Angiosarcoma (AS), constituting approximately 2% of all soft tissue sarcomas, is an aggressive endothelial malignancy. We report on the case of a 72-year-old man admitted with persistent melena and severe anemia, ultimately diagnosed with jejunal angiosarcoma (JAS) and associated lung and bone metastases. Temporary stabilization of his hemoglobin level was achieved via fasting, hemostasis, and blood transfusion. The initial plain CT identified multifocal solid lung nodules, but failed to reveal a primary digestive system lesion. Subsequent small enteroscopy localized a submucosal bulge in the jejunum, 70 cm from the pylorus. Following partial small bowel resection, the pathological examination confirmed a 0.9-cm × 0.8-cm × 0.7-cm angiosarcoma invading the intestinal wall and lamina propria. Immunohistochemical (IHC) staining showed strong positivity for CD31(++), alongside CD34(vascular+) and ERG(+). This report reviews the recent literature on JAS, summarizing the diagnostic and therapeutic strategies.

Background SLC7A11 is aberrantly overexpressed in many solid tumors, including colorectal cancer (CRC), but its complex 12-transmembrane structure has hindered effective antibody targeting. Methods We generated a human SLC7A11-specific murine monoclonal antibody (SLC7A11-Ab) using cell-based immunization and hybridoma technology. Subcutaneous and orthotopic CRC mouse models were established. Tumor immune microenvironment changes were assessed by multicolor immunofluorescence, flow cytometry, and single-cell RNA sequencing, with specific validation of effects on CD4⁺ and CD8⁺ T cells. Results High SLC7A11 expression correlated with regulatory T cell (Treg) activation, advanced tumor grade, lymphatic metastasis, and poor prognosis in CRC. SLC7A11-Ab blocked transporter function, inducing apoptosis and ferroptosis in multiple cancer cell types and showing significant antitumor efficacy in vivo. Mechanistically, SLC7A11 inhibition enhanced antitumor immunity by suppressing Treg activation and reducing tumor-associated macrophage infiltration, without impairing CD8⁺ T cell activation or function. Conclusion We developed a novel anti-SLC7A11 antibody with potent antitumor and immunomodulatory effects in CRC, highlighting SLC7A11 as a key regulator of tumor immune evasion and a promising therapeutic target.

Colorectal cancer (CRC) remains the leading cause of cancer mortality worldwide despite therapeutic advances. Guanylyl cyclase C (GUCY2C), an intestinal epithelial receptor, is emerging as a promising diagnostic and therapeutic target for CRC. Thus, we are interested in developing a monoclonal antibody probe targeting GUCY2C for both in vitro and in vivo diagnosis and treatment of CRC. Methods: The GUCY2C-specific monoclonal antibody, PR15-7, was generated by hybridoma fusion. We developed [89Zr]Zr-DFO-PR15-7 for PET imaging, Cy5-PR15-7 for near-infrared fluorescence I (NIR-I) detection, and ICG-PR15-7 for NIR-II-guided surgical navigation. The therapeutic potential was evaluated using [177Lu]Lu-DOTA-PR15-7 for targeted radiotherapy. Biologic properties and antitumor activity of PR15-7 probes were evaluated in vitro and in vivo. Results: PR15-7 showed strong GUCY2C binding affinity and tumor selectivity. PR15-7 probes in antibody-based PET and NIR imaging revealed 3 times higher signal intensity in GUCY2C-positive tumors compared with controls. The NIR-II probe ICG-PR15-7 enabled precise intraoperative tumor visualization and complete resection in orthotopic models. Therapeutic administration of [177Lu]Lu-DOTA-PR15-7 significantly inhibited tumor growth, with standardized tumor volumes at 16 d being markedly smaller than those in the control groups. Conclusion: We have established both optical and radionuclide probes with PR15-7 as a versatile therapeutic strategy, providing valuable insights into targeted therapy for CRC.

