Ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract, characterized by ongoing intestinal inflammation, epithelial damage, and mucosal injury. Despite the identification of C-C motif chemokine ligand 5 (CCL5) as a key mediator in UC, the precise mechanisms underlying its role in immune activation and inflammation remain unclear. This study aimed to investigate CCL5 as a critical immune modulator in UC, focusing on its effects on immune cell activation, particularly regulatory T cell (Treg) formation, and the molecular pathways involved in these processes. Using the dextran sulfate sodium salt (DSS)-induced UC model and CCL5 knockout (Ccl5-KO) mice, we demonstrated that CCL5 deficiency exacerbates intestinal inflammation during the acute phase of colitis, partly due to impaired interleukin-33 (IL-33)-induced Treg formation. In addition, we observed a positive correlation between CCL5 expression and forkhead box protein 3 (FOXP3) levels in inflamed colon tissues of UC patients, suggesting a role for CCL5 in Treg regulation. Mechanistically, CCL5 deficiency disrupted the PI3K/Akt/NF-κB signaling pathway, resulting in reduced IL-33 expression, which in turn impaired CD4+ T cell activation and FOXP3+ Treg formation via the JAK1/STAT5 pathway. In vivo rescue experiments confirmed that restoring IL-33 signaling could alleviate inflammation and partially recover Treg function. Collectively, these findings highlight CCL5 as a novel immune modulator of Treg formation and immune responses in UC and suggest that targeting CCL5 may offer a promising therapeutic strategy for managing UC and related inflammatory diseases.

RATIONALE:Elderly patients with severe COVID-19 frequently develop chronic critical illness marked by prolonged ventilation, multidrug-resistant infections, enteral-nutrition (EN) intolerance, and persistent inflammation-immunosuppression-catabolism syndrome, making liberation from the ventilator and recovery difficult. Integrative Chinese and Western medicine (ICWM) is hypothesized to modulate immunity and the gut-lung axis and to stabilize frail physiology during long ICU courses. PATIENT CONCERNS:An 87-year-old man with >10-year Parkinson's disease experienced septic shock, invasive ventilation, and tracheotomy after COVID-19, prompting a request for ICWM. DIAGNOSES:Severe pneumonia due to COVID-19 (CURB-65 score of 3); multiple organ dysfunction syndrome (respiratory failure, acute renal failure, and acute heart failure); sepsis; malnutrition; Parkinson's disease; and lower extremity venous thrombosis. The traditional Chinese medicine diagnosis was based on "epidemic disease," with dampness toxin stagnation in the lung, and spleen and kidney deficiency. INTERVENTIONS:A multidisciplinary team delivered individualized ICWM aligned with the "Shanghai Expert Consensus" and the traditional Chinese medicine principle of "benefiting qi and strengthening the body." Prescriptions were dynamically adjusted to syndrome evolution and to gastrointestinal tolerance, successively including Buzhong Yiqi decoction, Shenling Baizhu powder, Weijing decoction, Tounong decoction, and Shengxian decoction; when gastrointestinal absorption was limited or shock was present, intravenous Shenfu injection was added. Standard care comprised culture-guided antimicrobials, bronchoscopy-assisted secretion clearance, invasive ventilatory support, and nutrition therapy with EN. The ICWM plan was titrated specifically to address EN-intolerance diarrhea and to support nutritional rehabilitation. OUTCOMES:After treatment, intolerance symptoms improved; sputum cultures converted to negative by ICU day 41. The patient weaned from mechanical ventilation and the tracheal tube 10 days later, and remained afebrile without productive cough, enabling discharge to home convalescence. LESSONS:This case highlights the need for ICWM in critically ill patients, especially in those with chronic critical illness and persistent inflammation-immunosuppression-catabolism syndrome.

