Electrosynthesis of Transition Metal Coordinated Polymers for Active and Stable Oxygen Evolution.

Transition metal coordination polymers (TM-CP) are promising inexpensive and flexible electrocatalysts for oxygen evolution reaction in water electrolysis, while their facile synthesis and controllable regulation remain challenging. Here we report an anodic oxidation-electrodeposition strategy for the growth of TM-CP (TM=Fe, Co, Ni, Cr, Mn; CP=polyaniline, polypyrrole) films on a variety of metal substrates that act as both catalyst supports and metal ion sources. An exemplified bimetallic NiFe-polypyrrole (NiFe-PPy) features superior mechanical stability in friction and exhibits high activity with long-term durability in alkaline seawater (over 2000 h) and anion exchange membrane electrolyzer devices at current density of 500 mA cm-2. Spectroscopic and microscopic analysis unravels the configurations with atomically distributed metal sites induced by d-π conjugation, which transforms into a mosaic structure with NiFe (oxy)hydroxides embedded in PPy matrix during oxygen evolution. The superior catalytic performance is ascribed to the anchoring effect of PPy that inhibits metal dissolution, the strong substrate-to-catalyst interaction that ensures good adhesion, and the Fe/Ni-N coordination that modulates the electronic structures to facilitate the deprotonation of *OOH intermediate. This work provides a general strategy and mechanistic insight into building robust inorganic/polymer composite electrodes for oxygen electrocatalysis.

Immunotherapy in leukaemia.

Leukaemia is the common name for a group of malignant diseases of the haematopoietic system with complex classifications and characteristics. Remarkable progress has been made in basic research and preclinical studies for acute leukaemia compared to that of the many other types/subtypes of leukaemia, especially the exploration of the biological basis and application of immunotherapy in acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). In this review, we summarize the basic approaches to immunotherapy for leukaemia and focus on the research progress made in immunotherapy development for AML and ALL. Importantly, despite the advances made to date, big challenges still exist in the effectiveness of leukaemia immunotherapy, especially in AML. Therefore, we use AML as an example and summarize the mechanisms of tumour cell immune evasion, describe recently reported data and known therapeutic targets, and discuss the obstacles in finding suitable treatment targets and the results obtained in recent clinical trials for several types of single and combination immunotherapies, such as bispecific antibodies, cell therapies (CAR-T-cell treatment), and checkpoint blockade. Finally, we summarize novel immunotherapy strategies for treating lymphocytic leukaemia and clinical trial results.

Favoring CO Intermediate Stabilization and Protonation by Crown Ether for CO2 Electromethanation in Acidic Media.

The large-scale deployment of CO2 electroreduction is hampered by deficient carbon utilization in neutral and alkaline electrolytes due to CO2 loss into (bi)carbonates. Switching to acidic media mitigates carbonation, but suffers from low product selectivity because of hydrogen evolution. Here we report a crown ether decoration strategy on a Cu catalyst to enhance carbon utilization and selectivity of CO2 methanation under acidic conditions. Macrocyclic 18-Crown-6 is found to enrich potassium cations near the Cu electrode surface, simultaneously enhancing the interfacial electric field to stabilize the *CO intermediate and accelerate water dissociation to boost *CO protonation. Remarkably, the mixture of 18-Crown-6 and Cu nanoparticles affords a CH4 Faradaic efficiency of 51.2 % and a single pass carbon efficiency of 43.0 % toward CO2 electroreduction in electrolyte with pH=2. This study provides a facile strategy to promote CH4 selectivity and carbon utilization by modifying Cu catalysts with supramolecules.

Indications for Adjuvant Chemotherapy in Stage II Gastric Cancer After D2 Gastrectomy-A Chinese Multicenter Study.

