Hetlioz(®) (tasimelteon) is the first approved treatment in the United States for Non-24-Hour Sleep-Wake Disorder (Non-24). We present here data on the in vitro binding affinity of tasimelteon for both human melatonin receptors MT1 and MT2, as well as the extended screen of other receptors and enzymes. Results indicate that tasimelteon is a potent Dual Melatonin Receptor Agonist (DMRA) with 2.1-4.4 times greater affinity for the MT2 receptor believed to mediate circadian rhythm phase-shifting (Ki = 0.0692 nM and Ki = 0.17 nM in NIH-3T3 and CHO-K1 cells, respectively), than for the MT1 receptor (Ki = 0.304 nM and Ki = 0.35 nM, respectively). Tasimelteon was also shown to have no appreciable affinity for more than 160 other pharmacologically relevant receptors and several enzymes.

Background The utility of convalescent COVID-19 plasma (CCP) in the current pandemic is not well defined. We sought to evaluate safety and efficacy of CCP in severely or life threateningly ill COVID-19 patients when matched with a contemporaneous cohort. Methods Patients with severe or life threatening COVID-19 were treated with CCP according to FDA criteria, prioritization by an interdisciplinary team and based on CCP availability. Individual-level matched controls (1:1) were identified from patients admitted during the prior month when no CCP was available. Safety outcome was freedom from adverse transfusion reaction and efficacy outcome a composite of death or worsening O2 support. Demographic, clinical and laboratory data were analyzed by univariate and multivariable regression analyses accounting for matched design. Results Study patients (N=94, 47 matched pairs) were 62% male with mean age of 58 and 98% (90/94) were minority (53% Hispanic, 45% Black, non-Hispanic) in our inner-city population. Seven-day composite and mortality outcomes suggested a non-significant benefit in CCP treated patients (adjusted hazard ratio (aHR), 0.70; 95% confidence interval (CI), 0.23 to 2.12; P=0.52; aHR, 0.23; 95% CI, 0.04 to 1.51; P=0.13, respectively). Stratification by pre-transfusion mechanical ventilation status showed no differences between groups. No serious transfusion reactions occurred. Conclusion In this short-term matched cohort study, transfusion with CCP was safe and showed a non-significant association with study outcomes. Randomized and larger trials to identify appropriate timing and dosing of CCP in COVID-19 is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT04420988

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This project compared quantifiable measures of tumor vascularity obtained from contrast-enhanced high frequency (HF) and low frequency (LF) subharmonic ultrasound imaging (SHI) to 3 immunohistochemical markers of angiogenesis in a murine breast cancer model (since angiogenesis is an important marker of malignancy and the target of many novel cancer treatments). Nineteen athymic, nude, female rats were implanted with 5×106 breast cancer cells (MDA-MB-231) in the mammary fat pad. The contrast agent Definity (Lantheus Medical Imaging, N Billerica, MA) was injected in a tail vein (dose: 180µl/kg) and low frequency pulse-inversion SHI was performed with a modified Sonix RP scanner (Analogic Ultrasound, Richmond, BC, Canada) using a L9-4 linear array (transmitting/receiving at 8/4MHz in SHI mode) followed by high frequency imaging with a Vevo 2100 scanner (Visualsonics, Toronto, ON, Canada) using a MS250 linear array transmitting and receiving at 24MHz. The radiofrequency data was filtered using a 4th order IIR Butterworth bandpass filter (11–13MHz) to isolate the subharmonic signal. After the experiments, specimens were stained for endothelial cells (CD31), vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). Fractional tumor vascularity was calculated as contrast enhanced pixels over all tumor pixels for SHI, while the relative area stained over total tumor area was calculated from specimens. Results were compared using linear regression analysis. Out of 19 rats, 16 showed tumor growth (84%) and 11 of them were successfully imaged. HF SHI demonstrated better resolution, but weaker signals than LF SHI (0.06±0.017 vs. 0.39±0.059; p<0.001). The strongest overall correlation in this breast cancer model was between HF SHI and VEGF (r=−0.38; p=0.03). In conclusion, quantifiable measures of tumor neovascularity derived from contrast-enhanced HF SHI appear to be a better method than LF SHI for monitoring angiogenesis in a murine xenograft model of breast cancer (corresponding in particular to the expression of VEGF); albeit based on a limited sample size.

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