Selected Grantee Publications
- 666 results found
Utility of Pancreatic Tumor Scrapings for Organoid Development and Precision Medicine Strategies
Tsang, Journal of Pathology. 2026.
https://pubmed.ncbi.nlm.nih.gov/41588864
Research on pancreatic ductal adenocarcinoma (PDAC), one of the dreadful cancers with dismal prognosis, is hampered by limited availability of tumor materials. Patient-derived organoids (PDOs)—3D cell cultures that contain several cell types and mimic specific functions of an organ—hold promise for advancing personalized medicine. In this study, researchers created 10 PDAC PDOs from patient tumor scrapings and 8 PDOs using the standard method (both sexes used). Results showed that the tumor-scraping PDOs mirrored the architecture, cell variability, and molecular profiles of PDAC tumors in vivo (within a living organism). The tumor-scraping technique offered more uncontrolled cell growth, which better mimics PDAC than the standard method. These findings show that tumor-scraping PDOs are a more reliable, patient-specific, clinically relevant model for studying PDAC biology and response to therapies, leading to improved treatment strategies and better patient outcomes for this deadly cancer. Supported by ORIP (S10OD028632) and NCI.
A Programmable Bioresorbable Electrochemical Microneedle Sensor Array for Perioperative Monitoring of Organ Health
Li, Nature Biomedical Engineering. 2026.
https://pubmed.ncbi.nlm.nih.gov/41634417
Constant monitoring of organ function during the course of a surgical procedure—from pre-surgery evaluation to postoperative care—is needed to ensure the best patient outcomes. In this study, researchers created and tested a novel electrochemical sensor array system to monitor perioperative ischemia (the restriction of blood supply to organs during a surgical procedure) and organ transplant rejections. The system uses photolithography-free 3D-printed bioresorbable (material designed to dissolve in the human body over time) microneedles as sensors. Using a male rat model, the study showed that these sensors have a stable organ interfacing and successfully monitor outputs—including electrolytes, metabolites, and oxygen levels—for 7 or more days in real time. Also, the system underwent an FDA-approved biologically safe bioresorbable method after 2 to 3 weeks, eliminating retrieval requirements. These findings suggest a possible clinical application for organ monitoring during and after surgery to detect major complications early and provide timely interventions to advance perioperative care and critical care medicine. Supported by ORIP (S10OD032352), NCI, and NIGMS.
Matrix Stiffness Governs Fibroblasts’ Regulation of Gingival Immune Homeostasis
Makkar, Advanced Materials. 2026.
https://pubmed.ncbi.nlm.nih.gov/41656824
Periodontal disease, a major public health issue, involves the inflammation and softening of gum tissue. The extracellular matrix (ECM) surrounds cells, provides structural support, and enhances signaling. In this study, researchers determined whether softening of the ECM around gum tissue cells contributes to inflammation. Gingival fibroblasts (the cells that make the ECM) were isolated from healthy patient gum tissue biopsies. Using hydrogels matching healthy (stiff) and diseased (soft) gum tissue properties, researchers found that gingival fibroblasts in stiff substrates exhibited a suppressed immune response. Co-culture experiments showed that stiff hydrogels promoted myeloid cell differentiation (a precursor cell from bone marrow that can become different types of immune cells) into immunomodulatory dendritic cells, while ex vivo tissue crosslinking increased gum stiffness and reduced inflammatory cytokine production. These findings reveal that mechanical cues (external forces) significantly influence immune responses in the gum, and this could be a target for novel biomaterial-based periodontitis treatments. Supported by ORIP (S10OD032305), NIDCR, and NIGMS.
