Biology subjects

Guan, F.

Publications and source records attributed to Guan, F..

4 recordsLinked to original sources

bioRxiv2026

Concurrent Stereotactic Body Radiation Therapy and KRAS Inhibition Synergistically Improve Pre-clinical Pancreatic Cancer Treatment

Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging cancers to treat due to the dismal survival rate, poor post-treatment outcome and profound resistance to a wide range of therapies. With mutant KRAS being a key driver, small molecule inhibitors targeting KRAS or pan-RAS (KRASi) have demonstrated exciting preclinical and early clinical anti-tumor efficacy, and the pan-RAS(ON) inhibitor daraxonrasib (RMC-6236) recently achieved Phase 3 clinically meaningful improvements in patient survival compared to chemotherapy. But resistance to RAS/KRAS inhibitor inevitably develops, which limits and compromises the treatment outcome. In this study, we investigated the combination of stereotactic body radiation therapy (SBRT) and KRAS inhibition (MRTX1133 and daraxonrasib) in the treatment of preclinical PDAC models. We found that this combination strategy synergistically suppresses PDAC cell growth in vitro and enhances tumor control while minimizing local recurrence in orthotopically implanted KPC (LSL-KrasG12D/+;Trp53R172H/+;Pdx1-Cre) murine PDAC tumors in vivo. As radiation therapy (RT) induces ferroptosis in multiple cancer types and mutant KRAS promotes various anti-ferroptotic mechanisms, we tested the role of ferroptosis in promoting tumor-control efficacy. Intriguingly, the addition of a ferroptosis inhibitor, liproxstatin-1, to the combination therapy significantly abrogated the in vivo synergism between SBRT and KRAS inhibition, suggesting that treatment-induced ferroptosis at least partially drives the synergistic efficacy of this combination strategy. Our study indicates that this SBRT-KRASi combination has the potential to overcome treatment resistance and improve outcomes in PDAC patients. These data directly support the design of a planned multi-center Phase 2 clinical trial with this combination strategy in locally advanced PDAC.

cancer biology↗

bioRxiv2022

Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation

Osteoporosis is a highly prevalent disorder with a strong genetic component. Recent studies identify PLS3 as a novel bone regulator of bone metabolism and PLS3 mutations lead to a rare monogenic early-onset osteoporosis. However, the mechanism of PLS3 mutation leading to osteoporosis is unknown with no animal models carrying patient-derived PLS3 mutations generated. The effective treatment strategies for PLS3-related have not been established. Here we have constructed a novel rat model with clinically relevant hemizygous E10-16del mutation of PLS3 (PLS3E10-16del/0) that recapitulate the osteoporotic phenotypes with obviously thinner cortical thickness, significant decreases in yield load, maximum load, and breaking load of femora at 3, 6, 9 months compared to WT rats. Histomorphometric analysis indicates a significantly lower mineral apposition rate in PLS3E10-16del/0rats. Treatment with alendronate (ALN, 1.0 ug/kg per day) or teriparatide (TPTD, 40ug/kg five times weekly) for 8 weeks significantly improved bone mass and bone microarchitecture, and bone strength was significantly increased after TPTD treatment (P < 0.05). Thus, our results indicate the roles of PLS3 in the regulation of bone microstructure and bone strength, providing a novel animal model for the study of early-onset osteoporosis. Alendronate and teriparatide treatment could be a potential treatment for early-onset osteoporosis induced by PLS3 mutation.

genetics↗

bioRxiv2022

Medial prefrontal cortex Notch1 signalling mediates methamphetamine-induced psychosis via Hes1-dependent suppression of GABAB1 receptor expression.

Methamphetamine (METH), a widely abused stimulant drug, induces psychosis in approximately half of abusers; this effect is becoming a major concern for society. Although the Notch1 signalling pathway has been shown to play a part in the pathogenesis of some psychiatric disorders, its role in METH-induced psychosis (MIP) is still unknown. Here, we showed that Notch1 signalling was downregulated in the medial prefrontal cortex (mPFC) in a MIP mouse model. Direct genetic and pharmacological manipulations of Notch1 signalling bidirectionally altered MIP-related behaviours and governed neuronal activity in the mPFC. Moreover, Notch1 signalling negatively regulated GABAB1 receptor expression in the mPFC of MIP mice through Hes1, a transcriptional repressor in Notch1 signalling. Further, we show that Hes1 can directly bind to the GABAB1 receptor promoter. Notably, pharmacological regulation of the GABAB receptor in the mPFC reversed the changes in MIP-related behaviours caused by the dysfunction of Notch1 signalling. Together, our findings uncover a previously unrecognised Notch1-Hes1-GABAB1 receptor-dependent mechanism involved in regulating mPFC neuronal activity and behavioural phenotypes in MIP. Our work provides mechanistic insight into the aetiology and pathophysiology of MIP.

molecular biology↗

bioRxiv2020

The Profiling of Bisecting N-acetylglucosamine (GlcNAc) Modification in Human Amniotic Membrane by Glycomic and Glycoproteomic Analyses

It is acknowledged that the bisecting N-acetylglucosamine (GlcNAc) structure, a GlcNAc linked to the core {beta}-mannose residue via a {beta}1,4 linkage, represents a special type of N-glycosylated modification and has been reported to be involved in various biological processes, such as cell adhesion and fetal development. Clark et al. has found that the majority of N-glycans in human trophoblasts bearing a bisecting GlcNAc. This type of glycan has been reported to help trophoblasts get resistant to natural killer (NK) cell-mediated cytotoxicity, and this would provide a possible explanation for the question how could the mother nourish a fetus within herself without rejection. Herein, we hypothesized that human amniotic membrane which is the last barrier for the fetus may also express bisecting type glycans to protect the fetus. To test this hypothesis, glycomic analysis of human amniotic membrane was performed, and the bisecting N-glycans with high abundance were detected. In addition, we re-analyzed our proteomic data with high fractionation and amino acid sequence coverage from human amniotic membrane, which had been released for the exploration of human missing proteins. The presence of bisecting GlcNAc peptides was revealed and confirmed. A total of 41 glycoproteins with 43 glycopeptides were found to possess a bisecting GlcNAc, 25 of which are for the first time to be reported to have this type of modification. These results provide the profiling of bisecting GlcNAc modification in human amniotic membrane and benefit to the function studies of glycoproteins with bisecting GlcNAc modification and the function studies in immune suppression of human placenta. The mass spectrometry placenta data are available via ProteomeXchange (PXD010630).

cell biology↗