N6-methyladenosine (m6A), the most prevalent RNA modification, plays a crucial role in regulating macrophage homeostasis and intestinal immunity, although its mechanism remains largely unknown. A link between increased methyltransferase-like 3 (METTL3) expression in macrophages and intestinal inflammation has been confirmed. Herein, we sought to determine the role of METTL3-mediated macrophage activation in colitis. The dextran sulfate sodium (DSS)-induced experimental colitis model was established. Conditional knockout of METTL3 in myeloid cells mice (Mettl3fl/flLyz2Cre) and myeloid cells-specific deletion of IRAKM mice (Irakmfl/flLyz2Cre) were generated, respectively. The severity of colitis was measured using the disease activity index, colon length, and histopathological staining. Various techniques such as flow cytometry, western blot, quantitative PCR, and RNA-seq analysis were employed to assess polarization and the expression of inflammatory cytokines. Conditional knockout of Mettl3 in myeloid cells attenuated intestinal inflammation in experimental colitis. In vivo and in vitro studies confirmed that Mettl3 deletion skewed macrophages towards M2 activation. Mechanistically, Irakm, a negative regulator of TLR4 signaling, was identified as a target of METTL3-mediated m6A modification. METTL3 deficiency led to a higher level of IRAKM, which ultimately suppressed TLR signaling–mediated macrophage activation. Myeloid cells-specific deletion of Irakm mice were more susceptible to DSS-induced colitis than were wild-type mice. Colon-infiltrating M1 macrophages from Irakmfl/flLyz2Cre mice dramatically increased compared with those from their counterpart Irakmfl/fl mice. Additionally, deletion of IRAKM in bone marrow-derived macrophages (BMDMs) induced NF-κB activation and facilitated M1 polarization. Our study highlights the role of METTL3-IRAKM signaling in macrophage polarization and intestinal inflammation, providing a potential therapeutic target for the treatment of colitis.

Background:Colorectal cancer (CRC) progression is profoundly shaped by the tumor immune microenvironment. Increasing evidence suggests that dysregulated immune activation and immune evasion jointly contribute to tumor progression and therapeutic resistance. This study aims to identify novel immune-related biomarkers and explore combinatorial therapeutic strategies for overcoming immunosuppression in CRC by investigating the interplay between chloride channel accessory 1 (CLCA1)-mediated immune activation and serine proteinase inhibitor B9 (SERPINB9)-driven immune escape. Methods:Integrated multi-omics analyses were performed to identify key immune-related prognostic biomarkers in CRC and to construct a prognostic immune signature. The predictive performance of the model was validated in independent cohorts. Functional assays were conducted in female C57BL/6J mice to evaluate the effects of CLCA1 on tumor growth and immune cell infiltration. Mechanistic analyses were used to investigate the regulatory relationship between CLCA1 and SERPINB9. In addition, computational drug screening, together with structural and biophysical assays, was applied to identify candidate small molecules targeting CLCA1. Results:CLCA1 was identified as a central immune-related prognostic biomarker in CRC. A 14-gene immune signature effectively stratified patients into distinct risk groups and showed robust predictive value across independent cohorts. Functional studies demonstrated that CLCA1 overexpression suppressed tumor growth and promoted the infiltration of cytotoxic immune cells. Mechanistically, CLCA1 downregulated SERPINB9, a granzyme B (GZMB) inhibitor that plays a pivotal role in immune evasion. Notably, combined CLCA1/SERPINB9 expression status provided improved prognostic stratification compared with either marker alone. Computational screening further identified phloretin as a potential CLCA1-targeting compound, which was supported by structural and biophysical validation. Conclusions:These findings identify CLCA1 as a prognostic immune modulator and a potential therapeutic target in CRC. The functional interaction between CLCA1 and SERPINB9 highlights a mechanistic axis linking immune activation and immune escape. Moreover, phloretin emerges as a candidate small molecule for modulating CLCA1, although its in vivo immunomodulatory effects and target dependency require further validation.

