The present disclosure provides methods of treating a subject having a metabolic disorder or is at risk of developing a metabolic disorder or preventing a subject from developing a metabolic disorder, and methods of identifying subjects having an increased risk of developing a metabolic disorder.

The instant disclosure provides methods and compositions for the diagnosis, treatment and prevention of Marfan syndrome and related diseases, disorders and conditions. The disclosure further provides pharmaceutical compositions and kits for the diagnosis, treatment and prevention of Marfan syndrome and related diseases, disorders and conditions.

In one aspect, the invention provides a polypeptide derived from the dimer interface of BRAF, which is useful for treating various types of cancers. In certain embodiments, the polypeptide can be used to treat, prevent, and/or ameliorate a cancer such as but not limited to lung cancer.

Methods of treating a subject (e.g., a mammalian, preferably human, subject) with cancer, e.g., with melanoma, comprising administering a combination of an inhibitor of the non-canonical NFkB pathway and a checkpoint inhibitor.

The present disclosure relates to methods of treating neurodegeneration and neurodegenerative diseases comprising administering to a subject in need thereof a combination of a SARM1 inhibitor and a neuroprotective agent.

Herein are described peptide-based compositions for modifying Raf kinase protein Dimerization. These compositions, treatments, and methods of use are directed to peptides that display a binding affinity for the dimer interface of a Raf kinase protein, methods for modifying Raf kinase dimerization, and methods for inhibiting tumor growth. An embodiment of the disclosure is a peptide generated by modifying an ordered sequence chosen from SEQ ID NO: 1 which corresponds to amino acids 503-521 of B-Raf kinase. The peptides disclosed herein include a modification to an ordered sequence of amino acids derived from SEQ ID NO: 1 that can improve or otherwise alter binding affinity of the peptide to the dimer interface.

The disclosure provides compositions and methods useful for treating conditions related to Dual Leucine Zipper (DLK), e.g., neurodegenerative disorders including optic neuropathy. The disclosure provides gene constructs and vectors that regulate the activity of Dual Leucine Zipper Kinase (DLK) or Leucine Zipper Kinase (LZK). The disclosure also provides dominant negative DLK (DN-DLK) proteins that inhibit the kinase and/or signaling activity of DLK. The disclosure also provides vectors, pharmaceutical compositions, and methods of inhibiting DLK.

Cells produce electrophilic products with the potential to modify and affect the function of proteins. Chemoproteomic methods have provided a means to qualitatively inventory proteins targeted by endogenous electrophiles; however, ascertaining the potency and specificity of these reactions to identify the most sensitive sites in the proteome to electrophilic modification requires more quantitative methods. Here, we describe a competitive activity-based profiling method for quantifying the reactivity of electrophilic compounds against 1000+ cysteines in parallel in the human proteome. Using this approach, we identify a select set of proteins that constitute “hot spots” for modification by various lipid-derived electrophiles, including the oxidative stress product 4-hydroxynonenal (HNE). We show that one of these proteins, ZAK kinase, is labeled by HNE on a conserved, active site-proximal cysteine, resulting in enzyme inhibition to create a negative feedback mechanism that can suppress the activation of JNK pathways by oxidative stress.

It is intended to reveal a polynucleotide serving as a novel causative gene of a cancer and, on the basis of this finding, to provide a method for detecting the polynucleotide or a polypeptide encoded thereby, a kit and a primer set for the detection, a method for screening for a substance that inhibits the polypeptide, and a pharmaceutical composition for the treatment of a cancer, containing the inhibiting substance. The detection method of the present invention detects a BRAF fusion protein or a fusion gene encoding the fusion protein, or a PXN or GMDS fusion protein or a fusion gene encoding the fusion protein in a digestive organ-derived sample obtained from a subject.

It is intended to reveal a polynucleotide serving as a novel causative gene of a cancer and, on the basis of this finding, to provide a method for detecting the polynucleotide or a polypeptide encoded thereby, a kit and a primer set for the detection, a method for screening for a substance that inhibits the polypeptide, and a pharmaceutical composition for the treatment of a cancer, containing the inhibiting substance. The detection method of the present invention detects a BRAF fusion protein or a fusion gene encoding the fusion protein, or a PXN or GMDS fusion protein or a fusion gene encoding the fusion protein in a digestive organ-derived sample obtained from a subject.