Biology subjects

Lerner, M.

Publications and source records attributed to Lerner, M..

3 recordsLinked to original sources

bioRxiv2026

Transcription Factor Subtype Governs Response and Resistance to DLL3-Directed T-Cell Engagement in Small Cell Lung Cancer

Although small cell lung cancer (SCLC) comprises transcription factor (TF)-defined molecular subtypes (ASCL1, NEUROD1, POU2F3), the extent to which these subtypes predict response to clinically effective therapy in patients--and whether therapy can select for subtype switching--remains unknown. The recent approval of the DLL3xCD3 bispecific T-cell engager tarlatamab represents one of the first meaningful advances in relapsed small cell lung cancer (SCLC) in decades, yet responses remain heterogeneous and resistance is inevitable. Here, we inferred SCLC gene expression from circulating chromatin in prospectively collected patient plasma (46 patients; 167 samples), enabling interrogation of response and acquired resistance to tarlatamab. Parallel development of the first immunocompetent syngeneic mouse model to study tarlatamab response and resistance enabled functional validation. Across species, findings converged on a central principle: TF subtype governs both initial response and acquired resistance. Therapeutic response was significantly associated with ASCL1-subtype tumors, whereas NEUROD1-subtype tumors exhibited inferior responses and POU2F3-subtype tumors were uniformly resistant, consistent with DLL3 being a direct ASCL1 transcriptional target and most highly expressed in ASCL1-positive tumors. Strikingly, one mode of acquired resistance revealed therapeutic selection for a NEUROD1-high state with concomitant DLL3 downregulation. Other resistant tumors exhibited enrichment of regulatory and exhausted T-cell programs, highlighting tarlatamabs dual-targeting mechanism of action. Together, these results reveal that tarlatamab exerts selective pressure against ASCL1-driven lineages, facilitating resistance through loss of an antigen intrinsically linked to that state. These findings underscore the clinical relevance of TF-defined molecular subtypes in human SCLC. More broadly, they highlight the power of integrating longitudinal in vivo plasma transcriptional profiling from patient plasma with functional mouse modeling to uncover clinical and biological mechanisms of response and resistance to cell-surface-targeted therapies.

cancer biology↗

bioRxiv2026

Highly under-actuated dynamic manipulation: Dice stacking is mostly open-loop

Humans ability to grasp and dynamically manipulate objects with their hands is unmatched by current robots. To better understand human dynamic manipulation, we studied dice stacking, a task in which humans form a vertical stack of dice from a set of initially unstacked playing dice using an overturned cup and the surface of a table. This task is high dimensional and under-actuated, so it may superficially seem an incredible feat of state estimation and feedback control, but we show that this task is amenable to open-loop strategies. We simulated a cup with dice oscillated by fixed arm movement patterns using two different computer simulation frameworks with different contact models. These simulations showed that, for a range of arm and wrist movements, the dice naturally stack without any dice state feedback. We verified the predictions of these simulations with a physical robot. Thus, we have added dice stacking to the small list of dynamic manipulation tasks that can be robustly performed open-loop. We speculate that, for highly under-actuated tasks, humans may be biased to learn open-loop strategies over state feedback strategies. Future work could investigate the presence of such a bias in humans and its potential value for reinforcement learning algorithms.

animal behavior and cognition↗

bioRxiv2022

Drug-eluting biodegradable metals and metal-ceramic composites: High strength and delayed drug release

Biodegradable metals emerged as promising temporary bone implants. The integration of additional features such as local drug delivery (LDD) can also support their osteointegration, promote bone regeneration, and prevent biomaterial-centered infections that are difficult to treat. LDD is achieved by drug-eluting coatings or porous implants where the drug is impregnated after implant fabrication because the high temperatures used during conventional production processes would result in their thermal decomposition. We produced biodegradable iron (Fe)-based vancomycin (VH)-eluting metals and metal-ceramic composites by a simple high-pressure consolidation/cold sintering (CS) process at room temperature that display high mechanical strength and antibacterial activity. Aiming to expand the application of this production method and shed light into the drug loading and release mechanisms in this type of biomaterials, this work reports on the production and characterization of VH-loaded Fe and Fe-iron oxide (Fe2O3) composites (Fe-Fe2O3). We use focus ion beam milling for the first time to investigate the drug-metal interface and investigate the mechanical and degradation properties of VH-free and VH-loaded Fe and Fe-Fe2O3. Results show very high mechanical strength of drug-eluting Fe and Fe-Fe2O3 composites (up to than 780 MPa under compression, exceeding the maximum strength of cancellous bone more than three times) accompanied by a delayed drug release. Then, we confirm the good antimicrobial activity against Staphylococcus aureus and cell compatibility with the murine embryonic fibroblast cell line NIH/3T3 in vitro. Overall results confirm the promise of drug-eluting metals and metal-ceramic composites for LDD in bone.

bioengineering↗