Abstract Background Observational studies indicate a potential link between increased blood glucose levels and the development of oesophageal cancer. However, the causal relationship between glycemic traits and oesophageal cancer has not been clarified yet. The aim of this research was to examine if there is a genetic link between glycemic characteristics and oesophageal cancer through the use of Mendelian randomization analysis. Methods We conducted a TSMR analysis and MVMR using publicly available GWAS data on the European population. The primary analysis utilized the IVW method, which was subsequently validated through comprehensive complementary and sensitivity analyses. Results IVW analysis revealed a substantial correlation (OR = 1.612, P = 0.0228) between type 2 diabetes (T2DM) and oesophageal cancer. After accounting for body mass index (BMI), this association remained to be statistically significant in multivariate MR analyses (OR = 1.662, P = 0.0416). There was only a small amount of evidence indicating a possible link between oesophageal cancer and other glycemic traits after excluding the outliers. Conclusions Our study further supports the evidence that European individuals with T2DM are at an increased risk of developing oesophageal cancer. It implies that pharmacological or lifestyle treatments for individuals with T2DM could potentially be advantageous in the prevention of oesophageal tumor development.
Promoting photogenerated carriers separation and adjusting the activation path of the CO2 molecule are two effective solutions for improving the activity and selectivity of photocatalytic CO2 reduction. In this study, simultaneous phosphorylation and Bi modification are successfully introduced into BiOBr hierarchical spheres via a solvothermal reaction using red phosphorus as the additive. Remarkably, the synchronous phosphorylation and Bi modification of BiOBr lead to an improvement of CO2 conversion efficiencies, especially for the yield of CH4. Different characterization techniques were performed to explore the existence form of P and Bi modification, and the essence behind such an enhancement. Attributed to this in situ strategy, the regular hierarchical spheres morphology of BiOBr is preserved, and the Bi nanoparticles are well distributed with the average size of ca. 5 nm. Besides, the phosphorus exists in the form of BiPO4. The reasons for the enhanced photocatalytic activity are that the metal Bi modification could enhance the light harvesting and the selectivity of CH4; furthermore, the synchronous BiPO4 and Bi modification could improve the separation efficiency of photogenerated carriers and increase the surface charge transfer efficiency during the photocatalytic reaction process. We hope this work will provide a new perspective for fabrication of multivariate modification photocatalysts with highly efficient and highly selective photocatalytic CO2 reduction.
Abstract Background & Aims Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma, which contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown. Methods We used a dual recombinase mouse model to delete Hif1α or Hif2α in α-smooth muscle actin ( αSMA) -expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF- Hif2α expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, a HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade. Results CAF-specific deletion of HIF2, but not HIF1, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = 0.0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models. Conclusions Together, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.
Abstract Background In the evaluation of PD-L1 expression to select patients for anti-PD-1/PD-L1 treatment, uniform guidelines that account for different immunohistochemistry assays, different cell types and different cutoff values across tumor types are lacking. Data on how different scoring methods compare in breast cancer are scant. Methods Using FDA-approved 22C3 diagnostic immunohistochemistry assay, we retrospectively evaluated PD-L1 expression in 496 primary invasive breast tumors that were not exposed to anti-PD-1/PD-L1 treatment and compared three scoring methods (TC: invasive tumor cells; IC: tumor-infiltrating immune cells; TCIC: a combination of tumor cells and immune cells) in expression frequency and association with clinicopathologic factors. Results In the entire cohort, positive PD-L1 expression was observed in 20% of patients by TCIC, 16% by IC, and 10% by TC, with a concordance of 87% between the three methods. In the triple-negative breast cancer patients, positive PD-L1 expression was observed in 35% by TCIC, 31% by IC, and 16% by TC, with a concordance of 76%. Associations between PD-L1 and clinicopathologic factors were investigated according to receptor groups and whether the patients had received neoadjuvant chemotherapy. The three scoring methods showed differences in their associations with clinicopathologic factors in all subgroups studied. Positive PD-L1 expression by IC was significantly associated with worse overall survival in patients with neoadjuvant chemotherapy and showed a trend for worse overall survival and distant metastasis-free survival in triple-negative patients with neoadjuvant chemotherapy. Positive PD-L1 expression by TCIC and TC also showed trends for worse survival in different subgroups. Conclusions Our findings indicate that the three scoring methods with a 1% cutoff are different in their sensitivity for PD-L1 expression and their associations with clinicopathologic factors. Scoring by TCIC is the most sensitive way to identify PD-L1-positive breast cancer by immunohistochemistry. As a prognostic marker, our study suggests that PD-L1 is associated with worse clinical outcome, most often shown by the IC score; however, the other scores may also have clinical implications in some subgroups. Large clinical trials are needed to test the similarities and differences of these scoring methods for their predictive values in anti-PD-1/PD-L1 therapy.
This study aimed to investigate the effects of swimming exercise on cartilage, inflammatory markers, subchondral bone structure, and stride length in mice with knee osteoarthritis induced by anterior cruciate ligament (ACL) transection, and to explore the role of miR-143-3p in these effects. Thirty-six 3-month-old male C57BL/6 mice were randomly divided into three groups: control, exercise (swimming 30 min daily for one month), and exercise + miR-143-3p mimics (swimming exercise plus intra-articular injection of miR-143-3p mimics lentivirus once every two weeks for four weeks). Experimental groups underwent ACL transection to induce osteoarthritis. Interventions began two weeks post-modeling. Post-intervention, stride length analysis, histological analysis (including assessment of cartilage morphology and chondrocyte number), and micro-CT scanning (to assess subchondral bone structure) were performed. Inflammatory markers were measured in cartilage. Swimming exercise partially alleviated joint inflammation (as evidenced by reduced levels of IL-1β), protected cartilage (maintaining chondrocyte number and extracellular matrix homeostasis, as demonstrated by improved cartilage morphology), and enhanced subchondral bone structure. However, miR-143-3p supplementation partially inhibited these beneficial effects of swimming exercise. Both exercise groups showed gait impairment (reduced stride length) compared to controls, with no significant difference between the two exercise groups. Swimming exercise can mitigate osteoarthritis progression by protecting cartilage, improving subchondral bone structure, and reducing inflammation. However, miR-143-3p partially counteracts these protective effects.
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