Derivation and validation of a nomogram incorporating modifiable lifestyle factors to predict development of colorectal adenomas after negative index colonoscopy.

This retrospective cohort study aimed to identify baseline patient characteristics involving modifiable lifestyle factors that are associated with the development of colorectal adenomas, and establish and validate a nomogram for risk predictions among high-risk populations with negative index colonoscopy. A total of 83,076 participants who underwent an index colonoscopy at the Tianjin Union Medical Center between 2004 and 2019 were collected. According to meticulous inclusion and exclusion criteria, 249 subjects were enrolled and categorized into the primary and validation cohorts. Based on the primary cohort, we utilized the LASSO-Cox regression and the univariate/multivariate Cox proportional hazards (Cox-PH) regression parallelly to select variables, and incorporated selected variables into two nomogram models established using the multivariate Cox-PH regression. Comparison of the Akaike information criterion and the area under the receiver operating characteristic curve of the two models demonstrated that the nomogram model constituted by four covariates retained by the LASSO-Cox regression, including baseline age, body mass index, physical activity and family history of colorectal cancer (CRC) in first-degree relatives, performed better at predicting adenoma-free survival probabilities. Further validation including the concordance index, calibration plots, decision curve analysis and Kaplan-Meier survival curves also revealed good predictive accuracy, discriminating ability, clinical utility and risk stratification capacity of the nomogram model. Our nomogram will assist high-risk individuals with negative index colonoscopy to prevent colorectal adenoma occurrence and CRC morbidity with improved cost-effectiveness.

Influence of High-Risk Pathological Factors and their Interaction on the Survival Benefit of Adjuvant Chemotherapy in Stage II Rectal Cancer: A Retrospective Study.

Objectives: We investigated the impact of high-risk factors in stage II (TNM stage) rectal cancer patients to determine whether they benefit from adjuvant chemotherapy after surgery. Additionally, we explored the interaction between high-risk factors and adjuvant chemotherapy. Our study provides refined guidance for postoperative treatment in patients with stage II rectal cancer. Methods: The retrospective study included 570 stage II rectal adenocarcinoma patients who underwent total mesorectal excision surgery at Tianjin Union Medical Center from August 2012 to July 2019. We employed Cox regression models to assess the collected pathological and clinical factors, identifying the risk factors for overall survival (OS) and disease-free survival (DFS). Additionally, we thoroughly examined the interaction between various high-risk pathological factors and postoperative chemotherapy (ACT), including multiplicative interaction (INTM) and additive interaction (RERI). Results: Among the 570 stage II rectal cancer patients in this study, the average age was 62 years, with 58.9% (N=336) of the population being older than 60. Males accounted for the majority at 64.9% (N=370). Age was found to have an impact on whether patients received adjuvant chemotherapy after surgery (P<=0.001).Furthermore, age (HR: 1.916, 95% CI: 1.158-3.173, P=0.011; HR: 1.881, 95% CI: 1.111-3.186, P=0.019), TNM stage (HR: 2.216, 95% CI: 1.003-4.897, P=0.029; HR: 2.276, 95% CI: 1.026-5.048, P=0.043), the number of lymph nodes cleared during surgery (HR: 1.968, 95% CI: 1.112-3.483, P=0.017; HR: 1.864, 95% CI: 0.995-3.493, P=0.045), and lymphovascular invasion (HR: 2.864, 95% CI: 1.567-5.232, P=0.001; HR: 3.161, 95% CI: 1.723-5.799, P<0.001) were identified as independent risk factors for patients' overall survival (OS) and disease-free survival (DFS). Moreover, the interaction analysis, both multiplicative and additive, revealed significant interactions between the number of lymph nodes cleared during surgery and the administration of adjuvant chemotherapy. For OS (HR for multiplicative interaction: 0.477, p=0.045; RERI: -0.531, 95% CI: -1.061, -0.002) and for DFS (HR for multiplicative interaction: 0.338, p=0.039; RERI: -1.097, 95% CI: -2.190, -0.005). Conclusions: This study provides insights into the complex relationship between adjuvant chemotherapy (ACT) and survival outcomes in stage II rectal cancer patients with high-risk pathological factors. The findings suggest that the number of cleared lymph nodes plays a significant role in the efficacy of ACT and underscores the need for individualized treatment decisions in this patient population.

Liensinine sensitizes colorectal cancer cells to oxaliplatin by targeting HIF-1α to inhibit autophagy.

