SULT1A1-dependent sulfonation of alkylators is a lineage-dependent vulnerability of liver cancers.

Adult liver malignancies, including intrahepatic cholangiocarcinoma and hepatocellular carcinoma, are the second leading cause of cancer-related deaths worldwide. Most individuals are treated with either combination chemotherapy or immunotherapy, respectively, without specific biomarkers for selection. Here using high-throughput screens, proteomics and in vitro resistance models, we identify the small molecule YC-1 as selectively active against a defined subset of cell lines derived from both liver cancer types. We demonstrate that selectivity is determined by expression of the liver-resident cytosolic sulfotransferase enzyme SULT1A1, which sulfonates YC-1. Sulfonation stimulates covalent binding of YC-1 to lysine residues in protein targets, enriching for RNA-binding factors. Computational analysis defined a wider group of structurally related SULT1A1-activated small molecules with distinct target profiles, which together constitute an untapped small-molecule class. These studies provide a foundation for preclinical development of these agents and point to the broader potential of exploiting SULT1A1 activity for selective targeting strategies.

Optical couplers and step-index fibers fabricated using FDM 3D printers.

Step-index optical fiber preforms are manufactured and drawn into fibers using low-cost consumer-grade fused deposition modeling (FDM) 3D printers with no other specialist tooling. The fibers are fabricated from polyethylene terephthalate glycol (PETG) cladding with an acrylonitrile buatadiene styrene (ABS) core, resulting in V < 2.4 after drawing. The fibers are measured to have a loss of α ≈ 0.78 dB/cm, which matches previous polymer fibers manufactured using draw towers. The printing of multimode optical couplers with reliable 50:50 split ratios is also demonstrated. This work points toward the fabrication of useful and bespoke optical devices with low-cost 3D printers.

Cofactor Dynamics Couples the Protein Surface to the Heme in Cytochrome c, Facilitating Electron Transfer.

Electron transport through biomolecules and in biological transport networks is of great importance to bioenergetics and biocatalysis. More generally, it is of crucial importance to understand how the pathways that connect buried metallocofactors to other cofactors, and to protein surfaces, affect the biological chemistry of metalloproteins. In terms of electron transfer (ET), the strongest coupling pathways usually comprise covalent and hydrogen bonded networks, with a limited number of through-space contacts. Herein, we set out to determine the relative roles of hydrogen bonds involved in ET via an established heme-to-surface tunneling pathway in cytochrome (cyt) c (i.e., heme-W59-D60-E61-N62). A series of cyt c variants were produced where a ruthenium tris(diimine) photooxidant was placed at position 62 via covalent modification of the N62C residue. Surprisingly, variants where the H-bonding residues W59 and D60 were replaced (i.e., W59F and D60A) showed no change in ET rate from the ferrous heme to Ru(III). In contrast, changing the composition of an alternative tunneling pathway (i.e., heme-M64-N63-C62) with the M64L substitution shows a factor of 2 decrease in the rate of heme-to-Ru ET. This pathway involves a through-space tunneling step between the heme and M64 residue, and such steps are usually disfavored. To rationalize why the heme-M64-N63-C62 is preferred, molecular dynamics (MD) simulations and Pathways analysis were employed. These simulations show that the change in heme-Ru ET rates is attributed to different conformations with compressed donor-acceptor distances, by ∼2 Å in pathway distance, in the M64-containing protein as compared to the M64L protein. The change in distance is correlated with changes in the electronic coupling that are in accord with the experimentally observed heme-Ru ET rates. Remarkably, the M64L variation at the core of the protein translates to changes in cofactor dynamics at the protein surface. The surface changes identified by MD simulations include dynamic anion-π and dipole-dipole interactions. These interactions influence the strength of tunneling pathways and ET rates by facilitating decreases in through-space tunneling distances in key coupling pathways.

Mutant IDH Inhibits IFNγ-TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma.

Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate-dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate-mediated mechanisms: suppression of CD8+ T-cell activity and tumor cell-autonomous inactivation of TET2 DNA demethylase. Pharmacologic mIDH1 inhibition stimulates CD8+ T-cell recruitment and interferon γ (IFNγ) expression and promotes TET2-dependent induction of IFNγ response genes in tumor cells. CD8+ T-cell depletion or tumor cell-specific ablation of TET2 or IFNγ receptor 1 causes treatment resistance. Whereas immune-checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFNγ-TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for potentiating efficacy. SIGNIFICANCE: Mutant IDH1 inhibition stimulates cytotoxic T-cell function and derepression of the DNA demethylating enzyme TET2, which is required for tumor cells to respond to IFNγ. The discovery of mechanisms of treatment efficacy and the identification of synergy by combined CTLA4 blockade provide the foundation for new therapeutic strategies. See related commentary by Zhu and Kwong, p. 604. This article is highlighted in the In This Issue feature, p. 587.

Heterogeneous Aqueous CO2 Reduction Using a Pyrene-Modified Rhenium(I) Diimine Complex.

The development of molecular catalysts and materials that can convert carbon dioxide (CO2) into a value-added product is a great chemical challenge. Molecular catalysts set benchmarks in catalyst investigation and design, but their incorporation into solid-state materials, and optimization of the electrochemical operating conditions, is still needed. For example, rhenium(I) diimine catalysts show almost quantitative selectivity for the conversion of CO2 to carbon monoxide (CO) in acetonitrile (MeCN), but the modification of diimine backbones can be challenging if the goal is to incorporate such molecules into materials. Presented here is a rhenium(I) complex with a 2-(2'-quinolyl)benzimidazole (QuBIm-H) ligand, where N-alkylation with a pyrene derivative allows access to a catalyst that can be adsorbed onto electrodes for aqueous CO2 reduction chemistry. The rhenium(I) catalysts are inactive for homogeneous CO2 reduction in MeCN. However, when adsorbed on edge-plane graphite, the same complexes show good activity for heterogeneous aqueous CO2 reduction, with 90% selectivity for CO. Comparative electrochemical studies between covalent and noncovalent modification of the graphite surfaces were also carried out for related rhenium(I) tricarbonyl complexes.

Binary Silanization and Silver Nanoparticle Encapsulation to Create Superhydrophobic Cotton Fabrics with Antimicrobial Capability.

Cotton fabrics are functionalized with a binary solution of fluorine-free organosilanes and "encapsulated" with silver nanoparticles to achieve both superhydrophobic and antimicrobial properties. Derived from cellulose, cotton is one of the most abundant biologically generated materials and has been used in a wide variety of consumer goods. Nonetheless, cotton fabrics are not waterproof and prone to microbial contamination. Herein we report the rapid functionalization of cotton fabrics with a binary hexane solution of methyltrichlorosilane (MTS) and octadecyltrichlorosilane (OTS) at low concentration (0.17% v/v) followed by coating with colloidal silver nanoparticles (AgNP). The combined effects of binary silanization and AgNP encapsulation produced a surface that has remarkable water contact angle of 153 ± 2° and antimicrobial properties (against gram-negative Escherichia coli). The superior performance of the modified cotton fabrics produced with fluorine-free organosilanes and silver nanoparticles augments the potential of improving the functionality of abundant biopolymers to be waterproof and contamination-resistant.

Fast onset medications through thermally generated aerosols.

Smoking involves heating a drug to form a mixture of drug vapor and gaseous degradation products. These gases subsequently cool and condense into aerosol particles that are inhaled. Here, we demonstrate rapid and reliable systemic delivery of pure pharmaceutical compounds without degradation products through a related process that also involves inhalation of thermally generated aerosol. Drug is coated as a thin film on a metallic substrate and vaporized by heating the metal. The thin nature of the drug coating minimizes the length of time during which the drug is exposed to elevated temperatures, thereby preventing its thermal decomposition. The vaporized, gas-phase drug rapidly condenses and coagulates into micrometer-sized aerosol particles. For the commonly prescribed antimigraine drug rizatriptan, inhalation of these particles results in nearly instantaneous systemic drug action.