Perspective Of Precision Medicine Research Articles

Network Analysis-Based Disentanglement of the Symptom Heterogeneity in Asian Patients with Schizophrenia: Findings from the Research on Asian Psychotropic Prescription Patterns for Antipsychotics.

The symptom heterogeneity of schizophrenia is consistent with Wittgenstein’s analogy of a language game. From the perspective of precision medicine, this study aimed to estimate the symptom presentation and identify the psychonectome in Asian patients, using data obtained from the Research on Asian Psychotropic Prescription Patterns for Antipsychotics. We constructed a network structure of the Brief Psychiatric Rating Scale (BPRS) items in 1438 Asian patients with schizophrenia. Furthermore, all the BPRS items were considered to be an ordered categorical variable ranging in value from 1–7. Motor retardation was situated most centrally within the BPRS network structure, followed by depressive mood and unusual thought content. Contrastingly, hallucinatory behavior was situated least centrally within the network structure. Using a community detection algorithm, the BPRS items were organized into positive, negative, and general symptom clusters. Overall, DSM symptoms were not more central than non-DSM symptoms within the symptom network of Asian patients with schizophrenia. Thus, motor retardation, which results from the unmet needs associated with current antipsychotic medications for schizophrenia, may be a tailored treatment target for Asian patients with schizophrenia. Based on these findings, targeting non-dopamine systems (glutamate, γ-aminobutyric acid) may represent an effective strategy with respect to precision medicine for psychosis.

Influence of cytotoxic T lymphocyte antigen 4 genetic variants on acute rejection in kidney transplant patients: precision medicine perspective

The most effective and common treatment for end-stage renal disease is kidney transplantation.The personalized approach to kidney transplantation, which utilizes precision medicine principles, determines distinctive genomics characteristics of candidates/recipients that must be taken into account. Cytotoxic T lymphocyte associated protein 4 (CTLA4) may be a suitable candidate gene for studying allograft rejection. The aim of this study was to understand whether we can consider two common variants of the CTLA4 gene as a risk factor of transplant rejection in a group of Iranian population. Totally, 169 kidney transplant recipients, including acute rejections (N=39) and non-rejection (N=130) groups who underwent transplantation were included in this study. The genotyping of rs5742909 (-318C/T) and rs231775 (+49A/G) variants of the CTLA4 gene were performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The AG genotype frequency of rs231775 variant was the same in both patients with and without a history of rejection while, none of those groups had homozygote genotype. In rs5742909, both CT and TT frequencies of patients with rejected transplant were lower than patients with a normal outcome. The results of the presented study suggest that rs231775 and rs5742909 of CTLA4 genetic variants are not linked to acute rejection who underwent kidney transplantation. So, these variants cannot be considered as risk factors of acute allograft rejection in a group of Iranian renal transplantation recipients. However, the transplantation precision medicine may be an important area for the improvement of patients outcome as the precision medicine has already entered clinical practice in kidney transplantation.

Abstract 13685: Combined Genetic Defects of Sitosterolemia and Familial Hypercholesterolemia

Background: Familial hypercholesterolemia (FH) is an inherited disorder caused by mutations in the genes in the LDL receptor pathway, including LDLR , PCSK9 , APOB, and ARH . Defective uptake of LDL by the liver increases plasma LDL-cholesterol (LDL-C) levels, leading to an increased risk of coronary heart disease. The differential diagnosis of FH includes sitosterolemia which is a rare autosomal recessive disorder caused by mutations in ABCG5 or ABCG8 . Case presentation: Here we present a rare case of sitosterolemia with a genetic diagnosis of FH. A 64-years-old woman, clinically diagnosed as FH with Achilles tendon thickness (>18 mm on X-ray imaging), had been taking statins only intermittently due to muscle pains. The combinatorial therapy with ezetimibe decreased her plasma LDL-C levels to around 90-250 mg/dL with variable adherence to statins and dietary management. Further addition of a PCSK9 inhibitor (evolocumab) was largely ineffective with plasma LDL-C levels of 90-190 mg/dL. A systemic medical evaluation revealed persistent joint pains of unknown etiology and slightly decreased platelet count. These clinical features led us to suspect sitosterolemia. Biochemical and genetic analyses: Plasma concentration of sitosterol was elevated (16.8 mg/dL). Genetic testing was performed after obtaining informed consent. All procedures were subjected to approval by the human genome, gene analysis research ethics committee of the University of Tokyo. In addition to a heterozygous missense mutation in LDLR (p.Arg115His), a homozygous nonsense mutation in ABCG5 (p.Tyr188Ter) was identified. No rare variants were found in PCSK9 nor ABCG8 . Conclusions: To our knowledge, this is the first case of a combined genetic defect of sitosterolemia and FH. Atypical clinical manifestations such as large fluctuations of LDL-C levels, unresponsiveness to a PCSK9 inhibitor, arthralgia, and a reduced platelet count led to the genetic diagnosis. Our case is informative in the perspective of precision medicine, highlighting the importance of systemic medical evaluation to select patients who will be benefited more from genetic testing as well as the necessity of future drug development for this rare and intractable disease.