BACKGROUND: Oxaliplatin is the most common chemotherapeutic agent for patients with colorectal cancer. However, its anti-cancer efficacy is restricted by drug resistance occurring through several mechanisms, including autophagy. Liensinine exerts a considerable anti-tumor effect and can regulate autophagy. Inhibition of autophagy is a strategy to reverse resistance to oxaliplatin. The aim of this study was to check if liensinine can enhance the therapeutic efficacy of oxaliplatin in colorectal cancer and if so, elucidate its mechanism. METHODS: Two colorectal cancer cell lines, HCT116 and LoVo, and one normal intestinal epithelial cell, NCM-460 were used for in vitro experiments. Cell Counting Kit-8 (CCK-8), colony formation, and flow cytometry assays were used to evaluate the cytotoxicity of liensinine and oxaliplatin. Network pharmacology analysis and Human XL Oncology Array were used to screen targets of liensinine. Transfections and autophagy regulators were used to confirm these targets. The relationship between the target and clinical effect of oxaliplatin was analyzed. Patient-derived xenograft (PDX) models were used to validate the effects of liensinine and oxaliplatin. RESULTS: CCK-8 and colony formation assays both showed that the combination treatment of liensinine and oxaliplatin exerted synergistic effects. Results of the network pharmacology analysis and Human XL Oncology Array suggested that liensinine can inhibit autophagy by targeting HIF-1α/eNOS. HIF-1α was identified as the key factor modulated by liensinine in autophagy and induces resistance to oxaliplatin. HIF-1α levels in tumor cells and prognosis for FOLFOX were negatively correlated in clinical data. The results from three PDX models with different HIF-1α levels showed their association with intrinsic and acquired resistance to oxaliplatin in these models, which could be reversed by liensinine. CONCLUSIONS: Research on the relationship between HIF-1α levels and the clinical effect of oxaliplatin is lacking, and whether liensinine regulates HIF-1α is unknown. Our findings suggest that liensinine overcomes the resistance of colorectal cancer cells to oxaliplatin by suppressing HIF-1α levels to inhibit autophagy. Our findings can contribute to improving prognosis following colorectal cancer therapy.

Downregulation of GPX8 in hepatocellular carcinoma: impact on tumor stemness and migration.

PURPOSE: GPX8, which is found in the endoplasmic reticulum lumen, is a member of the Glutathione Peroxidases (GPXs) family. Its role in hepatocellular carcinoma (HCC) is unknown. METHODS: Immunohistochemical staining was used to detect the protein levels of GPX8 in HCC tissue microarrays. A short hairpin RNA lentivirus was used to knock down GPX8, and the main signaling pathways were investigated using transcriptome sequencing and a phosphorylated kinase array. The sphere formation assays, cloning-formation assays and cell migration assays were used to evaluate the stemness and migration ability of HCC cells. Identifying the GPX8-interacting proteins was accomplished through immunoprecipitation and protein mass spectrometry. RESULTS: The GPX8 protein levels were downregulated in HCC patients. Low expression of GPX8 protein was related to early recurrence and poor prognosis in HCC patients. GPX8 knockdown could enhance the stemness and migration ability of HCC cells. Consistently, Based on transcriptome analysis, multiple signaling pathways that include the PI3K-AKT and signaling pathways that regulate the pluripotency of stem cells, were activated after GPX8 knockdown. The downregulation of GPX8 could increase the expression of the tumor stemness markers KLF4, OCT4, and CD133. The in vivo downregulation of GPX8 could also promote the subcutaneous tumor-forming and migration ability of HCC cells. MK-2206, which is a small-molecule inhibitor of AKT, could reverse the tumor-promoting effects both in vivo and in vitro. We discovered that GPX8 and the 71-kDa heat shock cognate protein (Hsc70) have a direct interaction. The phosphorylation of AKT encouraged the translocation of Hsc70 into the nucleus and the expression of the PI3K p110 subunit, thereby increasing the downregulation of GPX8. CONCLUSION: The findings from this study demonstrate the anticancer activity of GPX8 in HCC by inactivating the Hsc70/AKT pathway. The results suggest a possible therapeutic target for HCC.

Andrographolide sensitizes KRAS-mutant colorectal cancer cells to cetuximab by inhibiting the EGFR/AKT and PDGFRß/AKT signaling pathways.

