This work focused on engineering bi-functionalized nanoparticles (NPs) based on carbon dots (CDs) to improve early cancer detection and treatment. Therefore, using folic acid (FA) as a targeting agent, the CDs were prepared to deliver high concentrations (HC) of doxorubicin (DOX) and gemcitabine (GEM) covalently and non-covalently to cancer cells. The prepared FA-CDs-DOX/GEM-HC NPs were characterized using ultraviolet-visible spectroscopy, fluorescence spectroscopy, and Fourier transform infrared spectroscopy. Assessment of the drug loading capacity (DLC) and drug loading efficiency (DLE) indicated that the non-covalent NPs have low DLC but high DLE compared to the relatively low DLE and high DLC of covalent NPs. In vitro drug release studies showed that the DOX/GEM release rate was faster at pH 5.0 in the non-covalent FA-CDs-DOX/GEM-HC NPs than covalent. Also, the non-covalent FA-CDs-DOX-HC NPs showed greater percentage cumulative drug release and lower cell viability in the MDA-MB-231 breast cancer cell line compared to covalent.

Sufficient blood concentrations of folate and the products from its metabolism are necessary for several cellular functions. The C677T MTHFR polymorphism, present in over half of the U.S. population, reduces the efficiency of folate metabolism and has been linked to the onset of multiple psychiatric disorders and cognitive decline. The intracellular parasite Toxoplasma gondii can infect the human brain and is associated with increased prevalence of psychiatric disorders and cognitive decline. In vitro studies have found that Toxoplasma gondii may salvage unmetabolized folate from host cells. Since the C677T MTHFR polymorphism and infection by Toxoplasma gondii both affect folate metabolism or availability, I used data from the third National Health and Nutrition Examination Survey to test the hypothesis that latent toxoplasmosis and the C677T MTHFR polymorphism interact to predict worse cognitive functioning in U.S. adults. I found a statistically significant interaction effect between Toxoplasma gondii infection and the C677T MTHFR polymorphism in predicting performance on a test of reaction time. Subjects who were not infected with Toxoplasma gondii experienced declines in reaction time with the presence of one or two alleles for the C677T MTHFR polymorphism. However, this association was reversed for subjects who were seropositive for Toxoplasma gondii. No interaction effects were observed when predicting performance on a test of processing speed or a test of short term memory. In conclusion, these findings suggest that the co-occurrence of Toxoplasma gondii infection and the C677T MTHFR polymorphism maybe associated with improved reaction time.

Sufficient blood concentrations of folate and the products from its metabolism arenecessary for several cellular functions. The C677T MTHFR polymorphism, present in over halfof the U.S. population, reduces the efficiency of folate metabolism and has been linked to theonset of multiple psychiatric disorders and cognitive decline. The intracellular parasiteToxoplasma gondii can infect the human brain and is associated with increased prevalence ofpsychiatric disorders and cognitive decline. In vitro studies have found that Toxoplasma gondiimay salvage unmetabolized folate from host cells. Since the C677T MTHFR polymorphism andinfection by Toxoplasma gondii both affect folate metabolism or availability, I used data fromthe third National Health and Nutrition Examination Survey to test the hypothesis that latenttoxoplasmosis and the C677T MTHFR polymorphism interact to predict worse cognitivefunctioning in U.S. adults. I found a statistically significant interaction effect betweenToxoplasma gondii infection and the C677T MTHFR polymorphism in predicting performanceon a test of reaction time. Subjects who were not infected with Toxoplasma gondii experienceddeclines in reaction time with the presence of one or two alleles for the C677T MTHFRpolymorphism. However, this association was reversed for subjects who were seropositive forToxoplasma gondii. No interaction effects were observed when predicting performance on a testof processing speed or a test of short term memory. In conclusion, these findings suggest thatthe co-occurrence of Toxoplasma gondii infection and the C677T MTHFR polymorphism maybe associated with improved reaction time.

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<p> Although immune checkpoint inhibitors block one mechanism of regulatory T cell (Treg) immunosuppression, no drug has been designed to inhibit all immunosuppressive activities of Tregs. We describe here a mechanism for manipulating Treg function in a tumor microenvironment without altering their properties in healthy tissues. For this purpose, we first identify a small molecule that binds specifically to Tregs in tumors but not in healthy tissues. We then exploit this binder to deliver an attached imaging agent or an immune activator specifically into tumor-resident Tregs. Analysis of the resulting tumors demonstrates that targeting of a Toll-like receptor 7 agonist to tumor Tregs inhibits their expression of FOXP3, PD-1, CTLA4, and HELIOS, resulting in 40-80% reduction in tumor growth and repolarization of other tumor-infiltrating immune cells to more inflammatory phenotypes. Since Tregs comprise <1% of cells in the tumor masses examined, these data argue that Tregs exert a disproportionately large effect on tumor immunity. The data also demonstrate that the immunosuppressive properties of Tregs can be manipulated without altering their properties in healthy tissues.</p>