Heterogeneity and Factorial Structure in Alzheimer's Disease: A Cognitive Perspective.

Alzheimer's disease (AD) patients show heterogeneous cognitive profiles which suggest the existence of cognitive subgroups. A deeper comprehension of this heterogeneity could contribute to move toward a precision medicine perspective. In this study, we aimed 1) to investigate AD cognitive heterogeneity as a product of the combination of within- (factors) and between-patients (sub-phenotypes) components, and 2) to promote its assessment in clinical practice by defining a small set of critical tests for this purpose. We performed factor mixture analysis (FMA) on neurocognitive assessment results of N = 230 patients with a clinical diagnosis of AD. This technique allowed to investigate the structure of cognitive heterogeneity in this sample and to characterize the core features of cognitive sub-phenotypes. Subsequently, we performed a tests selection based on logistic regression to highlight the best tests to detect AD patients in our sample. Finally, the accuracy of the same tests in the discrimination of sub-phenotypes was evaluated. FMA revealed a structure characterized by five latent factors and four groups, which were identifiable by means of a few cognitive tests and were mainly characterized by memory deficits with visuospatial difficulties ("Visuospatial AD"), typical AD cognitive pattern ("Typical AD"), less impaired memory ("Mild AD"), and language/praxis deficits with relatively spared memory ("Nonamnestic AD"). The structure of cognitive heterogeneity in our sample of AD patients, as studied by FMA, could be summarized by four sub-phenotypes with distinct cognitive characteristics easily identifiable in clinical practice. Clinical implications under the precision medicine framework are discussed.

A perspective of precision medicine in the management of COVID-19

The idea of precision medication is turning out progressively to be famous. The utilization of enormous information, genomics and other omics like metabolomics; proteomics and transcriptomics; could soon cause the fantasy of personalized medication to turn into a reality. The most recent advancements in precision medication permit the adjustment of helpful approaches in various pathologies based on the particular molecular interpretation of the patient. Precision medication (PM) represents a new way of thinking about infection detection; prevention and treatment. The use of PM grounds in an emerging COVID virulent disease is becoming more prominent. Various discoveries revealed that severe acute respiratory disorder COVID-2 (SARS CoV-2) is accountable for the Coronavirus disease -2019 (COVID-19), which caused slew of procedures to restrict viral spread, affecting people's habits and lifestyles. According to the viral genomic sequencing, the SARS-CoV-2 spike protein uses angiotensin-converting enzyme 2 (ACE2), which is established on the ciliated epithelial cells of the human lungs as its particular receptor. In this specific situation; precision medication is an integrative helpful methodology that thinks about conventional elements (i.e. age, sex, clinical aggregate), just as arising hereditary qualities and connections with natural components, to individualize prevention; diagnosis, treatments and prognosis. The aim of this review was to summarize how precision medicine is impactful in the management of COVID-19.

Metabolic reprograming of antioxidant defense: a precision medicine perspective for radiotherapy of lung cancer?

