Biomedical subjects

Wei Jiang

Publications and source records attributed to Wei Jiang.

At least 19 recordsLinked to original sources

PubMed2026

Factor IX Padua AAV gene therapy in adolescents with hemophilia B: a phase 1 trial.

Adeno-associated virus (AAV)-mediated factor IX Padua gene therapy has demonstrated good safety and efficacy in adult patients with hemophilia B, but its safety and efficacy in adolescent patients with hemophilia B remain unknown. Here we report a multicenter, single-arm, phase 1 study involving 11 adolescent participants (aged 12-18 years) with severe or moderately severe hemophilia B (factor IX coagulant activity (FIX:C) ≤2 IU dl-1) in China. All of them received the AAV gene therapy BBM-H901 at a dose of 5 × 1012 vector genomes per kilogram of body weight and were then enrolled in a 52-week follow-up. The primary endpoint was safety. No dose-limiting toxicity was observed throughout the study. The most common adverse events included elevation of white blood cell count, elevation of neutrophil count and rash associated with corticosteroid use. One serious adverse event and two grade 3 adverse events occurred. Abnormal liver function was observed in one participant, with elevated alanine aminotransferase (197.0 U l-1) and aspartate aminotransferase (75.0 U l-1) levels, which returned to normal 4 weeks after immunosuppression therapy. The key secondary endpoints included the mean (s.d.) FIX:C at week 52 following infusion, which was 41.8 (30.1) IU dl-1 (one-stage SynthASil method), and the mean annualized bleeding rate, which decreased from 13.9 to 0.5. In this study, we show that the gene therapy drug BBM-H901 for hemophilia B is safe in adolescent patients, providing initial insights into its efficacy. ClinicalTrials.gov identifier: NCT05709288 .

Journal Article↗

PubMed2026

Osimertinib With or Without Chemotherapy in Advanced Non-Small Cell Lung Cancer With EGFR and Concurrent TP53 Mutations: A Randomized Clinical Trial.

IMPORTANCE: Combination therapy has emerged as a promising therapeutic approach for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, its clinical benefit-risk profile remains a focus of ongoing debate. Identifying patients most likely to derive benefit from such regimens remains an unmet clinical need. OBJECTIVE: To prospectively compare the efficacy and safety of first-line osimertinib plus chemotherapy with osimertinib monotherapy for patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized, open-label, phase 3 study conducted at 17 sites in China. Between March 25, 2021, and July 11, 2024, a total of 294 eligible patients with treatment-naive, stage IV or recurrent nonsquamous NSCLC harboring concurrent TP53 and EGFR-sensitizing mutations were enrolled. INTERVENTIONS: Patients were randomized (1:1) to receive osimertinib plus chemotherapy (pemetrexed and carboplatin every 3 weeks for 4 cycles, followed by maintenance therapy of osimertinib plus pemetrexed; n = 146) or osimertinib monotherapy (n = 148). MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, response, safety, and quality of life. RESULTS: Among 294 enrolled patients, the median age was 57 years (range, 26-79 years), and 159 (54.1%) were female. The data cutoff date was November 11, 2025. At a median follow-up of 25.1 months for the osimertinib-chemotherapy group and 26.1 months for the osimertinib monotherapy group, median progression-free survival was significantly longer with osimertinib plus chemotherapy than with osimertinib monotherapy (34.0 vs 15.6 months; difference, 18.4 months [95% CI, 9.9-22.3]; hazard ratio, 0.44 [95% CI, 0.32-0.60]; P < .001). This benefit was consistent across prespecified subgroups, including those with brain metastases and L858R mutations. The overall survival data remained immature (30.6% maturity); however, a trend toward overall survival benefit with combination therapy was observed. The incidence of grade 3 or higher treatment-related adverse events was higher in the combination group, with no new safety signal identified. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, osimertinib plus chemotherapy significantly increased progression-free survival among patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. These findings provided a clinical rationale for individualized combination strategies in the management of patients with EGFR-mutated NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04695925.

Adult↗

PubMed2026

Label-Free Urinary Proteomics Uncovers Immune-Related Non-Invasive Biomarkers for Primary Biliary Cholangitis.

