Is Adherence to Imatinib Mesylate Treatment Among Patients with Chronic Myeloid Leukemia Associated with Better Clinical Outcomes in Qatar?

Background: Despite the revolutionary success of introducing tyrosine kinase inhibitors (TKIs), such as imatinib mesylate (IM), for treating chronic myeloid leukemia (CML), a substantial proportion of patients' treatments fail. Aim: This study investigates the correlation between patient adherence and failure of TKIs' treatment in a follow-up study. Methods: This is a follow-up study of a new cohort of CML patients. Adherence to IM is assessed using the Medication Event Monitoring System (MEMS 6 TrackCap, AARDEX Ltd). The 9-item Morisky Medication Adherence Scale, medication possession ratio (MPR) calculation, and the electronic medical records are used for identifying potential factors that influence adherence. Clinical outcomes are assessed according to the European LeukemiaNet 2013 guidelines via reverse transcriptase quantitative polymerase chain reaction measurement of the level of BCR-ABL1 transcripts in peripheral blood. Response is classified at the hematological, cytogenetic, and molecular levels into optimal, suboptimal, or failure. Results: A total of 36 CML patients (5 citizens and 31 noncitizen residents) consented to participate in the study. The overall mean MEMS score was 89. Of the 36 patients, 22 (61%) were classified as adherent (mean: 95) and 14 (39%) were classified as nonadherent (mean: 80.2). Adherent patients were significantly more likely to obtain optimal response (95%) compared to the nonadherent group (14.3%; P < 0.0001). The rate of poor adherence was as high as 39% using MEMS, which correlates with 37% treatment failure rate. The survey results show that 97% of patients increased the IM dose by themselves when they felt unwell and 31% of them took the missing IM dose when they remembered. Other factors known to influence adherence show that half of patients developed one or more side effects, 65% of patients experienced lack of funds, 13% of patients declared unavailability of the drug in the NCCCR pharmacy, and 72% of patients believed that IM would cure the disease. The MPR results reveal that 16% of patients had poor access to treatment through the hospital pharmacy. Discussion and conclusion: This is the first prospective study to evaluate CML patients' adherence and response to IM in Qatar. The high rate of treatment failure observed in Qatar is explained by poor adherence. An economic factor (unaffordable drug prices) is one of the main causes of nonadherence and efforts should be made locally to improve access to medication for cancer diseases. Other risk factors associated with poor adherence could be improved by close monitoring and dose adjustment. Monitoring risk factors for poor adherence and patient education that include direct communication between the health-care teams, doctors, nurses, pharmacists, and patients are essential components for maximizing the benefits of TKI therapy and could rectify this problem. The preliminary results show that patients' response to treatment may be directly linked to patients' adherence to treatment. However, further in-depth and specific analysis may be necessary in a larger cohort

Making Biomarkers Relevant to Healthcare Innovation and Precision Medicine

Translational medicine, the exchange between laboratory (bench) and the clinic (bedside), is decidedly taking on a vital role. Many companies are now focusing on a translational medicinal approach as a therapeutic strategy in decision making upon realizing the expenses of drug attrition in late-stage advancement. In addition, the utility of biomarkers in clinical decision and therapy guidance seeks to improve the patient outcomes and decrease wasteful and harmful treatment. Efficient biomarkers are crucial for the advancement of diagnoses, better molecular targeted therapy, along with therapeutic advantages in a broad spectrum of various diseases. Despite recent advances in the discovery of biomarkers, the advancement route to a clinically validated biomarker remains intensely challenging, and many of the candidate biomarkers do not progress to clinical applications, thereby widening the innovation gap between research and application. The present article will focus on the clinical view of biomarkers in a reverse design, addressing how a biomarker program should appear if it is expected to create an impact on personalized medicine and patient care

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

Regulative loop between beta-catenin and protein tyrosine phosphatase receptor type gamma (PTPRG) in chronic myeloid leukemia

