ABSTRACT
We report a Cu-catalyzed oxidative coupling of aliphatic amines with benzylic and aliphatic boronic esters to give high value alkyl amines, products found widely in applications from medicinal chemistry to materials science. This operationally simple reaction, which can be performed on gram scale, runs under mild conditions and exhibits broad functional group tolerance. The terminal oxidant of the reaction is O2 from the air, avoiding the need for additional chemical oxidants. Investigation into the reaction mechanism suggests that the boronic ester is activated by an aminyl radical, formed through oxidation of the amine by the Cu catalyst, to give a key alkyl radical intermediate. To demonstrate its utility and potential for late-stage functionalization, we showcase the method as the final step in the total synthesis of a TRPV1 antagonist.
ABSTRACT
INTRODUCTION: Guidelines on the management of pregnant individuals with von Willebrand disease (VWD) at the time of delivery recommend that von Willebrand factor (VWF) and factor VIII:C (FVIII:C) levels be ≥50% to prevent postpartum haemorrhage (PPH). Yet, high PPH rates persist despite these levels or with prophylactic factor replacement therapy to achieve these levels. AIMS: The current practice at our centre has been to target peak plasma VWF and FVIII:C levels of ≥100 IU/dL at time of delivery. The objective of this study was to describe obstetric outcomes in pregnant individuals with VWD who were managed at our centre. METHODS: Demographics and outcomes on pregnant individuals with VWD who delivered between January 2015 and April 2023 were collected. RESULTS: Forty-seven singleton deliveries (among 41 individuals) resulting in 46 live births and one foetal death were included. Twenty-one individuals had at least one prior birth by the start date of this study, of which 11 (52.4%) self-reported a history of PPH. Early PPH occurred in 12.8% (6/47) of deliveries. Two individuals required blood transfusion, of which one also had an unplanned hysterectomy and transfer to ICU. There were no thrombotic events reported. CONCLUSION: The strategy of targeting higher peak plasma VWF and FVIII:C levels (≥100 IU/dL) at the time of delivery may be effective in reducing the risk of delivery-associated bleeding complications in VWD patients. Yet, the rate of early PPH remains unsatisfactory compared to the non-VWD population.
Subject(s)
Hemostatics , Postpartum Hemorrhage , von Willebrand Diseases , Pregnancy , Female , Humans , von Willebrand Diseases/complications , von Willebrand Factor , Cohort Studies , Factor VIII , Postpartum Hemorrhage/etiologyABSTRACT
Despite increasing use of targeted therapies to treat cancer, anemia remains a common complication of cancer therapy. Physician concerns about the safety of intravenous (IV) iron products and erythropoiesis-stimulating agents (ESAs) have resulted in many patients with cancer receiving no or suboptimal anemia therapy. In this article, we present 4 patient cases that illustrate both common and complex clinical scenarios. We first present a review of erythropoiesis and then describe our approach to cancer-associated anemia by identifying the contributing causes before selecting specific treatments. We summarize clinical trial data affirming the safety and efficacy of currently available IV iron products used to treat cancer-associated anemia and illustrate how we use commonly available laboratory tests to assess iron status during routine patient management. We compare adverse event rates associated with IV iron vs red cell transfusion and discuss using first-line IV iron monotherapy to treat anemic patients with cancer, which decreases the need for ESAs. A possible mechanism behind ESA-induced tumor progression is discussed. Finally, we review the potential of novel therapies such as ascorbic acid, prolyl hydroxylase inhibitors, activin traps, hepcidin, and bone morphogenetic protein antagonists in treating cancer-associated anemia.
