[Comparative study of Wuhan-like and omicron-like variants of SARS-CoV-2 in experimental animal models].

INTRODUCTION: The variability of SARS-CoV-2 appeared to be higher than expected, the emergence of new variants raises concerns. The aim of the work was to compare the pathogenicity of the Wuhan and BA.1.1/Omicron variants in BALB/c mice and Syrian hamsters. MATERIALS AND METHODS: The study used strains of SARS-CoV-2: Dubrovka phylogenetically close to Wuhan-Hu-1, and LIA phylogenetically close to Omicron, BALB/c mice, transgenic mice B6.Cg-Tg(K18-ACE2)2Prlmn/HEMI Hemizygous for Tg(K18-ACE2)2Prlmn, Syrian golden hamsters. Animals were infected intranasally, pathogenicity was estimated by a complex of clinical, pathomorphological and virological methods. RESULTS: Comparative studies of SARS-CoV-2 Dubrovka and LIA strains on animal models demonstrated their heterogeneous pathogenicity. In parallel infection of BALB/c mice with Dubrovka and LIA variants, the infection proceeded without serious clinical signs and lung damage. Infection with the LIA strain resulted to a systemic disease with a high concentration of viral RNA in the lungs and brain tissues of animals. The presence of viral RNA in mice infected with the Dubrovka strain was transient and undetectable in the lungs by day 7 post-infection. Unlike the mouse model, in hamsters, the Dubrovka strain had a greater pathogenicity than the LIA strain. In hamsters infected with the Dubrovka strain lung lesions were more significant, and the virus spread through organs, in particular in brain tissue, was observed. In hamsters infected with the LIA strain virus was not detected in brain tissue. CONCLUSION: The study of various variants of SARS-CoV-2 in species initially unsusceptible to SARS-CoV-2 infection is important for monitoring zoonotic reservoirs that increase the risk of spread of new variants in humans.

Patterns of Response to Immune Checkpoint Inhibitors in Association with Genomic and Clinical Features in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC).

Background: We sought to compare patterns of response to immune checkpoint inhibitors (ICI) with respect to clinical and genomic features in a retrospective cohort of patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Methods: One hundred seventeen patients with R/M HNSCC treated with ICI were included in this study. Tumor growth kinetics (TGK) prior to and TGK upon immunotherapy (IO) was available for 49 patients. The TGK ratio (TGKR, the ratio of tumor growth velocity before and upon treatment) was calculated. Hyperprogression (HPD) was defined as TGKR ≥ 2. Results: HPD was documented in 18 patients (15.4% of the whole cohort). Patients with HPD had statistically significant shorter progression free survival (PFS) (median PFS 1.8 months (95% CI, 1.03-2.69) vs. 6.1 months for patients with non-HPD (95% CI, 4.78-7.47), p = 0.0001) and overall survival (OS) (median OS 6.53 months (95% CI, 0-13.39) vs. 15 months in patients with non HPD (95% CI, 7.1-22.8), p = 0.0018). In a multivariate Cox analysis, the presence of HPD remained an independent prognostic factor (p = 0.049). Primary site in the oral cavity and administration of ICI in the second/third setting were significant predictors of HPD in multivariate analysis (p = 0.028 and p = 0.012, respectively). Genomic profiling revealed that gene amplification was more common in HPD patients. EGFR gene amplification was only observed in HPD patients, but the number of events was inadequate for the analysis to reach statistical significance. The previously described MDM2 amplification was not identified. Conclusions: HPD was observed in 15.4 % of patients with R/M HNSCC treated with IO and was associated with worse PFS and OS. EGFR amplification was identified in patients with HPD.

Synthetic homoserine lactone analogues as antagonists of bacterial quorum sensing.

Quorum sensing (QS) is a density-dependent form of cell-cell communication that triggers the functional coordination of cooperative behaviors such as the production of virulence factors and biofilm formation. Quorum quenching (QQ) refers to all processes involved in the disruption of QS and is regarded as a promising strategy for treating bacterial infections. Herein, four compounds with closely related chemical structures to homoserine γ-lactone were synthesized and fully characterized. The compounds are termed TGK-series compounds. These compounds were subsequently tested in their QS inhibition activity using an E. coli Top 10 QS biosensor strain, a GFP QS reporter, that probes the capacity of bacteria to detect their cognate autoinducer N-(3-oxohexanoyl)-homoserine lactone (3OC6HSL) substrate by means of a single intracellular protein LuxR. All TGK-series compounds were found to significantly inhibit the ability of bacteria to produce GFP but without exerting toxicity when applied at a concentration of 50 µM. In parallel, the interaction of TGK-series compounds with LuxR were studied by molecular docking simulations. These studies revealed that TGK-series compounds bound to the natural substrate N-(3-oxo-octanoyl)-l-homoserine lactone (OOHL) binding site and that the binding ability of the compounds with the TraR protein (a surrogate of LuxR) was even more favorable in comparison with the natural substrate. It was also uncovered that TGK-series compounds form stronger hydrophobic interactions with the TraR protein than 3OC6HSL does, thus providing a rationale for the enhancement of the QQ activity of the synthetic TGK-series compounds. This study will serve to guide future works aimed to design promising novel QS inhibitor candidates on a rational basis.

Hyperprogression after immunotherapy in patients with malignant tumors of digestive system.

BACKGROUND: Immune checkpoint inhibitors (ICIs) were approved to have a significant antitumor activity in various tumor types. In practice, some patients do not seem to benefit from ICIs but rather to have accelerating disease. The aim of this study was to evaluate hyperprogression in patients with malignant tumors of digestive system treated with ICIs. METHODS: Medical records from consecutive patients with malignant tumors of digestive system treated with ICIs in Peking University Cancer Hospital were retrospectively collected. Tumor growth kinetics (TGK) on immunotherapy and TGK pre-immunotherapy were collected and TGK ratio (TGKR) was calculated. Hyperprogression was defined as TGKR≥2. RESULTS: From August 2016 to May 2017, 25 evaluable patients were identified from 45 patients with malignant tumors of digestive system. Five patients were considered as having hyperprogression. Three of 5 were neuroendocrine carcinomas (NECs) and the other 2 were adenocarcinomas. Four of 5 were treated with programmed cell death ligand 1 (PD-L1) inhibitor, the other one was treated with PD-L1 inhibitor combined with cytotoxic T lymphocyte associated antigen-4 (CTLA-4) inhibitor. Pseudoprogression was observed in 2 patients. CONCLUSIONS: Hyperprogression was observed in a fraction of patients with malignant tumors of digestive system treated with ICIs. Further investigation is urgently needed.