Philadelphia chromosome-positive T-cell acute lymphoblastic leukemia: a case report.

Philadelphia chromosome-positive (Ph+) T-cell acute lymphoblastic leukemia (T-ALL) is a rare and aggressive type of acute leukemia. The Philadelphia chromosome is the hallmark of chronic myeloid leukemia (CML). The differentiation between Ph+ T-ALL and T-cell lymphoblastic crisis of CML may be problematic in some cases.

A multicenter study of posttransplantation low-dose inotuzumab ozogamicin to prevent relapse of acute lymphoblastic leukemia.

The curative potential of allogeneic hematopoietic transplantation (allo-HCT) in patients with acute lymphoblastic leukemia (ALL) is hampered by relapse. Inotuzumab ozogamicin (INO) is an anti-CD22 monoclonal antibody bound to calicheamicin, which has significant activity against ALL. We hypothesized that low-dose INO would be safe and feasible after allo-HCT.

Phase I study of intra-osseous co-transplantation of a single-unit cord blood and mesenchymal stromal cells with reduced intensity conditioning regimens.

Cord blood (CB) is a valuable graft source for patients undergoing allogeneic hematopoietic cell transplant (HCT) who lack human leukocyte antigen (HLA)-matched donors. However, single-unit CB-HCT is limited by the insufficient cell dose and slow engraftment. To overcome these limitations, we combined a single-unit CB with third-party healthy donors' bone marrow (BM) derived mesenchymal stromal cells (MSCs) to improve engraftment and injected intra-osseously (IO) to enhance homing.

Targeted Marrow Irradiation Intensification of Reduced-Intensity Fludarabine/Busulfan Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation.

Reduced-intensity conditioning (RIC) regimens frequently provide insufficient disease control in patients with high-risk hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated intensification of fludarabine/busulfan (Flu/Bu) RIC with targeted marrow irradiation (TMI) in a dose escalation with expansion phase I clinical trial. TMI doses were delivered at 1.

A Phase I Study to Determine the Maximum Tolerated Dose of ex Vivo Expanded Natural Killer Cells Derived from Unrelated, HLA-Disparate Adult Donors.

The administration of allogeneic natural killer (NK) cells following a lymphodepleting chemotherapy regimen is emerging as a well-tolerated therapeutic approach in the management of various malignancies. Contrary to the expected complications of allogeneic T cell therapy, there remains no evidence of graft-versus-host disease (GVHD) mediated by NK cells in numerous clinical trials. On the contrary, preclinical and clinical studies suggest that NK cells do not induce GVHD and in fact may prevent its development following allogeneic hematopoietic cell transplantation (HCT).

Diffuse Large B Cell Lymphoma in Patients 80 Years and Older: Worse Survival After Treatment Without Increased Relapse Rates.

Background: Age is an adverse prognostic factor in diffuse large B cell lymphoma (DLBCL), but there are limited data on the outcomes of patients' ≥80 years, including those treated with dose reduced chemoimmunotherapy.

Patients And Methods: We conducted a retrospective analysis of 542 patients, 85 (16%) were ≥80 years of age.

Results: Although the very elderly group had more frequent comorbidities and decreased performance status, 89% received therapy.

Efficacy and cost-benefit of filgrastim administered after early assessment bone marrow biopsy during induction therapy for acute myeloid leukemia.

The role of filgrastim during acute myeloid leukemia (AML) induction therapy remains controversial. At our institution, newly diagnosed AML patients from 2003 through 2019 were retrospectively evaluated. Patients were stratified on whether they received filgrastim within 5 days after early assessment bone marrow (BMBx) and divided into early GCSF group (eGCSF) and no-eGCSF group.

Harnessing the immune system to overcome cytokine storm and reduce viral load in COVID-19: a review of the phases of illness and therapeutic agents.

Background: Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, previously named 2019-nCov), a novel coronavirus that emerged in China in December 2019 and was declared a global pandemic by World Health Organization by March 11th, 2020. Severe manifestations of COVID-19 are caused by a combination of direct tissue injury by viral replication and associated cytokine storm resulting in progressive organ damage.

Discussion: We reviewed published literature between January 1st, 2000 and June 30th, 2020, excluding articles focusing on pediatric or obstetric population, with a focus on virus-host interactions and immunological mechanisms responsible for virus associated cytokine release syndrome (CRS).

History of drug use in allogeneic hematopoietic cell transplant recipients.

Allogeneic hematopoietic cell transplant (HCT) is a curative therapy for malignant and non-malignant blood diseases. Drug use may be associated with adverse outcomes. We performed a retrospective analysis to assess non-relapse mortality (NRM) and overall survival (OS) in HCT patients with drug use.

Influence of gut microbiome on multiple myeloma: friend or foe?

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells, which typically evolves over time from its precursor, monoclonal gammopathy of undetermined significance. While the underlying mechanisms of this evolution remain elusive, immunomodulatory factors affecting the bone marrow (BM) microenvironment are suspected to play a role. There is an increasing evidence that the gut microbiome exerts an influence on its host's adaptive and innate immune systems, inflammatory pathways and the BM microenvironment.

Aggressive lymphoma subtype is a risk factor for venous thrombosis. Development of lymphoma - specific venous thrombosis prediction models.

Venous thromboembolic events (VTE) are a frequent complication of lymphoma. We conducted a retrospective analysis to compare VTE risk in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Subjects were randomly assigned to training and validation sets to identify risk factors of VTE and evaluate risk model performance, including the Khorana score.

