Personalized Drug Therapy Research Articles

Generation of a human induced pluripotent stem cell line (JSPHi002-A) from a patient with long-QT syndrome type 1 caused by KCNQ1 c.773A > T mutation

We generated an iPSCs line from the peripheral blood mononuclear cells (PBMCs) collected from a patient with long QT syndrome type 1 (LQT1) via a non-integrating system. We identified and verified a missense mutation in the KCNQ1 gene (c.773A > T) by whole-exome sequencing and Sanger sequencing. The established iPSC line was tested for pluripotency, differentiation potential, and karyotype. This cell-based model can help study the molecular mechanism and develop personalized drug therapies for LQT1.

Assessment of the effectiveness of the use of tumoroids for personalized drug therapies for solid tumors

The approach to the management of cancerous neoplasms, which aims to define the effective curative strategies in each patient, defines the requirement for the elaboration and use of modelling systems that replicate the structures and the biology of human solitary tumors. Three-dimensional cultures of spheroids/tumoroids, which are multi-cell aggregates of malignized cells, can create the intercellular connections of interest, gradients of the nutrients and oxygen, and cell polarity, all of which are absent in the conventional two-dimensional single-layer system. The present work is dedicated to a comparison study of in vitro viability and invasiveness of solid tumor cells of patients under the effect of chemopreparations and their combinations in view of evaluating the efficacy of the 3D-cell modelling system in the translational personalized medicine context. Cell cultures of patients who were treated at the N.N. Petrov National Medicine Research Center of oncology were used as a basis for the development of 3D-cell models. N.N. Petrov NMRC in 2015-2021. Tumor tissue pieces were acquired intraoperatively: 1 - leiomyosarcoma (LMS), 1 - rhabdomyosarcoma (RMS), 1 - synovial sarcoma (SS), 2 - myxofibrosarcoma (MFS), 2 - osteogenic sarcoma (OS), 1 - skin melanoma (MC), 1 - breast cancer (BC) (n=9). Our individual comparison of the effectiveness of in vitro chemotherapeutic agents against tumor cells of various origins cultivated in 2D and 3D model systems with real clinically relevant cases confirmed that the monolayer culture as the test system was less adequate for selecting and personalizing the treatment of malignant tumor patients: the 3D cell system proved itself in 77.7% of cases, and the monolayer culture - in 44.4% of cases. The combination of doxorubicin/iforsfamide and paclitaxel significantly suppressed the motility in the matrigel of spheroid cells, but did not affect tumor cell viability, which was seen in all but OS #921 and MK #929 cases. The cultivation of tumor cells in form of spheroids/tumoroids allows to utilize them as more adequate pre-clinical model as individual predictive test-system, enabling the personalized selection of therapy.

Serum Predose Metabolic Profiling for Prediction of Rosuvastatin Pharmacokinetic Parameters in Healthy Volunteers.

Rosuvastatin is a well-known lipid-lowering agent generally used for hypercholesterolemia treatment and coronary artery disease prevention. There is a substantial inter-individual variability in the absorption of statins usually caused by genetic polymorphisms leading to a variation in the corresponding pharmacokinetic parameters, which may affect drug therapy safety and efficacy. Therefore, the investigation of metabolic markers associated with rosuvastatin inter-individual variability is exceedingly relevant for drug therapy optimization and minimizing side effects. This work describes the application of pharmacometabolomic strategies using liquid chromatography coupled to mass spectrometry to investigate endogenous plasma metabolites capable of predicting pharmacokinetic parameters in predose samples. First, a targeted method for the determination of plasma concentration levels of rosuvastatin was validated and applied to obtain the pharmacokinetic parameters from 40 enrolled individuals; then, predose samples were analyzed using a metabolomic approach to search for associations between endogenous metabolites and the corresponding pharmacokinetic parameters. Data processing using machine learning revealed some candidates including sterols and bile acids, carboxylated metabolites, and lipids, suggesting the approach herein described as promising for personalized drug therapy.

