NeuroMix with MR Angiography: A Fast MR Protocol to Reduce Head and Neck CT Angiography for Patients with Acute Neurological Presentations.

BACKGROUND AND PURPOSE: Overuse of computed tomography (CT)-based cerebrovascular imaging in the emergency department (ED) and inpatient settings, notably CT angiography of the head and neck (CTAHN) for minor and non-focal neurological presentations, stresses imaging services and exposes patients to radiation and contrast. Furthermore, such CT-based imaging is often insufficient for definitive diagnosis, necessitating additional MR imaging. Recent advances in fast MRI may allow for timely assessment and reduced need for CTAHN in select populations. MATERIALS AND METHODS: We identified inpatients or ED patients who underwent CTAHN (including non-contrast and post-contrast CTH, with or without CT perfusion [CTP] imaging) followed within 24 hours by a 3T MRI study that included NeuroMix (an unenhanced 2.5 min multi-contrast sequence) and intracranial time-of-flight MR angiography (MRA; a 5 min sequence) during a 9-month period (April to December 2022). Cases were classified by 4 radiologists in consensus as to whether NeuroMix and NeuroMix+MRA detected equivalent findings, detected unique findings, or missed findings relative to CTAHN. RESULTS: 174 cases (mean age 67±16 yrs; 56% female) met the inclusion criteria. NeuroMix alone and NeuroMix+MRA protocols were determined to be equivalent or better compared to CTAHN in 71% and 95% of patients, respectively. NeuroMix always provided equivalent or better assessment of the brain parenchyma, with unique findings on NeuroMix and NeuroMix+MRA in 35% and 36% of cases, respectively, most commonly acute infarction or multiple microhemorrhages. In 8/174 cases (5%), CTAHN identified vascular abnormalities not seen on the NeuroMix+MRA protocol due to CTAHN's wider coverage of the cervical arteries. CONCLUSIONS: A fast MR imaging protocol consisting of NeuroMix+MRA provided equivalent or better information compared to CTAHN in 95% of cases in our population of patients with an acute neurological presentation. The findings provide a deeper understanding of the benefits and challenges of a fast unenhanced MR-first approach with NeuroMix+MRA, which could be used to design prospective trials in select patient groups, with the potential to reduce radiation dose, mitigate adverse contrast-related patient and environmental effects, and lessen the burden on radiologists and healthcare systems. ABBREVIATIONS: CTAHN = CTA Head and Neck including non-contrast and delayed post-contrast CT Head with or without CT perfusion, NeuroMix = unenhanced multi-contrast MR brain sequence.

FAAH inhibition ameliorates breast cancer in a murine model.

Breast cancer is the leading cancer among females worldwide. Disease outcome depends on the hormonal status of the cancer and whether or not it is metastatic, but there is a need for more efficacious therapeutic strategies where first line treatment fails. In this study, Fatty Acid Amide Hydrolase (FAAH) inhibition and endocannabinoids were examined as therapeutic alternatives. FAAH is an integral membrane enzyme that hydrolyzes endocannabinoids, rendering them inactive, and FAAH inhibition is predicted to increase cancer cell death. To test this, breast cancer cells were probed for FAAH expression using Western blot analysis, treated with FAAH inhibitors, exogenous endocannabinoids, and combinations of the two treatments, and assessed for viability. High levels of FAAH were observed in different breast cancer cell lines. FAAH inhibition was more effective than exogenous endocannabinoid treatment, and the combination of FAAH inhibitors and endocannabinoids was the most effective in inducing apoptosis of breast cancer cells in vitro. In addition, in vivo FAAH inhibition reduced breast cancer growth in immunodeficient mice. FAAH inhibition is a promising approach, and tremendous progress has been made in the field to validate this mechanism as an alternative to chemotherapy. Further research exploring the therapeutic potential and impact of FAAH expression on cancer cells is warranted.

Transplanted organoids empower human preclinical assessment of drug candidate for the clinic.

Pharmacodynamic (PD) studies are an essential component of preclinical drug discovery. Current approaches for PD studies, including the analysis of novel kidney disease targeting therapeutic agents, are limited to animal models with unclear translatability to the human condition. To address this challenge, we developed a novel approach for PD studies using transplanted, perfused human kidney organoids. We performed pharmacokinetic (PK) studies with GFB-887, an investigational new drug now in phase 2 trials. Orally dosed GFB-887 to athymic rats that had undergone organoid transplantation resulted in measurable drug exposure in transplanted organoids. We established the efficacy of orally dosed GFB-887 in PD studies, where quantitative analysis showed significant protection of kidney filter cells in human organoids and endogenous rat host kidneys. This widely applicable approach demonstrates feasibility of using transplanted human organoids in preclinical PD studies with an investigational new drug, empowering organoids to revolutionize drug discovery.

Discovery of a Potent and Selective TRPC5 Inhibitor, Efficacious in a Focal Segmental Glomerulosclerosis Model.

The nonselective Ca2+-permeable transient receptor potential (TRP) channels play important roles in diverse cellular processes, including actin remodeling and cell migration. TRP channel subfamily C, member 5 (TRPC5) helps regulate a tight balance of cytoskeletal dynamics in podocytes and is suggested to be involved in the pathogenesis of proteinuric kidney diseases, such as focal segmental glomerulosclerosis (FSGS). As such, protection of podocytes by inhibition of TRPC5 mediated Ca2+ signaling may provide a novel therapeutic approach for the treatment of proteinuric kidney diseases. Herein, we describe the identification of a novel TRPC5 inhibitor, GFB-8438, by systematic optimization of a high-throughput screening hit, pyridazinone 1. GFB-8438 protects mouse podocytes from injury induced by protamine sulfate (PS) in vitro. It is also efficacious in a hypertensive deoxycorticosterone acetate (DOCA)-salt rat model of FSGS, significantly reducing both total protein and albumin concentrations in urine.

Subclinical Burden of Coronary Artery Calcium in Patients With Coarctation of the Aorta.

Coronary computed tomography (CT) angiography is often performed in adults with coarctation of the aorta (CoA) for anatomic assessment. As this population ages, assessment of atherosclerotic cardiovascular disease burden is important. Thus, quantitative and qualitative coronary artery calcium (CAC) scores were assessed for patients with CoA ≥16 years of age, who were seen at a referral center. CoA patients had either coronary CT angiography or chest CT with interpretable coronary information performed for clinical indications (follow-up, preoperative, or for symptoms) from 2004 to 2017. Qualitative CAC was determined based on low-dose CT and lung cancer screening protocols. Quantitative CAC scores were compared with an age- and gender-matched control cohort of patients chosen from an emergency department database of patients who received coronary CT angiography for chest pain evaluation. Atherosclerotic cardiovascular disease 10-year predicted risk scores were calculated for both cohorts. Out of 131 patients with CoA (mean age 46.1 ± 15.3 years), 22 patients (17%) had multivessel atherosclerotic disease on qualitative assessment. In the subgroup of patients ≥40 years, those with CoA were more likely to have a quantitative CAC score ≥400 compared with those without CoA (14% vs 4%, p = 0.02). Median atherosclerotic cardiovascular disease risk score was 8% (interquartile range 2% to 12%) for CoA patients ≥40 years, and 5% (interquartile range 2% to 9%) for patient without CoA ≥40 years. In conclusion, we determined that CoA patients have subclinical atherosclerosis identifiable on CT in high rates when compared with patients without CoA. Atherosclerotic cardiovascular disease should be assessed in these patients for prevention and treatment.