Background: Chronic myeloid leukemia (CML) is initiated in bone marrow due to chromosomal translocation t(9;22) leading to fusion oncogene BCR-ABL. Targeting BCR-ABL by tyrosine kinase inhibitors (TKIs) has changed fatal CML into an almost curable disease. Despite that, TKIs lose their effectiveness due to disease progression. Unfortunately, the mechanism of CML progression is poorly understood and common biomarkers for CML progression are unavailable. This study was conducted to find novel biomarkers of CML progression by employing whole-exome sequencing (WES). Materials and Methods: WES of accelerated phase (AP) and blast crisis (BC) CML patients was carried out, with chronic-phase CML (CP-CML) patients as control. After DNA library preparation and exome enrichment, clustering and sequencing were carried out using Illumina platforms. Statistical analysis was carried out using SAS/STAT software version 9.4, and R package was employed to find mutations shared exclusively by all AP-/BC-CML patients. Confirmation of mutations was carried out using Sanger sequencing and protein structure modeling using I-TASSER followed by mutant generation and visualization using PyMOL. Results: Three novel genes (ANKRD36, ANKRD36B and PRSS3) were mutated exclusively in all AP-/BC-CML patients. Only ANKRD36 gene mutations (c.1183_1184 delGC and c.1187_1185 dupTT) were confirmed by Sanger sequencing. Protein modeling studies showed that mutations induce structural changes in ANKRD36 protein. Conclusions: Our studies show that ANKRD36 is a potential common biomarker and drug target of early CML progression. ANKRD36 is yet uncharacterized in humans. It has the highest expression in bone marrow, specifically myeloid cells. We recommend carrying out further studies to explore the role of ANKRD36 in the biology and progression of CML.

Background: Chronic myeloid leukemia (CML) results from chromosomal translocation t(9;22) leading to the formation of the BCR-ABL fusion oncogene. CML has three stages: the chronic phase (CP), the accelerated phase (AP), and the blast crisis (BC). Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML. TKIs work well in CP-CML, and these patients have a survival rate similar to the normal population, but TKIs are less effective in advanced-phase CML. Even with current advances in treatment, BC-CML patients have an average overall survival of less than a year. Early recognition of CML patients at risk of disease progression can help in timely interventions with appropriate TKIs or other therapeutic modalities. Although some markers of disease progression like BCR-ABL kinase domain, ASXL1, and GATA2 mutations are available, no universal and exclusively specific molecular biomarkers exist to early diagnose CML patients at risk of CML progression for timely therapeutic interventions to delay or minimize blast crisis transformation in CML. A recent study found that all BC-CML patients harbored the FANCD2 (c.2022-5C>T) mutation. Therefore, the current study was designed to detect this FANCD2 mutant in AP-CML (early progression phase) and to clinically validate its potential as a novel molecular biomarker of early CML progression from CP to AP. Methods: Our study comprised 123 CP-CML (control group) and 60 AP-CML patients (experimental group) from 2 oncology centers, from January 2020 to July 2023. Mean hemoglobin level, WBC count, platelet count, treatment type, hepatomegaly, splenomegaly, and survival status of AP-CML patients were significantly different from those of CP-CML patients. However, as these clinical parameters cannot help in the early detection of patients at risk of CML progression, there was a need for a clinically validated biomarker of AP-CML. DNA was extracted from the patients’ blood samples, and the FANCD2 gene was sequenced using an Illumina NextSeq500 next-generation sequencer (NGS). Results: The NGS analysis revealed a unique splice-site mutation in the FANCD2 gene (c.2022-5C>T). This mutation was detected in the majority (98.3%) of AP-CML patients but in none of the CP-CML patients or healthy control sequences from genomic databases. The mutation was confirmed by Sanger sequencing. FANCD2 is a member of the Fanconi anemia pathway genes involved in DNA repair and genomic stability, and aberrations of this gene are associated with many cancers. Conclusions: In conclusion, our study shows that the somatic FANCD2 (c.2022-5C>T) mutation is a new molecular biomarker for early CML progression. We recommend further clinical validation of this biomarker in prospective clinical trials.