BACKGROUND: Cetuximab, an inhibitor targeting EGFR, is widely applied in clinical management of colorectal cancer (CRC). Nevertheless, drug resistance induced by KRAS-mutations limits cetuximab's anti-cancer effectiveness. Furthermore, the persistent activation of EGFR-independent AKT is another significant factor in cetuximab resistance. Nevertheless, the mechanism that EGFR-independent AKT drives cetuximab resistance remains unclear. Thus, highlighting the need to optimize therapies to overcome cetuximab resistance and also to explore the underlying mechanism. PURPOSE: This work aimed to investigate whether and how andrographolide enhance the therapeutic efficacy of cetuximab in KRAS-mutant CRC cells by modulating AKT. METHODS: The viabilities of CRC cell lines were analyzed by CCK-8. The intracellular proteins phosphorylation levels were investigated by Human Phospho-kinase Antibody Array analysis. Knockdown and transfection of PDGFRß were used to evaluate the role of andrographolide on PDGFRß. The western blotting was used to investigate Wnt/ß-catenin pathways, PI3K/AKT, and EMT in KRAS-mutant CRC cells. The animal models including subcutaneous tumor and lung metastasis were performed to assess tumor response to therapy in vivo. RESULTS: Andrographolide was demonstrated to decrease the expression of PI3K and AKT through targeting PDGFRß and EGFR, and it enhanced cetuximab effect on KRAS-mutant CRC cells by this mechanism. Meanwhile, andrographolide helped cetuximab to inhibit Wnt/ß-catenin, CRC cell migration and reduced Vimentin expression, while increasing that of E-cadherin. Lastly, co-treatment with cetuximab and andrographolide reduced the growth of KRAS-mutant tumors and pulmonary metastases in vivo. CONCLUSIONS: Our findings suggest that andrographolide can overcome the KRAS-mutant CRC cells' resistance to cetuximab through inhibiting the EGFR/PI3K/AKT and PDGFRß /AKT signaling pathways. This research provided a possible theory that andrographolide sensitizes KRAS-mutant tumor to EGFR TKI.

Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA. METHODS: We performed integrated multiomics analysis in 116 iCCA samples, including whole-exome sequencing, bulk RNA-sequencing and proteome analysis. Based on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5-ethynyl-2'-deoxyuridine (EdU) assay, colony formation assay, RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase α (DGKA) in iCCA cells. RESULTS: Three metabolic subtypes (S1-S3) with subtype-specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune-suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog (KRAS)/AT-rich interactive domain 1A (ARID1A) mutations. Among the S2 subtype-specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen-activated protein kinase (MAPK) signaling. CONCLUSION: Via multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype.

Factors influencing advanced colorectal neoplasm anatomic site distribution in China: An epidemiological study based on colorectal cancer screening data.

OBJECTIVE: Existing studies indicate that advanced colorectal neoplasms exhibit distinct clinical and biological traits based on anatomical sites. However, in China, especially for advanced colorectal neoplasms, there's limited information available on these traits. Our primary objective is to comprehensively study the characteristics of advanced colorectal neoplasm patients in different anatomical sites in China. METHODS: We selected information from the colorectal cancer screening database in Tianjin, China, since 2010 as the study subject. We chose valid information from 3113 patients with comprehensive data and diagnosed advanced colorectal neoplasms (ANs) from a pool of 19,308 individuals to be included in the study. We then conducted further analysis to examine the correlation between these epidemiological data and tumor location. RESULTS: Among the 3113 patients, neoplasms in the left side of the colon accounted for the largest proportion, while neoplasms in the right side of the colon had the smallest proportion, followed by rectal neoplasms. The highest proportion of advanced colorectal neoplasms was found among men. In the age group of 39-49 years old, the proportion of left late-stage advanced colon neoplasms was equal to that of right late-stage advanced colon neoplasms, while late-stage advanced rectal neoplasms increased with age. Smoking, drinking, and a history of colon cancer in first-degree relatives showed statistically significant associations with the location distribution of advanced colorectal neoplasms. A history of appendicitis, appendectomy, cholecystitis, or cholecystectomy did not significantly affect the location distribution of advanced colorectal neoplasms. However, among patients with such histories, there was a statistically significant relationship between advanced colon neoplasms on the right and those on the left and in the rectum. Similar results were observed for BMI. CONCLUSION: Our research findings demonstrate that advanced colorectal neoplasms display unique epidemiological characteristics depending on their anatomical locations, and these distinctions deviate from those observed in Western populations. These insights contribute to a more comprehensive understanding of the topic and offer valuable guidance for future research in China. We advocate for further investigations centered on the anatomical location of colorectal neoplasms to enhance the precision of colorectal cancer (CRC) screening and treatment.