Interleukin-2 (IL-2) is a potent mediator of T-cell activation with significant potential for cancer immunotherapy, yet its clinical utility is severely constrained by its narrow therapeutic window. Here we report a chemically masked IL-2 prodrug (Cm-proIL2) that enables tumor-microenvironment-responsive cytokine activation through tumor-associated protease cleavage. Site-specific conjugation of a poly-(ethylene glycol) (PEG) moiety selectively masks peripheral receptor engagement, while PEG removal within the tumor microenvironment restores IL-2 receptor binding and reduces molecular size, thereby enhancing intratumoral lymphocyte penetration and effector T cell functionality. Building on this modular platform, we further engineered a PD-1-targeted nanobody fusion, PD1-Cm-proIL2, to enable the cis delivery of IL-2 activity to PD-1+ tumor-infiltrating T cells. PD1-Cm-proIL2 induces robust antitumor immunity, resulting in complete tumor regression and durable protection upon tumor rechallenge in a murine colorectal cancer model. Together, these findings demonstrate the feasibility of chemically masked, tumor-responsive cytokine activation as a strategy for improving the therapeutic index of IL-2-based immunotherapies.

Background: Current evidence suggests that neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) alone is insufficient for magnetic resonance imaging (MRI)–suspected lateral lymph node metastasis (LLNM) in rectal cancer. However, whether upfront TME with lateral lymph node dissection (LLND) is adequate, and whether adding nCRT before planned LLND confers additional benefit, remains controversial. Methods: Between May 2021 and September 2022, a total of 342 patients from 20 Chinese centers were enrolled, of whom 293 were included in the final analysis and received either long-course nCRT plus TME with LLND or upfront TME+LLND. Groups were balanced by propensity score matching. The primary endpoint was 3-year recurrence-free survival (RFS). Findings: After matching, the nCRT group had significantly better 3-year RFS (HR 0.54; 95% CI. 0.32–0.92; P=0.023) and locoregional recurrence-free survival (HR 0.37; 95% CI, 0.19–0.74; P=0.005); distant metastasis-free survival did not differ (HR 0.74; 95% CI, 0.37–1.47; P=0.385). In patients with pretreatment positive lateral nodes (n=141), nCRT also improved RFS (HR 0.53; 95% CI, 0.28–0.99; P=0.049) and local control (HR 0.35; 95% CI, 0.15–0.77; P=0.010). Pathologic complete response in lateral nodes after nCRT was 44.7% (34/76). Overall postoperative complication rates were similar between groups (19.8% vs 16.0%; P=0.474), as were severe complications (grade III–V, 9.4% vs 8.5%; P=0.811). Interpretation: In MRI-suspected LLNM, adding nCRT to TME with LLND significantly improves RFS and local control without increasing morbidity. Upfront surgery alone is insufficient. These findings support a combined treatment paradigm and confirm the necessity of nCRT in these patients.

Background: Accurate risk stratification is critical for the management of patients with clear cell renal cell carcinoma (ccRCC). This study aims to explore the predictive value of preoperative 18 F-FDG PET/CT metabolic parameter combined with clinicopathological features for postoperative disease-free survival (DFS) in ccRCC patients. Methods: Newly diagnosed ccRCC patients who underwent 18 F-FDG PET/CT prior to surgery were retrospectively reviewed. Maximum standardized uptake value (SUVmax) was acquired from the preoperative 18 F-FDG PET/CT. Clinicopathological features, including the tumor node metastasis (TNM) stage, body mass index (BMI), hemoglobin (Hb), World Health Organization (WHO)/the International Society of Urological Pathology (ISUP) grade, primary tumor size, carbonic anhydrase IX (CAIX), tumor-infiltrating lymphocytes (TILs), etc., were also obtained. Cox proportional hazards analyses were executed to identify prognostic factors for DFS. The predictive efficacy of the model was assessed by the area under the curve (AUC). Glycolysis genes in ccRCC were analyzed using the TCGA database. Results : 59 ccRCC patients were included and 26 (44.1%) cases developed disease progression. On univariate analysis, BMI (≤ 25.45 kg/m2), Hb (≤ 130 g/L), clinical symptoms, TNM stage (III/ IV), SUVmax (> 4.20), primary tumor size (> 5.75 cm), WHO/ISUP grade (G3/4), CAIX expression (1+), and high TILs were significant prognostic factors of inferior DFS ( P < 0.05). On multivariate analysis, SUVmax ( P =0.026, HR=4.248; 95%CI: 1.184-15.239), BMI ( P =0.002; HR=0.233; 95%CI: 0.094-0.580), and WHO/ISUP grade ( P =0.005, HR=5.888; 95%CI: 1.689-20.524) still maintained independency in prognosis prediction. The prognostic model composed of the above three independent predictors achieved excellent predictive efficacy by virtue of a C-index of 0.89, with AUC values of 0.922, 0.919, and 0.899 at 1-, 3-, and 5-year, respectively. Moreover, the glycolysis-related genes of GCKR and GCK were obviously upregulated in the disease-progression group. Conclusion: ccRCC patients with low preoperative BMI, elevated SUVmax, and high WHO/ISUP grade are more likely to develop disease progression after operation. Implementing closer surveillance or aggressive early intervention for these patients is recommended to optimize prognosis.

