Light-Controllable Binary Switch Activation of CAR T Cells

Major challenges to chimeric antigen receptor (CAR) T cell therapies include uncontrolled immune activity, off-tumor toxicities and tumor heterogeneity. To overcome these challenges, we engineered CARs directed against small molecules. By conjugating the same small molecule to distinct tumor-targeting antibodies, we show that small molecule specific-CAR T cells can be redirected to different tumor antigens. Such binary switches allow control over the degree of CAR T cell activity and enables simultaneous targeting of multiple tumor-associated antigens. We also demonstrate that ultraviolet light-sensitive caging of small molecules blocks CAR T cell activation. Exposure to ultraviolet light, uncaged small molecules and restored CAR T cell-mediated killing. Together, our data demonstrate that a light-sensitive caging system enables an additional level of control over tumor cell killing, which could improve the therapeutic index of CAR T cell therapies.     

Photoinduced Synthesis of P‐Perfluoroalkylated Phosphines from Triarylphosphines and Their Application in the Copper‐Free Cross‐Coupling of Acid Chlorides and Terminal Alkynes

A practical synthesis yielding P‐perfluoroalkylated phosphines from triarylphosphines and perfluoroalkyl iodides has been developed. The photoinduced reaction involves the substitution of aryl groups on the phosphorus atom with perfluoroalkyl groups to successfully afford P‐perfluoroalkylated phosphines. In addition, the P‐perfluoroalkylated phosphines were found to promote the Cu‐free cross‐coupling reaction of acid chlorides with terminal alkynes.

     

Iodine Excess as an Environmental Risk Factor for Autoimmune Thyroid Disease

The global effort to prevent iodine deficiency disorders through iodine supplementation, such as universal salt iodization, has achieved impressive progress during the last few decades. However, iodine excess, due to extensive environmental iodine exposure in addition to poor monitoring, is currently a more frequent occurrence than iodine deficiency. Iodine excess is a precipitating environmental factor in the development of autoimmune thyroid disease. Excessive amounts of iodide have been linked to the development of autoimmune thyroiditis in humans and animals, while intrathyroidal depletion of iodine prevents disease in animal strains susceptible to severe thyroiditis. Although the mechanisms by which iodide induces thyroiditis are still unclear, several mechanisms have been proposed: (1) excess iodine induces the production of cytokines and chemokines that can recruit immunocompetent cells to the thyroid; (2) processing excess iodine in thyroid epithelial cells may result in elevated levels of oxidative stress, leading to harmful lipid oxidation and thyroid tissue injuries; and (3) iodine incorporation in the protein chain of thyroglobulin may augment the antigenicity of this molecule. This review will summarize the current knowledge regarding excess iodide as an environmental toxicant and relate it to the development of autoimmune thyroid disease.     

Discovery of Protein Disulfide Isomerase P5 Inhibitors that Reduce the Secretion of MICA from Cancer Cells

In order to regulate the activity of P5, which is a member of the protein disulfide isomerase family, we screened a chemical compound library for P5‐specific inhibitors, and identified two candidate compounds (anacardic acid and NSC74859). Interestingly, anacardic acid inhibited the reductase activity of P5, but did not inhibit the activity of protein disulfide isomerase (PDI), thiol‐disulfide oxidoreductase ERp57, or thioredoxin. NSC74859 inhibited all these enzymes. When we examined the effects of these compounds on the secretion of soluble major histocompatibility complex class‐I‐related gene A (MICA) from cancer cells, anacardic acid was found to decrease secretion. In addition, anacardic acid was found to reduce the concentration of glutathione up‐regulated by the anticancer drug 17‐demethoxygeldanamycin in cancer cells. These results suggest that anacardic acid can both inhibit P5 reductase activity and decrease the secretion of soluble MICA from cancer cells. It might be a novel and potent anticancer treatment by targeting P5 on the surface of cancer cells.     