A Phase II Study of Midostaurin and 5-Azacitidine for Untreated Elderly and Unfit Patients With FLT3 Wild-type Acute Myelogenous Leukemia.

Background: Midostaurin, a multikinase inhibitor, is approved for treatment of FLT3-mutant acute myeloid leukemia (AML). A phase I study established that midostaurin 75 mg orally twice daily for 14 days with standard dose azacitidine was safe and tolerable in elderly patients with AML. Herein, we report the phase II expansion cohort of previously untreated elderly or unfit patients with AML.

Midostaurin: a novel therapeutic agent for patients with FLT3-mutated acute myeloid leukemia and systemic mastocytosis.

The development of FLT3-targeted inhibitors represents an important paradigm shift in the management of patients with highly aggressive fms-like tyrosine kinase 3-mutated (FLT3-mut) acute myeloid leukemia (AML). Midostaurin is an orally administered type III tyrosine kinase inhibitor which in addition to FLT3 inhibits c-kit, platelet-derived growth factor receptors, src, and vascular endothelial growth factor receptor. Midostaurin is the first FLT3 inhibitor that has been shown to significantly improve survival in younger patients with FLT3-mut AML when given in combination with standard cytotoxic chemotherapy based on the recently completed RATIFY study.

Midostaurin: an emerging treatment for acute myeloid leukemia patients.

Acute myeloid leukemia (AML) is a hematologic malignancy that carries a poor prognosis and has garnered few treatment advances in the last few decades. Mutation of the internal tandem duplication (ITD) region of fms-like tyrosine kinase (FLT3) is considered high risk for decreased response and overall survival. Midostaurin is a Type III receptor tyrosine kinase inhibitor found to inhibit FLT3 and other receptor tyrosine kinases, including platelet-derived growth factor receptors, cyclin-dependent kinase 1, src, c-kit, and vascular endothelial growth factor receptor.

Glutaredoxin regulates apoptosis in cardiomyocytes via NFkappaB targets Bcl-2 and Bcl-xL: implications for cardiac aging.

Cardiomyocyte apoptosis is a well-established contributor to irreversible injury following myocardial infarction (MI). Increased cardiomyocyte apoptosis is associated also with aging in animal models, exacerbated by MI; however, mechanisms for this increased sensitivity to oxidative stress are unknown. Protein mixed-disulfide formation with glutathione (protein glutathionylation) is known to change the function of intermediates that regulate apoptosis.

Covalent cross-linking of glutathione and carnosine to proteins by 4-oxo-2-nonenal.

The lipid oxidation product 4-oxo-2-nonenal (ONE) derived from peroxidation of polyunsaturated fatty acids is a highly reactive protein cross-linking reagent. The major family of cross-links reflects conjugate addition of side chain nucleophiles such as sulfhydryl or imidazole groups to the C triple bond C of ONE to give either a 2- or 3-substituted 4-ketoaldehyde, which then undergoes Paal-Knorr condensation with the primary amine of protein lysine side chains. If ONE is intercepted in biological fluids by antielectrophiles such as glutathione (GSH) or beta-alanylhistidine (carnosine), this would lead to circulating 4-ketoaldehydes that could then bind covalently to the protein Lys residues.

Mechanistic and kinetic details of catalysis of thiol-disulfide exchange by glutaredoxins and potential mechanisms of regulation.

Glutaredoxins are small, heat-stable proteins that exhibit a characteristic thioredoxin fold and a CXXC/S active-site motif. A variety of glutathione (GSH)-dependent catalytic activities have been attributed to the glutaredoxins, including reduction of ribonucleotide reductase, arsenate, and dehydroascorbate; assembly of iron sulfur cluster complexes; and protein glutathionylation and deglutathionylation. Catalysis of reversible protein glutathionylation by glutaredoxins has been implicated in regulation of redox signal transduction and sulfhydryl homeostasis in numerous contexts in health and disease.

Kinetic and mechanistic characterization and versatile catalytic properties of mammalian glutaredoxin 2: implications for intracellular roles.

Glutaredoxin (Grx)-catalyzed deglutathionylation of protein-glutathione mixed disulfides (protein-SSG) serves important roles in redox homeostasis and signal transduction, regulating diverse physiological and pathophysiological events. Mammalian cells have two Grx isoforms: Grx1, localized to the cytosol and mitochondrial intermembrane space, and Grx2, localized primarily to the mitochondrial matrix [Pai, H. V.

Molecular mechanisms and clinical implications of reversible protein S-glutathionylation.

Sulfhydryl chemistry plays a vital role in normal biology and in defense of cells against oxidants, free radicals, and electrophiles. Modification of critical cysteine residues is an important mechanism of signal transduction, and perturbation of thiol-disulfide homeostasis is an important consequence of many diseases. A prevalent form of cysteine modification is reversible formation of protein mixed disulfides (protein-SSG) with glutathione (GSH).

Mechanisms of reversible protein glutathionylation in redox signaling and oxidative stress.

Reversible protein S-glutathionylation (protein-SSG) is an important post-translational modification, providing protection of protein cysteines from irreversible oxidation and serving to transduce redox signals. Analogous to phosphatases, glutaredoxin (GRx) enzymes catalyze deglutathionylation of proteins, regulating diverse intracellular signaling pathways. Recently, other enzymes have been reported to exhibit deglutathionylating activity, but their contribution to intracellular protein deglutathionylation is uncertain.