Fluid balance in the early stages of severe acute pancreatitis (SAP) significantly impacts patient outcomes. This study aimed to identify the optimal fluid balance value affecting adverse outcomes in SAP patients to enhance fluid management. The study comprised two parts. Part 1 involved a retrospective review of 560 SAP patients at Ruijin Hospital (1996–2008) to determine the optimal fluid balance for in-hospital mortality using multivariable regression and ROC curve analysis. Part 2 prospectively examined 343 SAP patients in Emergency Intensive Care Unit at Ruijin Hospital (2020–2023) to validate findings regarding 30-day mortality and organ support. In Part 1, key independent risk factors for in-hospital mortality included age, weight, hypertension, APACHE II score, D0-D2/kg fluid balance, sugery and necrosis. The optimal predictive D0-D2/kg fluid balance value was found to be 48.4 ml/kg. In Part 2, exceeding this value indicated a higher risk for 30-day mortality (HR = 3.477) and increased need for mechanical ventilation (OR = 4.741) and blood purification (OR = 3.685). A D0-D2/kg fluid balance above 48.4 ml/kg correlates with poorer outcomes in SAP patients, providing guidance for clinicians in fluid management to improve prognosis.

Myeloid-derived suppressor cells (MDSCs) play a crucial role in tumor-associated immune suppression and in impeding immune checkpoint blockade (ICB) therapies; however, effective intervention strategies targeting MDSCs remain limited. In this study, we observed a positive correlation between spleen tyrosine kinase (SYK) activity in immune cells and tumor progression in human cancers. Utilizing a mouse model with a gain-of-function SYKS544Y mutation, we demonstrated that SYK activation promotes tumorigenesis in carcinogen-induced and xenograft models across multiple cancer types, largely through MDSC-dependent mechanisms. Mechanistically, SYK activates the JAK-STAT-CXCR2 signaling axis, enhancing MDSC migration and suppressing antitumor T cell responses. Notably, pharmacological inhibition of SYK not only inhibited tumor growth but also enhanced the therapeutic effect of anti-PD-1 in mouse models and patient-derived tumor organoid models. Our findings highlight the immunoregulatory role of SYK in tumor progression and suggest that targeting SYK represents a promising strategy to remodel the tumor microenvironment and enhance the efficacy of checkpoint blockade immunotherapy.

Abstract Background N6-methyladenosine (m6A) is the most abundant post-transcriptional modification, and METTL16 has recently emerged as a pivotal m6A methyltransferase in cancer. Cholesterol metabolic reprogramming and aberrant MAPK signaling sustain the malignant initiation and progression of colorectal cancer (CRC). However, whether - and how - m6A regulation, particularly by METTL16, interfaces with cholesterol metabolism and downstream oncogenic signaling in CRC remains unknown. Methods Differential expression of METTL16 in CRC was identified through bioinformatic analyses and validated by qRT-PCR, immunoblotting, and immunohistochemistry (IHC). The functional role of METTL16 in CRC progression was examined using in vitro assays and xenograft models. To identify downstream targets, RNA-seq and MeRIP-seq were performed, revealing MSMO1 as a METTL16-regulated gene. The mechanistic basis of the METTL16–MSMO1 axis was investigated through immunoprecipitation-Mass Spectrometry (IP-MS), co-immunoprecipitation (Co-IP), RNA immunoprecipitation (RIP), MeRIP-qPCR, and RNA stability assays. Cholesterol metabolism analyses were conducted to further characterize the metabolic consequences of METTL16–MSMO1 regulation. Results METTL16 was significantly upregulated in CRC and correlated with poor clinical outcomes. Mechanistically, METTL16 enhanced m6A modification of MSMO1, stabilizing its transcript via IGF2BP2 and disrupting intracellular cholesterol homeostasis, which triggered ER stress and activated MAPK-p38/ NF-κB signaling by promoting TAK1/TAB complex formation and TAK1 autophosphorylation, thereby driving CRC progression. Additionally, elevated cholesterol levels further reshaped global m6A methylation patterns and altered methyltransferase expression, suggesting a reciprocal feedback loop between cholesterol metabolism and epigenetic regulation. Conclusions These findings underscore the critical role of the METTL16–MSMO1 axis in driving cholesterol metabolic reprogramming that fuels MAPK-p38/NF-κB oncogenic signaling in CRC, highlighting promising biomarkers and therapeutic targets for improved disease management.