BACKGROUND: The benefit of adjuvant chemotherapy (AC) for patients with stage II gastric cancer remains controversial. This study aimed to explore the indications for adjuvant chemotherapy in patients with stage II gastric cancer by constructing an individual prediction model. PATIENTS AND METHODS: In this Chinese multicenter study, a total of 1012 patients with stage II gastric cancer after D2 radical gastrectomy were retrospectively analyzed. All patients were randomly assigned to a training cohort (n = 674) or a validation cohort (n = 338). A nomogram was constructed according to the training cohort. Concordance index (C-index), the area under the receiver operating characteristic (ROC) curves (AUC), calibration curves, and decision curve analysis (DCA) were applied to evaluate the performance of the nomogram. ROC curves and stratified survival were used to determine the patients' cutoff score for a benefit from adjuvant chemotherapy. An additional 338 patients were used as a validation cohort to validate the feasibility of using this nomogram to guide individualized therapy for patients with stage II gastric cancer. RESULTS: Univariate and multivariate analyses illustrated that age, sex, tumor location, size, carcinoembryonic antigen (CEA), hemoglobin (HB), and T stage were independent prognostic factors for overall survival (OS), and they were used to establish a nomogram. The cutoff value was determined by ROC curve analysis, and patients were divided into a high-risk group (< 239 points) and a low-risk group (≥ 239 points). There was no significant difference in the OS of low-risk patients in either the training cohort or the validation cohort. However, the OS of high-risk patients in the AC group was better than that of patients in the surgery-only group. CONCLUSIONS: This prediction model can be applied to guide treatment of patients with stage II gastric cancer. High-risk patients (< 239 points) are likely to benefit from AC after D2 radical gastrectomy.

Compliance with Oral Nutritional Supplementation among Gastric Cancer Patients at Nutritional Risk: A Cross-Sectional Study.

AIMS: To explore compliance with oral nutritional supplementation (ONS) and to identify the risk factors for noncompliance among gastric cancer patients based on the health belief model (HBM). METHODS: This prospective, observational study included gastric cancer patients at nutritional risk who were prescribed ONS from July to September 2020. Demographic factors, clinical factors, ONS-related factors, social factors and variables derived from the HBM were collected. The outcome of interest was compliance with ONS, which was measured by self-reported intake of ONS. Uni- and multivariate analyses of potential risk factors for noncompliance were performed. RESULTS: A total of 162 gastric cancer patients in the preoperative and adjuvant chemotherapy periods were analyzed. The compliance rate with ONS was 24.7%. Univariate analysis identified thirteen variables as risk factors for decreased compliance. Multivariate logistic analysis indicated that ONS compliance was independently associated with the treatment period, perceived barriers to ONS, the motivation to take ONS, and the timing of taking ONS. CONCLUSION: This study showed that overall ONS compliance among gastric cancer patients was notably low. Patients in the chemotherapy treatment period who took ONS at random times each day perceived more barriers to taking ONS and had a lower level of motivation were associated with lower compliance with ONS.

Clinicopathologic characteristics and prognosis of synchronous colorectal cancer: a retrospective study.

BACKGROUND: The clinical characteristics of synchronous colorectal cancer (SCRC) reported in previous studies differ significantly. Furthermore, little is known about the characteristics of early-onset synchronous colorectal cancer (EO-SCRC). The aim of this retrospective study was to identify the clinicopathological characteristics of SCRC and EO-SCRC and define their relevant prognostic factors. METHODS: Patients who underwent surgery for SCRC and primary unifocal colorectal cancer (PCRC) between January 2007 and December 2020 were included in this study. The clinical, histological, and molecular characteristics of the patient's tumours were analysed. The primary endpoint was overall survival (OS). Univariate and multivariate Cox regression analyses were used to assess the association between clinicopathological factors and patient survival. RESULTS: A total of 1554 patients were included in the analysis. Of these, 1132 (72.84%) had PCRC and 422 (27.16%) had SCRC. SCRC occurred more frequently in the elderly (P < 0.001) and in male patients (P = 0.002). The 5-year OS rate was 73.7% ± 2.0% for PCRC and 61.9% ± 3.9% for SCRC (P < 0.05). However, the Cox regression analysis showed that SCRC was not an independent prognostic factor for the prediction of OS. A total of 64 patients (15.17%) in the SCRC group had early-onset colorectal cancer (EOCRC), whereas 257 (22.70%) in the PCRC group had EOCRC (P = 0.001). The proportion of patients with deficient mismatch repair proteins (dMMR) in EO-SCRC subgroup was significantly higher than that in late-onset synchronous colorectal cancer (LO-SCRC) subgroup (23.44% vs. 10.34%, P = 0.006). Patients with EO-SCRC had more TNM stage IV (P < 0.001) and fewer opportunities for radical surgery (79.69% vs. 92.22%, P = 0.007) than those with early-onset primary unifocal colorectal cancer (EO-PCRC). There was no significant difference in 5-year OS between the EO-SCRC and LO-SCRC subgroups (P = 0.091) and between the EO-SCRC and EO-PCRC subgroups (P = 0.094). Multivariate analysis revealed that EOCRC was an independent good prognostic parameter for colorectal cancer (CRC) and SCRC. CONCLUSION: For patients with operative treatment, EO-SCRC is different from LO-SCRC and EO-PCRC. Patients with SCRC show a poorer survival rate than those with PCRC. However, SCRC is not an independent prognostic factor for CRC, whereas EOCRC is a good prognostic factor for CRC and SCRC.