Subject(s)
Anemia/etiology , Anemia/therapy , Neoplasms/complications , Neoplasms/therapy , Administration, Intravenous , Disease Progression , Erythrocyte Transfusion/adverse effects , Erythropoiesis/drug effects , Hematinics/therapeutic use , Humans , Iron/administration & dosage , Iron/adverse effects , Neoplasms/pathologyABSTRACT
BACKGROUND: Physicians treating patients with coronavirus disease 2019 (COVID-19) increasingly believe that the hyperinflammatory acute stage of COVID-19 results in a cytokine storm. The circulating biomarkers seen across the spectrum of COVID-19 have not been characterized compared with healthy controls, but such analyses are likely to yield insights into the pursuit of interventions that adequately reduce the burden of these cytokine storms. OBJECTIVE: To identify and characterize the host inflammatory response to severe acute respiratory syndrome coronavirus 2 infection, we assessed levels of proteins related to immune responses and cardiovascular disease in patients stratified as mild, moderate, and severe versus matched healthy controls. METHODS: Blood samples from adult patients hospitalized with COVID-19 were analyzed using high-throughput and ultrasensitive proteomic platforms and compared with age- and sex-matched healthy controls to provide insights into differential regulation of 185 markers. RESULTS: Results indicate a dominant hyperinflammatory milieu in the circulation and vascular endothelial damage markers within patients with COVID-19, and strong biomarker association with patient response as measured by Ordinal Scale. As patients progress, we observe statistically significant dysregulation of IFN-γ, IL-1RA, IL-6, IL-10, IL-19, monocyte chemoattractant protein (MCP)-1, MCP-2, MCP-3, CXCL9, CXCL10, CXCL5, ENRAGE, and poly (ADP-ribose) polymerase 1. Furthermore, in a limited series of patients who were sampled frequently, confirming reliability and reproducibility of our assays, we demonstrate that intervention with baricitinib attenuates these circulating biomarkers associated with the cytokine storm. CONCLUSIONS: These wide-ranging circulating biomarkers show an association with increased disease severity and may help stratify patients and selection of therapeutic options. They also provide insights into mechanisms of severe acute respiratory syndrome coronavirus 2 pathogenesis and the host response.
Subject(s)
COVID-19/blood , Cytokine Release Syndrome/blood , Cytokines/blood , Poly (ADP-Ribose) Polymerase-1/blood , Proteomics , SARS-CoV-2/metabolism , Adult , Biomarkers/blood , Female , Humans , MaleABSTRACT
Atopic dermatitis (AD) is a heterogeneous systemic inflammatory skin disease associated with dysregulated immune responses, barrier dysfunction and activated sensory nerves. To characterize circulating inflammatory profiles and underlying systemic disease heterogeneity within AD patients, blood samples from adult patients (N = 123) with moderate-to-severe AD in a phase 2 study of baricitinib (JAHG) were analysed. Baseline levels of 131 markers were evaluated using high-throughput and ultrasensitive proteomic platforms, patient clusters were generated based on these peripheral markers. We implemented a novel cluster reproducibility method to validate cluster outcomes within our study and used publicly available AD biomarker data set (73 markers, N = 58 patients) to validate our findings. Cluster reproducibility analysis demonstrated best consistency for 2 clusters by k-means, reproducibility of this clustering outcome was validated in an independent patient cohort. These unique JAHG patient subgroups either possessed elevated pro-inflammatory mediators, notably TNFß, MCP-3 and IL-13, among a variety of immune responses (high inflammatory) or lower levels of inflammatory biomarkers (low inflammatory). The high inflammatory subgroup was associated with greater baseline disease severity, demonstrated by greater EASI, SCORAD Index, Itch NRS and DLQI scores, compared with low inflammatory subgroup. African-American patients were predominantly associated with the high inflammatory subgroup and increased baseline disease severity. In patients with moderate-to-severe AD, heterogeneity was identified by the detection of 2 disease subgroups, differential clustering amongst ethnic groups and elevated pro-inflammatory mediators extending beyond traditional polarized immune responses. Therapeutic strategies targeting multiple pro-inflammatory cytokines may be needed to address this heterogeneity.
Subject(s)
Azetidines/therapeutic use , Dermatitis, Atopic/blood , Dermatitis, Atopic/drug therapy , Purines/therapeutic use , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use , Adult , Biomarkers/blood , Dermatitis, Atopic/complications , Female , Humans , Male , Middle Aged , Severity of Illness Index , Young AdultABSTRACT
PURPOSE: To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. METHODS: Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members. RESULTS: We found the heterozygous missense variant in the É-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis. CONCLUSION: Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.
Subject(s)
Optic Nerve/pathology , Protein Kinases/genetics , Retina/metabolism , Retinal Dystrophies/genetics , Exome/genetics , Female , Heterozygote , Humans , Hypohidrosis/genetics , Hypohidrosis/pathology , Male , Migraine Disorders/genetics , Migraine Disorders/pathology , Mutation, Missense/genetics , Optic Nerve/metabolism , Pedigree , Phenotype , Retina/pathology , Retinal Dystrophies/pathology , Splenomegaly/genetics , Splenomegaly/pathologyABSTRACT
D-dimer is an indirect marker of fibrinolysis and fibrin turnover; this molecule exhibits unique properties as a biological marker of hemostatic abnormalities as well as an indicator of intravascular thrombosis. D-dimer is a soluble fibrin degradation product that results from the systematic degradation of vascular thrombi through the fibrinolytic mechanism. Because of this, the D-dimer serves as a valuable marker of activation of coagulation and fibrinolysis in a number of clinical scenarios. Most commonly, D-dimer has been extensively investigated for excluding the diagnosis of venous thromboembolism (VTE) and is used routinely for this indication. In addition, D-dimer has been evaluated for determining the optimal duration of anticoagulation in VTE patients, for diagnosing and monitoring disseminated intravascular coagulation, and for monitoring other conditions in which the patient is at high risk of bleeding or thrombosis. Limitations of the assay include D-dimer elevation in a constellation of clinical scenarios (age, pregnancy, and cancer) and lack of clinical standardization.
