Journal of Personalized Medicine

Chronic pain (CP) severely disrupts the daily life of millions. Interoception (i.e., sensing the physiological condition of the body) plays a pivotal role in the aetiology and maintenance of CP. As pain is inherently an interoceptive signal, interoceptive frameworks provide important, but underutilized, approaches to this condition. Here we first investigated three facets of interoceptive perception in CP, compared with pain-free controls. We then introduce a novel interoceptive treatment and demonstrate its capacity to reduce pain severity in CP, potentially providing complementary analgesic treatments. Study 1 measured interoceptive accuracy, confidence and sensibility in patients (N = 60) with primary, secondary musculoskeletal, and neuropathic CP. Compared with matched controls, CP participants exhibited significantly lower interoceptive accuracy and interoceptive confidence. Pain severity was predicted positively by interoceptive accuracy, anxiety and depression, and negatively by interoceptive confidence. Study 2 tested a promising new interoceptive treatment for CP, in a single-blind between-subjects design (N = 51) with primary, secondary musculoskeletal, and neuropathic CP patients. The treatment specifically activates the C-Tactile system, by means of controlled stimulation of interoceptive unmyelinated afferents, at 3 cm/s with a force of 2.5 mN. This treatment led to significant pain reduction (mean 23%) in the CP treatment group after only 11 min, while CP controls who received comparable but non-interoceptive stimulation reported no change in pain intensity. These studies highlight the importance of interoceptive approaches to CP and demonstrate the potential of this novel method of C-Tactile stimulation to provide complementary analgesic treatments. Full article

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer which presents a high rate of relapse, metastasis, and mortality. Nowadays, the absence of approved specific targeted therapies to eradicate TNBC remains one of the main challenges in clinical practice. Drug discovery is a long and costly process that can be dramatically improved by drug repurposing, which identifies new uses for existing drugs, both approved and investigational. Drug repositioning benefits from improvements in computational methods related to chemoinformatics, genomics, and systems biology. To the best of our knowledge, we propose a novel and inclusive classification of those approaches whereby drug repurposing can be achieved in silico: structure-based, transcriptional signatures-based, biological networks-based, and data-mining-based drug repositioning. This review specially emphasizes the most relevant research, both at preclinical and clinical settings, aimed at repurposing pre-existing drugs to treat TNBC on the basis of molecular mechanisms and signaling pathways such as androgen receptor, adrenergic receptor, STAT3, nitric oxide synthase, or AXL. Finally, because of the ability and relevance of cancer stem cells (CSCs) to drive tumor aggressiveness and poor clinical outcome, we also focus on those molecules repurposed to specifically target this cell population to tackle recurrence and metastases associated with the progression of TNBC. Full article

Alzheimer’s disease (AD) and related dementias disproportionately impact racial and ethnic minorities. The racial and ethnic disparities in AD could be explained by differences in cerebral vascular disease pathology. Endothelin-1 (ET-1) is a potent vasoconstrictive peptide that regulates smooth muscle, endothelial cell, and pericyte contractions that may result in cerebral vascular constriction, leading to cerebral hypoperfusion; over time, ET-1 may result in neuronal injury contributing to the pathology of AD. Upregulation of the ET-1 system has been observed in African Americans when compared with non-Hispanic Whites. The role of the ET-1 system as a driver of ethnic disparities in AD requires further investigation. Targeting of the ET-1 system as a therapeutic intervention that could impact AD progression also needs further study. Dysregulation of ET-1 in Hispanic/Latino populations largely have been unexplored. Genetics linking ET-1 dysregulation and racial disparities in AD also needs further investigation. In this review, I examine how AD effects underserved minority populations and how dysregulation of the ET-1 system specifically predisposes ethnic minorities to AD. In addition, I examine the molecular interactions of the ET-1 system and amyloid beta, the role the ET-1 system in neurodegeneration, potential therapeutics for ET-1 dysregulation, and the impact on AD progression. Full article