Diagnosis of primary biliary cholangitis (PBC) currently depends on invasive liver biopsy or serum markers with inadequate diagnostic performance. This study aimed to identify non-invasive urinary protein biomarkers for PBC detection. Urine specimens from biopsy-verified PBC patients and healthy controls were processed through ultracentrifugation-based protein extraction, enzymatic digestion, and HPLC-ESI-IT/MS proteomic profiling; protein quantification was completed using Spectronaut v14.8. We identified 194 differentially expressed urinary proteins (109 upregulated, 85 downregulated) and screened 10 immune-related candidates through GO and KEGG enrichment. Pearson correlation further filtered three core proteins, osteopontin (SPP1/OPN), RAMP3 and S100A8, that correlated significantly with key PBC biochemical indices (ALP, GGT, AST, ALT, IgM, p < 0.05). Elevated urinary concentrations of OPN, RAMP3 and S100A8 were validated by ELISA in an independent cohort containing 30 PBC patients and 20 healthy volunteers. In summary, urinary OPN, RAMP3 and S100A8 are markedly increased in PBC patients and hold promise as non-invasive diagnostic biomarkers for PBC; however, their diagnostic specificity against other cholestatic and autoimmune liver diseases remains to be evaluated, and further confirmation in larger multicenter cohorts with disease control groups is warranted.

Humans↗

PubMed2026

Adjuvant apatinib therapy following concurrent chemoradiotherapy in patients with high-risk nasopharyngeal carcinoma: A multicenter, prospective phase 2 study.

PURPOSE: To assess the efficacy and safety of concurrent chemoradiotherapy (CCRT) combined with apatinib in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: This multicenter, prospective, phase II study enrolled patients with newly histologically confirmed LA-NPC, who were randomly assigned to receive CCRT followed by adjuvant apatinib (investigational arm) or CCRT alone (control arm). The investigational arm received 250 mg/day of oral apatinib administered every 28 days for up to six cycles after CCRT. The primary endpoint was 3-year progression-free survival (PFS) and secondary endpoints of overall survival (OS), distant metastasis-free survival (DMFS) and local recurrence-free survival (LRFS) of 3-year, and safety. RESULTS: From July 2018 to September 2020, 44 and 44 patients were randomized into the CCRT-alone and CCRT and apatinib groups, respectively. The median follow-up duration 56 (range: 40.0-58.6) months. The survival outcomes were the 3-year PFS, OS, and DMFS rates in the adjuvant apatinib following CCRT group were significantly higher than those observed in the CCRT-alone group((PFS, 78.6%vs. 54.5%, p = 0.027; OS, 88.1% vs. 75.0%, p = 0.029; DMFS, 85.4%vs. 59.1%, p = 0.009). The 3-year LRFS was similar between the groups. The grade 3-4 treatment-related adverse events(TRAEs) were higher in the former group than in the latter. The most common grade 3-4 non-hematology-related adverse events were hypertension (14.3%), hand-foot syndrome (9.5%), increased transaminase levels (7.1%), and headache (7.1%). CONCLUSION: Apatinib significantly improved the treatment effects of CCRT for high-risk LA-NPC patients. Therefore, CCRT and adjuvant apatinib may represent a promising option for this patient population.

Adjuvant therapy↗

PubMed2025

STT3A is essential for Wnt signaling and represents a target for cancers driven by RNF43 deficiency.

Abnormalities in the Wnt pathway are major drivers of cancer. RNF43 loss-of-function mutations are frequently detected in aggressive cancers lacking targeted therapies, underscoring the need to uncover key regulators and targets of this pathway. Using a double death trap (DDT) Wnt reporter and genome-wide CRISPR screen, we identified STT3A as an essential regulator of Wnt signaling. Genetic and pharmacological inhibition of STT3A suppressed aberrant Wnt activity caused by RNF43/ZNRF3 loss. Importantly, suppression of STT3A blocked the growth of RNF43-deficient cancer cell lines, patient-derived organoids, and spontaneous tumors. Mechanistically, STT3A regulates Wnt/β-catenin signaling via LRP6, but not LRP5. Glycosylation of LRP6 by STT3A is required for Wnt ligand binding. Notably, STT3A depletion displayed milder effects on bone homeostasis, as supported by phenotypes in STT3A-deficient patients. Together, this study established STT3A as a critical Wnt regulator through LRP6 glycosylation and a therapeutic target for RNF43-deficient cancers.