CD8+ T-Cell Antitumor Immunity via Human iNKT–DC Conjugates
Baiu, Cancer Immunology Research. 2026.
https://pubmed.ncbi.nlm.nih.gov/41236542
Invariant natural killer T (iNKT) cells and dendritic cells (DCs) are two types of immune cells that show promise as immunotherapies for cancer. DCs can activate T cells with specific antitumor activity in patients. In this study, researchers isolated cells from healthy donors and cancer patients (sex not stated) and analyzed whether iNKT cells could improve DC-based secondary therapies. Results showed that iNKT cells form stable complexes with DCs. These iNKT–DC complexes migrate together and show enhanced stimulatory abilities by efficiently activating CD8+ T cells. Using a 6- to 10‑week-old mouse xenograft (transplant of cells or tissue from one species to a different species) model for aggressive B-cell lymphoma (both sexes used), researchers showed that iNKT–DC complexes quickly reduced tumor mass and cleared antigen-specific B cells, highlighting that it is effective even at late-stage disease refractory periods (when cancer no longer responds to standard treatments). The treatment restored exhausted antitumor immunity through enhanced T-cell proliferation (increase in cell number) and function. These findings establish iNKT–DC complexes as a promising approach for cancer immunotherapy. Supported by ORIP (S10OD023526), NCI, NHLBI, NIAID, and NIDA.
LPS-Induced Structural Reorganization and Polymerization Drive Noncanonical Inflammasome Activation
Wang, Science Advances. 2026.
https://pubmed.ncbi.nlm.nih.gov/41477831
A key pathway activated by the immune system in response to microbes is the noncanonical inflammasome. The noncanonical inflammasome is activated by the presence of intracellular (within a cell) lipopolysaccharides (LPS)—a component of bacterial membranes. Caspases are a family of proteins that mediate the noncanonical inflammasome pathway to trigger cell death. The underlying interactions of molecules that trigger this pathway remain poorly understood. In this study, researchers found that the caspase activation and recruitment domains (CARDs)—a specific segment of caspase proteins—undergo a structural change in the presence of LPS, from unstructured when inactive to an α-helical structure upon LPS binding. This change in structure promotes CARD oligomerization (binding of several subunits into a larger arrangement). Advanced mass spectrometry techniques found a key area on the protein—a hydrophobic cleft—that is vital for LPS binding and oligomerization. These findings reveal critical structural mechanisms underlying LPS recognition and noncanonical inflammasome activation, advancing understanding of immunity. Supported by ORIP (S10OD028574), NIAID, and NIGMS.
Genetic Diagnosis and Discovery Enabled by Large Language Models
Tu, Advanced Science (Weinh). 2026.
https://pubmed.ncbi.nlm.nih.gov/41655254
Identifying genetic factors that influence disease susceptibility for specific populations is a challenge. Researchers tested whether large language models (LLMs) could help increase the pace of genetic diagnosis and discovery. Two LLMs, Med‑PaLM 2 and Gemini, were tasked with several genetic problems with sequentially increasing complexity. Using data obtained from mouse models, Med‑PaLM 2 correctly identified genes that cause specific traits. Med‑PaLM 2 identified Cadherin 23 and Crym mouse gene variants contributing to hearing loss. A 5- to 8‑week-old mouse model (sex not stated) confirmed that a Crym gene mutation contributes to hearing loss. Human genomic sequences were studied to identify genetic factors underlying hearing loss in 20 patients (sex not stated). In addition, Gemini identified the causative gene underlying rare diseases in five of six patients tested (both sexes used). These findings highlight that LLMs can help identify the genetic basis of diseases, which could improve health care by providing access to precision genomic health. Supported by ORIP (R24OD035408), NHGRI, and NIDCD.
High-Efficiency TadA Cytosine Base Editors for Precise Modelling of Human Disease Variants
Qin, Nature Biomedical Engineering. 2026.
https://pubmed.ncbi.nlm.nih.gov/41606292
Genetic testing identifies missense gene mutations (an amino acid change in a protein from a single nucleotide change in DNA), but these can be variants of unknown significance (VUS)—meaning they may or may not underlie disease development. An unmet need is understanding the functional relevance of these variants. Gene editing has several challenges—including efficiency and targeting constraints. In this study, researchers created a group of TadA-derived cytosine base editors, known as TCBE-Umax, that are optimized for zebrafish model organisms. This base editing technique improved gene editing efficiency, increased compatibility, and reduced off-target edits. Using zebrafish, researchers studied 15 VUS linked to hereditary hearing loss to demonstrate proof of concept. The TCBE-Umax is a powerful platform to use with model organisms to identify the functional significance of gene mutations. Supported by ORIP (R24OD034438).