Background Cone-beam computed tomography (CBCT) presents challenges for adaptive radiotherapy (ART) due to scatter artifacts and inaccurate CT numbers. While, deep learning-based synthetic CT (sCT) offers a potential solution, validation methods relying on deformable CT registration to assess sCT accuracy are prone to errors, particularly in the pelvic region. Therefore, a robust and clinically feasible validation approach is essential. Objective This study evaluated the feasibility of applying high-quality CBCT (HQCBCT) images, converted from CBCT using a deep learning model, for ART in rectal cancer. Methods We retrospectively evaluated rectal cancer patients who underwent radiotherapy. Original volumetric modulated arc therapy (VMAT) plans created on planning CT images were recalculated using bulk electron density assignment. Twenty patients with dose deviations < 1.5 % were selected. CBCT images were converted into HQCBCT images using a deep learning model. Multiple organs-at-risk (OARs), including the rectum, bladder, small intestine, left and right femoral heads, and spinal cord, were accurately delineated on CBCT and HQCBCT. Dose calculations on HQCBCT images were performed using native and bulk electron density values derived from the planning CT. Structural consistency was evaluated using the Dice similarity coefficient (DSC), 95th percentile Hausdorff distance (HD95), and volume difference (VD). Dosimetric accuracy of HQCBCT was assessed by comparing dosimetric parameters for target volumes and OARs, as well as gamma passing rates. Results For the rectum, bladder, small intestine, and spinal cord, mean DSCs exceeded 0.991, mean HD(95)s were within 0.12 mm, and mean VDs were within -0.86 %. The left and right femoral heads showed slightly lower consistency, with mean DSCs of 0.987 and 0.986, HD(95)s of 0.85 mm and 0.77 mm, and mean VDs of -1.43 % and -1.31 %, respectively. Dosimetric differences were within +/- 0.15 % for target volumes and +/- 0.60 % for OARs, satisfying clinical requirements. Mean gamma passing rates were 91.23 % (1 %/1 mm) and 99.37 % (2 %/2 mm). Conclusion HQCBCT images demonstrate adequate structural consistency and dosimetric accuracy, supporting their potential feasibility for ART in rectal cancer.

The Tianhe Procedure is a functional sphincter-preserving surgical approach developed for patients with rectal cancer following radiotherapy. This technique involves proximal extended resection of the colon beyond the pelvic cavity, followed by anastomosis of the non-irradiated proximal colon to the distal rectum or anal canal. This strategy aims to reduce the incidence of anastomotic complications and postoperative bowel dysfunction. However, there is currently a lack of standardized practice guidelines for implementing the Tianhe Procedure in China. Therefore, the Chinese Radiation Intestinal Injury Research Group, the Colorectal Surgery Group of Surgery Branch of the Chinese Medical Association, the Anorectal Branch of Chinese Medical Doctor Association, the Colorectal Cancer Committee of the Chinese Medical Doctor Association, the Colorectal Cancer Committee of China Anti-cancer Association, and the Gastrointestinal Surgical Branch of Guangdong Medical Doctor Association have jointly convened a panel of national experts to discuss and establish this standardized surgical procedure. This standard, based on the latest evidence from literature, research advancements, and expert experience, focuses on key aspects of the Tianhe Procedure, including its precise definition, indications, critical procedural steps, postoperative complications, and functional rehabilitation strategies. It aims to promote standardized implementation and broader clinical adoption of this innovative surgical technique.