Dysregulation of RNA N6-methyladenosine (m6A) modification in intestinal epithelial cells (IECs) compromises intestinal homeostasis, which is critical for maintaining gastrointestinal functions, immunity, and barrier integrity in inflammatory bowel disease (IBD). Here we explored the role of m6A modification, particularly through methyltransferase like 3 (METTL3), in IBD pathology and the apoptosis of intestinal stem cells (ISCs). Reduced m6A RNA methylation and METTL3 expression were detected in IBD tissues, which correlated with increased ISC apoptosis and spontaneous enteritis in METTL3-deficient models; mechanistically, Mettl3 depletion increased TRADD expression in a m6A-dependent manner, thereby augmenting the TNF-induced apoptosis pathway, whereas pharmacological inhibition of TRADD ameliorated the apoptotic phenotype in METTL3-deficient models and improved survival rates in the enteritis mouse model, suggesting a novel therapeutic avenue for IBD management. Collectively, METTL3-mediated m6A RNA methylation plays a pivotal role in maintaining intestinal homeostasis and is activated in ISCs to mitigate the hyperactivity of endogenous inflammatory signals; by modulating TRADD transcript metabolism, METTL3 limits excessive ISC apoptosis, providing insights into IBD pathogenesis and treatment strategies.

PURPOSE:This study aimed to develop a nomogram for predicting acute kidney injury (AKI) in patients with moderate severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP). METHODS:This study enrolled a total of 1,077 patients with MSAP and SAP, categorizing them into three groups: training (n = 646), internal validation (n = 278), and external validation (n = 153). In the training cohort, logistic regression analysis identified independent predictors of AKI in patients with MSAP and SAP. A nomogram was developed based on these independent predictors. The model's performance was assessed using the receiver operating characteristics (ROC) curve, precision-recall (PR) curve, calibration curve, and decision curve analysis (DCA). RESULTS:The incidence rates of AKI in the training set, internal validation set, and external validation set were 32.82%, 32.01%, and 27.45%, respectively. Independent predictors of AKI in patients with MSAP and SAP included: shock index (odds ratio [OR] = 7.42, 95% confidence interval [CI] 2.18-25.19), blood urea nitrogen (OR = 1.32, 95% CI 1.22-1.43), uric acid (OR = 1.002, 95% CI 1.000-1.003), serum calcium (OR = 0.38, 95% CI 0.18-0.79), triglycerides (OR = 1.02, 95% CI 1.004-1.041), hematocrit > 0.5 (OR = 3.24, 95% CI 1.10-9.59), serum sodium < 135 mmol/L (OR = 2.01, 95% CI 1.15-3.49), creatine kinase isoenzyme > 4 ng/mL (OR = 2.61, 95% CI 1.48-4.61), and thrombin time < 14 s (OR = 2.83, 95% CI 1.28-6.27). In the training, internal validation, and external validation sets, the areas under the ROC curves for the nomogram were 0.841, 0.789, and 0.853, respectively. Similarly, the areas under the PR curves were 0.807, 0.733, and 0.770. The calibration curves demonstrated that the predicted outcomes were well-aligned with the actual results. The decision curve analysis (DCA) indicated that the model had satisfactory clinical applicability. CONCLUSIONS:Nine indicators have been identified as independent predictors of AKI in patients with MSAP and SAP. The developed nomogram exhibits robust predictive capability and shows promise for clinical application.