Self-Organizing Ovarian Somatic Organoids Preserve Cellular Heterogeneity and Reveal Cellular Contributions to Ovarian Aging
Dipali, Aging Cell. 2026.
https://pubmed.ncbi.nlm.nih.gov/41459983
Ovarian follicles are the functional units of the ovary. They are surrounded by stroma (collagen-rich extracellular matrix). In this study, researchers created an innovative ovarian somatic organoid model using mouse ovarian tissue to reveal cellular changes underlying ovarian aging. Cultured in scaffold-free agarose micromolds, these self-organized organoids maintained diverse cell populations, produced extracellular matrix, and secreted hormones—mimicking natural ovarian function. Organoids from aged female mice displayed impaired aggregation and growth compared with young ones, as well as altered cellular composition. Matrix fibroblasts (the primary cell that creates extracellular matrix) from older female mice showed increased activity for actin cytoskeleton pathways and decreased activity for cell adhesion pathways—suggesting increased cellular stiffness that hinders organoid formation. Age-related morphological changes correlated with cytoskeletal alterations, and actin modulation experiments confirmed the cytoskeleton's role in organoid formation. This model revealed that cytoskeletal stiffness and compromised cell adhesion are key cellular changes contributing to ovarian aging. Supported by ORIP (P51OD011092, S10OD025120), NCI, and NICHD.
Multi-omics Analysis of a Pig-to-Human Decedent Kidney Xenotransplant
Schmauch, Nature. 2026.
https://pubmed.ncbi.nlm.nih.gov/41233547
A shortage in organs remains a critical issue for transplantation. Xenotransplantation (transplant of an organ from one species to a different species) of gene-edited pig organs is a potential solution to this challenge. Immune system reactions to xenotransplants cause rejection and transplant failure. In this study, researchers used comprehensive multi-omic analysis (large datasets of different types of molecules, including genetic and protein data) to identify the immune response in pig-to-human thymokidney xenotransplantation over 61 days in a male brain dead recipient. The analysis enabled early detection of sequential immune activation, with early B-cell expansion leading to antibody-mediated rejection (AMR) by day 33, and T-cell infiltration leading to combined AMR and cell-mediated rejection on day 49. Key drivers of this immune response included CXCL9+ macrophages, interactions between pig and human immune cells, activation of complement system, and tissue injury. These insights illustrate the orchestrated human immune cascade underlying xenograft failure and highlight potential therapeutic targets for improving long-term xenotransplantation outcomes. Supported by ORIP (S10OD020056), NCI, and NIAID.
Versatile HIV Rev-dependent Reporter Cell System for Stringent and Sensitive Quantification of Viral Reservoirs, Neutralizing Antibodies, and Restriction Factors
Spear, Retrovirology. 2026.
https://pubmed.ncbi.nlm.nih.gov/41673644
Accurate measurement of HIV reservoirs (immune cells infected with HIV but not actively producing new virus particles) are critical for research into curing HIV. Researchers developed and validated a panel of HIV Rev-dependent reporter (regulating fluorescent signaling through gene expression) cell lines derived from different T-lymphoblast cells. By requiring both proteins, Tat and Rev, for fluorescent reporter activation, these cell lines minimize nonspecific reporter activation to enable precise measures of viral outgrowth, neutralizing antibodies, and restriction factors. These cell lines will be useful for a broad range of applications for HIV research. Supported by ORIP (K01OD031968, R21OD037879) and NIAID.