Active targeting of a drug carrier to a specific target site is crucial to provide a safe and efficient delivery of therapeutics and imaging contrast agents. E-selectin expression is induced on the endothelial cell surface of vessels in response to inflammatory stimuli but is absent in the normal vessels. Thus, E-selectin is an attractive molecular target, and high affinity ligands for E-selectin could be powerful tools for the delivery of therapeutics and/or imaging agents to inflamed vessels. In this study, we identified a thiophosphate modified aptamer (thioaptamer, TA) against E-selectin (ESTA-1) by employing a two-step selection strategy: a recombinant protein-based TA binding selection from a combinatorial library followed by a cell-based TA binding selection using E-selectin expressing human microvascular endothelial cells. ESTA-1 selectively bound to E-selectin with nanomolar binding affinity (KD = 47 nM) while exhibiting minimal cross reactivity to P- and L-selectin. Furthermore, ESTA-1 binding to E-selectin on the endothelial cells markedly antagonized the adhesion (over 75% inhibition) of sLex positive HL-60 cells at nanomolar concentration. ESTA-1 also bound specifically to the inflamed tumor-associated vasculature of human carcinomas derived from breast, ovarian, and skin but not to normal organs, and this binding was highly associated with the E-selectin expression level. Similarly, intravenously injected ESTA-1 demonstrated distinct binding to the tumor vasculature in a breast cancer xenograft model. Together, our data substantiates the discovery of a thioaptamer (ESTA-1) that binds to E-selectin with high affinity and specificity, thereby highlighting the potential application of ESTA-1 for E-selectin targeted delivery.
Pearls cRelapse of anti-NMDA receptor (NMDAR) encephalitis should be considered in all patients with history of anti-NMDAR encephalitis presenting with new acute-onset encephalopathy or psychosis. c CSF antibody diagnostic testing is sensitive and specific for the initial diagnosis of anti-NMDAR encephalitis.c Although CSF antibody titers correlate more closely with disease severity than serum titers, the utility of comparison to baseline or remission titers in order to diagnose relapse is still under investigation. Oy-sters cLong-term clinical monitoring after anti-NMDAR antibody encephalitis is necessary for appropriate diagnosis and treatment of relapse, as the interpretation of elevated antibody titers without clinical change is of unclear significance. Although current confirmed cases suggest a median of 2 years between the initial episode and first relapse, increasing reports suggest that longer periods of monitoring may be needed.A 33-year-old right-handed woman with a history of anti-NMDA receptor (NMDAR) encephalitis presented with a 1-day history of vomiting and bizarre behavior in the context of recent cannabis and synthetic cannabinoid ingestion. She had been diagnosed 7 years earlier with anti-NMDAR encephalitis complicated by refractory epilepsy and treated with a 5-day course of IV methylprednisolone (IVMP), a 5-day course of IV immunoglobulin (IVIg), and 2 doses of rituximab. Her prior admission was characterized by a prolonged stay with slow clinical improvement ultimately resulting in complete resolution and no longer requiring antiepileptic medications. Anti-NMDAR immunoglobulin G (IgG) antibody was positive (titers not recorded) and CT chest/abdomen/pelvis, MRI pelvis, and transvaginal ultrasound were negative for malignancy. She was last seen at our institution 1.5 years prior to the current presentation without sequelae.On current presentation, the patient was initially hemodynamically stable with intact orientation and attention. Neurologic examination was significant only for diffuse hyperreflexia. Within an hour, she became acutely obtunded and developed orofacial dyskinesias, sensory anesthesia, tachycardia, and acral hyperhidrosis with no improvement over the next 3 days. Urine toxicology was positive for cannabinoids but basic laboratory studies (complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone, B 12 , folic acid, HIV, urinalysis) were unremarkable. On further workup, MRI brain with and without contrast was normal and showed neither T2 fluid-attenuated inversion recovery (FLAIR) changes nor enhancement. EEG showed diffuse slowing with no posterior dominant rhythm or epileptiform discharges. CSF showed 40 white blood cells (normal 0-5) with 90% lymphocytes and 10% monocytes, glucose 61 mg/dL (normal 50-80), protein 24.2 mg/dL (normal 15-45), and 0 red blood cells. CSF flow cytometry was negative for aberrant T-/B-cell populations, and cytology was negative for malignant cells. Routine CSF studies were negative for gram stain and culture, herpes simplex v...
Hypertension is a potent cardiovascular risk factor with deleterious end-organ effects and is especially prevalent among patients with chronic kidney disease. The SPRINT (Systolic Blood Pressure Intervention Trial) enrolled patients at an elevated cardiac risk including patients with mild to moderate chronic kidney disease and found that an intensive systolic blood pressure goal of <120 mm Hg significantly reduced the rates of adverse cardiovascular events and all-cause mortality and nonsignificantly reduced the rates of probable dementia; these results were consistent whether one had chronic kidney disease or not. However, results of intensive blood pressure therapy on chronic kidney disease progression were inconclusive, and there was an increased risk of incident chronic kidney disease and acute kidney injury, but the declines in kidney function appear to be hemodynamically driven and reversible. Overall, an intensive blood pressure target is effective in reducing cardiovascular disease and all-cause mortality and may reduce the risk of probable dementia in patients with mild to moderate chronic kidney disease. More studies are needed to determine its long-term effects on kidney function.
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