Coordinated immune networks in leukemia bone marrow microenvironments distinguish response to cellular therapy.

Understanding how intratumoral immune populations coordinate antitumor responses after therapy can guide treatment prioritization. We systematically analyzed an established immunotherapy, donor lymphocyte infusion (DLI), by assessing 348,905 single-cell transcriptomes from 74 longitudinal bone marrow samples of 25 patients with relapsed leukemia; a subset was evaluated by both protein- and transcriptome-based spatial analysis. In acute myeloid leukemia (AML) DLI responders, we identified clonally expanded CD8 cytotoxic T lymphocytes with in vitro specificity for patient-matched AML.

3-Year Outcomes of Balloon-Expandable Valves: 20-mm vs Larger Valves (≥23 mm).

Background: A prior Society of Thoracic Surgeons/American College of Cardiology TVT (Transcatheter Valve Therapy) Registry-based analysis reported similar 1-year clinical outcomes with small (20-mm) vs large (≥23-mm) balloon-expandable valves (BEV).

Objectives: The aim of this study was to describe mid-term 3-year clinical outcomes for small vs large BEV and the relationship between discharge echocardiographic mean gradient (MG) and different definitions of prothesis-patient mismatch (PPM) with clinical outcomes.

Methods: Using the TVT Registry with Centers for Medicare and Medicaid Services linkage, a propensity-matched analysis of patients receiving 20- vs ≥23-mm BEVs was performed.

Dual modality intravascular catheter system combining pulse-sampling fluorescence lifetime imaging and polarization-sensitive optical coherence tomography.

The clinical management of coronary artery disease and the prevention of acute coronary syndromes require knowledge of the underlying atherosclerotic plaque pathobiology. Hybrid imaging modalities capable of comprehensive assessment of biochemical and morphological plaques features can address this need. Here we report the first implementation of an intravascular catheter system combining fluorescence lifetime imaging (FLIm) with polarization-sensitive optical coherence tomography (PSOCT).

Coordinated Immune Cell Networks in the Bone Marrow Microenvironment Define the Graft versus Leukemia Response with Adoptive Cellular Therapy.

Understanding how intra-tumoral immune populations coordinate to generate anti-tumor responses following therapy can guide precise treatment prioritization. We performed systematic dissection of an established adoptive cellular therapy, donor lymphocyte infusion (DLI), by analyzing 348,905 single-cell transcriptomes from 74 longitudinal bone-marrow samples of 25 patients with relapsed myeloid leukemia; a subset was evaluated by protein-based spatial analysis. In acute myelogenous leukemia (AML) responders, diverse immune cell types within the bone-marrow microenvironment (BME) were predicted to interact with a clonally expanded population of CD8+ cytotoxic T lymphocytes (CTLs) which demonstrated specificity for autologous leukemia.

Aurora A kinase inhibition induces accumulation of SCLC tumor cells in mitosis with restored interferon signaling to increase response to PD-L1.

Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype) have durable responses to PD-L1. Some SCLCs are highly sensitive to Aurora kinase inhibitors, but early-phase trials show short-lived responses, suggesting effective therapeutic combinations are needed to increase their durability.

Latent human herpesvirus 6 is reactivated in CAR T cells.

Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6). Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4 T cells.

KDM6A epigenetically regulates subtype plasticity in small cell lung cancer.

Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1, POU2F3 and Inflammatory. Initially, SCLC subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoural subtype heterogeneity and plasticity between subtypes. Here, using a CRISPR-based autochthonous SCLC genetically engineered mouse model to study the consequences of KDM6A/UTX inactivation, we show that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumours that express both ASCL1 and NEUROD1.

Patients' Perspectives on Informational Support and Education in the Perinatal Period: "The Quicker They Could Be Done With Me, the Better".

Introduction: The overall purpose of this study was to elicit perspectives from a diverse group of postpartum individuals about their perinatal outpatient informational support and education. In addition, suggestions from participants are provided. Although informational support is crucial in the peripartum period, it is often inadequate or biased.

Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease.

The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells.

Mitochondrial DNA Mutations as Natural Barcodes for Lineage Tracing of Murine Tumor Models.

Unlabelled: Murine models are indispensable tools for functional genomic studies and preclinical testing of novel therapeutic approaches. Mitochondrial single-cell assay for transposase-accessible chromatin using sequencing (mtscATAC-seq) enables the dissection of cellular heterogeneity and clonal dynamics by capturing chromatin accessibility, copy-number variations (CNV), and mitochondrial DNA (mtDNA) mutations, yet its applicability to murine studies remains unexplored. By leveraging mtscATAC-seq in novel chronic lymphocytic leukemia and Richter syndrome mouse models, we report the detection of mtDNA mutations, particularly in highly proliferative murine cells, alongside CNV and chromatin state changes indicative of clonal evolution upon secondary transplant.

