A TIM-3-Fc decoy secreted by engineered T cells improves CD19 CAR T-cell therapy in B-cell acute lymphoblastic leukemia.

Relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging disease with dismal prognosis. Despite the revolutionary impact of CD19-directed chimeric antigen receptor (CAR19) T-cell therapy, >50% of patients relapse within a year. Both leukemia cell-intrinsic factors favoring immune escape and poor CAR T-cell persistence contribute to clinical failure.

Long-term mitochondrial and metabolic impairment in lymphocytes of subjects who recovered after severe COVID-19.

The underlying mechanisms explaining the differential course of SARS-CoV-2 infection and the potential clinical consequences after COVID-19 resolution have not been fully elucidated. As a dysregulated mitochondrial activity could impair the immune response, we explored long-lasting changes in mitochondrial functionality, circulating cytokine levels, and metabolomic profiles of infected individuals after symptoms resolution, to evaluate whether a complete recovery could be achieved. Results of this pilot study evidenced that different parameters of aerobic respiration in lymphocytes of individuals recuperated from a severe course lagged behind those shown upon mild COVID-19 recovery, in basal conditions and after simulated reinfection, and they also showed altered glycolytic capacity.

The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300-dependent stemness program.

Transcriptional cofactors of the ETO family are recurrent fusion partners in acute leukemia. We characterized the ETO2 regulome by integrating transcriptomic and chromatin binding analyses in human erythroleukemia xenografts and controlled ETO2 depletion models. We demonstrate that beyond its well-established repressive activity, ETO2 directly activates transcription of MYB, among other genes.

Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production.

Multiple myeloma is an incurable plasma cell malignancy. Most patients end up relapsing and developing resistance to antineoplastic drugs, like bortezomib. Antibiotic tigecycline has activity against myeloma.

Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo.

Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)-directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies.

Specific Cellular and Humoral Immune Responses to the Neoantigen RBD of SARS-CoV-2 in Patients with Primary and Secondary Immunodeficiency and Healthy Donors.

Patients with antibody deficiency disorders, such as primary immunodeficiency (PID) or secondary immunodeficiency (SID) to B-cell lymphoproliferative disorder (B-CLPD), are two groups vulnerable to developing the severe or chronic form of coronavirus disease caused by SARS-CoV-2 (COVID-19). The data on adaptive immune responses against SARS-CoV-2 are well described in healthy donors, but still limited in patients with antibody deficiency of a different cause. Herein, we analyzed spike-specific IFN-γ and anti-spike IgG antibody responses at 3 to 6 months after exposure to SARS-CoV-2 derived from vaccination and/or infection in two cohorts of immunodeficient patients (PID vs.

Alterations in the immune system persist after one year of convalescence in severe COVID-19 patients.

Introduction: Severe COVID-19 originates a myriad of alterations in the immune system during active disease, especially in the T and NK cell compartments, but several studies in the last year have unveiled some alterations that persist in convalescence. Although most of the studies follow the participants for a short recovery time, studies following patients up to three or six months still find alterations. We aimed at evaluating changes in the NK, T and B cell compartments after severe COVID-19 in participants with a median recovery time of eleven months.

An NMR-Based Model to Investigate the Metabolic Phenoreversion of COVID-19 Patients throughout a Longitudinal Study.

After SARS-CoV-2 infection, the molecular phenoreversion of the immunological response and its associated metabolic dysregulation are required for a full recovery of the patient. This process is patient-dependent due to the manifold possibilities induced by virus severity, its phylogenic evolution and the vaccination status of the population. We have here investigated the natural history of COVID-19 disease at the molecular level, characterizing the metabolic and immunological phenoreversion over time in large cohorts of hospitalized severe patients (n = 886) and non-hospitalized recovered patients that self-reported having passed the disease (n = 513).

Free triiodothyronine levels and age influences the metabolic profile and COVID-19 severity parameters in euthyroid and levothyroxine-treated patients.

