Associations of air pollution with all-cause dementia, Alzheimer’s disease, and vascular dementia: a prospective cohort study based on 437,932 participants from the UK biobank

ObjectiveTo prospectively assess whether air pollution, including PM2.5, PM10, and NOx, is associated with the risk of all-cause dementia, Alzheimer’s disease (AD), and vascular dementia, and to investigate the potential relationship between air pollution and genetic susceptibility in the development of AD.Methods and resultsOur study included 437,932 participants from the UK Biobank with a median follow-up period of over 10 years. Using a Cox proportional hazards model, we found that participants exposed to PM2.5 levels of ≥10 μg/m3 had a higher risk of developing all-cause dementia (HR = 1.1; 95% CI: 1.05–1.28; p < 0.05) compared to the group exposed to PM2.5 levels of <10 μg/m3. However, there was no significant association between PM10 levels of ≥15 μg/m3 and the risk of all-cause dementia, AD, or vascular dementia when compared to the group exposed to PM10 levels of <15 μg/m3. On the other hand, participants exposed to NOx levels of ≥50 μg/m3 had a significantly higher risk of all-cause dementia (HR = 1.14; 95% CI: 1.02–1.26; p < 0.05) and AD (HR = 1.26; 95% CI: 1.08–1.48; p < 0.05) compared to the group exposed to NOx levels of <50 μg/m3. Furthermore, we examined the combined effect of air pollution (PM2.5, PM10, and NOx) and Alzheimer’s disease genetic risk score (AD-GRS) on the development of AD using a Cox proportional hazards model. Among participants with a high AD-GRS, those exposed to NOx levels of ≥50 μg/m3 had a significantly higher risk of AD compared to those in the group exposed to NOx levels of <50 μg/m3 (HR = 1.36; 95% CI: 1.03–1.18; p < 0.05). Regardless of air pollutant levels (PM2.5, PM10, or NOx), participants with a high AD-GRS had a significantly increased risk of developing AD. Similar results were obtained when assessing multiple variables using inverse probability of treatment weighting (IPTW).ConclusionOur findings indicate that individuals living in areas with PM2.5 levels of ≥10 μg/m3 or NOx levels of ≥50 μg/m3 are at a higher risk of developing all-cause dementia. Moreover, individuals with a high AD-GRS demonstrated an increased risk of developing AD, particularly in the presence of NOx ≥ 50 μg/m3

Chronic Kidney Disease Promotes Cerebral Microhemorrhage Formation

Background Chronic kidney disease (CKD) is increasingly recognized as a stroke risk factor, but its exact relationship with cerebrovascular disease is not well-understood. We investigated the development of cerebral small vessel disease using in vivo and in vitro models of CKD. Methods CKD was produced in aged C57BL/6J mice using an adenine-induced tubulointerstitial nephritis model. We analyzed brain histology using Prussian blue staining to examine formation of cerebral microhemorrhage (CMH), the hemorrhagic component of small vessel disease and the neuropathological substrate of MRI-demonstrable cerebral microbleeds. In cell culture studies, we examined effects of serum from healthy or CKD patients and gut-derived uremic toxins on brain microvascular endothelial barrier. Results CKD was induced in aged C57BL/6J mice with significant increases in both serum creatinine and cystatin C levels (p \u3c 0.0001) without elevation of systolic or diastolic blood pressure. CMH was significantly increased and positively correlated with serum creatinine level (Spearman r = 0.37, p \u3c 0.01). Moreover, CKD significantly increased Iba-1-positive immunoreactivity by 51% (p \u3c 0.001), induced a phenotypic switch from resting to activated microglia, and enhanced fibrinogen extravasation across the blood–brain barrier (BBB) by 34% (p \u3c 0.05). On analysis stratified by sex, the increase in CMH number was more pronounced in male mice and this correlated with greater creatinine elevation in male compared with female mice. Microglial depletion with PLX3397 diet significantly decreased CMH formation in CKD mice without affecting serum creatinine levels. Incubation of CKD serum significantly reduced transendothelial electrical resistance (TEER) (p \u3c 0.01) and increased sodium fluorescein permeability (p \u3c 0.05) across the endothelial monolayer. Uremic toxins (i.e., indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide) in combination with urea and lipopolysaccharide induced a marked drop in TEER compared with the control group (p \u3c 0.0001). Conclusions CKD promotes the development of CMH in aged mice independent of blood pressure but directly proportional to the degree of renal impairment. These effects of CKD are likely mediated in part by microglia and are associated with BBB impairment. The latter is likely related to gut-derived bacteria-dependent toxins classically associated with CKD. Overall, these findings demonstrate an important role of CKD in the development of cerebral small vessel disease

Efficacy and safety of XELOX combined with anlotinib and penpulimab vs XELOX as an adjuvant therapy for ctDNA-positive gastric and gastroesophageal junction adenocarcinoma: a protocol for a randomized, controlled, multicenter phase II clinical trial (EXPLORING study)