3D Printed Individualized Frontal Neo-Ostium Implant in Endoscopic Sinus Surgery – a Proof of Concept Study

Abstract 3D-printing paves the way for personalized drug therapy via implants individualized for the patient specific anatomy in chronic paranasal sinus diseases. This study brings together the workflow of modeling, manufacturing, and sterilization of 3D-printed individualized frontal neo-ostium implants (FOI) for optimization of Endoscopic Sinus Surgery (ESS) and validates the implantability of the printed devices. The study sample consisted of six adult human cadavers. Digital volume tomography (DVT) images were taken before and after ESS. The FOI models were based on the post-ESS anatomy. The area to be implanted was analysed in the preand post-ESS DVT images for volume and surface area. A specialized surgeon in rhinology judged the implantability of the 3D-printed FOI. The mean values of volume and surface area tended to be larger in the post-operation situs than in preoperation DVT images and we are therefore not yet convinced that pre-operation images will reflect the correct anatomy for the personalization of the FOI. The workflow of manufacturing and implantation of individualized 3D-printed sterile FOI is established but future studies are needed for further improvement.

Frequency of Important CYP450 Enzyme Gene Polymorphisms in the Iranian Population in Comparison with Other Major Populations: A Comprehensive Review of the Human Data.

Genetic polymorphisms in cytochrome P450 genes can cause alteration in metabolic activity of clinically important medicines. Thus, single nucleotide variants (SNVs) and copy number variations (CNVs) in CYP genes are leading factors of drug pharmacokinetics and toxicity and form pharmacogenetics biomarkers for drug dosing, efficacy, and safety. The distribution of cytochrome P450 alleles differs significantly between populations with important implications for personalized drug therapy and healthcare programs. To provide a meta-analysis of CYP allele polymorphisms with clinical importance, we brought together whole-genome and exome sequencing data from 800 unrelated individuals of Iranian population (100 subjects from 8 major ethnics of Iran) and 63,269 unrelated individuals of five major human populations (EUR, AMR, AFR, EAS and SAS). By integrating these datasets with population-specific linkage information, we evolved the frequencies of 140 CYP haplotypes related to 9 important CYP450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) giving a large resource for major genetic determinants of drug metabolism. Furthermore, we evaluated the more frequent Iranian alleles and compared the dataset with the Caucasian race. Finally, the similarity of the Iranian population SNVs with other populations was investigated.

Періопераційний період у пацієнтів з ішемічною хворобою серця з високим ризиком

The aim – to analyze the perioperative period of high-risk patients with coronary artery disease. Materials and methods. 194 patients (age 64.2 ± 8.9 years) with surgery performed, discharged from the specialized clinic within period from 2009 to 2019. All patients underwent laboratory tests, ECG, echocardiography, coronary angiography and coronary artery bypass grafting (CABG). Results. All patients had hemodynamically significant coronary artery stenosis, which required CABG. Acute myocardial infarction at the time of admission was diagnosed in 12 (6.1 %) patients, unstable angina – in 72 (37.1 %) patients. Among comorbid conditions, type 2 diabetes mellitus was diagnosed in 50 (25.7 %) patients, impaired glucose tolerance – in 82 (42.2 %) patients, obesity – in 74 (38.1 %) patients, 86 (44.3 %) patients were overweight with a body mass index 25–29.9 kg/m2, and 75 (38.6 %) patients were diagnosed with chronic kidney disease. According to coronary angiography, the average number of stenosed coronary arteries was 3.5. The risk assessed by EuroSCORE II scale was 7.78 % (from 5.01 % to 68.25 %). Myocardial revascularization was performed on the working heart in 187 (96.3 %) patients, on-pump in 7 (3.6 %) cases. In the postoperative period, 40 (20.6 %) patients developed paroxysmal atrial fibrillations. Acute kidney injury with increase in creatinine by 50 % occurred in 2 (1.03 %) patients. Conclusions. Despite the high predicted mortality (7.78 % by the EuroSCORE II scale) all the patients were discharged on average in 8.4 ± 3.5 days. Careful preoperative diagnosis, preparation, risk stratification, determination of the term of surgery, choice of CABG method taking into account the anthropometric data, the state of the lower extremities veins, anatomical location of coronary arteries, their diameter and degree of damage, personalized drug therapy, allows to achieve good results with minimal complications. Key words: coronary artery disease, high-risk patients, coronary artery bypass grafting, comorbid conditions, off-pump.

CYP2B6 Functional Variability in Drug Metabolism and Exposure Across Populations-Implication for Drug Safety, Dosing, and Individualized Therapy.