Predicting pathologic complete response in locally advanced rectal cancer patients after neoadjuvant therapy: a machine learning model using XGBoost.

PURPOSE: Watch and wait strategy is a safe and effective alternative to surgery in patients with locally advanced rectal cancer (LARC) who have achieved pathological complete response (pCR) after neoadjuvant therapy (NAT); present restaging methods do not meet clinical needs. This study aimed to construct a machine learning (ML) model to predict pCR preoperatively. METHODS: LARC patients who received NAT were included to generate an extreme gradient boosting-based ML model to predict pCR. The group was divided into a training set and a tuning set at a 7:3 ratio. The SHapley Additive exPlanations value was used to quantify feature importance. The ML model was compared with a nomogram model developed using independent risk factors identified by conventional multivariate logistic regression analysis. RESULTS: Compared with the nomogram model, our ML model improved the area under the receiver operating characteristics from 0.72 to 0.95, sensitivity from 43 to 82.2%, and specificity from 87.1 to 91.6% in the training set, the same trend applied to the tuning set. Neoadjuvant radiotherapy, preoperative carbohydrate antigen 125 (CA125), CA199, carcinoembryonic antigen level, and depth of tumor invasion were significant in predicting pCR in both models. CONCLUSION: Our ML model is a potential alternative to the existing assessment tools to conduct triage treatment for patients and provides reference for clinicians in tailoring individual treatment: the watch and wait strategy is used to avoid surgical trauma in pCR patients, and non-pCR patients receive surgical treatment to avoid missing the optimal operation time window.

Triplet versus doublet neoadjuvant chemotherapy regimens for locally advanced gastric cancer: a propensity score matching analysis.

BACKGROUND: To investigate the differences between doublet and triplet neoadjuvant chemotherapy (NAC) regimens in efficacy and safety profile. METHODS: A total of 227 locally advanced gastric cancer (LAGC) patients who received NAC and sequential radical gastrectomy were reviewed. After propensity score matching (PSM), 140 patients with similar baseline characteristics were selected. Among them, 70 received doublet NAC regimens consisted of platinum and fluorouracil; the other 70 received triplet NAC regimens consisted of docetaxel, platinum, and fluorouracil. RESULTS: The efficacy of doublet and triplet regimens was comparable after propensity score matching in terms of tumor regression (pathological complete response, Doublet 11.4% vs. Triplet 15.7%, p = 0.642), achieving of R0 resection (Doublet 88.6% vs. Triplet 88.6%, p = 1), 1-year disease-free survival (DFS) (Doublet 77.1% vs. Triplet 68.6%, p = 0.178), 3-years overall survival (OS) (Doublet 54.3% vs. Triplet 60.9%, p = 0.941). Post-surgery complications were more common in the triplet cohort (Doublet 5.7% vs. Triplet 27.1%, p = 0.001), especially abdominal infection (Doublet 0% vs. Triplet 11.1%, p = 0.001). CONCLUSIONS: A more intense preoperative triplet NAC regimen does not bring extra downstage effect and survival benefit compared to a doublet regimen. It may even result in a higher risk of post-surgery complications.

Optimal Nutrition Formulas for Patients Undergoing Surgery for Colorectal Cancer: A Bayesian Network Analysis.

