FIX latex errors

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Nathan Dwarshuis 2021-07-25 22:59:33 -04:00
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@ -81,6 +81,9 @@
palindromic repeats} palindromic repeats}
\newacronym{mtt}{MTT}{3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide} \newacronym{mtt}{MTT}{3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide}
\newacronym{bmi}{BMI}{body mass index} \newacronym{bmi}{BMI}{body mass index}
\newacronym{a2b1}{A2B1}{integrin $\upalpha$1$\upbeta$1}
\newacronym{a2b2}{A2B2}{integrin $\upalpha$1$\upbeta$2}
\newacronym{til}{TIL}{tumor infiltrating lymphocytes}
%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%
% SI units for uber nerds % SI units for uber nerds
@ -1403,27 +1406,27 @@ subsets to be included in CAR T cell therapy given a disease state.
% the signaling and why this might matter % the signaling and why this might matter
There are several plausible explanations for the observed phenotypic differences There are several plausible explanations for the observed phenotypic differences
between beads and DMSs. First, the DMSs are composed of a collagen derivative between beads and DMSs. First, the DMSs are composed of a collagen derivative
(gelatin); collagen has been shown to costimulate activated T cells via α1β1 and (gelatin); collagen has been shown to costimulate activated T cells via
α2β1 integrins, leading to enhanced proliferation, increased IFNγ production, \gls{a2b1} and \gls{a2b2}, leading to enhanced proliferation, increased
and upregulated CD25 (IL2Rα) surface expression8,10,11,41,42. Second, there is IFN$\upgamma$ production, and upregulated CD25 (IL2R$\upalpha$) surface
evidence that providing a larger contact area for T cell activation provides expression8,10,11,41,42. Second, there is evidence that providing a larger
greater stimulation16,43; the DMSs have a rougher interface than the 5 µm contact area for T cell activation provides greater stimulation16,43; the DMSs
magnetic beads, and thus could facilitate these larger contact areas. Third, the have a rougher interface than the 5 µm magnetic beads, and thus could facilitate
DMSs may allow the T cells to cluster more densely compared to beads, as these larger contact areas. Third, the DMSs may allow the T cells to cluster
evidenced by the large clusters on the outside of the DMSs (Figure 1f) as well more densely compared to beads, as evidenced by the large clusters on the
as the significant fraction of DMSs found within their interiors (Supplemental outside of the DMSs (Figure 1f) as well as the significant fraction of DMSs
Figure 2a and b). This may alter the local cytokine environment and trigger found within their interiors (Supplemental Figure 2a and b). This may alter the
different signaling pathways. Particularly, IL15 and IL21 are secreted by T local cytokine environment and trigger different signaling pathways.
cells and known to drive memory phenotype4446. We noted that the IL15 and IL21 Particularly, IL15 and IL21 are secreted by T cells and known to drive memory
concentration was higher in a majority of samples when comparing beads and DMSs phenotype4446. We noted that the IL15 and IL21 concentration was higher in a
across multiple timepoints (Supplemental Figure 18) in addition to many other majority of samples when comparing beads and DMSs across multiple timepoints
cytokines. IL15 and IL21 are added exogenously to T cell cultures to enhance (Supplemental Figure 18) in addition to many other cytokines. IL15 and IL21 are
memory frequency,45,47 and our data here suggest that the DMSs are better at added exogenously to T cell cultures to enhance memory frequency,45,47 and our
naturally producing these cytokines and limiting this need. Furthermore, IL15 data here suggest that the DMSs are better at naturally producing these
unique signals in a trans manner in which IL15 is presented on IL15R to cytokines and limiting this need. Furthermore, IL15 unique signals in a trans
neighboring cells48. The higher cell density in the DMS cultures would lead to manner in which IL15 is presented on IL15R to neighboring cells48. The higher
more of these trans interactions, and therefore upregulate the IL15 pathway and cell density in the DMS cultures would lead to more of these trans interactions,
lead to more memory T cells. and therefore upregulate the IL15 pathway and lead to more memory T cells.
% TODO this mentions the DOE which is in the next aim % TODO this mentions the DOE which is in the next aim
When analyzing all our experiments comprehensively using causal inference, we When analyzing all our experiments comprehensively using causal inference, we
@ -1531,15 +1534,15 @@ manufacturing companies.
Finally, while we have demonstrated the DMS system in the context of CAR T Finally, while we have demonstrated the DMS system in the context of CAR T
cells, this method can theoretically be applied to any T cell immunotherapy cells, this method can theoretically be applied to any T cell immunotherapy
which responds to anti-CD3/CD28 mAb and cytokine stimulation. These include which responds to anti-CD3/CD28 mAb and cytokine stimulation. These include
tumor infiltrating lymphocytes (TILs), virus-specific T cells (VSTs), T cells \glspl{til}, virus-specific T cells (VSTs), T cells engineered to express
engineered to express γδTCR (TEGs), γδ T cells, T cells with transduced-TCR, and $\upgamma\updelta$TCR (TEGs), $\upgamma\updelta$ T cells, T cells with
CAR-TCR T cells5358. Similar to CD19-CARs used in liquid tumors, these T cell transduced-TCR, and CAR-TCR T cells5358. Similar to CD19-CARs used in liquid
immunotherapies would similarly benefit from the increased proliferative tumors, these T cell immunotherapies would similarly benefit from the increased
capacity, metabolic fitness, migration, and engraftment potential characteristic proliferative capacity, metabolic fitness, migration, and engraftment potential
of naïve and memory phenotypes5961. Indeed, since these T cell immunotherapies characteristic of naïve and memory phenotypes5961. Indeed, since these T cell
are activated and expanded with either soluble mAbs or bead-immobilized mAbs, immunotherapies are activated and expanded with either soluble mAbs or
our system will likely serve as a drop-in substitution to provide these bead-immobilized mAbs, our system will likely serve as a drop-in substitution to
benefits. provide these benefits.
\chapter{aim 2}\label{aim2} \chapter{aim 2}\label{aim2}