Humans↗

PubMed2025

Harnessing fern stress adaptations: From evolution and ecophysiology to molecular biology.

Ferns are the second most diverse vascular plant lineage after angiosperms and have been a key ecological component of Earth's biodiversity for more than 380 million years. Importantly, ferns are sister to seed plants, providing a critical outgroup for understanding the evolution of seed plant features. Ferns are remarkably resilient to abiotic and biotic stresses due to a long evolutionary history with adaptations to diverse habitats, stresses, and herbivores. As a result, ferns produce a multitude of secondary metabolites with unique bioactivities; these chemicals are potentially linked to the adaptation of ferns to herbivory, various abiotic and biotic stresses, and changing environments. Assembled reference genomes and the identification of key metabolic compounds of multiple ferns have already made significant contributions to human health and well-being. Here, we review the recent scientific advances in fern research, including evolution, stress resistance, metabolites and medicinal utilization, and comparative multi-omics applications. We propose that integrated investigations involving ecological, physiological, and molecular techniques will facilitate the future research translation of fern resources in diverse areas including soil remediation, biopesticides, and medicine. Advances in our understanding of fern molecular biology will provide new insights into the evolution of land plants and promote the utilization of ferns for heightened environmental restoration, crop protection and human health.

Ferns↗

PubMed2006

Synergistic regulation of the mouse orphan nuclear receptor SHP gene promoter by CLOCK-BMAL1 and LRH-1.

Small heterodimer partner (SHP; NR0B2) is an orphan nuclear receptor and acts as a repressor for wide variety of nuclear hormone receptors. We demonstrated here that mouse SHP mRNA showed a circadian expression pattern in the liver. Transient transfection of the mSHP promoter demonstrated that CLOCK-BMAL1, core circadian clock components, bound to E-box (CACGTG), and stimulated the promoter activity by 4-fold. Liver receptor homologue-1 (LRH-1; NR5A2) stimulated the mSHP promoter, and CLOCK-BMAL1 synergistically enhanced the LRH-1-mediated transactivation. Interestingly, SHP did not affect the CLOCK-BMAL1-mediated promoter activity, but strongly repressed the synergistic activation of CLOCK-BMAL1 and LRH-1. Furthermore, in vitro pull-down assays revealed the existence of direct protein-protein interaction between LRH-1 and CLOCK. In summary, this study shows that CLOCK-BMAL1, LRH-1 and SHP coordinately regulate the mSHP gene to generate the circadian oscillation. The cyclic expression of mSHP may affect daily activity of other nuclear receptors and contribute to circadian liver functions.

ARNTL Transcription Factors↗

PubMed2006

Synthesis and antitumor activity of CBI-bearing ester and carbamate prodrugs of CC-1065 analogue.

Prodrugs of a CBI-bearing CC-1065 analogue were synthesized. Antitumor activity of the compounds was evaluated against tumor cells in vitro and in mouse tumor models. Compounds 1 and 7, bearing methylpiperazine and DHA moieties, respectively, showed significant antitumor activity in both the L1210 leukemia and Lewis lung carcinoma mouse tumor models. For the carbamate prodrugs 1-4 and 6, there is a good correlation between the drug's potency both in vitro and in animal tumor models; however, there is no correlation between the prodrug's antitumor activity and the type of bonds linking the free drug. There are no significant differences between the antitumor activities of those that can or cannot be protonated at physiological pH. Compounds 6 and 7, each bearing a DHA moiety, did not show significantly improved antitumor activity compared to other prodrugs bearing DHA moieties, suggesting that DHA may not be used universally to significantly improve a drug's antitumor efficacy.

Animals↗

PubMed2006

Magnetism and magnetic isomers in free chromium clusters.

