Charles Schutt

Washington University in St. Louis | WUSTL , Wash U · Division of Oncology

Head and neck cell squamous-cell carcinomas (HNSCC) are a group of common cancers typically associated with tobacco use and human papilloma virus infection. Up to half of all cases will suffer a recurrence after primary treatment. As such, new therapies are needed, including therapies which promote the anti-tumor immune response. Prior work has cha...

Osteosarcoma is the most common pediatric and adult primary malignant bone cancer. Curative regimens target the folate pathway, downstream of serine metabolism, with high-dose methotrexate. Here, the rate-limiting enzyme in the biosynthesis of serine from glucose, 3-phosphoglycerate dehydrogenase (PHGDH), is examined, and an inverse correlation bet...

Background Many cancers silence the metabolic enzyme argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme for arginine biosynthesis within the urea cycle. Consequently, ASS1-negative cells are susceptible to depletion of extracellular arginine by PEGylated arginine deiminase (ADI-PEG20), an agent currently being developed in clinical tri...

At the forefront of cancer research is the rapidly evolving understanding of metabolic reprogramming within cancer cells. The expeditious adaptation to metabolic inhibition allows cells to evolve and acquire resistance to targeted treatments, which makes therapeutic exploitation complex but achievable. 3-phosphoglycerate dehydrogenase (PHGDH) is th...

Background: Administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) increases regulatory T cell (Treg) number and function with control of neuroinflammation and neuronal protection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease (PD). Recently, we demonstrated in an early phase 1 clinical...

Although patterns of neuronal degeneration are unique in PD and ALS, both disorders share common pathways and processes that support and possibly initiate neurodegeneration. Most of these processes are associated with induction, propagation, or consequences of neuroinflammation. Increased numbers of microglia that express reactive phenotypes and pr...

A potential therapeutic role for immune transformation in Parkinson’s disease evolves from more than a decade of animal investigations demonstrating regulatory T cell (Treg) nigrostriatal neuroprotection. To bridge these results to human disease, we conducted a randomized, placebo-controlled double-blind phase 1 trial with a well-studied immune mod...

Neuroprotective immunity is defined by transformation of T-cell polarity for therapeutic gain. For neurodegenerative disorders and specifically for Parkinson's disease (PD), granulocyte-macrophage colony stimulating factor or vasoactive intestinal peptide receptor 2 (VIPR2) agonists elicit robust anti-inflammatory microglial responses leading to ne...

Progressive nigrostriatal degeneration and neuroinflammation underlie the pathobiology of Parkinson’s disease (PD). Biomarkers to detect such pathogenic events remain in development. We report that manganese-enhanced magnetic resonance imaging (MEMRI) can be used to assess inflammatory activities related to deficits in neural connectivity in an exp...

Prions are transmissible agents that comprised of a misfolded protein PrPSc that is posttranslationally derived from the normal isoform PrPC. Prion strains are operationally defined by differences in the distribution and intensity of spongiform degeneration and distribution of PrPSc in the CNS. The mechanism by which prion strains are encoded is no...

PrPSc conformational stability assays for multiple hamster-adapted prion strains. A) Brain homogenate from prion-infected hamsters were subject to incubation with increasing concentrations of either SDS or Gdn-HCl, digested with PK and the remaining PrPSc was detected using a 96-well immunoassay. The corresponding [SDS]1/2 and [Gdn-HCl]1/2 values w...

Specificity of anti-PrP antibodies for PrPSc immunodetection in the CNS of hamsters. PrPSc immunohistochemistry was performed on sections of red nucleus of a mock-inoculated animal using the anti-PrP antibodies (A) 8b4, (B) BE12, (C) POM 3, (D) 3F4, (E) 6H4, and (F) POM19 whose epitopes span from the N-terminal to C-terminal of PrP (Table 2). Scale...

Intrasomal deposition of PrPSc in neurons is a property of short incubation period strains in hamsters. PrPSc immunohistochemistry was performed on CNS tissue of hamsters at the clinical stage of disease following infection with either the 263K (A–F), HaCWD (G–L), 22AH (M–R), 22CH (S–X), 139H (Y–DD), or ME7H (EE–JJ) agents using the anti-PrP antibo...

Specificity of immunolabeling and criteria of immunolabel co-localization. PrPSc immunofluorescence was performed on the reticular formation of a negative control mock-inoculated animal using the anti-PrP antibodies (A) 8b4, (B) BE12, (C) POM 3, (D) 3F4, (E) 6H4, or (F) POM19 and antibodies directed against (G) GFAP or (H) Iba-1. Non-specific bindi...

PMCA replication efficiency of hamster adapted prion strains. Western blot analysis of PrPSc following one round of PMCA that was performed on 10 fold serial dilutions of brain homogenate from hamster infected with either the (A) 263K, (B) HaCWD, (C) 22AH, (D) 22CH, (E) 139H, or (F) ME7H agents. A mock infected negative control was included in ever...

Semi-quantification of PrPSc deposition in neurons and glia from hamsters infected with 8 different prion strains using a panel of anti-PrP antibodies. (0.09 MB DOC)

Similar N-terminal truncation of PrPSc in astrocytes of hamster-adapted strains. Dual fluorescence PrPSc/GFAP immunohistochemistry was performed on CNS tissue of hamsters at the clinical stage of disease following infection with either the 263K (A–F), HaCWD (G–L), 22AH (M–R), 22CH (S–X), 139H (Y–DD), or ME7H (EE–JJ) agents using the anti-PrP antibo...

Processing of PrPSc in microglia is not strain specific. Dual fluorescence PrPSc/IbA-1 immunohistochemistry was performed on CNS tissue of hamsters at the clinical stage of disease infected with either the 263K (A–F), HaCWD (G–L), 22AH (M–R), 22CH (S–X), 139H (Y–DD), or ME7H (EE–JJ) agents using the anti-PrP antibodies 8B4 (A, G, M, S, Y, EE), BE12...

Prion strains are characterized by differences in the outcome of disease, most notably incubation period and neuropathological features. While it is established that the disease specific isoform of the prion protein, PrP(Sc), is an essential component of the infectious agent, the strain-specific relationship between PrP(Sc) properties and the biolo...

Prion strain interference can influence the emergence of a dominant strain from a mixture; however, the mechanisms underlying prion strain interference are poorly understood. In our model of strain interference, inoculation of the sciatic nerve with the drowsy (DY) strain of the transmissible mink encephalopathy (TME) agent prior to superinfection...

Co-inoculation of prion strains into the same host can result in interference, where replication of one strain hinders the ability of another strain to cause disease. The drowsy (DY) strain of hamster-adapted transmissible mink encephalopathy (TME) extends the incubation period or completely blocks the hyper (HY) strain of TME following intracerebr...