Two emerging techniques for mid-low rectal cancer treatment include robotic surgery (RoTME), and transanal total mesorectal excision (taTME). Additionally, using the superior pelvic diaphragm as a landmark helps protect pelvic autonomic nerves and reduces intraoperative risks. This study compares the long-term oncological and functional outcomes of taTME and RoTME in cT3/cT4 patients after neoadjuvant therapy using propensity score matching, while also evaluating the role of the superior pelvic diaphragm as a surgical guide. We retrospectively analyzed patients who underwent proctectomy between February 2017 and May 2019. After applying strict inclusion criteria, propensity score matching was performed. Additionally, we identified and included patients with a difficult pelvis for further analysis. Oncological outcomes were assessed using 3- and 5-year disease-free survival (DFS) and overall survival (OS), visualized with Kaplan-Meier curves. Pelvic nerve preservation was evaluated based on urinary dysfunction, while anal function was measured using the LARS score questionnaire. 75 patients underwent taTME and 203 underwent RoTME. After 1:2 propensity score matching, the groups comprised 75 taTME and 150 RoTME patients. All patients completed 60-month oncological follow-up, with anal function assessed at six months postoperatively. Compared to RoTME, taTME showed a lower anastomotic leak incidence but higher rate of diverting stomas, despite comparable baseline data.No significant differences were observed in intraoperative complications, functional outcomes, or long-term survival. Notably, identifying the superior pelvic diaphragm intraoperatively aided pelvic nerve preservation. Both RoTME and taTME prove feasible for treating cT3/cT4 lower rectal cancer post-nCRT. When performed beyond the learning curve, these techniques represent safe and reliable surgical options.

PURPOSE:Cancer cells rely on serine biosynthesis for growth, but its regulation in colorectal cancer (CRC) remains not well understood. This study identifies the m5C methyltransferase NSUN2 (NOP2/Sun domain family, member 2) as a key regulator of serine biosynthesis, revealing a novel mechanism driving CRC progression. METHODS:The expression and prognostic value of NSUN2 were evaluated using bioinformatics analyses and immunohistochemistry (IHC) assays. The effects of NSUN2 on cellular serine biosynthesis, intracellular reactive oxygen species (ROS) levels, and apoptosis levels were analyzed both in vitro and in vivo. Additionally, RNA sequencing, Methylated RNA Immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP), and RNA stability assays were utilized to screen and validate the association between NSUN2 and phosphoglycerate dehydrogenase (PHGDH). RESULTS:NSUN2 was found to be highly expressed in CRC and associated with poor patient survival. PHGDH, a direct downstream target of NSUN2, plays a crucial role in NSUN2-mediated serine biosynthesis. Furthermore, inhibition of NSUN2 significantly reduced the intracellular NADH/NAD+ and NADPH/NADP+ ratios, leading to an increase in ROS levels and apoptosis levels, thereby inhibiting CRC progression. Additionally, NSUN2 enhances PHGDH expression and mRNA stability by binding to the "reader" protein m5C-Aly/REF export factor (ALYREF). CONCLUSIONS:This study identified a novel NSUN2/ALYREF/m5C-PHGDH axis might be promising therapeutic targets for CRC.

Circulating cell-free DNA (cfDNA) has emerged as a promising noninvasive diagnostic tool for liquid biopsy, with abnormal DNA methylation serving as a key biomarker for cancer screening and early diagnosis. However, the low abundance and high fragmentation of cfDNA present significant challenges to the sensitivity and specificity of the current methylation detection methods. We aim to develop a highly sensitive methylation detection method for fragmented cfDNA that does not require bisulfite conversion. In this study, we combined double restriction enzyme digestion with specific terminal-mediated polymerase chain reaction (STEM-PCR) to establish a cfDNA methylation detection method, namely, the dRE-STEM method. The dRE-STEM method could detect methylated cfDNA on the PCR platform without the need for cumbersome bisulfite conversion. A case-control study was conducted to validate the diagnostic value of colorectal cancer (CRC)-related specific methylated locates using the dRE-STEM method. The dRE-STEM method successfully detected methylation ratios as low as 3% using just 4 ng of cfDNA input, and the best diagnostic model achieved 80.2% (95% CI, 70.6-87.4%) sensitivity and 80.9% (95% CI, 71.9-87.7%) specificity for CRC, significantly outperforming conventional protein markers. The dRE-STEM method offers a promising approach for accurate methylation quantification in low-abundance, highly fragmented cfDNA, making it particularly suitable for routine clinical practice.

