Biology subjects

Zhi, J.

Publications and source records attributed to Zhi, J..

5 recordsLinked to original sources

bioRxiv2026

Affinity Maturation Enables Dual Targeting of Cancer-Associated MUC1-Tn/STn and Drives Potent Tumor Control

A major challenge in solid tumor immunotherapy is identifying tumor-restricted antigens while overcoming intratumoral antigen heterogeneity. The truncated O-glycans Tn (GalNAc-O-Ser/Thr) and STn (Neu5Ac2-6GalNAc-O-Ser/Thr) are aberrantly displayed on the transmembrane glycoprotein MUC1 across a broad spectrum of epithelial malignancies, making MUC1-Tn/STn an attractive shared tumor-associated antigen class. However, heterogeneous intratumoral Tn/STn expression renders single-glycoform-specific antibodies vulnerable to antigen-driven escape. To address this challenge, we used structure-guided directed evolution and yeast surface display to affinity-mature the anti-MUC1-Tn antibody 5E5, generating variants with high-affinity dual recognition of MUC1-Tn and MUC1-STn. Co-crystal structures revealed that heavy-chain CDR loops cooperatively engage the GalNAc moiety primarily through hydrogen-bonding networks, in which HCDR3 residue 98 fine-tunes glycoform preference: Tyr98 favors MUC1-Tn recognition, whereas His98 enhances MUC1-STn engagement, while both support high-affinity recognition of both glycoforms. When reformatted as bispecific T-cell engagers, the affinity-matured variants mediated potent and durable cytolytic activity against cancer cells with heterogeneous glycan profiles, suppressed mixed Tn/STn tumors in vivo where the parental antibody failed, and showed enhanced activity in patient-derived tumor-like clusters. Together, these findings establish functional glycoform coverage as a design principle for antibody engineering, whereby a single paratope is optimized to recognize a defined spectrum of tumor-associated glycoforms while preserving antigen specificity, providing a strategy to overcome glycan heterogeneity in solid tumor immunotherapy.

cancer biology↗

bioRxiv2025

Engineering Apical Integrin-binding Cellular Patches to Directed Cell Reprogramming via Mechanical Remodeling

Engineering extracellular microenvironments to control stem cell fate remains a central challenge in regenerative medicine. Here, we develop ECM-mimetic cellular patches formed by the supramolecular assembly of laminin-derived, integrin-binding ligands. The resulting fibrillar networks exhibit well-defined molecular packing and nanoscale ligand distribution, enabling specific engagement of apical integrin {beta}1 on mesenchymal stem cells. This controlled interface converts molecular assembly into hierarchical mechanotransduction, coordinating cytoskeletal remodeling, nuclear deformation, and chromatin reorganization to drive neuronal reprogramming without genetic or chemical induction. Mechanistic studies reveal that the interplay between ligand assembly, spatial orientation, and network stability governs integrin activation and downstream transcriptional regulation These findings demonstrate how molecularly programmed assemblies can transform passive matrices into active, cell-instructive materials. This work establishes a framework for designing supramolecular systems that couple structural hierarchy with mechanotransductive control to direct stem cell fate and advance regenerative material strategies.

bioengineering↗

bioRxiv2024

Assembling Ruthenium Complexes to Form Ruthenosome Unleashing Ferritinophagy-mediated Tumor Suppression

AbstactWe introduce ruthenosomes, a fusion of liposomal and reactive oxygen species (ROS)-generating properties meticulously engineered as potent ferroptosis inducers (FINs), marking a significant advancement in metallodrug design for cancer therapy. Formed through the self-assembly of oleate-conjugated ruthenium complexes, these ruthenosomes exhibit exceptional cellular uptake, selectively accumulating in mitochondria and causing substantial disruption. This targeted mitochondrial damage significantly elevates ROS levels, triggering autophagy and selectively activating ferritinophagy. Together, these processes sensitize cancer cells to ferroptosis. In vivo, ruthenosomes effectively suppress colorectal tumor growth, underscoring their therapeutic potential. Our study pioneers a design strategy that transforms ruthenium complexes into liposome-like structures capable of inducing ferroptosis independent of light activation. By leveraging ruthenosomes as multifunctional nanocarriers, this research offers a versatile and powerful platform for ROS-mediated, ferroptosis-driven cancer cell eradication.

biochemistry↗

bioRxiv2020

DOT1L Complex Regulates Transcriptional Initiation 1 in Human Cells

DOT1L, the only H3K79 methyltransferase in human cells and a homolog of the yeast Dot1, normally forms a complex with AF10, AF17 and ENL/AF9, is dysregulated in most of the cases of mixed lineage leukemia (MLL) and is believed to regulate transcriptional elongation without much evidence. Here we show that the depletion of DOT1L reduced the global occupancy without affecting the traveling ratio or the elongation rate of Pol II, suggesting it not a major elongation factor. An examination of general transcription factors (GTFs) binding revealed globally reduced TBP and TFIIA occupancies near promoters after DOT1L loss, pointing to a role in transcriptional initiation. Proteomic studies uncovered that DOT1L regulates transcriptional initiation likely by facilitating the recruitment of TFIID. Moreover, ENL, a DOT1L complex subunit with a known role in DOT1L recruitment, also regulates transcriptional initiation. Furthermore, DOT1L stimulates H2B monoubiquitination by limiting the recruitment of human SAGA complex, and the connection between Dot1/DOT1L and SAGA complex is conserved between yeast and human. These results advanced current understanding of roles of DOT1L complex in transcriptional regulation and MLL.

molecular biology↗

bioRxiv2020

Surgery and Radioactive Iodine Therapeutic Strategy for Patients Greater than 60 Years of Age with Differentiated Thyroid Cancer

PurposeThe purpose of the current study was to determine whether older patients with differentiated thyroid cancer (DTC) who received surgical treatment had a better cause-specific survival (CSS) than patients who were recommended surgery, but declined, and whether patients who underwent post-operative RAI-131 therapy had an impact on CSS based on TNM staging and number of lymph node metastases for all total or near-total thyroidectomy patients. Patients and MethodsAll DTC patients information were obtained from the SEER*Stat 8.3.6 program, and only patients [≥] 60 years or older were considered. The patients were divided into two groups (underwent surgery and surgery recommend, but not performed). Furthermore, patients were grouped as follows: T4; N1b; M1; T1-3N0-1a; specific number of lymph node metastases; and total or near-total thyroidectomy. ResultsThe 120-month cause-specific survival (CSS) rate of females and males showed a gradual declining trend from 60-64 to [≥]80 years of age in the group that underwent surgery. The CSS rate of females and males showed a marked downward and irregular trend with an increase in age in the recommended, but no surgery group. Univariate analysis indicated that the surgery group had a higher 120-month CSS in females in most stages and males, compared with the no surgery group. RAI-131 therapy was associated with an improved 80-month CSS in T4/N1b/M1 females (P<0.0183) and males (P<0.0011). There was no CSS difference in females or males between the T1-3N0 and T1-3N1a patients. There was no statistical difference between the two subgroups. ConclusionsSurgical treatment should be recommended for elderly DTC patients because surgery can lead to a better CSS. High-risk patients achieve a higher benefit-to-risk ratio with RAI-131 therapy. To avoid the adverse effects associated with RAI-131 therapy, a multidisciplinary discussion should be arranged for intermediate- and low-risk patients.

cancer biology↗