This retrospective study evaluates the link between an adverse drug reaction (ADR) or a non-response to treatment and cytochromes P450 (CYP), P-glycoprotein (P-gp) or catechol-O-methyltransferase (COMT) activity in patients taking analgesic drugs for chronic pain. Patients referred to a pain center for an ADR or a non-response to an analgesic drug between January 2005 and November 2014 were included. The genotype and/or phenotype was obtained for assessment of the CYPs, P-gp or COMT activities. The relation between the event and the result of the genotype and/or phenotype was evaluated using a semi-quantitative scale. Our analysis included 243 individual genotypic and/or phenotypic explorations. Genotypes/phenotypes were mainly assessed because of an ADR (n = 145, 59.7%), and the majority of clinical situations were observed with prodrug opioids (n = 148, 60.9%). The probability of a link between an ADR or a non-response and the genotypic/phenotypic status of the patient was evaluated as intermediate to high in 40% and 28.2% of all cases, respectively. The drugs in which the probability of an association was the strongest were the prodrug opioids, with an intermediate to high link in 45.6% of the cases for occurrence of ADRs and 36.0% of the cases for non-response. This study shows that the genotypic and phenotypic approach is useful to understand ADRs or therapeutic resistance to a usual therapeutic dosage, and can be part of the evaluation of chronic pain patients. Full article

Many studies have focused on the early detection of Alzheimer’s disease (AD). Cerebral amyloid beta (Aβ) is a hallmark of AD and can be observed in vivo via positron emission tomography imaging using an amyloid tracer or cerebrospinal fluid assessment. However, these methods are expensive. The current study aimed to identify and compare the ability of magnetic resonance imaging (MRI) markers and neuropsychological markers to predict cerebral Aβ status in an AD cohort using machine learning (ML) approaches. The prediction ability of candidate markers for cerebral Aβ status was examined by analyzing 724 participants from the ADNI-2 cohort. Demographic variables, structural MRI markers, and neuropsychological test scores were used as input in several ML algorithms to predict cerebral Aβ positivity. Out of five combinations of candidate markers, neuropsychological markers with demographics showed the most cost-efficient result. The selected model could distinguish abnormal levels of Aβ with a prediction ability of 0.85, which is the same as that for MRI-based models. In this study, we identified the prediction ability of MRI markers using ML approaches and showed that the neuropsychological model with demographics can predict Aβ positivity, suggesting a more cost-efficient method for detecting cerebral Aβ status compared to MRI markers. Full article

The successful implementation of personalized medicine will rely on the integration of information obtained at the level of populations with the specific biological, genetic, and clinical characteristics of an individual. However, because genome-wide association studies tend to focus on populations of European descent, there is a wide gap to bridge between Caucasian and non-Caucasian populations before personalized medicine can be fully implemented, and rheumatoid arthritis (RA) is not an exception. In this review, we discuss advances in our understanding of genetic determinants of RA risk among global populations, with a focus on the Latin American population. Geographically restricted genetic diversity may have important implications for health and disease that will remain unknown until genetic association studies have been extended to include Latin American and other currently under-represented ancestries. The next few years will witness many breakthroughs in personalized medicine, including applications for common diseases and risk stratification instruments for targeted prevention/intervention strategies. Not all of these applications may be extrapolated from the Caucasian experience to Latin American or other under-represented populations. Full article

The development of high-throughput techniques has permitted the accumulation of enormous amounts of genomic information. As increasing numbers of studies aim to utilize individual genomic information for diagnostic, preventive, or therapeutic purposes, Institutional Review Boards (IRBs) have a greater opportunity to review such types of study protocols. An article published in the Journal of Personalized Medicine titled, “Ethical Considerations Related to Return of Results from Genomic Medicine Projects: The eMERGE Network (Phase III) Experience” identified the common concerns of IRBs in the process of reviewing such studies, and some concerns included the readability of informed consent materials, potential risks to participants, information sharing with family members, options for withdrawal or receiving limited results, and provisions to clear participant questions. Since there is an increase in the number of genomic medicine implementation studies worldwide, the insights provided by this study would assist future researchers in protocol preparation as well as aid project review by IRB members. Full article

Coronary artery disease (CAD) is a major cause of death all over the world. CAD is caused by atherosclerosis which is induced by the interaction of genetic factors and environmental factors. Genome-wide association studies have revealed the association of certain gene polymorphisms with susceptibility to CAD. Omentin 1 is an adipokine secreted by the visceral adipose tissues and has been reported to have anti-inflammatory, cardioprotective, and enhances insulin sensitivity. In this study, we examined the role of omentin-1 common single nucleotide polymorphisms (SNPs) (rs2274907 A > T and rs2274908 G > A) in CAD. We conclude that the AT genotype and the T allele of the rs2274907 A > T is associated with Cad in the south Indian population. Our results indicated that the rs2274907 SNP may be associated with CAD in this population. This finding needs further validation in well-designed and large-sample size studies before being introduced in clinical settings. Full article