BackgroundThe efficacy of current adjuvant chemotherapy for gastric adenocarcinoma/gastroesophageal junction adenocarcinoma (GA/GEJA) leaves much to be desired. ctDNA could serve as a potential marker to identify patients who are at higher risk of recurrence. Reinforcing standard adjuvant chemotherapy with immunotherapy has already been indicated to significantly improve clinical outcome, albeit such evidence is rare in GA/GEJA. Here, we intend to explore the clinical benefit of the reinforcement of adjuvant immunotherapy and antiangiogenics alongside with chemotherapy in patients who are deemed in high risk of recurrence by ctDNA analysis, which might shed light on further improvements in adjuvant therapy for GA/GEJA.Methods/DesignThis study is designed as a prospective, multicenter, randomized, controlled phase II study in patients histologically or cytologically diagnosed with GA/GEJA who underwent D2 gastrectomy and achieved R0 or R1 resection. From February 2022, a total of 300 stage III patients will be enrolled and subjected according to ctDNA sequencing results, and those with positive results will subsequently be randomized 1:1 to arm A or B. Patients in arm A will receive anlotinib, penpulimab and XELOX for 6-8 cycles, maintained with anlotinib and penpulimab for up to 1 year, while patients in arm B will receive XELOX alone for 6-8 cycles. ctDNA-negative patients will be assigned to arm C, and patients who are ctDNA positive but failed in randomization will be assigned to arm D. Patients in arms C and D will receive the investigator’s choice of therapy. The primary endpoint is the median disease-free survival (DFS) of arm A versus arm B determined via CT/MRI imaging. Secondary endpoints include the DFS of ctDNA positive patients versus ctDNA negative patients, the 2- and 3-year DFS rates, overall survival (OS), the impact of hallmark molecules on the treatment response, adverse events (AEs), and the impact of nutrition status or exercise on recurrence.DiscussionWe expect that ctDNA would be a strong prognostic factor and ctDNA-positive patients are at higher risk of relapse than ctDNA-negative patients. The addition of anlotinib and penpulimab to XELOX, may contribute to delaying relapse in ctDNA-positive patients.Trial registrationhttps://www.clinicaltrials.gov, identifier NCT05494060

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Interferon-γ acts as a regulator in the trade-off between phagocytosis and production performance in dwarf chickens

Abstract Background Interferon-γ (IFN-γ) is critical for innate and adaptive immunity against viral and bacterial infections. IFN-γ reportedly affects the phagocytic ability of monocytes and macrophages as well as regulates pituitary function in humans and mice. The present study analyzed the impact of IFN-γ on monocyte and macrophage phagocytosis, production performance, and pituitary function in vivo and in vitro (in dwarf chickens). IFN-γ was injected into dwarf chickens through a vein, and then, the laying rate, average egg weight, and levels of follicle-stimulating hormone (FSH) and IFN-γ were measured in treatment and control groups. For the in vitro experiment, the pituitary tissues were supplemented with IFN-γ, and the mRNA expression levels of follicle-stimulating hormone beta subunit (FSH-β), interferon gamma receptor 1 (IFNGR1), and interferon gamma receptor 2 (IFNGR2) in the pituitary were assessed. Results Monocyte and macrophage phagocytosis product (PP) was decreased by IFN-γ treatment in a dose-dependent manner in vitro. In the in vivo experiment, the level of IFN-γ in the treatment group was higher than that in the control group at 7 d (P < 0.05), 14 d (P < 0.01), and 21 d (P < 0.01) post-injection. Compared with the control group, monocyte and macrophage PP was lower in the treatment group after injection (P < 0.01). The laying rate was higher in the treatment group than in the control group at 2 and 3 wk post-injection (P < 0.05). There was a significant difference between the treatment and control groups in the levels of FSH at 1, 3, 7, and 14 d post-injection (P < 0.01). In the in vitro experiment, increased mRNA expression levels of FSH-β, IFNGR1, and IFNGR2 were observed in the treatment group after stimulation with 100 U/mL IFN-γ for 24 h compared to those in the control group (P < 0.05). Conclusions IFN-γ inhibited the phagocytosis of monocytes and macrophages; up-regulated the mRNA expression levels of the FSH-β, IFNGR1, and IFNGR2; enhanced the secretion of FSH; and improved the laying rate. IFN-γ might be an important regulator in the trade-off between the immune effect and production performance in dwarf chickens

Association of MLL3 and TGF-β signaling gene polymorphisms with the susceptibility and prognostic outcomes of Stanford type B aortic dissection

