Opportunities to Strengthen the National Disaster Medical System: The Military-Civilian NDMS Interoperability Study.

The definitive care component of the National Disaster Medical System (NDMS) may not be able to effectively manage tens of thousands of casualties resulting from a catastrophic disaster incident or overseas conflict. To address this potential national security threat, Congress authorized the US Secretary of Defense to conduct the NDMS Pilot Program to improve the interoperability, special capabilities, and patient capacity of the NDMS. The pilot's first phase was the Military-Civilian NDMS Interoperability Study, designed to identify broad themes to direct further NDMS research. Researchers conducted a series of facilitated discussions with 49 key NDMS federal and civilian (private sector) stakeholders to identify and assess weaknesses and opportunities for improving the NDMS. After qualitative analysis, 6 critical themes emerged: (1) coordination, collaboration, and communication between federal and private sector NDMS partners; (2) funding and incentives for improved surge capacity and preparedness for NDMS partners; (3) staffing capacity and competencies for government and private NDMS partners; (4) surge capacity, especially at private sector healthcare facilities; (5) training, education, and exercises and knowledge sharing between federal and private sector NDMS partners; and (6) metrics, benchmarks, and modeling for NDMS partners to track their NDMS-related capabilities and performance. These findings provide a roadmap for federal-level changes and additional operations research to strengthen the NDMS definitive care system, particularly in the areas of policy and legislation, operational coordination, and funding.

Long-term benefit of lurbinectedin as palliative chemotherapy in progressive malignant pleural mesothelioma (MPM): final efficacy and translational data of the SAKK 17/16 study.

BACKGROUND: The SAKK 17/16 study showed promising efficacy data with lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma. Here, we evaluated long-term outcome and analyzed the impact of lurbinectedin monotherapy on the tumor microenvironment at the cellular and molecular level to predict outcomes. MATERIAL AND METHODS: Forty-two patients were treated with lurbinectedin in this single-arm study. Twenty-nine samples were available at baseline, and seven additional matched samples at day one of cycle two of treatment. Survival curves and rates between groups were compared using the log-rank test and Kaplan-Meier method. Statistical significance was set at P value <0.05. RESULTS: Updated median overall survival (OS) was slightly increased to 11.5 months [95% confidence interval (CI) 8.8-13.8 months]. Thirty-six patients (85%) had died. The OS rate at 12 and 18 months was 47% (95% CI 32.1% to 61.6%) and 31% (95% CI 17.8% to 45.0%), respectively. Median progression-free survival was 4.1 months (95% CI 2.6-5.5 months). No new safety signals were observed. Patients with lower frequencies of regulatory T cells, as well as lower tumor-associated macrophages (TAMs) at baseline, had a better OS. Comparing matched biopsies, a decrease of M2 macrophages was observed in five out of seven patients after exposure to lurbinectedin, and two out of four patients showed increased CD8+ T-cell infiltrates in tumor. DISCUSSION: Lurbinectedin continues to be active in patients with progressing malignant pleural mesothelioma. According to our very small sample size, we hypothesize that baseline TAMs and regulatory T cells are associated with survival. Lurbinectedin seems to inhibit conversion of TAMs to M2 phenotype in humans.

Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion.

Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dexamethasone. Mechanistically, we identified that dexamethasone up-regulated the GSH metabolism regulating protein dipeptidase-1 (DPEP1) in a glucocorticoid receptor (GR)-dependent manner. DPEP1 knockdown reversed the phenotype of dexamethasone-induced ferroptosis sensitization. Ferroptosis inhibitors, the DPEP1 inhibitor cilastatin, or genetic DPEP1 inactivation reversed the dexamethasone-induced increase in tubular necrosis in freshly isolated renal tubules. Our data indicate that dexamethasone sensitizes to ferroptosis by a GR-mediated increase in DPEP1 expression and GSH depletion. Together, we identified a previously unknown mechanism of glucocorticoid-mediated sensitization to ferroptosis bearing clinical and therapeutic implications.

Anthranilamides with quinoline and ß-carboline scaffolds: design, synthesis, and biological activity.

In the present study, we report the design and synthesis of novel amide-type hybrid molecules based on anthranilic acid and quinoline or ß-carboline heterocyclic scaffolds. Three types of biological screenings were performed: (i) in vitro antiproliferative screening against a panel of solid tumor and leukemia cell lines, (ii) antiviral screening against several RNA viruses, and (iii) anti-quorum sensing screening using gram-negative Chromobacterium violaceum as the reporter strain. Antiproliferative screening revealed a high activity of several compounds. Anthranilamides 12 and 13 with chloroquine core and halogenated anthranilic acid were the most active agents toward diverse cancer cell lines such as glioblastoma, pancreatic adenocarcinoma, colorectal carcinoma, lung carcinoma, acute lymphoblastic, acute myeloid, chronic myeloid leukemia, and non-Hodgkin lymphoma, but also against noncancerous cell lines. Boc-protected analogs 2 and 3 showed moderate activities against the tested cancer cells without toxic effects against noncancerous cells. A nonhalogenated quinoline derivative 10 with N-benzylanthranilic acid residue was equally active as 12 and 13 and selective toward tumor cells. Chloroquine and quinoline anthranilamides 10-13 exerted pronounced antiviral effect against human coronaviruses 229E and OC43, whereas 12 and 13 against coronavirus OC43 (EC50 values in low micromolar range; selectivity indices from 4.6 to > 10.4). Anthranilamides 14 and 16 with PQ core inhibited HIV-1 with EC50 values of 9.3 and 14.1 µM, respectively. Compound 13 displayed significant anti-quorum/biofilm effect against the quorum sensing reporter strain (IC50 of 3.7 µM) with no apparent bactericidal effect.

Synthesis, Molecular Docking and Antiplasmodial Activities of New Tetrahydro-ß-Carbolines.

Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-ß-carbolines were designed, synthesized by the Pictet-Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide (7) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1S,3R)-7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.