p97 dysfunction underlies a loss of quality control of damaged membrane proteins and promotes oxidative stress and sickling in sickle cell disease.

Sickling is the central pathogenic process of sickle cell disease (SCD), one of the most prevalent inherited hemolytic disorders. Having no easy access to antioxidants in the cytosol, elevated levels of reactive oxygen species (ROS) residing at the plasma membrane in sickle red blood cells (sRBCs) easily oxidize membrane proteins and thus contribute to sickling. Although the ubiquitin-proteasome system (UPS) is essential to rapidly clear ROS-damaged membrane proteins and maintain cellular homeostasis, the function and regulatory mechanism of the UPS for their clearance in sRBCs remains unidentified.

Clinical Outcomes of Patients With Newly Diagnosed Acute Lymphoblastic Leukemia in a County Hospital System.

Background: Major advances in the treatment of acute lymphoblastic leukemia (ALL) over the past decade have resulted in 5-year overall survival (OS) rates of 80% in mature B cell ALL, 50% in precursor B cell ALL, 50% to 60% in T cell ALL, and 60% to 70% in Philadelphia chromosome-positive (Ph+) ALL, as reported in studies from large, specialized centers. However, many patients treated in the community have limited access to novel therapies and stem cell transplantation (HSCT).

Patients And Methods: The purpose of this retrospective cohort analysis was to evaluate the clinical outcomes of patients ≥ 16 years with newly diagnosed ALL treated from October 2007 to June 2019 in the Harris County Health System, Houston, TX.

Intravenous Bone Marrow Mononuclear Cells for Acute Ischemic Stroke: Safety, Feasibility, and Effect Size from a Phase I Clinical Trial.

Cellular therapy is a promising investigational modality to enhance poststroke recovery. We conducted a single-arm, phase I clinical trial to determine the safety and feasibility of intravenous (IV) administration of autologous bone marrow mononuclear cells (MNCs) after acute ischemic stroke (AIS). Patients with moderate severity of AIS underwent bone marrow harvest followed by IV reinfusion of MNCs within 24-72 hours of onset.

Elevated ecto-5'-nucleotidase: a missing pathogenic factor and new therapeutic target for sickle cell disease.

Although excessive plasma adenosine is detrimental in sickle cell disease (SCD), the molecular mechanism underlying elevated circulating adenosine remains unclear. Here we report that the activity of soluble CD73, an ectonucleotidase producing extracellular adenosine, was significantly elevated in a murine model of SCD and correlated with increased plasma adenosine. Mouse genetic studies demonstrated that CD73 activity contributes to excessive induction of plasma adenosine and thereby promotes sickling, hemolysis, multiorgan damage, and disease progression.

Structural and Functional Insight of Sphingosine 1-Phosphate-Mediated Pathogenic Metabolic Reprogramming in Sickle Cell Disease.

Elevated sphingosine 1-phosphate (S1P) is detrimental in Sickle Cell Disease (SCD), but the mechanistic basis remains obscure. Here, we report that increased erythrocyte S1P binds to deoxygenated sickle Hb (deoxyHbS), facilitates deoxyHbS anchoring to the membrane, induces release of membrane-bound glycolytic enzymes and in turn switches glucose flux towards glycolysis relative to the pentose phosphate pathway (PPP). Suppressed PPP causes compromised glutathione homeostasis and increased oxidative stress, while enhanced glycolysis induces production of 2,3-bisphosphoglycerate (2,3-BPG) and thus increases deoxyHbS polymerization, sickling, hemolysis and disease progression.

Hypoxia-mediated impaired erythrocyte Lands' Cycle is pathogenic for sickle cell disease.

Although Lands' cycle was discovered in 1958, its function and cellular regulation in membrane homeostasis under physiological and pathological conditions remain largely unknown. Nonbiased high throughput metabolomic profiling revealed that Lands' cycle was impaired leading to significantly elevated erythrocyte membrane lysophosphatidylcholine (LysoPC) content and circulating and erythrocyte arachidonic acid (AA) in mice with sickle cell disease (SCD), a prevalent hemolytic genetic disorder. Correcting imbalanced Lands' cycle by knockdown of phospholipase 2 (cPLA2) or overexpression of lysophosphatidycholine acyltransferase 1 (LPCAT1), two key enzymes of Lands' cycle in hematopoietic stem cells, reduced elevated erythrocyte membrane LysoPC content and circulating AA levels and attenuated sickling, inflammation and tissue damage in SCD chimeras.

Elevated adenosine signaling via adenosine A2B receptor induces normal and sickle erythrocyte sphingosine kinase 1 activity.

Erythrocyte possesses high sphingosine kinase 1 (SphK1) activity and is the major cell type supplying plasma sphingosine-1-phosphate, a signaling lipid regulating multiple physiological and pathological functions. Recent studies revealed that erythrocyte SphK1 activity is upregulated in sickle cell disease (SCD) and contributes to sickling and disease progression. However, how erythrocyte SphK1 activity is regulated remains unknown.

Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression.

Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates multicellular functions through interactions with its receptors on cell surfaces. S1P is enriched and stored in erythrocytes; however, it is not clear whether alterations in S1P are involved in the prevalent and debilitating hemolytic disorder sickle cell disease (SCD). Here, using metabolomic screening, we found that S1P is highly elevated in the blood of mice and humans with SCD.

Portal vein thrombosis after laparoscopic cholecystectomy.

Introduction: Portal vein thrombosis (PVT) is a relatively uncommon complication after abdominal surgery.

Case Report: We report an even more unusual case of PVT 10 days after an uncomplicated laparoscopic cholecystectomy, believed to be only the fourth reported case in the literature of this rare complication.

Conclusion: Albeit extremely rare, PVT should be included in the differential diagnosis for abdominal symptoms and/or elevated hepatic function tests after laparoscopic cholecystectomy.

Case of polycythemia vera concurrent with FIP1L1-PDGFRA-positive myeloproliferative neoplasm with eosinophilia.

We report an unusual case of a symptomatic patient who initially had high hemoglobin and low serum erythropoietin levels, fitting a clinical diagnosis of polycythemia vera. However, after treatment with hydroxyurea and serial phlebotomies had been started, the patient developed hypereosinophilia, fitting the category of a myeloproliferative neoplasm with eosinophilia associated with the FIP1L1-PDGFRA gene fusion, as confirmed by molecular analysis. We discuss the clinical presentation, evolution, response to treatment, and pathogenetic implications of this case.

Detrimental effects of adenosine signaling in sickle cell disease.

Hypoxia can act as an initial trigger to induce erythrocyte sickling and eventual end organ damage in sickle cell disease (SCD). Many factors and metabolites are altered in response to hypoxia and may contribute to the pathogenesis of the disease. Using metabolomic profiling, we found that the steady-state concentration of adenosine in the blood was elevated in a transgenic mouse model of SCD.

Dapsone induced methemoglobinemia in a patient with glioblastoma.

Primary brain tumor patients have multiple risk factors for Pneumocystis jiroveci and may require prophylaxis with TMP-SMZ or dapsone. Although dapsone is generally safe and efficacious, we present a case of a patient diagnosed with a brain stem glioblastoma who developed methemoglobinemia and haemolytic anemia after presenting with worsening confusion and cardiopulmonary system dysfunction. This case highlights one of the potentially severe complications associated with dapsone therapy.

Assessment of coronary heart disease risk by combined analysis of coagulation factors.

Objective: Prospective studies have reported a positive association of coagulation factors with risk of coronary heart disease (CHD). It is unclear whether these coagulation factors interact.

Methods And Results: Using a prospective case-cohort design, we analyzed by Cox proportional hazard regression interactions between soluble thrombomodulin (sTM) and fibrinogen, factor VIII (FVIII), FVII, or plasminogen activator inhibitor-1 (PAI-1) in 410 CHD cases and 721 non-cases from the Atherosclerosis Risk in Communities (ARIC).

Autologous peripheral stem cell transplant for POEMS syndrome: a case report.

Hematopoietic stem cell transplant has been used in the treatment of multiple myeloma. Its use in the treatment of POEMS syndrome is still under investigation. We describe the clinical course and long term follow-up of a patient with POEMS syndrome unresponsive to standard chemotherapy.

Interaction between soluble thrombomodulin and intercellular adhesion molecule-1 in predicting risk of coronary heart disease.

Background: Results from previous ARIC (Atherosclerosis Risk In Communities) analyses indicate that soluble intercellular adhesive molecule-1 (sICAM) and soluble thrombomodulin (sTM) levels are associated with risk of coronary heart disease (CHD) in an opposite direction. A high sICAM level increases the risk of CHD, whereas a high level of sTM has a lower risk of CHD. It was unclear whether there was an interaction between sTM and sICAM.

C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk In Communities (ARIC) study.

Background: Recent evidence implicates inflammation in the pathogenesis of coronary heart disease (CHD). C-reactive protein, a plasma marker of inflammation, is a marker of CHD risk but has been studied in few prospective investigations of the general population.

Methods And Results: We prospectively examined the association of CRP with incident CHD among middle-aged adults in the Atherosclerosis Risk In Communities (ARIC) study.

Factor XIIIA Val34Leu polymorphism does not predict risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) Study.

Factor XIII catalyzes the cross-linking of fibrin. Cross-sectional studies have suggested that a common polymorphism site at residue 34 of the A subunit of factor XIII (FXIIIA) with a substitution of Leu for Val (FXIIIA Val34Leu) was associated with reduced coronary heart disease (CHD). This association has not been examined in prospective studies.