ABSTRACT Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the intestine. In recent years, it has been unveiled that N6‐methyladenosine (also named m 6 A) modification, the most prevalent internal mRNA modification in mammalian cells, plays a pivotal role in the pathogenesis and development of IBD. m 6 A modification exerts on all four components of the intestinal barrier, including the intestinal mechanical barrier, intestinal chemical barrier, intestinal immunological barrier, and intestinal biological barrier. This paper reviews previous studies that focused on the role of m 6 A modification in IBD, aiming to elucidate the epigenetic mechanisms underlying IBD pathogenesis and progression, and offering novel perspectives for IBD diagnosis, treatment and prognosis prediction.

Colorectal cancer (CRC) exhibits heterogeneity based on tumour laterality, with right-sided tumours demonstrating distinct genetic, immunogenic and clinical behaviours compared to left-sided counterparts. In this study, we conducted single-cell RNA sequencing and spatial transcriptomics to dissect the distinct molecular landscapes of left- and right-sided CRC. We identified enhanced germinal centre B cell infiltration and CXCL13+ T cell enrichment, features linked to adaptive immune priming and better immunotherapy responsiveness. Right-sided CRC epithelial cells exhibited proliferative and immunogenic phenotypes, marked by upregulated immune-related pathways and chemokine-driven interactions with lymphocytes. Spatial analysis revealed organized tertiary lymphoid structure-immune microenvironment crosstalk in right-sided tumours, mediated by CCL19/21-CCR7 signalling. In contrast, left-sided CRC tumours displayed stromal-epithelial interactions favouring angiogenesis and metabolic reprogramming. Our findings established a laterality-specific immune microenvironment in CRC, providing insights for precise therapeutic strategies of left- and right-sided CRC.

PURPOSE:High-risk locally advanced rectal cancer (LARC) carries a substantial risk of distant recurrence, which limits disease-free survival (DFS). We compared total neoadjuvant therapy (TNT) integrating long-course radiotherapy (LCRT) with uninterrupted doublet chemotherapy (doublet-LC TNT) versus conventional neoadjuvant chemoradiotherapy (nCRT). METHODS:In this multicenter, randomized, phase III trial, patients with stage II/III LARC and at least 1 high-risk feature (cT4a-b, cN2, mesorectal fascia involvement, or cT3c-d with extramural vascular invasion) were enrolled. Patients were assigned to doublet-LC TNT (induction, concurrent, and consolidation capecitabine plus oxaliplatin with LCRT) before surgery or nCRT (capecitabine with LCRT) followed by surgery and adjuvant chemotherapy. The primary end point was DFS (ClinicalTrials.gov identifier: NCT03177382). RESULTS:Between June 6, 2017, and December 27, 2023, 458 patients were randomly assigned to doublet-LC TNT (n = 232) or nCRT (n = 226). At a median follow-up of 51 months, doublet-LC TNT improved 3-year DFS (74.8% v 66.0%; hazard ratio [HR], 0.674 [95% CI, 0.489 to 0.929]; P = .016). Metastasis-free survival (MFS; 77.7% v 67.6%; HR, 0.655 [95% CI, 0.469 to 0.915]) and pathologic complete response rates (pCR; 26.37% v 9.80%; P < .001) were higher with doublet-LC TNT, whereas locoregional failure remained low and comparable (6.03% v 6.19%; P = .943). Although grade ≥3 adverse events during the neoadjuvant phase were more frequent with doublet-LC TNT (27.59% v 8.56%; P < .001), severe toxicities during the entire treatment course (28.02% v 24.32%; P = .371) and major postoperative complications (3.98% v 2.94%; P = .567) were comparable. CONCLUSION:Compared with conventional nCRT, doublet-LC TNT improved DFS, MFS, and pCR rates with manageable toxicity. These findings support this intensified, doublet-based regimen as a standard option within the modern TNT paradigm. Further comparative studies are warranted to evaluate these results against other short-course radiotherapy‑based or nondoublet-concurrent TNT regimens.