Subject(s)
Disseminated Intravascular Coagulation/blood , Fibrin Fibrinogen Degradation Products/metabolism , Hemorrhage/blood , Pregnancy Complications, Hematologic/blood , Thrombosis/blood , Venous Thromboembolism/blood , Blood Coagulation Tests , Female , Humans , Male , PregnancyABSTRACT
Cancer-related anemia (CRA) is a commonly occurring problem for patients with cancer regardless of whether they are receiving treatment with chemotherapy or immunotherapy. It may result from one or more processes (decreased production, increased destruction, or increased loss of red blood cells, RBC). Perturbations in iron availability form the primary basis for anemia in many patients with cancer-related anemia. Functional iron deficiency (FID) anemia is a condition in which the patient has adequate or increased iron stores, but this iron pool is not available for erythropoiesis. Erythropoiesis-stimulating agents (ESAs) were the original treatment for FID; over time, however, if the supply of iron cannot keep pace with increased RBC synthesis driven by ESAs, FID may eventually lead to the lack or loss of ESA responsiveness. Subsequent clinical trials reported that intravenous (IV) iron could enhance the erythropoietic response to ESAs. This chapter reviews the pathogenesis of FID and summarizes the literature on the treatment of cancer- and chemotherapy-induced anemia. Clinical trials using IV iron with or without ESAs are reviewed in addition to the currently available IV iron products. The consensus conclusions from these trials, as well as guideline recommendations, support the use of IV iron in these patients to enhance ESA responsiveness, decrease ESA dosage, and reduce RBC transfusions. Little data have been published on the long-term safety of IV iron or its impact on tumor growth. This paper also briefly explores novel approaches for the treatment of FID anemia, which has relevance in treating not only cancer patients but also patients with benign inflammatory disorders.
Subject(s)
Anemia, Iron-Deficiency/drug therapy , Iron/administration & dosage , Neoplasms/complications , Administration, Intravenous , Anemia, Iron-Deficiency/etiology , Anemia, Iron-Deficiency/pathology , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Clinical Trials as Topic , Erythrocytes/cytology , Erythrocytes/drug effects , Erythrocytes/metabolism , Erythropoiesis/drug effects , Hematinics/pharmacology , Hematinics/therapeutic use , Humans , Neoplasms/drug therapyABSTRACT
Romiplostim is a thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenia purpura. When following FDA-approved romiplostim prescribing recommendations to withhold treatment for platelet counts above 400k/µL, some patients exhibit a precipitous decline in their platelet count potentially causing patient harm. We present two cases where stable platelet counts were achieved only through persistent weekly dosing of romiplostim despite platelet counts above 400k/µL on the day of administration. Therefore, continuous weekly dosing of romiplostim despite platelet count being above 400k/µL combined with twice weekly vigilant monitoring is an alternative method of romiplostim dosing that mitigates severe fluctuations in platelets. We also discuss important details, postulated mechanisms, and evidence-based mitigation strategies.
