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This technology includes a method for creating functional, brain region-specific neural spheroids that can be used for disease modeling and therapeutic testing of compounds for neurological diseases. The developed protocol uses somatic cells, including iPSC-derived neurons, as well as astrocytes using means such as 96- or 384-well ultra-low attachment round-bottom plates. Spheroids have been generated using this method that model brain regions such as the ventral tegmental area and prefrontal cortex, which are implicated in Parkinson’s and Alzheimer’s disease.

This technology includes the use of autophagy upregulators such as ML246/metarrestin to counteract the tolerance that can build up through the therapeutic use of cannabinoids. Long-term administration of cannabinoids rapidly introduces tolerance and physical dependence, limiting its medical use and may lead to addiction and withdrawal symptoms. Cannabinoids mediate their effect by binding to and activating the cannabinoid receptor 1 (CNR1/CB1). Chronic exposure leads to CNR1 being targeted for degradation through a process of autophagy.

This technology includes the identification and use of small molecules to rescue cells undergoing ferroptosis, a type of programmed cell death. These small molecules can be used as treatments in situations where epithelial cells are being damaged, including respiratory disorders, brain injury (including traumatic brain injury), renal injury, radiation-induced injury, and neurodegenerative disorders. Ferroptosis is a type of programmed cell death that is triggered by an increased presence of oxidants.

This technology includes the combination therapy of tyrosine kinase inhibitors (TKIs) and tigecycline as a potential new treatment for acute myeloid leukemia (AML). The existing treatments available for AML are not adequate; for patients older than 60, the prognosis is poor, with a two-year survival probability of less than 10%. Tigecycline is a glycylcycline antibiotic that induces cell death via inhibition of mitochondrial protein synthesis.

The present invention is directed to a synthesis of a dual-target inhibitor of cannabinoid-1 (CB1R) receptor and inducible nitric oxide synthase, and more specifically, to an improved process for synthesis of (S,1E,NE)-N-(1-aminoethylidene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide.

This technology includes processes for the synthesis of VBP15 (17a,21-dihydroxy-16a-methyl-pregna-1,4,9(11)-triene-3,20-dione) of high purity and large quantities as a treatment for Duchenne muscular dystrophy. The synthesis of VBP15 has several deficiencies which has hindered larger-scale preparation for clinical evaluation and potential manufacturing. The deficiencies included formation of significant levels of undesired epoxide impurity, formation of undesired ketone impurity, and resultant need for costly chromatographic purification.

This technology includes the use of the Anneal-Pool-Ligate-Sequence method (APLS) to quantify the cellular expression of dozens of genes for high throughput chemical library screening. This method is performed by culturing eucaryotic cells in 384-well format microplates, treating the cells with a library of chemicals, and producing cell lysates. Oligodeoxynucleotide (oligo) pairs representing (21) selected genes, and carrying index sequences for each well (384) and microplate (26), are annealed to mRNAs in cell lysates.

This technology includes a group of 20 drugs that can be further developed as a treatment for chordoma. Chordoma is a rare, slow-growing malignant tumor arising from remnants of the fetal notochord, with a high recurrence rate and no effective chemotherapy agents. These 20 drugs inhibited chordoma cell growth, with potencies ranging from 10 to 370 nM in the chordoma cell line UCH1 cells. These agents also had significant inhibitory effects on chordoma patient cells, C24, C25, and C32.

This technology includes the compositions and methods for inhibiting PIN1 for the treatment of disorders characterized by elevated PIN1 levels (e.g., immune disorders, proliferative disorders, and neurodegenerative disorders) with small molecules. Pin1 dysregulation has been associated with a number of pathological conditions. In particular, PIN1 has been shown to promote oncogenesis by modulating several oncogenic signaling pathways and its overexpression has been shown to correlate with poor clinical outcome.

Monoclonal antibodies (mAbs) have become a mainstay of therapy for many cancers. However, antibody therapy is not completely effective in some applications due to loss of the target surface antigen on cancer cells. Such mAb-induced “escape variants” are no longer sensitive to the therapeutic mAb therapy. It was observed that the escape variants carried covalently bound complement activation fragments, especially C3d. NIH inventors have generated several C3d-specific mouse and rabbit monoclonal antibodies to re-target cells that have escaped from mAb therapy.