Inducible Co-Stimulator (ICOS), as a T-cell–specific costimulatory receptor that enhances T-cell responses to foreign antigens, plays a crucial role in cancer immunity. However, its role in MSS/pMMR colorectal cancer (CRC) remains unclear. In this study, we demonstrated that ICOS expression decreases as the tumor stages advance and that high ICOS expression is associated with a favorable prognosis in MSS/pMMR CRC. Mechanistically, ICOS promoted the secretion of IFN-γ, TNF-α, and IL-12 in CD4+ T cells through the Akt/STAT1/T-bet axis, leading to the inhibition of MSS/pMMR-CRC-cell proliferation. Importantly, ICOS+ CD4+ T cells enhanced tumor responses to anti-PD-1 therapy in MSS/pMMR CRC. In conclusion, this study revealed that ICOS mediates antitumor immunity by promoting the secretion of cancer-suppressive cytokines. It also suggests that activation of ICOS serves a potential therapeutic strategy for MSS/pMMR CRC.

Background Laparoscopic surgery is increasingly used for rectal cancer, but the long-term oncological outcomes for low rectal cancer have not been fully established. We aimed to evaluate the 3-year survival outcomes of laparoscopic surgery versus open surgery in the treatment of low rectal cancer. Methods This multicentre, randomised, controlled, non-inferiority trial was conducted at 22 tertiary hospitals in China. Individuals aged 18-75 years with histologically confirmed cT1-2N0, cT3-4aN0, or cT1-4aN1-2 rectal adenocarcinoma within 5 cm from the dentate line were eligible for inclusion. Participants were randomly assigned (2:1) to undergo laparoscopic surgery or open surgery. Central randomisation was conducted using a web response system, and was stratified by clinical stage, age, sex, BMI, and American Society of Anesthesiologists classification. Investigators, patients and statisticians were not masked to group allocation. The primary outcome was 3-year disease-free survival, defined as the time from the date of surgery to the date of locoregional recurrence, distant metastasis, or death from any cause, whichever occurred first. Non-inferiority was defined as a lower limit of onesided 975% CI for group difference (laparoscopic surgery group minus open surgery group) of greater than -10%. The primary analyses were performed in the modified intention-to-treat population, which excluded patients with distant metastasis discovered during surgery and those who did not undergo surgery or underwent local resection only. The trial is registered with ClinicalTrials.gov, NCT01899547, and has been completed. Findings Between Nov 12, 2013, and June 6, 2018, 1070 patients were enrolled and randomly assigned to treatment. 1039 patients (685 in the laparoscopic surgery group and 354 in the open surgery group; median age 57 years, IQR 50 to 64; 620 [60%] male and 419 [40%] women) were included in the modified intention-to-treat analysis. 3-year disease-free survival was 814% (95% CI 782 to 841) in the laparoscopic surgery group and 798% (752 to 836) in the open surgery group (hazard ratio [HR] 092, 95% CI 069 to 123; p=056). The difference between groups was 160% (one-sided 975% CI -334 to infinity, p<00001 for non-inferiority). 3-year overall survival was 917% (95% CI 893 to 935) in the laparoscopic surgery group and 937% (906 to 958) in the open surgery group (HR 134, 95% CI 082 to 219; p=024). 3-year locoregional recurrence was 37% (95% CI 25 to 53) and 23% (11 to 43), respectively (HR 164, 95% CI 074 to 363; p=022). 5-year overall survival was 846% (95% CI 815 to 871) and 866% (825 to 898) in the open group (HR 116, 95% CI 082 to 164; p=041). Interpretation Laparoscopic surgery performed by experienced surgeons is non-inferior to open surgery for 3-year disease-free survival among patients with low rectal cancer. These results support the use of laparoscopic surgery for low rectal cancer. Funding The Key Clinical Specialty Discipline Construction Program of the National Health and Family Planning Commission of China; Minimally Invasive Medical Center Construction Program, Fujian Province, China; and Joint Funds for the Innovation of Science and Technology, Fujian Province, China. Copyright (c) 2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