Subject(s)
Purpura, Thrombocytopenic, Idiopathic/drug therapy , Receptors, Fc/administration & dosage , Receptors, Thrombopoietin/agonists , Recombinant Fusion Proteins/administration & dosage , Thrombopoietin/administration & dosage , Aged , Female , Humans , Male , Middle Aged , Platelet CountABSTRACT
ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, is a zinc-containing metalloprotease that cleaves von Willebrand factor (vWf). Previous publications by our laboratory have shown that ADAMTS-13 may also be involved in angiogenesis. For this study, we report the successful transient knockdown of endogenous ADAMTS-13 in human umbilical vein endothelial cells (HUVEC) via siRNA and the effects of reduced endogenous ADAMTS-13 on HUVEC angiogenesis functions. 15nM of ADAMTS-13 siRNA reduced HUVEC ADAMTS-13 protein levels by 90% after 24h incubation, whereas control siRNA did not affect endogenous ADAMTS-13 levels. Furthermore, this transfection did not affect the HUVEC endogenous protein level of ADAMTS-1, a related family member of ADAMTS-13 indicating the specificity of the siRNA. Transfection of HUVEC with 15nM of ADAMTS-13 siRNA resulted in a 21% decrease in proliferation after 24h incubation. The effects of ADAMTS-13 knockdown on migration of HUVEC across a scratch wound were also evaluated. 24h after transfection with control siRNA, there was increased cell migration across the scratch wound. This dramatic migration did not occur with ADAMTS-13 knockdown cells. Decreased protein levels of endogenous ADAMTS-13 also affected angiogenesis as measured by endothelial cell tube formation using a Matrigel matrix method. The tube lengths, sizes and junction numbers of the ADAMTS-13 knockdown cells were all significantly lower compared to control cells by about 40%. The protein level of vascular endothelial growth factor (VEGF), a well-known regulator of angiogenesis, was significantly decreased by 45% upon knockdown of ADAMTS-13. Moreover, activity of the AKT pathway, one of the VEGF angiogenesis downstream signaling pathways was down-regulated by ADAMTS-13 siRNA. These data indicate that in cultured endothelial cells, one role of endogenous ADAMTS-13 is regulation of angiogenesis, mediated through VEGF and AKT signaling pathway. Overall, our data suggest an additional model of endogenous ADAMTS-13 functionality, beyond that of cleaving von Willebrand factor.
Subject(s)
ADAMTS13 Protein/metabolism , Human Umbilical Vein Endothelial Cells/enzymology , Neovascularization, Physiologic , RNA Interference , RNA, Small Interfering/metabolism , ADAMTS13 Protein/genetics , Cell Movement , Cell Proliferation , Cells, Cultured , Down-Regulation , Humans , Proto-Oncogene Proteins c-akt/metabolism , RNA, Small Interfering/genetics , Signal Transduction , Time Factors , Transfection , Vascular Endothelial Growth Factor A/metabolism , von Willebrand Factor/metabolismABSTRACT
Severe plasma ADAMTS13 deficiency results in the clinical disorder thrombotic thrombocytopenic purpura. However, other potential pathophysiological roles of ADAMTS13 in endothelial cell biology remain unexplored. The goals of this study were to understand the angiogenic pathways ADAMTS13 activates and to identify the important structural components of ADAMTS13 that stimulate angiogenesis. Incubation of human umbilical vein endothelial cells (HUVEC) with 150 ng/mL (1 nM) of recombinant human ADAMTS13 induced VEGF expression by 53 % and increased VEGF mRNA by over sixfold, both within 10 min; the measured VEGF levels steadily decreased over 2 h, as shown by Western blot and ELISA. Phosphorylation of VEGFR2 was significantly enhanced in HUVEC after incubation with ADAMTS13 (1 nM). Structure-function analysis showed that an ADAMTS13 variant containing thrombospondin type 1 (TSP1) 2-8 repeats (TSP1 2-8), TSP1 2-8 plus CUB domains (TSP1 2-8 plus CUB), or TSP1 5-8 repeats plus CUB domains (TSP1 5-8 plus CUB) increased HUVEC proliferation by 41-54 % as compared to the EBM-2 controls. Chemotaxis assays further demonstrated that the TSP1 domains of ADAMTS13 increased HUVEC migration by 2.65-fold. Incubation of HUVEC with both ADAMTS13 variants containing TSP1 repeats and anti-VEGF IgG abrogated the enhanced effect of ADAMTS13 on proliferation, migration, and VEGFR2 phosphorylation. In conclusion, ADAMTS13-induced endothelial cell angiogenesis occurs via the upregulation of VEGF and phosphorylation of VEGFR2. This angiogenic activity depends on the C-terminal TSP1 repeats of ADAMTS13.
Subject(s)
ADAM Proteins/metabolism , Gene Expression Regulation, Developmental/physiology , Neovascularization, Physiologic/physiology , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , ADAMTS13 Protein , Blotting, Western , Cell Movement/physiology , Chemotaxis/physiology , DNA Primers/genetics , Enzyme-Linked Immunosorbent Assay , Human Umbilical Vein Endothelial Cells , Humans , Phosphorylation , Real-Time Polymerase Chain ReactionABSTRACT
Myeloid growth factors can reduce the risk of chemotherapy-induced neutropenia (CIN) and thus impact the survival of patients with cancer. Patients should be assessed for risk, taking into consideration patient-related risk factors and chemotherapy regimens. Patients stratified as having at least a 20% risk for CIN should be considered for prophylactic growth factors. The NCCN Guidelines for Myeloid Growth Factors provide category 1 recommendations for the daily use of filgrastim, tbo-filgrastim, and pegfilgrastim. Cancer-related anemia can be treated with erythropoiesis-stimulating agents, red blood cell transfusion, or intravenous iron.
