No abstract

Objective Sialylation on the crystallizable fragment (Fc) of anti-citrullinated protein antibodies (ACPAs), which is catalysed by β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) could attenuate inflammation of rheumatoid arthritis (RA). In this study, we screened the transcription factor of ST6GAL1 and elucidated the mechanism of transcriptionally up-regulating sialylation of ACPAs in B cells to explore its role in the progression of rheumatoid arthritis (RA). Methods Transcription factors interacting with the P2 promoter of ST6GAL1 were screened by DNA pull-down and LC-MS/MS, and verified by chromatin immunoprecipitation (ChIP), Dual luciferase reporter assay and Electrophoretic mobility shift assay (EMSA). The function of the CCCTC-binding factor (CTCF) on the expression of ST6GAL1 and the inflammatory effect of ACPAs were verified by knocking down and overexpressing CTCF in B cells. Collagen-induced arthritis (CIA) model was constructed from B cells-specific CTCF knockout mice to explore the effect of CTCF on arthritis progression. Results We observed that the level of ST6GAL1 and ACPAs sialylation decreased in serum of RA patients and were negatively correlated with DAS28 scores. Subsequently, CTCF was screened and verified as the transcription factor interacting with the P2 promoter of ST6GAL1, which enhances the sialylation of ACPAs, thus weakening the inflammatory activity of ACPAs. Furthermore, the above results were also verified in the CIA model constructed from B cell-specific CTCF knockout mice. Conclusion CTCF is the specific transcription factor of ST6GAL1 in B cells which up-regulates the sialylation of ACPAs in RA and attenuates the disease progression.

Background: BDC-1001 is a novel ISAC consisting of an investigational trastuzumab biosimilar chemically conjugated to a TLR7/8 agonist with a non-cleavable linker. BDC-1001 elicits myeloid activation and enhances antigen presentation leading to antibody-mediated effector functions that promote T-cell activation and a durable adaptive immune response.Methods: A 4-part, phase 1/2 dose-escalation/expansion study was initiated to evaluate BDC-1001 AE PD-1 inhibitor in pts with previously treated advanced/metastatic HER2-expressing (IHC2/3+) or amplified solid tumors (NCT04278144). Pts received BDC-1001 IV in a 3+3 design. Primary objectives are to evaluate safety, tolerability, dose-limiting toxicities (DLTs), and determine a recommended phase 2 dose (RP2D); secondary and exploratory objectives are to assess pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity.Results: From the completed monotherapy dose-escalation (Part 1) will be reported including safety, tolerability, PK, and PD biomarker data. The initial subset of pts enrolled include the following cancer types: breast, biliary, cervical, colorectal, lung, gastroesophageal, salivary, urinary tract, and endometrial. Preliminary results of the first 20 pts indicate that BDC-1001 appears well-tolerated. No DLTs have been observed, and the MTD has not been reached. AEs deemed related to BDC-1001 were grade 1-2, including infusion-related reactions and one event of decreased ejection fraction. Early evidence of clinical activity was observed in a pt with a partial response and other pts with stable disease. Increases in plasma biomarkers associated with TLR7/8 and myeloid cell activation (TNFa, CXCL10, MCP-1, MIP-1a) were observed. BDC-1001 treatment led to an increase in myeloid and T-cell infiltration in a subset of pts. Updated clinical and translational data are anticipated. Conclusions:In this first-in-human study, BDC-1001 appears well-tolerated with early evidence of clinical activity, including pts previously treated with anti-HER2 therapy. Dose escalation is ongoing.Clinical trial identification: NCT04278144.

Background: In China, the association between estrogen metabolism and breast cancer risk and the differences in metabolic pattern between breast cancer patients and controls are poorly understood. Methods: A total of 84 patients with invasive breast cancer and 47 controls with benign breast diseases were included in this study. Estrogen metabolites from their morning urine were determined by HPLC-MS/MS and evaluated in both groups, and the predictive value of each estrogen metabolite in the malignant group according to their menstrual status was analyzed. Results: Urinary concentration of estrogen metabolites 2-OHE1, 2-OHE2, 4-OHE2, 4-MeOE1, and 16ɑ-OHE1 were lower in postmenopausal patients with breast cancer, compared with benign controls, In logistic regression model, breast cancer risk increased with the decline in the levels of 4-OHE2 and 4-MeOE1. In premenopausal patients,, a difference in the level of 2-OHE2 was observed between both groups, and 2-OHE2 was found to have predictive value for breast cancer. Additionally, urinary 2-OHE2 level in premenopausal HR+ patients was considerably higher compared with HR- patients. Conclusions: We found that lower urinary levels of 4-OHE2 and 4-MeOE1had predictive value for breast cancer, and higher 2-OHE1 were associated with HR+ breast cancer in premenopausal women.