The invention relates to methods and pharmaceutical compositions for the treatment of Cytokine Release Syndrome (CRS). The invention also relates to methods for the diagnosis of patients suffering from Cytokine Release Syndrome. The inventors investigate iron homeostasis and the role of CD44-mediated iron endocytosis in the severe inflammatory response and Cytokine Release Syndrome, particularly in SARS-CoV-2 patients. The inventors demonstrate that during activation of M1 macrophages, iron endocytosis is upregulated in a CD44-dependent manner and that CD44 protein levels increase. This effect is specific to M1 macrophages, whereas levels of the canonical iron endocytosis protein TfR1/CD71 remain unchanged. In the present invention, the inventors provide in vitro evidences towards a direct role of CD44-mediated iron endocytosis in the severe inflammatory response such as Cytokine Release Syndrome observed in SARS-CoV-2 patients. Thus, the present invention relates to an antagonist of CD44/Hyaluronic Acid pathway for use in the treatment of cytokine release syndrome in a subject in need thereof, particularly severe COVID-19-related cytokine release syndrome.

The present invention relates to a method for detecting a spatial proximity of a first and a second epitope (11, 21) of a protein or of a first and a second protein (10, 20) of a protein complex (1) in a sample of a subject. The method comprises binding a first binding member (30) having a first oligonucleotide (31) conjugated thereto to the first epitope (11), binding a second binding member (40) having a second oligonucleotide (41) conjugated thereto to the second epitope (21), and determining whether a Fluorescence Resonance Energy Transfer (FRET) effect is present between a donor fluorophore (32) and an acceptor fluorophore (42), which are associated with the first oligonucleotide (31) and the second oligonucleotide (41), wherein the presence of the FRET effect indicates a spatial proximity of the first and the second oligonucleotide (31, 41) and, thus, the spatial proximity of the first and the second epitope (11, 21).

Methods and compositions are provided for treating individuals who have an oncogene-negative cancer. In some cases, such individuals have an oncogene-negative tumor(s). In some cases, they have an oncogene-negative lung cancer. In some cases, they have an oncogene-negative lung adenocarcinoma. In some cases, treatment includes administering an inhibitor of the Ras/MAPK pathway. In some cases, treatment includes administering an inhibitor of the Ras/MAPK pathway and an inhibitor of the PI3K-AKT pathway. Methods and compositions are also provided for testing candidate cancer therapeutics. In some cases, such methods include contacting an oncogene-negative cell, in culture or in vivo, with a candidate agent, where the cell has increased Ras/MAPK pathway activity and/or increased PI3K-AKT pathway activity.

Disclosures herein are directed to antibodies and epitope binding agents that specifically bind to the extracellular domain of Patched-1 and compositions thereof for use in clinical and non-clinical applications. Also provided are methods to treat and/or prevent Hedgehog pathway related disorders.

Translational activators are disclosed along with uses thereof and methods to discover translational activators. Many embodiments provide methods to treat diseases and disorders caused by global downregulation of protein synthesis, including (but not limited to) ribosomopathies and neurodegenerative disorders. Certain embodiments are directed to uses of translational activators for the manufacture of medicaments to treat diseases and disorders caused by global downregulation of protein synthesis, and further embodiments are directed to methods of discovering translational activators.

The present disclosure relates to a method for determining a risk of development or risk of presence of Alzheimer's disease in a human subject comprising analyzing an activity of a PIEZO1 receptor. The disclosure also relates to a kit for determining a risk of development or risk of presence of Alzheimer's disease according to the present method. The disclosure also relates to an in vitro use of a PIEZO1 receptor as a biomarker and determination of intracellular calcium level as a biomarker for determining a risk of development or risk of presence of Alzheimer's disease in a human subject.

The present invention provides methods and compositions for treating subjects suffering from a disorder associated with a nicotinic acetylcholine receptor (nAChR), methods for treating a subject having a disorder that would benefit from an increase in neural plasticity, and methods for modulating the plasticity of the primary visual cortex in subjects by modulating the expression, stability, and/or activity of Lynx1.