Adverse drug reactions (ADRs) are one of the major causes of morbidity and mortality worldwide. It is well-known that individual genetic make-up is one of the causative factors of ADRs. Approximately 14 million single nucleotide polymorphisms (SNPs) are distributed throughout the entire human genome and every patient has a distinct genetic make-up which influences their response to drug therapy. Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of antiretroviral, antimalarial, anticancer, and antidepressant drugs. These drug classes are commonly in use worldwide and face specific population variability in side effects and dosing. Parts of this variability may be caused by single nucleotide polymorphisms (SNPs) in the CYP2B6 gene that are associated with altered protein expression and catalytic function. Population variability in the CYP2B6 gene leads to changes in drug metabolism which may result in adverse drug reactions or therapeutic failure. So far more than 30 non-synonymous variants in CYP2B6 gene have been reported. The occurrence of these variants show intra and interpopulation variability, thus affecting drug efficacy at individual and population level. Differences in disease conditions and affordability of drug therapy further explain why some individuals or populations are more exposed to CYP2B6 pharmacogenomics associated ADRs than others. Variabilities in drug efficacy associated with the pharmacogenomics of CYP2B6 have been reported in various populations. The aim of this review is to highlight reports from various ethnicities that emphasize on the relationship between CYP2B6 pharmacogenomics variability and the occurrence of adverse drug reactions. In vitro and in vivo studies evaluating the catalytic activity of CYP2B6 variants using various substrates will also be discussed. While implementation of pharmacogenomic testing for personalized drug therapy has made big progress, less data on pharmacogenetics of drug safety has been gained in terms of CYP2B6 substrates. Therefore, reviewing the existing evidence on population variability in CYP2B6 and ADR risk profiles suggests that, in addition to other factors, the knowledge on pharmacogenomics of CYP2B6 in patient treatment may be useful for the development of personalized medicine with regards to genotype-based prescription.

Cytogenetic and Biochemical Genetic Techniques for Personalized Drug Therapy in Europe.

For many authorized drugs, accumulating scientific evidence supports testing for predictive biomarkers to apply personalized therapy and support preventive measures regarding adverse drug reactions and treatment failure. Here, we review cytogenetic and biochemical genetic testing methods that are available to guide therapy with drugs centrally approved in the European Union (EU). We identified several methods and combinations of techniques registered in the Genetic Testing Registry (GTR), which can be used to guide therapy with drugs for which pharmacogenomic-related information is provided in the European public assessment reports. Although this registry provides information on genetic tests offered worldwide, we identified limitations regarding standard techniques applied in clinical practice and the information on test validity rarely provided in the according sections.

Neuroendocrine Breast Cancer. Clinical Observation. Personalized Approach

Introduction. Neuroendocrine breast tumors represent a rare subtype of breast cancer, accounting for less than 1 % of all neuroendocrine neoplasms. Starting from their pathology definition, and going through their prevalence, prognosis and treatment, our knowledge is still really uncertain.Materials and methods. The article presents a rare clinical observation of a neuroendocrine breast tumor. A breast fibroadenoma was diagnosed at the initial diagnosis stage in a private clinic; after a surgical treatment and further morphological study, it was estimated: a diagnosis of Cancer in situ of the left breast T1N0M0, stage I. Next, 3D-conformal remote radiation therapy was performed on the area of the left breast.Results and discussion. After conducting positron emission tomography, multiple metastases were detected in the lymph nodes, bones, and liver. Additionally, micropreparations were consulted at the Federal Reference Center in St. Petersburg and at an independent third-party molecular biological laboratory in Germany (Munich). Given all the instrumental, molecular biological, histological and immunohistochemical studies of the patient, an individual regimen of drug therapy was selected.Conclusion. After 18 months of personalized drug therapy, we observed a positive trend and a significant decrease in metabolic activity according to positron emission tomography.

Ведение детей с бронхолегочной дисплазией на амбулаторном этапе: что необходимо знать неонатологу и участковому педиатру?

This article contains the most up-to-date information about bronchopulmonary dysplasia (BPD), which is the most common chronic lung disease in infants and a serious complication of prematurity and respiratory therapy in the neonatal period. This summary will be particularly valuable for pediatricians. We provided the information about epidemiology, etiopathogenesis, pathomorphology, clinical manifestations, diagnosis, diagnostic algorithm, classification and diagnostic criteria for BPD. We also covered the principles of outpatient management, including approaches to oxygen therapy, diet therapy, immunoprophylaxis of respiratory syncytial viral infection, personalized drug therapy for BPD and its complications, in particular pulmonary hypertension. We listed possible BPD complications (such as acute bronchiolitis, obliterating bronchiolitis, bronchial asthma, chronic obstructive pulmonary disease) and their prevention. Key words: outpatient management, bronchopulmonary dysplasia, diagnosis, immunoprophylaxis of respiratory syncytial virus infection, therapy

Pharmacogenetic Testing: A Tool for Personalized Drug Therapy Optimization.