The colon is the largest compartment of the immune system, with innate immune cells exposed to antigens in the environment. However, the mechanisms by which the innate immune system is instigated are poorly defined in colorectal cancer (CRC). Here, a population of CD16+ neutrophils that specifically accumulate in CRC tumor tissues by imaging mass cytometry (IMC), immune fluorescence, and flow cytometry, which demonstrated pro-tumor activity by disturbing natural killer (NK) cells are identified. It is found that these CD16+ neutrophils possess abnormal cholesterol accumulation due to activation of the CD16/TAK1/NF-κB axis, which upregulates scavenger receptors for cholesterol intake including CD36 and LRP1. Consequently, these region-specific CD16+ neutrophils not only competitively inhibit cholesterol intake of NK cells, which interrupts NK lipid raft formation and blocks their antitumor signaling but also release neutrophil extracellular traps (NETs) to induce the death of NK cells. Furthermore, CD16-knockout reverses the pro-tumor activity of neutrophils and restored NK cell cytotoxicity. Collectively, the findings suggest that CRC region-specific CD16+ neutrophils can be a diagnostic marker and potential therapeutic target for CRC.

PURPOSE Complete mesocolic excision (CME) is being increasingly used for the treatment of right-sided colon cancer, although there is still no strong evidence that CME provides better long-term oncological outcomes than D2 dissection. The controversy is mainly regarding the survival benefit from extended lymph node dissection emphasized by CME. METHODS This multicenter, open-label, randomized controlled trial (ClinicalTrials.gov identifier: NCT02619942 ) was performed across 17 hospitals in China. Patients diagnosed with stage T2-T4aNanyM0 or TanyN + M0 right-sided colon cancer were randomly assigned (1:1) to undergo either CME or D2 dissection during laparoscopic right colectomy. The primary outcome was the 3-year disease-free survival (DFS), and the main secondary outcome was the 3-year overall survival (OS). RESULTS Between January 11, 2016, and December 26, 2019, 1,072 patients were randomly assigned (536 patients to CME and 536 patients to D2 dissection). In total, 995 patients (median age 61 years, 59% male) were included in the primary analysis (CME [n = 495] v D2 dissection [n = 500]). No significant differences were found between the groups in 3-year DFS (hazard ratio [HR], 0.74 [95% CI, 0.54 to 1.02]; P = .06; 86.1% in the CME group v 81.9% in the D2 group) or in 3-year OS (HR, 0.70 [95% CI, 0.43 to 1.16]; P = .17; 94.7% in the CME group v 92.6% in the D2 group). CONCLUSION This trial failed to find evidence of superior DFS outcome for CME compared with standard D2 lymph node dissection in primary surgical excision of right-sided colon cancer. Standard D2 dissection should be the routine procedure for these patients. CME should only be considered in patients with obvious mesocolic lymph node involvement.

Growth differentiating Factor 15 (GDF15) is linked to several cancers, but its effect on chemoresistance in colorectal cancer (CRC) remains unclear. Here, we investigated the role of GDF15 in the chemotherapeutic response of CRC patients to oxaliplatin (L-OHP). GDF15 levels in serum and tumour tissues were detected in CRC patients have received L-OHP-based neoadjuvant chemotherapy. The effects of GDF15 neutralization or GDF15 knockdown on cell proliferation, apoptosis and intracellular reactive oxygen species (ROS) levels were analysed in vitro and in vivo. Co-immunoprecipitation (Co-IP), Chromatin Immunoprecipitation (ChIP) and luciferase reporter assays were used to explore the interaction between GDF15 and Nrf2. In this study, we found that GDF15 alleviates oxidative stress to induce chemoresistance of L-OHP in CRC. Mechanically, GDF15 posttranscriptionally regulates protein stability of Nrf2 through the canonical PI3K/AKT/GSK3β signaling pathway, and in turn, Nrf2 acts as a transcription factor to regulate GDF15 expression to form a positive feedback loop, resulting in the maintenance of redox homeostasis balance in CRC. Furthermore, a positive correlation between GDF15 and Nrf2 was observed in clinical CRC samples, and simultaneous overexpression of both GDF15 and Nrf2 was associated with poor prognosis in CRC patients treated with L-OHP. Simultaneous inhibition of both GDF15 and Nrf2 significantly increases the response to L-OHP in an L-OHP-resistant colorectal cancer cells-derived mouse xenograft model. This study identified a novel GDF15-Nrf2 positive feedback loop that drives L-OHP resistance and suggested that the GDF15-Nrf2 axis is a potential therapeutic target for the treatment of L-OHP-resistant CRC.