Radiotherapy plays a key role in the management of lung cancer patients in curative and palliative settings. Traditionally, radiotherapy was either given alone or in combination with surgery, classical cytotoxic chemotherapy, or both. Technical and physical innovations achieved during the last two decades have helped to enhance the accuracy of radiotherapy dose delivery and have facilitated geometric radiotherapy individualization. Furthermore, multimodal combinations with molecularly tailored drugs or immunotherapy yielded promising survival benefits in selected patients. Yet high locoregional failure rates and frequent development of metastases still limit the patient outcome. One major obstacle to successful treatment is the high molecular heterogeneity observed in lung cancer. So far, clinical radiotherapy does not routinely use the knowledge on molecular subtypes with regard to therapy individualization and predictive biomarkers are missing. Herein, altered cancer metabolism has attracted novel attention during recent years as it promotes tumor growth and progression as well as resistance to anticancer therapies. The present perspective will exemplarily highlight how clinically relevant molecular subtypes defined by co-occurring somatic mutations in KRAS-driven lung cancer impact the metabolic phenotype of cancer cells, how the metabolic phenotype supports intrinsic radioresistance by the improved antioxidant defense, and also discuss potential subtype-specific actionable metabolic vulnerabilities. Understanding metabolic phenotypes of radioresistance and metabolic bottlenecks of cancer cells undergoing radiotherapy in a cancer-specific context will offer largely unexploited future avenues for biological individualization and optimization of radiotherapy. Transcriptional profiles will provide additional benefit in defining metabolic phenotypes associated with radioresistance, particularly in cases, where such dependencies cannot be identified by specific somatic mutations.

Impulse control disorders and related behaviors in Parkinson's disease: risk factors, clinical and genetic aspects, and management.

To review recent findings and research directions on impulse control disorders and related behaviors (ICDRBs) in Parkinson's disease (PD). Longitudinal studies found that prevalence increases during PD progression, incident ICDRBs being around 10% per year in patients treated with dopaminergic therapies. Screening tools and severity scales already developed have been validated and are available in several countries and languages. The main clinical risk factors include young age, male gender, type, doses and duration of dopaminergic therapy, PD motor severity and dyskinesia, depression, anxiety, apathy, sleep disorders, and impulsivity traits. Genetic factors are suspected by a high estimated heritability, but individual genes and variants remain to be replicated. Management of ICDRBs is centered on dopamine agonist decrease, with the risk to develop withdrawal symptoms. Cognitive behavioral therapy and subthalamic nucleus deep brain stimulation also improve ICDRBs. In the perspective of precision medicine, new individual prediction models of these disorders have been proposed, but they need further independent replication. Regular monitoring of ICDRB during the course of PD is needed, particularly in the subject at high risk of developing these complications. Precision medicine will require the appropriate use of machine learning to be reached in the clinical setting.

Genome-Wide Analysis of Sex Disparities in the Genetic Architecture of Lung and Colorectal Cancers.

Almost all complex disorders have manifested epidemiological and clinical sex disparities which might partially arise from sex-specific genetic mechanisms. Addressing such differences can be important from a precision medicine perspective which aims to make medical interventions more personalized and effective. We investigated sex-specific genetic associations with colorectal (CRCa) and lung (LCa) cancers using genome-wide single-nucleotide polymorphisms (SNPs) data from three independent datasets. The genome-wide association analyses revealed that 33 SNPs were associated with CRCa/LCa at P < 5.0 × 10−6 neither males or females. Of these, 26 SNPs had sex-specific effects as their effect sizes were statistically different between the two sexes at a Bonferroni-adjusted significance level of 0.0015. None had proxy SNPs within their ±1 Mb regions and the closest genes to 32 SNPs were not previously associated with the corresponding cancers. The pathway enrichment analyses demonstrated the associations of 35 pathways with CRCa or LCa which were mostly implicated in immune system responses, cell cycle, and chromosome stability. The significant pathways were mostly enriched in either males or females. Our findings provided novel insights into the potential sex-specific genetic heterogeneity of CRCa and LCa at SNP and pathway levels.

Type I Interferons in Systemic Autoimmune Diseases: Distinguishing Between Afferent and Efferent Functions for Precision Medicine and Individualized Treatment.

A sustained increase in type I interferon (IFN-I) may accompany clinical manifestations and disease activity in systemic autoimmune diseases (SADs). Despite the very frequent presence of IFN-I in SADs, clinical manifestations are extremely varied between and within SADs. The present short review will address the following key questions associated with high IFN-I in SADs in the perspective of precision medicine. 1) What are the mechanisms leading to high IFN-I? 2) What are the predisposing conditions favoring high IFN-I production? 3) What is the role of IFN-I in the development of distinct clinical manifestations within SADs? 4) Would therapeutic strategies targeting IFN-I be helpful in controlling or even preventing SADs? In answering these questions, we will underlie areas of incertitude and the intertwined role of autoantibodies, immune complexes, and neutrophils.