Colorectal cancer (CRC) represents a prevalent and life-threatening malignancy, posing a significant global health challenge. Transcribed ultraconserved regions (T-UCRs), a specific category of long non-coding RNAs (lncRNAs) encoded within the human genome, have been demonstrated to play significant roles in the pathogenesis of multiple cancer types. However, their pathological role in CRC remains largely unexplored. In this study, we investigate two closely spaced T-UCRs, uc.263 and uc.264, located on chromosome 9, both of which are significantly upregulated in CRC tissues. Our findings further reveal that these two T-UCRs originate from a shared precursor RNA, designated as uc.263/264 in CRC cells. The uc.263/264 has been demonstrated to enhance cellular proliferation, growth, migration, and invasion, while simultaneously regulating the cell cycle and apoptosis. Mechanistically, uc.263/264 interacts with heterogeneous nuclear ribonucleoprotein K (hnRNPK), enhancing its protein stability and resulting in increased hnRNPK expression. Furthermore, uc.263/264 activates the Wnt signaling pathway, a process mediated by hnRNPK. Clinically, both uc.263/264 and hnRNPK are overexpressed in CRC patient samples, exhibiting a positive correlation in their expression levels. This suggests a functional regulatory axis between uc.263/264 and hnRNPK in CRC pathology. Collectively, our findings demonstrate that uc.263/264 can interact with the hnRNPK protein and upregulate its expression, thereby activating the Wnt signaling pathway and promoting the progression of CRC.

Terahertz (THz) waves, positioned between microwave and infrared in the electromagnetic spectrum, have promising applications in medical imaging and biomedicine. In this study, terahertz irradiation at 2.52 THz (100 mW/cm2) did not alter the proliferation of human umbilical vein endothelial cells (HUVECs), but significantly enhanced their angiogenic capacity. This enhancement was accompanied by increased levels of angiogenesis-related proteins such as VEGF in the culture supernatant. ATAC sequencing and RNA sequencing revealed a significant increase in the expression of cytoskeleton-associated genes, including PDXP and SH3BP1, post-irradiation. Additionally, intracellular calcium concentration, closely linked to angiogenesis, markedly increased following terahertz exposure. However, diltiazem significantly mitigated the enhanced angiogenic capacity induced by terahertz irradiation. In conclusion, terahertz irradiation promotes angiogenesis in HUVECs, partly by activating the VEGF signaling pathway through increased calcium fluxes.

PURPOSE:Internal iliac and obturator lymph nodes are common sites of metastasis in rectal cancer. This study developed a machine learning (ML) model using clinical data to predict lymph node metastasis and applied the Shapley Additive explanations (SHAP) method for interpretation. MATERIALS AND METHODS:Retrospectively, data from patients with rectal cancer at four Chinese centers-who underwent total mesorectal excision and lateral pelvic lymph node dissection without neoadjuvant therapy-were collected. Two centers provided training/test sets (3:1 ratio) and two centers supplied external validation. Lymph node enlargement was determined by imaging and confirmed by pathology. Five ML models were evaluated by AUC, accuracy, and F1 score. Key features included demographics, tumor stage, tumor-to-anal verge distance, imaging measurements, tumor histological differentiation, preoperative carcinoembryonic antigen, and carbohydrate antigen 19-9. SHAP was used to assess feature importance. RESULTS:Of the 411 cases (174 positives) in the training/test sets and 109 cases (43 positives) in external validation, the random forest (RF) model ranked second in terms of AUC and accuracy in the training set (0.999, 0.995), whereas it achieved the highest AUC and accuracy (0.877 and 0.788) in the test set. In the external validation, the RF model outperformed all other ML models (AUC of 0.899, accuracy of 0.827). Overall, the RF model demonstrates the superior overall performance. According to the SHAP analysis, the most important predictors of internal iliac and obturator lymph node metastasis were, in descending order, the short-axis diameter of enlarged lymph nodes, regional lymph node metastasis, and tumor-to-anal verge distance. At the individual patient level, SHAP force plots provided explanations of the RF model predictions for internal iliac and obturator lymph node metastasis. CONCLUSION:An interpretable ML model was developed that accurately predicts internal iliac and obturator lymph node metastasis using clinical data. SHAP analysis enhances understanding of feature contributions, supporting personalized treatment planning.