Optimal nutrition formulas for colorectal cancer patients underwent surgery remains uncertainty. We constructed an indirect comparison study to assess comparative efficacy of different immunonutrition formulas and standard nutrition in colorectal cancer patients underwent surgery. PubMed, the Cochrane Library, EMBASE, ClinicalTrials.gov and Web of Science databases were searched to identify RCTs that compared immunonutrition with standard nutrition or different immunonutrition formulas. Data on length of hospital stays (LOS), infectious complications (IC), noninfectious complications (NIC) and anastomotic leakage (AL) were extracted from the included RCTs for Bayesian network analysis using a random-effect model. Twelve articles that included 1032 individuals were incorporated into this study. The indirect comparison confirmed the potential improvement of arginine-based immunonutrition on IC (odds ratios [OR] = 0.43, 95%confidence interval [CI]: 0.17 to 0.95), glutamine on NIC (OR = 0.07 CI: 0.00 to 0.78) and LOS (MD=-3.91 CI: -6.33 to -1.69) and omega-3 polyunsaturated fatty acids on LOS (OR=-3.49 CI: -5.46 to -1.00). Results indicated that glutamine had the highest probability of reducing complications and hospital stays. As for colorectal cancer patients underwent surgery, this indirect comparison suggested some superiority of glutamine. Future more RCTs with larger scale are required to provide evidence for the optimal immunonutrition formulas.

Survival analysis of stage II gastric cancer patients after D2 gastrectomy: a Chinese people-based research.

OBJECTIVE: The benefit of adjuvant chemotherapy is still controversial for stage II gastric cancer patients. This study aims to identify prognostic factors to guide individualized treatment for stage II gastric cancer patients. METHODS: We retrospectively reviewed 1121 stage II gastric cancer patients who underwent D2 radical gastrectomy from 2007 to 2017 in the Sixth Affiliated Hospital of Sun Yat-sen University, FuJian Medical School Affiliated Union Hospital and Sun Yat-sen University Cancer Center. Propensity score matching was used to ensure that the baseline data were balanced between the adjuvant chemotherapy group and surgery-only group. Kaplan-Meier survival and multivariate Cox regression analyses were carried out to identify independent prognostic factors. RESULTS: In univariate analysis, after propensity score matching, age, tumor location, tumor size, CEA, T stage and N stage were associated with overall survival (OS). Multivariate analysis illustrated that age ≥ 60 years old, linitis plastica and T4 were independent risk factors for OS, but lower location and adjuvant chemotherapy were protective factors. CONCLUSION: Stage II gastric cancer patients with adverse prognostic factors (age ≥ 60, linitis plastica and T4) have poor prognosis. Adjuvant chemotherapy may be more beneficial for these patients.

Nomograms to predict cancer-specific mortality in colon adenocarcinoma with different types of villous architecture.

PURPOSE: The role of villous architecture in the prognosis of colon adenocarcinoma remains unclear. This study aimed to investigate the prognostic factors of colon adenocarcinoma with different types of villous architecture and to establish nomograms for predicting cancer-specific mortality. METHODS: This retrospective study included 10,427 patients with colon adenocarcinoma arising in adenomas with villous architectures. The patients were stratified into the tubulovillous adenocarcinoma cohort and villous adenocarcinoma cohort. The prognostic risk factors, which were incorporated into nomograms for survival prediction, were determined by the log-rank test and Cox hazard models. The Harrell's Concordance Index (C-index) and calibration curve were utilized to evaluate the prediction accuracy. RESULTS: The pathological type of villous architecture was independently associated with the mortality of the entire population. Age, race, tumor size, T/N/M stage, and chemotherapy were independent risk factors of mortality in both cohorts. Interestingly, tumor differentiation was a prognostic factor for tubulovillous adenocarcinoma rather than villous adenocarcinoma, while the retrieved lymph node number was a prognostic factor for villous adenocarcinoma rather than tubulovillous adenocarcinoma. Survival analysis showed that the mortality rate of villous adenocarcinoma was higher than that of tubulovillous adenocarcinoma (HR 1.361, P < 0.001). We then established nomograms to predict the mortality of both cohorts and found excellent discrimination and predictive accuracy (C-index 0.842 and 0.821). CONCLUSION: Villous architecture is a determinant of colon adenocarcinoma outcomes, which might prompt reports of villous architecture in colon adenocarcinoma specimens by pathologists. Our population-based nomograms could be useful for predicting the survival of patients with colon adenocarcinoma and guiding individualized treatments.