Abstract Objective This study aims to investigate the association of lysine methyltransferase 2 C (MLL3) and transforming growth factor β (TGF-β) signaling-related gene polymorphisms with the susceptibility of Stanford type B aortic dissection (AD) and its clinical prognostic outcomes. The methods involved investigating the MLL3 (rs10244604, rs6963460, rs1137721), TGFβ1 (rs1800469), TGFβ2 (rs900), TGFR1 (rs1626340) and TGFR2 (rs4522809) gene polymorphisms. Logistic regression was performed to investigate the association between 7 single nucleotide gene polymorphisms (SNPs) and Stanford type B aortic dissection. The GMDR software was used to analyze gene-gene and gene-environment interactions. The odds ratio (OR) with a 95% confidence interval (CI) was employed to evaluate the association of genes and Stanford type B AD risk. Results Genotypes and allele distributions in the case and control groups showed significant differences (P < 0.05). Logistic regression has shown that the Stanford Type B AD risk was highest in individuals with the rs1137721 CT genotype (OR = 4.33, 95% CI = 1.51–12.40). Additionally, WBC, drinking, hypertension, triglycerides (TG), and low-density lipoprotein (LDL-C) were independent risk factors for Stanford Type B AD. Logistic regression showed that the Stanford Type B AD risk was highest in individuals with the MLL3 (rs1137721)-TT + CT and TGFβ1 (rs4522809)-AA genotype (OR = 6.72, 95% CI = 1.56–29.84), and lowest in those with the MLL3 (rs1137721)-CC and TGFβ1 (rs4522809)-AA + GG genotype (OR = 4.38, 95% CI = 0.92–20.83). However, the 55-month median long-term follow-up did not show statistical significance. Conclusion Carriers of both TT + CT of MLL3 (rs1137721) and AA of TGFβ1 (rs4522809) polymorphisms may be closely related to the development of Stanford type B AD. MLL3 (rs1137721), WBC, and TG/TC were found to be associated with the morbidity of Stanford type B AD. MLL3 (KMT2C) is associated with the TGF-β signaling pathway protein. The risk of Stanford type B AD is related to the interactions of gene-gene and gene-environment

Magnetic Fullerene-DNA/Hyaluronic Acid Nanovehicles with Magnetism/Reduction Dual-Responsive Triggered Release

We created the dual-responsive nanovehicle that can effectively combine and abundantly utilize magnetic and glutathione (GSH)-reductive triggers to control the drug delivery and achieve more intelligent and powerful targeting. In the nanovehicles, paramagnetic fullerene (C₆₀@CTAF) was prepared via one-step modification of fullerene with magnetic surfactant CTAF by hydrophobic interaction for the first time. The perfect conjugation of C₆₀ and CTAF increased the solubility or dispersity of fullerenes and qualified CTAF with more powerful assembly capability with DNA. DNA molecule in the nanovehicles acted as an electrostatic scaffold to load anticancer drug Dox as well as the important building block for assembly with C₆₀@CTAF into C₆₀@CTAF/DNA. The further combination of deshielding and targeting functions in reduction-responsive disulfide modified HA-SS-COOH coating on C₆₀@CTAF/DNA complexes could reduce the agglomeration and regulate the morphology of C₆₀@CTAF/DNA complexes from irregular microstructures to more uniform ones. More importantly, the introduction of HA-SS-COOH provided a response to a simulating reductive extra-tumoral environment by efficient cleavage of disulfide linkages by GSH and site-specific drug delivery to HepG2 cells. Amazingly, the final nanovehicles presented an increased magnetic susceptibility compared with paramagnetic CTAF, and they “walked” under an applied magnetic field. Because of their facile fabrication, rapid responsiveness to extra tumoral environment, and external automatic controllability by external magnet, the drug delivery nanovehicles constructed by magnetic fullerene-DNA/hyaluronic acid might be of great interest for making new functional nucleic-acid-based drug carriers

Triglyceride-glucose index as a valuable predictor for aged 65-years and above in critical delirium patients: evidence from a multi-center study

Abstract Background The triglyceride-glucose index (TyG), an established indicator of insulin resistance, is closely correlated with the prognosis of several metabolic disorders. This study aims to investigate the association between the TyG index and the incidence of critical delirium in patients aged 65 years and older. Methods We focused on evaluating patients aged 65 years and older diagnosed with critical delirium. Data were obtained from the Medical Information Database for Intensive Care (MIMIC-IV) and the eICU Collaborative Research Database (eICU-CRD). Multivariate logistic regression and restricted cubic spline (RCS) regression were used to determine the relationship between the TyG index and the risk of delirium. Results Participants aged 65 years and older were identified from the MIMIC-IV (n = 4,649) and eICU-CRD (n = 1,844) databases. Based on optimal thresholds derived from RCS regression, participants were divided into two cohorts: Q1 (< 8.912), Q2 (≥ 8.912). The logistic regression analysis showed a direct correlation between the TyG index and an increased risk of critical delirium among ICU patients aged 65 and older. These findings were validated in the eICU-CRD dataset, and sensitivity analysis further strengthened our conclusions. In addition, the subgroup analysis revealed certain differences. Conclusion This study highlights a clear, independent relationship between the TyG index and the risk of critical delirium in individuals aged 65 years and older, suggesting the importance of the TyG index as a reliable cardio-cerebrovascular metabolic marker for risk assessment and intervention