Clonal evolution of the 3D chromatin landscape in patients with relapsed pediatric B-cell acute lymphoblastic leukemia.

Relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains one of the leading causes of cancer mortality in children. We performed Hi-C, ATAC-seq, and RNA-seq on 12 matched diagnosis/relapse pediatric leukemia specimens to uncover dynamic structural variants (SVs) and 3D chromatin rewiring that may contribute to relapse. While translocations are assumed to occur early in leukemogenesis and be maintained throughout progression, we discovered novel, dynamic translocations and confirmed several fusion transcripts, suggesting functional and therapeutic relevance. Genome-wide chromatin remodeling was observed at all organizational levels: A/B compartments, TAD interactivity, and chromatin loops, including some loci shared by 25% of patients. Shared changes were found to drive the expression of genes/pathways previously implicated in resistance as well as novel therapeutic candidates, two of which (ATXN1 and MN1) we functionally validated. Overall, these results demonstrate chromatin reorganization under the selective pressure of therapy and offer the potential for discovery of novel therapeutic interventions.

Landiolol for Treating Arrhythmias: A State-of-The-Art Review.

This article provides a state-of-the-art review on landiolol, a medication that was recently submitted for 7 approvals. Focusing on its pharmacology, pharmacokinetics, and pharmacodynamics, the analysis underscores landiolol's unique attributes compared to conventional beta-blockers, particularly esmolol. As a sympatholytic agent, landiolol exhibits a short half-life, high cardioselectivity, and minimal impact on blood pressure, setting it apart in the realm of arrhythmia treatment. The review explores landiolol's potential applications, emphasizing scenarios where other beta-blockers may be limited. A detailed examination of its efficacy in preventing postoperative atrial fibrillation reveals promising results from clinical trials, suggesting its utility in diverse surgical settings. Additionally, the article delves into landiolol's role in rate control for atrial fibrillation/flutter, treatment of ventricular tachycardia/fibrillation, and its use in managing sepsis-related tachyarrhythmias. The evolving landscape of landiolol's applications extends beyond cardiac care, including potential anti-inflammatory, antioxidative, analgesic, and anticancer effects. While the outcomes from various studies are promising, challenges persist, requiring further research to optimize dosing strategies, identify optimal patient populations, and elucidate mechanisms underlying its diverse effects. The potential expansion of landiolol's applications highlights the importance of ongoing clinical investigation, offering a promising avenue for enhancing arrhythmia management and addressing broader medical needs.

SETD2 mutations do not contribute to clonal fitness in response to chemotherapy in childhood B cell acute lymphoblastic leukemia.

Mutations in genes encoding epigenetic regulators are commonly observed at relapse in B cell acute lymphoblastic leukemia (B-ALL). Loss-of-function mutations in SETD2, an H3K36 methyltransferase, have been observed in B-ALL and other cancers. Previous studies on mutated SETD2 in solid tumors and acute myelogenous leukemia support a role in promoting resistance to DNA damaging agents. We did not observe chemoresistance, an impaired DNA damage response, nor increased mutation frequency in response to thiopurines using CRISPR-mediated knockout in wild-type B-ALL cell lines. Likewise, restoration of SETD2 in cell lines with hemizygous mutations did not increase sensitivity. SETD2 mutations affected the chromatin landscape and transcriptional output that was unique to each cell line. Collectively our data does not support a role for SETD2 mutations in driving clonal evolution and relapse in B-ALL, which is consistent with the lack of enrichment of SETD2 mutations at relapse in most studies.

Pharmacotherapy of refractory pulmonary arterial hypertension.

INTRODUCTION: Treatment of refractory pulmonary arterial hypertension (PAH) is challenging and rarely the focus of reviews. The purpose of this review is to discuss current treatment options of refractory PAH, along with the state of research of several new medications. AREAS COVERED: We conducted a comprehensive PubMed search on the relevant literature on treating PAH, with a focus on approved and investigational interventions for high-risk patients. Our strategy used keywords 'Treatment' AND 'Pulmonary Hypertension,' without date restrictions, ensuring a thorough survey of available literature for our review. EXPERT OPINION: By utilizing serial risk assessment to identify patients remaining intermediate or high-risk, more patients are likely to survive longer. This is done by earlier use of combination or triple therapy with prostacyclin drugs. Current medications for PAH are all essentially vasodilators that improve physiology, but do not truly modify the disease process. The potential application of new investigational medications is exciting as they work by novel pathways likely to change the landscape of refractory PAH treatment.

Minimal Residual Disease in Acute Lymphoblastic Leukemia: Current Practice and Future Directions.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and advances in its clinical and laboratory biology have grown exponentially over the last few decades. Treatment outcome has improved steadily with over 90% of patients surviving 5 years from initial diagnosis. This success can be attributed in part to the development of a risk stratification approach to identify those subsets of patients with an outstanding outcome that might qualify for a reduction in therapy associated with fewer short and long term side effects. Likewise, recognition of patients with an inferior prognosis allows for augmentation of therapy, which has been shown to improve outcome. Among the clinical and biological variables known to impact prognosis, the kinetics of the reduction in tumor burden during initial therapy has emerged as the most important prognostic variable. Specifically, various methods have been used to detect minimal residual disease (MRD) with flow cytometric and molecular detection of antigen receptor gene rearrangements being the most common. However, many questions remain as to the optimal timing of these assays, their sensitivity, integration with other variables and role in treatment allocation of various ALL subgroups. Importantly, the emergence of next generation sequencing assays is likely to broaden the use of these assays to track disease evolution. This review will discuss the biological basis for utilizing MRD in risk assessment, the technical approaches and limitations of MRD detection and its emerging applications.