Premature ovarian failure (POF) is a complex disease of which the etiology is influenced by numerous genetic variations. Several POF candidate genes have been reported. However, no causal genes with high odds ratio (OR) have yet been discovered. This study included 564 females of Korean ethnicity, comprising 60 patients with POF and 182 controls in the discovery set and 105 patients with POF and 217 controls in the replication set. We conducted genome-wide association analysis to search for novel candidate genes predicted to influence POF development using Axiom Precision Medicine Research Arrays and additive model logistic regression analysis. One statistically significant single nucleotide polymorphism (SNP), rs55941146, which encodes a missense alteration (Val > Gly) in the APBA3 gene, was identified with OR values for association with POF of 13.33 and 4.628 in the discovery and replication sets, respectively. No rs55941146 minor allele homozygotes were present in either cases or controls. The APBA3 protein binds FIH-1 that inhibits hypoxia inducible factor-1α (HIF-1α). HIF-1α contributes to granulosa cell proliferation, which is crucial for ovarian follicle growth, by regulating cell proliferation factors and follicle stimulating hormone-mediated autophagy. Our data demonstrate that APBA3 is a candidate novel causal gene for POF. Full article

The interaction between genetic susceptibility, epigenetic, endogenous, and environmental factors play a key role in the initiation and progression of autoimmune thyroid diseases (AITDs). Studies have shown that gut microbiota alterations take part in the development of autoimmune diseases. We have investigated the possible relationship between gut microbiota composition and the most frequent AITDs. A total of nine Hashimoto’s thyroiditis (HT), nine Graves–Basedow’s disease (GD), and 11 otherwise healthy donors (HDs) were evaluated. 16S rRNA pyrosequencing and bioinformatics analysis by Quantitative Insights into Microbial Ecology and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) were used to analyze the gut microbiota. Beta diversity analysis showed that gut microbiota from our groups was different. We observed an increase in bacterial richness in HT and a lower evenness in GD in comparison to the HDs. GD showed a significant increase of Fusobacteriaceae, Fusobacterium and Sutterella compared to HDs and the core microbiome features showed that Prevotellaceae and Prevotella characterized this group. Victivallaceae was increased in HT and was part of their core microbiome. Streptococcaceae, Streptococcus and Rikenellaceae were greater in HT compared to GD. Core microbiome features of HT were represented by Streptococcus, Alistipes, Anaerostipes, Dorea and Haemophilus. Faecalibacterium decreased in both AITDs compared to HDs. PICRUSt analysis demonstrated enrichment in the xenobiotics degradation, metabolism, and the metabolism of cofactors and vitamins in GD patients compared to HDs. Moreover, correlation studies showed that some bacteria were widely correlated with autoimmunity parameters. A prediction model evaluated a possible relationship between predominant concrete bacteria such as an unclassified genus of Ruminococcaceae, Sutterella and Faecalibacterium in AITDs. AITD patients present altered gut microbiota compared to HDs. These alterations could be related to the immune system development in AITD patients and the loss of tolerance to self-antigens. Full article

The study by Jha et al. (2019) demonstrated an association of the single nucleotide polymorphism (SNP) rs2274907 A>T with coronary artery disease (CAD) in 100 CAD patients and 100 matched healthy controls from a South Indian population. There are serious concerns with regard to the interpretations of the study findings. The genotypes of the SNP are not in Hardy–Weinberg equilibrium (HWE) in both cases (p < 0.0001) and controls (p = 0.006), which is indicative of a technical error due to a problematic genotyping method. In addition, the genotype and allele frequencies reported in the study do not match with the frequencies listed in the SNP database for Asian Indians. While the study by Jha et al. reported ”T” allele as the minor allele, the dbSNP database reported ”A” as the minor allele. In summary, it can be concluded that the data presented in the study suffer from genotyping as well as data interpretation error and, hence, the findings should be considered by the reader with caution. Full article

Medical and health science students represent future health professionals, and their perceptions are essential to increasing awareness on genomic medicine and pharmacogenomics. Lack of education is one of the significant barriers that may affect health professional’s ability to interpret and communicate pharmacogenomics information and results to their clients. Our aim was to assess medical and health science students’ knowledge, attitudes and perception for a better genomic medicine and pharmacogenomics practice in the United Arab Emirates (UAE). A cross-sectional study was conducted using a validated questionnaire distributed electronically to students recruited using random and snowball sampling methods. A total of 510 students consented and completed the questionnaire between December 2018 and October 2019. The mean knowledge score (SD) for students was 5.4 (±2.7). There were significant differences in the levels of knowledge by the year of study of bachelor’s degree students, the completion status of training or education in pharmacogenomics (PGX) or pharmacogenetics and the completion of an internship or study abroad program (p-values < 0.05. The top two barriers that students identified in the implementation of genomic medicine and pharmacogenomics were lack of training or education (59.7%) and lack of clinical guidelines (58.7%). Concerns regarding confidentiality and discrimination were stated. The majority of medical and health science students had positive attitudes but only had a fair level of knowledge. Stakeholders in the UAE must strive to acquaint their students with up-to-date knowledge of genomic medicine and pharmacogenomics. Full article

