Elevated blood pressure (BP) is reportedly associated with an increased risk of atrial fibrillation (AF). However, the association between cumulative BP exposure in midlife and incident AF in ...mid-to-late life remains unclear.
Participants enrolled in the ARIC (Atherosclerosis Risk in Communities) study with 4 consecutive BP measurements and no prevalent AF at baseline were included. Cumulative BP was calculated as the area under the curve from visit 1 to visit 4. Incident AF was identified by study visit ECGs, hospital discharge codes, or death certificates. A total of 9892 participants were included (44.6% men and mean age 62.9±5.7 years at visit 4) with 1550 (15.7%) individuals who developed new-onset AF during an average follow-up of 15.4 years. The incidence rates of AF per 1000 person-years across the 4 quartiles of cumulative systolic BP were 7.9, 9.2, 12.5, and 16.9, respectively. After multivariable adjustment, the hazard ratios for incident AF among participants in the highest quartile of cumulative systolic BP, pulse pressure, and mean arterial pressure were 1.48 (95% CI, 1.27-1.72), 1.81 (95% CI, 1.53-2.13), and 1.22 (95% CI, 1.05-1.41), respectively, compared with those in the lowest quartile. The addition of cumulative systolic BP or pulse pressure slightly improved the ability to predict new-onset AF.
Higher exposure to cumulative systolic BP, pulse pressure, and mean arterial pressure was significantly associated with increased risk of incident AF.
Transcription factor AP‐2 gamma (TFAP2C) is a known regulator of the estrogen receptor, and high expression of TFAP2C is associated with therapy resistance. This study identified PELP1 as a TFAP2C ...interacting protein. PELP1 is essential for optimal TFAP2C transcriptional functions. TFAP2C interactions with PELP1 confer a growth advantage to breast cancer (BC) cells by activating an oncogenic RET signaling thus contributing to BC progression and therapy resistance.
A significant proportion of estrogen receptor‐positive (ER+) breast cancer (BC) initially responds to endocrine therapy but eventually evolves into therapy‐resistant BC. Transcription factor AP‐2 gamma (TFAP2C) is a known regulator of ER activity, and high expression of TFAP2C is associated with a decreased response to endocrine therapies. PELP1 is a nuclear receptor coregulator, commonly overexpressed in BC, and its levels are correlated with poorer survival. In this study, we identified PELP1 as a novel interacting protein of TFAP2C. RNA‐seq analysis of PELP1 knockdown BC cells followed by transcription factor motif prediction pointed to TFAP2C being enriched in PELP1‐regulated genes. Gene set enrichment analysis (GSEA) revealed that the TFAP2C‐PELP1 axis induced a subset of common genes. Reporter gene assays confirmed PELP1 functions as a coactivator of TFAP2C. Mechanistic studies showed that PELP1‐mediated changes in histone methylation contributed to increased expression of the TFAP2C target gene RET. Furthermore, the TFAP2C‐PELP1 axis promoted the activation of the RET signaling pathway, which contributed to downstream activation of AKT and ERK pathways in ER+ BC cells. Concomitantly, knockdown of PELP1 attenuated these effects mediated by TFAP2C. Overexpression of TFAP2C contributed to increased cell proliferation and therapy resistance in ER+ BC models, while knockdown of PELP1 mitigated these effects. Utilizing ZR75‐TFAP2C xenografts with or without PELP1 knockdown, we provided genetic evidence that endogenous PELP1 is essential for TFAP2C‐driven BC progression in vivo. Collectively, our studies demonstrated that PELP1 plays a critical role in TFAP2C transcriptional and tumorigenic functions in BC and blocking the PELP1‐TFAP2C axis could have utility for treating therapy resistance.
With the advance of sequencing technology and microbiology, the microorganisms have been found to be closely related to various important human diseases. The increasing identification of human ...microbe-disease associations offers important insights into the underlying disease mechanism understanding from the perspective of human microbes, which are greatly helpful for investigating pathogenesis, promoting early diagnosis and improving precision medicine. However, the current knowledge in this domain is still limited and far from complete. Here, we present the computational model of Path-Based Human Microbe-Disease Association prediction (PBHMDA) based on the integration of known microbe-disease associations and the Gaussian interaction profile kernel similarity for microbes and diseases. A special depth-first search algorithm was implemented to traverse all possible paths between microbes and diseases for inferring the most possible disease-related microbes. As a result, PBHMDA obtained a reliable prediction performance with AUCs (The area under ROC curve) of 0.9169 and 0.8767 in the frameworks of both global and local leave-one-out cross validations, respectively. Based on 5-fold cross validation, average AUCs of 0.9082 ± 0.0061 further demonstrated the efficiency of the proposed model. For the case studies of liver cirrhosis, type 1 diabetes, and asthma, 9, 7, and 9 out of predicted microbes in the top 10 have been confirmed by previously published experimental literatures, respectively. We have publicly released the prioritized microbe-disease associations, which may help to select the most potential pairs for further guiding the experimental confirmation. In conclusion, PBHMDA may have potential to boost the discovery of novel microbe-disease associations and aid future research efforts toward microbe involvement in human disease mechanism. The code and data of PBHMDA is freely available at http://www.escience.cn/system/file?fileId=85214.
