Recent Advances in Molecular and Translational Medicine: Updates in Precision Medicine

The promise of pediatric precision medicine can achieve an earlier diagnosis for more precise treatment and prevention. This development can be much contributed by translational research strategy. This chapter will introduce the concepts of translational research and precision medicine and summarize three vital elements, including biobanking, “omics” technologies, and data resources and management that can support the developing capacity of translational research for pediatric precision medicine.

Bioinformatics plays an essential role in precision medicine. By developing analytical and computational frameworks, bioinformatics identifies and analyzes gene variants, altered patterns of transcripts and proteins, as well as other omics profiles generated by high-throughput platforms. The big data generated from biological samples require scalable algorithms, efficient computational workflows, and tools for interpretations. Precise diagnoses can be made upon identifying a particular pathogenic variant/mutation. Candidate (or actionable) targets for precise treatment can be obtained by analyzing molecular expression profiles from the disease states. This chapter describes the basis of bioinformatics and common workflows used to analyze and interpret omics datasets for precision medicine. This chapter also serves as the introduction to genomics, transcriptomics, proteomics, and metabolomics profiling, and thus complements other omics related chapters within this book.

Medical knowledge and healthcare information have dramatically expanded in the past decades. The advents of medical ultra-subspecialty, mandated regulatory agencies, and modern molecular techniques (–omics) have made the field of Medicine spread in both depth and breadth. Medicine has become extremely complex beyond the unaided human mind. Humans make majority of decisions using six or fewer data points, otherwise, the human brain can become mentally exhausted. Artificial intelligence (AI) has been designed to analyze seamlessly over thousands of data points, including complex nonlinear interaction between data points. A novel perspective of a future in medicine incorporates data-driven systems while AI and clinicians work collaboratively in conditional automation, similar to the current state of automatic vehicles. The role of human physicians may shift to back-up decision making and diagnosis of rare diseases, rather than routine, repetitive works. Given the expected growth in the field, physicians should be familiar with the opportunities and limitations of AI and machine learning. This chapter will lay out the principle concepts of artificial intelligence, machine learning and artificial neural networks and will explore the recent studies and possible implications of AI in medical specialties.

The process of making a genetic diagnosis was considered time-consuming and labor-intensive. The completion of Human Genome Project and the development of next generation sequencing technology has been changing the face of genetic diagnosis with the high-throughput analysis in timely and costly manners. It also rapidly expands the knowledge in the medical genetics field. However, new challenges, including variant interpretation, secondary findings and ethical issues, have arisen. Here we discuss current platforms of NGS, basis of pathogenicity prediction, approaches of NGS and their performance as well as ethical concerns.

Multiple drugs with various mechanisms of action are used simultaneously during the perioperative period. Opioids, inhalations, intravenous induction agents, neuromuscular blocking agents and sedative agents are the common drugs used. Even if the same dose of drug is administered, diverse individual responses usually occur. These various individual responses might relate to the patient’s pharmacogenomic variations. Thus, the genotype-phenotype relationship should be carefully considered in adults. Furthermore, developmental pharmacogenomics also plays important role in pediatric patients who have dynamic growth and development process from infants to adolescents. This review shows the pharmacogenetic aspects of these common anesthetic medications and future trends for perioperative pharmacogenomic testing.

Proteins are functional units of the cell. These functional units are directly responsible for normal as well as disease states; therefore an insightful approach based on proteomics could be instrumental for precision medicine. In this chapter, we have provided current and up-to-date information on modern proteomics spanning from technical approaches to the bioinformatics/data analysis sides, with a final aim to emphasize how proteomics could be beneficial to precision medicine.

Metabolomics is a growing “omics” field in investigational research and clinical care. Metabolomics is the study of metabolome, including both endogenous and exogenous small molecules generated in the body viametabolic processes. This discipline is young compared to its complements, such as genomics or transcriptomics. However, it promises to be a powerful tool for understanding normal and diseased physiological states and informing clinicians in diagnosing and treating patients. This chapter summarizes the concept of metabolomics, describes the metabolomic approaches, and provides a practical workflow of metabolomic data analysis to illustrate the current and potential applications of metabolomics in precision medicine.

