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Abstract Background The unmet post-treatment needs and issues of cancer survivors for follow-up care are still significant, matching appropriate and acceptable follow-up care to cancer survivors’ preferences, may increase adherence of survivors to health programs and quality of life. There is a knowledge gap about how cancer survivors measured their choices between different aspects of follow-up care. As discrete choice experiments (DCE) have been widely used in patient preference elicitation, we reviewed DCE on follow-up care for cancer survivors. Methods The electronic databases PubMed, The Cochrane Library, Embase, and Web of Science were searched, up to October 06, 2024. Original studies reporting preferences of cancer survivors for follow-up care elicited by DCE were eligible. Findings were presented using a narrative synthesis. Using two validated checklists to evaluate the quality of the included DCE studies. Results A total of 3525 records were identified and 9 papers were included. The studies were conducted in the Netherlands, Australia, the United Kingdom (UK) and China with 123 to 722 participants evaluated preferences of cancer survivors for follow-up care. Most of included cancer survivors were after completed the main treatment. Several key attributes for cancer survivors’ follow-up care were identified including healthcare provider, services offered, frequency of visits, contact mode, familiarity of healthcare provider with patients’ medical history/continuity of care. Conclusions The systematic review focusing on preferences of cancer survivors follow-up care and attributes identified in these studies, the results may inform healthcare providers should take cancer survivors preferences into account.

BackgroundGastric intestinal metaplasia is a common pathological feature in patients with Helicobacter pylori (H. pylori) infection. Rabeprazole was widely used as the first-line regimen for H. pylori infectious treatment. The objective of this study is to explore the mechanism of rabeprazole in gastric intestinal metaplasia treatment.MethodsReal-time PCR, Western blotting (WB) and ROS analysis were conducted to confirm that rabeprazole could induce ferroptosis to suppress gastric intestinal metaplasia. Cellular fraction, luciferase and chromatin immunoprecipitation (ChIP) were used to identify the mechanism underlying rabeprazole modulated ferroptosis.ResultsHerein, we found rabeprazole treatment led to inhibit CDX2 and MUC2 expression, alleviating gastric intestinal metaplasia, which was attributed to enhanced ferroptosis characterized by decreased GPX4 expression. Inhibition of ferroptosis by ferrostatin-1 (Fer-1) could reverse decreased CDX2 and MUC2 expression caused by rabeprazole. Mechanically, Rabeprazole could inhibit CREB phosphorylation and nuclear translocation, which further decreased the binding of CREB to GPX4 promoter, reducing GPX4 transactivity. Moreover, endogenous PKA interacted with CREB, and this interaction was drastically destroyed in response to rabeprazole treatment. Most importantly, enhanced ferroptosis was observed in H. pylori-infected gastric intestinal metaplasia in comparison to HC control.ConclusionThese findings suggested that rabeprazole induced ferroptosis to reduce CDX2 expression in gastric epithelial cells through PKA/CREB cascade signaling, implying that targeting ferroptosis could be a promising strategy in improving gastric intestinal metaplasia during H. pylori-infected patients.

Abstract Paraneoplastic syndromes occur in cancer patients and originate from dysfunction of organs at a distance from the tumor or its metastasis. A wide range of organs can be affected in paraneoplastic syndromes; however, the pathological mechanisms by which tumors influence host organs are poorly understood. Recent studies in the fly uncovered that tumor secreted factors target host organs, leading to pathological effects. In this study, using a Drosophila gut tumor model, we characterize a mechanism of tumor-induced kidney dysfunction. Specifically, we find that Pvf1, a PDGF/VEGF signaling ligand, secreted by gut tumors activates the PvR/JNK/Jra signaling pathway in the principal cells of the kidney, leading to mis-expression of renal genes and paraneoplastic renal syndrome-like phenotypes. Our study describes an important mechanism by which gut tumors perturb the function of the kidney, which might be of clinical relevance for the treatment of paraneoplastic syndromes.

Objective. Microfold cells (M cells) are specific intestinal epithelial cells for monitoring and transcytosis of antigens, microorganisms, and pathogens in the intestine. However, the mechanism for M-cell development remained elusive. Materials and Methods. Real-time polymerase chain reaction, immunofluorescence, and western blotting were performed to analyze the effect of sorbitol-regulated M-cell differentiation in vivo and in vitro, and luciferase and chromatin Immunoprecipitation were used to reveal the mechanism through which sorbitol-modulated M-cell differentiation. Results. Herein, in comparison to the mannitol group (control group), we found that intestinal M-cell development was inhibited in response to sorbitol treatment as evidenced by impaired enteroids accompanying with decreased early differentiation marker Annexin 5, Marcksl1, Spib, sox8, and mature M-cell marker glycoprotein 2 expression, which was attributed to downregulation of receptor activator of nuclear factor kappa-В ligand (RANKL) expression in vivo and in vitro. Mechanically, in the M-cell model, sorbitol stimulation caused a significant upregulation of phosphodiesterase 4 (PDE4) phosphorylation, leading to decreased protein kinase A (PKA)/cAMP-response element binding protein (CREB) activation, which further resulted in CREB retention in cytosolic and attenuated CREB binds to RANKL promoter to inhibit RANKL expression. Interestingly, endogenous PKA interacted with CREB, and this interaction was destroyed by sorbitol stimulation. Most importantly, inhibition of PDE4 by dipyridamole could rescue the inhibitory effect of sorbitol on intestinal enteroids and M-cell differentiation and mature in vivo and in vitro. Conclusion. These findings suggested that sorbitol suppressed intestinal enteroids and M-cell differentiation and matured through PDE4-mediated RANKL expression; targeting to inhibit PDE4 was sufficient to induce M-cell development.