Eph receptor B2 (EPHB2) is overexpressed in some tumors and relevant to unfavorable outcomes of tumor patients. By searching Gene Expression Profiling Interactive Analysis and KM Plot websites, we discovered that EPHB2 was highly expressed in patients with esophageal cancer, leading to poor prognosis. However, the role and molecular mechanism of EPHB2 in esophagus cancer is unknown. Our study aims to unveil the underlying mechanism by which EPHB2 modulates the biological properties of esophagus cancer cells. After si-EPHB2 transfection, the malignant biological properties of esophagus cancer cells were determined by several biological experiments. IWP-4 was applied to block Wnt/β-catenin signaling pathway. The expressions of autophagy and Wnt/β-catenin signaling pathway relevant molecules were tested by western blot assay. An increased expression of EPHB2 was happened in esophagus cancer samples and loss of EPHB2 diminished esophagus cancer cells proliferation, migration, and invasion. Moreover, our data showed that depletion of EPHB2 blocked the autophagy and in-activated Wnt/β-catenin signaling pathway in esophagus cancer cells. While, IWP-4 treatment inhibited the autophagy and limited esophagus cancer cells proliferation, migration, and invasion. Moreover, EPHB2 knocked down strengthened the effect of IWP-4 treatment in regulating esophagus cancer cells proliferation, migration, and invasion. Finally, we illustrated that EPHB2 regulated the biological properties of esophagus cancer cells by modulating autophagy and Wnt/β-catenin signaling pathway. Our study illustrated that EPHB2 might be a worthwhile target considering for the treatment of esophagus cancer.

Due to its decade-long progression, colorectal cancer (CRC) is most suitable for population screening to achieve a significant reduction in its incidence and mortality. DNA methylation has emerged as a potential marker for the early detection of CRC. However, the current mainstream methylation detection method represented by bisulfite conversion has issues such as tedious operation, DNA damage, and unsatisfactory sensitivity. Herein, a new high-performance CRC screening tool based on the promising specific terminal-mediated polymerase chain reaction (STEM-PCR) strategy is developed. CRC-related methylation-specific candidate CpG sites are first prescreened through The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases using self-developed bioinformatics. Next, 9 homebrew colorectal cancer DNA methylated STEM‒PCR assays (ColoC-mSTEM) with high sensitivity (0.1%) and high specificity are established to identify candidate sites. The clinical diagnostic performance of these selected methylation sites is confirmed and validated by a case-control study. The optimized diagnostic model has an overall sensitivity of 94.8% and a specificity of 95.0% for detecting early-stage CRC. Taken together, ColoC-mSTEM, based on a single methylation-specific site, is a promising diagnostic approach for the early detection of CRC which is perfectly suitable for the screening needs of CRC in primary healthcare institutions.

Although anti-TNF antibodies are extensively used to treat Crohn's disease (CD), a significant proportion of patients, up to 40%, exhibit an inadequate response to this therapy. Our objective was to identify potential targets that could improve the effectiveness of anti-TNF therapy in CD. Through the integration and analysis of transcriptomic data from various CD databases, we found that the expression of AQP9 was significantly increased in anti-TNF therapy-resistant specimens. The response to anti-TNF therapy in the CD mouse model was significantly enhanced by specifically inhibiting AQP9. Further experiments found that the blockade of AQP9, which is dominantly expressed in macrophages, decreased inflamed macrophage functions and cytokine expression. Mechanistic studies revealed that AQP9 transported glycerol into macrophages, where it was metabolized to LPA, which was further metabolized to LPA, resulting in the activation of the LPAR2 receptor and downstream hippo pathway, finally promoting the expression of cytokines, especially IL23 and IL1β⊡ Taken together, the expansion of AQP9+ macrophages is associated with resistance to anti-TNF therapy in Crohn’s disease. These findings indicated that AQP9 could be a potential target for enhancing anti-TNF therapy in Crohn’s disease.