Brain-derived neurotrophic factor (BDNF) and its tropomyosin-related kinase B (TrkB) receptor might contribute to normal lung functioning and immune responses; however, their role in asthma remains unclear. Plasma BDNF concentrations, as well as BDNF and NTRK2 (TrkB gene) polymorphisms, were investigated in 120 asthma patients and 120 healthy individuals using enzyme-linked immunosorbent assay and polymerase chain reaction, respectively. The genotype and allele frequencies of BDNF Val66Met (rs6265) and NTRK2 rs1439050 polymorphisms did not differ between healthy individuals and asthma patients, nor between patients grouped according to severity or different asthma phenotypes. Although plasma BDNF concentrations were higher among healthy subjects carrying the BDNF Val66Met GG genotype compared to the A allele carriers, such differences were not detected in asthma patients, suggesting the influences of other factors. Plasma BDNF concentration was not affected by NTRK2 rs1439050 polymorphism. Asthma patients had higher plasma BDNF concentrations than control subjects; however, no differences were found between patients subdivided according to asthma severity, or Type-2, allergic, and eosinophilic asthma. Higher plasma BDNF levels were observed in asthma patients with aspirin sensitivity and aspirin-exacerbated respiratory disease. These results suggest that plasma BDNF may serve as a potential peripheral biomarker for asthma, particularly asthma with aspirin sensitivity. Full article

Advanced therapy-refractory solid tumors bear a dismal prognosis and constitute a major challenge in offering effective treatment strategies. In this real-world retrospective analysis of our precision medicine platform MONDTI, we describe the molecular profile of 554 patients diagnosed with 17 different types of advanced solid tumors after failure of all standard treatment options. In 304 cases (54.9% of all patients), a molecular-driven targeted therapy approach could be recommended, with a recommendation rate above 50% in 12 tumor entities. The three highest rates for therapy recommendation per tumor classification were observed in urologic malignancies (90.0%), mesothelioma (78.6%), and male reproductive cancers (71.4%). Tumor type (p = 0.46), expression of p-mTOR (p = 0.011), expression of EGFR (p = 0.046), and expression of PD-L1 (p = 0.023) had a significant impact on the targeted therapy recommendation rate. Therapy recommendations were significantly more often issued for men (p = 0.015) due to gender-specific differences in the molecular profiles of patients with head and neck cancer and malignant mesothelioma. This analysis demonstrates that precision medicine was feasible and provided the basis for molecular-driven therapy recommendations in patients with advanced therapy refractory solid tumors. Full article

We have entered an era of direct-to-consumer (DTC) genomics. Patients have relayed many success stories of DTC genomics about finding causal mutations of genetic diseases before showing any symptoms and taking precautions. However, consumers may also take unnecessary medical actions based on false alarms of “pathogenic alleles”. The severity of this problem is not well known. Using publicly available data, we compared DTC microarray genotyping data with deep-sequencing data of 5 individuals and manually checked each inconsistently reported single nucleotide variants (SNVs). We estimated that, on average, a person would have ~5 “pathogenic” alleles reported due to wrongly reported genotypes if using a 23andMe genotyping microarray. We also found that the number of wrongly classified “pathogenic” alleles per person is at least as significant as those due to wrongly reported genotypes. We show that the scale of the false alarm problem could be large enough that the medical costs will become a burden to public health. Full article

