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COVID-19 affects vulnerable populations including elderly individuals and patients with cancer. Natural Killer (NK) cells and innate-immune TRAIL suppress transformed and virally-infected cells. ACE2, and TMPRSS2 protease promote SARS-CoV-2 infectivity, while inflammatory cytokines IL-6, or G-CSF worsen COVID-19 severity. We show MEK inhibitors (MEKi) VS-6766, trametinib and selumetinib reduce ACE2 expression in human cells. Chloroquine or hydroxychloroquine increase cleaved active SP-domain of TMPRSS2, and this is potentiated by MEKi. In some human cells, remdesivir increases ACE2-promoter luciferase-reporter expression, ACE2 mRNA and protein, and ACE2 expression is attenuated by MEKi. We show elevated cytokines in COVID-19- (+) patient plasma (N=9) versus control (N=11). TMPRSS2, inflammatory cytokines G-CSF, M- CSF, IL-1a, IL-6 and MCP-1 are suppressed by MEKi alone or in combination with remdesivir. MEKi enhance NK cell (but not T-cell) killing of target-cells, without suppressing TRAIL-mediated cytotoxicity. We generated a pseudotyped SARS-CoV-2 virus with a lentiviral core but with the SARS-CoV-2 D614 or G614 SPIKE (S) protein on its envelope and used VSV-G lentivirus as a negative control. Our results show infection of human bronchial epithelial cells or lung cancer cells and that MEKi suppress infectivity of the SARS-CoV-2-S pseudovirus following infection. We show a drug class-effect with MEKi to promote immune responses involving NK cells, inhibit inflammatory cytokines and block host-factors for SARS-CoV-2 infection leading also to suppression of SARS-CoV-2-S pseudovirus infection of human cells in a model system. MEKi may attenuate coronavirus infection to allow immune responses and antiviral agents to control COVID-19 disease progression and severity.

e18319 Background: ICH E6 (R2) has increased the level of scrutiny that we have for the data we collect in clinical trials. The emphasis is on quality-by-design with a quality management system to be incorporated and a focus on using a risk-based approach. This can be time-consuming and expensive - though the goal of this addendum is to improve quality AND efficiency, whilst ensuring patient safety and integrity of trial results. We therefore, piloted a proactive, concise and consistent method for utilizing a risk-based approach with central monitoring. Methods: Our method included 1) identifying risks within our data with 8 standard Key Risk Indicators (KRIs) across different study phases and different therapeutic areas together with 2) an off-the-shelf web-based tool for uniform and efficient review by a team of central monitors to assess which data may need more examination. These 8 KRIs are indicated in the list below, in order of the categories within the TransCelerate Risk Assessment and Categorization Tool: (S)AE rates, Enrollment Rates, Screen Failure Rates, Discontinuation Rate, Protocol Deviation Rates, Overdue Query Rate, Data Latency, and Identification of Potential Fraudulent data. Results: 15 studies were configured with the same KRIs and Visual Analytics; histograms, line- and pie-charts and data tables allowing for interactive data visualization and drill down. This represents research across different Phases 1-3 and observational studies. Based upon qualitative survey analysis from the central monitoring team 5/8 KRIs were found to be extremely valuable to focus on study quality, identifying earlier issues in study conduct for the project teams and Sponsors, while the remaining 3 were less valuable. Conclusions: We Our Risk Management team aims to increase the quality of data and ease of implementation of ICHE6 (R2) by focusing on the areas that matter the most, however identifying those areas and managing those data can sometimes be challenging. Through this innovation we have proven some core KRIs of trials that should be most closely monitored to aid decision making and will continue to evaluate to develop core oncology specific KRIs that will allow a more consistent review of data.

The aim of this paper is to analyze the slopes stability under seismic loading using a global numerical dynamic approach. This approach allows important parameters that are generally ignored by traditional engineering methods such as the soil deformability, the dynamic amplification, non linear soil behavior, the spatial and temporal variability of the seismic loading and the reinforcement element… The present study is conducted by using measures recorded during real earthquakes (Turkey, 1999) & (Lebanon, 2008). Elastoplastic soil behavior analysis leads to monitor the evolution of the slope state after an earthquake and to clarify the most probable failure circles. A parametric study according to the reinforcement length, position, inclination and the number of elements has been studied in order to define the optimal reinforcement scheme for slopes under seismic loading. This study contains also the stability analysis of an existing foundation near the slope’s crest. It will focus on the reinforcement in order to give recommendation for the most appropriate scheme that minimize the settlement of the foundation due to earthquake effect.

In vitro, bexarotene inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts. Our previous phase I study in non-M3 AML showed evidence of leukemic response as manifested by reduction in bone marrow blast counts (15% response rate), improved platelet counts (41%) and improved neutrophil counts (26%). Based on these results, a phase II trial in non-M3 AML was initiated at the phase I MTD. In the current phase II trial, bexarotene (300mg/m2) was administered daily as monotherapy until disease progression or unacceptable side effects occurred. Fourteen patients have been enrolled: 8M/6F, median age 74 (range 20–83), 9 secondary AML (MDS or prior chemotherapy), 9 primary refractory or relapsed < 1 year after induction, 5 no prior induction chemotherapy, 5 requiring hydroxyurea at the time of enrollment for leukemic blast control, 4 prior allogeneic stem cell transplant, 12 blood transfusion dependent, 11 platelet transfusion dependent, and 8 neutropenic. Overall, no significant adverse events were noted. All patients received prophylactic antihyperlipidemic agents and achieved good lipid control. Two patients developed mild hypothyroidism related to bexarotene. Five patients were evaluable with bone marrow biopsy at 2 months: 1 50% reduction in absolute blasts, 1 SD and 3 PD. Similar to data from our prior phase I study, evidence of clinical activity was manifested as platelet count response in 1 patient and neutrophil increases attributable to bexarotene in 2 patients. When combining the results of our phase I experience (27 patients) with our phase II data (14 patients), there is a suggestion of increased activity in patients with 5q minus abnormalities with 4/7 (57%) benefiting (2 BM response, 4 neutrophil improvements and 1 platelet response). Conversely rates of clinical benefit were lower in patients with multiple (>3) cytogenetic abnormalities (2/13), relapse after stem cell transplant (1/9) or requiring hydroxyurea for peripheral blast control at the time of study enrollment (0/10). Bexarotene is very well tolerated at the dose level studied. Early evidence for clinical activity has been seen as exemplified by improvement in platelet count, increased neutrophil counts and decreased bone marrow blasts. In summary, we conclude that bexarotene is an active agent in a subgroup of patients with AML. Study enrollment continues with amended inclusion criteria to focus on patients more likely to benefit from treatment.