make informed choices for targeted therapies. However, their wider clinical implementation has been limited by a lack of robust evidence. Suitable evidence is required before a biomarker’s clinical use, and also before its use in a clinical trial. We have undertaken a review of five pharmacogenetic biomarker-guided randomised controlled trials (RCTs) and evaluated the evidence used by these trials to justify biomarker inclusion. We assessed and quantified the evidence cited in published rationale papers, or where these were not available, obtained protocols from trial authors. Very different levels of evidence were provided by the trials. We used these observations to write recommendations for future justifications of biomarker use in RCTs and encourage regulatory authorities to write clear guidelines. Full article