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Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)–ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR–Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR–Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53 . Abrogation of CLCF1 through eCNTFR–Fc appears most effective in tumors driven by oncogenic KRAS . We observed a correlation between the effectiveness of eCNTFR–Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate, suggesting that the mechanism of action may be related to altered guanosine triphosphate loading. Overall, we nominate blockade of CLCF1–CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment. A first-in-class engineered receptor decoy that neutralizes CLCF1–CNTFR signaling exhibits antitumor activity in preclinical models of lung adenocarcinoma driven by some mutant KRAS variants and other oncogenic genotypes.

Development of cancer therapeutics requires a thorough evaluation of drug efficacy in vitro before animal testing and subsequent clinical trials. Three‐dimensional (3‐D) in vitro models have therefore been investigated for drug screening. In this study, we have developed a novel in vitro model in which multicellular aggregates, or spheroids, were incorporated into 3‐D porous scaffolds. Drug resistance assays showed that spheroid‐seeded scaffolds have much higher drug resistance than monolayer cultures, spheroids on flat substrates, or scaffolds seeded with dispersed cells. Furthermore, spheroid‐seeded scaffolds demonstrated higher lactate production leading to acidosis, and higher expression of angiogenic factors. These data suggest that the spheroid‐seeded 3‐D scaffolds might serve as a useful in vitro system for screening cancer therapeutics. (Cancer Sci 2010; 101: 2637–2643)

Interleukin-6 (IL-6) family cytokines signal through multimeric receptor complexes, providing unique opportunities to create novel ligand-based therapeutics. The cardiotrophin-like cytokine factor 1 (CLCF1) ligand has been shown to play a role in cancer, osteoporosis, and atherosclerosis. Once bound to ciliary neurotrophic factor receptor (CNTFR), CLCF1 mediates interactions to coreceptors glycoprotein 130 (gp130) and leukemia inhibitory factor receptor (LIFR). By increasing CNTFR-mediated binding to these coreceptors we generated a receptor superagonist which surpassed the potency of natural CNTFR ligands in neuronal signaling. Through additional mutations,we generated a receptor antagonist with increased binding to CNTFR but lack of binding to the coreceptors that inhibited tumor progression in murine xenograft models of nonsmall cell lung cancer. These studies further validate the CLCF1–CNTFR signaling axis as a therapeutic target and highlight an approach of engineering cytokine activity through a small number of mutations.

Optimizing enzymes to function in novel chemical environments is a central goal of synthetic biology, but optimization is often hindered by a rugged, expansive protein search space and costly experiments. In this work, we present TeleProt, an ML framework that blends evolutionary and experimental data to design diverse protein variant libraries, and employ it to improve the catalytic activity of a nuclease enzyme that degrades biofilms that accumulate on chronic wounds. After multiple rounds of high-throughput experiments using both TeleProt and standard directed evolution (DE) approaches in parallel, we find that our approach found a significantly better top-performing enzyme variant than DE, had a better hit rate at finding diverse, high-activity variants, and was even able to design a high-performance initial library using no prior experimental data. We have released a dataset of 55K nuclease variants, one of the most extensive genotype-phenotype enzyme activity landscapes to date, to drive further progress in ML-guided design.

Pro-inflammatory cytokines in the tumor microenvironment (TME) can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the CLCF1-CNTFR signaling axis in lung adenocarcinoma (LUAD) and generated a high affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and an autochthonous, highly aggressive genetically-engineered mouse model (GEMM) of LUAD driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. We observed a correlation between effectiveness of eCNTFR-Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze GTP, suggesting that the mechanism of action may be related to altered GTP loading. Overall, we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the TME.

A porcine skin model was developed to characterize the dose-dependent response to high-dose radiation. The dorsal skin of a mini pig was divided into four paraspinal sections, with 11 small irradiation fields (2 cm × 2 cm) in each section, and a single fraction of 15, 30, 50 or 75 Gy was delivered to each section using a 6 MeV electron beam. A spectrophotometer measured gross skin changes, and a biopsy for each radiation dose was performed in the 1st, 2nd, 4th, 6th and 9th weeks for histology, immunostaining with anti-CD31, and western blotting with IL-6 and TGF-β1 to determine the degree of skin damage. After a 4-week latency period, erythema and dry desquamation, moist desquamation, and ulceration appeared at 4, 6 and 9 weeks, respectively. Gross skin toxicity was more pronounced, occurred early and continued to progress with irradiation >50 Gy, whereas complete healing was observed 12 weeks after 15 Gy. Spectrophotometry showed erythema indices rapidly increased during the first 4 weeks after irradiation. The number of eosinophils began rising sharply at 4 weeks and normalized after reaching peaks at 7–8 weeks. Microvessel density showed a biphasic pattern with a transient peak at 1 week, a nadir at 4–6 weeks, and maximum recovery at 9 weeks. Increase in the levels of IL-6 and TGF-β1 was detected soon after irradiation. Most of these parameters indicated complete healing of the skin 12 weeks after 15 Gy. Our porcine skin model provides an effective platform for studying high-dose radiation-induced skin injury, in particular histologic and molecular changes, during the early latency period.