Effects of art therapy in cancer care: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of art therapy on cancer patients' quality of life and physical and psychological symptoms. METHODS: The databases PubMed, Embase, Web of Science, The Cochrane Library, Clinical Trial.gov, the China National Knowledge Infrastructure (CNKI), Wanfang and the Chinese Biomedical Literature Database (CBM) were searched from their inception up to 20 August 2019. Trials examining the effects of art therapy on physical and psychological symptoms and quality of life versus a control group were included. The methodological quality of the included randomised controlled trials was assessed using the risk of bias tool of Cochrane Handbook. Meanwhile, the Newcastle-Ottawa Quality Assessment Scale (NOS) was used to evaluate the methodological quality of the non-randomised studies. RESULTS: Twelve studies involving 587 cancer patients were included. The results revealed that art therapy significantly reduced anxiety symptoms (standard mean difference [SMD] = -0.46, 95% confidence interval [CI] [-0.90, 0.02], p = .04), depression symptoms (SMD = -0.47, 95% CI [-0.72, 0.21], p < .01), and fatigue (SMD = -0.38, 95% CI [-0.68, -0.09], p = .01) in cancer patients. Art therapy also significantly improved the quality of life of cancer patients (SMD = 0.43, 95% CI [0.18, 0.68], p < .01). CONCLUSIONS: Art therapy had a positive effect on quality of life and symptoms in cancer patients and can be used as a complementary treatment for cancer patients.

Analysis and external validation of a nomogram to predict peritoneal dissemination in gastric cancer.

OBJECTIVE: Peritoneal dissemination is difficult to diagnose by conventional imaging technologies. We aimed to construct a nomogram to predict peritoneal dissemination in gastric cancer (GC) patients. METHODS: We retrospectively analyzed 1,112 GC patients in Sun Yat-sen University Cancer Center between 2001 and 2010 as the development set and 474 patients from The Sixth Affiliated Hospital, Sun Yat-sen University between 2010 and 2016 as the validation set. The clinicopathological variables associated with gastric cancer with peritoneal dissemination (GCPD) were analyzed. We used logistic regression analysis to identify independent risk factors for peritoneal dissemination. Then, we constructed a nomogram for the prediction of GCPD and defined its predictive value with a receiver operating characteristic (ROC) curve. External validation was performed to validate the applicability of the nomogram. RESULTS: In total, 250 patients were histologically identified as having peritoneal dissemination. Logistic regression analysis demonstrated that age, sex, tumor location, tumor size, signet-ring cell carcinoma (SRCC), T stage, N stage and Borrmann classification IV (Borrmann IV) were independent risk factors for peritoneal dissemination. We constructed a nomogram consisting of these eight factors to predict GCPD and found an optimistic predictive capability, with a C-index of 0.791, an area under the curve (AUC) of 0.791, and a 95% confidence interval (95% CI) of 0.762-0.820. The results found in the external validation set were also promising. CONCLUSIONS: We constructed a highly sensitive nomogram that can assist clinicians in the early diagnosis of GCPD and serve as a reference for optimizing clinical management strategies.

A nomogram to predict prognosis for gastric cancer with peritoneal dissemination.

OBJECTIVE: To identify independent prognostic factors to be included in a nomogram to predict the prognosis of gastric cancer patients with peritoneal dissemination. METHODS: This is a retrospective study on 684 patients with a histological diagnosis of gastric cancer with peritoneal dissemination from the Sun Yat-sen University Cancer Center as the development set, and 62 gastric cancer patients from the Sixth Affiliated Hospital of Sun Yat-sen University as the validation group. Chi-square test and Cox regression analysis were used to compare the clinicopathological variables and the prognosis of gastric cancer patients with peritoneal dissemination. The Harrell's concordance index (C-index) and calibration curve were determined for comparisons of predictive ability of the nomogram. RESULTS: Univariate and multivariate analyses showed that serum carcinoembryonic antigen (CEA) level (P=0.032), ascites grading (P=0.008), presence of extraperitoneal metastasis (P<0.001), seeding status (P=0.016) and performance status (P=0.009) were independent prognostic factors for gastric cancer patients with peritoneal dissemination in the development set. The nomogram model was constructed using these five factors. Internal validation showed that the C-index of the model was 0.641. For the external validation, the C-index of this model was 0.709. CONCLUSIONS: We developed and validated a nomogram to predict the prognosis for gastric cancer patients with peritoneal dissemination. This nomogram may play an important clinical role in guiding palliative therapy for these types of patients, although it may need more data for optimization.

The effect of periodontal treatments on endothelial function in degrees of periodontitis patients: A systematic review and meta-analysis.