Metabolic reprogramming is required to fight infections and thyroid hormones are key regulators of metabolism. We have analyzed in hospitalized COVID-19 patients: 40 euthyroid and 39 levothyroxine (LT4)-treated patients in the ward and 29 euthyroid and 9 LT4-treated patients in the intensive care unit (ICU), the baseline characteristics, laboratory data, thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), the FT3/FT4 ratio, 11 antiviral cytokines and 74 metabolomic parameters. No evidence for significant differences between euthyroid and LT4-treated patients were found in the biochemical, metabolomic and cytokines parameters analyzed.

A Novel Bead-Capture Nanopore Sequencing Method for Large Structural Rearrangement Detection in Cancer.

Rapid, cost-effective genomic stratification of structural rearrangements in cancer is often of vital importance when determining treatment; however, existing diagnostic cytogenetic and molecular testing fails to deliver the required speed when deployed at scale. Next-generation sequencing-based methods are widely used, but these can lack sensitivity and require batching of samples to be cost-effective, with long turnaround times. Here we present a novel method for rearrangement detection from genomic DNA based on third-generation long-read sequencing that overcomes these time and cost issues.

Biomarkers of stable and decompensated phases of heart failure with preserved ejection fraction.

Background: Heart failure with preserved ejection fraction (HFpEF) is a disorder related to patient comorbidities and aging. Whether mitochondrial dysfunction is present during HFpEF decompensation versus the stable phase is largely unknown. The aim of the present study was to identify mitochondrial and cell metabolism blood biomarkers in older patients with acute and stable HFpEF.

The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients with AML harboring a constitutively active internal tandem duplication mutation (ITD) in the FMS-like kinase tyrosine kinase (FLT3) receptor generally have a poor prognosis. Several tyrosine kinase/FLT3 inhibitors have been developed and tested clinically, but very few (midostaurin and gilteritinib) have thus far been FDA/EMA-approved for patients with newly diagnosed or relapse/refractory FLT3-ITD AML.

Prognostic significance of FLT3-ITD length in AML patients treated with intensive regimens.

FLT3-ITD mutations are detected in approximately 25% of newly diagnosed adult acute myeloid leukemia (AML) patients and confer an adverse prognosis. The FLT3-ITD allelic ratio has clear prognostic value. Nevertheless, there are numerous manuscripts with contradictory results regarding the prognostic relevance of the length and insertion site (IS) of the FLT3-ITD fragment.

Variant Philadelphia t(X;9;22)(q22?;q34;q11.2) can be successfully treated with second generation tyrosine kinase inhibitors: A case report and literature review.

Chronic myeloid leukemia (CML) is characterized by the reciprocal translocation between chromosomes 9 and 22: t(9;22)(q34;q11). However, 5-10% of patients with CML have complex variant translocations involving at least a third chromosome; only a few cases affect the X chromosome. Therefore, the data available regarding their features and the response to treatment is limited.

Engraftment characterization of risk-stratified AML in NSGS mice.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Disease heterogeneity is well documented, and patient stratification determines treatment decisions. Patient-derived xenografts (PDXs) from risk-stratified AML are crucial for studying AML biology and testing novel therapeutics.

Autoimmune neutropenia associated with influenza virus infection in childhood: a case report.

Background: Although neutropenia is relatively frequent in infants and children and is mostly a benign condition with a self-limited course, it can lead to life-threatening severe infections. Autoimmune neutropenia is a relatively uncommon hematological disorder characterized by the autoantibody-induced destruction of neutrophils. It is usually triggered by viral infections with very few documented cases after influenza virus.

Impact of BCR-ABL1 Transcript Type on Response, Treatment-Free Remission Rate and Survival in Chronic Myeloid Leukemia Patients Treated with Imatinib.

The most frequent -p210 transcripts in chronic myeloid leukemia (CML) are e14a2 and e13a2. Imatinib (IM) is the most common first-line tyrosine-kinase inhibitor (TKI) used to treat CML. Some studies suggest that transcript types confer different responses to IM.

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo.

Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity.