Background and Objectives: This study aimed to identify demographic and clinical factors at the time of critical care consultation associated with mortality or intensive care unit acceptance in a predominantly Afro-Caribbean population during the first wave of the COVID19 pandemic. Materials and Methods: This retrospective, single-center observational cohort study included 271 COVID19 patients who received a critical care consult between March 11 and April 30, 2020 during the first wave of the COVID19 pandemic at State University of New York Downstate Health Sciences University. Results: Of the 271 patients with critical care consults, 33% survived and 67% expired. At the bivariate level, age, blood urea nitrogen, and blood neutrophil percentage were significantly associated with mortality (mean age: survivors, 61.62 ± 1.50 vs. non-survivors, 68.98 ± 0.85, p < 0.001). There was also a significant association between neutrophil% and mortality in the univariate logistic regression model (quartile 4 vs. quartile 1: odd ratio 2.73, 95% confidence interval (1.28–5.82), p trend = 0.044). In the multivariate analyses, increasing levels of procalcitonin and C-reactive protein were significantly associated with mortality, adjusting for age, sex, and race/ethnicity (for procalcitonin quartile 4 vs. quartile 1: odds ratio 5.65, 95% confidence interval (2.14–14.9), p trend < 0.001). In contrast, higher platelet levels correlated with significantly decreased odds of mortality (quartile 4 vs. quartile 1, odds ratio 0.47, 95% CI (0.22–0.998), p trend = 0.010). Of these factors, only elevated procalcitonin levels were associated with intensive care unit acceptance. Conclusions: Procalcitonin showed the greatest magnitude of association with both death and likelihood of intensive care unit acceptance at the bivariate level. Our data suggests that procalcitonin reflects pneumonia severity during COVID-19 infection. Thus, it may help the intensivist identify those COVID19 patients who require intensive care unit level care.

Acute lung injury (ALI), a common condition in critically ill patients, has limited treatments and high mortality. Aging is a risk factor for ALI. Sirtuins (SIRTs), central regulators of the aging process, decrease during normal aging and in aging-related diseases. We recently showed decreased SIRT7 expression in lung tissues and fibroblasts from patients with pulmonary fibrosis compared to controls. To gain insight into aging-related mechanisms in ALI, we investigated the effects of SIRT7 depletion on lipopolysaccharide (LPS)-induced inflammatory responses and endothelial barrier permeability in human primary pulmonary endothelial cells. Silencing SIRT7 in pulmonary artery or microvascular endothelial cells attenuated LPS-induced increases in ICAM1, VCAM1, IL8, and IL6 and induced endomesenchymal transition (EndoMT) with decreases in VE-Cadherin and PECAM1 and increases in collagen, alpha-smooth muscle actin, TGFβ receptor 1, and the transcription factor Snail. Loss of endothelial adhesion molecules was accompanied by increased F-actin stress fibers and increased endothelial barrier permeability. Together, these results show that an aging phenotype induced by SIRT7 deficiency promotes EndoMT with impaired inflammatory responses and dysfunction of the lung vascular barrier.