Abstract Background Metabolic reprogramming is a critical event for cell fate and function, making it an attractive target for clinical therapy. The function of metabolic reprogramming in Helicobacter pylori (H. pylori)-infected gastric intestinal metaplasia remained to be identified. Methods Xanthurenic acid (XA) was measured in gastric cancer cells treated with H. pylori or H. pylori virulence factor, respectively, and qPCR and WB were performed to detect CDX2 and key metabolic enzymes expression. A subcellular fractionation approach, luciferase and ChIP combined with immunofluorescence were applied to reveal the mechanism underlying H. pylori mediated kynurenine pathway in intestinal metaplasia in vivo and in vitro. Results Herein, we, for the first time, demonstrated that H. pylori contributed to gastric intestinal metaplasia characterized by enhanced Caudal-related homeobox transcription factor-2 (CDX2) and mucin2 (MUC2) expression, which was attributed to activation of kynurenine pathway. H. pylori promoted kynurenine aminotransferase II (KAT2)-mediated kynurenine pathway of tryptophan metabolism, leading to XA production, which further induced CDX2 expression in gastric epithelial cells. Mechanically, H. pylori activated cyclic guanylate adenylate synthase (cGAS)-interferon regulatory factor 3 (IRF3) pathway in gastric epithelial cells, leading to enhance IRF3 nuclear translocation and the binding of IRF3 to KAT2 promoter. Inhibition of KAT2 could significantly reverse the effect of H. pylori on CDX2 expression. Also, the rescue phenomenon was observed in gastric epithelial cells treated with H. pylori after IRF3 inhibition in vitro and in vivo. Most importantly, phospho-IRF3 was confirmed to be a clinical positive relationship with CDX2. Conclusion These finding suggested H. pylori contributed to gastric intestinal metaplasia through KAT2-mediated kynurenine pathway of tryptophan metabolism via cGAS-IRF3 signaling, targeting the kynurenine pathway could be a promising strategy to prevent gastric intestinal metaplasia caused by H. pylori infection. Video Abstract

After people migrate to a different religious landscape, they will have multiple candidate religions to choose from, and some people may convert to a new religion. This study argues that both individual-level characteristics and a religion’s organizational traits are involved in religious conversion. Using cross-sectional samples of Chinese overseas students and scholars in the US in 2018 (n = 1911), we deployed mixed multinomial models to demonstrate how conversion, measured as intergenerational and personal religious changes, is associated with individual-level factors and organizational traits of religions. We found that the choice between Christianity, Buddhism, and Chinese folk religion, compared with no religion, is associated with unique individual-level characteristics. For religious organizational traits, missionary intensity and organized activity intensity are generally associated with a higher likelihood of conversion. This study distinguishes the different levels of the operating mechanism in conversion and points out an interactive and heterogenous model for individuals’ choice of various competing religions.

Background: Alteration of polyol pathway is a critical event in serials of disease, including inflammatory bowel disease (IBD). Shikonin, an inhibitor of PKM2, has been reported to exert a wide range of biological and pharmacological properties. However, the function of shikonin-mediated polyol pathway in IBD remained to be addressed. Methods: We conducted WB and qPCR to analyze the effect of shikonin on intestinal epithelial cell differentiation. IF, IP, luciferase assay and ChIP were employed to demonstrate the mechanism that shikonin regulated cell differentiation through polyol pathway. Elisa was used to measure the serum sorbitol in subjects enrolled in this study, and the clinical sample was collected to detect PKM2, AR and NRF2 expression. Results: Herein, we showed that shikonin treatment in HT-29 and CaCO2 cells not only contributed to CDX2 and its targets expression, including MUC2 and villin, leading to cell differentiation, but also induced NRF2-mediated AKR1B1 and AKR1B10 expression, resulting in increasing AR activity. A synergistic effect on CDX2-mediated cell differentiation was observed in CaCO2 cells in response to cotreatment with shikonin and AR agonist bortezomib for 24 hours, while aldose reductase inhibitor fidarestat treatment in CaCO2 cells reversed the enhanced CDX2 expression caused by shikonin. Mechanistically, PKM2 interacted with NRF2, and this interaction was enhanced in response to shikonin stimulation, resulting in NRF2 phosphorylation and nuclear translocation, which further increased AKR1B1 and AKR1B10 transactivation. Moreover, both AKR1B1 and AKR1B10 expression were decreased, while PKM2 was increased in intestinal epithelial cells labeled with E-cadherin in patients with IBD, and a negative clinical relationship was observed between PKM2 and AKR1B1/AKR1B10, respectively. What's more, the serum sorbitol level was decreased in patients with IBD. Conclusion: These results suggested that shikonin could promote intestinal cell differentiation through NRF2-mediated polyol pathway, implying that shikonin may be a promising therapeutic drug for the treatment of IBD.