We have used the Stern-Gerlach deflection technique to study magnetism in chromium clusters of 20-133 atoms at temperatures between 60 and 100 K. We observe that these clusters have large magnetic moments and respond superparamagnetically to applied magnetic fields. Using superparamagnetic theory, we have determined the moment per atom for each cluster size and find that it often far exceeds the moment per atom present anywhere in the bulk antiferromagnetic lattice. Remarkably, our cluster beam contains two magnetically distinguishable forms of each cluster size with > or =34 atoms. We attribute this observation to structural isomers.

Journal Article↗

PubMed2006

Inhibition of LXRalpha signaling by vitamin D receptor: possible role of VDR in bile acid synthesis.

The expression of cholesterol 7alpha-hydroxylase (CYP7alpha), the rate-limiting enzyme in the catabolism of cholesterol to bile acid, is stimulated by oxysterol receptor, liver X receptor alpha (LXRalpha) and negatively regulated by a bile acid receptor, farnesoid X receptor. In the current study, we demonstrated that 1,25-(OH)(2)D3 blunted the LXRalpha-mediated induction of CYP7alpha mRNA in H4IIE rat hepatoma cells. In co-transfection experiments in HepG2 cells, VDR repressed the activity of rat CYP7alpha promoter in a ligand-dependent manner through inhibition of LXRalpha signaling. We also confirmed the ability of VDR to repress LXRalpha transcriptional activation using a synthetic LXRalpha responsive reporter. Deletion analyses revealed that the ligand-binding domain of VDR was required for the suppression and the DNA-binding domain was dispensable. Given the fact that VDR can be activated by the secondary bile acid as well as 1,25-(OH)(2)D3, the crosstalk between LXRalpha and VDR signaling in regulation of bile acid metabolism provides a possible contribution of VDR to modulate bile acid and cholesterol homeostasis, and highlights a physiological function of VDR beyond calcium metabolism in the body.

Animals↗

PubMed2006

Organocatalytic enantioselective conjugate additions to enones.

Conjugate addition reactions of a wide range of nucleophilic enol species with enones, catalyzed by a cinchona alkaloid derived thiourea organocatalyst, have been developed with attending good yields and high enantioselectivities under a mild reaction condition. The general method provides an efficient approach to the preparation of versatile building blocks possessing various functional groups.

Alkenes↗

PubMed2006

DNA cleavage mediated by copper superoxide dismutase via two pathways.

The known action of Cu, Zn superoxide dismutase (Cu(2)Zn(2)SOD) that converts O(2)(-) to O(2) and H(2)O(2) plays a crucial role in protecting cells from toxicity of oxidative stress. However, the overproduction of Cu(2)Zn(2)SOD does not result in increased protection but rather creates a variety of unfavorable effects, suggesting that too much Cu(2)Zn(2)SOD may be injurious to the cells. The present study examined the DNA cleavage activity mediated by a Cu(n)SOD that contains 1-4 copper ions, in order to obtain an insight into the aberrant copper-mediated oxidative chemistry in the enzyme. A high SOD activity was observed upon metallation of the apo-form of Cu(2)Zn(2)SOD with Cu(II), indicating that nearly all of the Cu(II) in the Cu(n)SOD is as active as the Cu(II) in the copper site of fully active Cu(2)Zn(2)SOD. Using a supercoiled DNA as substrate, significant DNA cleavage was observed with the Cu(n)SOD in the presence of hydrogen peroxide or mercaptoethanol, whereas DNA cleavage with free Cu(II) ions can occur only <5% under the same conditions. Comparison with other proteins shows that the DNA cleavage activity is specific to some proteins including the Cu(n)SOD. The steady state study suggests that a cooperative action between the SOD protein and the Cu(II)may appear in the DNA cleavage activity, which is independent of the number of Cu(II) in the Cu(n)SOD. The kinetic study shows that a two-stage reaction was involved in DNA cleavage. The effects of various factors including EDTA, radical scavengers, bicarbonate anion, and carbon dioxide gas molecules on the Cu(n)SOD-mediated DNA cleavage activity were also investigated. It is proposed that DNA cleavage occurs via both hydroxyl radical oxidation and hydroxide ion hydrolysis pathways. This work implies that any form of the copper-containing SOD enzymes (including Cu(2)Zn(2)SOD and its mutants) might have the DNA cleavage activity.