Introduction. Chronic Myeloid Leukemia (CML) is a myeloproliferative disease characterized by the presence of the oncogene BCR-ABL1, which acts as tyrosine kinase. PTPRG (Protein Tyrosine Phoshatase Receptor type \u3b3) is a tumor suppressor gene down- regulated by hypermethylation of its promoter region in CML. Previous studies demonstrated that a re-expression of PTPRG is correlated with a decreased clonogenic capability of CML cells, as shown by the down-regulation of Ki67, and with an increased cellular differentiation related to a PTPRG-mediated overexpression of GATA-1 and Cyclin D1. In addition, its restored expression was observed in patients with a good response to TKI therapy. In order to understand the regulation between this phosphatase and BCR- ABL1, we searched for PTPRG putative interactors among proteins downstream BCR-ABL1 driven pathways and we focused on b-Catenin, that is at the same time a PTPRG substrate and its transcriptional regulator. Methods. Cells: PTPRG negative cell line K562, with a stable transfection of exogenous PTPRG, and PTPRG positive cell line LAMA-84, treated with a specific siRNA and with a new PTPRG small drug inhibitor. Pull-down assay with purified, recombinant intracellular domain of PTPRG demonstrated a direct interaction between PTPRG and b-Catenin, while Western Blotting or Immunofluorescence were applied to detect a specific dephospho- rylation pattern in presence of PTPRG. Chromatin Immunoprecipitation showed us the binding between DNMT1(b-Catenin transcriptional target) and PTPRG promoter region. Results. We demonstrated that PTPRG binds and dephosphorylates b-Catenin, phosphorylated by BCR-ABL1, causing its cytoplasmic destabilization and the resulting degradation in CML cell lines with an exogenous or endogenous expression of PTPRG (K562 and LAMA-84 cell lines). Consequently, this regulation leads to MYC down-expression and p21/WAF1 increased expression, explaining the slow-down of proliferation in presence of PTPRG. On the contrary, we demonstrated that an increased expression of b-Catenin in PTPRG negative CML cell lines is correlated with an over-expression of the DNA (cytosine-5)-methyltransferase 1 (DNMT1) that is responsible of PTPRG promoter hypermethylation and that an inhibition after a treatment with 5-Azacydine or a down-regulation of this enzyme is closely related to PTPRG re-expression both at mRNA and protein levels. Conclusions. We show for the first time a mechanism that involves b-Catenin degradation control and the consequent down-regulation of genes regulated by the TCF/b-Catenin transcription complex. In return, b-Catenin up-regulation is correlated with an over-expression of DNMT1 that contributes to an hypermethylation of PTPRG promoter region. We hypothesized a regulative loop between PTPRG and b-Catenin and that an imbalance of the system in favor of one or the other could determine a different proliferation fate of CML cells and their clinical aggressiveness

Principal molecular pathways affected in autism spectrum disorder

Autism spectrum disorder (ASD) development is a highly multifaceted process as evidenced by the complexity of the factors involved in the etiology of ASD, including genetic and nongenetic factors. Several forms of ASD result from genetic alterations in genes that regulate the process of protein synthesis. A growing body of evidence suggests that abnormal synaptic protein synthesis might contribute to ASD and ASD-like clinical features. Several reports of different mutated genes responsible for ASD cases and genetic models have emerged, revealing dysregulation of many crucial signaling pathways. In this chapter, the authors summarize the various factors described to contribute to ASD, both genetic and nongenetic, and their association with WNT, SHH, RA, FGF, and BMP/TGF-β signaling pathways. In addition, the authors discuss the scope for additional research for a better understanding of the pathophysiology of ASD in the context of disrupted signaling pathways, which could help open the doors to identify possible gene targets and novel therapeutic strategies

Ptprg and BCR/ABL1 Expression In CML Patients At Diagnosis and Upon TKI Treatment: Preliminary Results

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