β-thalassemia is a genetic disorder resulting from defects in the β-globin gene. Patients having a compatible human leukocyte antigen (HLA) matched donor can be cured by transplantation of allogeneic hematopoietic stem cells (HSCs). However, some recipients have a high risk of morbidity/mortality due to graft versus host disease (GVHD) or graft rejection. Importantly, most patients do not have such HLA matchrelated donor issues. Thus, the infusion of autologous HSCs modified with a lentiviral vector expressing the β-globin therapeutic gene in the erythroid progenitors is a promising approach to fully cure the disease. Here we review the history of β- thalassemia treatment, particularly the development of the β-globin lentiviral vector, with emphasis on clinical applications and future perspectives in a new era of medicine.

So far, there are 538 kinases found in the human proteome. Most of these kinases play a critical role in normal and aberrant signaling biology. In the last three decades, the kinase research field has exploded with myriad unknown findings related to kinases and their disease association. Based on these seminal findings, we can now assert that >85% of identified kinases are dysregulated in at least one or more diseases. Due to these remarkable statistics, novel kinase targeting strategies have been utilized, primarily involving small molecule inhibitors. So far, the FDA has approved around 80 kinase inhibitors (mostly small molecule inhibitors). Here in this chapter, we provide a description of kinases and their families, kinase-disease association and an up-to-date status of kinase-based therapeutics.

Therapeutic cancer drugs have been developedfor specific cancer cell targets with no sideeffects and can remain stable until eliminating the cancer cells. Differentcompositions and alteredexpressions of lipids and proteins on cell membrane between normal and cancer cells have been an interesting development for targeted cancer cell therapy. A good choice of various anticancer drugs is anticancer peptides which are easy to synthesize and modify, stable in blood circulation and specific to the cancer cells. The molecular mechanism of the anticancer peptides for cancer eradication begins with the delivery of the specific anticancer peptides to the cancer cells. Then, the interaction of the cell membrane and the anticancer peptides via receptors or charge interaction leads to membrane disruption via pore formation and then apoptosis. Moreover, the anticancer peptides could be modified to improve cell permeability, stability in blood circulation without degradation or digestion, and cancer specificity. Currently, many anticancer peptides are ongoing in clinical trials to examine the efficacy with no side effects for clinical use in future therapy.

Combiningthe advancements in genetic engineering technologies and the principle knowledge of cancer immunology, chimeric antigen receptor (CAR) T cell therapy has emerged as a promising therapeutic modality for cancers. The function of CARs is to redirect the immune response to attack cancer cells in a specific manner. Up to date, multiple CAR configurations have been designed to ensure safety and to enhance in vivo persistence and therapeutic potency. A number of clinical trials of CAR T therapy for pediatric solid tumors are underway, mainly focusing on neuroblastoma patients. Although CAR T therapy has been approved by the US Food and Drug Administration (FDA) for hematological malignancies, disappointing response rates have been reported in solid cancers due to several hindrances. Proper target antigen selection, inefficient T cell trafficking, and the immunosuppressive nature of the tumor microenvironment (TME) are the main factors limiting CAR T function. In order for CAR T therapy to become successful in this matter, these challenges must be addressed. The future of CAR T therapy is moving toward the development of the “off-the-shelf” universal CAR T product in the hope of providing cancer treatment to a large population. This chapter reviews the principles of CAR design, current clinical trials, limitations, and future prospects of CAR T cells for pediatric solid tumors.

Hematopoietic stem cell transplant (HSCT) is a curative treatment for many diseases especially inherited genetic diseases such as thalassemia, inherited bone marrow failure syndromes, primary immunodeficiencies, Gaucher disease, Hunter syndrome, or other mucopolysaccharidoses. The two main elements of HSCT are the conditioning regimen and an available donor. The conditioning regimen included combined chemotherapy, monoclonal antibody, or radiation, while the available donor might be HLA-identical or HLA-mismatched.