Deciphering intratumoral heterogeneity of hepatocellular carcinoma with microvascular invasion with radiogenomic analysis.

BACKGROUND AND AIMS: The recurrence and metastasis of hepatocellular carcinoma (HCC) are mainly caused by microvascular invasion (MVI). Our study aimed to uncover the cellular atlas of MVI+ HCC and investigate the underlying immune infiltration patterns with radiomics features. METHODS: Three MVI positive HCC and three MVI negative HCC samples were collected for single-cell RNA-seq analysis. 26 MVI positive HCC and 30 MVI negative HCC tissues were underwent bulk RNA-seq analysis. For radiomics analysis, radiomics features score (Radscore) were built using preoperative contrast MRI for MVI prediction and overall survival prediction. We deciphered the metabolism profiles of MVI+ HCC using scMetabolism and scFEA. The correlation of Radscore with the level of APOE+ macrophages and iCAFs was identified. Whole Exome Sequencing (WES) was applied to distinguish intrahepatic metastasis (IM) and multicentric occurrence (MO). Transcriptome profiles were compared between IM and MO. RESULTS: Elevated levels of APOE+ macrophages and iCAFs were detected in MVI+ HCC. There was a strong correlation between the infiltration of APOE+ macrophages and iCAFs, as confirmed by immunofluorescent staining. MVI positive tumors exhibited increased lipid metabolism, which was attributed to the increased presence of APOE+ macrophages. APOE+ macrophages and iCAFs were also found in high levels in IM, as opposed to MO. The difference of infiltration level and Radscore between two nodules in IM was relatively small. Furthermore, we developed Radscore for predicting MVI and HCC prognostication that were also able to predict the level of infiltration of APOE+ macrophages and iCAFs. CONCLUSION: This study demonstrated the interactions of cell subpopulations and distinct metabolism profiles in MVI+ HCC. Besides, MVI prediction Radscore and MVI prognostic Radscore were highly correlated with the infiltration of APOE+ macrophages and iCAFs, which helped to understand the biological significance of radiomics and optimize treatment strategy for MVI+ HCC.

Marsdenia tenacissima enhances immune response of tumor infiltrating T lymphocytes to colorectal cancer.

Introduction: Tumor-infiltrating T lymphocytes in the tumor microenvironment are critical factors influencing the prognosis and chemotherapy outcomes. As a Chinese herbal medicine, Marsdenia tenacissima extract (MTE) has been widely used to treat cancer in China. Its immunoregulatory effects on tumor-associated macrophages is well known, but whether it regulates tumor-infiltrating T-cell functions remains unclear. Method: We collected 17 tumor samples from MTE-administered colorectal cancer patients, 13 of which showed upregulation of CD3+/CD8+ tumor-infiltrating T cells. Further in vitro and in vivo experiments were performed to investigate the regulatory effects of MTE on tumor-infiltrating T cells and immune escape of tumors. Results: Under single and co-culture conditions, MTE inhibited TGF-ß1 and PD-L1 expression in the colorectal cancer (CRC) cell lines HCT116 and LoVo. In Jurkat cells, MTE inhibited FOXP3 and IL-10 expression, increased IL-2 expression, but had no effect on PD-1 expression. These findings were confirmed in vitro using subcutaneous and colitis-associated CRC mouse models. MTE also increased the density of CD3+/CD8+ tumor-infiltrating T cells and exhibited considerable tumor-suppressive effects in these two tumor mouse models. Conclusions: Our findings suggested that MTE inhibits the immune escape of cancer cells, a precipitating factor increasing the immune response of T lymphocytes.

Platycodin D represses ß-catenin to suppress metastasis of cetuximab-treated KRAS wild-type colorectal cancer cells.

Cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, is extensively used for clinical therapy in KRAS wild-type colorectal cancer (CRC) patients. However, some patients still cannot get benefit from the therapy, because metastasis and resistance occur frequently after cetuximab treatment. New adjunctive therapy is urgently needed to suppress metastasis of cetuximab-treated CRC cells. In this study, we used two KRAS wild-type CRC cells, HT29 and CaCo2, to investigate whether platycodin D, a triterpenoid saponin isolated from Chinese medicinal herb Platycodon grandifloras, is able to suppress the metastasis of cetuximab-treated CRC. Label-free quantitative proteomics analyses showed that platycodin D but not cetuximab significantly inhibited expression of ß-catenin in both CRC cells, and suggested that platycodin D counteracted the inhibition effect of cetuximab on cell adherence and functioned in repressing cell migration and invasion. Western blot results showed that single platycodin D treatment or combined platycodin D and cetuximab enhanced inhibition effects on expressions of key genes in Wnt/ß-catenin signaling pathway, including ß-catenin, c-Myc, Cyclin D1 and MMP-7, compared to single cetuximab treatment. Scratch wound-healing and transwell assays showed that platycodin D combined with cetuximab suppressed migration and invasion of CRC cells, respectively. Pulmonary metastasis model of HT29 and CaCo2 in nu/nu nude mice consistently showed that combined treatment using platycodin D and cetuximab inhibited metastasis significantly in vivo. Our findings provide a potential strategy to inhibit CRC metastasis during cetuximab therapy by addition of platycodin D.

The accuracy of the FIT in detecting advanced neoplasm is highest in young people aged 40 to 49 years: an analysis based on sex and age.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers and is associated with high incidence and mortality rates worldwide. CRC has caused a tremendous loss of human health and wealth. The incidence and mortality of colorectal carcinoma are increasing in young adults. Early cancer detection and prevention are made possible through screening. At present, the faecal immunochemical test (FIT) is a noninvasive method that can be used for the large-scale clinical screening of CRC status. Therefore, this study, based on CRC screening results in Tianjin from 2012 to 2020, was conducted to analyse the major differences in diagnostic performance parameters according to sex and age. METHODS: This study was based on 39,991 colonoscopies performed for individuals in the Tianjin CRC screening program from 2012 to 2020. Of these individuals, they had complete FIT and colonoscopy results. The differences in FIT results were analysed by sex and age. RESULTS: According to this study, males were generally more likely to develop advanced neoplasms (ANs) than females, and the prevalence increased with age. Males with negative FIT results were more likely to have advanced neoplasms than females with positive results. The accuracy of the FIT in detecting ANs in each age group was 54.9%, 45.5%, 48.6% and 49.5% in the 40-49, 50-59, 60-69, and ≥ 70 age groups, respectively. CONCLUSIONS: The FIT detected ANs with highest accuracy in the 40-49 age group. Our research can provide guidance to formulate CRC screening strategies.

Inhibition of macrophages inflammasome activation via autophagic degradation of HMGB1 by EGCG ameliorates HBV-induced liver injury and fibrosis.

Background: Liver fibrosis is a reversible wound-healing response that can lead to end-stage liver diseases without effective treatment, in which HBV infection is a major cause. However, the underlying mechanisms for the development of HBV-induced fibrosis remains elusive, and efficacious therapies for this disease are still lacking. In present investigation, we investigated the effect and mechanism of green tea polyphenol epigallocatechin-3-gallate (EGCG) on HBV-induced liver injury and fibrosis. Methods: The effect of EGCG on liver fibrosis was examined in a recombinant cccDNA (rcccDNA) chronic HBV mouse model by immunohistochemical staining, Sirius red and Masson's trichrome staining. The functional relevance between high mobility group box 1 (HMGB1) and inflammasome activation and the role of EGCG in it were analyzed by Western blotting. The effect of EGCG on autophagic flux was determined by Western blotting and flow cytometric analysis. Results: EGCG treatment efficiently was found to alleviate HBV-induced liver injury and fibrosis in a recombinant cccDNA (rcccDNA) chronic HBV mouse model, a proven suitable research platform for HBV-induced fibrosis. Mechanistically, EGCG was revealed to repress the activation of macrophage NLRP3 inflammasome, a critical trigger of HBV-induced liver fibrosis. Further study revealed that EGCG suppressed macrophage inflammasome through downregulating the level of extracellular HMGB1. Furthermore, our data demonstrated that EGCG treatment downregulated the levels of extracellular HMGB1 through activating autophagic degradation of cytoplasmic HMGB1 in hepatocytes. Accordingly, autophagy blockade was revealed to significantly reverse EGCG-mediated inhibition on extracellular HMGB1-activated macrophage inflammasome and thus suppress the therapeutic effect of EGCG on HBV-induced liver injury and fibrosis. Conclusion: EGCG ameliorates HBV-induced liver injury and fibrosis via autophagic degradation of cytoplasmic HMGB1 and the subsequent suppression of macrophage inflammasome activation. These data provided a new pathogenic mechanism for HBV-induced liver fibrosis involving the extracellular HMGB1-mediated macrophage inflammasome activation, and also suggested EGCG administration as a promising therapeutic strategy for this disease.

