Search for: All records

Inhibition of overexpressed enzymes is among the most promising approaches for targeted cancer treatment. However, many cancer-expressed enzymes are “nonlethal,” in that the inhibition of the enzymes’ activity is insufficient to kill cancer cells. Conventional antibody-based therapeutics can mediate efficient treatment by targeting extracellular nonlethal targets but can hardly target intracellular enzymes. Herein, we report a cancer targeting and treatment strategy to utilize intracellular nonlethal enzymes through a combination of selective cancer stem-like cell (CSC) labeling and Click chemistry-mediated drug delivery. A de novo designed compound, AAMCHO [N-(3,4,6-triacetyl- N-azidoacetylmannosamine)-cis-2-ethyl-3-formylacrylamideglycoside], selectively labeled cancer CSCs in vitro and in vivo through enzymatic oxidation by intracellular aldehyde dehydrogenase 1A1. Notably, azide labeling is more efficient in identifying tumorigenic cell populations than endogenous markers such as CD44. A dibenzocyclooctyne (DBCO)-toxin conjugate, DBCO-MMAE (Monomethylauristatin E), could next target the labeled CSCs in vivo via bioorthogonal Click reaction to achieve excellent anticancer efficacy against a series of tumor models, including orthotopic xenograft, drug-resistant tumor, and lung metastasis with low toxicity. A 5/7 complete remission was observed after single-cycle treatment of an advanced triple-negative breast cancer xenograft (~500 mm³). 

Categorical judgments can systematically bias the perceptual interpretation of stimulus features. However, it remained unclear whether categorical judgments directly modify working memory representations or, alternatively, generate these biases via an inference process down-stream from working memory. To address this question we ran two novel psychophysical experiments in which human subjects had to reverse their categorical judgments about a stimulus feature, if incorrect, before providing an estimate of the feature. If categorical judgments indeed directly altered sensory representations in working memory, subjects’ estimates should reflect some aspects of their initial (incorrect) categorical judgment in those trials. We found no traces of the initial categorical judgment. Rather, subjects seemed to be able to flexibly switch their categorical judgment if needed and use the correct corresponding categorical prior to properly perform feature inference. A cross-validated model comparison also revealed that feedback may lead to selective memory recall such that only memory samples that are consistent with the categorical judgment are accepted for the inference process. Our results suggest that categorical judgments do not modify sensory information in working memory but rather act as top-down expectations in the subsequent sensory recall and inference process. 

Making a categorical judgment can systematically bias our subsequent perception of the world. We show that these biases are well explained by a self-consistent Bayesian observer whose perceptual inference process is causally conditioned on the preceding choice. We quantitatively validated the model and its key assumptions with a targeted set of three psychophysical experiments, focusing on a task sequence where subjects first had to make a categorical orientation judgment before estimating the actual orientation of a visual stimulus. Subjects exhibited a high degree of consistency between categorical judgment and estimate, which is difficult to reconcile with alternative models in the face of late, memory related noise. The observed bias patterns resemble the well-known changes in subjective preferences associated with cognitive dissonance, which suggests that the brain’s inference processes may be governed by a universal self-consistency constraint that avoids entertaining ‘dissonant’ interpretations of the evidence.