Burke Neurological Institute

University of Vermont and State Agricultural College

Ishraq Alim, I

Rajiv R Ratan

Harry Ostrer

Saravanan Karuppagounder

Johnny C Loke

Robert Hondal

Heritable pathogenic variants in the mismatch repair (MMR) pathway, also known as Lynch Syndrome (LS), can lead to the development of colon cancer and other cancers. Following mismatch, a complex of proteins consisting of MLH1, MSH2, MSH6 and PMS2 translocate into the nucleus to signal recruitment of repair mechanisms. Flow cytometry-based, functional variant assays (FVAs), were developed to determine whether variants in these MMR repair genes and/or other related genes would augment the nuclear translocation of MLH1 and MSH2 and downstream nuclear phosphorylation of ATM and ATR in response to DNA mismatches. Each assay distinguished pathogenic variants in MMR repair genes (MLH1, MSH2, PMS2 and MSH6) from benign controls. The combination of multiple assays provided robust separation between heterozygous pathogenic variant carriers and benign controls. The ability to produce distinct molecular phenotypes by these assays suggest FVA assays of MMR pathways could be used to identify LS and associated risk of colon and other cancers and could act as an adjunct to MMR gene sequencing panels in categorizing variants.

Methods and compositions for diagnosing and treating, germline mismatch repair deficiencies, lynch syndrome and assessing germline risks of cancer

This invention relates to methods of administering compounds containing selenium, selenocysteine, or a selenocysteine peptide to treat, for example, conditions associated with selenium deficiency, or ferroptoptic, parthanototic, and endoplasmic reticulum stress, and/or cancer. The methods of treatment may activate or inhibit (via TFAP2C and Sp1 proteins) the adaptive homeostatic response of the selenome. The compounds may contain a targeting sequence that causes them to be delivered to specific organs and/or tissues. The compounds may be administered, for example, orally, intranasally, intravenously, or by a minimally invasive catheter or BrainPath.

Methods of treatment comprising Selenoprotein P fragment-containing compounds

Selenium-based therapies

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New York, NY, United States of America

Ishraq Alim, I