Pharmacogenomics is a study of how the genome background is associated with drug resistance and how therapy strategy can be modified for a certain person to achieve benefit. The pharmacogenomics (PGx) testing becomes of great opportunity for physicians to make the proper decision regarding each non-trivial patient that does not respond to therapy. Although pharmacogenomics has become of growing interest to the healthcare market during the past five to ten years the exact mechanisms linking the genetic polymorphisms and observable responses to drug therapy are not always clear. Therefore, the success of PGx testing depends on the physician’s ability to understand the obtained results in a standardized way for each particular patient. The review aims to lead the reader through the general conception of PGx and related issues of PGx testing efficiency, personal data security, and health safety at a current clinical level.

Current Status of Stem Cell-Derived Therapies for Parkinson's Disease: From Cell Assessment and Imaging Modalities to Clinical Trials.

Curative therapies or treatments reversing the progression of Parkinson’s disease (PD) have attracted considerable interest in the last few decades. PD is characterized by the gradual loss of dopaminergic (DA) neurons and decreased striatal dopamine levels. Current challenges include optimizing neuroprotective strategies, developing personalized drug therapy, and minimizing side effects from the long-term prescription of pharmacological drugs used to relieve short-term motor symptoms. Transplantation of DA cells into PD patients’ brains to replace degenerated DA has the potential to change the treatment paradigm. Herein, we provide updates on current progress in stem cell-derived DA neuron transplantation as a therapeutic alternative for PD. We briefly highlight cell sources for transplantation and focus on cell assessment methods such as identification of genetic markers, single-cell sequencing, and imaging modalities used to access cell survival and function. More importantly, we summarize clinical reports of patients who have undergone cell-derived transplantation in PD to better perceive lessons that can be drawn from past and present clinical outcomes. Modifying factors include (1) source of the stem cells, (2) quality of the stem cells, (3) age of the patient, (4) stage of disease progression at the time of cell therapy, (5) surgical technique/practices, and (6) the use of immunosuppression. We await the outcomes of joint efforts in clinical trials around the world such as NYSTEM and CiRA to further guide us in the selection of the most suitable parameters for cell-based neurotransplantation in PD.

Gender-related trends
 in key epidemiological indicators of lung cancer
 in the Republic of Kazakhstan, 2014-2018

Relevance: Over the past decades, lung cancer (LC) incidence worldwide is adding about 1.5% each year. The risk of LC
 development increases 4-5 times with age. The mortality-to-incidence ratio (MIR) in LC is the most unfavorable – up to 95.6%
 of patients die.
 The purpose of this study was to analyze the epidemiological situation with lung cancer in the Republic of Kazakhstan
 over the past five years, with the assessment of key epidemiological indicators by gender.
 Results: In the previous five years (2014-2018), the men to women ratio among LC patients was equal to 4.2:1 and remained
 stable. A gradual decline in mortality (16‰ in 2014 to 12.9‰ in 2018) correlated with the MIR dynamic pattern (67.5% in
 2014 to 60.0% in 2018). The standardized LC incidence in men was declining steadily (46.8‰ in 2014 to 43.0‰ in 2018). A
 more evident decrease in male mortality from LC (32.0‰ in 2014 to 24.2‰ in 2018) was due to the progress recently achieved
 in LC diagnostics and treatment in the Republic of Kazakhstan. On the contrary, the LC incidence in women increased by 2.6% a
 year (7.6‰ in 2014 to 7.8‰ in 2018). The female mortality from LC was declining steadily (4.6‰ in 2014 to 3.5‰ in 2018),
 with a negative growth rate of minus 31.4%.
 Conclusion: The analysis of epidemiologic indicators for LC in the Republic of Kazakhstan showed a general downward
 trend in incidence and mortality regardless of gender. However, we can expect an increase in the female incidence of LC in sync
 with the global trend. The study period has witnessed the improvement in both the primary diagnostics (due to the renewal of
 diagnostic equipment in the country) and treatment of LC (through the introduction in the Republic of methods of molecular
 genetic studies which are the basis for the state-financed personalized drug therapy with targeted agents).