OBJECTIVE: This article focus on patients with moderate-to-severe periodontitis and periodontitis patients with cardiovascular disease. After they received periodontal initial therapy or antimicrobial drug treatment, was there any improvement in endothelial function during short- and long-term followups? METHOD: Relevant randomized controlled trials and clinical trials up to 30th June 2024 were identified and retrieved from electronic databases including PubMed, Cochrane Library, Web of Science and CNKI databases, with periodontitis therapy, periodontal disease and endothelial function as the keywords. The weighted (WMD) or standardized mean difference (SMD) was calculated using a fixed- or random-effect model and assessed heterogeneous results. RESULT: Generally, 14 studies published between 2004 and 2022 were eligible for the meta-analysis, which are all randomised clinical trials. A total of 491 periodontitis patients were screened. All participants received whole-mouth supragingival and subgingival scaling and root planing of the teeth, some trials combined with antimicrobial drug treatment as well as extracting teeth that could not be saved. The outcome indicators were measured by flow-mediated dilatation(FMD) levels. The results of the short term (≤3 months) periodontitis initial therapy group showed positive results (WMD = -3.78,95%CI = [-5.49,-2.07], P<0.0001), while the results of the long term (6 months) periodontitis therapy group exhibited significant difference (WMD = -0.96,95%CI = [-2.06,0.14],P = 0.09). Furthermore, study population were categorized according to the severity of periodontitis, the presence of comorbidities, endothelial dysfunction, and the inclusion of extractions and antimicrobial therapy in the treatment process. The effects of each of these factors on FMD were explored and the results of these subgroups all support periodontitis therapy. CONCLUSION: The results showed that periodontal treatment enhances endothelial function. Additionally, after subgroup analysis of long-term and short-term follow-up, patients with severe periodontitis, and different periodontal treatments, periodontal therapy was shown to increase FMD levels.

ELMO1 ameliorates intestinal epithelial cellular senescence via SIRT1/p65 signaling in inflammatory bowel disease-related fibrosis.

Background: Intestinal fibrosis is a common complication in inflammatory bowel disease (IBD), which still lacks of reliable markers and therapeutic options. Cellular senescence has been considered an important mechanism of intestinal fibrosis, but the underlying molecular link remains elusive. Methods: Tissues were stained using α-smooth muscle actin (α-SMA), fibronectin, and collagen I as markers of myofibroblastic differentiation. Cellular senescence was confirmed through Lamin B1 staining, senescence-associated ß-galactosidase staining, and the expression of senescence-associated secretory phenotype (SASP) factors. We explored the relationship between senescence of intestinal epithelial cells (IECs) and intestinal fibrosis, as well as the molecular mechanism underlying this interaction. The effects of irisin on cellular senescence and fibrosis were determined. Results: Here, we identify engulfment and cell motility protein 1 (ELMO1) as a novel biomarker for intestinal cellular senescence and fibrosis. In fibrostrictured tissues from patients and murine models with IBD, significantly high levels of cellular senescence score and factors were noted, which positively correlated with the fibrotic regulator fibronectin. Senescent IECs, not fibroblast itself, released SASP factors to regulate fibroblast activation. Prolonging exposure to severe and persistent injurious stimuli decreased ELMO1 expression, which dampened SIRT1 deacetylase activity, enhanced NF-κB (p65) acetylation, and thereby accelerated cellular senescence. Deletion of ELMO1 led to senescent IECs accumulation and triggered premature fibrosis in murine colitis. Furthermore, irisin, inhibiting the degradation of ELMO1, could downregulate p65 acetylation, reduce IECs senescence, and prevent incipient intestinal fibrosis in murine colitis models. Conclusions: This study reveals ELMO1 downregulation is an early symbol of intestinal senescence and fibrosis, and the altered ELMO1-SIRT1-p65 pathway plays an important role in intestinal cellular senescence and IBD-related fibrosis.

The EIF3H-HAX1 axis increases RAF-MEK-ERK signaling activity to promote colorectal cancer progression.