Effectiveness of cognitive remediation in schizophrenia: What works and what does not work?

Introduction: Cognitive function in schizophrenia is one of the main elements related to functional outcomes. Although there is enough evidence that cognitive remediation (CR) is beneficial, there is still a limited understanding of how the active therapy ingredients contribute to brain changes and translate into improved real-world functioning. Objectives: Identify neurobiological, psychopathological, cognitive, and functional CR response or resistance predictors in schizophrenia, considering both cognitive and functional outcomes. Results: We still lack a precise understanding of how CR produce its effects with different programs, different numbers of sessions, with and without a therapist. CR exerts its maximal benefit when delivered in the context of psychiatric rehabilitation, but it is not yet clear what are the mechanisms of integrated treatment effectiveness. Only a few studies have looked for the relationship between CR response or resistance and the biological, socio-demographic, clinical and cognitive features in schizophrenia. The current knowledge on efficacy predictors of CR is sparse and include: age, illness duration, premorbid adjustment, baseline cognitive performance, intrinsic motivation, hostility, disorganized symptoms, neurobiological reserve, genetic polymorphisms, antipsychotics amount, the type of CR, etc. All of these limitations may have contributed to the poor implementation of CR in national and international guidelines, as well as in clinical practice. Conclusions: It is important that future research shift from studies of group efficacy to individual efficacy of treatments, in the perspective of precision medicine. Issues related to individual effectiveness predictors and interactions between specific pharmacologic, specific CR technique and individual patients’ characteristics should be further addressed.DisclosureNo significant relationships.

A COVID-19 risk score combining chest CT radiomics and clinical characteristics to differentiate COVID-19 pneumonia from other viral pneumonias.

With the continued transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) throughout the world, identification of highly suspected COVID-19 patients remains an urgent priority. In this study, we developed and validated COVID-19 risk scores to identify patients with COVID-19. In this study, for patient-wise analysis, three signatures, including the risk score using radiomic features only, the risk score using clinical factors only, and the risk score combining radiomic features and clinical variables, show an excellent performance in differentiating COVID-19 from other viral-induced pneumonias in the validation set. For lesion-wise analysis, the risk score using three radiomic features only also achieved an excellent AUC value. In contrast, the performance of 130 radiologists based on the chest CT images alone without the clinical characteristics included was moderate as compared to the risk scores developed. The risk scores depicting the correlation of CT radiomics and clinical factors with COVID-19 could be used to accurately identify patients with COVID-19, which would have clinically translatable diagnostic and therapeutic implications from a precision medicine perspective.

The Role of Liquid Biopsy in Hepatocellular Carcinoma Prognostication.

Simple SummaryHepatocellular carcinoma (HCC) is one of the deadliest cancer. Clinical guidelines for the management of HCC endorse algorithms deriving from clinical variables whose performances to prognosticate HCC is limited. Liquid biopsy is the molecular analysis of tumor by-products released into the bloodstream. It offers minimally-invasive access to circulating analytes like DNA, RNA, exosomes and cells. This technology demonstrated promising results for various applications in cancers, including prognostication. This review aimed to provide a comprehensive overview of the contribution of liquid biopsy in HCC prognostication. The results suggested that liquid biopsy may be a polyvalent and valuable tool to prognosticate HCC.Showing a steadily increasing cancer-related mortality, the epidemiological evolution of hepatocellular carcinoma (HCC) is concerning. Numerous strategies have attempted to prognosticate HCC but their performance is modest; this is partially due to the heterogeneous biology of this cancer. Current clinical guidelines endorse classifications and scores that use clinical variables, such as the Barcelona Clinic Liver Cancer (BCLC) classification. These algorithms are unlikely to fully recapitulate the genomic complexity of HCC. Integrating molecular readouts on a patient-basis, following a precision-medicine perspective, might be an option to refine prognostic systems. The limited access to HCC tissue samples is an important limitation to these approaches but it could be partially circumvented by using liquid biopsy. This concept consists of the molecular analysis of products derived from a solid tumor and released into biological fluids, mostly into the bloodstream. It offers an easy and minimally-invasive access to DNA, RNA, extracellular vesicles and cells that can be analyzed with next-generation sequencing (NGS) technologies. This review aims to investigate the potential contributions of liquid biopsy in HCC prognostication. The results identified prognostic values for each of the components of liquid biopsy, suggesting that this technology may help refine HCC prognostication.