Objective: Exploring the prevalence of alteration in left ventricular (LV) geometry by echocardiography and their correlation with cardiovascular (CV) risk factors and cardiovascular diseases (CVD). Background: Alterations in LV geometry, by echocardiography, is an important prognostic determinant of CVD morbidity and mortality. Yet it is an underutilized tool and has yet to be established in laboratories. Methods: Left ventricular mass index (LVMI) and relative wall thickness (RWT) were calculated by M-mode echocardiography. Patients were classified into four groups based on RWT and LVMI: normal geometry, concentric remodeling (CR), eccentric left ventricular hypertrophy (eLVH), and concentric left ventricular hypertrophy (cLVH). Results: LV geometry patterns revealed normal geometry prevalence (43.46%), followed by CR (30.76%). The commonest CV risk factor was hypertension (HTN) (85%), followed by diabetes mellitus (DM) (72%). A strong association was identified between CVD and LV geometry changes (p-value < 0.005). CVD prevalence among total patients was 66.5% within this group; coronary artery disease (CAD) prevalence was 55.5% (p-value < 0.029), and heart failure (HF) prevalence was 29.6% (p-value < 0.001). Conclusion: We strongly reinforce routine echocardiograms in determining LVM, RWT, and LV geometry patterns. It is an important, underutilized diagnostic and prognostic tool in risk stratification of patients with CVD and altered LV geometry and mass. Future studies for incorporating LVM and RWT in clinical decision algorithms are warranted.

Background: Type 2 diabetes mellitus (T2DM) is a chronic disease with significant cardiovascular (CV) implications. The management of diabetes plays a crucial role in reducing the risk of cardiovascular disease (CVD) and improving patient outcomes. This review examines the impact of various therapeutic strategies and their relevance to specific demographic groups, particularly the elderly and those with chronic kidney disease (CKD). Methods: A comprehensive literature review was conducted focusing on randomized controlled trials (RCTs), meta-analyses, systematic reviews, and large observational studies from PubMed, Cochrane Library, and Google Scholar. Results: Metformin and sodium-glucose cotransporter-2 (SGLT2) inhibitors consistently reduced CV mortality by 20–38% compared to other treatments. Incretin-based therapies like liraglutide and semaglutide reduced major adverse cardiovascular events (MACE) by 13–26%. Lifestyle interventions lowered CV risk when combined with medications. SGLT2 inhibitors conferred renal and CV protection in patients with CKD. Bariatric surgery (BS) has been associated with significant improvements in CV outcomes. Conclusion: Metformin, SGLT2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), BS, and lifestyle modification conferred CV benefits. Management of type 2 diabetes with a view to reducing CV risk requires an individualized approach, taking into account patient characteristics, comorbidities, and the CV risk profiles of various treatment options.

Innovative advancements in the twenty-first-century technologies have revealed new genetic, immunological, and cellular biological mechanisms that contribute to understanding the biology and pathogenesis of pediatric as well as adulthood diseases. These advancements have sparked a significant revolution in the diagnosis, prognosis, and treatment of different cancers including hematological malignancies, particularly leukemia. Numerous molecular genetic assays have been developed to select optimal drugs and clinical protocols for leukemia patients. This personalized approach to treatment aims to achieve better clinical outcomes with reduced drug side effects. Genomic medicine has made basic genetic testing necessary for every clinic and hospital. This book provides an account of classical and novel developments in pediatric acute lymphoblastic leukemia (ALL) as most common childhood malignancy, that have resulted from state-of-the-art genetic, cell biological, and immunological research during the last three decades. Moreover, it also provides deep insights into the innovation in differential diagnosis, risk stratification, patient-tailored treatment, and accurate therapeutic follow-up for timely therapeutic interventions in the recent era of modern science and technology innovations of the twenty-first century that has fascinatingly improved clinical outcome of this deadly disease of the childhood.

Background: Chronic Myeloid Leukemia (CML) is initiated in bone marrow due to chromosomal translocation t(22;9) leading to fusion oncogene BCR-ABL. Targeting BCR-ABL by tyrosine kinase inhibitors (TKI) have changed fatal CML into an almost curable disease. Despite that, TKIs lose their effectiveness due to disease progression. Unfortunately, mechanism of CML progression is poorly understood and common biomarkers for CML progression are unavailable. This study was conducted to find out novel biomarkers of CML progression by employing whole exome sequencing (WES).Materials and Methods: WES of accelerated phase (AP-) and blast crisis (BC-) CML patients was carried out, with chronic phase CML (CP-CML) patients as control. After DNA library preparation and exome enrichment, clustering and sequencing was carried out using Illumina platforms. Statistical analysis was carried out using [SAS/STAT] software version 9.4 and R package employed to find mutations shared exclusively by all AP-/BC-CML. Confirmation of mutations was carried out using Sanger sequencing and protein structure modelling using I-Tasser followed by mutant generation and visualization using PyMOL. Results: Three novel genes (ANKRD36, ANKRD36B and PRSS3) were mutated exclusively in all AP-/BC-CML patients. Only ANKRD36 gene mutations (c.1183_1184 delGC and c.1187_1185 dupTT) were confirmed by Sanger sequencing. Protein modelling studies showed that mutations induce structural changes in ANKRD36 protein. Conclusions: Our studies show that ANKRD36 is a potential common biomarker and drug target of early CML progression. ANKRD36 is yet uncharacterized in human. It has the highest expression in bone marrow, specifically myeloid cells. We recommend carrying out further studies to explore the role of ANKRD36 in biology and progression of CML.