RESUMEN
The pathophysiology of sickle cell disease (SCD) is driven by chronic inflammation fueled by damage associated molecular patterns (DAMPs). We show that elevated cell-free DNA (cfDNA) in patients with SCD is not just a prognostic biomarker, it also contributes to the pathological inflammation. Within the elevated cfDNA, patients with SCD had a significantly higher ratio of cell-free mitochondrial DNA (cf-mtDNA)/cell-free nuclear DNA compared with healthy controls. Additionally, mitochondrial DNA in patient samples showed significantly disproportionately increased hypomethylation compared with healthy controls, and it was increased further in crises compared with steady-state. Using flow cytometry, structured illumination microscopy, and electron microscopy, we showed that circulating SCD red blood cells abnormally retained their mitochondria and, thus, are likely to be the source of the elevated cf-mtDNA in patients with SCD. Patient plasma containing high levels of cf-mtDNA triggered the formation of neutrophil extracellular traps (NETs) that was substantially reduced by inhibition of TANK-binding kinase 1, implicating activation of the cGAS-STING pathway. cf-mtDNA is an erythrocytic DAMP, highlighting an underappreciated role for mitochondria in sickle pathology. These trials were registered at www.clinicaltrials.gov as #NCT00081523, #NCT03049475, and #NCT00047996.
Asunto(s)
Anemia de Células Falciformes/sangre , Ácidos Nucleicos Libres de Células/sangre , Metilación de ADN , ADN Mitocondrial/sangre , Adulto , Anciano , Biomarcadores/sangre , Trampas Extracelulares/metabolismo , Femenino , Humanos , Inflamación/sangre , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Nucleotidiltransferasas/metabolismo , Transducción de SeñalAsunto(s)
Anemia de Células Falciformes/complicaciones , Sobrecarga de Hierro/diagnóstico , Sobrecarga de Hierro/etiología , Adolescente , Adulto , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/terapia , Niño , Preescolar , Estudios Transversales , Manejo de la Enfermedad , Transfusión de Eritrocitos/efectos adversos , Femenino , Ferritinas/sangre , Humanos , Lactante , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/terapia , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
PURPOSE: To characterize the most common ophthalmic conditions seen in the emergency department (ED) DESIGN: Cross-sectional study METHODS: This is a multicenter study of 64,988 patients who visited the Bascom Palmer Eye Institute, Massachusetts Eye and Ear, Wills Eye Hospital, and Johns Hopkins Hospital/Wilmer Eye Institute from January 1, 2019, until December 31, 2019. Demographic and primary diagnosis data were extracted including gender, age, race, ethnicity, insurance type, and ophthalmology consult status. Descriptive statistics were performed on all data using STATA IC 14 (64-bit). RESULTS: A total of 64,988 patients with primary ocular diagnoses were seen across all 4 EDs. The majority of patients were White (63.1%), non-Hispanic/Latino (64.8%), and female (52.3%). The most frequently seen age group was 50-64 years (28.6%). The most common diagnoses across all institutions were conjunctivitis (7.91%), corneal abrasions (5.61%), dry eye (4.49%), posterior vitreous detachments (4.15%), chalazions (3.71%), corneal ulcers (3.01%), subconjunctival hemorrhages (2.96%), corneal foreign bodies (2.94%), retinal detachments (2.51%), and glaucoma (2.12%). Specifically, viral conjunctivitis (2283 of 5139, 44.4%) and primary open-angle glaucoma (382 of 1379, 27.7%) were the most frequently seen subtypes of conjunctivitis and glaucoma. CONCLUSIONS: The most regularly treated ophthalmic conditions in high-volume EDs tend to be lower acuity diagnoses. To combat ED overcrowding and rising health care costs in the United States, we suggest diverting eye-related ED visits to a specialized eye ED service or same-day eye clinic appointment in addition to expanding education for patients and primary care clinicians.
Asunto(s)
Conjuntivitis , Glaucoma de Ángulo Abierto , Glaucoma , Humanos , Femenino , Estados Unidos/epidemiología , Persona de Mediana Edad , Estudios Transversales , Servicio de Urgencia en HospitalRESUMEN
(1) Background: Despite advances in surgical approaches and drug development, ovarian cancer is still a leading cause of death from gynecological malignancies. Patients diagnosed with late-stage disease are treated with aggressive surgical resection and chemotherapy, but recurrence with resistant disease is often observed following treatment. There is a critical need for effective therapy for late-stage ovarian cancer. Photoimmunotherapy (PIT), using an antibody conjugated to a near infrared (NIR) dye, constitutes an effective theranostic strategy to detect and selectively eliminate targeted cell populations. (2) Methods: Here, we are targeting program death ligand 1 (PD-L1) using NIR-PIT in a syngeneic mouse model of ovarian cancer. PD-L1 PIT-mediated cytotoxicity was quantified in RAW264.7 macrophages and ID8-Defb29-VEGF cells in culture, and in vivo with orthotopic ID8-Defb29-VEGF tumors. (3) Results: Treatment efficacy was observed both in vitro and in vivo. (4) Conclusions: Our data highlight the need for further investigations to assess the potential of using NIR-PIT for ovarian cancer therapy to improve the treatment outcome of ovarian cancer.