Development of a deep pathomics score for predicting hepatocellular carcinoma recurrence after liver transplantation.

BACKGROUND AND PURPOSE: Tumor recurrence after liver transplantation (LT) impedes the curative chance for hepatocellular carcinoma (HCC) patients. This study aimed to develop a deep pathomics score (DPS) for predicting tumor recurrence after liver transplantation using deep learning. PATIENTS AND METHODS: Two datasets of 380 HCC patients who underwent LT were enrolled. Residual convolutional neural networks were used to identify six histological structures of HCC. The individual risk score of each structure and DPS were derived by a modified DeepSurv network. Cox regression analysis and Concordance index were used to evaluate the prognostic significance. The cellular exploration of prognostic immune biomarkers was performed by quantitative and spatial proximity analysis according to three panels of 7-color immunofluorescence. RESULTS: The overall classification accuracy of HCC tissue was 97%. At the structural level, immune cells were the most significant tissue category for predicting post-LT recurrence (HR 1.907, 95% CI 1.490-2.440). The C-indices of DPS achieved 0.827 and 0.794 in the training and validation cohorts, respectively. Multivariate analysis for recurrence-free survival (RFS) showed that DPS (HR 4.795, 95% CI 3.017-7.619) was an independent risk factor. Patients in the high-risk subgroup had a shorter RFS, larger tumor diameter and a lower proportion of clear tumor borders. At the cellular level, a higher infiltration of intratumoral NK cells was negatively correlated with recurrence risk. CONCLUSIONS: This study established an effective DPS. Immune cells were the most significant histological structure related to HCC recurrence. DPS performed well in post-LT recurrence prediction and the identification of clinicopathological features.

Platycodin D sensitizes KRAS-mutant colorectal cancer cells to cetuximab by inhibiting the PI3K/Akt signaling pathway.

Cetuximab is a monoclonal antibody against epidermal growth factor receptor that blocks downstream signaling pathways of receptor tyrosine kinases, including Ras/Raf/MAPK and PI3K/Akt, thereby inhibiting tumor cell proliferation and inducing cancer cell apoptosis. Owing to KRAS mutations, the effectiveness of cetuximab is usually limited by intrinsic drug resistance. Continuous activation of the PI3K/Akt signaling pathway is another reason for cetuximab resistance. Platycodin-D, a bioactive compound isolated from the Chinese herb Platycodon grandiflorum, regulates Akt in different trends based on tissue types. To investigate whether platycodin-D can sensitize KRAS-mutant colorectal cancer cells to cetuximab by inhibiting the PI3K/Akt signaling pathway, HCT116 and LoVo cells were treated with cetuximab and platycodin-D. LY294002 and SC79 were used to regulate Akt to further evaluate whether platycodin-D sensitizes cells to cetuximab by inhibiting Akt. Our results confirmed that platycodin-D increased the cytotoxic effects of cetuximab, including inhibition of growth, migration, and invasion, via downregulation of PI3K and Akt phosphorylation in HCT116 and LoVo cells both in vitro and in vivo. Given these data, platycodin-D may sensitize KRAS-mutant colorectal cancer cells to cetuximab via inhibition of the PI3K/Akt signaling pathway.

STING signaling activation inhibits HBV replication and attenuates the severity of liver injury and HBV-induced fibrosis.

The covalently closed circular DNA (cccDNA) of HBV plays a crucial role in viral persistence and is also a risk factor for developing HBV-induced diseases, including liver fibrosis. Stimulator of interferon genes (STING), a master regulator of DNA-mediated innate immune activation, is a potential therapeutic target for viral infection and virus-related diseases. In this study, agonist-induced STING signaling activation in macrophages was revealed to inhibit cccDNA-mediated transcription and HBV replication via epigenetic modification in hepatocytes. Notably, STING activation could efficiently attenuate the severity of liver injury and fibrosis in a chronic recombinant cccDNA (rcccDNA) mouse model, which is a proven suitable research platform for HBV-induced fibrosis. Mechanistically, STING-activated autophagic flux could suppress macrophage inflammasome activation, leading to the amelioration of liver injury and HBV-induced fibrosis. Overall, the activation of STING signaling could inhibit HBV replication through epigenetic suppression of cccDNA and alleviate HBV-induced liver fibrosis through the suppression of macrophage inflammasome activation by activating autophagic flux in a chronic HBV mouse model. This study suggests that targeting the STING signaling pathway may be an important therapeutic strategy to protect against persistent HBV replication and HBV-induced fibrosis.