Classification of cirrhosis based on clinical stages is rapid and based on five stages at present. Two other relevant events, hepatic encephalopathy (HE) and spontaneous bacterial peritonitis (SBP), can be considered in a clinical perspective but no study has implemented a seven-stage classification and confirmed its value before. In addition, long-term validation of the Model for End-Stage Liver Disease (MELD) in large cohorts of patients with cirrhosis and comparison with clinical findings are insufficient. Therefore, we performed a study to address these items. From the Chang-Gung Research Database (CGRD), 20,782 patients with cirrhosis were enrolled for an historical survival study. The MELD score, the five-stage clinical score (i.e., occurrence of esophageal varices (EV), EV bleeding, ascites, sepsis) and a novel seven-stage clinical score (i.e., occurrence of EV, EV bleeding, ascites, sepsis, HE, SBP) were compared with their Cox models by receiver operating characteristic (ROC) analysis. The addition of HE and SBP to the seven-stage model had a 5% better prediction result than the five-stage model did in the survival ROC analysis. The result showed that the seven clinical stages are associated with an increased risk for mortality. However, the predicted performances of the seven-stage model and MELD system are likely equivalent. In conclusion, the study (i) proved that clinical staging of cirrhosis based on seven items/stages had higher prognostic value than the five-stage model and (ii) confirmed the validity of the MELD criteria vs. clinical assessment. Full article

This study aimed to assess the prognostic value of computed tomography (CT)-attenuation and ¹⁸F-fluorodeoxyglucose (FDG) uptake of periprostatic adipose tissue (PPAT) for predicting disease progression-free survival (DPFS) in patients with prostate cancer. Seventy-seven patients with prostate cancer who underwent staging FDG positron emission tomography (PET)/CT were retrospectively reviewed. CT-attenuation (HU) and FDG uptake (SUV) of PPAT were measured from the PET/CT images. The relationships between these PPAT parameters and clinical factors were assessed, and a Cox proportional hazard regression test was performed to evaluate the prognostic significance of PPAT HU and SUV. PPAT HU and SUV showed significant positive correlations with tumor stage and serum prostate-specific antigen level (PSA) (p < 0.05). Patients with high PPAT HU and SUV had significantly worse DPFS than those with low PPAT HU and SUV (p < 0.05). In multivariate analysis, PPAT SUV was a significant predictor of DPFS after adjusting for tumor stage, serum PSA, and tumor SUV (p = 0.003; hazard ratio, 1.50; 95% confidence interval, 1.15–1.96). CT-attenuation and FDG uptake of PPAT showed significant association with disease progression in patients with prostate cancer. These imaging findings may be evidence of the role of PPAT in prostate cancer progression. Full article

Renal dysfunction is common in patients with diabetes mellitus (DM). Previous findings from a meta-analysis of GWAS indicated that the variation of RAB38/CTSC is highly associated with the urinary albumin-to-creatinine ratio (UACR) in European populations. In addition, RAB38 knockout rats showed an increase in urinary albumins. Although the prevalence of chronic kidney disease is high in Taiwan, the role of genetic variants in diabetic renal function is still unclear. In the current study, 275 diabetic nephropathy (DN) patients were recruited to perform a genetic association study. Our results indicated that rs1027027, rs302647, and rs302646 in RAB38 were significantly associated with urinary protein-to-creatinine ratio (UPCR) levels in DN patients. Importantly, after analysis stratified by gender, a significant genetic influence on UPCR levels was observed in the male population. The findings confirmed the roles of gender and variants of RAB38 in the risk of UPCR in Diabetic Nephropathy patients. Full article

Despite promising advances in the medical management of spinal cord injury (SCI), there is still no available effective therapy to repair the neurological damage in patients who experience this life-transforming condition. Recently, we performed a phase II/III placebo-controlled randomized trial of safety and efficacy of growth hormone (GH) treatment in incomplete chronic traumatic spinal cord injury. The main findings were that the combined treatment of GH plus rehabilitation treatment is feasible and safe, and that GH but not placebo slightly improves the SCI individual motor score. Moreover, we found that an intensive and long-lasting rehabilitation program per se increases the functional outcome of SCI individuals. To understand the possible mechanisms of the improvement due to GH treatment (motor score) and due to rehabilitation (functional outcome), we used a proteomic approach. Here, we used a multiple proteomic strategy to search for recovery biomarkers in blood plasma with the potential to predict response to somatropin treatment and to delayed intensive rehabilitation. Forty-six patients were recruited and followed for a minimum period of 1 year. Patients were classified into two groups based on their treatment: recombinant somatropin (0.4 mg) or placebo. Both groups received rehabilitation treatment. Our strategy allowed us to perform one of the deepest plasma proteomic analyses thus far, which revealed two proteomic signatures with predictive value: (i) response to recombinant somatropin treatment and (ii) response to rehabilitation. The proteins implicated in these signatures are related to homeostasis, inflammation, and coagulation functions. These findings open novel possibilities to assess and therapeutically manage patients with SCI, which could have a positive impact on their clinical response. Full article