Transcription factors (TFs) are the mainstay of cancer and have a widely reported influence on the initiation, progression, invasion, metastasis, and therapy resistance of cancer. However, the ...prognostic values of TFs in breast cancer (BC) remained unknown. In this study, comprehensive bioinformatics analysis was conducted with data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. We constructed the co-expression network of all TFs and linked it to clinicopathological data. Differentially expressed TFs were obtained from BC RNA-seq data in TCGA database. The prognostic TFs used to construct the risk model for progression free interval (PFI) were identified by Cox regression analyses, and the PFI was analyzed by the Kaplan-Meier method. A receiver operating characteristic (ROC) curve and clinical variables stratification analysis were used to detect the accuracy of the prognostic model. Additionally, we performed functional enrichment analysis by analyzing the differential expressed gene between high-risk and low-risk group. A total of nine co-expression modules were identified. The prognostic index based on 4 TFs (NR3C2, ZNF652, EGR3, and ARNT2) indicated that the PFI was significantly shorter in the high-risk group than their low-risk counterpart (p < 0.001). The ROC curve for PFI exhibited acceptable predictive accuracy, with an area under the curve value of 0.705 and 0.730. In the stratification analyses, the risk score index is an independent prognostic variable for PFI. Functional enrichment analyses showed that high-risk group was positively correlated with mTORC1 signaling pathway. In conclusion, the TF-related signature for PFI constructed in this study can independently predict the prognosis of BC patients and provide a deeper understanding of the potential biological mechanism of TFs in BC.
The emerging strategies of accelerating the cleavage reaction in tumors through locally enriching the reactants is promising. Yet, the applications are limited due to the lack of the ...tumor‐selectivity for most of the reactants. Here we explored an alternative approach to leverage the rate constant by locally inducing an in vivo catalyst. We found that the desilylation‐induced cleavage chemistry could be catalyzed in vivo by cationic micelles, and accelerated over 1400‐fold under physiological condition. This micelle‐catalyzed controlled release platform is demonstrated by the release of a 6‐hydroxyl‐quinoline‐2‐benzothiazole derivative (HQB) in two cancer cell lines and a NIR dye in mouse tumor xenografts. Through intravenous injection of a pH‐sensitive polymer micelles, we successfully applied this strategy to a prodrug activation of hydroxyl camptothecin (OH‐CPT) in tumors. Its “decaging” efficiency is 42‐fold to that without cationic micelles‐mediated catalysis. This micelle‐catalyzed desilylation strategy unveils the potential that micelle may act beyond a carrier but a catalyst for local perturbing or activation.
Cationic micelles accelerate desilylation‐induced cleavage chemistry over 1400‐fold under physiological conditions. This micelle‐catalyzed desilylation strategy unveils the potential that micelles may act beyond carriers but as in vivo catalysts for local perturbing or activation.
The cardiovascular symptoms of CA include dyspnea on exertion (46.9%), lower limbs edema (71.9%), nocturnal paroxysmal (18.8%), hypotension (28.1%), chest pain (6.3%), syncope (15.6%) and cardiac ...arrest (6.3%).
Micelles In their Research Article on page 19750, Zhibo Liu et al. report a cationic micelle as an in vivo catalyst for tumor‐localized desilylation‐induced cleavage chemistry.