Subject(s)
Anemia/chemically induced , Anemia/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemotherapy-Induced Febrile Neutropenia/drug therapy , Colony-Stimulating Factors/therapeutic use , Iron/administration & dosage , Neoplasms/complications , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemotherapy-Induced Febrile Neutropenia/prevention & control , Humans , Neoplasms/drug therapy , Practice Guidelines as Topic , Risk AssessmentSubject(s)
Anemia, Aplastic/drug therapy , Benzoates/administration & dosage , Hydrazines/administration & dosage , Hyperpigmentation/chemically induced , Pyrazoles/administration & dosage , Adult , Anemia, Aplastic/blood , Benzoates/blood , Color , Female , Gene Expression , Humans , Hydrazines/blood , Hyperpigmentation/blood , Hyperpigmentation/diagnosis , Pyrazoles/blood , Receptors, Thrombopoietin/agonists , Receptors, Thrombopoietin/genetics , Receptors, Thrombopoietin/metabolism , Severity of Illness IndexABSTRACT
Cancer-related anemia (CRA) is due to multiple etiologies, including chemotherapy-induced myelosuppression, blood loss, functional iron deficiency, erythropoietin deficiency due to renal disease, marrow involvement with tumor as well as other factors. The most common treatment options for CRA include iron therapy, erythropoietic-stimulating agents (ESAs), and red cell transfusion. Safety concerns as well as restrictions and reimbursement issues surrounding ESA therapy for CRA have resulted in suboptimal treatment. Similarly, many clinicians are not familiar or comfortable using intravenous iron products to treat functional iron deficiency associated with CRA. This article summarizes our approach to treating CRA and discusses commonly encountered clinical scenarios for which current clinical guidelines do not apply.
Subject(s)
Anemia/diagnosis , Anemia/therapy , Neoplasms/complications , Anemia/epidemiology , Anemia/etiology , Erythrocyte Transfusion , Erythropoietin/therapeutic use , Humans , Iron/administration & dosage , Iron/therapeutic use , Malnutrition/complications , Prevalence , Treatment OutcomeABSTRACT
INTRODUCTION: Numerous clinical trials affirm the efficacy and safety of IV iron to treat cancer-related anemia (CRA). Nonetheless, evaluation and treatment of CRA remains suboptimal. AREAS COVERED: This review summarizes CRA therapy with a focus on iron deficiency and its treatment. The literature search was conducted using the National Library of Medicine (PubMed) database from 2004 to 2024. Topics reviewed include CRA pathophysiology, laboratory diagnosis of iron deficiency, a summary of clinical trial results using IV iron to treat CRA, and safety aspects. EXPERT OPINION: Despite overwhelming positive efficacy and safety data, IV iron remains underutilized to treat CRA. This is likely due to persistent (unfounded) concerns about IV iron safety and lack of physician awareness of newer clinical trial data. This leads to poor patient quality of life and patient exposure to anemia treatments that have greater safety risks than IV iron. Solutions to this problem include increased educational efforts and considering alternative treatment models in which other providers separately manage CRA. The recent availability of new oral iron therapy products that are effective in treating anemia of inflammation has the potential to dramatically simplify the treatment of CRA.
Subject(s)
Iron , Neoplasms , Humans , Neoplasms/complications , Iron/therapeutic use , Iron/metabolism , Anemia, Iron-Deficiency/drug therapy , Anemia, Iron-Deficiency/etiology , Anemia/etiology , Anemia/drug therapy , Dietary Supplements , Quality of Life , Clinical Trials as TopicABSTRACT
Acquired haemophilia A (AHA) is a potentially life-threatening bleeding disorder occurring in patients without a previous personal or family history of bleeding. Development of immune-mediated autoantibodies against coagulation factor VIII is associated with a wide range of clinical disorders including pregnancy, autoimmune disorders, malignancy, or with no apparent disease. There exists great potential for morbidity and mortality related to acute and recurrent bleeding episodes, making prompt diagnosis and treatment necessary. The two primary goals of treatment focus on cessation of bleeding and eradication of the acquired factor VIII inhibitor. No randomized clinical trials have been conducted regarding treatment, so expert clinical opinion guides therapeutic intervention. This current report provides a profile of patient characteristics, an algorithm for diagnosis, and outlines treatment recommendations based upon current guidelines and clinical experience. As first-line interventions for acute bleeding and inhibitor eradication are generally accepted, we will emphasize discussion of second-line therapeutic options.