Identifying Drug Sensitivity Subnetworks with NETPHIX

SummaryPhenotypic heterogeneity in cancer is often caused by different patterns of genetic alterations. Understanding such phenotype-genotype relationships is fundamental for the advance of personalized medicine. We develop a computational method, named NETPHIX (NETwork-to-PHenotype association with eXclusivity) to identify subnetworks of genes whose genetic alterations are associated with drug response or other continuous cancer phenotypes. Leveraging interaction information among genes and properties of cancer mutations such as mutual exclusivity, we formulate the problem as an integer linear program and solve it optimally to obtain a subnetwork of associated genes. Applied to a large-scale drug screening dataset, NETPHIX uncovered gene modules significantly associated with drug responses. Utilizing interaction information, NETPHIX modules are functionally coherent and can thus provide important insights into drug action. In addition, we show that modules identified by NETPHIX together with their association patterns can be leveraged to suggest drug combinations.

Data-driven microbiota biomarker discovery for personalized drug therapy of cardiovascular disease

Cardiovascular disease (CVD) is the most wide-spread disorder all over the world. The personalized and precision diagnosis, treatment and prevention of CVD is still a challenge. With the developing of metagenome sequencing technologies and the paradigm shifting to data-driven discovery in life science, the computer aided microbiota biomarker discovery for CVD is becoming reality. We here summarize the data resources, knowledgebases and computational models available for CVD microbiota biomarker discovery, and review the present status of the findings about the microbiota patterns associated with the therapeutic effects on CVD. The future challenges and opportunities of the translational informatics on the personalized drug usages in CVD diagnosis, prognosis and treatment are also discussed.

Advances in Antimicrobial Microneedle Patches for Combating Infections.

Skin infections caused by bacteria, viruses and fungi are difficult to treat by conventional topical administration because of poor drug penetration across the stratum corneum. This results in low bioavailability of drugs to the infection site, as well as the lack of prolonged release. Emerging antimicrobial transdermal and ocular microneedle patches have become promising medical devices for the delivery of various antibacterial, antifungal, and antiviral therapeutics. In the present review, skin anatomy and its barriers along with skin infection are discussed. Potential strategies for designing antimicrobial microneedles and their targeted therapy are outlined. Finally, biosensing microneedle patches associated with personalized drug therapy and selective toxicity toward specific microbial species are discussed.

Genetic Variations and Frequencies of the Two Functional Single Nucleotide Polymorphisms of SLCO1B1 in the Thai Population.

AimTo investigate the variations and the frequencies of the SLCO1B1 gene in the Thai population.MethodsCollected samples were categorized into five regions of Thailand. DNA samples were genotyped for two variants, c.388A>G and c.521T>C of the SLCO1B1, using TaqMan® real-time PCR.ResultsThe minor allele frequencies (MAFs) of two single nucleotide polymorphisms (SNPs) were not significantly different among the five regions. The most frequent haplotype was SLCO1B1*1b (frequency: 0.654), followed by *1a (frequency: 0.217), *15 (frequency: 0.128), and *5 (frequency: 0.001). We observed a similar frequency of OATP1B1 transporter phenotypes compared to other populations. 75.85% of the Thai subjects showed normal OATP1B1 activity, 22.5% showed intermediate OATP1B1 activity, and 1.58% showed low OATP1B1 activity.ConclusionThis study reported the frequencies of the SLCO1B1 variants and the subsequent OATP1B1 activity in a large cohort of Thais that can provide important information for the guidance of personalized drug therapy.

Network-based approaches elucidate differences within APOBEC and clock-like signatures in breast cancer

BackgroundStudies of cancer mutations have typically focused on identifying cancer driving mutations that confer growth advantage to cancer cells. However, cancer genomes accumulate a large number of passenger somatic mutations resulting from various endogenous and exogenous causes, including normal DNA damage and repair processes or cancer-related aberrations of DNA maintenance machinery as well as mutations triggered by carcinogenic exposures. Different mutagenic processes often produce characteristic mutational patterns called mutational signatures. Identifying mutagenic processes underlying mutational signatures shaping a cancer genome is an important step towards understanding tumorigenesis.MethodsTo investigate the genetic aberrations associated with mutational signatures, we took a network-based approach considering mutational signatures as cancer phenotypes. Specifically, our analysis aims to answer the following two complementary questions: (i) what are functional pathways whose gene expression activities correlate with the strengths of mutational signatures, and (ii) are there pathways whose genetic alterations might have led to specific mutational signatures? To identify mutated pathways, we adopted a recently developed optimization method based on integer linear programming.ResultsAnalyzing a breast cancer dataset, we identified pathways associated with mutational signatures on both expression and mutation levels. Our analysis captured important differences in the etiology of the APOBEC-related signatures and the two clock-like signatures. In particular, it revealed that clustered and dispersed APOBEC mutations may be caused by different mutagenic processes. In addition, our analysis elucidated differences between two age-related signatures—one of the signatures is correlated with the expression of cell cycle genes while the other has no such correlation but shows patterns consistent with the exposure to environmental/external processes.ConclusionsThis work investigated, for the first time, a network-level association of mutational signatures and dysregulated pathways. The identified pathways and subnetworks provide novel insights into mutagenic processes that the cancer genomes might have undergone and important clues for developing personalized drug therapies.