Malignant gliomas are largely refractory to immune checkpoint blockade (ICB) therapy. To explore the underlying immune regulators, we examine the microenvironment in glioma and find that ...tumor-infiltrating T cells are mainly confined to the perivascular cuffs and express high levels of CCR5, CXCR3, and programmed cell death protein 1 (PD-1). Combined analysis of T cell clustering with T cell receptor (TCR) clone expansion shows that potential tumor-killing T cells are mainly categorized into pre-exhausted/exhausted and effector CD8+ T subsets, as well as cytotoxic CD4+ T subsets. Notably, a distinct subpopulation of CD4+ T cells exhibits innate-like features with preferential interleukin-8 (IL-8) expression. With IL-8-humanized mouse strain, we demonstrate that IL-8-producing CD4+ T, myeloid, and tumor cells orchestrate myeloid-derived suppressor cell infiltration and angiogenesis, which results in enhanced tumor growth but reduced ICB efficacy. Antibody-mediated IL-8 blockade or the inhibition of its receptor, CXCR1/2, unleashes anti-PD-1-mediated antitumor immunity. Our findings thus highlight IL-8 as a combinational immunotherapy target for glioma.
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•With CCR5 and CXCR3 expression, T cells reside mainly at perivascular cuffs in TME•Glioma-killing T cells include pre-/exhausted, effector CD8+ T, and cytotoxic CD4+ T subsets•IL-8+CD4+ T (Th8) lineage exhibits innate-like feature and orchestrates TIME•Inhibition of the IL-8-CXCR1/CXCR2 axis reprograms TME and leverages ICB efficacy
Massive MDSC infiltration, pro-tumor TAM polarization, and angiogenesis in glioma constitute barriers to counteract ICB-elicited antitumor immunity. Liu et al. show that IL-8, derived from tumor, myeloid, and T cells, plays a pivotal role in orchestrating TIME in glioma, and blockade of the IL-8-CXCR1/CXCR2 axis unleashes anti-PD-1 efficacy in IL-8-humanized mice.
New Findings
What is the central question of this study?
Massive infusion can destroy the endothelial glycocalyx. We compared the serum concentrations of endothelial glycocalyx components and atrial ...natriuretic peptide and the outcomes of patients with different levels of stroke volume variation (SVV).
What is the main finding and its importance?
With a decrease in SVV, the serum concentrations of endothelial glycocalyx components and atrial natriuretic peptide increased, whereas the oxygenation index decreased. When the intraoperative SVV was maintained at 7−10%, the patients had better postoperative recovery and shorter postoperative hospital stays. Therefore, it is advisable to maintain the SVV between 7 and 10%.
Dynamic haemodynamic parameters, such as stroke volume variation (SVV), can be used for blood volume monitoring. However, studies have determined the SVV threshold but not the optimal level. The endothelial glycocalyx (EG) plays an important role in maintaining vascular permeability. Moreover, rapid and massive infusion can lead to the degradation, shedding and destruction of the EG. We aimed to explore the effects of different SVV values (11–14, 7–10 or 3–6%) on the EG in 54 patients who were scheduled for elective colorectal tumour surgery and to identify the optimal peri‐operative fluid therapy strategy. The concentrations of EG degradation products (heparin sulphate, hyaluronic acid and syndecan‐1) and atrial natriuretic peptide were higher when the SVV was maintained between 3 and 6% after fluid therapy compared with pre‐infusion (P < 0.05). Comparison of postoperative complications and hospitalization time among the three SVV levels was not statistically significant (P > 0.05). The postoperative hospitalization time in patients with SVV of 7–10% was shorter than that in patients with SVV of 3–6%. Infusion of a large volume of fluid, with increasing EG degeneration and atrial natriuretic peptide concentrations, might be related to postoperative outcomes.
Cleavage chemistry offers a new chance to activate chemotherapeutic prodrugs in a tumor‐selective manner, yet developing spatiotemporally controllable cleavage chemistry with deep tissue penetration ...is still a great challenge. Herein, we present a novel radiotherapy‐triggered cleavage chemistry that enables controlled drug release in tumors. Quaternary ammonium groups are identified as masking groups that can be efficiently removed by hydrated electrons (e−aq) from water radiolysis. The subsequently released tertiary amines can be anti‐cancer toxins or readily release functional molecules via 1,6‐elimination. This radiotherapy‐induced cleavage works successfully in living cells and tumor‐bearing mice, showing remarkable treatment efficacy when the mice are given carfilzomib prodrug and radiotherapy. This strategy provides a new perspective for combinational radiochemotherapy, which is the first‐line treatment for over 50 % of cancer patients.
Water radiolysis can generate many reactive particles, such as hydroxyl radicals and hydrated electrons (e−aq). A radiation‐induced e−aq‐mediated cleavage reaction based on a quaternary ammonium structure, which can precisely release a prodrug in vitro and in vivo, has been developed as a chemical tool for the future application of radiochemotherapy.
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