The interaction between tumor and the immune system is still poorly understood. Significant clinical responses have been achieved in cancer patients treated with antibodies against the CTLA4 and PD-1/PD-L1 checkpoints; however, only a small portion of patients responded to the therapies, indicating a need to explore additional co-inhibitory molecules for cancer treatment. B7-H3, a member of the B7 superfamily, was previously shown by us to inhibit T-cell activation and autoimmunity. In this study, we have analyzed the function of BT-H3 in tumor immunity. Expression of B7-H3 was found in multiple tumor lines, tumor-infiltrating dendritic cells, and macrophages. B7-H3-deficient mice or mice treated with an antagonistic antibody to B7-H3 showed reduced growth of multiple tumors, which depended on NK and CD8^＋ T cells. With a putative receptor expressed by cytotoxic lymphocytes, B7-H3 inhibited their activation, and its deficiency resulted in increased cytotoxic lymphocyte function in tumor-bearing mice. Combining blockades of B7-H3 and PD-1 resulted in further enhanced therapeutic control of late-stage tumors. Taken together, our results indicate that the B7-H3 checkpoint may serve as a novel target for immunotherapy against cancer.

We present Ask WhAI, a systems-level framework for inspecting and perturbing belief states in multi-agent interactions. The framework records and replays agent interactions, supports out-of-band queries into each agent's beliefs and rationale, and enables counterfactual evidence injection to test how belief structures respond to new information. We apply the framework to a medical case simulator notable for its multi-agent shared memory (a time-stamped electronic medical record, or EMR) and an oracle agent (the LabAgent) that holds ground truth lab results revealed only when explicitly queried. We stress-test the system on a multi-specialty diagnostic journey for a child with an abrupt-onset neuropsychiatric presentation. Large language model agents, each primed with strong role-specific priors (\"act like a neurologist\", \"act like an infectious disease specialist\"), write to a shared medical record and interact with a moderator across sequential or parallel encounters. Breakpoints at key diagnostic moments enable pre- and post-event belief queries, allowing us to distinguish entrenched priors from reasoning or evidence-integration effects. The simulation reveals that agent beliefs often mirror real-world disciplinary stances, including overreliance on canonical studies and resistance to counterevidence, and that these beliefs can be traced and interrogated in ways not possible with human experts. By making such dynamics visible and testable, Ask WhAI offers a reproducible way to study belief formation and epistemic silos in multi-agent scientific reasoning.

Vitronectin is a prominent constituent of the extracelluar matrix (ECM) that plays a key role in inflammation by regulating cell adhesion, migration, and complement activation. Together with other inflammatory biomarkers, lipids, and hydroxyapatite, an ECM component, vitronectin, accumulates in abnormal deposits and drusen associated with age-related macular degeneration (AMD). Using an engineered polypeptide (VnHX) containing the hexmopexin-like domain (HX) of vitronectin, we found that the HX domain directly promotes hydroxyapatite (HAP) accumulation. Next, we screened humanized single-chain variable fragments (scFvs) against vitronectin that inhibit the interaction between VnHX and HAP, leveraging the binding of VnHX to HAP. We then tested these scFvs for their ability to block Vn-containg deposits secreted by stem cell-derived retinal pigment epithelium (RPE). In this in vitro drusen model, treatment with the anti-vitronectin antibodies decreased vitronectin accumulation. Furthermore, the antibody treatment led to decreased accumulation of C5b-9 and clusterin, indicating alterations in the complement pathway and cellular stress. These results support that vitronectin has a functional role drusen accumulation and possibly in AMD progression. Vitronectin would be a novel, promising therapeutic target for AMD.

Tumor heterogeneity plays a critical role in tumor development and response to treatment. In small-cell lung cancer (SCLC), intratumoral heterogeneity is driven in part by the Notch signaling pathway, which reprograms neuroendocrine cancer cells to a less/non-neuroendocrine state. Here we investigated the atypical Notch ligand DLL3 as a biomarker of the neuroendocrine state and a regulator of cell-cell interactions in SCLC. We first built a mathematical model to predict the impact of DLL3 expression on SCLC cell populations. We next tested this model using a single-chain variable fragment (scFv) to track DLL3 expression in vivo and a new mouse model of SCLC with inducible expression of DLL3 in SCLC tumors. We found that high levels of DLL3 promote the expansion of a SCLC cell population with lower expression levels of both neuroendocrine and non-neuroendocrine markers. This work may influence how DLL3-targeting therapies are used in SCLC patients.