Animals↗

PubMed2006

HBXIP, cellular target of hepatitis B virus oncoprotein, is a regulator of centrosome dynamics and cytokinesis.

Hepatitis B virus accounts for more than 1 million cancer deaths annually, but the mechanism by which this virus promotes hepatocellular carcinoma remains unclear. The hepatitis B virus genome encodes an oncoprotein, HBx, which binds various cellular proteins including HBXIP. We show here that HBXIP is a regulator of centrosome duplication, required for bipolar spindle formation in HeLa human carcinoma cells and primary mouse embryonic fibroblast cells. We found that most cells deficient in HBXIP arrest in prometaphase with monopolar spindles whereas HBXIP overexpression causes tripolar or multipolar spindles due to excessive centrosome replication. Additionally, a defect in cytokinesis was seen in HBXIP-deficient HeLa cells, with most cells failing to complete division and succumbing eventually to apoptosis. Expression of viral HBx in HeLa cells mimicked the effects of HBXIP overexpression, causing excessive centrosome replication, resulting in tripolar and multipolar spindles and defective cytokinesis. Immunolocalization and fluorescent protein tagging experiments showed that HBXIP associates with microtubules of dividing cells and colocalizes with HBx on centrosomes. Thus, viral HBx and its cellular target HBXIP regulate centrosome dynamics and cytokinesis affecting genetic stability. In vivo experiments using antisense oligonucleotides targeting HBXIP in a mouse model of liver regeneration showed a requirement for HBXIP for growth and survival of replicating hepatocytes. Thus, HBXIP is a critical regulator of hepatocyte cell growth in vivo, making it a strong candidate for explaining the tumorigenic actions of viral HBx.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Essential role of phosphorylation of MCM2 by Cdc7/Dbf4 in the initiation of DNA replication in mammalian cells.

We report the identification of Cdc7/Dbf4 phosphorylation sites in human MCM2 and the determination of the role of Cdc7/Dbf4 phosphorylation of MCM2 in the initiation of DNA replication. Using immunoblotting, immunofluorescence, and high-speed automated cell-imaging analyses with antibodies specific against MCM2 and Cdc7/Dbf4 phosphorylated MCM2, we show that the chromatin recruitment and phosphorylation of MCM2 are regulated during the cell cycle in HeLa cells. Chromatin-bound MCM2 is phosphorylated by Cdc7/Dbf4 during G1/S, which coincides with the initiation of DNA replication. Moreover, we show that baculovirus-expressed purified MCM2-7 complex and its phosphomimetic MCM2E-7 complex display higher ATPase activity when compared with the nonphosphorylatable MCM2A-7 complex in vitro. Furthermore, suppression of MCM2 expression in HeLa cells by siRNA results in the inhibition of DNA replication. The inhibition can be rescued by the coexpression of wild type MCM2 or MCM2E but not MCM2A. Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells.

Adenosine Triphosphatases↗

PubMed2006

Is there a pre-RC checkpoint that cancer cells lack?

Critical for genomic integrity, accurate DNA replication is tightly regulated by the convergence of prereplication protein complexes (pre-RCs) to "license" replicating origins on DNA in G(1) and is activated by S-phase promoting kinases that selectively target and trigger origin firing in S-phase. To present, a checkpoint mechanism monitoring pre-RC complex formation and activation has yet to be elucidated. However, perturbation of these protein complexes has yielded divergent phenotypes in recent reports: normal cells arrest in the cell cycle, whereas cancerous cells arrest and die. These data implicate a mechanism by which normal cells sense pre-RC deficiency and then signal for cell cycle arrest. The potential for therapeutic exploits of this disparity between normal and cancer cells is apparent. Here, we explore recent data supporting the existence of a pre-RC checkpoint that ensures faithful pre-RC formation, a cell cycle mechanism that is intriguingly compromised in cancer cells.