Machine learning application for patient stratification and phenotype/genotype investigation in a rare disease.

Alkaptonuria (AKU, OMIM: 203500) is an autosomal recessive disorder caused by mutations in the Homogentisate 1,2-dioxygenase (HGD) gene. A lack of standardized data, information and methodologies to assess disease severity and progression represents a common complication in ultra-rare disorders like AKU. This is the reason why we developed a comprehensive tool, called ApreciseKUre, able to collect AKU patients deriving data, to analyse the complex network among genotypic and phenotypic information and to get new insight in such multi-systemic disease. By taking advantage of the dataset, containing the highest number of AKU patient ever considered, it is possible to apply more sophisticated computational methods (such as machine learning) to achieve a first AKU patient stratification based on phenotypic and genotypic data in a typical precision medicine perspective. Thanks to our sufficiently populated and organized dataset, it is possible, for the first time, to extensively explore the phenotype-genotype relationships unknown so far. This proof of principle study for rare diseases confirms the importance of a dedicated database, allowing data management and analysis and can be used to tailor treatments for every patient in a more effective way.

Disease Control Biomarker to Predict Sorafenib Susceptibility in Advanced Stage Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) has two first-line treatments, those are sorafenib and lenvatinb. But because of predictive biomarker's absence, these two agents have poor response rates and overall survival period. Disease control biomarker could be a method that potentially improves the effectiveness of sorafenib, one of two agents. Here, we aimed to develop a clinical useful biomarker that predicts disease control of sorafenib. Methods: Using nanostring nCounter, we analyzed expression levels of 770 genes in 73 advanced-stage HCC patients with sorafenib trearment. With the 770 genes expression levels of 73 patients, we identified differentially expressed genes (DEGs) and computed combination of weighted gene expression for disease control biomarker. To validate gene signature, we analyzed cross validation and meta-analysis. For predicted poor responders, we listed up recommended medicine, analyzing individual DEGs by meta-analysis. Results: 8-gene signature showed 0.90 of area under the curves (AUC), 91.78% of accuracy. In cross validation, 8-gene signature showed well-performance with 83.67% of cross validation accuracy. Also, when classification with 8-gene signature, median overall survival (median OS) was improved 27.3 months from 11.3months. In promising alternative agents for predicted poor responders, recommended agents were listed up individually based on individual gene expression. Conclusions: 8-gene signature provides a best compromise between sorafenib effectiveness and coverage of sorafenib treatment patients. In perspective of precision medicine, our process of precision medicine recommendation can be drive the precision medicine one step forward.

The Potential of Clinical Decision Support Systems for Prevention, Diagnosis, and Monitoring of Allergic Diseases.

Clinical decision support systems (CDSS) aid health care professionals (HCP) in evaluating large sets of information and taking informed decisions during their clinical routine. CDSS are becoming particularly important in the perspective of precision medicine, when HCP need to consider growing amounts of data to create precise patient profiles for personalized diagnosis, treatment and outcome monitoring. In allergy care, several CDSS are being developed and investigated, mainly for respiratory allergic diseases. Although the proposed solutions address different stakeholders, the majority aims at facilitating evidence-based and shared decision-making, incorporating guidelines, and real-time clinical data. We offer here an overview on existing tools, new developments and novel concepts and discuss the potential of digital CDSS in improving prevention, diagnosis and monitoring of allergic diseases.

Identification of 15 T Cell Restricted Genes Evaluates T Cell Infiltration of Human Healthy Tissues and Cancers and Shows Prognostic and Predictive Potential.