SPR imaging of photo-cross-linked small-molecule arrays on gold

Identification of small-molecule ligands for a protein of interest can facilitate the analysis of the protein's functions in biological systems. Small-molecule microarrays have allowed for rapid detection of such ligand-protein interactions in a high-throughput manner, although a label on a protein is needed to observe these interactions. By combining SPR imaging technology with our recently developed photo-cross-linked small-molecule array platform, we developed a novel platform that allows in situ observation of interactions between photo-cross-linked small molecules on gold surfaces and nonlabeled proteins in solution. Interactions of estrogenic and androgenic substances with estrogen receptor alpha were observed using this platform.     

Analysis and evaluation of the ionic interaction of the novel soft contact lenses using the zwitterionic polymer gel

In the zwitterionic polymer gel which has cationic and anionic groups inside, it forms a complex to producing stability by adding thermal energy. We reported the behavior induced by the ionic interaction of them and the impact that a nonionic surfactant could exert on the complex formation. We had heating experiments of the zwitterionic polymer gel in PBS with a nonionic surfactant added. We analyzed DSC and measured the diameter, stress and flexure of heated the gel. As the result, it has been demonstrated that formation of strong ionic interactions inside the gel can be achieved by heating them in a solution containing the nonionic surfactant. It has been also demonstrated that the ratio of bound water is increased within the gel, promising an enhanced strength. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Protease susceptibility of beta-lactoglobulin adsorbed on stainless steel surface as evidence of contribution of its specific segment to adsorption

beta-Lactoglobulin (beta-Lg) is a major constituent of fouling deposits in the dairy industry. To determine the interaction between beta-Lg and stainless steel surfaces, beta-Lg irreversibly adsorbed on stainless steel particles was subjected to lysyl endopeptidase treatment and the course of fragmentation was compared with that observed for beta-Lg in solution. The results showed a distinct difference between the courses of fragmentation: a fragment (residues 102-135) was liberated readily from beta-Lg in solution but scarcely from beta-Lg irreversibly adsorbed on stainless steel particles. This result strongly suggests that residues 102-135 include a segment primarily responsible for the interaction of beta-Lg with stainless steel surfaces. This supports our previous results [Sakiyama et al., J. Biosci. Bioeng., 88, 536-541 (1999)] that showed that residues 125-135 of beta-Lg have a strong affinity toward stainless steel surfaces and probably a major contribution to the adsorption of beta-Lg.     

A Fuzzy AHP Approach to Evaluating Machine Tool Alternatives

Selecting process of a machine tool has been very important issue for companies for years, because the improper selection of a machine tool might cause of many problems affecting negatively on productivity, precision, flexibility and company’s responsive manufacturing capabilities. On the other hand, selecting the best machine tool from its increasing number of existing alternatives in market are multiple-criteria decision making (MCDM) problem in the presence of many quantitative and qualitative attributes. Therefore, in this paper, an analytic hierarchy process (AHP) is used for machine tool selection problem due to the fact that it has been widely used in evaluating various kinds of MCDM problems in both academic researches and practices. However, due to the vagueness and uncertainty on judgments of the decision-maker(s), the crisp pair wise comparison in the conventional AHP seems to insufficient and imprecise to capture the right judgments of decision-maker(s). That is why; fuzzy number logic is introduced in the pair wise comparison of AHP to make up for this deficiency in the conventional AHP. Shortly, in this study, an intelligent approach is proposed, where both techniques; fuzzy logic and AHP are come together, referred to as fuzzy AHP. First, the fuzzy AHP technique is used to weight the alternatives under multiple attributes; second Benefit/Cost (B/C) ratio analysis is carried out by using both the fuzzy AHP score and procurement cost, of each alternative. The alternative with highest B/C ratio is found out and called as the ultimate machine tool among others. In addition, a case study is also presented to make this approach more understandable for a decision-maker(s).     

In Situ Time-Resolved XAFS of Transitional States of Pt/C Cathode Electrocatalyst in an MEA During PEFC Loading with Transient Voltages

The transitional states of a Pt/C cathode electrocatalyst in the membrane electrode assembly of a polymer electrolyte fuel cell during loading with transient voltages were systematically analyzed by in situ time-resolved X-ray absorption fine structure with time resolution of 100 ms. The results suggest that the local coordination of the Pt cathode electrocatalyst was unaffected by the transient voltages during both rapid and gradual loading over 0–30 s.