Background:The tumor microenvironment (TME) plays an important role in regulating gastric cancer (GC) progression. The infiltration of M0 macrophages into the TME negatively affects the prognosis of patients with various tumors. Methods:The data were obtained from the TCGA and GEO databases and our hospital (107 patients). The expression of IQGAP3 was knocked down in AGS and NCI-N87 GC cells. Cell proliferation, migration, and invasion assays were performed. RNA sequencing was performed on GC cells with different IQGAP3 expression. AGS and THP-1 cells were mixed to create a co-cultured subcutaneous tumor model in nude mice. Tumor growth in the mice was observed by using luciferin fluorescence and the tumor tissues were subjected to immunohistochemistry. Results:The expression of IQGAP3 was increased in GC tissues (P < 0.001) and was associated with infiltration of M0 macrophages and a poor prognosis for GC patients (P < 0.01). Knockdown of IQGAP3 resulted in decreased expression of CXCL13 (P < 0.001) and less phosphorylation of pSTAT3 and pERK1/2 (P < 0.001). The expression of CXCL13 was decreased after the pSTAT3 and pERK1/2 phosphorylation inhibitors were added. In the co-culture experiment, the M0/THP-1 ratio decreased significantly in the low-IQGAP3-expression group (P < 0.001). However, adding recombinant human CXCL13 proteins to the low IQGAP3 expression group increased the M0/THP-1 ratio. In vivo, tumor growth and M0 macrophage infiltration were both suppressed in the group with low IQGAP3 expression. Conclusion:IQGAP3 is a potential pro-carcinogenic factor in GC. IQGAP3 promotes the expression and secretion of CXCL13 via the ERK1/2 and STAT3 pathways, thereby causing M0 macrophages to infiltrate the TME.

INTRODUCTION:Anti-nephrin autoantibodies have been discovered in patients with minimal change disease (MCD) and primary focal segmental glomerulosclerosis (FSGS), especially in those with active nephrotic syndrome. METHODS:Here, we investigated the prevalence and clinical significance of anti-nephrin antibodies in 596 adult Chinese patients (436 with MCD and 160 with primary FSGS) diagnosed by kidney biopsy. RESULTS:Anti-nephrin IgG and IgM were detected using ELISA, with validation through antigen-inhibition ELISA and Western blotting. Clinical data at biopsy and during the follow-up period were analyzed. Anti-nephrin antibodies were detected in 43% of all patients, with 30% testing positive for anti-nephrin IgG, 26% for anti-nephrin IgM, and 13.1% for both antibodies. The prevalence of anti-nephrin antibodies was higher in patients with nephrotic-range proteinuria who were not receiving steroids or immunosuppressants (51.1%). Patients with positive anti-nephrin antibodies exhibited more severe nephrotic syndrome, higher rates of relapse, and a shorter relapse-free period compared to those negative for these antibodies. Clinical features were similar between those with IgG and IgM. Notably, patients with both anti-nephrin IgG and IgM had the most severe proteinuria and the highest relapse frequency, suggesting a dose-dependent effect. Longitudinal analysis revealed that anti-nephrin antibodies significantly decreased during clinical remission, while they reappeared preceding proteinuria relapse. CONCLUSIONS:Our study shows that anti-nephrin antibodies, including IgG and IgM, are detectable in adult patients with MCD and primary FSGS and are associated with active nephrotic syndrome and frequent relapse. These antibodies may serve as valuable biomarkers and potential therapeutic targets.