Management of chronic myeloid leukaemia : current treatment options, challenges, and future strategies

Small molecule therapy is a critical component of targeted anticancer treatment, with tyrosine kinase inhibitors (TKIs) being the first compounds to treat the clonal Chronic Myelogenous Leukaemia (CML) translocation t (9;22) (q34; q11) effectively since 2001. TKIs, such as imatinib, have improved the 10-year survival rate of CML patients to 80%. They bind the kinase and inhibit downstream signaling pathways. However, therapy failure may be seen in 20-25% of CML patients due to intolerance or inadequacy related to dependent or independent mechanisms. This review aimed to summarize current treatment options involving TKIs, resistance mechanisms and the prospective approaches to overcome TKI resistance. We highlight -dependent mechanisms of TKI resistance by reviewing clinically-documented mutations and their consequences for TKI binding. In addition, we summarize independent pathways, including the relevance of drug efflux, dysregulation of microRNA, and the involvement of alternative signaling pathways. We also discuss future approaches, such as gene-editing techniques in the context of CML, as potential therapeutic strategies

Attention-deficit hyperactivity disorder : genetic, pharmacogenetic, and metabolomic insights

ADHD is a neurodevelopmental disorder that affects children, adolescents, and adults at a high rate around the globe, resulting in significant impairment. Inattention, impulsivity, restlessness, and hyperactivity are all hallmarks of ADHD. Symptoms may persist into adulthood in 55–66% of all cases. The causes of ADHD remain unclear, but it is believed to be a complex disease with a variety of contributing variables, including heredity, neurodevelopmental problems, severe brain traumas, neuroinflammation, consanguineous marriages, prematurity, and exposure to environmental toxins. Numerous genetic polymorphisms linked with ADHD have been discovered in the twenty-first century. These findings have already given a starting point for the study of ADHD biology and innovative treatment options. Pharmacotherapy using methylphenidate (MPH) seems to be the first-line treatment option for adults with ADHD. Moreover, research has been done on genes that influence the response to MPH among ADHD-affected individuals. Furthermore, a few peripheral biomarkers have been discovered in ADHD adults. In this chapter, the authors summarize current evidence on genetic, pharmacogenetic, and biochemical (metabolomics) investigations in ADHD. Also, the authors address the neurobiology of ADHD, with a focus on functional or structural alterations in the brain of ADHD-affected individuals and their connections with complicated chromosomal variants using imaging genetics methods. In addition, the biological mechanisms involved in ADHD have been summarized. Finally, the scope for additional research for a better understanding of the pathophysiology of ADHD in the context of disrupted signaling pathways is reviewed, which could eventually lead to the discovery of possible therapeutic targets and novel treatment strategies