T cell gene signatures are used to evaluate T cell infiltration of non-lymphoid tissues and cancers in both experimental and clinical settings. However, some genes included in the available T cell signatures are not T cell-restricted. Herein, we propose a new human T cell signature that has been developed via a six-step procedure and comprises 15 T cell restricted genes. We demonstrate the new T cell signature, named signature-H, that differs from other gene signatures since it shows higher sensitivity and better predictivity in the evaluation of T cell infiltration in healthy tissues as well as 32 cancers. Further, results from signature-H are highly concordant with the immunohistochemistry methods currently used for assessing the prognosis of neuroblastoma, as demonstrated by the Kaplan–Meier curves of patients ranked by tumor T cell infiltration. Moreover, T cell infiltration levels calculated using signature-H correlate with the risk groups determined by the staging of the neuroblastoma. Finally, multiparametric analysis of tumor-infiltrating T cells based on signature-H let us favorably predict the response of melanoma to the anti-PD-1 antibody nivolumab. These findings suggest that signature-H evaluates T cell infiltration levels of tissues and may be used as a prognostic tool in the precision medicine perspective after appropriate clinical validation.

A Digital Evaluation of T-Cell Infiltration of Human Cancers and Its Use as a Prognostic and Predictive Tool

T-cell signatures are used to evaluate T-cell infiltration of non-lymphoid tissues in experimental and clinical settings. However, none of the T-cell signatures reported so far are optimal. This paper describes the development of a new human T-cell signature comprising 15 genes that are overexpressed at least tenfold in resting and activated T cells as compared to non-lymphoid tissues and cell lines. We demonstrate that signature-H shows high sensitivity for evaluating T-cell infiltration in healthy tissues and in the 32 cancers investigated. Further, signature-H works as well as immunohistochemistry methods for assessing the prognosis of neuroblastoma. Finally, we used a multiparametric tool that includes T-cell infiltration based on the new signature to predict the response of melanoma to the anti-PD-1 antibody nivolumab and obtained positive results. These preliminary findings suggest that the new T-cell signature can be used as a prognostic tool and in tailoring treatment, in the precision medicine perspective.

Mass Spectrometry in Advancement of Redox Precision Medicine.

Redox (portmanteau of reduction-oxidation) reactions involve the transfer of electrons between chemical species in biological processes fundamental to life. It is of outmost importance that cells maintain a healthy redox state by balancing the action of oxidants and antioxidants; failure to do so leads to a multitude of diseases including cancer, diabetes, fibrosis, autoimmune diseases, and cardiovascular and neurodegenerative diseases. From the perspective of precision medicine, it is therefore beneficial to interrogate the redox phenotype of the individual-similar to the use of genomic sequencing-in order to design tailoredstrategies for disease prevention and treatment. This chapter provides an overview of redoxmetabolism and focuses on how mass spectrometry (MS) can be applied to advance our knowledge in redox biology and precision medicine.

Proteoglycans Are Attractive Biomarkers and Therapeutic Targets in Hepatocellular Carcinoma.

Proteoglycans, which consist of a protein core and glycosaminoglycan chains, are major components of the extracellular matrix and play physiological roles in maintaining tissue homeostasis. In the carcinogenic tissue microenvironment, proteoglycan expression changes dramatically. Altered proteoglycan expression on tumor and stromal cells affects cancer cell signaling pathways, which alters growth, migration, and angiogenesis and could facilitate tumorigenesis. This dysregulation of proteoglycans has been implicated in the pathogenesis of diseases such as hepatocellular carcinoma (HCC) and the underlying mechanism has been studied extensively. This review summarizes the current knowledge of the roles of proteoglycans in the genesis and progression of HCC. It focuses on well-investigated proteoglycans such as serglycin, syndecan-1, glypican 3, agrin, collagen XVIII/endostatin, versican, and decorin, with particular emphasis on the potential of these factors as biomarkers and therapeutic targets in HCC regarding the future perspective of precision medicine toward the “cure of HCC”.

The heterogeneity of depression based on precision medicine

Depression is a heterogeneous disease. The heterogeneity of depression is mainly manifested in morbidity, pathogenesis, clinical manifestation, treatment and prognosis. Heterogeneity of depression has brought great difficulties to the treatment. In the field of the study and treatment of depression has not to receive attention.This paper reviews the influencing factors, clinical manifestations and possible mechanisms of depression heterogeneity, and focus on how to design a more effective individualized scheme for depressive heterogeneity from the perspective of precision medicine . Key words: Depression; Precision medicine; Heterogeneity