NLRP3 inflammasome has emerged as a crucial regulator of inflammatory bowel disease (IBD) characterized by a chronic inflammatory disease of the gastrointestinal tract. The expression of MCT4 is significantly increased in intestinal mucosal tissue of IBD, which has been identified to regulate intestinal barrier function. However, the function of MCT4 in cell pyroptosis remained unknown. In this study, we have established a stable cell line with MCT4 overexpression in HT-29 and CaCO2 cells, respectively. Functional analysis revealed that ectopic expression of MCT4 in CaCO2 cells contributed to cell pyroptosis as evidenced by LDH assay, which is largely attributed to Caspase-1-mediated canonical pyroptosis, but not Caspase-4 and Caspase-5, leading to cleave pro-IL-1β and IL-18 into mature form and release mediated by cleaved GSDMD. Mechanically, MCT4 overexpression in HT-29 and CaCO2 cell triggered the phosphorylation of ERK1/2 and NF-κB p65, while inhibition of MCT4 by MCT inhibitor α-Cyano-4-hydroxycinnamic acid (α-CHCA) in HT-29 and CaCO2 cells led to a significant downregulation of ERK1/2 and NF-κB activity. What’s more, blockade of ERK1/2-NF-κB pathway could reverse the promotion effect of MCT4 on IL-1β expression. Importantly, both MCT4 and Caspase-1, GSDMD were significantly increased in patients with IBD, and a positive clinical correlation between MCT4 and Caspase-1 expression was observed (p < 0.001). Taken together, these findings suggested that MCT4 promoted Caspase-1-mediated canonical cell pyroptosis to aggravate intestinal inflammation in intestinal epithelial cells (IECs) through the ERK1/2-NF-κB pathway.

Insect ion transport peptides (ITPs) are important regulators of many physiological processes and they exert their functions by interacting with their receptors (ITPRs). In the current study, we comprehensively investigated the physiological functions of ITPR in the lepidopteran model insect, the silkworm (Bombyx mori), using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) genome editing technique. Mutations in silkworm ITPR (BNGR-A2) resulted in a prolongnation of the larval stage by 3.5-day as well as failure in wing expansion of moths. The BNGR-A2 mutation accelerated food transition throughout the digestive tract, which is 1.55-fold that of wild type (WT) insects. Excretion was 1.56-fold of WT insects during the larval stage, resulting in the loss of body water content. Loss of BNGR-A2 function induced significant upregulation of nitric oxide synthase (NOS) enzyme activity and nitric oxide (NO) content, as well as downstream Ca2+/NO/cGMP signaling pathways. Key genes in insulin and ecdysone signaling pathways were also affected by BNGR-A2 disruption. Our data show that ITPR plays key roles in regulating insect water homeostasis and development.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent and fatal disease worldwide. The function of club cells, which are considered progenitor/stem cells of the bronchial epithelium, and their secreted protein CC16, have been proposed as potential targets for COPD treatment. This study aimed to investigate the role of the TGF-β1/ALK5 signaling pathway in club cell function and COPD progression. C57BL/6J mice were divided into Normal group (exposed to fresh air) and COPD group (exposed to incremental cigarette smoke extract for 12 weeks). The COPD mice were further divided into COPD group, DMSO group, and LY2109761 group (injected with 150 mg/kg LY2109761, a TGF-β1 inhibitor). Tissue staining was used to assess lung damage, and the expression of CC16 was measured. The levels of inflammatory factors and DNA damage-related indicators were also measured. The involvement of the MEK/ERK signaling pathway was determined. COPD mice exhibited severe lung damage and impaired club cell function. Activation of the TGF-β1/ALK5 and MEK/ERK pathways were observed in COPD mice. However, administration of LY2109761 in COPD mice inactivated the TGF-β1/ALK5 and MEK/ERK pathways. Administration of LY2109761 also alleviated pulmonary fibrosis, downregulated the levels cleaved caspase-3, IL-4, IL-5, IL-13, IL-12, and IFN-γ, and limited the phosphorylation of Chk1. Moreover, LY2109761 enhanced CC16 expression and decreased lung cell apoptosis. Inactivation of the TGF-β1/ALK5 axis inhibits the MEK/ERK signaling pathway, enhances club cell function, and alleviates lung tissue damage. These findings suggest that TGF-β1 is a potential therapeutic target for COPD. [ABSTRACT FROM AUTHOR]