In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities.

Unlabelled: Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice and recapitulated the process of transformation from indolent CLL into large cell lymphoma [i.e.

Right Coronary Artery Dissection After Ross Procedure.

The Ross procedure is a surgical option for the treatment of aortic valve stenosis that is performed in a select subset of patients. This case report highlights the rare complication of a coronary artery dissection that occurred in the early postoperative period after a Ross procedure. The importance of timely recognition, swift intervention, and multidisciplinary team collaboration is discussed in the postoperative management of this complex cardiac surgery patient.

Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma.

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. Approximately half of patients with refractory large B cell lymphomas achieve durable responses from CD19-targeting CAR-T treatment; however, failure mechanisms are identified in only a fraction of cases. To gain new insights into the basis of clinical response, we performed single-cell transcriptome sequencing of 105 pretreatment and post-treatment peripheral blood mononuclear cell samples, and infusion products collected from 32 individuals with large B cell lymphoma treated with either of two CD19 CAR-T products: axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel).

Multidisciplinary approach to coronary artery revascularization: Optimal strategy for high-risk patients.

High-risk patients that are not candidates for conventional coronary artery bypass grafting surgery can undergo coronary artery revascularization through less invasive procedures. Hybrid approaches have emerged to address coronary artery disease in this subset of patients. This case report highlights the successful application of a multidisciplinary heart team approach for hybrid coronary revascularization in a very high-risk patient with complex coronary anatomy, who would not otherwise be a candidate for conventional modalities of revascularization.

Understanding repeat hospitalizations in intermediate-to-high risk aortic stenosis patients following transcatheter aortic valve replacement.

Objectives: We describe the causes, timing and predictors of readmissions and analyze its impact on clinical outcomes in intermediate-to-high-risk patients with severe symptomatic aortic stenosis (AS) who underwent transcatheter aortic valve replacement (TAVR).

Background: Intermediate-high risk TAVR patients with severe AS have an increased risk for hospital readmissions due to the high burden of comorbidities.

Methods: Patients who underwent TAVR from 2012 to 2018 at a single tertiary cardiac center were included and followed for 1 year.

Label-Free Visualization and Quantification of Biochemical Markers of Atherosclerotic Plaque Progression Using Intravascular Fluorescence Lifetime.

Objectives: This study aimed to systematically investigate whether plaque autofluorescence properties assessed with intravascular fluorescence lifetime imaging (FLIm) can provide qualitative and quantitative information about intimal composition and improve the characterization of atherosclerosis lesions.

Background: Despite advances in cardiovascular diagnostics, the analytic tools and imaging technologies currently available have limited capabilities for evaluating in situ biochemical changes associated with luminal surface features. Earlier studies of small number of samples have shown differences among the autofluorescence lifetime signature of well-defined lesions, but a systematic pixel-level evaluation of fluorescence signatures associated with various histological features is lacking and needed to better understand the origins of fluorescence contrast.

The Molecular Pathophysiology of Concussion.

After a concussion, a series of complex, overlapping, and disruptive events occur within the brain, leading to symptoms and behavioral dysfunction. These events include ionic shifts, damaged neuronal architecture, higher concentrations of inflammatory chemicals, increased excitatory neurotransmitter release, and cerebral blood flow disruptions, leading to a neuronal crisis. This review summarizes the translational aspects of the pathophysiologic cascade of postconcussion events, focusing on the role of excitatory neurotransmitters and ionic fluxes, and their role in neuronal disruption.

The effects of repetitive head impacts on postural control: A systematic review.

Objectives: The purpose of our study was to investigate the association between repetitive head impact (RHI) exposure and postural control.

Design: Systematic review.

Methods: PubMed, Embase and PsycInfo were searched using a self-developed search term including the keywords balance OR postural control AND repetitive OR sub-concussive head impacts.

Technical Considerations for TAVR in the Treatment of Stentless Bioprosthetic Aortic Valve Insufficiency in LVAD Patients.

An 80-year-old man with a history of bicuspid AV complicated by severe AI presented with progressive NYHA class III symptoms and severe bioprosthetic AV insufficiency. Transcatheter aortic valve replacement was planned via transfemoral approach. We encountered several technical challenges and describe them herein.

Interstitial lung abnormality is prevalent and associated with worse outcome in patients undergoing transcatheter aortic valve replacement.

Background: Interstitial lung abnormality (ILA) is found in 5-10% of the general population and is associated with increased mortality risk. Risk factors for ILA, including advanced age and smoking history also increase the risk for aortic stenosis (AS). Transcatheter aortic valve replacement (TAVR) has become an increasingly utilized intervention for patients with severe AS, and requires a high-resolution computed tomography (HRCT) of the chest to assess aortic valve dimensions.