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Petrus, M.

Publications and source records attributed to Petrus, M..

2 recordsLinked to original sources

MedMisBench: Measuring Epistemic Resilience of LLMs Under Misleading Medical Context

Large language models (LLMs) now reach expert-level scores on medical licensing exams, encouraging the assumption that high scores imply safe medical judgment while patients increasingly use them for health advice. We show this assumption is fragile: when misleading context is injected into questions that LLMs originally answer correctly, they abandon the correct answer. We call the ability to maintain correct judgment under adversarial context epistemic resilience, and introduce MedMisBench to measure it. MedMisBench contains 10,932 medical question items and 48,889 misleading context-option pairs spanning medical reasoning, agentic capability, and patient-journey evaluation. Across 11 model configurations, mean accuracy falls from 71.1% on original questions to 38.0% under focused misleading context, with 51.5% attack success. The most damaging injections are formal, rule-like fabrications: authority-framed falsehoods reach 69.5% attack success and exception-poisoning claims reach 64.1%. A 14-member clinical panel from 7 countries identified serious potential harm in 38.2% of reviewed cases. MedMisBench exposes a structural blind spot in LLM evaluation in medical settings: existing benchmarks measure what models know, but not whether they preserve correct medical judgment under misleading context.1

bioengineering↗

Identification of small molecule agonists of fetal hemoglobin expression for the treatment of sickle cell disease

Induction of fetal hemoglobin (HbF) has been shown to be a viable therapeutic approach to treating sickle cell disease and potentially other {beta}-hemoglobinopathies. To identify targets and target-modulating small molecules that enhance HbF expression, we engineered a human umbilical-derived erythroid progenitor reporter cell line (HUDEP2_HBG1_HiBiT) by genetically tagging a HiBiT peptide to the carboxyl (C)-terminus of the endogenous HBG1 gene locus, which codes for {gamma}-globin protein, a component of HbF. Employing this reporter cell line, we performed a chemogenomic screen of approximately 5000 compounds annotated with known targets or mechanisms that have achieved clinical stage or approval by the US Food and Drug Administration (FDA). Among them, 10 compounds were confirmed for their ability to induce HbF in the HUDEP2 cell line. These include several known HbF inducers, such as pomalidomide, lenalidomide, decitabine, idoxuridine, and azacytidine, which validate the translational nature of this screening platform. We identified avadomide, autophinib, triciribine, and R574 as novel HbF inducers from these screens. We orthogonally confirmed HbF induction activities of the top hits in both parental HUDEP2 cells as well as in human primary CD34+ hematopoietic stem and progenitor cells (HSPCs). Further, we demonstrated that pomalidomide and avadomide, but not idoxuridine, induced HbF expression through downregulation of several transcriptional repressors such as BCL11A, ZBTB7A, and IKZF1. These studies demonstrate a robust phenotypic screening workflow that can be applied to large-scale small molecule profiling campaigns for the discovery of targets and pathways, as well as novel therapeutics of sickle cell disease and other {beta}-hemoglobinopathies. Key PointsO_LIEstablished a robust HbF luciferase reporter cell line to monitor endogenous {gamma}-globin expression for a chemogenomic screen of compounds for the treatment of sickle cell disease. C_LIO_LILead hit compounds were mechanistically confirmed for their ability to decrease expression of several transcriptional repressors such as BCL11A, ZBTB7A, and IKZF1. C_LI Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/601536v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@7f86f6org.highwire.dtl.DTLVardef@75b613org.highwire.dtl.DTLVardef@49fc9org.highwire.dtl.DTLVardef@196472e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