Duvelisib for critically ill patients with coronavirus disease 2019: An investigator-initiated, randomized, placebo-controlled, double-blind pilot trial

BACKGROUND: Despite improvements in prevention and treatment, severe coronavirus disease 2019 (COVID-19) is associated with high mortality. Phosphoinositide 3-kinase (PI3K) pathways contribute to cytokine and cell-mediated lung inflammation. We conducted a randomized, placebo-controlled, double-blind pilot trial to determine the feasibility, safety, and preliminary activity of duvelisib, a PI3Kδγ inhibitor, for the treatment of COVID-19 critical illness. METHODS: We enrolled adults aged ≥18 years with a primary diagnosis of COVID-19 with hypoxic respiratory failure, shock, and/or new cardiac disease, without improvement after at least 48 hours of corticosteroid. Participants received duvelisib (25 mg) or placebo for up to 10 days. Participants had daily semi-quantitative viral load measurements performed. Dose modifications were protocol driven due to adverse events (AEs) or logarithmic change in viral load. The primary endpoint was 28-day overall survival (OS). Secondary endpoints included hospital and intensive care unit length of stay, 60-day OS, and duration of critical care interventions. Safety endpoints included viral kinetics and AEs. Exploratory endpoints included serial cytokine measurements and cytometric analysis. RESULTS: Fifteen patients were treated in the duvelisib cohort, and 13 in the placebo cohort. OS at 28 days was 67% (95% confidence interval [CI], 38%-88%) compared to 62% (95% CI, 32%-86%) for placebo ( CONCLUSIONS: In this pilot study, duvelisib did not significantly improve 28-day OS compared to placebo for severe COVID-19. Duvelisib appeared safe in this critically ill population and was associated with reduction in cytokines implicated in COVID-19 and acute respiratory distress syndrome, supporting further investigation. CLINICAL TRIALS REGISTRATION: NCT04372602

Preclinical validation of a novel metastasis‐inhibiting Tie1 function‐blocking antibody

Abstract The angiopoietin (Ang)–Tie pathway has been intensely pursued as candidate second‐generation anti‐angiogenic target. While much of the translational work has focused on the ligand Ang2, the clinical efficacy of Ang2‐targeting drugs is limited and failed to improve patient survival. In turn, the orphan receptor Tie1 remains therapeutically unexplored, although its endothelial‐specific genetic deletion has previously been shown to result in a strong reduction in metastatic growth. Here, we report a novel Tie1 function‐blocking antibody (AB‐Tie1‐39), which suppressed postnatal retinal angiogenesis. During primary tumor growth, neoadjuvant administration of AB‐Tie1‐39 strongly impeded systemic metastasis. Furthermore, the administration of AB‐Tie1‐39 in a perioperative therapeutic window led to a significant survival advantage as compared to control‐IgG‐treated mice. Additional in vivo experimental metastasis and in vitro transmigration assays concurrently revealed that AB‐Tie1‐39 treatment suppressed tumor cell extravasation at secondary sites. Taken together, the data phenocopy previous genetic work in endothelial Tie1 KO mice and thereby validate AB‐Tie1‐39 as a Tie1 function‐blocking antibody. The study establishes Tie1 as a therapeutic target for metastasis in a perioperative or neoadjuvant setting

The future of the river Oder

The man-made environmental disaster in the summer of 2022, resulting in masses of dead fish, mussels and snails, has caused severe damage to the Oder River ecosystem. Policymakers, authorities, NGOs and the public are currently discussing how the river can be helped – and how the risk of such major ecological and economic damage can be reduced in the future. This IGB Policy Brief provides a concise summary of what is known about the causes of the fish kill, and what measures we recommend to policymakers and authorities to restore and preserve the River Oder habitat and its important ecosystem services. The Leibniz Institute of Freshwater Ecology and Inland Fisheries (IGB), Germany’s largest freshwater research centre, has been working on the Oder for decades. On this basis, IGB scientists identify problem areas and evidencebased recommendations for action

Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells

Interaction between the chemokine receptor CXCR4 and its chief ligand CXCL12 plays a critical role in the retention and migration of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) microenvironment. In this study, qualitative and quantitative effects of long-term pharmacologic inhibition of the CXCR4/CXCL12 axis on the HSPC compartment were investigated by using 3 structurally unrelated small molecule CXCR4 antagonists. A >10-fold increase in mobilization efficiency was achieved by administering the antagonists as a subcutaneous continuous infusion for 2 weeks compared to a single bolus injection. A concurrent increase in self-renewing proliferation leading to a twofold to fourfold expansion of the HSPC pool in the BM was observed. The expanded BM showed a distinct repopulating advantage when tested in serial competitive transplantation experiments. Furthermore, major changes within the HSPC niche associated with previously described HSPC expansion strategies were not detected in bones treated with a CXCR4 antagonist infusion. Our data suggest that prolonged but reversible pharmacologic blockade of the CXCR4/CXCL12 axis represents an approach that releases HSPC with efficiency superior to any other known mobilization strategy and may also serve as an effective method to expand the BM HSPC pool