Ephrin receptor A2 (EphA2) is part of the Ephrin family of cell-cell junction proteins highly overexpressed in several solid tumors, and is associated with poor prognosis. We developed a novel EphA2-targeted docetaxel nanoliposome, leveraging organ specificity through enhanced permeability effect and cellular specificity through EphA2 targeting. The goal of the study was to develop the diagnostic framework enabling the clinical implementation of EphA2-based exclusion criteria in future MM-310 trials. We used qFACS and an in vitro assay for liposome (Ls)-cell interaction to identify the minimum number of EphA2 receptors to enable antibody-mediated internalization of Ls. We developed an IHC assay able to differentiate EphA2 - vs + cell lines. We characterized EphA2 staining pattern in tumor samples of various indications and developed a scoring algorithm that allows selection of patients in early clinical trials. While non targeted Ls do not associate with cells in vitro, there is a strong correlation between EphA2 expression and EphA2-Ls cell association independent of the cell line origin. We used the non-targeted Ls to determine the extent of non-specific binding that can be achieved (∼340 Ls/cell) and used partitioning to determine the minimum number of EphA2 receptors necessary to mediate targeting (∼3000 receptors/cell). We have developed and validated a qIHC assay for EphA2 (precision ∼90%, linearity 0.8 and reproducibility ∼5%). We stained a set of ∼200 tumor samples from various indications. EphA2 was found to be expressed in tumor cells, tumor-associated myofibroblasts, and tumor-associated blood vessels. Using an inclusive cutoff of 10%, EphA2 prevalence was found to range from 50% to 100% in the tumor types evaluated. No significant difference in staining was seen between metastasis and primary tumors in matched samples. In summary, we developed a diagnostic framework for prospective selection of EphA2+ patients for MM-310 trials based on a mechanistic single cell cut-off, and a clinical-grade IHC assay. Cancer CellsTumor associated myofibroblastsTumor associated blood vesselsEphA2 Overall ScoreBladder19/20 (95%)0/20 (0%)16/20 (80%)19/20 (95%)Gastric18/20 (90%)3/20 (15%)17/20 (85%)20/20 (100%)Head & Neck16/19 (84%)0/19 (0%)9/19 (47%)19/19 (100%)Lung24/41 (58%)1/41 (2.4%)24/41 (58%)28/41 (68%)Lung-FNA7/9 (78%)––7/9 (78%)Ovarian10/18 (55%)7/18 (39%)17/18 (95%)17/18 (95%)Pancreatic15/19 (79%)0/19 (0%)11/19 (58%)17/19 (89%)Prostate7/23 (27%)7/23 (27%)9/23 (28%)12/23 (52%)TNBC6/77 (7%)0/77 (0%)34/77 (44%)37/77 (48%) Citation Format: Walid S. Kamoun, Shinji Oyama, Tad Kornaga, Theresa Feng, Lia Luus, Minh T. Pham, Dmitri B. Kirpotin, James D. Marks, Melissa Geddie, Lihui Xu, Alexey A. Lugovskoy, Monica Murphy, Carl Morrisson, Daryl C. Drummond. Nanoliposomal targeting of Ephrin receptor A2 (EphA2): Clinical translation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 750.

Rationale: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, has led to a global health crisis unlike any our contemporaries have witnessed before. SUNY Downstate Health Sciences University was designated as one of three COVID-19-only hospitals on March 28, 2020. This retrospective, single-center observational study grants a unique perspective surrounding the experience of the critical care service at a public institution serving a predominantly Afro-Caribbean, inner city population. Methods: Between March 11 and April 30, 2020, the critical care service was consulted for a total of 271 COVID-19 patients. We queried the electronic medical record for patient visits with critical care consult notes and collected data on demographics, comorbidities, ICU acceptance, treatment strategies, and clinical outcomes. Non-COVIDrelated consults were excluded. Chi-squared tests compared categorical variables, and independent samples ttest assessed differences in continuous variables based on mortality and ICU admission status. Logistic regression models determined if various factors independently predicted the odds of mortality. We conducted retrospective analyses to identify factors associated with survival and ICU acceptance. Results: Of the 271 patients with critical care consults, 33% (n=89) survived and 67% (n=182) expired. At the bivariate level, age, BUN, and neutrophil percentage were significantly associated with mortality, with age showing the strongest correlation (age: survivors, 61.62±1.50 vs. non-survivors, 68.98±0.85, p<0.001). There was a significant association between neutrophil percentage and mortality in the univariate logistic regression model (Q4 vs. Q1, OR 2.73, 95% CI (1.28 -5.82), p trend = 0.044). In the multivariate analyses, procalcitonin exhibited a positive correlation with the odds of mortality, adjusting for age, sex, and race/ethnicity (procalcitonin: Q4 vs. Q1, OR 5.65, 95% CI (2.14 -14.9), p trend <0.001). Adjusting for the same covariates, platelets exhibited a negative correlation with the odds of mortality (Q4 vs. Q1, OR 0.47, 95% CI (0.22 -0.998), p trend = 0.010). Interestingly, of these factors, only elevated procalcitonin levels were associated with an increased likelihood of ICU acceptance. Conclusions: This retrospective, observational study during the first peak of the COVID-19 pandemic identified key factors linked to disease severity and outcomes. Of note, procalcitonin was the factor most strongly associated with both mortality and likelihood of ICU acceptance at the bivariate level. Respiratory failure is the primary cause of death in COVID-19, and our data suggests that procalcitonin is a useful marker that accurately reflects the severity of lung involvement during SARS-CoV-2 infection.