Animals↗

PubMed2006

A multifunctional arithmetical processor model integrated inside a single molecule.

Improving the processing power of molecules remains the challenge for molecular logic and computation. Here we report a 2-phenylimidazo[4,5-f][1,10]phenanthroline (PIPH)-based three-state molecular switch by controlling its unique emission and absorption spectra in the acid and base condition. On one hand, PIPH can perform simultaneously the functions of an "AND" gate and an "XOR" gate, capable of operating as a half-adder, and the "off-on-off" function as well as comparison function by monitoring its fluorescent spectral changes. On the other hand, the molecule can also implement in parallel the functions of an "XOR" gate and two "INH" gates by monitoring its absorption spectral changes, which constructs two half-subtractors. The cooperative operation of comparator and half-subtractor makes general subtraction operation become possible, which is discussed conceptually in the report.

Journal Article↗

PubMed2006

Divalent-metal-dependent nucleolytic activity of Cu, Zn superoxide dismutase.

The known action of Cu, Zn superoxide dismutase (holo SOD) that converts O2- to O2 and H2O2 plays a crucial role in protecting cells from toxicity of oxidative stress. However, the overproduction of holo SOD does not result in increased protection but rather creates a variety of unfavorable effects, suggesting that too much holo SOD may be injurious to the cells. In the in vitro study, we report a finding that the holo SOD from bovine erythrocytes and its apo form possess a divalent-metal-dependent nucleolytic activity, which was confirmed by UV-vis absorption titration of calf thymus DNA (ctDNA) with the holo SOD, quenching of holo SOD intrinsic fluorescence by ctDNA, and by gel electrophoresis monitoring conversion of DNA from the supercoiled DNA to nicked and linear forms, and fragmentation of a linear lambdaDNA. Moreover, the DNA cleavage activity was examined in detail under certain reaction conditions. The steady-state study indicates that DNA cleavage supported by both forms of SOD obeys Michaelis-Menten kinetics. On the other hand, the assays with some other proteins indicate that this new function is specific to some proteins including the holo SOD. Therefore, this study reveals that the divalent-metal-dependent DNA cleavage activity is an intrinsic property of the holo SOD, which is independent of its natural metal (copper and zinc) sites, and may provide an alternative insight into the link between SOD enzymes and neurodegenerative disorders.

Animals↗

PubMed2006

Interferon-alpha differentially rescues CD4 and CD8 T cells from apoptosis in HIV infection.

OBJECTIVE: To examine the effects of interferon-alpha (IFN-alpha) on T cell survival and activation in HIV infection. DESIGN: The effects of IFN-alpha on spontaneous apoptosis and CD38 expression among T cell subsets were determined in vitro and studied in relation to CD4 cell counts, plasma HIV RNA levels and the age of the subjects. METHODS: Peripheral blood mononuclear cells from 48 HIV-infected persons and 17 healthy donors were incubated in vitro overnight with or without the addition of IFN-alpha. Percentages of apoptotic cells (positive for annexin V) and CD38 cells were determined among T cell subsets. RESULTS: IFN-alpha inhibited spontaneous apoptosis of CD4 and CD8 T lymphocytes. This protective activity was impaired in CD4 T cells from HIV-infected persons. The reduced protection of IFN-alpha among CD4 cells from HIV-infected persons was not related to the percentages of activated (CD38 or CD45RO+CD38+) cells. Surprisingly, IFN-alpha induced CD38 expression among CD8 T cells from HIV-infected persons, and the magnitude of this effect was directly related to circulating CD4 T cell count. The CD8 T cell subset that expressed CD38 in response to IFN-alpha was defined as CD28 negative, CD62 ligand (CD62L) intermediate/negative. CONCLUSIONS: Heightened expression of IFN-alpha in HIV infection may contribute to the phenotypic activation state that characterizes chronic infection while a diminished responsiveness of CD4 T cells to the protective effect of this cytokine may contribute to differential survival of CD4 and CD8 T cells in HIV disease.

ADP-ribosyl Cyclase 1↗