Eukaryotic initiation translation factor 3 subunit h (EIF3H) plays critical roles in regulating translational initiation and predicts poor cancer prognosis, but the mechanism underlying EIF3H tumorigenesis remains to be further elucidated. Here, we report that EIF3H is overexpressed in colorectal cancer (CRC) and correlates with poor prognosis. Conditional Eif3h deletion suppresses colorectal tumorigenesis in AOM/DSS model. Mechanistically, EIF3H functions as a deubiquitinase for HAX1 and stabilizes HAX1 via antagonizing ßTrCP-mediated ubiquitination, which enhances the interaction between RAF1, MEK1 and ERK1, thereby potentiating phosphorylation of ERK1/2. In addition, activation of Wnt/ß-catenin signaling induces EIF3H expression. EIF3H/HAX1 axis promotes CRC tumorigenesis and metastasis in mouse orthotopic cancer model. Significantly, combined targeting Wnt and RAF1-ERK1/2 signaling synergistically inhibits tumor growth in EIF3H-high patient-derived xenografts. These results uncover the important roles of EIF3H in mediating CRC progression through regulating HAX1 and RAF1-ERK1/2 signaling. EIF3H represents a promising therapeutic target and prognostic marker in CRC.

Small extracellular vesicles derived from adipose mesenchymal stem cells alleviate intestinal fibrosis by inhibiting the FAK/Akt signaling pathway via MFGE8.

BACKGROUND: Intestinal fibrosis is one of the most frequent and severe complications of Crohn's disease. Accumulating studies have reported that adipose mesenchymal stem cell-derived small extracellular vesicles (AMSC-sEVs) could alleviate renal fibrosis, hepatic fibrosis, etc., while their potential for treating intestinal fibrosis remains uncertain. Therefore, this study aims to determine the therapeutic effects of AMSC-sEVs on intestinal fibrosis and identify the mechanisms underlying these effects. METHODS: AMSC-sEVs were characterized using transmission electron microscopy, nanoparticle tracking analysis, and western blot. Whether AMSC-sEVs exert antifibrotic effects was investigated in two different murine models of intestinal fibrosis. Besides, AMSC-sEVs were co-cultured with primary human fibroblasts and CCD18co during transforming growth factor (TGF)-ß1 stimulation. Label-free proteomics and rescue experiments were performed to identify candidate molecules in AMSC-sEVs. Transcriptome sequencing revealed changes in mRNA levels among different groups. Lastly, proteins related to relevant signaling pathways were identified by western blotting, and their expression and activation status were assessed. RESULTS: AMSC-sEVs positively expressed CD63 and Alix and presented a classical "rim of a cup" and granule shape with approximately 43-100 nm diameter. AMSCs significantly alleviated intestinal fibrosis through secreted sEVs in vitro and in vivo. The milk fat globule-EGF factor 8 (MFGE8) was stably enriched in AMSC-sEVs and was an active compound contributing to the treatment of intestinal fibrosis by AMSCs. Mechanistically, AMSC-sEV-based therapies attenuated intestinal fibrosis by inhibiting the FAK/Akt signaling pathway. CONCLUSIONS: MFGE8-containing AMSC-sEVs attenuate intestinal fibrosis, partly through FAK/Akt pathway inhibition.

Zinc finger protein 180 induces an apoptotic phenotype by activating METTL14 transcriptional activity in colorectal cancer.

Zinc finger protein 180 (ZNF180) is a multifunctional protein that interacts with nucleic acids and regulates various cellular processes; however, the function of ZNF180 in colorectal cancer (CRC) remains unclear. The present study investigated the role and function of ZNF180 in CRC, and aimed to reveal the underlying molecular mechanism. The results revealed that ZNF180 was downregulated in CRC tissues and was associated with a good prognosis in patients with CRC. Additionally, the expression of ZNF180 was downregulated by methylation in CRC. In vivo and in vitro experiments revealed that ZNF180 overexpression was functionally associated with the inhibition of cell proliferation and the induction of apoptosis. Mechanistically, chromatin immunoprecipitation­PCR and luciferase assays demonstrated that ZNF180 markedly regulated the transcriptional activity of methyltransferase 14, N6­adenosine­methyltransferase non­catalytic subunit (METTL14) by directly binding to and activating its promoter region. Simultaneous overexpression of ZNF180 and knockdown of METTL14 indicated that the reduction of METTL14 could suppress the effects of ZNF180 on the induction of apoptosis. Clinically, the present study observed a significant positive correlation between ZNF180 and METTL14 expression levels, and low expression of ZNF180 and METTL14 predicted a poor prognosis in CRC. Overall, these findings revealed a novel mechanism by which the ZNF180/METTL14 axis may modulate apoptosis and cell proliferation in CRC. This evidence suggests that this axis may serve as a prognostic biomarker and therapeutic target in patients with CRC.