Expression of the transcription factor FOXC2 is induced and necessary for successful epithelial-mesenchymal transition, a developmental program that when activated in cancer endows cells with metastatic potential and the properties of stem cells. As such, identifying agents that inhibit the growth of FOXC2-transformed cells represents an attractive approach to inhibit chemotherapy resistance and metastatic dissemination. From a high throughput synthetic lethal screen, we identified a small molecule, FiVe1, which selectively and irreversibly inhibits the growth of mesenchymally transformed breast cancer cells and soft tissue sarcomas of diverse histological subtypes. FiVe1 targets the intermediate filament and mesenchymal marker vimentin (VIM) in a mode which promotes VIM disorganization and phosphorylation during metaphase, ultimately leading to mitotic catastrophe, multinucleation, and the loss of stemness. These findings illustrate a previously undescribed mechanism for interrupting faithful mitotic progression and may ultimately inform the design of therapies for a broad range of mesenchymal cancers.vimentin | epithelial-to-mesenchymal transition | cancer stem cell | mitosis | drug discovery F or many tumor types, resistance to conventional chemotherapy and subsequent tumor relapse have been attributed to the presence of a slower cycling, drug-resistant population of cells termed cancer stem cells (CSCs) or tumor initiating cells. We and others have demonstrated that activation of a latent embryonic program, called the epithelial-mesenchymal transition (EMT), endows epithelial-derived cancer cells with the properties of stem cells as well as migratory and metastatic potential (1). Cells undergoing EMT exhibit the loss of epithelial cell-cell contacts (e.g., E-cadherin), the induction of matrix degrading proteases (e.g., matrix metalloproteinases), and the acquisition of motility-inducing intermediate filaments [e.g., vimentin (VIM)], features which promote metastatic progression by allowing dissemination from the local tumor niche (2). A number of transcription factors (e.g., Snail, Twist, ZEB1) and microenvironment-derived extracellular signaling molecules (e.g., TGF-β1) are capable of inducing the EMT transcriptional program. Among these factors, we have demonstrated that the transcription factor Forkhead Box C2 (FOXC2) is a central regulator of EMT in breast cancer (3, 4). FOXC2 expression is both up-regulated and required for the induction of CSC properties by the classical EMT-inducing factors Twist, Snail, and TGF-β1 (4

The fleeting lifetimes of the transition states (TSs) of chemical reactions make determination of their three-dimensional structures by diffraction methods a challenge. Herein we use packing interactions within the core of a protein to stabilize the planar TS for rotation around the central C-C bond of biphenyl so that it can be directly observed by x-ray crystallography. The computational protein design software Rosetta was used to design a pocket within threonyl-transfer RNA synthetase from the thermophile Pyrococcus abyssi that forms complementary van der Waals interactions with a planar biphenyl. This latter moiety was introduced biosynthetically as the side chain of the noncanonical amino acid p-biphenylalanine. Through iterative rounds of computational design and structural analysis we identified a protein in which the side chain of p-biphenylalanine is kinetically trapped in the energetically disfavored, coplanar conformation of the TS of the bond rotation reaction.

SIGNIFICANCEPDE4 inhibitors are clinically validated molecules with considerable efficacy but relatively low safety profile in treating chronic inflammatory diseases. Therefore, the potential expansion of clinical indications of these molecules is relatively unexplored.Bringing to bear medicinal chemistry and bio-conjugation methods, we generated αhuCD11a-PDE4 and its mouse equivalent αmuCD11a-PDE4, which target the pan-immune cell surface antigen CD11a and demonstrated potent in vitro suppression of inflammation that is explicitly receptor-dependent. Pharmacokinetic and pharmacodynamic analysis of αmuCD11a in vivo revealed translation of these effects. With antibody-based therapies becoming a mainstay in the treatment of inflammation, this study provides critical validation for a new paradigm which could lead to second generation PDE4 inhibitors with an improved safety and efficacy.

No abstract

Background and Objectives: About 30% of patients with acute kidney injury (AKI) may require ongoing dialysis in the outpatient setting after hospital discharge. A 2017 CMS policy change allows Medicare beneficiaries with AKI requiring dialysis to receive outpatient treatment in dialysis facilities. Outcomes for these patients have not been reported. We compare patient characteristics and mortality among AKI dialysis patients and non-AKI incident dialysis patients. Design, setting, participants, and measurements: Retrospective cohort design, using 2017 Medicare Claims to follow outpatient AKI dialysis patients and non-AKI incident dialysis patients up to 365 days. Outcomes are unadjusted and adjusted mortality using Kaplan-Meier estimation for unadjusted survival probability, Poisson regression for monthly mortality, and Cox proportional hazards modeling for adjusted mortality. Results: 10,821 of 401,973 (3%) Medicare dialysis patients had at least one AKI claim, and 52,626 patients were Medicare non-AKI incident dialysis patients. AKI dialysis patients were more likely to be White (76% vs 70%), non-Hispanic (92% vs 87%), and age 60 or greater (82% vs 72%) compared to non-AKI incident dialysis patients. Unadjusted mortality was markedly higher for AKI dialysis patients compared to non-AKI incident dialysis patients. Adjusted mortality differences between both cohorts persisted through month 4 of the follow-up period (all P<0.01) then declined and were no longer statistically significant. Adjusted monthly mortality stratified by Black and other race between AKI dialysis patients vs non-AKI incident dialysis patients was lower throughout month 4 (1.5 v .60, 1.20 v 0.84, 1.00 v 0.80, 0.95 v 0.74, all P<0.001 which persisted through month 7. Overall adjusted mortality risk was 22% higher for AKI dialysis patients (1.22, CI 1.17, 1.27). Conclusions: In fully adjusted analyses AKI dialysis patients had higher early mortality compared to non-AKI incident dialysis patients, but these differences declined after several months. Differences were also observed by age, race and ethnicity within both patient cohorts.