The present invention provides methods for detecting and/or treating a subject having an aneurysm or at risk for developing an aneurysm. It has been discovered that a key metabolite of the kynurenine (Kyn) pathway, a major route for the metabolism of essential amino acid tryptophan (Trp) into nicotinamide adenine dinucleotide (NAD+), plays a critical role in the formation of aneurysms, for example abdominal aortic aneurysms. In particular, it has been discovered that 3-Hydroxyanthranilic acid (3-HAA), a product of kynureninase (KYNU), plays a causative role in the formation of aneurysms by, for example exerting pro-inflammatory effects on vascular smooth muscle cells. It has further been discovered that elevated levels of 3-HAA are indicative of the presence and/or progression of an aneurysm, and 3-HAA levels correlate with the size (aortic diameter) of the aneurysm.

Formulations of creatine, preferably phosphocreatine and most preferably disodium phosphocreatine, combined with cyclodextrin exhibit improved uptake across digestive mucosa, including intestinal, esophageal, and stomach mucosa. In particular, the formulations of the present invention are designed for protection of the cyclodextrin as it comes in contact with gastric juices so as to allow thereafter for unexpectedly improved site-specific intestinal release.

Formulations of creatine, preferably phosphocreatine and most preferably disodium phosphocreatine, combined with cyclodextrin exhibit improved uptake across digestive mucosa, including intestinal, esophageal, and stomach mucosa. In particular, the formulations of the present invention are designed for protection of the cyclodextrin as it comes in contact with gastric juices so as to allow thereafter for unexpectedly improved site-specific intestinal release.

Disclosed herein is a recombinant nucleic acid, comprising: a mitochondrial targeting sequence; a mitochondrial protein coding sequence, wherein said mitochondrial protein coding sequence encodes a polypeptide comprising a mitochondrial protein; and a 3′UTR nucleic acid sequence. Also disclosed is a pharmaceutical composition comprising the recombinant nucleic acid and a method of treating Leber's hereditary optic neuropathy (LHON) using the pharmaceutical composition.

Disclosed herein is a recombinant nucleic acid, comprising: a mitochondrial targeting sequence; a mitochondrial protein coding sequence, wherein said mitochondrial protein coding sequence encodes a polypeptide comprising a mitochondrial protein; and a 3′UTR nucleic acid sequence. Also disclosed is a pharmaceutical composition comprising the recombinant nucleic acid and a method of treating Leber's hereditary optic neuropathy (LHON) using the pharmaceutical composition.

Methods of treating cancer or reducing the incidence of relapse of a cancer in a subject comprising co-administration of Toll-like receptor (TLR) 4 ligand, such as an HMGN1 protein, and a TLR 7 or 8 ligand, and optionally an immune checkpoint inhibitor, to the subject in need of such therapy. The TLR4-mediated immune-stimulating effect is synergistically enhanced by ligands of TLR7 or 8, and the immune checkpoint inhibitor. Also described here is a nanoparticle delivery platform for the co-administration of the TLR 4 ligand and the TLR 7 or 8 ligand.

Methods of treating cancer or reducing the incidence of relapse of a cancer in a subject comprising co-administration of Toll-like receptor (TLR) 4 ligand, such as an HMGN1 protein, and a TLR 7 or 8 ligand, and optionally an immune checkpoint inhibitor, to the subject in need of such therapy. The TLR4-mediated immune-stimulating effect is synergistically enhanced by ligands of TLR7 or 8, and the immune checkpoint inhibitor. Also described here is a nanoparticle delivery platform for the co-administration of the TLR 4 ligand and the TLR 7 or 8 ligand.

The disclosure provides methods of treating a tumor/cancer by administering naltrexone or an analogue thereof, followed by a recovery phase, and then administering a small molecule signaling inhibitor such as PI3-kinase inhibitors, AKT inhibitors, taxanes, antimetabolites, alkylating agents and/or cell cycle inhibitors. The disclosure also provides diagnostic methods for assessing a therapeutic response to the methods of treatment.

The disclosure provides methods of treating a tumor/cancer by administering naltrexone or an analogue thereof, followed by a recovery phase, and then administering a small molecule signaling inhibitor such as PI3-kinase inhibitors, AKT inhibitors, taxanes, antimetabolites, alkylating agents and/or cell cycle inhibitors. The disclosure also provides diagnostic methods for assessing a therapeutic response to the methods of treatment.

The invention provides methods for treating various conditions using derivatives of cyclopamine having the following formula:

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