Anti-parasite drug ivermectin can suppress ovarian cancer by regulating lncRNA-EIF4A3-mRNA axes.

RelevanceIvermectin, as an old anti-parasite drug, can suppress almost completely the growth of various human cancers, including ovarian cancer (OC). However, its anticancer mechanism remained to be further studied at the molecular levels. Ivermectin-related molecule-panel changes will serve a useful tool for its personalized drug therapy and prognostic assessment in OCs.PurposeTo explore the functional significance of ivermectin-mediated lncRNA-EIF4A3-mRNA axes in OCs and ivermectin-related molecule-panel for its personalized drug therapy monitoring.MethodsBased on our previous study, a total of 16 lncRNA expression patterns were analyzed using qRT-PCR before and after ivermectin-treated different OC cell lines (TOV-21G and A2780). Stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomics was used to analyze the protein expressions of EIF4A3 and EIF4A3-binding mRNAs in ovarian cancer cells treated with and without ivermectin. A total of 411 OC patients from the Cancer Genome Atlas (TCGA) database with the selected lncRNA expressions and the corresponding clinical data were included. Lasso regression was constructed to examine the relationship between lncRNA signature and OC survival risk. The overall survival analysis between high-risk and low-risk groups used the Kaplan-Meier method. Heatmap showed the correlation between risk groups and clinical characteristics. The univariate and multivariate models were established with Cox regression.ResultsSILAC-based quantitative proteomics found the protein expression levels of EIF4A3 and 116 EIF4A3-binding mRNAs were inhibited by ivermectin in OC cells. Among the analyzed 16 lncRNAs (HCG15, KIF9-AS1, PDCD4-AS1, ZNF674-AS1, ZNRF3-AS1, SOS1-IT1, LINC00565, SNHG3, PLCH1-AS1, WWTR1-AS1, LINC00517, AL109767.1, STARD13-IT1, LBX2-AS1, LEMD1-AS1, and HOXC-AS3), only 7 lncRNAs (HCG15, KIF9-AS1, PDCD4-AS1, ZNF674-AS1, ZNRF3-AS1, SOS1-IT1, and LINC00565) were obtained for further lasso regression when combined with the results of drug testing and overall survival analysis. Lasso regression identified the prognostic model of ivermectin-related three-lncRNA signature (ZNRF3-AS1, SOS1-IT1, and LINC00565). The high-risk and low-risk groups based on the prognostic model were significantly related to overall survival and clinicopathologic characteristics (survival status, lymphatic invasion, cancer status, and clinical stage) in OC patients and remained independent risk factors according to multivariate COX analysis (p < 0.05).ConclusionThose findings provided the potential targeted lncRNA-EIF4A3-mRNA pathways of ivermectin in OC, and constructed the effective prognostic model, which benefits discovery of novel mechanism of ivermectin to suppress ovarian cancer cells, and the ivermectin-related molecule-panel changes benefit for its personalized drug therapy and prognostic assessment towards its predictive, preventive, and personalized medicine (PPPM) in OCs.Electronic supplementary materialThe online version of this article (10.1007/s13167-020-00209-y) contains supplementary material, which is available to authorized users.

PG-path: Modeling and personalizing pharmacogenomics-based pathways.

A pharmacogenomics-based pathway represents a series of reactions that occur between drugs and genes in the human body after drug administration. PG-path is a pharmacogenomics-based pathway that standardizes and visualizes the components (nodes) and actions (edges) involved in pharmacokinetic and pharmacodynamic processes. It provides an intuitive understanding of the drug response in the human body. A pharmacokinetic pathway visualizes the absorption, distribution, metabolism, and excretion (ADME) at the systemic level, and a pharmacodynamic pathway shows the action of the drug in the target cell at the cellular-molecular level. The genes in the pathway are displayed in locations similar to those inside the body. PG-path allows personalized pathways to be created by annotating each gene with the overall impact degree of deleterious variants in the gene. These personalized pathways play a role in assisting tailored individual prescriptions by predicting changes in the drug concentration in the plasma. PG-path also supports counseling for personalized drug therapy by providing visualization and documentation.